By Philip R. Fischer, MD, DTM&H

Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN; Department of Pediatrics, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates

SYNOPSIS: Multisystem inflammatory syndrome in children (MIS-C) can be a devastating post-COVID-19 complication, but treatment seems effective. High-dose steroids and intravenous immune globulin (IVIG) are commonly used, although new studies give conflicting findings as to whether it is best to use both treatments together.

SOURCES: McArdle AJ, Vito O, Patel H, et al. Treatment of multisystem inflammatory syndrome in children. N Engl J Med 2021;385:11-22.

Son MBF, Murray N, Friedman K, et al. Multisystem inflammatory syndrome in children — initial therapy and outcomes. N Engl J Med 2021;385:23-34.

Two similar studies reported simultaneously in the New England Journal of Medicine gave very different results as to whether the combination of steroids and intravenous immune globulin (IVIG) is better than the use of a single agent as initial treatment of multisystem inflammatory syndrome in children (MIS-C). McArdle and colleagues found no difference in outcomes whether patients received steroids or IVIG or both, while Son and colleagues found that adding steroids to IVIG was more effective in reducing the risk of subsequent cardiovascular dysfunction.

For 16 months now, a rare but potentially serious inflammatory syndrome has been reported in children following infection with SARS-CoV-2. Initially, the condition seemed to be a Kawasaki-like disease, and the condition now called MIS-C has been more completely characterized, while remaining poorly understood. The condition typically occurs two to six weeks after infection with SARS-CoV-2, whether or not the patient was symptomatic or ill with COVID-19. Fever, abdominal pain, vomiting, and fatigue are common; organ failure with shock is possible; extreme elevation of levels of inflammatory markers is common. Treatment often requires inotropic support. Similarities to Kawasaki disease (often with conjunctivitis and rash, sometimes with coronary aneurysms) prompted therapeutic trials of IVIG. The associated inflammatory findings suggestive of a cytokine storm prompted trials of steroids. Children usually recovered — without randomized, blinded, controlled studies guiding treatment decisions.

McArdle and colleagues invited pediatricians from around the world to submit data about patients with presumed post-COVID inflammatory illnesses through a web-based data collection tool. Based on the number of patients receiving various treatments, they categorized patients related to initial treatment with IVIG, IVIG and steroids, or steroids alone. From June 2020 into February 2021, clinicians from 81 hospitals in 34 countries submitted patient information. A total of 614 individuals were included, and the majority (81%) met Centers for Disease Control and Prevention (CDC) criteria for a diagnosis of MIS-C. (Thirty-seven percent of patients concurrently met criteria for a diagnosis of Kawasaki disease.)

Of these 614 patients, 40% were treated initially with IVIG alone, 34% with IVIG plus steroids, and 16% with steroids alone. (Others received other immunomodulation alone or as combinations of treatments.) The need for new inotropic support or mechanical ventilation more than two days after initiation of treatment was not different based on what the initial treatment had been. Reductions in disease severity following treatment also were not different based on the type of initial treatment used. These similar outcomes were found whether or not the patients met formal MIS-C diagnostic criteria. Neither left ventricular dysfunction nor biomarker/inflammatory levels varied based on the initial treatment modality given. Two percent of patients, equally mixed between treatment groups, died.

Son and colleagues analyzed surveillance data from 58 U.S. hospitals from March through October 2020. Inclusion was based on meeting six criteria, as detailed by the CDC: serious illness prompting hospitalization, age younger than 21 years, fever for at least 24 hours, laboratory evidence of inflammation, involvement of at least two organ systems, and confirmed SARS-CoV-2 infection or association with an infected person. Patients were categorized based on the treatment their treating physicians used. Outcomes (at least two days after initiation of treatment) were followed.

