Reactivation of Epstein-Barr Virus Triggers Inflammatory Shock in Children

PIMS is a severe inflammatory shock in children that can occur several weeks after a coronavirus infection and can be life-threatening. The exact cause of the disease was previously unknown. Researchers at Charité – Universitätsmedizin Berlin and the Leibniz Institute German Rheumatism Research Center (DRFZ) now report in the journal Nature that in affected children, a previously existing, dormant infection with the Epstein-Barr virus becomes reactive and triggers an excessive inflammatory reaction. These findings open up new treatment options, possibly not only for PIMS.

Coronavirus is generally mild in children, but in very rare cases, young sufferers become seriously ill: Weeks after the acute infection, even if it was mild or asymptomatic, their immune systems go haywire and attack their organs. For example, the children develop heart failure, skin rashes, and high fever. To prevent organ failure, their immune systems must be rested in the hospital—in half of cases, even in the intensive care unit. The cause of the condition, known as Pediatric Inflammatory Multisystem Syndrome (PIMS), has still not been conclusively determined.

"Previously, potential causes of PIMS have been discussed, for example, as the coronavirus persisting in the body or the immune system turning against itself," says Prof. Tilmann Kallinich, Head of the Rheumatology Section at the Charité's Department of Pediatrics with a focus on Pulmonology, Immunology, and Intensive Care Medicine, and one of the two lead authors of the study. "We have now found evidence that the resurgence of a second pathogen, the Epstein-Barr virus, is instead responsible for the inflammatory shock. Simply put, it awakens from its dormant state because the children's immune system is disrupted by the coronavirus infection and can no longer keep the dormant infection in check."

Epstein-Barr virus infection flares up again

The Epstein-Barr virus (EBV) is known as the causative agent of infectious mononucleosis, which is associated with flu-like symptoms and sometimes requires many weeks of recovery. However, the infection usually goes unnoticed; around 90 percent of people become infected with the pathogen during their lifetime. "Even after an acute infection has been overcome, the virus is not yet eliminated from the body," explains Tilmann Kallinich, who also heads a liaison working group at the DRFZ. "The Epstein-Barr virus nests in various cells of the body and thus evades the immune system. In this way, it survives in humans for a lifetime. It can flare up again years after the initial infection, for example, if the immune system is weakened."

The research team has now also observed such a flare-up of Epstein-Barr virus infection in children with PIMS. For the study, they examined 145 children between the ages of 2 and 18 who had been treated for PIMS at the Charité Children's Hospital or hospitals in Lyon (France), Naples (Italy), Ankara (Turkey), or Santiago (Chile). For comparison, they used 105 children who had also experienced a coronavirus infection but had not developed PIMS. In the blood of the children with PIMS, the researchers found traces of the Epstein-Barr virus, as well as antibodies and large amounts of specific immune cells against the virus – an indication of the body's active fight against the pathogen.

Trigger of reactivation: the messenger substance TGFβ

"We also discovered that while the immune cells are fighting the Epstein-Barr virus, they are fighting with blunt weapons, so to speak," explains Dr. Mir-Farzin Mashreghi, Deputy Scientific Director of the DRFZ and a scientist at the Department of Pediatrics with a focus on Pulmonology, Immunology, and Intensive Care Medicine at the Charité. He led the study together with Tilmann Kallinich. "The immune cells are no longer able to kill the EBV-infected body cells." As the researchers were able to demonstrate, this is due to unusually large amounts of the messenger substance TGFβ (Transforming Growth Factor beta), which the children's bodies produce as a result of the coronavirus infection. TGFβ is an anti-inflammatory molecule; it inhibits the function of immune cells and reduces their effectiveness against the Epstein-Barr virus.  

Mir-Farzin Mashreghi summarizes the new findings on the development of PIMS as follows: "In some children, the coronavirus infection triggers a system that escalates: The messenger substance TGFβ prevents the immune cells from keeping the Epstein-Barr virus in check, allowing it to multiply again. The body then produces more immune cells to fight the virus, but these remain nonfunctional. This ultimately culminates in an extreme inflammatory reaction that can damage organs and be potentially fatal."

TGFβ blockade as a possible therapeutic approach for PIMS and Long COVID

The inflammatory cascade can be effectively interrupted with medication in the hospital, and the vast majority of children recover from PIMS. To date, anti-inflammatory drugs such as immunoglobulins or cortisone preparations have been used to treat PIMS. "Our findings suggest that early and targeted blockade of TGFβ could also help against PIMS," summarizes Tilmann Kallinich. "The new findings may also be relevant for other coronavirus-related clinical pictures."

There is also evidence that the reactivation of dormant viruses plays a role in long COVID. "Perhaps there are parallels here to the processes in PIMS, in which case TGFβ inhibitors would be potential candidates for therapy against long COVID," says Mir-Farzin Mashreghi. "We also know that high TGFβ levels in adults are associated with severe COVID-19 courses. We therefore suspect that the course of COVID-19 disease can be beneficially influenced by TGFβ blockade." Further studies are now needed to investigate whether TGFβ inhibitors are actually effective in coronavirus-related illnesses.

Reference: Goetzke CC, Massoud M, Frischbutter S, et al. TGFβ links EBV to multisystem inflammatory syndrome in children. Nature. 2025:1-10. doi: 10.1038/s41586-025-08697-6

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