Multisystem Inflammatory Syndrome in Children (MIS-C) Interim Guidance

Jul 30, 2020
This article is from the American Academy of Pediatrics. What is the case definition of multisystem inflammatory syndrome in children (MIS-C)? The CDC issued a Health Advisory on May 14, 2020, that outlines the following case definition for MIS-C:

This article is from the American Academy of Pediatrics.

What is the case definition of multisystem inflammatory syndrome in children (MIS-C)?

The CDC issued a Health Advisory on May 14, 2020, that outlines the following case definition for MIS-C:

  • An individual aged <21 years presenting with fever,1 laboratory evidence of inflammation,2 and evidence of clinically severe illness requiring hospitalization, with multisystem (≥2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or neurological); AND
  • No alternative plausible diagnoses; AND
  • Positive for current or recent SARS-CoV-2 (COVID-19) infection by RT-PCR, serology, or antigen test; or COVID-19 exposure within the 4 weeks prior to the onset of symptoms.

What are the common signs and symptoms of MIS-C?

Signs and symptoms include persistent fever, inflammation (on the basis of blood test results), and evidence of organ dysfunction or shock.

Although different presentations have been described, some common symptoms may include:

  • Kawasaki disease-like features: conjunctivitis, red eyes, red or swollen hands and feet,rash; red cracked lips, swollen glands. In some children, coronary artery enlargement and sometimes aneurysms have been seen. Some children presenting with Kawasaki disease-like syndrome have been noted to have a broader age range and presentation with more gastrointestinal (abdominal pain or diarrhea) and neurologic (headaches/meningitis) manifestations.
  • Toxic shock syndrome-like features with hemodynamic instability.
  • Cytokine storm/macrophage activation or hyperinflammatory features.
  • Abnormal clotting, poor heart function, diarrhea and gastrointestinal symptoms, acute kidney injury.
  • Shortness of breath suggestive of congestive heart failure. Respiratory symptoms typically reported in adults with COVID-19 may not be present in pediatric patients with MIS-C.

Common laboratory findings in case reports have included:

  • An abnormal level of inflammatory markers in the blood, including elevated ESR/CRP and ferritin, LDH.
  • Lymphopenia <1000, thrombocytopenia <150,000, neutrophilia.
  • Elevated B-type natriuretic peptide (BNP) or NT-proBNP (pro-BNP), hyponatremia, elevated D-dimers.

When should you suspect MIS-C as part of your differential diagnosis?

MIS-C is a rare complication temporally associated with COVID-19. Any child with suspected MIS-C should also be evaluated for infectious and noninfectious etiologies.

Persistent fever without a clear clinical source is the first clue. Any fever that is accompanied by symptoms concerning in their severity or coincident with recent exposure to a person with COVID-19 should raise suspicions.

Some children clinically progress rapidly and may develop hemodynamic compromise. These children should be followed and cared for in a hospital with tertiary pediatric/cardiac intensive care units.

When should I perform testing for MIS-C and what sort of testing should I start with in the outpatient or emergency room setting?

Evaluate a child with persistent fever (≥3 days) who is moderately to severely ill with clinical signs of organ dysfunction (e.g. gastrointestinal, respiratory, skin, or neurologic). Initial evaluation should include measurement of vital signs, assessment of perfusion and oxygen saturation. Early consultation and coordination with the nearest infectious disease or rheumatology specialist and pediatric referral center for optimal testing and management should be considered. Laboratory screening for systemic inflammation may be considered and initial lab screenings may include a complete blood cell count (CBC) with differential, urine analysis, ESR, CRP, ferritin, LDH, comprehensive metabolic panel, pro-BNP, troponin, and fibrinogen.

Evaluation of severely ill appearing or hemodynamically fragile patients

Severely ill-appearing patients and those in compensated shock or shock should be evaluated and treated in the emergency department/critical care setting. Laboratory tests, as described above, should be performed for initial evaluation regardless of duration of fever. Consultation with pediatric subspecialists at a local or regional pediatric referral center should be initiated.

