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Episode #55 – A MIS-Chievous Case

55 Cover Art OPT

Summary

Drs. Jimmy McCluskey and Alice Sato discuss multisystem inflammatory syndrome in children (MIS-C)

Table of Contents

Credits

Hosts: Jimmy McCluskey, Sara Dong

Guest: Alice Sato

Writing: Jimmy McCluskey, Sara Dong

Producing/Editing/Cover Art/Infographics: Sara Dong

Our Guests

Guest Consultant

Alice Sato, MD, PhD

Dr. Alice Sato is an Assistant Professor in Division of Pediatric Infectious Diseases at University of Nebraska Medical Center & Children’s Hospital in Omaha, NE.  She completed her medical school training at the University of Pennsylvania followed by residency at Thomas Jefferson University.  She then did her fellowship at Case Western Reserve University in Cleveland, OH.


Check out her PIDS Member Spotlight here

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Guest Co-Host

Jimmy McCluskey, MD

Jimmy McCluskey is an internal medicine and pediatric resident at the University of Nebraska Medical Center.

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Culture

Jimmy shared his love for Paul Offitt’s books, and he recently read Overkill.

Alice mentioned Hank and John Green as well as enjoying some of the James Webb space telescope images!

Consult Notes

Case Summary

3 year old previously healthy boy who presented with 3 days of fever, fatigue, anorexia, and rash who was ultimately diagnosed with MIS-C after SARS-CoV-2 infection

Key Points

Case definition of MIS-C

Case definitions differ slightly among different organizations like the World Health Organization (WHO), Centers for Disease Control and Prevention (CDC), and the Royal College of Paediatrics and Child Health (RCPCH)

However, they generally include:

  • Unremitting fever > 38°C
  • Epidemiologic link to SARS-CoV-2
  • At least 2 of the following
    • Rash
    • Gastrointestinal symptoms
    • Edema of hands/feet
    • Oral mucosal changes
    • Conjunctivitis 
    • Lymphadenopathy
    • Neurologic symptoms  

Access to case definitions:

MIS-C Signs & Symptoms

  • Fever (unremitting, greater than 38°C)
      • Higher temperature (40C vs 38.9) compared with other fever syndromes
      • 90% have fever for more than 4 days
  • Mucocutaneous findings: rash (60%), conjunctivitis (56%), edema of the hands/feet (9%), red/cracked lips, and strawberry tongue
  • Myocardial dysfunction: cardiac conduction abnormalities, shock 
  • Gastrointestinal symptoms
      • Abdominal pain in 80%, nausea vomiting in 58%, diarrhea in 49%
  • Lymphadenopathy
  • Neurologic involvement (8.1%): headache, altered mental status, seizures, cranial nerve palsies, meningismus, cerebral edema, and ischemic or hemorrhagic stroke

The usual duration between acute infection and onset of MIS-C symptoms has been reported at 2-6 weeks, although there have been rare reports of onset >6 weeks later.  In general this time frame can be difficult to discern, especially when children were asymptomatic at the time of acute infection.

Some items often on the differential diagnosis of MIS-C
  • MIS-C
  • Kawasaki disease (KD)
      • One-quarter to one-half of patients with MIS-C meet full criteria for KD
      • Most patients with KD present before age 5, while MIS-C patients are 6-12 years old, however younger patients are more likely to have a mixed picture
      • LV dysfunction and shock are more common in MIS-C than KD
      • CAAs are more common in KD than MIS-C
      • Gastrointestinal and neurologic symptoms are less common in KD compared with MIS-C
      • MIS-C patients likely have more notable lymphopenia, thrombocytopenia, elevated CRP
  • Toxic shock syndrome
  • Bacterial sepsis
  • Acute COVID-19
  • Viral myopericarditis 
  • Macrophage activation syndrome (MAS)
  • Other systemic viral illness (adenovirus, Epstein Barr Virus, Cytomegalovirus) 
  • Pneumonia
  • Appendicitis
  • Rocky Mountain Spotted Fever or other tick-borne illness
  • Brucella 
  • New onset leukemia or lymphoma

References

Diagnosis/evaluation of MIS-C

A tiered diagnostic approach is recommended in patients without life-threatening manifestations; this includes performing an initial screening evaluation (Tier 1), and thereafter proceeding to a complete diagnostic evaluation (Tier 2) only in patients with laboratory results from the Tier 1 screening that are concerning.

