MIS-C is a rare, severe postinfectious hyperinflammatory disorder occurring 2–6 weeks after SARS-CoV-2 infection, characterized by persistent fever, multiorgan involvement, and potentially life-threatening cardiovascular compromise. [1-2] Median age at diagnosis is 8–9 years, with a slight male predominance (57–59%) and disproportionate representation of Black and Hispanic children. [2]
1. History
- Duration and character of fever: Persistent fever ≥38.0°C for >24 hours (CDC) or ≥3 days (WHO) — this is a universal feature (99%) [3]
- GI symptoms: Vomiting, diarrhea, and abdominal pain are prominent (70–87%) — severe abdominal pain may mimic appendicitis or intussusception [2][4]
- Mucocutaneous findings: Rash (59%), nonpurulent conjunctivitis (57%), oral mucosal changes (42%) [2]
- Neurologic symptoms: Headache (29%), irritability, altered mental status/confusion (2%) [2][5]
- Timing relative to COVID-19: Ask about known SARS-CoV-2 infection or exposure within the prior 2–8 weeks; many children had asymptomatic or mild initial infection [1][4]
- Important negatives: Exudative pharyngitis, vesicular rash, and oral ulcerations are NOT typical and should prompt consideration of alternative diagnoses [6]
2. Alarm Features
- Hemodynamic instability/shock: Hypotension, tachycardia, poor perfusion — up to 50–73% require vasoactive support [2]
- Myocardial dysfunction: Decreased LVEF, elevated troponin/BNP — present in up to 50% [2][7]
- Altered mental status or confusion [2]
- Signs of macrophage activation syndrome (MAS): Rapidly rising ferritin, cytopenias, hepatosplenomegaly [3]
- Respiratory distress requiring noninvasive or mechanical ventilation (up to 30%) [2]
- Arrhythmias or conduction abnormalities including AV block (up to 20%) [3][7]
3. Medications
- First-line treatment: IVIG 2 g/kg (ideal body weight, max 100 g) + low-to-moderate dose glucocorticoids (methylprednisolone 1–2 mg/kg/day) per ACR guidance [7]
- Refractory disease escalation: High-dose IV pulse glucocorticoids (10–30 mg/kg/day), anakinra (>4 mg/kg/day IV or SC), or infliximab [3][7]
- Do NOT give a second dose of IVIG if refractory — risk of volume overload and hemolytic anemia [3][7]
- Antiplatelet therapy: Low-dose aspirin for coronary artery involvement [2]
- Anticoagulation: Considered based on degree of coronary dilation and thromboembolic risk; wide practice variation [2][8]
- Caution: Assess cardiac function and fluid status before IVIG — patients with depressed function may need divided dosing (1 g/kg/day × 2 days) or concurrent diuretics [3][7]
4. Diet
- NPO considerations in acutely ill patients with shock or potential surgical abdomen
- Hydration: Aggressive IV fluid resuscitation often needed for shock, but balance with risk of volume overload in patients with myocardial dysfunction
- No specific dietary triggers or long-term dietary management are established for MIS-C
5. Review of Systems
- Cardiovascular: Chest pain, palpitations, exercise intolerance, syncope
- GI: Nausea, vomiting, diarrhea, abdominal pain (can be severe)
- Dermatologic: Rash, extremity swelling/erythema
- HEENT: Conjunctival injection, lip changes, strawberry tongue
- Neurologic: Headache, irritability, confusion, lethargy
- Respiratory: Dyspnea, cough (less prominent than GI/cardiac)
- Musculoskeletal: Myalgias, arthralgias
- Renal: Decreased urine output (assess for AKI)
6. Collateral History and Family History
- COVID-19 exposure: Household contacts, school/daycare outbreaks, community prevalence within prior 4–8 weeks
- Vaccination status: COVID-19 vaccination is protective against MIS-C [9]
- Family history: No strong hereditary predisposition identified, but family history of autoimmune/autoinflammatory conditions may be relevant
- Social context: Access to follow-up care is critical given the need for serial cardiac monitoring
7. Risk Factors
- Prior SARS-CoV-2 infection (even asymptomatic) 2–8 weeks prior [1][4]
- Age: Median 8–9 years; broader range than Kawasaki disease [2]
- Race/ethnicity: Increased incidence in Black, Afro-Caribbean, and Hispanic children [3][7]
- Male sex (slight predominance) [2]
- Comorbidities: Obesity (25–31% had ≥1 comorbidity, with obesity being most common), asthma [2][10]
