Age and Ferritin Levels May Predict MIS-C Severity

Older age and higher ferritin levels at hospital admission predict severe illness in COVID-related multisystem inflammatory syndrome in children (MIS-C), according to a Canadian multicenter cohort study.

The adjusted absolute risk for admission to an intensive care unit (ICU) was 43.6% among children aged 6 years and older and 46.2% in children aged 13 to 17 years, compared with 18.4% in children aged 5 years or younger.

“We do not understand why teens get more severe MIS-C than younger children,” senior author Joan Robinson, MD, of the University of Alberta in Edmonton, Canada, told Medscape Medical News. “It is possible that more exposures to other coronaviruses in the past result in them having a more robust immune response to SARS-CoV-2, which results in more inflammation.”

The data were published April 11 in the Canadian Medical Association Journal.

A Multinational Study

The study included data on 232 children admitted with probable or confirmed MIS-C at 15 hospitals in Canada, Iran, and Costa Rica between March 1, 2020, and March 7, 2021. The median age of the children was 5.8 years, 56.0% were boys, and 21.6% had comorbidities.

Although cardiac involvement was common (58.6%), and almost one third of the cohort (31.5%) was admitted to an ICU, “recovery was typically rapid, with 85% of patients discharged within 10 days,” said Robinson, for the Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC).

Older Age as a Risk

The results suggest that older age is associated with increased risk of severe MIS-C. “However, one would then predict that adults would be at even higher risk than teens, whereas the same syndrome in adults (MIS-A) is very, very rare,” said Robinson.

The study also found that children admitted with ferritin levels greater than 500 μg/L, signaling greater inflammation, also had an increased risk for ICU admission, compared with those with lower levels (adjusted risk difference, 18.4%; relative risk, 1.69). “This is presumably because the more inflammation that the child has, the more likely they are to have inflammation of the heart, which can lead to low blood pressure,” said Robinson.

Features of MIS-C

Among all patients with MIS-C, gastrointestinal involvement was common (89.2%), as were mucocutaneous findings (84.5%). Children with MIS-C had fever for a median duration of 6 days. “Clinicians who see children in their practice commonly have to determine why a child is febrile. Our study shows that one mainly has to consider MIS-C if febrile children have a rash and one or more of vomiting, diarrhea, or abdominal pain,” said Robinson.

The study also found that patients with MIS-C who were admitted to the hospital in the latter part of the study period (November 1, 2020, to March 7, 2021) were slightly more likely to require ICU admission, compared with those admitted between March 1 and October 31, 2020. “We cannot provide a clear explanation [for this],” the authors noted. “The features of severe MIS-C were widely publicized by May 2020, so it seems unlikely that severe cases were missed early in the study period. SARS-CoV-2 variants of concern have replaced the wild-type virus. It is possible that the immune response to circulating variants alters the severity of COVID-19 and MIS-C, when compared with wild-type virus.”

Despite initial concerns that pediatric COVID-19 vaccines might cause MIS-C, Robinson says data suggest this is rarely, if ever, the case, and that vaccines actually prevent the syndrome. She says further studies will be needed to assess MIS-C risk following reinfection with SARS-CoV-2. “I am an optimistic person, and it is my hope that MIS-C following reinfection is rare,” she said. “If this is the case, perhaps we will see very few cases once almost all children have been immunized and/or had SARS-CoV-2 infection.”

"Differences Across Countries"

Commenting on the findings for Medscape Medical News, Adrienne Randolph, MD, a pediatrician at Harvard Medical School in Boston, Massachusetts, and senior author of a large case series of patients with MIS-C, said that the Canadian study is valuable because it includes children from three countries. “It’s very interesting that there are differences across countries,” she said. “The patients in Iran had the highest percentage (58.7%) going into the ICU, whereas Costa Rica had the lowest percentage (9.2%), and the percentage going to the ICU in Canada (34.7%) was less than the percentages we see in the US — which is pretty consistently about 60% to 70% of MIS-C patients going into the ICU.” Randolph was not involved in the current study.

Reasons for differences in the rates of ICU visits will be important to explore in the effort to standardize diagnostic criteria, stratification of severity, and recommendations for treatment of MIS-C, said Randolph.

“What is consistent is that the younger kids, zero to 5 years, in general are less ill,” she said. “That’s been consistent across multiple countries.” It’s unclear whether the cause of this difference is that parents observe younger patients more closely than they do teenagers, or whether other aspects of adolescence, such as prevalence of obesity and attendant inflammation, are at work, said Randolph.

What is also unclear is why hospitalized patients with MIS-C had higher percentages of ICU admission in the latter part of the study period, compared with the earlier period. “Did the patients change, or did practice change as we got to understand the disease process?” asked Randolph. “It could be that they got better at the diagnosis and were weeding out some of the patients who they realized didn’t need to be hospitalized. At the very beginning, we had a very low threshold to admit patients, because we didn’t know, and then, over time, people understood what was going on and felt more comfortable monitoring them as outpatients.”

This study was partially funded by a Janeway Foundation Research Grant to support data collection. Robinson disclosed no conflicts of interest. Randolph reported receiving royalties from UpToDate and personal fees from the La Jolla Pharmaceutical Company.

CMAJ. April 11, 2022; 194:E513-E523. Full text.

Kate Johnson is a Montreal-based freelance medical journalist who has been writing for more than 30 years about all areas of medicine.

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