# Multisystem Inflammatory Syndrome in Children (MIS-C)

## Introduction

Multisystem inflammatory syndrome in children (MIS-C) is a serious post-infectious hyperinflammatory condition temporally associated with SARS-CoV-2 infection. First described in April 2020, MIS-C typically presents 2-6 weeks after acute COVID-19 infection (often asymptomatic or mild) and shares features with Kawasaki disease, toxic shock syndrome, and macrophage activation syndrome. While the incidence of MIS-C has declined with increasing population immunity through vaccination and natural infection, understanding this condition remains important as a model of post-infectious immune dysregulation and because it continues to occur with new SARS-CoV-2 variants.

## Epidemiology

The estimated incidence of MIS-C is approximately 1 in 3,000-4,000 SARS-CoV-2 infections in children with pre-Omicron variants, and significantly lower with Omicron and subsequent variants. The peak age is 6-12 years, which is older than typical Kawasaki disease. There is a male predominance (approximately 60%) and a disproportionate impact on Black, Hispanic, and other minority children. MIS-C typically occurs 2-6 weeks after SARS-CoV-2 infection, with cases often clustering 4-6 weeks after a regional COVID-19 surge. COVID-19 vaccination significantly reduces MIS-C risk by approximately 90%.

## Pathophysiology

The proposed mechanism involves post-infectious immune dysregulation rather than direct viral injury. The SARS-CoV-2 spike protein may act as a superantigen, triggering polyclonal T-cell activation. This leads to massive cytokine release (a cytokine storm) with elevated IL-6, IL-10, TNF-alpha, and IFN-gamma. Endothelial activation and injury contribute to multiorgan involvement. Antibody-mediated mechanisms may also play a role through immune complexes and autoantibody formation. Coronary artery involvement similar to Kawasaki disease suggests shared pathways of vascular inflammation.

<image>Pathophysiology diagram of MIS-C showing the timeline from SARS-CoV-2 infection through a 2-6 week latent period, followed by immune dysregulation involving superantigen-mediated T-cell activation, macrophage activation, cytokine storm (with key cytokines labeled), endothelial injury, and the resulting multisystem organ involvement including cardiac, gastrointestinal, hematologic, and mucocutaneous manifestations</image>

## Case Definition (CDC)

The CDC case definition requires an individual aged under 21 years presenting with fever of 38.0 degrees Celsius or higher for 24 hours or more (or report of subjective fever lasting 24 hours or more), laboratory evidence of inflammation (elevated CRP, ESR, fibrinogen, procalcitonin, D-dimer, ferritin, LDH, IL-6, or neutrophilia, lymphopenia, or low albumin), multisystem involvement of 2 or more organ systems (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or neurologic), evidence of SARS-CoV-2 infection (positive RT-PCR, antigen test, or serology, or exposure to a confirmed COVID-19 case within 4 weeks), and no alternative plausible diagnosis.

## Clinical Presentation

| System | Frequency | Key Manifestations |
|--------|-----------|-------------------|
| Gastrointestinal | ~90% | Abdominal pain, vomiting, diarrhea (can mimic appendicitis) |
| Cardiac | ~80% | Myocardial dysfunction, coronary artery changes, shock |
| Mucocutaneous | 60-70% | Rash, conjunctivitis, oral changes (overlaps with Kawasaki) |
| Hematologic | >80% | Lymphopenia, thrombocytopenia, elevated D-dimer |
| Neurologic | 20-30% | Headache, irritability, encephalopathy |
| Renal | 10-20% | AKI |

### Cardiac Involvement (80%)

Myocardial dysfunction with reduced left ventricular ejection fraction, often moderate to severe, is the most common cause of ICU admission. Coronary artery abnormalities including dilation or aneurysm formation (similar to Kawasaki disease) occur in 15-25% of cases. Valvular regurgitation (mitral and/or aortic) and pericardial effusion (present in up to 25%) may be seen. Arrhythmias including first, second, or third-degree heart block may occur and may require temporary pacing. Shock, which may be vasodilatory, cardiogenic, or mixed, occurs in 50-80% of patients and requires vasoactive support. Elevated troponin and BNP/NT-proBNP are sensitive markers of myocardial involvement.

