Multisystem Inflammatory Syndrome in Children (MIS-C) and COVID-19

SUMMARY:

While most children will be asymptomatic or exhibit mild symptoms, SARS-CoV-2 infection has been temporally associated with a syndrome now labeled by the CDC as Multisystem Inflammatory Syndrome in Children (MIS-C). It was first identified in the UK. The underlying mechanism for this severe inflammatory syndrome is not yet understood, but some speculate that the antibody following illness may be generating an overly vigorous immune response in these children and teens. MIS-C can appear weeks after initial infection. According to the CDC, “there have been very few cases of death reported in hospitalized patients”.

Key Features

  • Presentation is that of an inflammatory syndrome and appears to overlap with Kawasaki Disease, Toxic Shock Syndrome, bacterial sepsis and macrophage activation syndromes
  • Kawasaki Disease
    • Inflammation of blood vessels in children (including coronary arteries)
    • Findings include rash, conjunctivitis, and swollen hands or feet which can also be seen in Pediatric Multi-System Inflammatory Syndrome | However cardiac inflammation is greater in Pediatric Multi-System Inflammatory Syndrome and can affect teens, while Kawasaki disease is usually seen in younger children
  • Findings in Pediatric Multi-System Inflammatory Syndrome include
    • Inflammatory markers: Abnormal Fibrinogen | High CRP | High D-Dimers | High ferritin | Hypoalbuminaemia | Lymphopenia | Neutrophilia in most – normal neutrophils in some
    • Fever:  Persistent >38.5°C
  • Additional presenting signs and symptoms may include
    • Abdominal symptoms
    • Rash
    • Myocarditis (and other cardiovascular changes)
  • Some children will develop cardiogenic or vasogenic shock with evidence of single or multi-organ failure
    • Cardiac, respiratory, renal, gastrointestinal or neurological system failure

CDC Recommendations

Case Definition for MIS-C

  • An individual aged <21 years presenting with fever*, laboratory evidence of inflammation**, 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 infection by RT-PCR, serology, or antigen test or exposure to a suspected or confirmed COVID-19 case within the 4 weeks prior to the onset of symptoms

Notes

  • *Fever: >38.0°C for ≥24 hours, or report of subjective fever lasting ≥24 hours
  • **Evidence of inflammation: Including, but not limited to, one or more of the following
    • 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
  • Even if patients fulfill full or partial criteria for Kawasaki disease, the case should still be reported if they meet the case definition for MIS-C
  • Consider MIS-C in any pediatric death with evidence of SARS-CoV-2 infection

Evaluation

  • Laboratory Testing
    • Test for evidence of inflammation as listed above
    • SARS-CoV-2: RT-PCR or antigen test
    • Antibody testing (where feasible) | Test prior to IVIG or other antibody treatment
  • Baseline cardiac tests including but not limited to
    • Echocardiogram
    • Electrocardiogram
    • Cardiac enzyme or troponin testing (per the center’s testing standards)
    • B-type natriuretic peptide (BNP) or NT-proBNP
  • Additional testing should be guided by patient’s clinical findings

Work Up

  • Obtain history of any past COVID-19 like symptoms or close contact with someone who may have COVID-19
  • Rule out microbial cause, including
    • Bacterial sepsis | Staphylococcal or streptococcal shock syndromes | Infections associated with myocarditis such as enterovirus
    • Note: Do “not delay seeking expert advice while waiting for results of these investigations”
  • Requires quick recognition and referral to in-patient specialist as patient may require further intensive/critical care
    • Additional specialists may include those with expertise in pediatric infectious diseases, cardiology, and rheumatology

KEY POINTS:

Treatment

  • Treat all children with this presentation as suspected COVID-19
  • Blood cultures and empiric antibiotics should be started as per local sepsis protocols
  • No current data available for efficacy of various treatments | However, information is available in the literature based on experience of various institutions
  • Supportive care
    • Fluid resuscitation
    • Inotropic support
    • Respiratory support
    • ECMO (rarely)
  • Anti-inflammatory measures
    • Intravenous immunoglobulin (IVIG)
    • Steroids
    • Aspirin: Frequently used due to concern for coronary involvement | Aspirin is a mainstay for the treatment of Kawasaki Disease
  • Antibiotics: Routinely used to treat potential sepsis while awaiting bacterial culture

Prognosis

The RCPCH expert panel add that

  • Most of the children were very ill but recovered
  • It is a syndrome where there is a pattern to the features that leads physicians to suspect the diagnosis
  • Dr Sanjay Patel, consultant in pediatric infectious diseases at Southampton Children’s Hospital, recommends that if there is concern, recommendations remain to get medical help, alert the child’s physician and if necessary obtain emergency services | In addition, Dr. Patel states

It’s very important to keep this in perspective. It’s a very rare condition and because of that parents shouldn’t be alarmed. We’re talking about a really small number of cases, each of which was picked up and treated by experts in our health system. It remains extremely unlikely that a child will become unwell with COVID-19, and it’s even more unlikely that a child will become unwell with this condition.

Learn More – Primary Sources:

CDC: Information for Healthcare Providers about Multisystem Inflammatory Syndrome in Children (MIS-C)

CDC: Multisystem Inflammatory Syndrome (MIS-C)

NYSDOH: Health Advisory: Pediatric Multi-System Inflammatory Syndrome Potentially Associated with Coronavirus Disease (Covid-19) In Children

Royal College of Paediatrics and Child Health Guidance: Paediatric multisystem inflammatory syndrome temporally associated with COVID-19

Royal College of Paediatrics and Child Health: Leading paediatricians publish case definition for illness affecting children during COVID-19

NYC 2020 Health Alert #13: Pediatric Multi-System Inflammatory Syndrome Potentially Associated with COVID-19

NEJM: Multisystem Inflammatory Syndrome in U.S. Children and Adolescents

GHR: Kawasaki Disease