November 2020:
Multisystem inflammatory syndrome in children (MIS-C)

by Donna Castellone, MS, MT (ASCP) SH • November 11, 2020

The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.


An autoimmune disorder that triggered Kawasaki syndrome was discovered in January 1967 in Tokyo. One theory included an infective trigger to a superantigen. It was found that this affected children under the age of 5, predominantly boys. It's annual incidence is 10-100/100,000 children.(1) Children so far have fortunately not been very affected by COVID-19 and have comprised 1.7-2% of national cases. They present as either asymptomatic or mild symptoms.(2)

The WHO reported a Kawasaki disease (KD) and toxic shock (TSS) like syndrome emerging in Europe and North American in children which appeared to be related to them being exposed to COVID-19 and occurred after up to 3 weeks post infection or exposure. This was defined as Multisystem Inflammatory syndrome (MIS-C).(1)(3) Diagnosis of this disorder is difficult since it shares similarities with toxic shock and Kawasaki disease.

There is no specific test that confirms Kawasaki disease, but it is based on clinical symptoms, blood tests and echo cardiogram of the heart. Patients present with erythema, rash, swelling and redness of hands and feet, conjunctivitis and swelling of the lymph nodes.

The presentation of MIS-C occurs several weeks post infection and PCR COVID-19 tests may be negative, but positive for the antibodies. This supports the theory that it is not an acute infection of the virus but a hyper inflammatory response of the body that leads to the involvement of multiple organs including the heart. Children affected are between 5-15 years of age and presented with a fever for 3 days, symptoms resembling Kawasaki disease including rash, conjunctivitis, GI pain including vomiting, low blood pressure, neck pain, and the ability to affect different organs including the heart. Treatment is aimed at reducing the inflammatory response, these medications include steroids, immunoglobulins, antibiotics and immune modulators.(4)


Laboratory Evidence:
Markers of hyperinflammation are pronounced in this syndrome. These include elevated ESR, CRP, procalcitonin, ferritin and IL6. Thromboembolic events are rare. Patients present with increased levels of D-dimer and fibrinogen relative to inflammation. Also elevated are white blood cells with high numbers of neutrophils with many mature forms with lymphopenia. RBCs and platelet count may be either normal or decreased. Acute kidney injury and low albumin levels are common.(5) Raised IL-6 levels indicate a post-infectious response to COVID-19 and it is a pro-inflammatory cytokine in the pathogenesis of KD as well as an independent risk for the development of coronary lesions. TNF-α is a well established pro-inflammatory cytokine that occurs in both chronic and acute inflammatory responses and in viral infection is released by natural killer cells and macrophages. Increased levels in COVID-19 patients can correlate with worse prognosis.(6) It is very important to note MIS-C patients will most likely test negative for RT-PCR testing since this is a post infection disorder. Testing for the development of antibodies is an important test that will indicate post exposure to COVID-19.


Distinguishing between Kawasaki and MIS-C
Initially, there was a challenge in differentiating patients with MIS-C versus Kawasaki disease or toxic shock syndrome. There are several characteristic laboratory findings that can distinguish MIS-C from KD which include findings of ventricular natriuretic peptide, higher CRP levels and very high troponin levels which can suggest myocardial damage.(7) KD is a vasculitis that presents with high fever and acute mucocutaneous inflammation and is typically self limiting but may be complicated with myocardial dysfunction and thrombotic events. TSS is a lethal disease as a result of the release of bacterial toxins, it is treated by hemodynamic stabilization and antibiotics.(8)

A proposed theory to distinguish between KD and MIS-C may be the platelet count. When compared KD to TSS, patients with TSS had significantly lower platelet counts (188 vs 383 g/L). This may be due to the difference in underlying immunopathogenesis. In KD the fundamental pathogenesis is thought to be immune complex mediated. When treated with IVIg it will compete with immunoglobulin Fc receptors on inflammatory cells preventing activation of these cells. If left untreated, these cells are activated and recruit platelets resulting in thrombocytosis which is seen in KD. When a viral associated hyperinflammatory response such as MIS-C, mediators are being secreted to eliminate the virus. This results in bone marrow suppression resulting in thrombocytopenia.(9)


It is very important for clinicians and parents to be aware of MIS-C syndrome as a result of COVID-19. Understanding the difference between KD and MIS-C and the absence of a positive PCR COVID-19 test but a positive antibody test is critical in the diagnosis of this disorder.


  1. What is multisystem inflammatory syndrome in children (MIS-C) and how is it linked to COVID-19? May 2020
  2. Multisystem inflammatory syndrome in Children associated with Covid-19 May 2020
  4. Multisystem inflammatory disease in children.,pain%2C%20rash%2C%20bloodshot%20eyes%2C%20or%20
  5. Viner, RM., Whittaker, E., Kawasaki- like disease: emerging complication during the COVID 19 Pandemic, Lancet, VOL 395 June 2020
  6. Sperotto, F., Friedman, K. G., Son, M., VanderPluym, C. J., Newburger, J. W., & Dionne, A. (2020). Cardiac manifestations in SARS-CoV-2-associated multisystem inflammatory syndrome in children: a comprehensive review and proposed clinical approach. European journal of pediatrics, 1–16. Advance online publication.
  7. De Paulis, Milena,O., Danielle B., Vieira, RP., Pinto, IC., etal. Multisystem Inflammatory Syndrome Associated With COVID-19 With Neurologic Manifestations in a Child: A Brief Report. The Pediatric Infectious Disease Journal: October 2020 - Volume 39 - Issue 10.
  8. Rajapakse, N., Dixit, D., Human and novel coronavirus infections in children: a review. Pediatric and Internation Child Health, June 2020.
  9. M. Ahmed et al. Multisymptom Inflammatory Response: A systematic review EClinicalMedicine 26 (2020)
  10. Yeo, WS., NG., QS, Distinguishing between typical Kawasaki disease and multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2, Medical Hypotheses 144 (2020)