Multisystem Inflammatory Syndrome

1. See Also
   1. Covid19
   2. Kawasaki Disease
2. Epidemiology
   1. First identified during Spring 2020 with onset of Covid19 pandemic
   2. Age
      1. Initially identified in children and unlike Kawasaki Disease (age <11 years) extended to age 21
      2. Age range from 1 week to 21 years (median 7-9 years)
      3. Has since been reported in adults
         1. Morris (2020) MMWR Morb Mortal Wkly Rep 69:1450-56 [PubMed]
         2. https://www.cdc.gov/mmwr/volumes/69/wr/mm6940e1.htm
   3. Gender
      1. Boys represent 60% of cases (similar to Kawasaki Disease)
   4. Race (U.S.)
      1. Hispanic or Latino: 32%
      2. Non-Hispanic Black: 30%
3. Pathophysiology
   1. Systemic inflammatory condition as a complication of COVID-19, and similar to Kawasaki Disease
4. Indications: Evaluation for MIS-C
   1. Suspected or confirmed COVID-19 within prior 4 weeks AND
   2. Fever >3 days AND
   3. No other apparent explanation AND
   4. Two or more of the following systems involved (or unexplained Fever >5 days)
      1. Gastrointestinal findings (80% of patients)
         1. Abdominal Pain
         2. Diarrhea
         3. Nausea or Vomiting
      2. Neurologic findings (20% of patients)
         1. Headache
         2. Irritability
         3. Lethargy
         4. Altered Mental Status
         5. Neurologic deficits
      3. Head and Neck Symptoms
         1. Conjunctivitis (40%)
         2. Cough
         3. Congestion
         4. Pharyngitis
         5. Oral Lesions or other oral changes
            1. Red Cracked Lips (23%)
            2. Strawberry Tongue (4.5%)
         6. Cervical Lymphadenopathy (4%)
      4. Dyspnea
      5. Swelling of hands or feet
      6. Urethritis
      7. Arthralgias or Arthritis
      8. Dermatologic findings
         1. Polymorphic rash
         2. Scaling or peeling of skin (Exfoliative Dermatitis)
5. Labs
   1. Background
      1. Inflammatory markers are typically higher than in Kawasaki Disease
   2. First-Line - Tier 1 Screening
      1. Complete Blood Count with Platelets and differential
         1. White Blood Cell Count increased (12-22k, mean 17k)
            1. Associated with Left Shift (Neutrophil predominance) and lymphocytopenia
            2. Contrast with only mildly elevated White Blood Cell Counts in Kawasaki Disease
         2. Anemia (Hgb 8.3-10.3 g/dl, mean 9.2 g/dl)
         3. Thrombocytopenia (104-210 k/uL, mean 151 k/uL)
            1. Contrast with Thrombocytosis in Kawasaki Disease
      2. Comprehensive metabolic panel
         1. Electrolytes
         2. Renal Function tests
         3. Liver Function Tests
         4. Serum Albumin
            1. Levels 2.1 to 2.7 g/dl (mean 2.4 g/dl)
            2. Contrast with normal Serum Albumin in Kawasaki Disease
      3. Erythrocyte Sedimentation Rate
      4. C-Reactive Protein
         1. Levels 16 - 34 mg/dl (mean 22 mg/dl)
      5. Covid19 Test (typically nasopharyngeal PCR)
   3. First-Line - Tier 2 Screening
      1. Indications for Tier 2 tests (from Tier 1 Screening)
         1. C-Reactive Protein or CRP >5 mg/L or Erythrocyte Sedimentation Rate or ESR >40 mm/h AND
         2. At least one of the following
            1. Absolute Lymphocyte Count <1000/ul
            2. Platelet Count <150,000/ul
            3. Serum Sodium <135 mmol/L
            4. Neutrophilia
            5. Hypoalbuminemia (e.g. Serum Albumin <3 g/dl)
      2. Tier 2 Tests
         1. INR and PTT
         2. D-Dimer
            1. Levels 2.1 to 8.2 ng/ml (mean 3.6 ng/ml)
         3. Serum Troponin
            1. Levels 0.008 to 0.294 mcg/L (mean 0.045 mcg/L)
            2. Contrast with typically normal serum Troponin In Kawasaki Disease
         4. NT-BNP
            1. Levels 174 to 10,548 pg/ml (mean 788 pg/ml)
            2. Contrast with typically normal NT-BNP in Kawasaki Disease
         5. Urinalysis (and consider Urine Culture)
         6. Blood Culture
