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Multisystem inflammatory syndrome in children (MIS-C) linked to COVID-19 is associated with reactivation of Epstein-Barr virus (EBV), leading to an altered immune response, according to a study published in Nature.

COVID-19 primarily affects older adults, but SARS-CoV-2 can also pose a significant risk to children. Since the pandemic began, MIS-C cases have been reported in pediatric patients presenting with symptoms resembling toxic shock syndrome and Kawasaki disease.

Although rare, MIS-C had an estimated incidence of 0.07% among patients with COVID-19 younger than 18 years during the 2020-2021 wave in Southern Italy. It is a severe condition that often requires intensive care and affects multiple organs, including the heart, with myocarditis and pericarditis observed in approximately 34% of cases.

Study Findings

An international research team analyzed cytokines and chemokines in the blood of 124 patients with MIS-C (mean age, 8.7 years) and compared them with 36 healthy children, 57 children with asymptomatic or mild SARS-CoV-2 infection, 39 with moderate infection, and two with severe infection.

Patients with MIS-C exhibited significantly elevated transforming growth factor (TGF)–beta levels (398 pg/mL), which were approximately three times higher than those in uninfected children and 2.6 times higher than those in children with acute SARS-CoV-2 infection. Immune cells in patients with MIS-C also showed activation of TGF-beta–induced genes. 

This surge in TGF-beta creates an immune environment conducive to the reactivation of viruses such as EBV.

“TGF-beta can do two things: First, it suppresses the cytotoxicity of T-cells, which normally target EBV-infected B cells. Therefore, although T cells recognize EBV-infected B cells, they fail to eliminate them efficiently. Second, TGF-beta promotes the lytic cycle of EBV,” Mir-Farzin Mashreghi, PhD, deputy scientific director of the German Rheumatology Research Center in Berlin, Germany, and the lead researcher of the study, explained to Univadis Italy, a Medscape Network platform.

Two key findings support the role of EBV reactivation. Researchers observed a significantly higher prevalence of EBV seropositivity in patients with MIS-C (80.7%) than in healthy children (56.0%), similar to the rates in patients with multiple sclerosis, in whom EBV is a known primary risk factor.

Additionally, RNA analysis of B cells from patients with MIS-C consistently detected active EBV, but this finding was absent in healthy children or those with mild COVID-19. Active EBV was observed in only one child with severe COVID-19 who did not have MIS-C.

Immune Mechanisms

“Elevated TGF-beta levels observed only in patients with MIS-C impair interactions between immune cells, reducing the cytotoxic capacity of T lymphocytes, and consequently, surveillance over EBV-infected B lymphocytes. This mechanism (elevated TGF-beta levels, altered lymphocyte function, and EBV reactivation) amplifies the inflammatory response, contributing to the hyperinflammatory state observed in MIS-C,” noted Martina Votto, MD, PhD, from the Department of Clinical-Surgical, Diagnostic, and Pediatric Sciences at the University of Pavia in Pavia, Italy, in an interview with Univadis Italy. Votto was not involved in the study.

Researchers have also identified an expansion of T cells expressing TCRVβ21.3, similar to EBV-reactive lymphocyte clones capable of eliminating EBV-infected B cells. “This study adds an important piece to understanding the complex immunological mechanisms of MIS-C, opening new perspectives on the pathogenesis, diagnosis, and treatment of this condition,” Votto added.

The exact mechanism by which SARS-CoV-2 triggers TGF-beta activation remains unclear. “In 2021, we published studies showing that in severely ill patients with COVID-19 requiring intensive care, TGF-beta levels are extremely high, comparable to those observed in these children,” said Mashreghi.

He continued, “Previous studies by other groups have shown that SARS-CoV-2 can activate TGF-beta in at least two ways to evade the immune response: Through the virus’s nucleoprotein and through the interaction of the spike protein with integrins. Therefore, there are several clues that SARS-CoV-2 infection may directly cause the elevated TGF-beta levels we measured. For now, however, these are just hypotheses.”

Regarding EBV reactivation and why this mechanism occurs in only a small percentage of patients, Mashreghi noted, “There’s some hypothesis that persistent SARS-CoV-2 infection could induce the hyperinflammatory syndrome, for instance, if a hidden viral reservoir persists somewhere, inducing TGF-beta. However, we were unable to identify such reservoirs in our patient cohort.

MIS-C did not disappear entirely after the acute phase of the pandemic. “The highest rate we observed during the pandemic was 1 child in 800 developing this disease; then, the rate dropped to 1 in 4000 during Omicron. We believe that this decrease is due to the population now having greater immunity against the virus. Vaccination campaigns for children have reduced the incidence of MIS-C. However, we believe that this could still be a problem because children are born, contract EBV infections, and may experience their first COVID-19 infection at the same time. Therefore, we expect that this condition could increase. Additionally, I want to emphasize that one of our co-authors, Alexandre Belot, published an article in The New England Journal of Medicine describing prepandemic MIS-C cases. This suggests that other coronaviruses could also induce MIS-C. This fact was simply overlooked in the past because this condition was very rare,” Mashreghi cautioned.

Therapeutic Options

The study’s findings open the door to targeted diagnostic and therapeutic options, Votto explained: “Identifying TGF-beta as a key mediator of MIS-C pathogenesis could lead to the development of targeted therapies to modulate its activity. Additionally, the discovery of T cells expressing TCRVβ21.3 could pave the way for novel diagnostic and therapeutic strategies based on cell-mediated immunity. Finally, TGF-beta levels and markers of EBV reactivation could be used to identify and stratify children at higher risk of developing MIS-C after SARS-CoV-2 infection.”

The involvement of EBV in MIS-C further highlights the role of viral infections in increasing the risk for various diseases long after the acute infection. EBV, in particular, is involved in multiple sclerosis and may also be a risk factor for other autoimmune diseases. Moreover, several viruses, including some considered “benign,” such as herpes, increase the risk for neurodegenerative diseases even years after infection. “I think we should really stop thinking of viruses such as EBV as harmless just because 95% of the adult population is positive. In situations where the immune system is weakened, individuals are vulnerable to reactivation episodes that can cause secondary pathologies, including autoimmune diseases,” concluded Mashreghi.

This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.