ACR Updates Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With COVID Save
A Task Force from the ACR has provided an updated (version 3) guidance for the diagnosis and management of Multisystem Inflammatory Syndrome in Children (MIS-C), a COVID related condition characterized by fever, inflammation, and multiorgan dysfunction. The current guidance also applies to children with hyperinflammation during COVID-19, the acute, infectious phase of SARS–CoV-2 infection.
The task force included 9 pediatric rheumatologists and 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Guidance recommendations are based on consensus via a modified Delphi process. Approved guidance statements only incuded those with moderate or high levels of consensus.
Here are the particulars:
The document details the four different proposed criteria for the diagnosis of MIS-C, and the ACR recommends that you have
- Fever > 39*C
- Evidence of SARS-CoV-2
- and any two of the following:
- GI manifestations
- Edema (hands or feet)
- Oral mucosal changes
- Neurologic symptoms
The evaluation should include labs such as a CMP, procalcitonin, cytokine panel, and Serologic test includingSARS–CoV-2 IgG, IgM, and IgA.
For patients who are hospitalized, first line treatment should include IVIG 2 gm/kg AND methylprednisolone IV 1-2 mg/kg per day. For those who are refractory, treatment should be intensifed with methylprednisolone IV 10-30 mg/kg per day OR, high dose anakinra or infliximab 5-10 mg/kg IV for one dose.
The following are guidance statements:
- The vast majority of children with COVID-19 present with mild symptoms and have excellent outcomes. MIS-C remains a rare complication of SARS–CoV-2 infections.
- MIS-C is temporally associated with SARS–CoV-2 infections. Therefore, the prevalence of the virus in a given geographic location, which may change over time, should inform management decisions.
- Given the high prevalence of COVID-19 in certain communities, seropositivity to SARS–CoV-2 (nucleocapsid or spike protein) may no longer adequately distinguish between MIS-C and other overlapping syndromes, although a negative finding on antibody test should prompt consideration of alternative diagnoses.
- A child “under investigation” for MIS-C should also be evaluated for other possible infections and non–infection-related conditions (e.g., malignancy) that may explain the clinical presentation.
- Patients “under investigation” for MIS-C may require additional diagnostic studies (not described in Figure 1), including, but not limited to, imaging of the chest, abdomen, and/or central nervous system and lumbar puncture.
- Outpatient evaluation for MIS-C may be appropriate for assessing well-appearing children with stable vital signs and for ensuring that physical examinations provide close clinical follow-up.
- Patients “under investigation” for MIS-C should be considered for admission to the hospital for further observation while the diagnostic evaluation is completed, especially if the patient displays any of the following symptoms:
- abnormal vital signs (tachycardia, tachypnea);
- respiratory distress of any severity;
- neurologic deficits or change in mental status (including subtle manifestations);
- evidence of renal or hepatic injury (including mild injury);
- marked elevations in inflammation markers;
- abnormal EKG findings or abnormal levels of BNP or troponin T.
- Children admitted to the hospital with MIS-C should be managed by a multidisciplinary team that includes pediatric rheumatologists, cardiologists, infectious disease specialists, and hematologists. Depending on the clinical manifestations, other subspecialties may need to be consulted as well; these include, but are not limited to, pediatric neurology, nephrology, hepatology, and gastroenterology.
Differentiating MIS-C from Kawasaki's Disease
Several epidemiologic, clinical, and laboratory features of MIS-C may differ from KD in the following ways:
- There is an increased incidence of MIS-C in patients of African, Afro-Caribbean, and Hispanic descent, but a lower incidence in those of East Asian descent.
- Patients with MIS-C encompass a broader age range, have more prominent GI and neurologic symptoms, present more frequently in a state of shock, and are more likely to display cardiac dysfunction (ventricular dysfunction and arrhythmias) than children with KD.
- At presentation, patients with MIS-C tend to have lower platelet counts, lower absolute lymphocyte counts, and higher CRP levels than patients with KD.
- Ventricular dysfunction is more frequently associated with MIS-C whereas KD more frequently manifests with coronary artery aneurysms; however, MIS-C patients without KD features can develop CAA.
- Moderate to highEpidemiologic studies of MIS-C suggest that younger children are more likely to present with KD-like features, while older children are more likely to develop myocarditis and shock.
Cardiac management of MIS-C
- Patients with MIS-C and abnormal BNP and/or troponin T levels at diagnosis should have these laboratory parameters trended over time until they normalize.
