Effective Treatments Identified for Pediatric Complication of COVID

Derick Alison
Derick Alison
9 Min Read

PHOENIX — First-line treatment with methylprednisolone and second-line treatment with tocilizumab (Actemra) shortened hospital stays for children with pediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS; also referred to as multisystem inflammatory syndrome in children [MIS-C]), according to results of a two-stage clinical trial from the RECOVERY collaborative group.

In 214 children randomly assigned to either methylprednisolone, intravenous immunoglobulin, or usual care in the first stage of the trial, the mean duration of hospital stay for those on methylprednisolone was 6.9 days compared with 7.6 days for usual care. The mean duration of stay for children who received first-line immunoglobulin (7.4 days) was not significantly different from usual care, reported Nazima Pathan, PhD, of the University of Cambridge in England, at the Society of Critical Care Medicine Critical Care Congress.

In a second randomization, which included 70 children with persistent fever and inflammation who required second-line care, duration of hospital stay was 6.6 days for those randomized to tocilizumab compared with 9.9 days for usual care. There was less benefit for those randomized to anakinra (Kineret) compared with usual care (8.5 vs 9.9 days).

Findings from the study were also published in Lancet Child & Adolescent Health.

“We now know that treatment with methylprednisolone in the first instance and tocilizumab when inflammation is persistent can be beneficial in reducing inflammation and the length of hospital stays for children with [pediatric] multisystem inflammatory syndrome associated with COVID-19,” said co-investigator Saul Faust, MBBS, of the University of Southampton in England, in a statement.

“We also found that treatment with immunoglobulin and anakinra have no beneficial effect on these outcomes,” Faust added. “We recommend that the trial results be used to inform updates of clinical guidelines.”

“In terms of safety outcomes, there were two deaths, which were not associated with any particular intervention,” Pathan said during her presentation. “The main concern is the risk of cardiovascular sequelae from PIMS-TS, and there wasn’t any association with any of the interventions.” There were few cardiac arrhythmias, bleeding, or thrombotic events in any group, she noted.

“Interestingly,” Pathan added, “although both of these drugs are anti-inflammatory, we did observe a higher use of inotropes and an increase in the number of days on inotropes for both.” The effect was most notable for tocilizumab, which was associated with 0.6 days on inotropes compared with 0.2 for standard care. “So there’s evidence of a post probability of harm for that particular outcome,” she said.

First described in April 2020, patients with PIMS-TS or MIS-C present with clinical and laboratory evidence of multisystem inflammation; erythematous mucocutaneous changes; and organ dysfunction particularly affecting the brain, heart, and gut, the researchers explained.

PIMS-TS has not been as common for Omicron and subsequent SARS-CoV-2 variants, although if it were to recur on a wider global basis, methylprednisolone could be considered the first-line treatment of choice due to treatment effect, affordability, and widespread availability, the researchers noted.

The reason for the decreased incidence of PIMS-TS is not fully known, Mary Beth Son, MD, and Adrienne Randolph, MD, of Boston Children’s Hospital, noted in an editorial accompanying the study. However, “it seems likely that differences in SARS-CoV-2 strains and protection from natural and vaccine-induced immunity have led to progressively milder illness,” they wrote.

“As the need for evidence-based treatment protocols for MIS-C is less pressing now, perhaps the lessons from RECOVERY and other pandemic collaborations derive from their demonstration of success,” Son and Randolph suggested. “Such collaborations have made major contributions to understanding the pathophysiology, treatment, and prevention of COVID-19 and MIS-C.”

Though Son and Randolph also noted an important limitation of the trial: the common use of protocol treatments within the usual care group in the first randomization, which diminished differences in outcomes between treatment and usual care. As many as 44% of children in the usual care group received intravenous immunoglobulin and 50% to 58% received corticosteroids after the first random assignment, they said.

“This probably indicates lack of clinical equipoise among treating clinicians, as evidence of effective combination therapy for children with cardiovascular dysfunction was published during the trial period,” they suggested. “The results of this pragmatic trial are an important contribution to the literature but should be interpreted in the setting of this and other limitations.”

The researchers conducted the randomized, open-label, platform trial during the pandemic, from May 2020 to January 2022. It was conducted at 51 hospitals in the U.K. Eligible patients were younger than 18 and had been admitted to a hospital for PIMS-TS. They enrolled 237 patients, with 23 entering the second randomization directly, while 214 patients entered the first. The mean age was 9.5 years and 55% were male. More than half of patients (55%) were Black, Asian, or minority ethnic, and 44% were white.

The researchers used intention-to-treat and Bayesian analysis to jointly assess the efficacy of each intervention compared with usual care. The primary outcome was length of hospital stay.

Limitations of the trial included its small sample size and the relative short duration of hospital stays.

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    Jeff Minerd is a freelance medical and science writer based in Rochester, NY.

Disclosures

The RECOVERY trial is supported by the U.K. Research and Innovation/National Institute for Health Research and by core funding provided by Wellcome, the Bill & Melinda Gates Foundation, the Department for International Development, Health Data Research U.K., and the Medical Research Council Population Health Research Unit.

Pathan reported no conflicts of interest. Faust acts on behalf of University Hospital Southampton NHS Foundation Trust as an investigator or in the provision of consultative advice on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by manufacturers of vaccines and antimicrobials, including Janssen, Pfizer, Moderna, AstraZeneca, GSK, Novavax, Sanofi, Medimmune, Merck, Iliad, and Valneva. He receives no personal financial payment for this work. Co-authors reported multiple relationships with industry.

Son and Randolph reported no relevant conflicts of interest.

Son declares grants from the U.S. Centers for Disease Control and Prevention and royalties from UpToDate.

Randolph declares relationships with the U.S. National Institutes of Health, CDC, UpToDate, St. Jude, Thermo Fisher, the International Sepsis Forum, Institut Merieux, participation on data safety monitoring and medical advisory boards, and has received reagents from Illumina.

Primary Source

The Lancet Child & Adolescent Health

Source Reference: Faust SN et al “Immunomodulatory therapy in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS, MIS-C; RECOVERY): a randomised, controlled, open-label, platform trial” Lancet Child Adolesc Health 2024; DOI: 10.1016/S2352-4642(23)00316-4.

Secondary Source

The Lancet Child & Adolescent Health

Source Reference: Son MBF, Randolph AG “The RECOVERY trial of PIMS-TS: Important lessons from the pandemic” Lancet Child Adolesc Health 2024; DOI: 10.1016/S2352-4642(23)00341-3.

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