What testing is needed for hospitalized children?

Any child sick enough to warrant admission for fever, abdominal pain, diarrhea, and/or organ dysfunction in whom MIS-C is suspected should be cared for in a hospital with tertiary pediatric/cardiac intensive care units. Although decisions about additional testing will be made by the multidisciplinary team managing the patient, pediatricians can prepare families for an expanded laboratory and cardiac workup that may include:

  • Chest radiograph, echocardiogram, EKG,
  • Expanded laboratory tests including troponin, pro-BNP, triglycerides, creatine kinase, amylase, blood and urine culture, D-dimer, prothrombin time/partial thromboplastin time (PT/PTT), INR, CRP, ferritin, LDH, comprehensive metabolic panel, and fibrinogen, if not already conducted.
  • In all cases, COVID-19 testing should be performed with RT-PCR assay and serologic testing. Later serology may be needed if all negative initially. Serologic tests must be sent prior to administration of Intravenous Immunoglobulin (IVIG).

What is the recommended treatment approach for MIS-C?

Clinicians who suspect MIS-C in a child should use a multidisciplinary approach involving many pediatric specialists, including but not limited to cardiology, infectious disease, immunology, hematology, rheumatology, pediatric hospital medicine, and critical care, to guide individual patient treatment.

  • Patients with MIS-C have been treated with IVIG, 1 to 2 grams/kg; cardiac function and fluid status influence timing of therapy.
  • Patients have also been treated with steroid therapy (ranging from 2 to 30 mg/kg/day of methylprednisolone depending on severity of illness) and biologics (eg, anakinra, 2 to 10 mg/kg/day, subcutaneously or intravenously, divided every 6 to 12 hours).
  • Patients treated with steroids and/or biologics often go home with a 3-week taper of steroids and/or biologics.
  • Given the need for early intervention and the need to initiate treatment for multiple possible etiologies, many patients have received concurrent antibiotic therapy.
  • Hematology consultation for assessment of clotting risk and treatment/prophylaxis is recommended (eg, low-dose aspirin, at a minimum, for patients with Kawasaki disease-like syndrome or enoxaparin in patients with thrombosis).

What infection prevention and control recommendations should be followed for MIS-C patients?

Patients who are hospitalized with suspected MIS-C should be considered patients under investigation for COVID-19. RT-PCR and antibody testing for COVID-19 (if available) should be performed. Local infection control policies should be followed.

Patients in whom MIS-C is diagnosed should be reported to the local public health department.

What is the recommended follow-up for MIS-C patients?

Patients in whom MIS-C has been diagnosed should have close outpatient pediatric cardiology follow-up starting 2 to 3 weeks after discharge.

1Fever >38.0°C for ≥24 hours, or report of subjective fever lasting ≥24 hours.

2Including, but not limited to, one or more of the following: an elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, procalcitonin, D-dimer, ferritin, lactic acid dehydrogenase (LDH), or interleukin 6 (IL-6), elevated neutrophils, reduced lymphocytes and low albumin.


American College of Rheumatology. Clinical guidance for pediatric patients with multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 and hyperinflammation in COVID-19.

Centers for Disease Control and Prevention. Multisystem Inflammatory Syndrome (MIS-C).

Children’s Hospital of Philadelphia. Emergency Department, ICU and Inpatient Clinical Pathway for Evaluation of Possible Multisystem Inflammatory Syndrome in Children (MIS-C).

Dufort EM, Koumans EH, Chow EJ, et al. Multisystem inflammatory syndrome in children in New York state. Published online ahead of print, June 29, 2020 Jun 29. N Engl J Med. 2020;10.1056/NEJMoa2021756. doi:10.1056/NEJMoa2021756.

Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem inflammatory syndrome in U.S. children and adolescents. Published online ahead of print June 29, 2020. N Engl J Med. 2020;10.1056/NEJMoa2021680. doi:10.1056/NEJMoa2021680.

Whitaker E, Bamford A, Kenny J, et al. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. JAMA. Published online June 8, 2020. doi:10.1001/jama.2020.10369.

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