Multisystem Inflammatory Syndrome in Children: A Complication of COVID-19

One of the ongoing challenges of a new infectious disease is deciphering the complications that can come with it. This is true with the rapid emergence of COVID-19, which now requires many researchers and physicians to determine which long-term health conditions COVID-19 patients develop in the ensuing weeks, months and years can be attributed to the virus. This is particularly necessary since all COVID-19 survivors will develop health issues over the course of their lives, and the vast majority of them will be seemingly due to another cause.

Many infections can lead to post-infection syndromes. For example, acquired immune deficiency syndrome, caused by the human immunodeficiency virus, is probably the best known. But toxic shock syndrome, Guillain-Barré syndrome, rheumatic fever, erythema multiforme, hemolytic uremic syndrome and post-streptococcal glomerulonephritis are also well-known and well-studied conditions that can be triggered by a viral or bacterial infection.

Now, with hundreds of millions of people around the world contracting COVID-19, and millions of them progressing to acute infections requiring hospitalization, medical researchers have a unique opportunity to mine data and watch for emerging conditions associated with COVID-19 and SARS-CoV-2, the virus that causes it — one of which is multisystem inflammatory syndrome in children (MIS-C).

What is MIS-C?

Also known as pediatric multisystem inflammatory syndrome,¹ MIS-C is marked by severe inflammation of organs and tissues, persistent fever and gastrointestinal (GI) distress,² and it appears to be an autoimmune response to a viral infection.

Since MIS-C has only recently been identified and is currently defined by its symptoms, a more detailed understanding of what constitutes MIS-C has not yet been determined. Research into the specific nature of the inflammation is still in its early stages. Therefore, for now, MIS-C is a term used to describe symptoms in children who exhibit inflammation and fever after contracting COVID-19, with no other discernible cause. The Centers for Disease Control and Prevention (CDC) notes that 99 percent of patients diagnosed with MIS-C test positive for the SARS-CoV-2 virus, and the other 1 percent had close contact with someone diagnosed with COVID-19. As of late June, CDC was reporting more than 4,100 cases of MIS-C in the United States alone.³

In addition, physicians and researchers have noted that some adults are also exhibiting similar symptoms. This is now known as multisystem inflammatory syndrome in adults (MIS-A).² The diseases are otherwise identical, but when patients are 21 years and older, it is classified as MIS-A. For unknown reasons, MIS-C is far more prevalent than MIS-A even though children are statistically less likely to contract COVID-19 and typically have far less severe cases of the virus than adults. 

Causes of MIS-C

While there is an overwhelming temporal association between COVID-19 and MIS-C, researchers have not yet identified any proof to definitively tie the condition to COVID-19.² Nevertheless, most research is progressing with the assumption that the SARS-CoV-2 virus is the triggering agent for a number of reasons.

For instance, researchers noted a spike in the number of patients with lingering fever, inflammation and GI symptoms at the same time hospitalizations due to COVID-19 were spiking. As such, it was theorized early that these symptoms could be tied to a recent SARS CoV-2 infection.⁴ Further, the symptoms had no other discernable underlying cause, and the collection of symptoms had never been seen in these numbers. 

Thus, it’s not surprising that the sudden appearance of thousands of patients manifesting a distinct set of symptoms during a global pandemic certainly makes the SARS-CoV-2 connection a logical place to begin research. 

Recently, researchers at Mt. Sinai Hospital announced they have discovered a possible clue as to the cause and trigger for MIS-C: Patients displaying symptoms also have two specific T cells in an “exhausted state” from overexposure to pathogens.⁵

Symptoms and Progression of MIS-C

Since symptoms of MIS-C may manifest weeks after COVID-19 and many pediatric cases of COVID-19 are so mild that they are never diagnosed, parents may not make the connection. Typically, symptoms will appear between three weeks and six weeks after COVID-19 infection.⁶

It should be noted that not every patient will exhibit the same symptoms; however, the Mayo Clinic identifies any combination of two or more simultaneous symptoms — with no other recognizable cause — to be of concern:

• Fever lasting more than 24 hours

• Vomiting

• Diarrhea

• Extreme fatigue

• Accelerated heartbeat

• Accelerated breathing

• Abdominal pain

• Rash

• Redness or swelling of the lips or tongue

• Redness or swelling of the hands or feet

• Enlarged lymph nodes

• Red eyes

• Headache, dizziness, light-headedness

Severe symptoms requiring emergency medical care include any of the following (Figure 1):

• Severe stomach pain

• Difficulty breathing

• Confusion

• Pale, gray or blue-colored skin, lips or nail beds

• Inability to wake up or stay awake

If left untreated, the inflammation associated with MIS-C can damage the heart, lungs, blood vessels, kidneys, brain, eyes, digestive system and/or skin. And, the damage can become permanent and can lead to death.² 

Diagnosing and Treating MIS-C

MIS-C was first described mere months after the COVID-19 outbreak began in the United States, when researchers first suspected there could be severe complications from the virus. In the year since MIS-C was first noted, public health officials have isolated a specific set of criteria to diagnosis the condition.

