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The best treatment strategy for COVID-linked multisystem inflammatory syndrome in children (MIS-C) remains unclear after dueling observational studies came to disparate conclusions.

Starting treatment off with both IV immunoglobulin (IVIG) and glucocorticoids was associated with a lower risk of cardiovascular dysfunction on or after day 2 compared with initial IVIG alone (17% vs 31%; risk ratio [RR] 0.56, 95% CI 0.34-0.94).

Those propensity score-matched results were confirmed by those from an inverse probability-weighted analysis on the 518 children seen at 58 U.S. centers in the CDC's Overcoming COVID-19 surveillance registry, reported Adrienne G. Randolph, MD, of Boston Children's Hospital, and colleagues in the .

Patients treated with the combination versus IVIG alone were less likely to get adjunctive therapy (34% vs 70%; RR 0.49, 95% CI 0.36-0.65), but the risk of fever was not affected (31% and 40%; RR 0.78, 95% CI 0.53-1.13).

However, among 614 children from 32 countries in the Best Available Treatment Study (BATS) Consortium, glucocorticoids alone or added to IVIG looked numerically but not significantly better than IVIG alone in inverse probability-weighted comparisons for the composite of inotropic support or mechanical ventilation by day 2 or later or death.

Disease severity reduction likewise didn't significantly differ across the groups, noted Michael Levin, PhD, of Imperial College London, and colleagues, in their study also published in the .

However, one secondary finding was in line with the U.S. results: lower risk of escalation of immunomodulatory treatment after IVIG plus glucocorticoids compared with IVIG alone.

While the findings largely conflict otherwise, the "confidence intervals for inferences about treatment effect admit the possibility of actual benefit from one or more of the treatments relative to the others," Levin's group cautioned about their results.

Another recent series of 111 children in a national published in JAMA showed that IVIG plus methylprednisolone was better than IVIG alone for relieving fever.

Clinicians have relied on immunomodulatory medications as a "best guess" for MIS-C treatment based on its semblance to Kawasaki disease, macrophage activation syndrome, and staphylococcal toxic shock syndrome, they noted.

The speed with which experts achieved consensus on diagnostic criteria and the need for rapid immunomodulation was a "triumph of collaboration," acknowledged Roberta DeBiasi, MD, of Children's National Hospital and Research Institute and George Washington University School of Medicine in Washington, D.C., in an .

"However, in the absence of randomized, controlled clinical trials, consensus around specific immunomodulatory therapies has been more elusive, given the speed with which centers have had to establish cohorts and deliver treatment," she wrote.

Potential reasons for the differences between the BATS and U.S. studies included disparate genetic backgrounds, different time periods, and observational designs that cannot fully compensate for potentially confounding factors, she suggested.

The U.S. data came before substantial circulation of variants, covering surveillance data on MIS-C inpatients under age 21 seen from March 15 to October 31, 2020. BATS included the time when variants were circulating -- June 2020 through February 2021.

Moreover, neither study was powered to look at outcomes with biologic agents, such as anakinra (Kineret) and infliximab (Remicade), DeBiasi noted. "In this regard, clinicians must avoid the pitfall of interpreting a lack of data as a lack of efficacy. Randomized, controlled trials to evaluate the safety and efficacy of regimens comparing biologic agents with glucocorticoids (with or without IVIG) have not yet been performed."

In BATS, only 22 of the 614 included children with suspected MIS-C (490 met WHO criteria for it) received biologic agents or other treatment combinations, while the largest proportion received IVIG alone or with glucocorticoids as the primary treatment (246 and 208, respectively). Another 99 received glucocorticoids alone and 39 received no immunomodulatory therapy.

In the U.S. data, 518 (87%) of the 596 patients with MIS-C (by CDC criteria) received at least one immunomodulatory treatment during hospitalization. Most received IVIG with glucocorticoids (47%), followed by the combination of IVIG, glucocorticoids, and a biologic (21%). Another 17% (89 patients) received IVIG alone, and 16% (81 patients) received glucocorticoids only, a biologic alone, or some other combination.

Long-term outcomes aren't clear yet, DeBiasi added, specifically for impact on coronary abnormalities, prolonged or permanent cardiac dysfunction, or scarring, as well as pulmonary issues, mental health, neurodevelopment, and quality of life. "Meanwhile, continued collaboration across centers is essential to decreasing the short-term incidence of death and complications, particularly as COVID-19 continues to circulate internationally, and to evaluating the effect of vaccination in younger age groups."