Researchers Find an Epigenetic Signature Linked With MIS-C

Carla Nieto Martínez

July 29, 2022

MADRID, Spain — For pediatric specialists, one of the enigmas of SARS-CoV-2 infection has been the greater resistance of pediatric patients to experiencing severe COVID-19 symptoms and the presence, in a small percentage, of the so-called multisystem inflammatory syndrome in children (MIS-C) or pediatric multisystem syndrome, a serious condition that requires admission to the intensive care unit in 60% of cases.

Until now, the factors involved in the appearance of this syndrome were unknown, but an investigation that has been published recently analyzed the implication of epigenetics in the control of the immune response and viral activity. The results have shown the existence of changes at this level linked to the development of MIS-C, at least in the cohort group studied.

The study was carried out by the group of Manel Esteller, MD, director of the Josep Carreras Leukemia Research Institute (IJC), and Aurora Pujol, MD, head of the Neurometabolic Diseases Group of the Bellvitge Biomedical Research Institute (IDIBELL) and member of the Center for Biomedical Network Research on Rare Diseases (CIBERER), both in Barcelona, Spain. The study compared the epigenome of healthy children, children with COVID-19 without MIS-C, and children with the syndrome. The results have made it possible to define an epigenetic signature associated with MIS-C, which the authors named EPIMISC.

"The vast majority of children infected with SARS-CoV-2 are asymptomatic or have a mild clinical condition, with symptoms of the common cold," Pujol told Medscape Spanish Edition. "However, rare cases present with MIS-C, a serious inflammatory disease that can affect multiple organs, such as the heart, brain, intestines, kidneys, or skin, as well as the vascular system, in addition to the lungs. Together with Esteller and national (SCOURGE) and international (COVIDHGE) consortiums, we wanted to try to understand the characteristics of these children that make them different from the general population from a genomic and epigenomic point of view."

Similarities in Adults

Regarding the characteristics of the epigenetic signature described in this research, Pujol highlighted that MIS-C is an inflammation process due to an exaggerated reaction of the organism to the viral infection.

"For example, the genes identified in this signature are molecules that organize the response of T-cells (ZEB2) or the response of natural killer lymphocytes (SH2D1B) or the complex factor of HLA-DRB1 antigens, in addition to other genes with a role demonstrated in inflammation, such as CUL2 and AIM2," she said. "The importance of these genes has been shown for other viral infections and in SARS-CoV-2 infection in adult patients."

For the authors, this last finding has been one of the most interesting and raises the possibility of extrapolating the evidence from this research to COVID-19 in adults. "Indeed, we found that several of these genes with epigenomic changes are common among the study of adult patients with COVID-19 and the study of children with MIS-C, so these are findings that reinforce each other," said Pujol. "Likewise, we confirm the nature of the inflammatory immune complication after infection, which is what leads to severe disease. In other words, it is not the virus itself, but the exacerbated reaction of the immune system of these patients to the virus that leads them to develop severe disease."

What can the identification of this epigenetic signature mean for early diagnosis and management of MIS-C? "If we could transfer it from the research laboratory to clinical practice, it could help identify patients at risk of suffering from an exacerbated immune reaction or MIS-C, which would allow treatment to be changed early and avoid these complications. Likewise, drugs targeted against specific proteins, such as ZEB2 or SH2D1B, could be useful in controlling the exacerbated immune reaction," said Pujol.

This opinion was shared by Pere Soler-Palacín, MD, of the Pediatric Infectious Pathology and Immunodeficiency Unit of the Vall d'Hebron Children's Hospital in Barcelona. Soler-Palacín is a member of the Spanish Society of Pediatric Infectious Diseases (SEIP) and coauthor of the study. He told Medscape Spanish Edition that the demonstration of alterations in the methylation of genes involved in the inflammatory response and the generation of an epigenetic signature can allow the detection of patients with a higher risk of presenting severe forms, as well as a better understanding of the immunological mechanism involved in MIS-C.

