Multisystem Inflammatory Syndrome in Children (MIS-C)

MIS-C is a rare multisystem inflammatory condition that affects children & adolescents. It is associated with exposure to SARS-CoV-2 (COVID-19) and is similar to Kawasaki disease.

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What is MIS-C?

Multisystem inflammatory syndrome in children (MIS-C) is a rare systemic inflammatory disease that affects children & adolescents and is linked to COVID-19.

In the UK and Europe, the condition is referred to as pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), whereas in the US it is referred to as MIS-C. The World Health Organisation refers to it as a pediatric multisystem inflammatory syndrome (PMIS).

MIS-C/PIMS-TS is very similar to Kawasaki disease. Kawasaki disease is a rare disease that affects children under the age of 5 primarily and is characterized by a fever that can last around 5 days alongside a bodily rash, swollen glands, red fingers & toes, and red eyes.

It is not transmissible between individuals. However, MIS-C/PIMS-TS also shares clinical and pathological features with other pediatric inflammatory syndromes that are non-Kawasaki.

MIS-C/PIMS-TS tends to affect a very small population of children and adolescents between the ages of 0 and 19 years of age, whereas Kawasaki disease affects children around the age of 4-5 years. So far, only a relatively few cases have been reported in the UK, France, Italy, and the US (to date).

What are the Symptoms and Features of MIS-C?

The symptoms of MIS-C/PIMS-TS match many features of Kawasaki disease, but also symptoms of other pediatric inflammatory conditions including toxic shock syndrome, septic shock, and macrophage activation syndrome.

According to the World Health Organisation (WHO), the main features of MIS-C/PIMS-TS include 2 or more of the following:

• Fever that persists longer than 3 days
• A rash present on the face, hands or feet
• Hypotension (low blood pressure)
• Myocardial dysfunction – myocarditis, pericarditis or valvulitis
• Gastrointestinal problems – abdominal pain, diarrhea and vomiting

According to the CDC (US), other symptoms may include neck pain, bloodshot eyes (conjunctivitis), and feeling of fatigue. If symptoms are severe, including trouble breathing, pain in the chest that does not go away, confusion, blue lips, or face, then emergency care is required urgently.

Symptoms may present alongside COVID-19 or may develop a few weeks after an initial COVID-19 (SARS-CoV-2) infection, thus the name ‘temporally associated with SARS-CoV-2 (TS)”. For a diagnosis to be made, evidence of COVID-19 by PCR/antigen test is made. In some cases, there may not be any positive tests for SARS-CoV-2, but it may be associated with close contact with COVID-19 patients.

The clinical & pathological features of MIS-C/PIMS-TS tend to have:

• Elevates serum markers of inflammation – CRP & ESR
• High levels of fibrinogen, D-dimers (coagulopathy), troponin and ferritin
• No underlying microbial cause of inflammation e.g. bacterial sepsis
• Cytokine storm with high serum IL-6 levels
• Multisystem involvement (>2 organs) e.g. cardiac, renal, respiratory, hematological, gastrointestinal, dermatological or neurological
• Cardiac involvement with features of macrophage activation syndrome – abnormal ECG and CT scans (coronary artery dilatation)
• Leukopenia – reduced number of leukocytes (white blood cells)

In some affected children, recovery is spontaneous if the condition is not too severe. However, if the condition is moderate-severe and includes features of toxic shock syndrome, severe hypotension, and coronary arterial aneurysm development, then emergency admission to a pediatric intensive care unit is urgently required.

Furthermore, the highest prevalence of MIS-C/PIMS-TS seems to be in those with Afro-Caribbean descent, as well as those with African American, Caribbean, and Hispanic ancestry. To date, no (or very limited) cases have been reported in many Asian countries with a high COVID-19 epidemic.

However, Kawasaki disease is more prevalent in Asian countries such as Japan and South Korea. Socioeconomic and environmental factors also need to be considered for the high prevalence amongst certain demographics.

