Infectious Disease

MIS-C mystery persists even as rheumatologists’ arsenal proves key to treatment

March 26, 2021

9 min read


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Cron reports personal fees from Novartis, grants and personal fees from SOBI, and a professional relationship with Pfizer. Grom reports a professional relationship with SOBI.


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As physicians around the world scrambled throughout early 2020 to respond to the exploding COVID-19 pandemic, the one promising development appeared to be that children were at relatively low risk compared with adults.

Then, in May 2020, the CDC officially recognized and began tracking a completely new disease, one that appeared to specifically target children and adolescents following a SARS CoV-2 infection, causing fever and inflammation of the heart, lungs, kidneys, brain, skin, eyes or gastrointestinal organs. That entity has become known as multisystem inflammatory syndrome in children, or MIS-C, and although rare, it has been increasingly reported in children’s hospitals across the country.

“Seeing 80 of these children in a relatively short period of time, particularly our first-year fellow who was on service throughout all of that — he could almost diagnose them in his sleep based on the story he hears from the emergency room doctor,” Randy Q. Cron, MD, PhD, told Healio Rheumatology. Source: Adobe Stock

According to the CDC, more than 1,000 children had been diagnosed with MIS-C between mid-May, 2020, and Oct. 1, 2020. By Feb. 1, that number had surpassed 2,000. As of March 1, a total of 2,617 children in the United States have been diagnosed with the disease, and 33 have died. In addition, although its causes and path of physiology are still unknown, all patients with MIS-C have either tested positive for SARS CoV-2 or had been in contact with someone with COVID-19.

“We were seeing kids in the hospital late last fall, and some had COVID-19 and others, who had been infected with COVID-19 earlier, had MIS-C — and they were all at the hospital at the same time,” Randy Q. Cron, MD, PhD, professor of pediatrics and director of pediatric rheumatology at the University of Alabama at Birmingham, told Healio Rheumatology. “So, it was confusing, particularly to non-immunologists or non-rheumatologists as to the nomenclature or what these children had, and how to treat them, because COVID-19 and MIS-C are separate entities, but they were kind of coexisting during the same time frame.”

Randy Q. Cron

Adding to this confusion, MIS-C shares many features with Kawasaki disease — such as conjunctivitis, red eyes, red or swollen hands and feet, rash, red cracked lips and swollen neck lymph nodes — as well as with macrophage activation syndrome.

Fortunately, its recommended treatments are also similar.

Once again — twice, now, in the same pandemic — rheumatologists’ regular armamentarium against autoimmune and inflammatory disease was proving indispensable.

Rheumatologists on the front lines — again

The American College of Rheumatology recommends a stepwise progression of immunomodulatory therapies to treat patients with MIS-C, starting with high-dose intravenous immunoglobulin (IVIG). Glucocorticoids should be used as adjunctive therapy in patients with severe disease, or as intensification therapy in those with refractory disease. Prior to IVIG treatment, providers should assess the patient’s cardiac function and fluid status. Those demonstrating depressed cardiac function may require close monitoring and diuretics with IVIG administration.

IVIG as a first-tier therapy will be familiar exercise for any rheumatologist who has treated Kawasaki disease. According to Cron, it is just one of many similarities between the two conditions.

“In some cases, it’s close to impossible to distinguish MIS-C from Kawasaki disease,” he said. “Early on, in some of the reports out of Italy and the United Kingdom, these children, particularly the younger ones, had a lot of the features of Kawasaki disease — the fever, the rash, the red eyes, the chapped lips.”

MIS-C can also resemble cytokine storms like macrophage activation syndrome, particularly in how it presents in patients aged 10 years or older. In these patients, symptoms can include abdominal pain, vomiting and diarrhea, but with shock, landing them in the emergency room after many days of fever.

“It’s not exactly the same, but they do share some features,” Cron said.

These similarities — both in presentation and treatment — have led to pediatric rheumatologists becoming highly involved in diagnosing and managing MIS-C.

“It depends on the center, but at least at ours, and I believe at many centers, pediatric rheumatologists tend to be very involved in this, because we are using our arsenal of medicine to treat it,” he said. “In our center, we were seeing a lot of kids in January and part of February. I think we saw more than 80 children in Birmingham, at the children’s hospital, with MIS-C.”