Resemblance to Kawasaki Disease

"In any case, we must be aware that we currently do not have the possibility of carrying out studies of this type quickly in current clinical practice, so these results must be understood as pieces of a puzzle in any infectious and inflammatory process that includes the causal agent itself and the host response from a genetic and epigenetic point of view," said Soler-Palacín. "Only with this complete vision will we be able to move toward truly personalized medicine."

On the other hand, the study also revealed that this epigenetic signature resembles that of Kawasaki disease. "From the beginning of the appearance of cases of MIS-C, these similarities were clinically evident. Kawasaki disease is a childhood inflammatory syndrome of unknown cause in which several factors had been speculated to be involved, such as toxic chemicals or viral agents, although the agent involved had not been clearly identified. For example, one of the viral agents postulated in Kawasaki is the H1N1 influenza virus, due to the peak of cases of this disease that were detected during this pandemic in 2009," said Pujol.

"The epigenomic signature that we have found may suggest that Kawasaki disease could be caused by some other virus in the coronaviridae family, such as those that cause the common cold," she added. Pujol pointed out that these findings should be confirmed in a cohort with more patients and, if possible, with different ethnic groups, since the patients included in this study come from Spanish hospitals.

Soler-Palacín explained that the similarities and differences between MIS-C and Kawasaki disease have been studied since the beginning of the pandemic, with the description of the first conditions of the syndrome.

"Although there is a partial clinical, inflammatory, and immunological overlap, some evidence has been pointed out, such as that shown in this study regarding epigenetic factors, that reinforces the theory of a viral basis also in Kawasaki disease, an entity of which despite years of extensive research efforts, the cause is still unknown," he added.

Refining Diagnostic Criteria

Antonio Soriano-Arandes, MD, of the Pediatric Infectious Pathology and Immunodeficiency Unit of Vall d'Hebron Children's Hospital, who did not participate in this research, told Medscape, "In relation to the MIS-C cases registered in Spain, it is estimated that the prevalence was 11.0 (95% CI, 9.3-12.9) per 100,000 people under 18 years of age, with an incidence of 27.3 (95% CI, 23.05-31.6) per 100,000 SARS-CoV-2 infections." Soriano-Arandes is a member of the Spanish Society of Pediatric Infectious Diseases.

"The primary manifestations of this syndrome are fever (higher than 39° C in more than 80% of cases), which is an essential criterion to define a case of MIS-C, according to the World Health Organization; gastrointestinal manifestations, such as vomiting, abdominal pain or diarrhea (in approximately 90% of cases); skin lesions in the form of rash or edema, which may or may not affect the mucous membranes; conjunctivitis; and signs of neurological involvement, such as obtundation, prostration, or seizures," explained Soriano-Arandes.

He also described the challenges that pediatric specialists face in relation to cases of MIS-C. "In the near future, the main challenge is to improve the definition criteria for cases of MIS-C. The results of studies such as the one in question can undoubtedly contribute to fine-tuning these criteria."

"An objective is also to evaluate potential scales or severity scores that combine clinical and analytical parameters and allow a much better adjustment of the treatment administered, based on their results. And finally, we have the challenge of being able to demonstrate whether there is a change in the incidence that may be related to preventive measures such as vaccines or virological factors, such as the appearance of new SARS-CoV-2 variants of concern," said Soriano-Arandes.

"We plan to continue including cases, and an interesting factor could be introducing the possibility of observing any changes with different variants of SARS-CoV-2," said Pujol. "In principle, it would not be expected, because we have seen similarities with signatures of other viruses, such as that of the common flu or influenza, which is from a rather different family, although it causes similar clinical conditions."

Pujol, Soler-Palacín, and Soriano-Arandes reported no relevant financial conflict of interest.

Follow Carla Nieto of Medscape Spanish Edition on Twitter: @carlanmartinez.

This article was translated from the Medscape Spanish edition.

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