- Unvaccinated status: COVID-19 vaccination reduces MIS-C risk [9]
8. Differential Diagnosis
The following table compares key distinguishing features:
- Kawasaki disease: Younger age (<5 years), more prominent mucocutaneous features, coronary artery aneurysms more common; less shock/LV dysfunction; higher platelets, lower CRP [3][7][11]
- Toxic shock syndrome (staphylococcal/streptococcal): Positive blood cultures, identifiable source of infection; MIS-C typically culture-negative [11-12]
- Bacterial sepsis: Positive cultures, focal source; MIS-C has sterile cultures with disproportionate inflammation
- Acute appendicitis: Severe abdominal pain in MIS-C can mimic surgical abdomen [4]
- Viral myocarditis (non-COVID): Typically isolated cardiac involvement without multisystem inflammation
- Macrophage activation syndrome/HLH: Overlapping features; can coexist with MIS-C [3]
- Adenovirus infection: Can cause multisystem illness in children [2]
9. Past Medical History
- Prior COVID-19 infection (confirmed or suspected)
- Pre-existing cardiac conditions (may complicate assessment)
- Obesity, asthma, chronic lung disease — associated with more severe outcomes [2][10]
- Immunodeficiency — management approach is identical in children with HIV [13]
- Prior episodes of MIS-C — recurrence is rare but reported
10. Physical Exam
- Vitals: Fever (universal), tachycardia, hypotension (shock in up to 50%), tachypnea
- Cardiovascular: Gallop rhythm, muffled heart sounds (pericardial effusion), poor perfusion, delayed capillary refill
- Skin: Diffuse maculopapular or erythematous rash; extremity edema/erythema (less common than KD) [5]
- HEENT: Bilateral nonpurulent conjunctival injection, cracked/erythematous lips, strawberry tongue, cervical lymphadenopathy
- Abdomen: Diffuse tenderness (can mimic acute abdomen), hepatomegaly
- Neurologic: Irritability, meningismus, altered sensorium
- Extremities: Edema, erythema of hands/feet (less frequent than KD)
11. Lab Studies
Tier 1 (initial)
- CBC with differential: Expect neutrophilia, lymphopenia, thrombocytopenia, anemia [2][5][11]
- CRP: Markedly elevated (median ~22 mg/dL vs 6.7 in KD) [5]
- ESR, procalcitonin
- CMP: Hypoalbuminemia (median 2.4 g/dL), transaminitis, renal function [5]
- Troponin and BNP/NT-proBNP: Elevated in majority; NT-proBNP median ~788 pg/mL [2][5]
- D-dimer: Markedly elevated (median ~3,578 ng/mL) [5]
- Fibrinogen, ferritin (often 500–2,000 ng/dL), LDH [3]
- SARS-CoV-2 PCR and serology [3]
- Blood cultures (to exclude bacterial sepsis)
Tier 2 (additional)
- Cytokine panel (IL-6, IL-10, soluble IL-2R) if available
- Coagulation studies (PT/INR, PTT)
- Urinalysis
- Serial trending of troponin, BNP, CRP until normalization [3][7]
12. Imaging
- Echocardiogram (first-line, essential): Assess LV function (EF), coronary artery dimensions with z-scores, valvular function, pericardial effusion [3][7]
- Chest X-ray: Pleural effusions (35%), pulmonary edema, cardiomegaly
- Abdominal imaging (US or CT): If surgical abdomen suspected — may show mesenteric lymphadenitis, bowel wall thickening, ascites
- Cardiac MRI: Indicated 2–6 months post-acute illness in patients with significant LV dysfunction (EF <50%) to evaluate for myocardial fibrosis/scarring [3][7]
- Cardiac CT: For suspected distal coronary artery aneurysms not well visualized on echo [3][7]
The following figure illustrates the spectrum of organ system involvement and cardiovascular outcomes in MIS-C:
13. Special Tests
- SARS-CoV-2 serology (antibody testing): Critical for diagnosis — many patients are PCR-negative but serology-positive [3]
- Diagnostic scoring tools: Validated scores can distinguish MIS-C from COVID-19, KD, and TSS (AUC 0.87–0.97) [11]
- Coronary artery z-scores: Body surface area–normalized measurements essential for tracking [3][7]
- Global longitudinal strain (GLS): May detect subclinical myocardial dysfunction even when EF is normal; 22% with normal LVEF had abnormal GLS [16]
14. ECG
- Obtain ECG on all patients at presentation [2]
- Findings: ST-segment changes, QTc prolongation, premature atrial/ventricular contractions [2]
- Conduction abnormalities: AV block identified in up to 20%, including progression to second- and third-degree block [3][7]
