American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 3

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 SARS-CoV-2 infection. Recommendations are also provided for children with hyperinflammation during COVID-19, the acute, infectious phase of SARS-CoV-2 infection.

Methods: The Task Force is 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 guidance was approved in June 2020 and updated in November 2020 and October 2021, and consists of 41 final guidance statements accompanied by flow diagrams depicting the diagnostic pathway for MIS-C and recommendations for initial immunomodulatory treatment of MIS-C.

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 SARS–CoV‐2. ¹Due to the difficulty in establishing an epidemiologic linkage to a preceding SARS–CoV‐2 infection given the evolving COVID‐19 pandemic, the diagnosis of MIS‐C must be determined based on the totality of the history, examination, and laboratory studies. Patients may have MIS‐C even in the absence of preceding COVID‐19–like illness or a clear history of exposure to SARS–CoV‐2, especially in the setting of high community prevalence. 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 SARS–CoV‐2. ¹Intravenous immunoglobulin (IVIG) dosing is 2 gm/kg based on ideal body weight, with maximum dose of 100 gm. 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. ³In select patients with mild disease or contraindications to glucocorticoids, IVIG alone may be appropriate as first‐line treatment for MIS‐C. These patients should be monitored closely and intensification therapy should be added at the first signs of clinical worsening. ⁴Refractory disease is defined as persistent fevers and/or ongoing and significant end‐organ involvement. ⁵Infliximab should not be used in patients with MIS‐C and features of macrophage activation syndrome.