Of all the questions raised by the COVID-19 pandemic, its effect on children has been one of the most perplexing. Early reports from Italy and the United Kingdom, then New York City and other infection centers, underlined a mysterious increase in what appeared to be Kawasaki disease cases.
Most children had what appeared to be classic Kawasaki. Some had more severe symptoms. And some had manifestations so dramatic they were classified as a new condition, multisystem inflammatory syndrome in children (MIS-C).
“Italy has been the first Western country to be hit by the COVID-19 pandemic and the first to see these new cases of Kawasaki disease,” said Angelo Ravelli, MD, professor of pediatrics and head of rheumatology, Giannina Gaslini Institute, Genoa, Italy. “I would favor the hypothesis that the two diseases are representing a spectrum, with Kawasaki disease having milder symptoms and MIS-C more severe features. There are differences and also overlapping presentations.”
Dr. Ravelli discussed the evolving Italian experience during the ACR Convergence 2020 session Pediatric COVID-19 Hyper-Inflammation: Decipher Clues & Enhance Collaborations. The session is available on demand for registered ACR Convergence attendees through March 11.
MIS-C affected older children, with a mean onset age of 7.6 years versus 2.7 years for Kawasaki, Dr. Ravelli said. MIS-C patients had fewer coronary artery abnormalities and far more cardiac symptoms, including myocarditis, pericarditis, heart failure, and shock. MIS-C patients also had more gastrointestinal symptoms, including diarrhea, vomiting, and abdominal pain, than Kawasaki patients.
At the same time, most MIS-C patients tested positive for SARS-CoV-2 antibody and negative for SARS-CoV-2 virus. Far more MIS-C patients were admitted for ICU care than Kawasaki patients, but overall length of hospital stay and survival were similar.
Peaks in MIS-C admissions lagged peaks in COVID-19 cases by about a month, Dr. Ravelli noted. Other human coronaviruses have also been implicated in the development of Kawasaki disease.
“The condition is probably related to an abnormal immunological inflammatory reaction to the virus, not the viral infection,” he said.
Case series reports of MIS-C also showed a disproportionate impact on Black and Hispanic children, similar to the disparate impact of COVID-19 in general, said Mary Beth F. Son, MD, rheumatology program director, Boston Children’s Hospital, and assistant professor of pediatrics, Harvard Medical School.
“Racial, ethnic, and socioeconomic disparities are a factor in MIS-C,” Dr. Son said. “And there are likely genetic and biologic underpinnings as well.”
Most MIS-C children, 80%, have cardiac involvement, Dr. Son said, and most have GI symptoms. Hematologic, mucocutaneous, respiratory, and other symptoms vary by age.
A CDC review of clinical phenotypes found three classes of roughly equal numbers:
- Class 1 had multiorgan involvement with shock, myocarditis, and abdominal pain.
- Class 2 had respiratory involvement, including pneumonia and ARDS, and the highest mortality rate.
- Class 3 had less organ involvement and shock, had more rash and mucocutaneous symptoms, and was younger.
All three classes had similar numbers of coronary artery aneurysms.
“This underpins the need for coronary angiograms of all children with MIS-C,” Dr. Son said.
The ACR issued its first MIS-C clinical guidance in July 2020, she said. The guidance offered a diagnostic algorithm, recommendations for cardiac management, immunomodulatory treatment for MIS-C, and treatment recommendations for hyperinflammation in acute COVID-19.
Guidelines recommend high-dose intravenous immunoglobulin therapy, followed by low-to-moderate-dose glucocorticoids. Anakinra may be helpful in refractory disease.
All patients need serial lab testing and cardiac assessment and slow tapering off immunomodulatory medications. A fast taper can produce rebound symptoms.
“All of our treatments to date have been based on observation and expert consensus,” Dr. Son cautioned. “We need an evidence base.”
Multiple MIS-C studies are under way, she added. And because MIS-C lags COVID-19 infection, it is possible that broad vaccination could virtually eliminate both conditions.
“It is possible that next winter we will be less concerned with MIS-C,” she said. “For now, we still have to get through this winter.”