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.

Figure 1.

Diagnostic pathway for multisystem inflammatory syndrome in children (MIS-C). Moderate-to-high consensus was reached by the Task Force in the development of this diagnostic pathway for MIS-C associated with severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2). ¹An epidemiologic link to SARS–CoV-2 infection is defined as a child with any of the following criteria: positive for SARS–CoV-2 by polymerase chain reaction (PCR), positive for SARS–CoV-2 by serology, preceding illness resembling coronavirus disease 2019 (COVID-19), or close contact with an individual with confirmed or suspected COVID-19 in the past 4 weeks. ²Suggestive clinical features include rash (polymorphic, maculopapular, or petechial, but not vesicular), gastrointestinal symptoms (diarrhea, abdominal pain, or vomiting), oral mucosal changes (red and/or cracked lips, strawberry tongue, or erythema of the oropharyngeal mucosa), conjunctivitis (bilateral conjunctival infection without exudate), and neurologic symptoms (altered mental status, encephalopathy, focal neurologic deficits, meningismus, or papilledema). ³The complete metabolic panel (CMP) includes measurement of sodium, potassium, carbon dioxide, chloride, blood urea nitrogen, creatinine, glucose, calcium, albumin, total protein, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and bilirubin. ⁴Procalcitonin, cytokine panel, and blood smear test results should be sent, if available. ⁵Serologic test results should be sent if not sent in tier 1 evaluation, and if possible, SARS–CoV-2 IgG, IgM, and IgA test results should be sent. CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; ALC = absolute lymphocyte count; CBC = complete blood cell count; BNP = B-type natriuretic peptide; PT = prothrombin time; PTT = partial thromboplastin time; LDH = lactate dehydrogenase; u/a = urinalysis; EKG = electrocardiogram.

Figure 2.

Algorithm for initial immunomodulatory treatment of multisystem inflammatory syndrome in children (MIS-C). Moderate-to-high consensus was reached by the Task Force in the development of this treatment algorithm for MIS-C associated with severe acute respiratory syndrome coronavirus 2. ¹Intravenous immunoglobulin (IVIG) dosing is 2 gm/kg based on ideal body weight. Cardiac function and fluid status should be assessed before IVIG is given. In some patients with cardiac dysfunction, IVIG may be given in divided doses (1 gm/kg daily over 2 days). ²Methylprednisolone or another steroid at equivalent dosing may be used. ³Refractory disease is defined as persistent fevers and/or ongoing and significant end-organ involvement. ⁴Low-to-moderate–dose glucocorticoids (methylprednisolone 1–2 mg/kg/day) may be considered for first-line therapy in some MIS-C patients with concerning features (ill appearance, highly elevated B-type natriuretic peptide levels, unexplained tachycardia) who have not yet developed shock or organ-threatening disease. ⁵If the patient was given low-to-moderate–dose glucocorticoids as first-line therapy, methylprednisolone IV dosing should be 10–30 mg/kg/day for intensification treatment.