Severe COVID-19 Reaction in Children Carries a Distinctive Epigenetic Signature

At the height of the coronavirus pandemic, hospitals in hot zones like New York City were bursting with incoming patients. Remarkably, very few of them were under 18. The reason is still a mystery, but somehow most children and teens appear to be protected from getting the worst of COVID-19. 

This assumption was tested in April 2020, when doctors from the UK and US documented a presentation in children of a severe shock-like illness similar to Kawasaki disease or toxic shock syndrome. The episodes were all associated with SARS-CoV-2 infection, the virus that causes COVID-19, after laboratory testing showed positive serology. 

Today, this condition is known as “multisystem inflammatory syndrome in children,” MIS-C for short. Although rare, it is considered a serious health condition that often requires intensive care hospitalization. Without proper diagnosis and treatment, MIS-C could reportedly lead to organ failure in the heart, lungs, or kidneys. And in some cases, MIS-C could result in lasting organ damage or even death.

To better understand the occurrence of this syndrome and its relationship to SARS-CoV-2, scientists from the Cancer Epigenetics group at the Josep Carreras Leukemia Research Institute (IJC) in Spain conducted a study to investigate the epigenetic changes linked to activating MIS-C. In particular, they sought to find target loci regulated by DNA methylation that could be changed at the onset of MIS-C. 

The original study, published in the journal EClinicalMedicine, was led by Dr. Manel Esteller, IJC director, ICREA research professor, and professor of genetics at the University of Barcelona, along with Dr. Aurora Pujol, ICREA professor and Bellvitge Biomedical Research Institute’s head of the neurometabolic diseases group. IJC research associate Dr. Verónica Dávalos and Ph.D. student Carlos A. García-Prieto contributed as first-authors of the study.

As Dr. Esteller explains, COVID-19 in adults is typically characterized by lung issues that cause shortness of breath or difficulty breathing. However, in the studied rare syndrome, the same virus in children affects many more organs, and the consequences can be critical and long-lasting.

“As the bases for the disorder are unknown,” says Esteller, “we decided to compare the epigenome of healthy children, children with COVID-19 without MIS-C, and children with COVID-19 who experienced MIS-C. We found that MIS-C is characterized by specific deregulation of epigenetic cellular programming that leads to a landscape of hyperinflammation that can damage tissues.”

The researchers named the distinctive epigenetic signature EPIMISC in line with their previous COVID-19 epigenetic studies. Interestingly, the EPIMSC profile appears to be very similar to that of Kawasaki Syndrome, a severe inflammatory illness linked with the influenza virus H1N1 that peaked in 2009.

Two of the DNA methylation changes and the EPIMISC signature, in general, have also been identified in some extreme cases of COVID-19 in adults. The team previously defined that signature last year as EPICOVID in an article published online in eBioMedicine.

Taking together, the two articles confirm that MIS-C and adult severe acute respiratory distress syndrome are both post-inflammatory complications that should be treated differently in the beginning phase of SARS-CoV-2 viral infection.

The research team believes that pharmacological inhibition of the Cullin-2 (CUL2) gene, a mediator of inflammation, might prevent a hyperinflammatory response. This would be especially beneficial to MIS-C patients who do not respond to standard treatment. 

“It is interesting to see that two disorders that exhibit similar clinical manifestations, MIS-C and Kawasaki, also share a common epigenetic signature, which is different to the epigenetic signature caused by other viruses including HIV,” noted Dr. Pujol.

To add to that, “it seems that in both syndromes, MIS-C and Kawasaki, there is an exaggerated reaction of the children’s immune system against a viral attack,” added Dr. Esteller. “Knowing the mechanisms triggering both diseases will give us better tools to diagnose and treat them.”

Source: V. Davalos, et al. Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): A multicenter, retrospective study. EClinicalMedicine, June 25, 2022.

Reference: Discovered epigenetic alterations associated with the COVID-19 related severe inflammatory syndrome in childhood. Josep Carreras Leukaemia Research Institute, June 27, 2022.

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