What is Multisystem Inflammatory Syndrome in Children (MIS-C)?
Multisystem inflammatory syndrome in children (MIS-C) is a rare condition associated with COVID-19. Evidence supports that MIS-C is a post-infectious illness, occurring between two to six weeks following SARS-CoV-2 infection. A child can develop MIS-C regardless if their acute infection was asymptomatic or symptomatic.

# What are the Features of MIS-C?
The case definition of a person under investigation or a confirmed case of MIS-C used in B.C. is adapted from the case definition developed by the World Health Organization (see appendix A).
There is likely a spectrum of disease severity and phenotypes in children affected by MIS-C. However, the majority of children with MIS-C are usually sick enough to require hospitalization and, often, intensive care. Children with MIS-C may initially present with mild symptoms, which can progress quickly. Presenting symptoms usually reflect systemic inflammation and often have similarities to Kawasaki disease (KD), toxic shock syndrome (TSS) and macrophage activation syndrome. Prominent features include:  

# When to Consider MIS-C?
There should be a low threshold to consider and evaluate for MIS-C in children who present with unexplained fever for three days or more, even if they are well-appearing on initial presentation and especially within two months following a known COVID-19 infection or exposure. The initial infection with SARS-CoV2 may have been asymptomatic, therefore, MIS-C should still be considered in children without a previous history of infectious symptoms. 

# Treatment
The management of MIS-C differs from that of severe acute COVID-19. Severe acute COVID-19 infection remains rare in pediatrics and any suspected cases of COVID-19 should be discussed with specialists at BCCH as this is a separate entity from MIS-C but may require active therapy.
Evidence for the optimal management of MIS-C should be guided by these specialists. The majority of children require early fluid resuscitation. The mainstay of treatment has been early use of intravenous immunoglobulin (IVIg) with or without intravenous steroids. Some children have required immunomodulatory therapy (biologic treatments) for refractory symptoms as guided by a rheumatologist. Low dose aspirin is recommended in children with MIS-C who have features of KD or coronary aneurysms seen on echocardiogram, in consultation with rheumatology. Even with treatment, children with MIS-C require serial monitoring of clinical and laboratory parameters, cardiac imaging and close follow up post-discharge (see disposition section).

# Disposition
All follow up appointments should be made and clearly communicated to families prior to discharge. Discharge documentations should be sent to all relevant specialist involved in the patient's care. The longterm sequalae of MIS-C is still unknown but being studied.
- Primary care provider: All patients evaluated for MIS-C should be seen by their primary care provider within one week of discharge, regardless if they were a confirmed case or not.  Pediatrics: Children hospitalized with MIS-C should be referred to a pediatrician on discharge for follow up. For those with abnormal inflammatory markers or laboratory findings at discharge, repeat bloodwork should be considered prior to this visit.  Cardiology: Confirmed cases of MIS-C will require a repeat echocardiogram, typically four to six weeks after discharge, as guided by cardiology.  Rheumatology: Follow up will depend on the severity of illness and discharge medications, as guided by rheumatology.
- Haematology: For children who were started on prophylactic/therapeutic anticoagulation in hospital, the dose and duration of therapy should be clearly communicated to the family prior to discharge, if applicable. Follow up will be guided by haematology.  Mental health: Families with children who were hospitalized for MIS-C should be offered mental health support in the community as needed.  Others: Follow up with other specialties (e.g., neurology, immunology) will depend on their clinical features and course in hospital.  Return to emergency department: Families should be counselled on when to bring their child back to the emergency department. Reasons to return include: o Persisting fever > 38 degrees Celsius. o Recurrence of presenting symptoms or child becomes unwell with other symptoms. o New appearance of respiratory distress or shortness of breath.
Appendix A: Case Definition for MIS-C

# Confirmed case
Children 0-19 years of age requiring hospitalization with fever for three days or more and two of the following: a) Acute gastrointestinal symptoms (abdominal pain, vomiting, diarrhea); b) Rash or bilateral non-purulent conjunctivitis or muco-cutaneous inflammation signs (oral, hands or feet); c) Hypotension or shock; d) Features of myocardial dysfunction or pericarditis or valvulitis or coronary abnormalities: ECHO findings or elevated troponin/ brain natriuretic peptide (BNP)/ natriuretic peptide tests (NT-proBNP); e) Evidence of coagulopathy: Abnormal prothrombin time/ partial thromboplastin time (PT/PTT), elevated d-dimer;

# And
Elevated markers of inflammation such as erythrocyte sedimentation rate, C-reactive protein, or procalcitonin;

# And
No other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes, and no alternative plausible obvious diagnosis;

# And
Evidence of SARS-CoV-2 infection (positive NAAT test, antigen test and/or serology) or close contact 1 with a confirmed or probable (lab-probable or epi-link probable) COVID-19 case. 2

# Appendix B: Full MIS-C Evaluation
To be performed in addition to workup of alternative diagnosis, including sepsis.
- Complete blood count (CBC) with differential.
- Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP).
- Electrolytes, blood urea nitrogen (BUN), creatinine.
- Liver function tests (LFTs), lactate dehydrogenase (LDH), albumin.
- Ferritin, d-dimer, prothrombin time/ partial thromboplastin time (PT/PTT).
- Troponin, brain natriuretic peptide (BNP).
- Urinalysis.
- SARS-CoV-2 testing: o SARS CoV-2 polymerase chain reaction (PCR): Respiratory (nasopharyngeal swab/saline gargle/ sputum/ bronchoalveolar lavage); o SARS CoV2 antigen o SARS CoV-2 serology: Contact local medical microbiology on call for approval and fill out serology request form. Obtain serology pre-IVIG whenever possible. - Type and Screen (for those receiving IVIG).
- Electrocardiogram (EKG).
- Chest X-ray (CXR).
- Echocardiogram.
- Consider all usual bacterial or viral illnesses and alternative diagnoses and test as appropriate (e.g., cultures, other infectious studies).
For further clinical guidance on COVID-19 in children, see Clinical Reference Group Recommendation: Pediatric Clinical Guidance for COVID-19.