- EKGs should be performed at a minimum of every 48 hours in MIS-C patients who are hospitalized and during follow-up visits. If conduction abnormalities are present, patients should be placed on continuous telemetry while in the hospital, and Holter monitors should be considered during follow-up.
- Echocardiograms conducted at diagnosis and during clinical follow-up should include evaluation of ventricular/valvular function, pericardial effusion, and coronary artery dimensions with measurements indexed to body surface area using z-scores.
- Echocardiograms should be repeated at a minimum of 7–14 days and 4–6 weeks after presentation. For those patients with cardiac abnormalities occurring in the acute phase of their illness, an echocardiogram 1 year after MIS-C diagnosis could be considered. Patients with LV dysfunction and/or CAAs will require more frequent echocardiograms.
- Cardiac MRI may be indicated 2–6 months after MIS-C diagnosis in patients who presented with significant transient LV dysfunction in the acute phase of illness (LV ejection fraction <50%) or persistent LV dysfunction. Cardiac MRI should focus on myocardial characterization, including functional assessment, T1/T2-weighted imaging, T1 mapping and extracellular volume quantification, and late gadolinium enhancement.
- Cardiac CT should be performed in patients with suspected presence of distal CAAs that are not well seen on echocardiogram.
Immunomodulatory treatment in MIS-C
Patients under investigation for MIS-C without life-threatening manifestations should undergo diagnostic evaluation for MIS-C as well as other possible infections and non–infection-related conditions before immunomodulatory treatment is initiated.
Patients “under investigation” for MIS-C with life-threatening manifestations may require immunomodulatory treatment for MIS-C before the full diagnostic evaluation can be completed.
After evaluation by specialists with expertise in MIS-C, some patients with mild symptoms may only require close monitoring without immunomodulatory treatment. The panel noted uncertainty around the empiric use of IVIG to prevent CAAs in this setting.
A stepwise progression of immunomodulatory therapies should be used to treat MIS-C, with IVIG and low-to-moderate–dose glucocorticoids considered first-tier therapy in most hospitalized patients High-dose glucocorticoids, anakinra, or infliximab should be used as intensification therapy in patients with refractory disease
IVIG should be given to MIS-C patients who are hospitalized and/or fulfill KD criteria.
IVIG (typically 2 gm/kg, based on ideal body weight, maximum 100 gm) should be used for treatment of MIS-C.
Cardiac function and fluid status should be assessed in MIS-C patients before IVIG treatment is provided. Patients with depressed cardiac function may require close monitoring and diuretics with IVIG administration.
In some patients with cardiac dysfunction, IVIG may be given in divided doses (1 gm/kg daily over 2 days).
Low-to-moderate–dose glucocorticoids (1–2 mg/kg/day) should be given with IVIG as dual therapy for treatment of MIS-C in hospitalized patients.
In patients with refractory MIS-C, despite a single dose of IVIG, a second dose of IVIG is not recommended given the risk of volume overload and hemolytic anemia associated with large doses of IVIG.
In patients who do not respond to IVIG and low-to-moderate–dose glucocorticoids, high-dose, IV pulse glucocorticoids (10–30 mg/kg/day) should be considered, especially if a patient requires high-dose or multiple inotropes and/or vasopressors.
High-dose anakinra (>4 mg/kg/day IV or SC) should be considered for treatment of MIS-C refractory to IVIG and glucocorticoids in patients with MIS-C and features of MAS or in patients with contraindications to long-term use of glucocorticoids.
Infliximab (5–10 mg/kg/day IV x 1 dose) may be considered as an alternative biologic agent to anakinra for treatment of MIS-C in patients refractory to IVIG and glucocorticoids, or in patients with contraindications to long-term use of glucocorticoids. Infliximab should not be used to treat patients with MIS-C and features of MAS.
Serial laboratory testing and cardiac assessment should guide immunomodulatory treatment response and tapering. Patients may require a 2–3-week, or even longer, taper of immunomodulatory medications.
Antiplatelet and anticoagulation therapy in MIS-C
Low-dose aspirin (3–5 mg/kg/day; maximum 81 mg/day) should be used in patients with MIS-C and continued until the platelet count is normalized and normal coronary arteries are confirmed at ≥4 weeks after diagnosis. Treatment with aspirin should be avoided in patients with active bleeding, significant bleeding risk, and/or a platelet count of ≤80,000/μl.
