Multisystem Inflammatory Syndrome in Children

Multisystem inflammatory syndrome in children is a post-infectious hyperinflammatory illness that follows SARS-CoV-2 infection, with fever, raised inflammatory markers and involvement of two or more organ systems. Cardiac dysfunction, shock and coronary artery changes may occur.

A usual case definition requires age under 21 years, fever of 24 hours or more, laboratory evidence of inflammation, severe illness needing hospital care with multisystem involvement, no alternative diagnosis and recent SARS-CoV-2 infection or exposure.

It develops 2 to 6 weeks after infection, usually in school age children and adolescents. Cases have become less frequent since the early waves of the pandemic, but still occur. Most children recover fully with treatment.

Pathophysiology.

The syndrome is thought to be driven by dysregulated immune activation after viral clearance, with cytokine release, autoantibodies and endothelial injury. Superantigen like activation of T cells has been proposed.

The result is vasculitis like inflammation, capillary leak, myocardial injury and a hypercoagulable state.

• Persistent fever (3 days or more), abdominal pain, vomiting and diarrhoea (the commonest presentation and often mistaken for appendicitis).
• Rash, conjunctivitis without discharge, oral changes, extremity oedema and cervical lymphadenopathy.
• Cardiovascular: tachycardia, hypotension, shock, arrhythmia, myocarditis and coronary artery dilatation or aneurysm.
• Neurological features (headache, irritability, meningism), and respiratory features in some.

Red flags.

• Shock, hypotension or poor perfusion.
• Chest pain, arrhythmia, raised troponin or reduced ventricular function.
• Altered consciousness, severe abdominal pain, or signs of coagulopathy.

• Blood tests: full blood count (lymphopenia, neutrophilia, thrombocytopenia), CRP (usually over 100 mg/L), ESR, ferritin, D-dimer, fibrinogen, troponin, BNP or NT-proBNP, liver and renal function, albumin, sodium and triglycerides.
• SARS-CoV-2 PCR and serology. Blood culture and other infection screening.
• ECG, and echocardiography at presentation, repeated at 1 to 2 weeks and 4 to 6 weeks, with coronary artery measurements.
• Chest X-ray, abdominal ultrasound for appendicitis or lymphadenopathy, and MRI when indicated.

Differential diagnosis. Kawasaki disease, toxic shock syndrome, sepsis, bacterial gastroenteritis, appendicitis, viral myocarditis, macrophage activation syndrome, haemophagocytic lymphohistiocytosis and juvenile idiopathic arthritis.

Resuscitation and supportive care.

• Treat shock with cautious fluid boluses of 10 mL/kg of 0.9% sodium chloride, reassessing after each bolus, and early inotropes (adrenaline 0.05 to 0.3 micrograms/kg/min or noradrenaline 0.05 to 0.5 micrograms/kg/min) for fluid refractory shock.
• Admit children to a unit with paediatric intensive care and cardiology access if shock, cardiac involvement or organ failure exists.
• Give antibiotics (ceftriaxone 50 to 80 mg/kg once daily) until cultures are negative.

Immunomodulation.

• Intravenous immunoglobulin 2 g/kg as a single infusion (maximum 100 g), given slowly with cardiac monitoring in those with ventricular dysfunction.
• Methylprednisolone 1 to 2 mg/kg/day IV (maximum 60 mg), or 10 to 30 mg/kg for 3 days (maximum 1 g) for severe disease, followed by oral prednisolone tapered over 2 to 3 weeks.
• Anakinra 2 to 10 mg/kg/day SC or IV in divided doses for refractory disease, with infliximab as an alternative.

Antithrombotic therapy.

• Aspirin 3 to 5 mg/kg once daily (maximum 81 mg), continued until coronary arteries are normal at 4 to 6 weeks.
• Enoxaparin 0.5 mg/kg SC every 12 hours as thromboprophylaxis in older children or those with raised D-dimer, severe ventricular dysfunction or coronary artery aneurysm, with anti-Xa monitoring.

Monitoring. Troponin, CRP, ferritin, D-dimer and daily clinical review. Repeat echocardiography at 1 to 2 weeks and 4 to 6 weeks, and cardiac MRI at 3 to 6 months for ventricular dysfunction.

Referral and escalation. Early discussion with paediatric intensive care, cardiology, rheumatology and infectious disease services.

Special groups. Delay live vaccines for 11 months after immunoglobulin. Children on aspirin need influenza vaccination and early review for influenza or varicella exposure because of the risk of Reye syndrome.