### Gastrointestinal Involvement (90%)

Gastrointestinal symptoms are the most common presenting features and include abdominal pain, vomiting, and diarrhea. The presentation can mimic acute appendicitis or an acute abdomen, often leading to surgical consultation before MIS-C is diagnosed. Imaging may reveal terminal ileitis, mesenteric lymphadenitis, and ascites. Hepatitis with elevated transaminases occurs in some cases.

### Mucocutaneous Features (60-70%)

Mucocutaneous features include rash (polymorphous, maculopapular, or erythroderma), non-purulent bilateral conjunctival injection, oral mucosal changes (red cracked lips, strawberry tongue), and extremity changes (edema, erythema of hands and feet). These features overlap considerably with Kawasaki disease criteria.

### Hematologic

Hematologic abnormalities include lymphopenia (unlike Kawasaki disease where lymphocyte counts are often normal), thrombocytopenia (unlike Kawasaki disease which often shows thrombocytosis), elevated D-dimer and fibrinogen reflecting coagulopathy and thrombotic risk, and anemia.

### Neurologic (20-30%)

Neurologic manifestations include headache, irritability, and lethargy, with encephalopathy, meningism, and seizures occurring less commonly.

### Respiratory

Respiratory involvement is less prominent than in acute COVID-19 and may include pleural effusions, mild lung infiltrates, or respiratory failure secondary to cardiac dysfunction.

<image>Body systems diagram illustrating the multisystem involvement in MIS-C, with each organ system labeled and its specific manifestations listed: cardiac (myocarditis, coronary changes, shock), gastrointestinal (abdominal pain, vomiting, diarrhea, hepatitis), mucocutaneous (rash, conjunctivitis, oral changes), hematologic (lymphopenia, thrombocytopenia, coagulopathy), neurologic (headache, encephalopathy), and renal (AKI), with approximate frequency of involvement for each system</image>

## Diagnostic Evaluation

### Laboratory Studies

Inflammatory markers include CRP (markedly elevated, often greater than 10 mg/dL), ESR, procalcitonin, and ferritin. Cardiac biomarkers include troponin (elevated indicates myocardial injury) and BNP/NT-proBNP (elevated indicates cardiac dysfunction or volume overload). Coagulation studies show D-dimer (often markedly elevated), fibrinogen, and PT/PTT. CBC typically reveals lymphopenia, thrombocytopenia (or thrombocytosis in Kawasaki-like presentations), anemia, and neutrophilia. Chemistry panels may show hyponatremia, AKI with elevated creatinine, elevated transaminases, and low albumin. IL-6 is elevated and may guide tocilizumab therapy. SARS-CoV-2 testing includes PCR from nasopharyngeal swab and IgG serology, which may be the only positive test if the acute infection occurred weeks prior.

### Imaging

Echocardiography assesses left ventricular function, coronary arteries (measured by Z-scores), valvular function, and pericardial effusion, and should be obtained at diagnosis, at 2 weeks, and at 6-8 weeks. Cardiac MRI is indicated for persistent myocardial dysfunction and can detect myocardial edema and fibrosis. Abdominal imaging (CT or ultrasound) is obtained if gastrointestinal symptoms predominate and may show mesenteric lymphadenitis, terminal ileitis, ascites, and bowel wall thickening.

### Differential Diagnosis

The differential diagnosis includes Kawasaki disease (younger age, prominent coronary involvement, thrombocytosis rather than thrombocytopenia, less myocardial dysfunction), toxic shock syndrome (staphylococcal or streptococcal with positive cultures and similar shock presentation), sepsis (positive blood cultures with overlapping inflammatory markers), macrophage activation syndrome/HLH (extremely elevated ferritin, pancytopenia, hypofibrinogenemia), appendicitis (GI symptoms may dominate but imaging differentiates), and myocarditis from other viral etiologies.