Of 596 eligible patients admitted to one of the 58 participating hospitals during the study period, 518 (87%) received at least one immunomodulating therapy. The median age of subjects was 8.7 years (range, 0-20.9), 42% were female, 35% were Black and/or Hispanic, and 75% had been healthy previously. The majority had five or more organ systems involved, and 38% met diagnostic criteria for Kawasaki disease (either complete or incomplete). The patients who received IVIG alone tended to be younger and to meet criteria for a Kawasaki disease diagnosis. Overall, 2% of patients died.

Of the 518 children who received an immunomodulating treatment sometime during the hospitalization, 17% received IVIG only, 47% received IVIG and a steroid (usually methylprednisolone 2 mg/kg/day), 21% received IVIG and a steroid and a biologic agent (such as anakinra), and 16% received some other combination of treatments. (For treatment initially at the time of hospitalization, IVIG alone was most common [37%], with almost as many [30%] receiving IVIG and a steroid; fewer patients were initially treated with a biologic agent.) Sicker patients tended to receive multiple immunomodulating treatments; 47% of patients received vasopressors. Propensity score matching was used to try to account for some of the confounding factors.

The use of IVIG plus steroids yielded a significant lower risk (0.56) of cardiac dysfunction as compared to treatment with IVIG alone, and it also was associated with less subsequent escalation of care to include additional immunomodulating modalities. Acknowledging the obvious limitations of a non-randomized study, the authors’ careful analysis did show benefit in initial treatment of MIS-C with combined IVIG and steroids.

COMMENTARY

MIS-C is a rare and incompletely understood complication of SARS-CoV-2 infection. In the United States, MIS-C occurs in approximately 5.1 children per 1 million person months (and 316 per 1 million identified SARS-CoV-2 infections).1 It is relatively more common in younger than in older children, and it is more common in Black, Hispanic, and Asian persons than in whites.1

The two divergent observational studies described provide some basis for encouragement. Despite the need for inpatient and, often, intensive care with inotropes and ventilation, most children recovered, and only 2% died. In an editorial commentary accompanying these two papers, Roberta DeBiasi cites an even more optimistic figure of less than 1% of children with MIS-C dying in the United States.2 Treatment, including whatever immunomodulation is employed, seems to help children recover.

Of course, there were many factors making these two studies dissimilar: variations in treating physician management decisions, patients included, location, time (with resulting variations in viral variants in circulation), and statistical analyses. The divergent findings in the studies are not surprising. And, whether one or another solo or combination management regimen is best, children with critical life-threatening illness did recover with immunomodulatory treatment. As DeBiasi said, a lack of data to say which modality is best should not be interpreted as a lack of efficacy of the treatments.2

Other investigators continue to evaluate possible treatments of MIS-C. A nationwide study in France involving 111 children with MIS-C showed that those who received IVIG and steroids, as compared to IVIG alone, had less treatment failure, less requirement for new hemodynamic support with inotropes, and less subsequent development of left ventricular dysfunction.3

Over the months of the Son study, solo treatment became less common, and combined therapies became more common. Even while awaiting more definitive data, it is reasonable that a child sick enough to be hospitalized with MIS-C be given IVIG and steroids; escalation to a biologic, such as anakinra, or even plasmapheresis can be considered when the illness worsens or recovery stalls. Eventually, there will be more data about which virus and patient factors can be used at the time of presentation to predict which treatment regimen would be most efficacious. And, as vaccination becomes available for children and as the pandemic wanes, perhaps MIS-C also will become even more rare. 

REFERENCES

  1. Payne AB, Gilani Z, Godfred-Cato S, et al. Incidence of multisystem inflammatory syndrome in children among US persons infected with SARS-CoV-2. JAMA Netw Open 2021;4:e2116420.
  2. DeBiasi RL. Immunotherapy for MIS-C – IVIG, glucocorticoids, and biologics. N Engl J Med 2021;385:74-75.
  3. Ouldali N, Toubiana J, Antona D, et al. Association of intravenous immunoglobulins plus methylprednisolone vs immunoglobulins alone with course of fever in multisystem inflammatory syndrome in children. JAMA 2021;325:855-864.