ACR Updates Clinical Guidance for the Management of COVID-19-Associated Multisystem Inflammatory Syndrome in Children

The American College of Rheumatology (ACR) updated its guidance for the management of COVID-19-associated multisystem inflammatory syndrome in children (MIS-C) and hyperinflammation. The full report was published in Arthritis & Rheumatology.

The task force consisted of 9 pediatric rheumatologists, 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Overall, an additional 33 revised statements were approved by the task force for the third version of the guidance.

Guidance Statements for MIS-C

• The majority of pediatric patients with COVID-19 present with mild symptoms and have good outcomes, and MIS-C is being considered a rare complication.
• Management decisions should be informed by the prevalence of SARS-CoV-2 in a given geographic area, which may change over time.

Guidance for Diagnostic Evaluation of MIS-C

• While seropositivity to SARS-CoV-2 may not distinguish between MIS-C and overlapping syndromes, a negative antibody test should prompt rheumatologists to consider other diagnoses.
• Pediatric patients with suspected MIS-C should be evaluated for other infections and conditions, such as malignancy, which could explain the clinical presentation. These patients may require additional diagnostic studies, such as imaging of the chest, abdomen or central nervous system, and lumbar puncture.
• Rheumatologists can consider outpatient care, with close clinical follow-up, for children with MIS-C who present with stable vital signs.
• Rheumatologists should consider hospital admission for patients with a suspicion of MIS-C during diagnostic evaluation, particularly if the patient has abnormal vital signs, respiratory distress, neurologic deficits or change in mental status, evidence of renal or hepatic injury, elevated inflammation, or abnormal findings for electrocardiogram (EKG), B-type natriuretic peptide (BNP), or troponin T.
• Hospitalized children with MIS-C should receive care from a multidisciplinary team that includes pediatric rheumatologists, cardiologists, infectious disease specialists, and hematologists, with possible consult from pediatric neurology, nephrology, hepatology, and gastroenterology.

MIS-C and Kawasaki Disease (KD) Phenotypes

• MIS-C and KD may have similar clinical features, including conjunctival infection, oropharyngeal findings (red and/or cracked lips, strawberry tongue), rash, swollen and/or erythematous hands and feet, and cervical lymphadenopathy.
• Differences may include higher incidence of MIS-C among individuals of African, Afro-Caribbean, and Hispanic descent and lower incidence among individuals of East Asian descent. Patients with MIS-C vs KD are of a broader age range, more frequently appear in a state of shock, have more prominent gastrointestinal and neurologic symptoms, and are more likely to present with cardiac dysfunction (ventricular dysfunction and arrhythmias), lower platelet counts, lower absolute lymphocyte counts, and higher C-reactive protein (CRP) levels.
• Ventricular dysfunction tends to be associated with MIS-C while KD is linked with coronary artery aneurysms (CAA); however, patients with MIS-C without KD features can also develop CAA.
• Patients with MIS-C who are younger are more likely to present with similar symptoms as KD while older children are more likely to present myocarditis and shock.

Cardiac Management of MIS-C

• Patients with MIS-C with BNP or troponin T levels in the abnormal range should have these parameters trended over time until normalization.
• Patients should undergo EKG at least every 48 hours when hospitalized and during follow-up visits. Abnormalities in the scans should prompt placement on continuous telemetry at the hospital. Holter monitors can be considered during follow-up.
• An EKG at diagnosis and during clinical follow-up should involve ventricular/valvular function, pericardial effusion, and coronal artery dimensions, with measurements accounting for body surface area via z-scores.
• An EKG should be repeated at least every 2 weeks and 4 to 6 weeks following presentation. A 1-year follow-up EKG may be considered for patients who present with cardiac abnormalities in the acute phase of disease. More frequent EKGs may be needed if patients have left ventricular dysfunction or CAA.
• Cardiac magnetic resonance imaging (MRI) may be necessary 2 to 6 months after MIS-C if patients presented with significant transient left ventricular dysfunction in the acute phase of disease (LV ejection fraction <50%) or persistent left ventricular dysfunction. The cardiac MRI should focus on evaluating the myocardial tissue, with functional assessment, T1/T2-weighted imaging, T1 mapping and extracellular volume quantification, and late gadolinium enhancement.
• Patients with suspected distal CAAs not seen well on EKG should undergo cardiac computed tomography (CT).