## Management

### Immunomodulatory Therapy

IVIG (2 g/kg, maximum 100 g) is the first-line treatment, based on extrapolation from Kawasaki disease treatment and observational MIS-C data. Corticosteroids are given as methylprednisolone 1-2 mg/kg/day IV for moderate disease, or pulse methylprednisolone (10-30 mg/kg/day for 1-3 days, maximum 1 g) for severe or refractory disease. The BEST-ROAR trial demonstrated that combination IVIG plus corticosteroids resulted in faster recovery and less need for adjunctive therapy compared to IVIG alone. Anakinra (IL-1 receptor antagonist) at 2-10 mg/kg/day subcutaneous or IV is used for refractory cases unresponsive to IVIG plus steroids. Tocilizumab (IL-6 receptor antagonist) is considered for refractory cases with markedly elevated IL-6. Infliximab (TNF inhibitor) may be used for refractory Kawasaki-like features.

### Hemodynamic Support

Fluid resuscitation should use judicious fluid boluses of 10-20 mL/kg with reassessment after each bolus, given the risk of cardiogenic shock. Vasoactive agents include epinephrine for cardiogenic shock, norepinephrine for vasodilatory shock, and milrinone for myocardial dysfunction with elevated systemic vascular resistance. Excessive fluids should be avoided in the setting of myocardial dysfunction, and early vasoactive support is preferred. Mechanical circulatory support with ECMO may be life-saving for refractory shock, though it is rarely needed.

### Anticoagulation and Antiplatelet Therapy

Low-dose aspirin (3-5 mg/kg/day, maximum 81 mg) is given to all MIS-C patients until the platelet count normalizes and coronary arteries are confirmed normal at 4 weeks or later. Enoxaparin at therapeutic anticoagulation doses is used for documented thrombosis or coronary aneurysm with a Z-score of 10 or greater, while prophylactic dosing is used for moderate-to-severe disease with elevated D-dimer. MIS-C confers significant thrombotic risk due to endothelial activation and coagulopathy.

### Follow-Up

Cardiology follow-up includes echocardiography at 2 weeks and 6-8 weeks, with cardiac MRI at 2-6 months for those with left ventricular dysfunction or myocardial injury. Most patients achieve complete recovery of cardiac function within 1-4 weeks. Coronary artery abnormalities typically resolve, but long-term follow-up is recommended. Return to physical activity is guided by cardiac evaluation and is typically restricted for 3-6 months after diagnosis. Exercise stress testing should be performed before clearance for competitive sports.

## Clinical Pearls

MIS-C typically presents 2-6 weeks after SARS-CoV-2 infection, and acute COVID testing may be negative while serology is positive. Gastrointestinal symptoms (abdominal pain, vomiting, diarrhea) are the most common presenting features and can mimic a surgical abdomen. Myocardial dysfunction with reduced ejection fraction is the most common cause of ICU admission, though most children recover cardiac function completely. Lymphopenia and thrombocytopenia help distinguish MIS-C from classic Kawasaki disease, which typically shows thrombocytosis. Combination therapy with IVIG plus corticosteroids is superior to IVIG alone based on available evidence. COVID-19 vaccination dramatically reduces the risk of MIS-C and should be recommended for all eligible children.

## References

1. Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem inflammatory syndrome in US children and adolescents. *New England Journal of Medicine*. 2020;383(4):334-346.
2. Son MBF, Murray N, Friedman K, et al. Multisystem inflammatory syndrome in children — initial therapy and outcomes (BEST-ROAR study). *New England Journal of Medicine*. 2021;385(1):23-34.
3. 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. *Arthritis & Rheumatology*. 2022;74(4):e1-e20.
4. Dufort EM, Koumans EH, Chow EJ, et al. Multisystem inflammatory syndrome in children in New York State. *New England Journal of Medicine*. 2020;383(4):347-358.