COVID-19-associated multisystem inflammatory syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Harmeet Kharoud M.D.[2]

Synonyms and keywords: Multisystem Inflammatory Syndrome in Children (MIS-C)

Overview

Multisystem Inflammatory Syndrome in Children (MIS-C) is a condition that causes inflammation of some parts of the body like heart, blood vessels, kidneys, digestive system, brain, skin, or eyes. According to recent evidence, it is suggested that children with MIS-C had antibodies against COVID-19 suggesting children had COVID-19 infection in the past. This syndrome appears to be similar in presentation to Kawasaki disease, hence also called Kawasaki -like a disease. It also shares features with staphylococcal and streptococcal toxic shock syndromes, bacterial sepsis, and macrophage activation syndromes.

Classification of Disease Severity of MIS-C

• Mild Disease
• Children with MIS-C fall under this category who-
  • require minimal to no respiratory support.
  • minimal to no organ injury
  • normotensive
  • Do not meet the criteria for ICU admission.
• Severe Disease
• Children with MIS-C fall under this category who-
  • have significant oxygen requirements (HFNC, BiPAP, mechanical ventilation).
  • have a mild-severe organ injury and ventricular dysfunction.
  • have a vasoactive requirement.
  • meet the criteria for ICU admissions

Pathophysiology

• The excat pathophysiological mechanism of MIS-C is unclear. Since there is a lag time between MIS-C appearance and COVID-19 infection it is suspected to be causing by antibody dependent enhancement.
• Another hypothesis is that since coronavirus block type1 and type III interferons, it results in delayed cytokine response in children with initially high viral load or whose immune response is unable to control infections causing MIS-C. Therefore, IFN responses result in viral clearance when the viral load is low resulting in mild infection. However, when the viral load is high and /or immune system is not able to clear the virus, the cytokine storm result in multisystem inflammatory syndrome in children (MIS-C).
• It is also suspected that since MIS-C presents predominantly with gastrointestinal manifestations, it replicates predominantly in the gastrointestinal tract.

Differentiating Any Disease from other disease

It should be differentiated from following diseases

• Bacterial sepsis
• Staphylococcal and streptococcal toxic shock syndrome
• Kawasaki disease.
• More information about the differential diagnosis could be found here.

Epidemiology and Demographics

• According to a recent study among the 186 children with MIS-C, the rate of hospitalization was 12% between March 16 and April 15 and 88% between April 16 and May 20.
• 80% of the children were admitted to the intensive care unit and 20% of the children required mechanical ventilation.
• 4% of the children required extracorporeal membrane oxygenation.
• The mortality rate among 186 children with MIS-C was 2%.

Age

• Among the 186 children with MIS-C distribution of age group was
  • <1yr-7%
  • 1-4yr-28%
  • 5-9yr-25%
  • 10-14yr-24%
  • 15-20yr-16%.

Gender

• Among the 186 children with MIS-C

Comorbidities

• Children with MIS-C had following underlying comorbidities.
  • Clinically diagnosed Obesity-8%
  • BMI-Based Obesity-29%
  • Cardiovascular diasease-3%
  • Respiratory disease-18%
  • Autoimmune disease or immunocompromising condition-5%

Organ System Involved

• 71% of children had involvement of at least four organ systems.

The most common organ system involved in MIS-C children among a total of 186 children were.

• Gastrointestinal(92%)
• Cardiovascular(80%)
• Hematologic(76%)
• Mucocutaneous(74%)
• Pulmonary(70%)
• Historical perspective

Complications and Prognosis

Complications

• Severe myocardial infarction
• Cardiac failure/arrest
• ARDS
• Hypervolemia
• Acute Kidney Injury
• Peritonitis
• Thrombotic complications.

Diagnosis

Diagnostic Criteria

In May 2020, the Centers for Disease Control and Prevention (CDC) set the criteria for multisystem inflammatory syndrome in children (MIS-C):

• Severe disease course leading to hospitalization
• Individuals younger than 21 years old
• Fever (body temperature, >38.0°C) or report of subjective fever present at least 24 hours
• Laboratory evidence of inflammation
• Multisystem organ involvement (at least two systems)
• Laboratory-confirmed SARS-CoV-2 infection

History and Symptoms

COVID-19 associated multisystem inflammatory syndrome is associated with the following symptoms:

• Fever lasting 24 hours or longer.
• Vomiting
• Diarrhea
• Abdominal pain
• Difficulty Breathing
• Chest pain
• Headache
• Sore throat
• New onset confusion

Physical Examination

COVID-19 associated multisystem inflammatory syndrome is associated with the following physical examination findings:

• Skin rash
• Conjuctivitis
• Redness or swelling of the lips and tongue
• Redness or swelling of the hands or feet
• Lymphadenopathy
• Lethargy
• Cyanosis

Laboratory Findings

COVID-19 associated multisystem inflammatory syndrome is associated with the following laboratory findings:

• High ESR
• Lymphopenia
• Neutrophilia
• Anemia
• Thrombocytopenia

Less common laboratory findings include:

• Abnormal fibrinogen
• Hypoalbuminaemia
• Elevated creatiine kinase (CK)
• Elevated LDH
• Elevated triglycerides

Inflammatory biomarkers

Elevation of inflammatory markers including ESR, C reactive protein, and procalcitonin are usually seen in MIS-C. Increased level of Interleukin-6 (IL-6), Interleukin-10(IL-10) d-dimer, serum ferritin, prothrombin time have also been seen in MIS-C.

Cardiac biomarkers

Elevation of cardic enzymes including cardiac troponins (cardiac troponin I(cTnI) and cardiac troponin T (cTnT)) and Brain natriuretic peptide (BNP)) has been observed in MIS-C patients.

• To view the complete physical examination in COVID-19, click here.
• To view the laboratory findings on COVID-19, click here.

Treatment

Medical Therapy

• All the children with MIS-C are treated as suspected COVID-19.
• Mild to Moderate cases of MIS-C are managed supportively.
• Supplemental oxygen is required in children with low oxygen saturation.
• Fluid resuscitation in 10 ml/kg aliquots with reevaluation after each bolus. Maintain euvolemia. Avoid hypervolemia.
• Anti-inflammatory treatments with Intravenous immunoglobulin(IVIG) with or without corticosteroids have shown a good response rate.
• Aspirin has been used primarily for its antiplatelet effect. It is recommended in all patients with MIS-C.
• Anakinra is considered if fevers last more than 24 hours post steroids/IVIG or in the moderate or severe presentation.
• Tocilizumab is also considered if fevers last more than 24 hours post steroids/IVIG or in the moderate or severe presentation.
• Empiric antibiotics like vancomycin, ceftriaxone, and clindamycin are given for community-acquired shock presentation until cultures are negative for 48 hours.

Presentation	Treatment
Mild Disease	Symptomatic Treatment
Severe Disease	Symptomatic Treatment IVIG(IV) Corticosteroids(IV/PO) Consider adding Anakinra or Tocilizumab if fever persist for more than 24 hours post steroids and IVIG use.

Prevention of MIS-C

• MIS-C can be prevented by reducing the risk of child exposure to COVID-19 infection.