ACR Recommendations for the Management of MIS-C

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The American College of Rheumatology (ACR) recently released guidance for the clinical management of multisystem inflammatory syndrome in children (MIS-C) associated with severe acute respiratory coronavirus 2 (SARS-CoV-2) and hyperinflammation in coronavirus disease 2019 (COVID-19). Developed by the ACR MIS-C and COVID-19 Related Hyperinflammation Task Force, these guidelines include the diagnostic evaluation and treatment of SARS-CoV-2-associated MIS-C and hyperinflammation in children with COVID-19. The full report is published on the ACR website.

ACR Recommendations for the Management of MIS-C

General Statements

The ACR task force noted that MIS-C is a relatively rare complication of infection with SARS-CoV-2, with a majority of children with COVID-19 presenting with mild symptoms and showing excellent outcomes.

Because MIS-C is temporally associated with SARS-CoV-2 infection, the prevalence of the virus may change over time, and thus, clinical decisions should be taken accordingly.

Diagnostic Evaluation of MIS-C

The task force has recommended that a child with suspected SARS-CoV-2-associated MIS-C should receive testing for other infectious and noninfectious etiologies, too. These patients may receive additional diagnostic tests, including those of the chest, abdomen, and/or central nervous system.

Suggestive symptoms of MIS-C include rash, gastrointestinal symptoms, oral mucosal changes, conjunctivitis, and neurologic symptoms. In patients with stable vital signs and good physical examinations, outpatient care, along with follow-up care, may be considered. However, most patients with suspected MIS-C should be hospitalized, particularly if they present with abnormal vital signs; respiratory distress of any severity; neurologic deficits; renal or hepatic injury; elevated inflammatory markers (C-reactive protein [CRP], ≥10.00 mg/dL); or abnormal electrocardiogram (EKG), B-type natriuretic peptide (BNP), or troponin T. Patients who present with shock, respiratory distress, neurologic changes (including altered mental status, encephalopathy, papilledema), or features of Kawasaki disease must be hospitalized for further evaluation, regardless of MIS-C status.

Patients with suspected MIS-C should be managed by a multidisciplinary team of pediatric rheumatologists, cardiologists, infectious disease specialists, and hepatologists. Consultation with other specialties may also be considered.

Distinguishing MIS-C From Kawasaki Disease

Patients with Kawasaki disease not associated with SARS-CoV-2 should continue to receive standard care.

Although MIS-C and Kawasaki disease may have overlapping clinical features, including conjunctival injection, red/cracked lips, strawberry tongue, and erythematous hands and feet, the task force has suggested several distinguishing epidemiologic and clinical features between the 2 conditions. Some of them include increased incidence of MIS-C in patients of African, Afro-Caribbean, and Hispanic descent; decreased incidence of MIS-C in patients of East Asian descent; broader age range and more prominent gastrointestinal and neurologic symptoms in patients with MIS-C vs Kawasaki disease; lower platelet counts, lower absolute lymphocyte counts, and higher CRP levels in patients with MIS-C.

Cardiac Management of MIS-C

According to the task force, EKGs should be performed at least every 48 hours, both for inpatient and outpatient cases with MIS-C. In patients with abnormal EKG values, telemetry should be considered, with the use of Holter monitors during follow-up. Echocardiograms should include a comprehensive evaluation of ventricular/valvar function, pericardial effusion, and coronary artery dimensions, and be repeated at least 7 to 14 days and 4 to 6 weeks after initial MIS-C presentation. The task force noted that patients with left ventricular dysfunction and/or coronary artery aneurysms may require more frequent EKGs.

Cardiac MRI may be performed 2 to 6 months after initial presentation in patients with significant transient left ventricular dysfunction. Patients with abnormal BNP and troponin T at initial presentation should be regularly retested for these parameters until normalization.

Immunomodulatory Treatment in MIS-C

While immunomodulatory therapy may not be required in patients with mild symptoms of MIS-C, patients with more severe presentation should undergo a stepwise progression of therapies. Specifically, high-dose intravenous immunoglobin (1-2 mg/kg) and low to moderate dose glucocorticoids may be considered as first-line immunomodulatory therapies. High-dose glucocorticoids may also be considered in patients with life-threatening complications, such as shock.

Anakinra may be considered as a treatment option for patients with MIS-C who do not respond or who have contraindications to other immunomodulatory therapies. Laboratory testing should be conducted periodically to assess treatment response; patients may require 2 to 3 weeks to be tapered off immunomodulatory medications.

Antiplatelet and Anticoagulation Therapy

Patients with MIS-C, features of Kawasaki-like disease, and/or thrombocytosis (platelet count, ≥450,000/μL) should receive low-dose aspirin (3-5 mg/kg/d) to normalize platelet count; however, this should be avoided in patients with platelet count ≤80,000/μL.

Patients with coronary artery abnormalities should receive treatment with low-dose aspirin and therapeutic anticoagulants. Patients with thrombosis or an ejection fraction <35% should also receive therapeutic anticoagulation, specifically with enoxaparin.

Antiplatelet and anticoagulation therapies should be continued until at least 2 weeks postdischarge, or for longer in patients whose laboratory values do not normalize.   

Recommendations for Hyperinflammation in Children With COVID-19

General Statements

The task force indicated that children with comorbidities and those receiving immunosuppressive medications, including moderate to high-dose glucocorticoids, are at higher risk for severe outcomes in COVID-19. Children with COVID-19 may present with similar symptoms to adults, some of which may include fever, respiratory tract symptoms, abdominal pain, and diarrhea.

Immunomodulatory Treatment

In children with COVID-19, immunomodulatory treatment should be administered if symptoms, including acute respiratory distress syndrome; shock/cardiac dysfunction; elevated lactate dehydrogenase, D-dimer, interleukin (IL)-6, IL-2 receptor, and/or ferritin levels; or depression lymphocyte count, albumin, and/or platelet count.

Appropriate immunomodulatory treatment in children with COVID-19 and for hyperinflammation may include glucocorticoids and anakinra (>4 mg/kg/d). Patients receiving anakinra should be monitored for liver function test abnormalities.

The task force also recommended tocilizumab to reduce mortality and intensive care admission rates in children with severe COVID-19 pneumonia and hyperinflammation. However, tocilizumab may increase risk for certain bacterial and fungal infections; weight-based dosing should be employed, and patients should be monitored for laboratory abnormalities.

The present literature suggests that anakinra may be the optimal first-line immunomodulatory therapy for children with hyperinflammation and COVID-19.

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