Understanding MIS-C: A Post-COVID Inflammatory Syndrome in Children

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• What is MIS-C?
• MIS-C vs. Kawasaki Disease
• Clinical Presentation and Symptoms
• Diagnosis and Testing
• Treatment Options
• Prognosis and Recovery
• Full Transcript

What is MIS-C?

Multisystem Inflammatory Syndrome in Children (MIS-C) is a serious post-infectious condition. Dr. Randy Cron, MD, describes it as an unexpected development that emerged during the COVID-19 pandemic. It occurs in a very small subset of children approximately one month after a SARS-CoV-2 infection. The condition is driven by a dysregulated immune response, often described as a cytokine storm. This inflammatory response can affect multiple organ systems in the body. Dr. Randy Cron, MD, notes that genetic risk factors may predispose certain children to developing MIS-C.

MIS-C vs. Kawasaki Disease

MIS-C shares significant clinical overlap with Kawasaki disease, particularly in younger children. Dr. Randy Cron, MD, explains that children aged five and under with MIS-C often present with features identical to Kawasaki disease. Both conditions involve systemic inflammation and vasculitis, with a primary concern being potential damage to the coronary arteries. This similarity led experts to initially suspect a Kawasaki-like syndrome when MIS-C first appeared. The connection has also provided new insights, suggesting that some cases of Kawasaki disease may be triggered by prior coronavirus infections.

Clinical Presentation and Symptoms

The symptoms of MIS-C vary significantly by age group. Dr. Randy Cron, MD, details that younger children typically present with a sustained fever for five or more days. They often have a rash, enlarged lymph nodes in the neck, and changes to the mouth and lips, such as a "strawberry tongue." Swelling of the hands and feet is also common. In contrast, teenagers often present more severely, in a state of shock. They may have low blood pressure, a high heart rate, and rapid breathing, mimicking septic shock. A surprisingly high percentage of these older children require intensive care and medications to support heart function and blood pressure.

Diagnosis and Testing

Diagnosing MIS-C involves confirming a recent COVID-19 infection and identifying the characteristic inflammatory syndrome. Dr. Randy Cron, MD, emphasizes that by the time symptoms of MIS-C appear, the PCR test for active SARS-CoV-2 infection is often negative. Instead, diagnosis relies on antibody testing to prove a previous infection. This is crucial because up to 40% of children may have had an asymptomatic infection. The clinical diagnosis is then made based on the combination of fever, multi-organ involvement, and markedly elevated inflammatory markers, in the absence of another plausible cause.

Treatment Options

Treatment for MIS-C is centered on modulating the overactive immune response. Dr. Randy Cron, MD, explains that the first-line therapy is intravenous immunoglobulin (IVIG), a treatment borrowed from Kawasaki disease protocols. IVIG is a pooled antibody product that helps calm inflammation. For children who do not respond adequately to IVIG, glucocorticoids (steroids) are added. In refractory cases, advanced biologic therapies like IL-1 or TNF blockers can be used. The goal of treatment is to rapidly control inflammation, support organ function, and most importantly, prevent damage to the coronary arteries.

Prognosis and Recovery

Despite its alarming presentation, the prognosis for MIS-C is generally favorable with prompt treatment. Dr. Randy Cron, MD, reports that at his institution, the average hospital stay was five days. He notes that children get better rather quickly, even those who required intensive care. However, he cautions that the condition is not benign, with a worldwide mortality rate reported between 1.5% and 2%. In the most severe cases, some children have required Extracorporeal Membrane Oxygenation (ECMO) for cardiac support. Fortunately, with early intervention using IVIG and steroids, most children make a full recovery.

Full Transcript

Dr. Anton Titov, MD: What is MIS-C? Why does it happen?

Dr. Randy Cron, MD: That's a great question. First of all, MIS-C was a surprise to almost all of us. We didn't expect this to come at us; it kind of came out of left field.

One thing about the current coronavirus pandemic is that, for the most part, it spares children from severe disease. The infection itself, although there are subsets of children who unfortunately do get hospitalized for severe infection. However, this entity, MIS-C or multisystem inflammatory syndrome in children, also affects young adults, and that's called MIS-A. But it's basically the same process we think.

It occurs almost exactly a month after infection—they give a window of two to six weeks. But from my anecdotal experience, it's almost exactly a month after a child has been infected. It just affects a very small subset of kids. We don't really know the risk factors there, although we're starting to learn a few of the genetic risk factors that may put certain children at risk for developing this and not others.