He added: “Seeing 80 of these children in a relatively short period of time, particularly our first-year fellow who was on service throughout all of that — he could almost diagnose them in his sleep based on the story he hears from the emergency room doctor.”

Alexei Grom, MD, pediatric rheumatologist and professor of pediatrics at the Cincinnati Children’s Hospital Medical Center and the University of Cincinnati, said his facility was “completely overwhelmed” in January and February by patients with MIS-C.

During this time, Grom said he and his team were seeing about a dozen new patients with MIS-C every week.

“We did not have enough time to pay enough attention to our regular patients with rheumatic disease,” he told Healio Rheumatology. “Typically, we have a team on call, so we had to come up with extra people to be on call to fulfill these additional emergencies.”

Although ICU physicians often represent the true “first line” for patients first presenting with MIS-C, Grom said rheumatologists are almost always brought in to manage immunosuppressant therapy for each case.

“We are most familiar with those medications, and I think that is the main reason we typically get involved,” he said. “And, I think, with the proper treatment — at least in our experience in Cincinnati — the vast majority of patients do recover very nicely.”

“The only concern, and what distinguishes this condition, is the very high risk for myocarditis — inflammation in the heart muscle,” Grom added. “In some of these cases, this may lead to, eventually, fibrosis, and that may affect the conduction system of the heart.”

According to Grom, these potential long-term impacts are just some of the major unknown aspects of this disease.

Mysteries of MIS-C

Despite researchers’ and clinicians’ valiant work in recognizing MIS-C’s clinical and laboratory characteristics, as well as the common demographics shared by those who generally develop the disease, much remains uncertain. Its cause, path of physiology, and its long-term effects are, as of this writing, total mysteries.

The possible effects and complications of MIS-C’s cardiac symptoms weigh particularly heavy on Grom’s mind.

According to the CDC, some patients with the disease develop myocarditis and cardiac dysfunction, a common driver of patients with MIS-C requiring ICU treatment. Grom added that it is possible patients who recover from the disease may begin to exhibit long-term, or even permanent, cardiac symptoms.

“Certainly MIS-C is a new entity that we had not seen before, and many of these kids end up in the intensive care unit, mainly because of significant cardiac complications,” he said. “I think some of them probably may have long-term sequela. In general, my feeling is that kids do relatively well with the infection itself, but this complication is certainly life-threatening and, again, my concern is that in some of the kids there will be some permanent cardiac sequela.”

According to Grom, some patients who recover from MIS-C may develop arrythmia and require long-term care. However, he stated that this risk is “relatively low.”

It also remains unknown why the disease mainly targets children. Data collected by the CDC states that most cases of MIS-C are among children and adolescents between the ages of 1 and 14 years, with a median age of 9 years.

A related condition, known as multisystem inflammatory syndrome in adults, or MIS-A, has been reported among those aged 21 years and older, but it is rare, according to Cron.

“We see a lot of this in teenagers,” Cron said. “I’m not sure why we don’t see it so much in young adults. Either it is being missed or there is something really unique about not being an adult that keeps you from getting this.”

Regarding the disease mechanism that appears to only impact children or teenagers, Cron remarked: “No one has any idea as far as I know.”

Researchers have hypothesized that children who have more recently been exposed to different coronaviruses, such as the common cold, may be at increased risk of developing MIS-C, but such ideas are merely conjecture at this point, according to Cron.

“No one really even knows what the path of physiology of this is,” he added. “It seems like it’s more of an adaptive immune response, like your lymphocytes, your T cells and your B cells — maybe your dendritic cells — that are contributing to this entity. But even as rheumatologists, we see things like reactive arthritis or serum sickness that happen usually within the first 2 weeks after an infection. This is sometimes as early as 3 weeks but can be as far out as 2 months, so there is something going on that I think no one at this point understands.”

“I have given a few talks on this, and one of the titles I use is ‘Who would have predicted MIS-C?’ because it just sort of came out of the blue,” he added. “It happened right when we were feeling good about kids in general not requiring hospitalization as often as adults.”