   4. Additional Testing to consider based on Consultation
      1. Fibrinogen
      2. Factor VIII and Von-Willebrand profile
      3. Antithrombin III
      4. Procalcitonin
      5. Serum Ferritin
         1. Levels 359 to 1280 ng/ml (mean 610 ng/ml)
      6. Serum Triglycerides
      7. Total IgG
      8. Mycoplasma PCR
      9. Tick-Borne Illness Serology (e.g. Lyme Disease, Babesiosis, Anaplasmosis, Rickettsia - depending on region)
      10. Antiphospholipid Antibody profile and Lupus Anticoagulant Profile
      11. Cytokine Panel (e.g. IL1, IL6, IL8, TNFa)
      12. Lactate Dehydrogenase
      13. Uric Acid
      14. Peripheral Smear
6. Diagnostics
   1. Electrocardiogram
      1. ST Segment Changes
      2. Premature Beats
      3. QTc Prolongation
      4. Atrioventricular Block
      5. Sustained Arrhythmia
   2. Echocardiogram (suspected MIS-C)
      1. Ventricular dysfunction in 30% of cases (rare in Kawasaki Disease)
      2. Coronary Artery dilatation and aneurysms
7. Imaging
   1. First-Line
      1. Chest XRay
8. Differential Diagnosis
   1. Multisystem Infammatory Syndromes
      1. Covid19
      2. Kawasaki Disease
   2. Other Infections
      1. Toxic Shock Syndrome
      2. Septic Shock
      3. Mycoplasma pneumonia
      4. Viral Infections (e.g. Adenovirus, other Enteroviruses)
      5. Measles
      6. Tick-Borne Illness
      7. Leptospirosis
      8. Rheumatic Fever
   3. Rheumatologic Conditions
      1. Vasculitis
      2. Systemic Lupus Erythematosus (SLE)
      3. Juvenile Idiopathic Arthritis
      4. Macrophage Activation Syndrome
      5. Hemophagocytic lymphohistiocytosis
   4. Adverse Drug Reaction
      1. See Serious Cutaneous Adverse Reaction
      2. Stevens-Johnson Syndrome
      3. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS Syndrome)
   5. Miscellaneous
      1. Malignancy
9. Management: Indications for Inpatient Evaluation and Management
   1. Cardiac involvement
   2. Hypoxia
   3. Dehydration
   4. Lymphocytes <1000/ul
   5. Platelets <150k or >450k
   6. C-Reactive Protein or CRP >30 mg/L
   7. Erythrocyte Sedimentation Rate or ESR >40 mm/h
   8. Serum Albumin <3 g/dl
   9. Significant Anemia for age
   10. Coagulopathy
10. Management: General
    1. See Covid19 for respiratory management
    2. Multispecialty Consultation (Infectious disease, hematology and oncology, cardiology, rheumatology)
    3. Immunomodulatory agents, antiplatelet agents and Anticoagulation per Consultation
       1. Intravenous Immune Globulin (IVIG) 2 g/kg in single dose
       2. Low dose Aspirin 3-5 mg/kg/day
       3. Consider Systemic Corticosteroids
       4. Consider Immunomodulator
          1. Anakinra (Kineret, IL-1 Receptor Antagonist)
    4. Consider empiric antibiotics when Septic Shock is considered in differential diagnosis
       1. Ceftriaxone (or if Immunocompromised, Cefepime) AND
       2. Consider Vancomycin (if Septic Shock, Meningitis, Central Line) AND
       3. Consider Metronidazole (if suspected abdominal source of infection) AND
       4. Consider Doxycycline (if suspected Tick Borne Illness)
11. Complications
    1. Hypotension or Shock
       1. More common in MIS-C than in Kawasaki Disease
12. Resources
    1. Children's Hospital of Philadelphia MIS-C Evaluation Protocol
       1. https://www.chop.edu/clinical-pathway/multisystem-inflammatory-syndrome-mis-c-clinical-pathway
    2. Multisystem Inflammatory Syndrome (CDC)
       1. https://www.cdc.gov/mis/hcp/index.html
    3. American College of Rheumatology
       1. https://www.rheumatology.org/Portals/0/Files/ACR-COVID-19-Clinical-Guidance-Summary-MIS-C-Hyperinflammation.pdf
13. References
    1. (2020) University of Minnesota Masonic Guidance on Emergency Management MIS-C in Children
    2. Darby (2021) Am Fam Physician 104(3): 244-52 [PubMed]
    3. Jiang (2020) Lancet Infect Dis [PubMed]
       1. https://www.thelancet.com/action/showPdf?pii=S1473-3099%2820%2930651-4