Table 2.

Comparison of current published society MIS-C clinical management guidelines with regard to immune modulation therapy

	PIMS-TS National Consensus Management Study Group18	Guidance from the Rheumatology Study Group of the Italian Society of Pediatrics19	American College of Rheumatology clinical guidance-version 317	Practice recommendations in Switzerland29
Date of online publication	September 18, 2020	February 8, 2021		May 26, 2021
Primary immunomodulation therapy	IVIG	IVIG	IVIG and low-moderate dose glucocorticoids	IVIG
Adjunct immunomodulation therapy	KD phenotype: High dose glucocorticoids	Glucocorticoids Anakinra	See above	Glucocorticoids
Indication for adjunct immunomodulation therapy	KD phenotype: High-risk children including those younger than 12 months and those with coronary artery changes	Glucocorticoids: in case of heart involvement, severe disease, impending sHLH or toxic shock syndrome Anakinra: in case of severe sHLH or shock with cardiac failure
Rescue immunomodulation therapy	Second dose of IVIG High-dose glucocorticoids Biological therapy should be considered as a third-line option in children who do not respond to IVIG and glucocorticoids (for those recruited in the RECOVERY trial tocilizumab or standard of care, if not recruited in RECOVERY trial the agent of choice for KD phenotype is infliximab and for nonspecific presentation phenotype, the choice is left to the clinician to choose from the following agents: tocilizumab, anakinra, and infliximab)	Second dose of IVIG Anakinra	High-dose glucocorticoids Anakinra (preferred anticytokine therapy) Infliximab (except in patients with features of MAS) Second dose of IVIG is not recommended	Anakinra Other biologics (tocilizumab, infliximab) Second dose of IVIG
Indication for rescue immunomodulation therapy	Indication for second dose of IVIG: not responded or partially responded to the first dose Indication for high-dose glucocorticoids: unwell 24 hours after infusion of IVIG, particularly with ongoing pyrexia	Persistent disease activity 48 hours after first-line treatment	Persistent fever and/or ongoing and significant end organ involvement	No clinical improvement 24-36 hours after IVIG treatment with persistent fever and/or inflammation
Special comment	All children who meet the criteria for the RECOVERY trial should be invited to participate in the first stage of randomization for the trial Management is divided according to phenotype: KD phenotype vs nonspecific presentation phenotype For the nonspecific presentation phenotype, indications for therapy include: evidence of CAA, meeting the criteria for toxic shock syndrome, evidence of progressive disease, and extended duration of fever (> 5 days). In other words those not meeting above criteria can be observed. No guidance was provided on tapering immunomodulatory medications	Although different doses of steroids were suggested depending on severity and cardiac involvement, no guidance was provided on tapering immunomodulatory medications	Immunomodulatory treatment may be withheld in some patients with mild symptoms Patients might require a 2- to 3-week, or even longer, taper of immunomodulatory medications, guided by serial laboratory and cardiac evaluations	The guidelines suggest considering immunomodulation therapy (IVIG, prednisolone) in patients who present with undefined inflammatory phenotype (not shock or KD phenotype) In other words, immunomodulatory treatment may be withheld in some patients Slow wean of steroids, taper over 2-6 weeks depending on the clinical course and considering the clinical and biochemical (such as CRP, D-dimer, and ferritin levels) response

MIS-C was first described on April 26, 2020.

CAA, coronary artery abnormality; CRP, C-reactive protein; IVIG, intravenous immunoglobulin; KD, Kawasaki disease; MAS, macrophage activation syndrome; MIS-C, multisystem inflammatory syndrome in children; PIMS-TS, pediatric inflammatory multisystem syndrome temporally associated with COVID-19; RECOVERY, Randomised Evaluation of COVID-19 Therapy; sHLH, secondary hemophagocytic lymphohistiocytosis.