Immunomodulatory Treatment in MIS-C

• Patients with suspected MIS-C that does not present as life-threatening should be evaluated for MIS-C and other infections and noninfection-related conditions before receiving immunomodulatory treatment.
• However, if MIS-C presents with life-threatening manifestations, immunomodulatory treatment can be administered prior to a full diagnostic evaluation.
• Patients with mild symptoms may only need close monitoring, not immunomodulatory treatment, after being evaluated by specialists with expertise in MIS-C. There is uncertainty around the empiric use of intravenous immunoglobulin (IVIg) for preventing CAA in this setting.
• Immunomodulatory therapies should be used with stepwise progression to treat MIS-C. IVIg and low to moderate-dose glucocorticoids can be considered as first-tier therapy for most hospitalized patients, with intensification therapy of high-dose glucocorticoids, anakinra, or infliximab in patients with refractory disease.
• If patients with MIS-C are hospitalized or have KD criteria, they should receive IVIg.
• IVIg (dosage based on ideal body weight, typically 2 gm/kg, with a maximum 100 g) is the recommended treatment for MIS-C. Hospitalized patients with MIS-C should receive 1 to 2 mg/kg/day of glucocorticoids with IVIg.
• Patients with MIS-C should undergo assessments of cardiac function and fluid status before receiving IVIg. If patients have depressed cardiac function, they may need closer monitoring and administration of diuretics.
• Some patients with cardiac dysfunction may receive IVIg in divided doses of 1 g/kg daily over a period of 2 days.
• Patients with refractory MIS-C should not receive a second dose of IVIg because of risk for volume overload and hemolytic anemia that is linked to large doses of IVIg.
• Rheumatologists should consider use of high-dose IV pulse glucocorticoids (10-30 mg/kg/day) in patients with an inadequate response to IVIg and low to moderate dose glucocorticoids, especially among patients who require high-dose or multiple inotropes and/or vasopressors.
• If MIS-C is refractory to IVIg and glucocorticoids, high-dose anakinra (>4 mg/kg/day IV or subcutaneous) should be considered if the patient has features of macrophage activation syndrome (MAS) or contraindications to long-term use of glucocorticoids.
• Infliximab should not be used to treat MIS-C and features of MAS. However, infliximab (5-10 mg/kg/day IV x 1 dose) may be considered as an alternative biologic agent to anakinra in the treatment of patients with MIS-C refractory to IVIg and glucocorticoids or with contraindications to long-term use of glucocorticoids.
• Immunomodulatory treatment response and tapering should be based on serial laboratory testing and cardiac assessment. Patients may need at least a 2- to 3-week taper of immunomodulatory medications.

Antiplatelet and Anticoagulation Therapy in MIS-C

• Patients with MIS-C should be receive treatment with low-dose aspirin (3-5 mg/kg/day; maximum 81 mg/day) until platelet counts normalize and stable coronary artery status is confirmed, at least 4 weeks after diagnosis. Rheumatologists should avoid using aspirin in patients with active bleeding, significant bleeding risk, and/or a platelet count of 80,000/μl and lower.
• Risk factors for thrombosis in MIS-C include central venous catheterization, age older than 12 years, malignancy, admission to intensive care unit (ICU), and D-dimer levels elevated to more than 5 times the upper limit of normal. Higher-intensity anticoagulation should be considered on a case-by-case basis, taking into account presence of risk factors balanced with risk for bleeding.
• Patients with MIS-C with CAAs should receive anticoagulation therapy, according to the American Heart Association recommendations for KD.
• Patients with MIS-C with maximal z-scores between 2.5 and 10.0 should receive low-dose aspirin. If z-scores are higher than 10, low-dose aspirin and therapeutic anticoagulation with enoxaparin (antifactor Xa level, 0.5-1.0) may be considered for at least 2 weeks before transitioning to vitamin K antagonist therapy (international normalized ratio [INR], 2-3) or direct-acting oral anticoagulants, provided the CAA z-score is higher than 10.
• Patients with MIS-C with an ejection fraction (EF) of less than 35% should receive low-dose aspirin and therapeutic anticoagulation until EF levels surpass 35%.
• Patients with MIS-C with thrombosis should receive low-dose aspirin and therapeutic anticoagulation for 3 months, until the thrombosis resolves. Repeat imaging of thrombosis must be conducted 4 to 6 weeks following diagnosis, and anticoagulation therapy can be discontinued if the thrombosis has resolved.
• Patients with MIS-C who do meet the criteria for thrombosis should receive antiplatelet and anticoagulation therapeutic management care that is personalized for their risk for thrombosis.

