The isolation of RNA from SARS-CoV-2 was measured through RT-PCR and serological assays that measured the concentration of circulating IgG, IgM and IgA antibodies. Epidemiological protocols, including contact tracing, were also performed. 

Tulane University

This systematic review of 953 MIS-C cases compiles data regarding epidemiological risk factors of disease and common clinical manifestations. After analyzing the case studies, the authors argued for the WHO case definition of MIS-C as it best represented the longitudinal research. 


Systematic Review of 953 MIS-C Cases 

Hoste, L., Van Paemel, R., & Haerynck, F. (2021). Multisystem inflammatory syndrome in children related to COVID-19: a systematic review. European journal of pediatrics, 180(7), 2019–2034. https://doi.org/10.1007/s00431-021-03993-5

Multisystem inflammatory syndrome in children related to COVID-19: a systematic review

Severe Covid-19 disease is associated with well-documented comorbidities, like age, cardiovascular and respiratory diseases. However, SARS-CoV-2 infections in children has been described as relatively benign, resulting in minimal hospitalizations and a low mortality rate. Since the beginning of the pandemic, hospitals within Europe and North America have recorded cases of multisystem inflammatory disease in pediatric patients with or previously exposed to Covid-19. Early descriptions have included a wide variety of clinical symptoms, which overlap with other inflammatory conditions like Kawasaki disease and toxic shock syndrome. Nevertheless, MIS-C is a unique condition in which a significant proportion of patients are affected by severe or fatal disease. 

The Origin of MIS-C

Numerous clinical symptoms, encompassing a wide spectrum of organ systems, are associated with MIS-C. The clinical heterogeneity has made diagnoses difficult and misdiagnoses a frequent event. This review has compiled a list of clinical manifestations that a majority of MIS-C patients presented. 
- Fever (922/928; 99.4%)
- Gastrointestinal symptoms (598/699; 85.6%)
- Abdominal pain (315/539; 58.4%)
- Vomiting (306/532; 57.5%)
- Diarrhea (268/532; 50.4%)
- Cardiovascular symptoms (307/387; 79.3%)
- Tachycardia (194/253: 76.7%)
- Hypotension (416/695; 59.9%)
- Myocarditis (128/309; 41.4%)
- Pericardial Effusion (114/511; 22.3%)
- Respiratory Symptoms (295/587; 50.3%)
- Upper respiratory tract symptoms (95/397; 23.9%)
- Dyspnea (101/378; 26.7%)


Clinical Manifestations Recorded by the Review

SARS-CoV-2 Testing & Diagnostic Criteria

The WHO case definition, which aids clinician in diagnosing MIS-C, comprehensively covered the clinical manifestations of the disease and relationship with SARS-CoV-2. Using the definition to detect MIS-C cases within the records, only 4 mild cases were missed by researchers. However, these 4 cases did not present with multisystem inflammation, a key factor of MIS-C defined by the WHO. 
The case definition from the CDC was only relevant to 62% of cases. 31 cases were missed by the authors due to the lack of multi-organ dysfunction, failing to achieve the CDC diagnostic criteria.


Case Definitions of MIS-C

3/4ths of patients were given intravenous immunoglobulins to support the immune system. Corticosteroids, effective at reducing inflammation, were prescribed in 516 cases out of the 908 studied. Heparin was an anti-thrombotic that was used to reduce the likelihood of thromboses. Treatments that inhibit the innate immune system, specifically cytokine signaling pathways, were prescribed, including: 
- Anakinra (IL-1R inhibitor)
- IL-6 inhibitors (tocilizumab, siltuximab)
- TNFɑ inhibitors (infliximab)
Certain patients had to receive mechanical and non-invasive ventilation due to severe pulmonary inflammation. 


Therapeutic Management of Disease

73.3% of recorded cases were characterized by intensive care treatment, with a median duration of stay of 4 days and a median hospitalization stay of 8 days. 86% of cases experienced severe disease; however, the patients were generally older and suffered from more gastrointestinal and cardiovascular symptoms than a mild course of MIS-C. Laboratory tests done in patients with severe manifestations of MIS-C showed lower WBC counts; increased lymphopenia; higher CRP and ferritin; higher platelet counts, D-dimer and troponin. Of the eighteen deaths reported, 16.7% were patients less than 1 year old, 50% were between the ages of 5-12, and 33.3% were older than 13 years. The majority of patients were male (72.3%) and Black (62.5%). Comorbidities exacerbating fatal cases included obesity, acute leukemia, glucose-6-phosphate dehydrogenase deficiency, asthma and certain neurological conditions. 

Prognosis & Outcomes 

In a study of 186 pediatric patients with MIS-C in 26 states, KD–like features were documented in 74 patients (40%), but 60% of those patients would not have met the complete or incomplete criteria for KD. KD usually affects children under the age of 5. On the other hand, MIS-C has been suggested to affect adolescents and children older than 5 years old. MIS-C also has different cardiovascular involvement compared with KD.

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