Central venous catheterization, age >12 years, malignancy, ICU admission, and D-dimer levels elevated to >5 times the upper limit of normal are independent risk factors for thrombosis in MIS-C. Higher-intensity anticoagulation should be considered in children with MIS-C on an individual basis, taking into consideration the presence of these risk factors balanced with the patient's risk of bleeding.
MIS-C patients with CAAs should receive anticoagulation therapy according to the American Heart Association recommendations for KD. MIS-C patients with a maximal z-score of 2.5–10.0 should be treated with low-dose aspirin. Patients with a z-score of ≥10.0 should be treated with low-dose aspirin and therapeutic anticoagulation with enoxaparin (anti–factor Xa level 0.5–1.0) for at least 2 weeks, and then can be transitioned to VKA therapy (INR 2–3) or DOAC as long as the CAA z-score exceeds 10.
MIS-C patients with an EF <35% should receive low-dose aspirin and therapeutic anticoagulation (defined as enoxaparin administered subcutaneously, with target anti–factor Xa levels of 0.5–1.0 or warfarin/VKA (INR 2–3) or DOAC Moderate) until EF exceeds 35%.
MIS-C patients with documented thrombosis should receive low-dose aspirin and therapeutic anticoagulation (see definition above) for 3 months, pending resolution of thrombosis. Repeat imaging of thrombosis at 4–6 weeks post-diagnosis should be acquired, and anticoagulation can be discontinued if resolved.
For MIS-C patients who do not meet the above criteria, the approach to antiplatelet and anticoagulation therapeutic management should be tailored to the patient’s risk for thrombosis.
Hyperinflammation in COVID-19
Children, particularly infants, with medical complexity including type I diabetes, complex congenital heart disease, neurologic conditions, obesity, or asthma and those receiving immunosuppressive medications may be at higher risk for severe COVID-19. Racial and ethnic minorities may also be at higher risk.
Children and adults admitted to the hospital with COVID-19 present with similar symptoms, including fever, upper respiratory tract symptoms, abdominal pain, and diarrhea.
Hospitalized children requiring supplemental oxygen or respiratory support due to COVID-19 should be considered for immunomodulatory therapy. Substantial elevation in inflammation markers (including LDH, D-dimer, IL-6, IL-2R, CRP, and/or ferritin, and depressed lymphocyte count, albumin level, and/or platelet count) may support this decision and prove useful in monitoring.
Dexamethasone (0.15–0.3 mg/kg/day, maximum 6 mg, for up to 10 days) should be used as first-line immunomodulatory treatment in children with persistent oxygen requirement due to COVID-19, although other glucocorticoids may be equally effective.
Children with increasing oxygen requirements and elevated inflammation markers due to COVID-19 who have not improved with glucocorticoids alone should receive secondary immunomodulatory therapy.
Tocilizumab and baricitinib have both demonstrated efficacy in clinical trials of adults with COVID-19 and should be considered as agents for secondary immunomodulatory therapy in children, and the decision of which to choose will depend on availability, patient age, and comorbidities (such as renal failure or thrombosis).
Tofacitinib can be considered as an alternative medication for secondary immunomodulatory therapy if tocilizumab and baricitinib are not available or contraindicated.
The benefit of secondary immunomodulatory therapy in COVID-19 appears to be greatest when given early in the course of clinical deterioration (within 24 hours of escalation to high-flow oxygen, noninvasive ventilation, or ICU admission).
Secondary immunomodulatory therapy should be used in combination with glucocorticoids. Tocilizumab may be given at a dose of 8 mg/kg IV (maximum 800 mg) and may be re-dosed ≥8 hours later if there is insufficient clinical response. Baricitinib may be given orally for up to 14 days to children with normal renal function, at a dose of 2 mg daily in children age 2 years to <9 years , and 4 mg daily in children age ≥9 years.
Children with COVID-19 treated with secondary immunomodulatory therapy should be monitored for secondary infections and LFT abnormalities. Children receiving tocilizumab should also be monitored for hypertriglyceridemia and infusion reactions. Children receiving baricitinib should also be monitored for thrombosis and thrombocytosis.
There is insufficient experience in adults with COVID-19, along with extremely limited performance history in the pediatric population, to recommend for or against the use of other IL-6 or JAK inhibitors in children with COVID-19.
Given the conflicting data from clinical trials of anakinra in adults with COVID-19 pneumonia, there is insufficient evidence to recommend for or against the use of anakinra in children with COVID-19 and hyperinflammation.