Multisystem Inflammatory Syndrome in Children U10.-; U10.9;

MIS-C is the acronym for "Multisystem Inflammatory Syndrome in Children" and refers to a new disease that can occur in children and adolescents 2 to 4 weeks after a COVID-19 infection.

The World Health Organization (WHO) has developed its own criteria that must be met in order for a diagnosis of MIS-C to be made. These criteria include six points:

• Age 0-19 years
• Fever for at least three days
• signs of disease in at least two different organs (skin/mucous membranes/eyes, hypotension low blood pressure or shock, heart disease, blood clotting disorders, acute gastrointestinal symptoms)
• elevated inflammation levels
• no other more likely explanation
• Evidence of coronavirus infection, either by detection of the virus, determination of antibodies, or contact with an infected person.

MIS-C is a rare disease. The first cases were described in the UK in March 2020. Similar case reports subsequently occurred in countries with high COVID-19 case rates. In the US, 570 cases were recorded in the period from March to July 2020. Increasingly clustered cases are occurring in Europe. In a larger case series, the median age of patients was 11 years (8-14years).

MIS-C occurs in association with SARS-CoV-2 infection, even when affected children and adolescents have not shown symptoms of COVID-19. Why the syndrome develops is not known. It is thought that the body's immune response to the SARS-CoV-2 coronavirus overreacts and initiates a general inflammatory process (Rowley AH 2020).

M:w=7:3; patients belonging to an ethnic minority (78%) were overrepresented (Davies P et al 2020).

Admissions were made under the following diagnoses: gastroenteritis (33%), sepsis (24% ), sepsis-like illness (20%), fever of unknown etiology (FUO) (16%). In the relevant clinical studies, all affected children were characterized by markedly reduced AZ at the time of hospitalization. They were hypotensive, tachycardic, dyspneic with clouding of consciousness. There had been fever for at least three days; furthermore, almost all affected complained of gastrointestinal complaints such as abdominal pain, nausea or diarrhea. About half of them showed macular exanthema, enanthema and a distinct conjunctivitis. Furthermore, lymph node swelling was found. Summary case reviews revealed the following symptoms (Riphagen S et al 2020, Rowley AH 2020, Toubiana J et al 2020, Whittaker E et al 2020):

• Fever (100%)
• hypotension to shock (87 %)
• abdominal pain (62 %)
• vomiting (63 %)
• Diarrhoea (64 %)
• Exanthema (52 %)
• Conjunctivitis (45 % )

The diagnosis is made on the basis of the WHO criteria. Other severe diseases that may cause similar symptoms, such as sepsis, intestinal infections and severe cardiac or pulmonary diseases of other etiologies, are excluded.

Elevated troponin, natriuretic peptide type B, C-reactive protein, ferritin, lactate dehydrogenase and D-dimers as well as neutrophil granulocytes, interleukin 6 and 17 and interferon gamma. Furthermore: anemia, lymphopenia, hypoalbuminemia and abnormal coagulation indices.

SARS-CoV-2 polymerase chain reaction test results were positive in 26 %); SARS-CoV-2 IgG test results were positive in 87 %. Overall, 78% had evidence of current or previous SARS-CoV-2 infection. (Whittaker E et al. 2020)

• Kawasaki disease
• Hemophagocytic lymphohistiocytosis
• Toxic shock syndrome

• Macrophage activation syndrome

In the study, 29 of 58 children developed shock (with biochemical evidence of myocardial dysfunction); they require inotropic support and mechanical ventilation if necessary. In 14 % of the cases evidence of coronary artery dilatations or an aneurysm (Whittaker E et al. 2020).

In many ways, MIS-C is similar to Kawasaki syndrome. Nearly half of patients with MIS-C also meet criteria for Kawasaki syndrome. Treatment of MIS-C is aimed at curbing the excessive response of the immune system:

• Glucocorticoids

Further (anbalogous to Kawasaki syndrome):

• intravenous immunoglobulins
• Acetylsalicylic acid
• Alternatively or complementarily: cytokine antagonists.
• About one in four patients requires intensive care. In rare cases, affected individuals also require artificial respiration (Whittaker E et al 2020).

The outcome of the patient is favorable, sequelae (especially cardiovascular) are observed in <10% of cases. Fatal courses are rare.

1. Davies P et al. (2020) Intensive care admissions of children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the UK: a multicentre observational study. Lancet Child Adolesc Health 4:669-677.
2. German Society for Paediatric Infectiology, e.V. Homepage
3. Dufort EM et al. Multisystem inflammatory syndrome in children in New York State. N Engl J Med 2020;383:347-58.
4. Feldstein LR et al.(2020) Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med 383:334-46.
5. Lami F et al.(2020) The "perfect" storm: Current evidence on pediatric inflammatory multisystem disease during SARS-CoV-2 pandemic. Acta Biomed 91:e2020034.
6. Levin M (2020) Childhood multisystem inflammatory syndrome - a new challenge in the pandemic. N Engl J Med 383:393-395.
7. Morris SB et al.(2020) Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection - United Kingdom and United States, March-August 2020. MMWR Morb Mortal Wkly Rep. ePub: 2 October 2020.
8. Riphagen S et al (2020) Hyperinflammatory shock in children during COVID-19 pandemic. Lancet 395:1607-1608.
9. Rowley AH (2020) Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children. Nat Rev Immunol 20:453-454.
10. Toubiana J et al. (2020) Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study. BMJ 369:m2094.
11. Whittaker E et al. (2020) PIMS-TS Study Group and EUCLIDS and PERFORM Consortia. Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2. JAMA 324: 259-269.