Nature study: PIMS is due to reactivation of the Epstein-Barr virus
PIMS is a severe inflammatory shock in children that can occur several weeks after a coronavirus infection and can become life-threatening. The exact cause of the clinical picture was previously unknown. Researchers from Charité – Universitätsmedizin Berlin and the Leibniz Institute German Rheumatism Research Centre (DRFZ) have now reported in the journal Nature* that in affected children, a previously dormant infection with the Epstein-Barr virus becomes active again and causes an excessive inflammatory reaction. The findings open up new treatment options, possibly not only for PIMS.
Corona is mostly mild in children, but in very rare cases the young sufferers become seriously ill: weeks after the acute infection, even if it was mild or asymptomatic, their immune system goes crazy and attacks the organs. For example, the children develop heart failure, skin rashes and high fever. To prevent organ failure, their immune system has to be quietened down in hospital – in half of cases even in intensive care. The cause of the clinical picture, which is known as Pediatric Inflammatory Multisystem Syndrome (PIMS), has not yet been conclusively clarified.
‘One potential cause of PIMS that has been discussed so far is that the coronavirus survives in the body or that the immune system turns against itself,’ says Prof Tilmann Kallinich, Head of the Section of Rheumatology at the Department of Paediatrics with a focus on Pneumology, Immunology and Intensive Care Medicine at Charité 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 responsible for the inflammatory shock instead. To put it simply, it wakes up from its dormant state because the children’s immune system is confused by the coronavirus infection and can no longer keep the dormant infection in check.’
Infection with Epstein-Barr virus flares up again The Epstein-Barr virus (EBV) is known as the causative agent of Pfeiffer’s glandular fever, which is accompanied by flu-like symptoms and sometimes requires many weeks of recovery. However, the infection usually goes unnoticed, with around 90 per cent of people becoming infected with the pathogen in the course of their lives. ‘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 in the body and thus escapes the immune defence. In this way, it survives in humans for a lifetime. It can flare up again years after the first infection, for example if the immune system is weakened.’
The research team has now also found such a flare-up of an 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 paediatric clinic or hospitals in Lyon (France), Naples (Italy), Ankara (Turkey) or Santiago (Chile). For comparison, it used 105 children who had also experienced a corona 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 quantities of specific immune cells against the virus – an indication that the body was actively fighting the pathogen.
Trigger for reactivation: the messenger substance TGFβ
‘We also discovered that although the immune cells fight against the Epstein-Barr virus, they do so with blunt weapons, so to speak,’ explains Dr Mir-Farzin Mashreghi, Deputy Scientific Director of the DRFZ and scientist at the Department of Paediatrics with a focus on Pneumology, Immunology and Intensive Care Medicine at Charité. Together with Tilmann Kallinich, he was in charge of the study. ‘The immune cells are no longer able to kill the EBV-infected body cells.’ As the researchers were able to prove, this is due to unusually large quantities 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 that inhibits the function of immune cells and reduces their effectiveness against the Epstein-Barr virus.
Mir-Farzin Mashreghi summarises the new findings on the development of PIMS as follows: ‘In some children, the coronavirus infection triggers an escalating system: the messenger substance TGFβ prevents the immune cells from keeping the Epstein-Barr virus in check, which can therefore multiply again. As a result, the body produces more immune cells against the virus, but they are still unable to function. This ultimately culminates in an extreme inflammatory reaction that damages organs and can be potentially fatal.’
TGFβ blockade as a possible therapeutic approach for PIMS and long COVID The inflammatory cascade can be easily broken in hospital with medication, and the vast majority of children recover after PIMS. Until now, anti-inflammatory drugs such as immunoglobulins or cortisone preparations have been used to treat PIMS. ‘Our findings suggest that the early and targeted blockade of TGFβ could also help against PIMS,’ summarises Tilmann Kallinich. ‘However, the new findings may also be relevant for other corona-related diseases.’
There are also indications that the reactivation of dormant viruses plays a role in long COVID. ‘Perhaps there are parallels here with 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 progression. We therefore suspect that the course of COVID-19 can be favourably influenced by TGFβ blockade.’ Further studies must now investigate whether TGFβ inhibitors are actually effective in corona-related diseases.
*Goetzke CC et al. TGFβ links EBV to multisystem inflammatory syndrome in children. Nature 2025 Mar 12. doi: 10.1038/s41586-025-08697-6
About PIMS
Pediatric Inflammatory Multisystem Syndrome (PIMS) is an inflammatory multisystem disease in babies, children and adolescents that can occur four to eight weeks after infection with SARS-CoV-2. It is also known as Multisystem Inflammatory Syndrome in Children (MIS-C) and resembles Kawasaki syndrome, particularly in younger children, and Toxic Shock Syndrome in older children. It is estimated that one in 800 children has developed PIMS after being infected with the original variant of the coronavirus. After infection with the coronavirus variant Omikron, which has dominated since the end of 2021, around one in 4,000 children develop PIMS.
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1 – PIMS is an inflammatory shock in children after a corona infection that can become life-threatening © Charité