Hyperinflammation in COVID-19

• Children, especially infants, who receive immunosuppressive medications or have conditions such as type 1 diabetes, complex congenital heart disease, neurologic conditions, obesity, or asthma may be at higher risk for severe COVID-19.
• Children and adults hospitalized with COVID-19 have similar symptoms, such as fever, upper respiratory tract symptoms, abdominal pain, and diarrhea.
• Children who are hospitalized and need supplemental oxygen or respiratory support due to COVID-19 should be considered for immunomodulatory therapy. Monitoring elevated inflammation levels, including lactate dehydrogenase (LDH), D-dimer, interleukin (IL)-6, IL-2R, CRP, and/or ferritin, and depressed lymphocyte count, albumin level, and/or platelet count) may be useful in decision-making.
• Dexamethasone (0.15-0.3 mg/kg/day, maximum 6 mg, for up to 10 days) should be used as first-line immunomodulatory treatment for children with persistent oxygen needs due to COVID-19 (. Other glucocorticoids may also be similarly effective.
• Secondary immunomodulatory therapy should be considered for children with increasing oxygen requirements and inflammation markers due to COVID-19 whose condition has not improved with glucocorticoids.
• Rheumatologists should consider use of tocilizumab and baricitinib, which are shown to be successful in clinical trials of adults with COVID-19, for secondary immunomodulatory therapy in children. Selection depends on availability, patient age, and comorbidities.
• Tofacitinib can be considered as an alternative medication to tocilizumab or baricitinib for secondary immunomodulatory therapy.
• Secondary immunomodulatory therapy in COVID-19 may be most beneficial when it is provided within 24 hours of escalation to high-flow oxygen, noninvasive ventilation, or admission to ICU.
• Secondary immunomodulatory therapy should be used in combination with glucocorticoids.
• An 8 mg/kg IV (up to 800 mg) dose of tocilizumab can be given and redosed at least 8 hours later if clinical response is insufficient. Baricitinib may be given orally (2 mg daily for children aged 2 to 8 years and 4 mg daily for children aged at least 9 years) up to 2 weeks if the patient has normal renal function.
• Patients with COVID-19 receiving secondary immunomodulatory therapy should be monitored for secondary infections and liver function test abnormalities. In addition, those receiving tocilizumab should be monitored for hypertriglyceridemia and infusion reactions. Patients receiving baricitinib should be monitored for thrombosis and thrombocytosis.
• A recommendation regarding other IL-6 or JAK inhibitors for children with COVID-19 may not yet be possible due to limited experience in adults with COVID-19 and history of pediatric population.
• Clinical trials of anakinra in adults with COVID-19 pneumonia have showed conflicting data, and therefore, there is insufficient evidence for a recommendation regarding its use.

“For now, our understanding of pediatric SARS–CoV-2 infections is rudimentary and will continue to change as higher-quality evidence becomes available,” the authors said. “Thus, the recommendations contained in this document should be interpreted in the setting of this shifting landscape and will be modified prospectively as our understanding of COVID-19 improves. For these reasons, this guidance does not replace the critical role of clinical judgment that is essential to address the unique needs of individual patients.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 

Reference

Henderson LA, Canna SW, Friedman KG, et al. 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. Arthritis Rheumatol. Published online February 3, 2022. doi:10.1002/art.42062