ACR recommends 'stepwise approach' to immunomodulatory therapy in MIS-C linked to COVID-19
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A stepwise approach to immunomodulatory drugs is recommended for children with multisystem inflammatory syndrome linked to COVID-19, with IVIG and glucocorticoids as first-tier agents, noted updated American College of Rheumatology guidance.
The ACR initially announced its “Clinical Guidance for Pediatric Patients with Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with SARS-CoV-2 and Hyperinflammation in COVID-19” on June 18. This document was later revised in November, with a new flow diagram and recommendations for initial MIS-C immunomodulatory treatment added. The resulting “Version 2” of the guidance was published this month in Arthritis & Rheumatology.
“Unlike adults, the vast majority of children with COVID-19 have mild symptoms,” Lauren A. Henderson, MD, MMSc, of Boston Children’s Hospital and Harvard Medical School, and colleagues wrote. “However, there are children who have significant respiratory disease, and some children may develop a hyperinflammatory response similar to what has been observed in adults with COVID-19. Furthermore, in late April 2020, reports emerged of children with a different clinical syndrome resembling Kawasaki Disease (KD) and toxic shock syndrome; these patients frequently had evidence of prior exposure to SARS-CoV-2.”
“While this constellation of symptoms has been given many names, for the purposes of this discussion we will use, “Multisystem Inflammatory Syndrome in Children” (MIS-C),” they added. “For a number of reasons, there is an urgent need to provide guidance to health care providers evaluating patients in whom MIS-C is a diagnostic consideration. In addition, pediatric rheumatologists are often asked to recommend immunomodulatory therapy for patients with a hyperinflammatory state due to acute SARS-CoV-2 infection.”
For the original guidelines, the ACR assembled a task force of nine pediatric rheumatologists, two adult rheumatologists, two pediatric cardiologists, two pediatric infectious disease specialists and one pediatric critical care physician. The panel’s first meeting, on May 22, saw members form four workgroups to address clinical questions related to MIS-C and hyperinflammation in COVID-19. Each workgroup generated preliminary statements supported by evidence and shared with the entire task force.
Members then conducted two rounds of anonymous voting, as well as two webinars in which they discussed the results to achieve consensus. They also used a nine-point scale to determine the appropriateness of each statement, with consensus rated as either low, moderate or high based on dispersion of the votes along the numeric scale. Approved guidance statements had to be classified as either moderate or high on the consensus scale.
For the latest revision, workgroup leaders identified guidance statements that should be modified based on clinical experience and newly available literature. Panelists then reviewed these revised statements, along with the supporting literature, prior to a webinar in October, where they discussed the proposed changes. An anonymous vote was held, in which revised guidance statements that received a moderate or high degree of consensus were approved.
The initial guidelines released in June contained 40 final guidance statements, accompanied by a flow diagram showing the diagnostic pathway for MIS‐C. In the revised guideline, published in December, a new flow diagram and 22 revised statements, including recommendations for initial immunomodulatory treatment.
According to these recommendations, patients with suspected life-threatening MIS-C may require immunomodulatory treatment before the full diagnostic evaluation can be finished. A stepwise progression of immunomodulatory therapies should be used to treat MIS-C, with intravenous immunoglobulin (IVIG) considered the first-tier therapy. Glucocorticoids should be used as adjunctive therapy in patients with severe disease, or as intensification therapy in those with refractory disease. IVIG should be given to MIS-C patients who are hospitalized and/or meet the criteria for Kawasaki Disease.
Treatment for MIS-C should involve high dose IVIG — typically 2 gm per kg, based on ideal body weight. Providers should assess cardiac function and fluid status prior to IVIG treatment, with those demonstrating depressed cardiac function possibly requiring close monitoring and diuretics with IVIG administration.
A second dose of IVIG is not recommended in patients with refractory MIS-C, due to the risk of volume overload and hemolytic anemia associated with large doses of IVIG. Serial laboratory testing and cardiac assessment should guide immunomodulatory treatment response and tapering. Patients may require 2 to 3 weeks — or even longer — to taper immunomodulatory medications.
The guidelines also come with a few caveats.
Although their work is supported by scientific literature and recommendations from public health institutions, the guideline’s authors cautioned that the available data remains low in quality, and often extrapolated from experiences with adults.
“This approach is particularly problematic when confronting clinical questions regarding MIS-C, which to date has been reported primarily in children,” Henderson and colleagues wrote. “This unique manifestation of COVID-19 in children and adolescents highlights the need to prioritize and fund rigorous research in the pediatric population. For now, our understanding of pediatric SARS-CoV-2 infections is rudimentary and will continue to change as higher quality evidence becomes available.”
“Thus, the recommendations contained in this document should be interpreted in the setting of this shifting landscape and will be modified prospectively as our understanding of COVID-19 improves,” they added. “For these reasons, this guidance does not replace the critical role of clinical judgment that is essential to address the unique needs of individual patients.”
Perspective
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As the COVID-19 pandemic rages on, rheumatology health care professionals continue to immerse themselves in the latest scientific information available on all aspects of COVID-19 in order to provide the best care for their patients. This has never been truer for pediatric rheumatology health care professionals who have been called upon to assist in the diagnosis and treatment of pediatric patients with multisystem inflammatory syndrome (MIS-C) a unique syndrome seen in the late phases of COVID-19 infections.
Henderson and colleagues have put forth the second version of the ACR Clinical Guidance for MIS-C associated with SARS-CoV-2 and hyperinflammation in COVID-19. This document goes into great detail on how the task force reached consensus on each recommendation statement after an exhaustive review of available literature and case studies worldwide.
Of note are the recommendations for a two-tiered approach in the evaluation of children with a suspension of MIS-C, the similarities and difference between MIS-C and Kawasaki Disease and an explanation of hyperinflammation seen in the initial phase of severe COVID-19 infections.Recommendations on treatment regimens, including IVIG, glucocorticoids and immunomodulators, along with follow-up care are also included.
MIS-C is not unique to children with autoimmune diseases as it often occurs in otherwise healthy children who have contracted COVID-19. ACR’s latest guidance document for MIS-C will not only be beneficial for pediatric rheumatology health care professionals, but also for general pediatric health care professionals, who are often the first to identify these sick children, initiate a work-up and refer them to more specialized care when necessary.
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