The Latest on the Mysterious Inflammatory Syndrome in Children

A pediatrician makes sense of the latest data on the mysterious inflammatory syndrome associated with the novel coronavirus

Photo: cottonbro/Pexels

Despite the worldwide devastation caused by the novel coronavirus, SARS-CoV-2, one reprieve has been its limited effect on the health of children. This notion came into question, however, in early May with the emergence of a mysterious inflammatory syndrome unique to kids and found to be associated with Covid-19. Since then, more information has been sought on what is now called multisystem inflammatory syndrome in children or MIS-C.

What is MIS-C?

The American College of Rheumatology, the U.S. Centers for Disease Control and Prevention (CDC), and the World Health Organization (WHO) define MIS-C in slightly varying ways, but it broadly includes fever, a positive test for SARS-CoV-2 or a clear exposure, elevated markers of inflammation, and evidence that multiple organ systems are affected (for example, two or more of the following symptoms: rash, swelling of the hands or feet, red eyes, blood clots, swollen lymph nodes, abdominal pain, diarrhea, seizure, or stroke). Similar to another enigmatic pediatric condition, Kawasaki disease, MIS-C is thought to be an abnormal immune response to the novel coronavirus that often occurs after the acute infection has passed.

MIS-C vs. Kawasaki disease

Although often labeled a rare condition, Kawasaki disease (KD) is the second most common blood vessel inflammatory disease of childhood, and one in 5,000 children are affected by it. I’ve cared for numerous children with KD in the hospital, and the appearance of a new Kawasaki-like phenomenon in the setting of a viral pandemic is not necessarily unexpected.

KD is thought to be caused by an aberrant immune response to a virus, but, despite extensive research, no particular virus has ever been identified. Some think KD is related to viruses in general rather than one specific virus. In addition to KD, other diseases of inflammation and immune dysregulation such as rheumatic fever and Guillain-Barré syndrome have been found to occur in children after recovering from an infection. So with the arrival and rapid worldwide spread of a brand new virus, SARS-CoV-2, it would actually be a surprise if there weren’t an increase in the prevalence of post-infectious complications akin to KD and other inflammatory syndromes.

Signs and symptoms

In a recent study from the New England Journal of Medicine (NEJM) titled, “MIS-C in U.S. Children and Adolescents,” researchers sought to better understand the many facets of this newly described syndrome. Investigators reviewed 186 cases of MIS-C in 26 states across the country. They found that 90% of the patients experienced four or more days of fever. The most common organ system affected was the gastrointestinal tract (92% of patients) followed by the heart and blood vessels (80%), blood and blood cells (76%), skin and mucous membranes (74%), and the lungs and upper airway (70%).

Another study simultaneously published in the NEJM by another group of researchers showed nearly identical results among a group of 95 children in New York state. The authors produced an insightful table (below) to demonstrate how age influences the organ systems involved.

Syndrome Clusters According to Age Group among Patients with MIS-C, NEJM 2020, open access. Note: myocarditis is another term for inflammation of heart muscle tissue. Credit: The New England Journal of Medicine

The table above indicates that symptoms of MIS-C in younger patients do indeed mimic KD including cutaneous manifestations (like a rash) which are common in KD. This makes sense because most cases of KD occur in younger children aged six months to five years. The involvement of the remaining organ systems (GI tract, heart, and neurologic systems) occurred at a higher frequency in older children. Thus, it appears that older children with MIS-C have symptoms that are less like KD when compared to younger children.

An additional recently published study in the Journal of the American Medical Association observed 27 children in the United Kingdom with MIS-C and found that 15% had neurologic symptoms including headaches, changes in mental activity, muscle weakness, and reduced reflexes. Neurologic improvement was seen in everyone affected.

The most alarming of the potential consequences of KD are coronary artery aneurysms which are dilations of the blood vessels that supply the muscle tissue of the heart. Coronary aneurysms can lead to a heart attack, but thankfully, are rare when KD is appropriately treated. Results from the U.S. study indicate these aneurysms occurred in 8% of patients with MIS-C.


According to the U.S. study, the average age of children with MIS-C was eight, and 62% were male. Both NEJM investigations found minorities to be disproportionately affected. The authors write, “The percentage of patients in our series who were Black or Hispanic was also higher than in the U.S. population overall.”

Treatment and outcomes

As expected, children with MIS-C were treated with medications designed to dampen their abnormally heightened immune response. Intravenous immunoglobulin (70%–77%) and systemic corticosteroids (49%–64%) were the most common pharmaceuticals administered.

The median length of hospitalization per the U.S. study was seven days with 80% of patients requiring intensive care. Mechanical ventilation was needed for 20% of the children studied, and, unfortunately, 2% died.

Timing of onset

Authors of the U.S. study write that, Almost one-third of the patients tested negative for SARS-CoV-2 by RT-PCR but had detectable antibodies.” This finding suggests, “that a substantial proportion of the patients in this series were infected with SARS-CoV-2 at least one to two weeks before the onset of MIS-C.” A chart from the New York study describes this observation (below). Notice that there is about a six-week lag between when cases of Covid-19 begin to increase and when cases of MIS-C rise in number.

Pediatric Cases of Covid-19 and of MIS-C in New York State, NEJM 2020, open access. Credit: The New England Journal of Medicine

The main takeaways

How do these recent studies contribute to the understanding of MIS-C? They provide valuable insight into the timing of disease presentation, the prevalence of various symptoms, and key demographic information such as race, gender, and age. This data also raises the possibility that MIS-C may represent two separate post-infectious inflammatory conditions — one in younger children that mimics KD, and the other in older children that resembles toxic shock.

From a medical perspective, questions remain regarding the efficacy of treatment and the overall prognosis of MIS-C. Dr. Michael Levin, from the department of pediatric infectious disease at Imperial College London, suggests future investigations should be aimed at answering, “What treatments may prevent progression to shock and multiorgan failure, and will treatment prevent coronary-artery aneurysms? Are children with self-resolving inflammation at risk for aneurysms, and what cardiac follow-up is needed?”

What about parental concerns and public health implications? Decisions are on the horizon regarding whether or not schools should open this fall. Other important considerations include children’s participation in fall sports or performing arts. Based solely on data from New York state, researchers established an incidence of MIS-C of only two per 100,000 children as compared to 322 per 100,000 for SARS-CoV-2 infection. While MIS-C may be rare, it causes significant harm to those affected. This highlights the need for continued conversation about what reasonable precautions can and should be taken to reduce children’s risk of exposure to SARS-CoV-2.

Children face a multitude of risks every day, and the safety of each step they take is immeasurably important to their caretakers and loved ones. As more is uncovered about the effects of Covid-19 on children, we will be better equipped to navigate this pandemic and guide the children we care about as they take their next steps.

Husband, Father, Health and science writer, Interpreter of medical jargon, Hospitalist physician, Board certified in internal medicine and pediatrics

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