More Questions Than Answers About MIS-C, Experts Say

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New research provides further insight into the clinical characteristics of the inflammatory condition linked to COVID-19 in children, but many questions are still unanswered, according to investigators.

Although pediatric multisystem inflammatory syndrome associated with severe acute respiratory syndrome coronavirus 2 infection (MIS-C) has clinical features that overlap those of Kawasaki disease (KD) and toxic shock syndrome (TSS), some of the characteristics are unique, according to the findings of two case series published online June 8 in JAMA. In particular, researchers have observed a wider spectrum of illness than previously reported, as well as distinct disease patterns and cardiac findings that warrant long-term surveillance.

In one study, Elizabeth Whittaker, MD, PhD, of the Department of Infectious Diseases at Imperial College London, United Kingdom, and colleagues compared the clinical course of 58 children admitted to eight hospitals in England who met the criteria for MIS-C with that of children diagnosed with KD (1132), KD shock syndrome (45), or TSS (37) in the United States and Europe from 2012 to 2020. Of the 58 children, 45 had evidence of current or previous COVID-19 infection. Seven had preexisting underlying conditions, including three with asthma.

On presentation, all children had fever, half had abdominal pain (53%), and half had a rash (52%). Half of the children developed shock (50%) and required inotropic support or fluid resuscitation. Additional clinical features included conjunctival injection (45%); mucus membrane changes and red cracked lips (29%); headache (26%); enlarged lymph nodes (16%); kidney damage (22%); swollen hands and feet (16%); sore throat (10%); and confusion (9%).

All 58 patients had signs of inflammation, including elevated levels of C-reactive protein (CRP), ferritin, and neutrophils. Eight children (14%) had dilated coronary arteries or aneurysms. During hospitalization, four children developed abnormal heart rhythms, 25 (43%) required mechanical ventilation, and two (3%) required extracorporeal membrane oxygenation for severe heart dysfunction. Of the 58 children, 13 met the American Heart Association criteria for KD, and 23 had fever and inflammation without characteristics of shock or KD.

Compared with the KD and KD shock syndrome cohorts, the children with MIS-C were older (median age, 9 years, vs 2.7 for patients with KD), had higher CRP levels, higher white blood cell and neutrophil counts, lower platelet counts, higher fibrinogen levels, greater elevation of troponin levels, and more profound lymphopenia and anemia, the authors note. Relative to the TSS cohort, patients with MIS-C were older and had lower hemoglobin levels and higher CRP and alanine aminotransferase levels.

"Three Provisional Clinical Patterns"

On the basis of their findings, the researchers identified three patterns of disease among the MIS-C cohort:

Persistent fever and elevated levels of inflammatory markers without features of KD, shock, or organ failure (23 children)
Signs and symptoms that meet the diagnostic criteria for KD (13 children)
Shock (29 children), often with clinical, echocardiographic, and laboratory evidence of heart damage

These distinctions have management implications, Whittaker explained in a news release from Imperial College London. This syndrome can make a child extremely ill; therefore, "it's important to characterize the disease properly so we can provide close monitoring and the best treatment."

Despite the differences from the other inflammatory syndromes, to date, treatment for MIS-C has been similar, according to senior author Michael Levin, MD, also from Imperial College London. "Although this new disorder is distinct from Kawasaki disease, it has generally been managed using the same treatments. We have the impression that this helps, but we don't know for certain, so more research is needed," he told Medscape Medical News.

The link to COVID-19 is also unclear. "The inflammatory syndrome seems to follow either very mild or asymptomatic previous infection," Levin explained. "We still do not know why most children have mild SARS-CoV-2, and a very small number develop this rare but serious syndrome. This is currently being investigated. There may be genetic or environmental factors involved."

In a research letter published in the same issue of JAMA, Eva W. Cheung, MD, of the Department of Pediatrics, Columbia University Irving Medical Center, New York City, and colleagues describe the clinical course and management of 17 patients hospitalized with the inflammatory syndrome at New York's Columbia University Irving Medical Center/New York–Presbyterian Morgan Stanley Children's Hospital. All children had evidence of recent SARS-CoV-2 infection.