Tier 1

  • Complete blood count with differential
  • Complete metabolic panel
  • Erythrocyte sedimentation rate (ESR)
  • C-reactive protein (CRP)
      • The overwhelming majority of cases involve elevated levels of inflammation markers, particularly CRP, and values higher than 10 to 20 mg/dl are common
  • Testing for SARS–CoV-2 by polymerase chain reaction (PCR) or serology

To enter the second stage of testing it is recommended that patients should have elevated ESR and/or CRP levels and at least 1 other suggestive laboratory feature: 

  • Lymphopenia
      • Lower absolute lymphocyte count (OR 8.33 per unit decrease in 109 cells/L) was predictive of severe MIS-C
  • Neutrophilia
  • Thrombocytopenia
  • Hyponatremia
  • Hypoalbuminemia

Tier 2 

Because some patients with MIS-C can decompensate rapidly, children with concerning findings should be admitted to the hospital while Tier 2 testing is pursed

  • EKG
      • Electrical conduction abnormalities like atrioventricular block (20% of patients)
      • Progression to second- and third-degree block has been observed1
  • Echocardiogram
      • Cardiac involvement has been reported in MIS-C patients in every retrospective cohort study published to date
      • Quantification of left ventricular (LV) size, systolic function, and ejection fraction (EF) using end-diastolic volume with z-score
          • Abnormalities in LVEF was reported in 20–55% of MIS-C cases
      • Evaluation of all coronary artery segments and normalization of coronary artery measurements to body surface area using z-scores 
          • Coronary artery dilation and/or coronary artery aneurysm (CAA) was initially reported in about 20% of cases of MIS-C,  but later closer to 13%
  • Changes in the ESR and CRP level
  • Blood cultures
  • Coagulation studies (INR/PT/PTT)
  • Fibrinogen 
  • D-dimer 
  • Ferritin 
  • Procalcitonin 
  • Lactate dehydrogenase (LDH) 
  • Cytokine and chemokine measurements can assist in the diagnostic evaluation including levels of interleukin-6 (IL- 6), tumor necrosis factor (TNF), IL-10, IL-18, IFNγ
  • Peripheral blood smear

Additional References:



Management

The management approaches noted below are consistent with published guidance.  Here are links to important references for clinical guidance from national/international organizations:

There are no randomized controlled clinical trials that compare therapeutic approaches in MIS-C or specific dosing regimens

Treatment considerations will depend somewhat on the clinical presentation:

  • To start, supportive care for children presenting in shock [and/or close monitoring for children who are not]
      • Resuscitation as necessary: Place PIV/IO (2 sites if possible), 20ml/kg NS bolus x3 if needed, vasoactive agents if needed
      • Consider empiric antibiotics with ceftriaxone (100mg/kg, max 2000mg) and vancomycin (15mg/kg, max 1000mg) within 30 minutes pending culture results

A stepwise approach to immunomodulatory treatment in MIS-C is recommended

  • First line: dual therapy with intravenous immunoglobulin (IVIG) and glucocorticoids
      • Overcoming COVID-19 and Best Available Treatment Study (BATS) showed initial combination IVIG and glucocorticoid treatment (most treated with methylprednisolone 2.0 mg/kg/day) was associated with a lower risk of cardiovascular dysfunction and need for adjunctive immunomodulatory therapy on day 2 compared with IVIG alone
      • Overall, the IVIG & steroid recommendations are based on case series where majority of patients had recovery of cardiac function (along with indirect application of data supporting use in patients with similar conditions like Kawasaki disease).  You’ll see these major studies in references below
    • Glucocorticoid therapy is typically methylprednisolone 1-2 mg/kg/d in two divided doses, with transition to oral dosing of prednisolone or prednisone by time of discharge (tapered off over 2-3 weeks)
    • IVIG should be given at a dose of 2 g/kg based on ideal body weight, with a maximum dose of 100 gm 
        • If cardiac function and fluid status are abnormal, the rate of IVIG infusion can be slowed or given in divided doses over 2 days
        • Generally this will be given as single dose, but for patients with severe LV dysfunction and volume concerns, dose could be potentially divided over two days.  A second dose is generally avoided due to risk of volume overload and hemolytic anemia
        • IVIG alone might be reasonable in children with mild disease, no evidence of cardiovascular dysfunction, and a preexisting condition that may warrant avoidance of steroids (such as diabetes or obesity) 
  • Antithrombotic therapy
      • ASA: low-dose (3–5 mg/kg/day, up to 81 mg once daily) is recommended in all MIS-C patients without active bleeding or significant bleeding risk
          • ASA should be continued until normalization of the platelet count and confirmed normal coronary arteries at ≥4 weeks after diagnosis
          • Anti-acid treatments should be used to prevent gastrointestinal complications in MIS-C patients taking steroids and ASA
      • Enoxaparin (anti–factor Xa level 0.5–1.0) 
          • For patients with a coronary artery z-score ≥ 10.0 for at least 2 weeks and then can be transitioned to warfarin or a direct-acting oral anticoagulant
          • Consider for moderate to severe LV dysfunction (EF <35%)

