In early 2020, as people across the world became aware of and took precautions against COVID-19, the serious—sometimes fatal—disease caused by the SARS-CoV-2 coronavirus, many took a small measure of comfort in believing that children infected with the disease were left relatively unharmed.

But in late April 2020, physicians in Europe and the United States began to report a small but growing number of cases of children afflicted with a new multisystem inflammatory syndrome that appeared to be associated with COVID-19. Doctors began treating very sick children, many of whom tested positive for COVID-19, with some combination of fever, red eyes, swollen hands and feet, rash, and gastrointestinal problems, all of which are symptoms related to inflammation.

At first, doctors noted similarities between these symptoms and those associated with other inflammatory syndromes, such as Kawasaki disease and toxic shock syndrome. But as they began to see more of these children, they began to suspect they were seeing something different. The condition was first called PMIS (pediatric multisystem inflammatory syndrome) but is now officially known as multisystem inflammatory syndrome in children, or MIS-C. 

Because MIS-C has only recently been identified, the medical community is still trying to understand what causes it, as well as its long-term health consequences. And while it is now apparent that MIS-C is an inflammatory response to infection by SARS-CoV-2, the mechanism behind the development of the syndrome is not yet well understood. What is clear is that MIS-C is a serious health issue that requires prompt medical attention. Fortunately, it is also rare, and the vast majority of children affected by it survive.  

“This new entity seen in children is a severe post-infectious manifestation of the virus,” says Marietta Vázquez, MD, a Yale Medicine pediatric infectious disease specialist. “It calls for us to be vigilant to its presentation without panic, as it remains rare.”

MIS-C is a serious though rare condition in children in which the body’s own immune system overreacts to a SARS-CoV-2 infection, resulting in inflammation of multiple organ systems throughout the body. It can affect the heart, blood vessels, gastrointestinal organs, lungs and other respiratory organs, kidneys, skin, eyes, and nervous system, and it can lead to shock, impaired organ function, and even organ failure. In most cases, though, children experience inflammation in only a few of these organs.

MIS-C shows similarities to other known inflammatory disorders, including Kawasaki disease and toxic shock syndrome.

• Kawasaki disease is an inflammatory syndrome of unknown cause that mostly affects children, and is characterized by vasculitis, or inflammation of the blood vessels. It can cause fever, rash, red eyes, swollen hands and feet, swollen lymph nodes in the neck, and dry and red lips and tongue.
• Toxic shock syndrome is an inflammatory condition caused by a bacterial infection that, like MIS-C, can result in low blood pressure, fever, and rash.

According to Centers for Disease Control and Prevention (CDC), as of May 2021, there have been over 3,700 cases of MIS-C in the United States, which has resulted in 35 deaths. The syndrome has been diagnosed in children ranging from 1 to 20 years of age, though the majority of cases occur in children aged 1 to 14 years. Black and Hispanic or Latino children account for a disproportionate number of cases, and males make up around 60% of documented cases.

MIS-C can occur in children with no known underlying health conditions, though children who are overweight or obese may be at slightly elevated risk for developing the syndrome.

An inflammatory syndrome similar to MIS-C has been reported in adults. Known as multisystem inflammatory syndrome in adults (MIS-A), it occurs after exposure to SARS-CoV-2 and affects multiple organs.

Although the cause of MIS-C is not yet known, it is considered to be a late immune response to SARS-CoV-2 infection. In 99% of documented MIS-C cases, children either tested positive for a current SARS CoV-2 infection or had antibodies to the coronavirus, meaning they had a previous infection. In the remaining 1% of cases, children had been exposed to someone with COVID-19. 

What’s more, the number of cases of MIS-C tends to rise around 2 to 5 weeks following a surge in COVID-19 cases within a geographic region.

Scientists are still trying to understand the relationship between COVID-19 and MIS-C and why it affects some children and adolescents, but not others.     