Of the 17 children, all had a fever for a median of 5 days; 88% had gastrointestinal symptoms; 76% had shock at presentation; 65% had a rash; 65% had conjunctivitis; 53% had red, swollen lips; 47% had headache or other neurologic symptoms; and 41% had respiratory symptoms. Additional symptoms included myalgia, cervical lymphadenopathy, hypoxia, and skin desquamation. Eight cases met the criteria for KD and five for incomplete KD.

In all 17 children, levels of inflammatory markers were elevated; 16 had high serum interleukin-6 (IL-6) levels, and 15 had high levels of NT-proBNP (N-terminal–pro hormone B-type natriuretic peptide), an indicator of heart failure. Fourteen children had high levels of troponin T. In 12 children, levels of lymphocyte white blood cells were reduced, and 11 had high levels of band cells. Although nine patients had low oxygen levels, none required mechanical ventilation. Abnormal heart rhythms were reported in three children, and one child had an aneurysm.

"The observed pattern of cytokine expression suggests an interferon signaling component, along with IL-6 and IL-10 production, seen in KD and acute pulmonary COVID-19 infection," the authors write. They note, however, that the lack of elevated levels of tumor necrosis factor–alpha or IL-13 distinguish MIS-C sequalae from those of acute pulmonary COVID-19 infections. Given the occurrence of abnormal heart findings, long-term surveillance is warranted, they note.

Is MIS-C a Form of Kawasaki Disease?

In addition to informing management of these rare inflammatory conditions in children, the similarities and the differences between MIS-C and KD may help provide critical insight into the etiology of KD, which "[f]ive decades of clues have not elucidated," Brian McCrindle, MD, MPH, of the University of Toronto, Canada, and Cedric Manlhiot, PhD, of Johns Hopkins University in Baltimore, Maryland, write in an accompanying editorial.

"Careful determination of the unique features of SARS-CoV-2 and the epidemiology, clinical features, genetic and immunologic susceptibility, and pathophysiologic pathways of both MIS-C and KD may help to inform the etiologic and pathophysiologic framework for both conditions," they write.

For example, the fact that MIS-C appears to affect older children in comparison with KD and is associated with more gastrointestinal symptoms and a lower prevalence of "classic" clinical signs of KD "could be associated with 1 or more factors influencing immunomodulation and susceptibility," they state. "These observations suggest some areas where susceptibility and immune-modulating factors for MIS-C and KD may contribute differently for each condition."

McCrindle and Manlhiot raise the possibility that MIS-C could be a form of KD. "There has never been a global outbreak of KD where it might be traced to a specific trigger, but this may now be the case," they write. "It might be that this is what a specific, unique, and ubiquitous form of KD looks like, providing an important opportunity for investigations to determine factors associated with variations."

The fact that children with MIS-C respond to treatments that that are effective against KD indicates an important connection, McCrindle told Medscape Medical News. "We don't know if this is a specific form of KD or just something similar. However, the patients tend to respond to similar anti-inflammatory treatments that we give to Kawasaki disease patients. They just may need more and longer treatment."

The true incidence, prevalence, and full clinical spectrum of MIS-C are still unknown, and there are far more questions than answers at this point, McCrindle said. "We know that only a subset of children develop [MIS-C], and it's probably a rare subset, but we don't yet know which kids are the most susceptible." The pattern of disease severity is also uncertain. "The reports have all been about severe cases, but likely there are many less severe cases that we are not seeing," he said.

Findings from these and other recent research in patients with MIS-C "mark the beginning of an important time of focused discovery, which will likely have relevance to an entire host of inflammatory conditions," the editorial authors conclude.

McCrindle has received personal fees from Janssen and has served as an investigator for Janssen and Mession. Fraisse has financial relationships with Abbott, Occulutech, and Medtronic. Shimizu has received grants from the Gordon and Marilyn Macklin Foundation. Orange has financial relationships with ADMA Bioogics, CSL, Bhering, Gigagen, Grifols, and Takeda. The remaining authors have disclosed no relevant financial relationships.

JAMA. Published online June 8, 2020. Whittaker et al, Full text; Cheung et al, Full text; Editorial

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