It presents throughout childhood. The younger children, five or under, resemble another rheumatologic condition called Kawasaki disease. Initially, that's what people in Europe, where they were seeing this first before the bigger wave hit the United States in the Northeast in early 2020, thought this was—maybe Kawasaki disease—because in the younger children, they have very similar features to Kawasaki disease.

Kawasaki disease is also a rare condition, but it's inflammation of blood vessels. Most concerning is that some of the blood vessels involved in Kawasaki disease can be the ones that supply blood to the heart muscle itself—the coronary arteries.

Children present for Kawasaki disease with fever almost uniformly. In fact, it requires five days of sustained fever, five days in a row. Then they have other features such as rashes, enlarged lymph nodes in their neck, changes to their mouth and lips like strawberry-appearing tongue. They can start out with swelling of their hands and feet, and then it later begins to peel. There are a variety of other features.

These children with MIS-C occur about a month after a coronavirus infection, and it can be even an infection where they didn't even know they were infected. Up to 40% of individuals who are infected with this virus may be completely asymptomatic or not even know that they're sick. But we can test for those with antibody testing to show that they've had the virus previously.

Usually, by the time they show up with MIS-C, the polymerase chain reaction that detects the virus at the molecular level is often negative or very barely detectable, again suggesting that it's not active infection at this point. But somehow the immune system has responded. In a sense, it's also probably taught us that what we call Kawasaki disease may be more of a syndrome, some of which may be triggered by things like coronaviruses, including this particular SARS-CoV-2.

Nonetheless, the kids under five present very much like that. The older children, teenagers for example, often present in shock. They'll have fever like the younger children; they may or may not have a rash. But they end up in the emergency room in a state of shock, as if they are septic—like people who have blood that's infected with bacteria, for example. But here, again, it's not an infectious process; it's post-infectious.

They have very low blood pressure, high heart rate, and they're breathing fast—not because their lungs are sick like in COVID, but because they're in a state of shock. So they get volume replacement, for example, normal saline infusions, and that can help some. But a surprisingly high percentage of these children end up requiring intensive care.

They may even have to get medicines to support their heart and blood pressure, like pressors such as epinephrine or dopamine, for example—sometimes multiple of those medicines.

Dr. Randy Cron, MD: The treatment initially, because of the concern with the possibility of the coronary arteries being involved—since this was so similar, at least in the younger kids, to Kawasaki disease—we used intravenous immunoglobulin, which is a pool of antibodies from multiple donors. We don't know exactly how or why it works, but it was shown in the early '80s definitively in a large randomized trial that it could lower the ability to have these enlargements of the coronary arteries or balloon-like aneurysms of the coronary arteries.

It may have occurred prior to IVIG in up to a quarter of the kids, down to less than 2%. So it was a dramatically changing, effective therapy for Kawasaki disease. But because of the similarities, particularly in the younger kids, that was what we reached for first. Our colleagues in Europe—Italy and the UK, for example, and other parts of Western Europe—were reporting on this.

By the time it hit the Northeast—New York, Boston area, Philadelphia—our colleagues started using intravenous immunoglobulin as well. That seems to help the children. For which that was not enough, they would also receive glucocorticoids or steroids, which can also help refractory Kawasaki disease. So kids who sometimes get IVIG—it doesn't necessarily knock out the fever or other aspects of that disease.

But for MIS-C, after IVIG, if that wasn't working, they would often get corticosteroids. Surprisingly, for example, at our Children's Hospital in Birmingham, Alabama, we pretty much saw the bulk of the ones who needed hospitalization in the state of Alabama. We've probably seen close to 150 kids over the last two years with this. Fortunately, none of them have died from this, although the mortality is reported around 1.5 to 2% worldwide. So it's not benign.

But as sick as these kids come in, they get better rather quickly. That's good. The average length of stay at our hospital—and being in Alabama, where it hit us later than the northeastern United States—we had the benefit of learning from our colleagues around the world, including our colleagues in the northeastern United States.

So we knew upfront to give these children intravenous immunoglobulin and have a very low bar for giving them steroids. Even if that wasn't enough, we could use some of these newer biologic agents like IL-1 blockade. Some people have been using TNF blockade, which has also been shown to be beneficial for children with refractory Kawasaki disease.

Nonetheless, the kids at our hospital, at least, the average length of stay was five days, despite the fact that many of them did require going to the intensive care unit. At worst, some children require something called ECMO or extracorporeal membrane oxygenation. So if their heart's not working, you can kind of bypass that for them. But it's a pretty scary endeavor.