In nearly all known cases, children with MIS-C have had a fever of 100.4°F or higher for at least 24 hours. In most cases, the fever persists for 4 to 7 days. Other symptoms associated with MIS-C may include but are not limited to:

• Diarrhea, vomiting, or stomach pain
• Skin rash
• Red eyes (conjunctival hyperemia)
• Cough
• Respiratory problems, including feeling “short of breath” or having an increased rate of breathing
• Chest pain or discomfort
• Swollen hands or feet
• Swollen lymph nodes in the neck
• Red, cracked lips
• Swollen red tongue with bumps that resembles a strawberry (known as “strawberry tongue”)
• Headache
• Confusion
• Fatigue
• Sore throat
• Myalgia (muscle pain) 

Symptoms of MIS-C usually begin 2 to 5 weeks after infection with the novel coronavirus. In the majority of cases, COVID-19 runs a mild course in children and is often asymptomatic. Because of this, children can have COVID-19 but may be unaware that they have an infection.

There is no diagnostic test for MIS-C. Doctors instead diagnose the condition by assessing the child’s history, conducting a physical examination, and evaluating a series of lab tests.

The Centers for Disease Control and Prevention (CDC) has established the following set of criteria, all of which should be met for a diagnosis of MIS-C:

• The patient is 21 years of age or younger and has had a fever of 100.4°F (38°C) for at least 24 hours (or if the individual’s temperature has not been measured, the individual has felt feverish for at least 24 hours).
• Blood work shows indications of inflammation.
• The patient requires treatment at a hospital (often in the intensive care unit) due to severe illness that includes dysfunction of two or more organs, in particular of the heart, blood vessels, gastrointestinal organs, lungs and other respiratory organs, kidneys, skin, or nervous system.
• Absence of other diagnoses that explain inflammatory symptoms such as a bacterial infection
• A positive test for current or past infection by SARS-CoV-2, the virus that causes COVID-19, or failing a positive test, evidence of exposure to someone with the virus within four weeks of the onset of symptoms of MIS-C 

In practice, this means that both symptoms and the possibility of exposure to COVID-19 will be taken into consideration. If the child has not undergone prior COVID-19 testing, the doctor will order a test. The doctor will also order blood tests to check markers of inflammation and organ function, as well as for a possible bacterial or viral infection. Because MIS-C can affect the heart, the doctor may recommend an electrocardiogram (sometimes called ECG or EKG), a painless test that measures heart function. If the patient has gastrointestinal symptoms, the doctor may order an ultrasound or CT (computed tomography) scan of the abdomen. Finally, if there are respiratory symptoms, the child may need a chest X-ray or CT scan so that the doctor can examine the lungs for signs of inflammation or infection.

Many children with MIS-C will need to be cared for in the intensive care unit, where medical providers can treat and closely monitor their condition. Depending on the severity of the illness and the particular organs involved, the child may also need to be under the care of other specialists, such as a cardiologist, rheumatologist, hematologist, infectious disease specialist, or critical care physician.

The hallmark of MIS-C is widespread inflammation across multiple organ systems. For example, MIS-C can cause myocarditis (inflammation of the heart muscle), cardiac dysfunction, liver problems, seizures and other neurologic disorders, respiratory failure, and acute kidney injury (rapid loss of kidney function). That’s why it is critical that children with MIS-C receive prompt medical treatment.

Treatment typically includes supportive care, which means that the focus is on relieving symptoms and preventing complications while the patient recovers. This usually involves the delivery of intravenous fluids and medications including antibiotics, with the goal of reducing fever, keeping blood pressure up, and eliminating any underlying bacterial infections.

Given that the symptoms of MIS-C are caused by the body’s own exaggerated immune response, doctors may also administer medications to temporarily suppress the body’s immune system. Immune suppression gives the patient’s body time to heal, helping to avert long-term organ damage.

Drugs commonly used to suppress immune response in children with MIS-C include steroids and certain biologic drugs that are typically used in people with autoimmune disorders and rheumatoid arthritis. Patients may also receive intravenous immunoglobulin, a medication containing antibodies (proteins that help fight off viral and other infections).

In some cases, children with MIS-C require breathing or cardiac support via mechanical ventilation or extracorporeal membrane oxygenation (ECMO) treatment. Patients whose heart is affected by MIS-C may be given inotropes, a type of medication that alters the strength of heart contractions.

Though MIS-C is a serious condition that usually requires hospitalization, with prompt medical attention, the vast majority of children with it recover. Most patients regain functionality of organs affected by MIS-C, though because it is a new disorder, researchers are still learning about its long-term health implications.