What Causes MIS-C?

MIS-C/PIMS-TS was first reported in the UK, Italy, and France, and cases were reported during a high prevalence of the COVID-19 epidemic. Thus, scientists and clinicians initially thought it was associated with the presence of SARS-CoV-2. MIS-C/PIMS-TS is associated with a positive SARS-CoV-2 (COVID-19) infection.

Much like Kawasaki disease, the exact cause of the disease is still unknown – though it is thought to be an autoimmune/autoinflammatory response to SARS-CoV-2 infection. Most affected children will have IgG antibodies against SARS-CoV-2 (~90% in one study) or have had a positive PCR test. The risk to children overall is very low, even with a positive COVID-19 result.

Some scientists have suggested that a cytokine storm may be critical in the development of MIS-C/PIMS-TS. Coronaviruses are known to inhibit type I and III interferons – thus suggesting why MIS-C/PIMS-TS develops in a delayed manner post-SARS-CoV-2 infection.

Those with an abnormally high initial viral load may be more susceptible to developing a cytokine storm. Furthermore, SARS-CoV-2 also infects gastrointestinal epithelia, and the condition may be due to mesenteric lymph node inflammation.

In most cases, MIS-C/PIMS-TS occurs weeks after a SARS-CoV-2 infection (COVID-19) and is thought to be a delayed post-viral immunological reaction in those with a potential genetic predisposition to such.

A diagnosis will usually be made by taking blood tests to look at serum levels of inflammatory markers, as well as cardiac ultrasounds (ECHO), chest X-rays, and testing for a positive SARS-CoV-2 infection.

Although most cases have a positive SARS-CoV-2 IgG test or positive PCR test, there may be some rare cases not associated with any positive SARS-CoV-2 result. In such cases where clinical symptoms appear, all other forms of microbial infection must be excluded.

It is important to note that we are still learning about MIS-C/PIMS-TS and how COVID-19 leads to the condition, and the exact cause of the condition is still unknown. Furthermore, a key question is why does the condition lead to a Kawasaki-like syndrome.

Over time with more cases and research, the exact biological mechanisms may become more apparent and pave way for more robust therapeutic options.

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How is MIS-C Treated?

Treatment strategies currently depend on the clinical presentation and severity of the disease; however, many will undergo intravenous immunoglobulin therapy and/or the administration of corticosteroids. Doing so results in a clinically favorable outcome in all patients in one French study (published in BMJ).

Many children will need to be admitted to a pediatric intensive care unit to undergo stronger therapy, however, discharge rates are very high. Those that also develop shock syndrome may need fluid resuscitation and vasoactive agents due to sustained hypotensive shock.

Those with cardiac dysfunction (myocarditis), inotropic agents may be given. Those with the most severe respiratory symptoms may need mechanical ventilation or oxygen therapy and tend to have higher systemic inflammation markers than those not needing ventilation.

In summary, MIS-C (PIMS-TS) is a rare multisystem inflammatory condition that affects children and adolescents aged 0 to 19 years who have tested positive for COVID-19 (SARS-CoV-2 infection).

Clinical features are similar to Kawasaki disease, but children also exhibit other symptoms related to other pediatric inflammatory syndromes. In some cases, spontaneous recovery can be made, but in others with more severe symptoms, hospital admission is required to combat the inflammation and cardiac complications that may occur.  

Further Reading

• All Coronavirus Disease COVID-19 Content
• What Mutations of SARS-CoV-2 are Causing Concern?
• What is the Clinical Impact of COVID-19 on Cancer Patients?
• Can Pets Get COVID-19?
• An Overview of the SARS-CoV-2 Vaccines

Written by

Osman Shabir

Osman is a Neuroscience PhD Research Student at the University of Sheffield studying the impact of cardiovascular disease and Alzheimer's disease on neurovascular coupling using pre-clinical models and neuroimaging techniques.