The findings of a 2021 study led by the Cedars-Sinai Medical Center team may help doctors better understand multisystem inflammatory syndrome in children (MIS-C), a severe complication of infection with COVID-19. The study first appeared in the peer-reviewed publication Journal of Clinical Investigation and was authored by the Cedars-Sinai team in collaboration with partners at Martin Luther University Halle-Wittenberg in Germany. 

Tracing the value of biomarkers

This research offers the potential to use distinctive MIS-C biomarkers to more accurately predict the course of disease in young patients. It may also help physicians develop potentially lifesaving new treatments. 

The study looked at data from a small cohort of patients to pinpoint a set of pathogenic trajectories that ended up as MIS-C. The researchers also examined blood proteins potentially able to act as biomarkers that would help predict symptom severity and thus better inform doctors about the optimal treatment for each patient. 

Rare but terrifying

Only a few children develop MIS-C, but it can be fatal. The condition involves inflammation of various parts of the body, which can include the brain, lungs, heart, kidneys, and even the skin and eyes. While scientists do not yet understand the exact cause of MIS-C, they have shown that many children who manifest the condition have either been infected with SARS-CoV-2, the virus that causes COVID-19, or have been in close contact with an infected person.

The complications of MIS-C can appear even weeks after a child has been diagnosed with COVID-19. The median age of patients with MIS-C is nine years old.

Given prompt and appropriate medical care, most children who develop MIS-C have improved. Most pediatric patients in the U.S. presenting with the condition have required hospitalization in the intensive care unit. 

Particularly if left untreated, the condition can worsen and result in death for a small number of patients.

From May 2020 to the last week in August 2021, the Centers for Disease Control and Prevention received more than 4,400 reports of cases of MIS-C. Out of those cases, more than three dozen children died.  

Accumulating urgency

With many schools reopening under less-than-optimum conditions and the spread of the Delta variant of COVID-19, parents and physicians are more concerned than ever about how the disease affects children. Statistics for summer 2021 showed more children being hospitalized than earlier in the pandemic. Physicians also noted troubling issues of equity: MIS-C is especially prevalent among Black and Latinx children. 

These are all among the reasons why the director of Cedars-Sinai’s Pediatric Infectious Diseases Division told media outlets that the pathfinding study on biomarkers is especially important. 

An immune system running riot

Research is slowly clearing away some of the unknowns surrounding MIS-C. Scientists now view it as an autoimmune disorder, in which the patient’s own immune system goes into hyperdrive, perhaps in response to the large-scale tissue damage that some people sustain from infection with SARS-CoV-2. This causes the immune system to literally attack the patient’s own organs. 

Pediatric patients with MIS-C typically show up with the same “cytokine storms” that doctors had previously marked in adult patients with severe inflammatory responses to SARS-CoV-2. Among the symptoms are long-term fever, inflammation of the heart, shock, and acute respiratory or neurological system crises. 

Connecting the dots

Previously, the Cedars-Sinai team published a 2020 study that can be considered a precursor to the newer one on biomarkers. In the earlier research, conducted with the University of Pittsburgh School of Medicine, the scientists discovered similarities in the biological reactions that characterize MIS-C, the cytokine storm phenomenon, and toxic shock syndrome, which has long been recognized as a rare outcome in cases of bacterial infection.

When doctors first identified MIS-C in their child patients earlier in the pandemic, they noted its multiple resemblances to toxic shock and Kawasaki syndrome, whose symptoms include fever, rash, and swelling of the lymph glands and extremities.

The researchers built a truly interdisciplinary team to conduct the biomarker study, with Cedars-Sinai and five partner organizations contributing specialists from a variety of fields in order to keep the project moving quickly. This dream team relied on a number of advanced technologies, including RNA sequencing, antibody analysis, and proteomics, the analysis of cell proteins. The researchers also analyzed immune system signaling, the complex biological process that allows the body to identify and respond to infectious agents.

The key limitation of this study, as the team acknowledges, was its small subject size of 69 children. Some had been diagnosed with MIS-C, others had not, and still others had been diagnosed with Kawasaki syndrome. Still, this study can serve as an anchor to see if its findings can be replicated in further research. 

Symptoms? Get help promptly

The CDC urges parents to be alert for the signs of MIS-C, while understanding that not every child with the condition will develop the same symptoms. The typical scenario involves persistent fever, along with one or more other symptoms such as headache, extreme tiredness, rash, bloodshot eyes, vomiting, diarrhea, clammy skin, and difficulty breathing.

Anyone who suspects a child might be developing MIS-C should contact the child’s pediatrician right away. Symptoms that require an immediate call to emergency services include persistent chest pressure or pain, labored breathing, difficulty remaining awake, new confusion, and gray, blue, or abnormally pale skin, nails, or lips. 

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