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.

Clinical progress note: Multisystem inflammatory syndrome in children

“…Based on the ACR statement, clinicians should suspect MIS-C in patients with the following: fever, known or suspected epidemiologic link to SARS-CoV-2, and at least two suggestive clinical features such as rash, GI symptoms, extremity swelling, oral mucosal changes, conjunctivitis, lymphadenopathy, or neurological symptoms. 12 If a patient meets clinical criteria without an alternative etiology, the provider should proceed with lab evaluation (Figure 1). Lab evaluation can be approached in a tiered fashion with initial screening labs and if the patient is hemodynamically unstable or Tier 1 screening reveals elevated C-reactive protein (CRP)/erythrocyte sedimentation rate (ESR) and at least one additional abnormal laboratory result, the full evaluation is suggested including additional lab work and cardiac testing (Table 1).…”

“…If patients do not demonstrate clinical improvement, additional treatment may include higher dose glucocorticoids (methylprednisolone 10−30 mg/kg/day) or other immunomodulators such as anakinra (IL-1 blockade) or infliximab (TNF-α blockade). High-dose anakinra is recommended by the ACR as the second line in refractory MIS-C. 12 A second dose of IVIG is not recommended due to the risk of hemolytic anemia and fluid overload. 12 A significant proportion of MIS-C patients present with shock or hemodynamic instability with up to 40%−50% of MIS-C patients requiring inotropic support.…”

“…High-dose anakinra is recommended by the ACR as the second line in refractory MIS-C. 12 A second dose of IVIG is not recommended due to the risk of hemolytic anemia and fluid overload. 12 A significant proportion of MIS-C patients present with shock or hemodynamic instability with up to 40%−50% of MIS-C patients requiring inotropic support. [5][6][7][8]10 Given the increased risk of thrombosis in MIS-C and known hypercoagulability in the adult COVID-19 population, low-dose aspirin (3−5 mg/kg/day) should be administered during the acute phase and continued until the platelet count is normalized and normal coronary arteries are confirmed at >4 weeks after diagnosis.…”

“…[5][6][7][8]10 Given the increased risk of thrombosis in MIS-C and known hypercoagulability in the adult COVID-19 population, low-dose aspirin (3−5 mg/kg/day) should be administered during the acute phase and continued until the platelet count is normalized and normal coronary arteries are confirmed at >4 weeks after diagnosis. 12 Due to the risk of coronary artery thrombosis, patients with coronary artery aneurysms or z-scores of ≥10 should undergo therapeutic anticoagulation with enoxaparin for at least 2 weeks, then transition to a vitamin K antagonist (VKA) or direct-acting oral anticoagulant (DOAC) until the z-score is <10. 10,12 Other MIS-C patients requiring therapeutic anticoagulation (defined as enoxaparin, VKA, or DOAC) include those with moderate to severe left ventricular dysfunction (defined as EF < 35%) until EF > 35%, and those with documented thrombus treated for 3 months or until thrombus is resolved.…”

“…12 Due to the risk of coronary artery thrombosis, patients with coronary artery aneurysms or z-scores of ≥10 should undergo therapeutic anticoagulation with enoxaparin for at least 2 weeks, then transition to a vitamin K antagonist (VKA) or direct-acting oral anticoagulant (DOAC) until the z-score is <10. 10,12 Other MIS-C patients requiring therapeutic anticoagulation (defined as enoxaparin, VKA, or DOAC) include those with moderate to severe left ventricular dysfunction (defined as EF < 35%) until EF > 35%, and those with documented thrombus treated for 3 months or until thrombus is resolved. 12 After initial diagnosis, inpatient providers should continue to trend laboratory assessments, particularly complete blood count, CRP, ESR, and BNP and/or troponin levels, until the patient shows clear clinical improvement.…”