What is Multisystem Inflammatory Syndrome in Children (MIS-C)?

What is Multisystem Inflammatory Syndrome in Children (MIS-C)?

MIS-C is a rare but severe hyperinflammatory condition that occurs 2-6 weeks after SARS-CoV-2 infection in children, characterized by persistent fever, multiorgan involvement (particularly cardiac, gastrointestinal, and mucocutaneous systems), elevated inflammatory markers, and evidence of recent COVID-19 exposure. 1

Core Diagnostic Criteria

MIS-C requires all of the following elements based on CDC/WHO/RCPCH definitions 1:

Age and Fever

• Age: Children and adolescents under 21 years (CDC) or 0-19 years (WHO) 1
• Fever: Temperature ≥38.0°C for ≥24 hours or subjective fever lasting ≥24 hours 1

Multiorgan Involvement

At least two or more organ systems must be affected 1:

• Cardiovascular (97.8%): Myocardial dysfunction, pericarditis, valvulitis, coronary abnormalities, shock, or hypotension 1, 2
• Gastrointestinal (71-97.8%): Abdominal pain, diarrhea, vomiting 1, 2, 3
• Mucocutaneous (68-86.7%): Rash (polymorphic, maculopapular, or petechial), conjunctivitis without exudate, red/cracked lips, strawberry tongue, swollen hands/feet 1, 2
• Hematologic (100%): Coagulopathy, thrombocytopenia, lymphopenia 1, 2
• Respiratory (26.7-28%): Respiratory distress, cough 2, 3
• Neurologic (15.6%): Altered mental status, encephalopathy, focal deficits, meningismus, headache 1, 2
• Renal (13.3%): Acute kidney injury 2

Laboratory Evidence of Inflammation

Must demonstrate elevated markers including 1:

• Elevated CRP, ESR, procalcitonin, D-dimer, ferritin, LDH, or IL-6 1
• Neutrophilia with lymphopenia 1
• Hypoalbuminemia 1

Link to SARS-CoV-2

Evidence of current or recent COVID-19 by 1:

• Positive PCR, antigen test, or serology for SARS-CoV-2 1
• Likely COVID-19 contact within prior 4 weeks 1
• Note: Only 77.8% test positive; negative testing does not exclude MIS-C if epidemiologic link exists 2

Exclusion Criteria

No alternative microbial diagnosis that explains the clinical presentation 1

Epidemiology and Timing

• Incidence: Rare complication occurring in approximately 0.69-2 per 1,000 SARS-CoV-2 infections in children under 21 years 1, 4
• Temporal relationship: Typically emerges 2-6 weeks after peak COVID-19 incidence in a geographic area 1, 5
• Demographics: Increased incidence in children of African, Afro-Caribbean, and Hispanic descent; lower incidence in East Asian descent 1
• Age distribution: Median age 7-8.6 years, but ranges from 3 months to 21 years 4, 3

Clinical Severity and Outcomes

Acute Severity

• ICU admission: 68-71% of cases require intensive care 4, 6
• Shock: 14-20% develop shock requiring inotropic support 4, 6
• Mechanical ventilation: 22.2% require respiratory support 6
• ECMO: 4.4% require extracorporeal membrane oxygenation 6

Cardiac Manifestations

• Myocarditis: 38-45.1% develop myocardial dysfunction with depressed ejection fraction 4, 2, 6
• Pericarditis: 20% of cases 4
• Coronary artery abnormalities: 13% develop coronary aneurysms 4
• Cardiac sequelae: 20% of myocarditis cases and 26.3% of coronary aneurysm cases had not fully resolved at discharge 4

Mortality

• Overall mortality: 0.68-1.7% with prompt recognition and treatment 4, 6
• Prognosis: Most children survive with timely immunomodulatory therapy, but long-term outcomes remain under investigation 1, 6

Key Laboratory Findings

Typical laboratory abnormalities include 1, 4, 2:

• CRP: Median 155 mg/L (commonly >10-20 mg/dL) 4, 2
• Ferritin: Median 535 ng/mL 4
• Procalcitonin: Median 1.6 ng/mL 4
• WBC: Median 14.2 × 10⁹/mm³ with neutrophilia 4
• Troponin: Elevated in 41.3% 4
• NT-pro-BNP: Elevated in 49.6%; higher levels predict shock and correlate with disease severity 4
• Thrombocytopenia and lymphopenia at presentation 1

Distinction from Kawasaki Disease

While MIS-C shares overlapping features with Kawasaki disease (KD), key differences exist 1:

Similarities

• Conjunctivitis, oral mucosal changes, rash, swollen/erythematous extremities, cervical lymphadenopathy 1

Differences

• Age range: MIS-C affects broader age range including adolescents 1
• Symptoms: MIS-C has more prominent gastrointestinal and neurologic symptoms 1
• Cardiac: MIS-C more frequently presents with shock, arrhythmias, and ventricular dysfunction rather than coronary aneurysms alone 1
• Laboratory: MIS-C patients have lower platelet counts, lower lymphocyte counts, and higher CRP at presentation 1
• Age pattern: Younger children with MIS-C more likely to have KD-like features; older children more likely to develop myocarditis and shock 1

Clinical Importance

MIS-C remains a rare complication of SARS-CoV-2 infections, but requires high clinical suspicion because patients can decompensate rapidly despite initial stability. 1, 7 The vast majority of children with COVID-19 have mild symptoms and excellent outcomes; MIS-C represents a severe but uncommon post-infectious complication requiring prompt recognition and immunomodulatory treatment to prevent mortality and long-term cardiac sequelae 1, 4.