- Frequency: ECGs should be obtained at minimum every 48 hours during hospitalization [3][7]
- Telemetry: Continuous monitoring if any conduction abnormality is present [3]
15. Assessment
- MIS-C is a clinical diagnosis based on case definitions from the CDC, WHO, or RCPCH, requiring fever + multisystem involvement + evidence of inflammation + link to SARS-CoV-2 + exclusion of other causes [3]
- Severity spectrum: Ranges from mild (fever + rash + inflammation without organ damage) to fulminant (shock, multiorgan failure, ECMO requirement) [7]
- Age-dependent phenotype: Younger children more likely to present with KD-like features; older children more likely to develop myocarditis and shock [3][7]
- Complications: Coronary artery aneurysms (~13%), myocardial fibrosis/scarring, arrhythmias, thromboembolic events [2][7]
- Mortality: Rare at 1.4–1.9%, but notably most fatalities occurred in previously healthy children [2]
16. Treatment Plan
Initial stabilization
- ABCs, IV access, continuous monitoring
- Fluid resuscitation for shock (judicious if myocardial dysfunction suspected)
- Inotropes/vasopressors as needed (required in up to 73%) [2]
- Respiratory support (NIV or mechanical ventilation as indicated)
Immunomodulatory therapy (ACR stepwise approach): [7]
- First-line: IVIG 2 g/kg (ideal body weight, max 100 g) + methylprednisolone 1–2 mg/kg/day
- Refractory disease: High-dose pulse steroids (10–30 mg/kg/day), anakinra (>4 mg/kg/day), or infliximab
- Do not repeat IVIG — escalate to biologics or high-dose steroids instead
- Steroid taper: 2–3 weeks or longer, guided by serial labs and cardiac assessment [3]
Antithrombotic therapy
- Low-dose aspirin for coronary artery involvement [2]
- Anticoagulation based on individual risk assessment [2][8]
Severity-guided approach (emerging evidence): Biomarker-guided escalation — mild disease (low CRP/ferritin) may respond to IVIG + steroids alone; severe disease with MAS features may benefit from early anakinra [17]
17. Disposition
- Admit all patients meeting MIS-C criteria with abnormal vitals, cardiac involvement, or organ dysfunction [7]
- ICU admission: Required in ~60–80% — indications include shock, need for vasoactive support, significant LV dysfunction, respiratory failure, arrhythmias [2][18]
- ECMO: For refractory cardiorespiratory failure (1.4% in large cohorts) [19]
- Outpatient monitoring: May be considered for well-appearing children with mild symptoms, reassuring vitals, and ensured close follow-up [7]
- Discharge criteria: Afebrile, normotensive, well-hydrated, no supplemental oxygen requirement, normalizing inflammatory markers [12]
Specialist consultation triggers
- Cardiology (all patients)
- Rheumatology
- Infectious disease
- Critical care (if hemodynamically unstable)
- Hematology (if significant coagulopathy)
18. Follow-Up / Return Precautions
Structured follow-up schedule (ACR/AHA recommendations): [2-3][7]
- 1–2 weeks: Repeat labs (CRP, troponin, BNP), ECG, echocardiogram
- 4–6 weeks: Repeat echocardiogram, labs, ECG
- 4–6 months: Cardiac MRI if initial LVEF <50% [3][7]
- 10–12 months: Echocardiogram if cardiac abnormalities during acute phase
- Holter monitoring and exercise stress testing as clinically indicated
Prognosis: The MUSIC study (1,204 participants) demonstrated that 95% returned to >90% of pre-MIS-C health by 6 months; nearly all LV dysfunction and coronary aneurysms resolved. [19] However, ~21% had persistently abnormal GLS at 2 months, suggesting possible subclinical dysfunction. [16]
Return precautions — counsel families to return immediately for:
- Recurrent fever
- Chest pain, palpitations, syncope, or exercise intolerance
- Worsening abdominal pain, vomiting, or poor oral intake
- Lethargy, confusion, or irritability
- Signs of poor perfusion (mottled skin, cool extremities)
Activity restriction: Exercise restriction should be guided by cardiology, particularly in patients with myocardial involvement — typically restricted until cardiac function normalizes and cleared by cardiology. [7]
References
1. Treatment of Multisystem Inflammatory Syndrome in Children. — McArdle AJ, Vito O, Patel H, et al. The New England Journal of Medicine. 2021.