Dangers of ‘MIS-C until proven otherwise’

One thing that is clear about MIS-C is that its upward and downward trends have, so far, echoed those of COVID-19. According to Cron, spikes in MIS-C numbers “perfectly trail” spikes in COVID-19 by about 1 month.

“You can plot them,” Cron said. “You have to put them on different scales because the Y axis is going to be different, but they look the same, just a month apart.”

In such an environment, in the middle of a pandemic, Cron said that MIS-C has become the most likely culprit when a previously healthy teenager presents in the emergency room with, for example, a several-days-old fever and severe abdominal pain.

However, he cautioned there is a risk for misdiagnoses in defaulting too often to MIS-C, particularly when the disease mimics so many other conditions.

“In that setting, in the middle of a pandemic, it’s going to be a diagnosis of MIS-C until proven otherwise,” he said. “Having said that, we’ve gotten calls even from outside hospitals with children who they may have thought had MIS-C, because they’ve seen so many cases, but there are other things happening, too. One of the kids was re-diagnosed with systemic juvenile idiopathic arthritis, which can present with macrophage activation syndrome, so that child kind of mimicked MIS-C.”

“Also, some kids probably have straight-up Kawasaki disease — whatever entity that is, because still people don’t really know what triggers that,” Cron added. “So, you have to keep your mind open to other diagnoses, despite the fact that if a child presents in shock or had been previously healthy in the middle of a pandemic, you are likely going to be right that they have MIS-C. However, you also have to make sure you rule other things out. That’s part of the definition, too — you have to rule out other causes.”

Grom is similarly weary of the rush to diagnose all likely cases as MIS-C, stating that providers have risen to the challenge of recognizing the disease’s clinical pattern and learning how to manage it properly, but must now take care to consider all likely possibilities when assessing new patients.

To illustrate his point, he noted that his facility had three patients who “clearly met” the diagnostic criteria for MIS-C, but were later found to have other diseases, including one child who was ultimately re-diagnosed with a viral infection completely unrelated to COVID-19.

“I have a feeling that at some point we got maybe excessively comfortable with this diagnosis and stopped thinking about alternative possibilities,” Grom said. “Just recently I can tell you over the last few weeks, we had three patients here in Cincinnati who clearly met the diagnostic criteria for MIS-C, but in fact turned out to have something else. I think that is becoming a challenge right now. We recognize the clinical pattern and we have several sets of diagnostic criteria, but we still need to think about other possibilities, and not lump all of these patients into one group.”

“My point is that, yes, we kind of recognize this pattern, and now with the COVID epidemic still going on we are often too quick to diagnose it,” he added. “I think it is still important to remember there are other conditions with very similar clinical features, and as clinicians we need to be very thorough to rule them out.”

Biomarker may separate MIS-C from mimics

According to a prospective study conducted by Grom and colleagues from the Cincinnati Children’s Hospital Medical Center and the University of Cincinnati, MIS-C may be distinguished from Kawasaki disease by elevated levels of the biomarker CXCL9.

The resulting paper, which is currently being reviewed for publication by The Lancet Rheumatology, additionally states that the stratification of CXCL9 levels in patients with MIS-C provides support for macrophage activation syndrome pathophysiology in some of those with severe MIS-C.

“Typically, we use this biomarker to diagnose interferon-driven pathologic processes including macrophage activation syndrome,” said Grom. “There were MIS-C patients with relatively normal CXCL9 levels and relatively high CXCL9 levels. Those with low levels in fact behaved much more like Kawasaki disease patients, and in fact a significant proportion of those patients in that group developed coronary artery abnormalities. The other group, with high CXCL9 levels, behaved more like macrophage activation syndrome patients. None of the patients in that group developed coronary artery abnormalities.”

According to Grom, this would have important implications for the diagnosis and management of MIS-C going forward.

“At the moment, we are trying to understand a little bit better the nature of the biology of this heterogeneity,” he said. “We are wondering in fact whether these two groups should be handled differently in terms of treatment and monitoring approaches.”

For more information:

Randy Q. Cron, MD, PhD, can be reached at 1825 University Blvd., Shelby Building, 306, Birmingham, AL, 35294; email:

Alexei Grom, MD, can be reached at 3333 Burnet Ave., Cincinnati, OH, 45229; email:


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