Updated guidance for healthcare providers on multisystem inflammatory syndrome in children (MIS-C) recognizes the evolving nature of the disease and offers strategies for pediatric rheumatologists, who also may be asked to recommend treatment for hyperinflammation in children with acute COVID-19.

Dr Lauren Henderson

Guidance is needed for many reasons, including the variable case definitions for MIS-C, the presence of MIS-C features in other infections and childhood rheumatic diseases, the extrapolation of treatment strategies from other conditions with similar presentations, and the issue of myocardial dysfunction, write Lauren A. Henderson, MD, MMSC, of Boston Children’s Hospital, and members of the American College of Rheumatology MIS-C and COVID-19–Related Hyperinflammation Task Force.

However, “Modifications to treatment plans, particularly in patients with complex conditions, are highly disease-, patient-, geography-, and time-specific, and therefore must be individualized as part of a shared decision-making process,” the authors said. The updated guidance was published this month in Arthritis & Rheumatology.

Update Needed in Wake of Omicron

“We continue to see cases of MIS-C across the United States due to the spike in SARS-CoV-2 infections from the Omicron variant,” and therefore updated guidance is important at this time, Henderson told Medscape Medical News.

“MIS-C remains a serious complication of COVID-19 in children and the ACR wanted to continue to provide pediatricians with up-to-date recommendations for the management of MIS-C,” she said.

“Children began to present with MIS-C in April 2020. At that time, little was known about this entity. Most of the recommendations in the first version of the MIS-C guidance were based on expert opinion,” she explained. However, “over the last 2 years, pediatricians have worked very hard to conduct high-quality research studies to better understand MIS-C, so we now have more scientific evidence to guide our recommendations.

“In version 3 of the MIS-C guidance, there are new recommendations on treatment. Previously, it was unclear what medications should be used for first-line treatment in patients with MIS-C. Some children were given intravenous immune globulin (IVIG) while others were given IVIG and steroids together. Several new studies show that children with MIS-C who are treated with a combination of IVIG and steroids have better outcomes. Accordingly, the MIS-C guidance now recommends dual therapy with IVIG and steroids in children with MIS-C.”  

Diagnostic Evaluation

The guidance calls for maintaining a broad differential diagnosis of MIS-C, given that the condition remains rare, and that most children with COVID-19 present with mild symptoms and have excellent outcomes, the authors noted. The range of clinical features associated with MIS-C include fever, mucocutaneous findings, myocardial dysfunction, cardiac conduction abnormalities, shock, gastrointestinal symptoms, and lymphadenopathy.

Some patients also experience neurologic involvement in the form of severe headache, altered mental status, seizures, cranial nerve palsies, meningismus, cerebral edema, and ischemic or hemorrhagic stroke. Given the nonspecific nature of these symptoms, “it is imperative that a diagnostic evaluation for MIS-C include investigation for other possible causes, as deemed appropriate by the treating provider,” the authors emphasized. Other diagnostic considerations include the prevalence and chronology of COVID-19 in the community, which may change over time, they said.

MIS-C and Kawasaki Disease Phenotypes

Earlier in the pandemic, when MIS-C first emerged, it was compared to Kawasaki disease (KD). “However, a closer examination of the literature shows that only about one quarter to one half of patients with a reported diagnosis of MIS-C meet the full diagnostic criteria for KD,” the authors write. Key features that separate MIS-C from KD include the greater incidence of KD among children in Japan and East Asia vs the higher incidence of MIS-C among non-Hispanic Black children. In addition, children with MIS-C have shown a wider age range, more prominent gastrointestinal and neurologic symptoms, and more frequent cardiac dysfunction, compared with those with KD.

Cardiac Management

Close follow-up with cardiology is essential for children with MIS-C, according to the authors. The recommendations call for repeat echocardiograms for all children with MIS-C at a minimum of 7-14 days, then again at 4-6 weeks after the initial presentation. The authors also recommended additional echocardiograms for children with left ventricular dysfunction and cardiac aortic aneurysms. 

MIS-C Treatment

Current treatment recommendations emphasize that patients under investigation for MIS-C with life-threatening manifestations may need immunomodulatory therapy before a full diagnostic evaluation is complete, the authors said. However, patients without life-threatening manifestations should be evaluated before starting immunomodulatory treatment to avoid potentially harmful therapies for pediatric patients who don’t need them, they added.

When MIS-C is refractory to initial immunomodulatory treatment, a second dose of IVIG is not recommended, but intensification therapy is advised with either high-dose (10-30 mg/kg/day) glucocorticoids, anakinra, or infliximab. However, there is little evidence available for selecting a specific agent for intensification therapy.

The task force also advises giving low-dose aspirin (3-5 mg/kg/day, up to 81 mg once daily) to all MIS-C patients without active bleeding or significant bleeding risk until normalization of the platelet count and confirmed normal coronary arteries at ≥ 4 weeks after diagnosis.

COVID-19 and Hyperinflammation

The Task Force also noted a distinction between MIS-C and severe COVID-19 in children. Although many children with MIS-C are previously healthy, most children who develop severe COVID-19 during an initial infection have complex conditions or comorbidities such as developmental delay or genetic anomaly, or chronic conditions such as congenital heart disease, type 1 diabetes, or asthma, the authors said. They recommend that “hospitalized children with COVID-19 requiring supplemental oxygen or respiratory support should be considered for immunomodulatory therapy in addition to supportive care and antiviral medications.”

The authors acknowledged the limitations and evolving nature of the recommendations, which will continue to change and do not replace clinical judgement for the management of individual patients. In the meantime, the ACR will support the Task Force in reviewing new evidence and providing revised versions of the current document.

Many questions about MIS-C remain, Henderson told Medscape Medical News. “It can be very hard to diagnose children with MIS-C because many of the symptoms are similar to those seen in other febrile illness of childhood,” she emphasized. “We need to identify better biomarkers to help us make the diagnosis of MIS-C. In addition, we need studies to provide information about what treatments should be used if children fail to respond to IVIG and steroids. Finally, it appears that vaccination [against SARS-CoV-2] protects against severe forms of MIS-C, and studies are needed to see how vaccination protects children from MIS-C.”

The development of the guidance was supported by the American College of Rheumatology. Lead author Henderson disclosed relationships with companies including Sobi, Pfizer, and Adaptive Biotechnologies (less than $10,000) and research support from the Childhood Arthritis and Rheumatology Research Alliance and research grant support from Bristol-Myers Squibb.

Arthritis Rheumatol. Published Feb. 3, 2022. Full text

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