2. SARS-CoV-2 Infection and Associated Cardiovascular Manifestations and Complications in Children and Young Adults: A Scientific Statement From the American Heart Association. — Jone PN, John A, Oster ME, et al. Circulation. 2022.
3. American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 2. — Henderson LA, Canna SW, Friedman KG, et al. Arthritis & Rheumatology. 2021.
4. Kawasaki Disease: Contemporary Perspectives. — Day-Lewis M, Son MBF, Lo MS. The Lancet. Child & Adolescent Health. 2024.
5. Kawasaki Disease and Multisystem Inflammatory Syndrome in Children: An Overview and Comparison. — Darby JB, Jackson JM. American Family Physician. 2021.
6. Update on Diagnosis and Management of Kawasaki Disease: A Scientific Statement From the American Heart Association. — Jone PN, Tremoulet A, Choueiter N, et al. Circulation. 2024.
7. 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. — Henderson LA, Canna SW, Friedman KG, et al. Arthritis & Rheumatology. 2022.
8. MIS-C: Diagnosis, Management, and Outcomes. — El Rassi C, El Darzi R, Abou Mansour M, Arabi M. Open Forum Infectious Diseases. 2026.
9. Pathogenesis, Immunology, and Immune-Targeted Management of the Multisystem Inflammatory Syndrome in Children (MIS-C) or Pediatric Inflammatory Multisystem Syndrome (PIMS): EAACI Position Paper. — Feleszko W, Okarska-Napierała M, Buddingh EP, et al. Pediatric Allergy and Immunology : Official Publication of the European Society of Pediatric Allergy and Immunology. 2023.
10. Health Impairments in Children and Adolescents After Hospitalization for Acute COVID-19 or MIS-C. — Maddux AB, Berbert L, Young CC, et al. Pediatrics. 2022.
11. Distinguishing Multisystem Inflammatory Syndrome in Children From COVID-19, Kawasaki Disease and Toxic Shock Syndrome. — Godfred-Cato S, Abrams JY, Balachandran N, et al. The Pediatric Infectious Disease Journal. 2022.
12. COVID-19 and Multisystem Inflammatory Syndrome in Children and Adolescents. — Jiang L, Tang K, Levin M, et al. The Lancet. Infectious Diseases. 2020.
13. Guidelines for the Prevention and Treatment of Opportunistic Infections in Children With and Exposed to HIV. — Bill G. Kapogiannis, Franklin Yates, Wei Li, et al Office of AIDS Research Advisory Council (2025). 2025.
14. Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. — Feldstein LR, Rose EB, Horwitz SM, et al. The New England Journal of Medicine. 2020.
15. Characteristics and Outcomes of US Children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19. — Feldstein LR, Tenforde MW, Friedman KG, et al. The Journal of the American Medical Association. 2021.
16. Longitudinal Assessment of Cardiac Function Following Multisystem Inflammatory Syndrome in Children Associated With COVID-19. — Das N, Hill R, Trivedi M, et al. Pediatric Cardiology. 2023.
17. Multisystem Inflammatory Syndrome in Children With Tailored Therapy and Six-Month Outcome. — Demir OO, Aykac K, Cheng AHH, et al. Pediatric Research. 2026.
18. Longitudinal Outcomes for Multisystem Inflammatory Syndrome in Children. — Farooqi KM, Chan A, Weller RJ, et al. Pediatrics. 2021.
19. Six-Month Outcomes in the Long-Term Outcomes After the Multisystem Inflammatory Syndrome in Children Study. — Truong DT, Trachtenberg FL, Hu C, et al. JAMA Pediatrics. 2025.