Optimal therapy for post-COVID syndrome in kids proves elusive

Two new real-world studies evaluated the use of intravenous immune globulin (IVIG) therapy plus glucocortioids for treatment of post–COVID-19 multisystem inflammatory syndrome in children (MIS-C), one finding a lower risk of new or persistent cardiovascular dysfunction with the combination treatment and the other showing no lessening in disease severity or time to recovery.

The studies and a related editorial were published last week in the New England Journal of Medicine.

Drug combo may help protect the heart

In the first study, the Overcoming COVID-19 Investigators, led by Boston Children's Hospital researchers, analyzed surveillance data on 518 MIS-C patients 20 years and younger receiving at least one immune response-enhancing drug at 58 US hospitals from Mar 15 to Oct 31, 2020.

Initial treatment with IVIG and glucocorticoids in 103 patients was tied to a lower risk of cardiovascular dysfunction on or after 2 days than IVIG alone (17% vs 31%; risk ratio [RR], 0.56). The combination therapy was also associated with a lower risk of left ventricular dysfunction (8% vs 17%; RR, 0.46) and shock necessitating the use of vasopressors (13% vs 24%; RR, 0.54).

Patients given IVIG and glucocorticoids were less likely to require additional immune-enhancing treatments than those given IVIG alone (34% vs 70%; RR, 0.49). But there was no difference in the risk of fever or in length of intensive care unit (ICU) stay.

Five or more organ systems were affected in 55% of patients, while 38% met at least some of the criteria for Kawasaki disease, 74% required ICU care, and 2% died. Of the 518 patients, 97% underwent at least one echocardiogram, which revealed left ventricular dysfunction in 42% and coronary artery aneurysms in 13%.

Of all patients, 89% received only IVIG; 47% were given both IVIG and glucocorticoids; 21% received IVIG, glucocorticoids, and a biologic anti-inflammatory drug; and 16% received glucocorticoids only, a biologic only, glucocorticoids and a biologic, or IVIG plus a biologic. Forty-seven percent of patients received vasopressors. Patients given IVIG alone tended to be younger than those given combination treatment, and half had characteristics of Kawasaki disease.

Median patient age was 8.7 years, 42% were female, 35% were Black, 34% were Hispanic or Latino, and 75% had been healthy before their COVID-19 illness.

The authors noted that MIS-C outbreaks may continue amid the ongoing pandemic and the emergence of more transmissible or severe variants in the United States and abroad. "Additional evidence-based studies are needed to examine the generalizability of our findings across a broad range of geographic regions and practice settings," they wrote.

Implications for low- and middle-income countries

The second study, led by Imperial College London researchers as part of the Best Available Treatment (BATS) Consortium, involved analyzing physician-uploaded data on 614 children with suspected MIS-C in 32 countries from Jun 20, 2020 through Feb 14, 2021.

Of the 614 children, 40.1% were given IVIG alone, while 33.9% received IVIG and glucocorticoids, 16.1% were given only glucocorticoids, 3.6% received other therapeutic combinations (eg, biologics), and 6.4% received no immune-enhancing treatment.

Among patients given IVIG and glucocorticoids, 27.0% required ventilation or died (adjusted odds ratio [aOR] for combination vs IVIG alone, 0.77). In those given only glucocorticoids, 17.2% met those endpoints (aOR, 0.54). In total, 1% of patients who received IVIG alone died, compared with 3% given IVIG and glucocorticoids, and 4% who received only glucocorticoids.

The chances of lesser disease severity were comparable in the combination and glucocorticoid-alone groups, compared with IVIG alone (aOR for combination therapy, 0.90; aOR for glucocorticoids alone, 0.93).

Escalation of treatments to improve immune response occurred less often in patients who received both IVIG and glucocorticoids than among those given IVIG alone (OR, 0.18), but a comparison of those given glucocorticoids or IVIG alone was inconclusive (OR, 1.31).

"The high rates of escalation to additional treatments in patients receiving single agents may be explained by a failure of the initial treatment or by the severity of illness, as well as by a greater readiness to escalate therapy when only one treatment was given," the researchers said. 

Patients in all three groups began to recover after a similar period of time, and no link was identified between any of the three treatment regimens and organ failure, inflammation, or release from the hospital.

"We found no evidence that recovery from MIS-C differed after primary treatment with IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone, although significant differences may emerge as more data accrue," the authors wrote.

They added that ongoing enrollment and analysis of larger numbers of MIS-C patients are required to provide definitive evidence, which is particularly important in the treatment of MIS-C in low- and middle-income countries.

"IVIG and biologic agents are costly and have limited availability in many countries, so evidence to support their use in preference to cheaper anti-inflammatory agents such as glucocorticoids is needed," they said.

Lack of statistical power

In the editorial, Roberta De Biasi, MD, of Children's National Hospital and Research Institute in Washington, DC, said that in the absence of evidence from randomized, clinical trials, which have been hindered by the relatively rarity of MIS-C, physicians had to rapidly reach a consensus on diagnostic criteria and the use of immunomodulation—although optimal therapeutic regimens have not been established.

De Biasi pointed out that while the two studies seem to have reached conflicting conclusions, they reported on different populations, used data from two different periods in the pandemic, and used statistical modeling methods that may not have compensated for important confounding factors (eg, criteria used to start immune-enhancing treatments). And neither study was able to determine the most effective treatment for MIS-C.

"Specifically, neither study was powered to include an evaluation of approaches that steer away from broad immunosuppression with glucocorticoids and that focus on more targeted and titratable treatments with biologic agents, such as anakinra and infliximab," she wrote. "In this regard, clinicians must avoid the pitfall of interpreting a lack of data as a lack of efficacy." 

Last, De Biasi wrote, the effects of the therapies studied on long-term outcomes such as progression or resolution of coronary abnormalities, persistent or permanent cardiac dysfunction, or scarring are still unknown.

"Systematic and comprehensive long-term follow-up for these and other noncardiac outcomes—including sequelae involving pulmonary issues, mental health, neurodevelopment, and quality of life—are sorely needed in the pediatric population and will launch soon," she said.

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