Management of MIS-C is generally done in the inpatient setting, although there might be some well-appearing children who can be managed in outpatient setting with close clinical follow-up.

Refractory disease: persistent fevers and/or significant end-organ involvement after 24 hours of completing initial immunomodulatory therapy

  • Second line: in refractory disease intensification therapy is recommended with either high-dose (10–30 mg/kg/day) glucocorticoids, anakinra, or infliximab >> these therapies are generally based on a case by case basis
    • High-dose anakinra, a recombinant human IL-1 receptor antagonist, can be considered (>4 mg/kg/day and often 5–10 mg/kg/day)
    • Infliximab (TNF inhibitor) may also be used  

References:

A key point that Alice mentioned is that MIS-C is a multisystem disease that requires multidisciplinary care coordination!

 This is variable by center, but generally will include: emergency medicine and general pediatrics teams, rheumatology, cardiology, intensivists, hematologists, neurologists, and of course, ID!

*MIS-C evaluation and management will be variable between clinicians and centers.  For some examples of prior/current MIS-C evaluation pathways, you can view some examples here:

Follow up & Outcomes

Some epidemiology notes

Incidence

  • MIS-C still appears to be a relatively rare complication of SARS-CoV-2 infection in children
  • In the United States, April to June 2020 the incidence of MIS-C was about 316 per 1,000,000 SARS-CoV-2 infections

Age

  • MIS-C has generally been noted in older children and adolescents
  • The median age of patients with MIS-C is 9 years with half of children between the ages of 5 and 13 years

Sex

  • 61% of reported patients are male

Ethnicity 

  • 57% of the reported patients with race/ethnicity information available (N=8,143) occurred in children who are Hispanic/Latino (2,145 patients) or Black, Non-Hispanic (2,489 patients)

SARS-CoV-2 variant

  • In Southeast England, MIS-C rates per confirmed SARS-CoV-2 infections in 0-16 years-old’s were 56% lower during pre-vaccine Delta, 66% lower during post-vaccine Delta, and 95% lower during the Omicron period1

Recurrence

  • Recurrent KD is 1.7% for European populations and 3.5% for Asian populations
  • There are no reported cases of recurrent MIS-C however there is a reported case of a patient with MIS-C who developed reinfection with SARS-CoV-2 and did not develop MIS-C a second time

Additional references

MIS-A

As of about June 2021, 221 cases of MIS-A had been reported

Patel P, DeCuir J, Abrams J, Campbell AP, Godfred-Cato S, Belay ED. Clinical Characteristics of Multisystem Inflammatory Syndrome in Adults: A Systematic Review. JAMA Netw Open. Sep 01 2021;4(9):e2126456. doi:10.1001/jamanetworkopen.2021.26456

Vaccination/prevention

Episode Art & Infographics

Infographics

Find all the Febrile infographics here!

Goal

Listeners will be able to understand the epidemiology, diagnosis, and management of multisystem inflammatory syndrome in children (MIS-C) after SARS-CoV-2 infection

Learning Objectives

After listening to this episode, listeners will be able to:

  • Identify typical components of MIS-C case definition (such as CDC case definition)
  • Compare and contrast the signs and symptoms of MIS-C with Kawasaki disease
  • Describe the evidence and strategies for management of MIS-C

Disclosures

Our guest (Alice Sato) as well as Febrile podcast and hosts report no relevant financial disclosures

Citation

Sato, A.., McCluskey, J., Dong, S. “#55: A MIS-Chievous Case”. Febrile: A Cultured Podcast. https://player.captivate.fm/episode/e7a7ec6d-2119-4342-96cb-267de816e05a

Transcript

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