American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS–CoV‐2 and Hyperinflammation in Pediatric COVID‐19: Version 2

Abstract

Objective. To provide guidance on the management of Multisystem Inflammatory Syndrome in Children (MIS-C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Recommendations are also provided for children with hyperinflammation during coronavirus disease 2019 (COVID-19), the acute, infectious phase of SARS-CoV-2 infection. Methods. The Task Force was composed of 9 pediatric rheumatologists and 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS-C and hyperinflammation in COVID-19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved anonymous voting and webinar discussion. A 9-point scale was used to determine the appropriateness of each statement (median scores of 1-3 for inappropriate, 4-6 for uncertain, and 7-9 for appropriate). Consensus was rated as low, moderate, or high based on dispersion of the votes. Approved guidance statements were those that were classified as appropriate with moderate or high levels of consensus, which were prespecified before voting. Results. The first version of the guidance was approved in June 2020, and consisted of 40 final guidance statements accompanied by a flow diagram depicting the diagnostic pathway for MIS-C. The document was revised in November 2020, and a new flow diagram with recommendations for initial immunomodulatory treatment of MIS-C was added. Conclusion. Our understanding of SARS-CoV-2-related syndromes in the pediatric population continues to evolve. This guidance document reflects currently available evidence coupled with expert opinion, and will be revised as further evidence becomes available. Due to the rapidly expanding information and evolving evidence related to COVID-19, which may lead to modification of some guidance statements over time, it is anticipated that updated versions of this article will be published, with the version number included in the title. Readers should ensure that they are consulting the most current version. Guidance developed and/or endorsed by the American College of Rheumatology (ACR) is intended to inform particular patterns of practice and not to dictate the care of a particular patient. The ACR considers adherence to this guidance to be voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances. Guidance statements are intended to promote beneficial or desirable outcomes but cannot guarantee any specific outcome. Guidance developed or endorsed by the ACR is subject to periodic revision as warranted by the evolution of medical knowledge, technology, and practice.

COVID–19 infection and stroke risk

“…(2) Hypercoagulability: the construction of thrombus can be aided by the inflammation. Severe COVID-19 leads to a cytokine storm as an expression of hyperactive host immune system response to the virus and the inflammation can cause coagulopathy as a consequence of sepsis (Henderson et al 2020;Mangalmurti and Hunter 2020). This event has been termed sepsis-induced coagulopathy (SIC) and is comorbid with high D-dimer levels and elevated fibrinogen (Iba et al 2019;Tang et al 2020).…”

Presumptive Neonatal Multisystem Inflammatory Syndrome in Children Associated with Coronavirus Disease 2019

“…10 The trigger for initiating a dysregulated immune response to COVID-19 infection manifesting as MIS-C remains unknown. [1][2][3]8,9 Rostad et al have reported that patients with MIS-C had high titers of SARS-COV-2 receptor binding domain IgG antibodies compared with other hospitalized patients with and without COVID-19 infection, these titers correlated with markers of inflammation and length of stay. 11 In our patient, IgM antibodies were negative suggesting passive transfer of maternal IgG.…”

“…When compared with Kawasaki disease (KD), a similar but distinct entity, the patients tend to be older-of Hispanic or African decenthave prominent gastrointestinal and cardiovascular involvement with thrombocytopenia and lymphopenia. 2 In this report, we describe a case of presumptive neonatal MIS-C like disease with the intent of increasing awareness of this possibility in critically ill neonates born to mothers infected with SARS-CoV-2 infection even when the clinical features are atypical.…”

Lessons learned: new insights on the role of cytokines in COVID-19

“…Cron outlined treatment options, which included immunomodulatory agents such as intravenous immunoglobulin infusions, as used for KD, glucocorticoids, anakinra (IL-1 receptor antagonist) and infliximab (a monoclonal antibody to TNF); antimicrobials, including remdesivir and broad-spectrum antibiotics (as some patients' clinical pictures resemble bacterially induced toxic shock syndrome); and, in severe cases, mechanical ventilation, pressor support and anticoagulants 8,9,14,15 . Updated treatment guidelines were published recently by the American College of Rheumatology 16 .…”

“…To investigate MIS-C from a systems biology perspective, similar to studying COVID-19 in adults, Dusan Bogunovic (Icahn School of Medicine at Mount Sinai) described analyses of about 40 patients treated at Mount Sinai in New York who presented with the symptoms of MIS-C and who met diagnostic criteria 16 . Treatment with an IL-6R blocker and intravenous immunoglobulin led to discharge, usually within 5 days, with universally favorable outcomes.…”