CDC has now issued a three-step diagnostic tool:⁷

• An individual under the age of 21 years presenting with fever over 100.4 degrees Fahrenheit for more than 24 hours, laboratory evidence of inflammation, and evidence of clinically severe illness requiring hospitalization, with multisystem organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological)

• No alternative plausible diagnoses

• Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology or antigen test; or exposure to a suspected or confirmed COVID-19 case within the four weeks prior to the onset of symptoms

To determine if there is multi-organ involvement, CDC recommends — but does not limit physicians to — the following tests:

• Elevated C-reactive protein

• Erythrocyte sedimentation rate

• Fibrinogen, procalcitonin

• D-dimer

• Ferritin

• Lactic acid dehydrogenase

• Interleukin 6, elevated neutrophils, reduced lymphocytes and low albumin

While popular media accounts of MIS-C have associated the condition with serious cases of COVID-19, there have also been diagnosed cases in which patients were asymptomatic during COVID-19 infection. And, a small number of MIS-C patients apparently never developed COVID-19 but were exposed to those who did. So while parents may insist their child never had COVID-19, physicians need to run the full gamut of tests.

In fact, CDC recommends even suspected cases of Kawasaki syndrome be reported to public health authorities as a possible case of MIS-C. However, testing should obviously continue to make a definitive diagnosis. In addition, MIS-C can manifest with symptoms similar to those of sepsis or toxic shock syndrome, which also need to be ruled out before a final diagnosis is possible.² 

Once MIS-C is diagnosed, patients should be admitted to the hospital as soon as possible if they are not already there so treatment can begin immediately to protect organs and other tissues from permanent damage due to inflammation.

According to the Mayo Clinic, specific treatment will depend on which organs are inflamed. Steroids may be used to reduce inflammation, while intravenous immune globulin can help repair the immune system. When the lungs are affected, oxygen or even a ventilator may be required to assist with breathing. In a few extreme cases, extracorporeal membranous oxygenation has been used. To prevent sepsis in the inflamed areas, antibiotics may be prescribed even before cultures are run.⁷

Fortunately, most patients recover quickly and completely with proper treatment. However, since MIS-C is a recently discovered condition, the long-term prognosis is not yet clear. Follow-up examinations are recommended until more is learned.⁵ 

Preventing MIS-C

Since infection by the SARS-CoV-2 virus is the suspected trigger, preventing infection is the only way to prevent MIS-C.

Children 12 years and older can now receive the Pfizer-BioNTech vaccine. But, children younger than 12 years should take normal precautions to try to prevent infection (Figure 2):

• Wash hands frequently

• Avoid touching the face

• Avoid those who are coughing, sneezing or otherwise appear ill

• Practice social distancing

• Wear a cloth mask

• Clean and disinfect surfaces in the home

Ongoing Research

MIS-C has been recognized only since 2020, and it is likely it has existed for less than two years, since the SARS-CoV-2 virus made the jump to humans.

While the speed of research to date has been impressive, much still needs to be learned, including the trigger that leads some patients with COVID-19 to develop MIS-C, the specific biological causes of the inflammation, and any new treatments to reduce the damage MIS-C can cause.

The National Institutes of Health (NIH) has launched the Collaboration to Assess Risk and Identify Long-Term Outcomes for children with COVID-19, and MIS-C is a major area of study for this new program. Because inflammation poses the greatest risk to patients with MIS-C, the new program is led by the National Heart, Lung and Blood Institute with assistance from the National Institute of Allergy and Infectious Diseases. 

This effort has already approved and provided funding for three main areas of research:⁸

• Long-Term Outcomes after the Multisystem Inflammatory Syndrome In Children (MUSIC) will coordinate through the Pediatric Heart Network to focus on cardiovascular complications from MIS-C.

• Pharmacokinetics, Pharmacodynamics and Safety Profile of Understudied Drugs Administered to Children per Standard of Care (POPS) will be coordinated through the Pediatric Trials Network and will focus on the efficacy of treating children with medicines that have shown promise in treating COVID-19 in adults.

• Pediatric Research Immune Network on SARS-CoV-2 and MIS-C (PRISM) will study the immunological aspects of SARS-CoV-2 infection in children. 

Other research already funded by NIH includes Predicting Viral-Associated Inflammatory Disease Severity in Children with Laboratory Diagnostics and Artificial Intelligence (PreVAIL kIds), which seeks ways to use artificial intelligence to identify patients most likely to develop MIS-C.

While clinicaltrials.gov lists only a handful of current studies being conducted for MIS-C, that number includes two trials studying the use of stem cells to fight the condition, one of which is being conducted at Duke University and the other at Singapore-based Mesoblast International Sàrl.

Another study, conducted by the Tuberculosis Research Centre in India in conjunction with NIH, is comparing different strains of the SARS-CoV-2 virus to determine if some are more likely to lead to the development of MIS-C.

And, a few other studies are following the long-term outcome of children diagnosed with MIS-C. But these studies will take years to determine outcomes and decades to come to a close.

Given how recently this condition was identified, it is likely numerous other studies in the pipeline have yet to receive U.S. Food and Drug Administration approval. 

Looking Ahead

With COVID-19 increasingly appearing to be endemic and as new seasonal variants emerge, MIS-C is likely here to stay. Widespread inoculations and growing immunity among those who have contracted the disease should eventually drive case numbers of COVID-19 down, particularly with periodic vaccine boosters to address new variants. Reducing the number of COVID-19 cases will have the added benefit of reducing MIS-C cases, assuming the temporal associations eventually lead to a more tangible link between the virus and the syndrome. However, the unfortunate reality is pediatricians and emergency room physicians will likely have to add MIS-C to the list of conditions to diagnose and treat for the foreseeable future.

The good news is there is nothing to suggest MIS-C is going to become more common, unless new strains of the virus appear that affect the body differently. And, hopefully, with more and improved vaccines for the SARS-CoV-2 virus, it will become increasingly rare.