March 19, 2025, 6:39 pm | Read time: 6 minutes
A few weeks after a COVID-19 infection, children can experience a rare but potentially severe inflammatory reaction: multisystem inflammatory syndrome, known as MIS-C or PIMS. Affected individuals suffer from high fever, rashes, and in severe cases, even organ failure. The exact cause of this excessive immune reaction was previously unclear. A new study now provides a possible explanation.
Initially, the treatment of multisystem inflammatory syndrome focused on alleviating symptoms. Now, for the first time, there are indications of a possible trigger–and thus new perspectives for targeted therapies.
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Overview
Background of the Study
While most children recover well from a COVID-19 infection, a few develop MIS-C weeks later–an immune phenomenon that can affect multiple organs. Scientists suspected various causes, including the persistence of coronaviruses in the body or a misguided immune response.
Researchers from Charité and the German Rheumatism Research Center (DRFZ) have now found evidence that a COVID-19-induced reactivation of the Epstein-Barr virus (EBV) could contribute to the development of MIS-C. EBV is a globally widespread pathogen that can cause mononucleosis and remains in the body for life. It is usually kept in check by the immune system. However, after a COVID-19 infection, this balance might be disrupted, allowing the virus to become active again and potentially trigger an immune response.1
What and Why Was Investigated?
The aim of the study was to better understand the possible mechanisms behind MIS-C. The scientists examined blood samples from 145 children with MIS-C and 221 control children who had a COVID-19 infection without MIS-C.
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Multisystem Inflammatory Syndrome
The disease is characterized by inflammation in multiple organs such as the heart, lungs, gastrointestinal tract, skin, mucous membranes, and kidneys–all following a COVID-19 infection. The exact development of this excessive immune reaction was previously unexplained.2
The problem is that the inflammatory syndrome can affect infants, children, and adolescents. It typically occurs four to eight weeks after a SARS-CoV-2 infection. It is also known as Pediatric Inflammatory Multisystem Syndrome (PIMS). In contrast, the symptoms in older children are more similar to toxic shock syndrome.
A research team from Charité and the German Rheumatism Research Center (DRFZ) therefore investigated whether a reactivation of the Epstein-Barr virus (EBV) could play a role. The Epstein-Barr virus is a globally widespread pathogen that causes mononucleosis but remains in the body for life. It is usually kept in check by the immune system. However, after a COVID-19 infection, this balance might be disrupted. As a result, the virus can become active again and possibly trigger a massive immune response.
The Following Was Investigated
The scientists specifically looked for traces of EBV in the blood of children with MIS-C. They also compared the results with children who had overcome COVID-19 without MIS-C. Immunological factors that could favor the resurgence of the infection were also examined. A total of 145 children aged two to 18 years were studied, who were treated for MIS-C in hospitals in Berlin, Lyon, Naples, Ankara, and Santiago. For control, 221 children who had a COVID-19 infection without MIS-C were included.
Blood samples from all participants were analyzed to look for traces of Epstein-Barr virus reactivation. The researchers searched for viral DNA sequences, specific antibodies, and T-cells that are active against the virus. A particular focus was on the investigation of the messenger substance “Transforming Growth Factor Beta” (abbreviated as TGFβ), which regulates the immune system and may inhibit the fight against the Epstein-Barr virus.
The study combined immunological analyses with molecular biological detection methods to determine whether a reactivation of the Epstein-Barr virus plays a role in MIS-C and whether the messenger substance TGFβ is involved in this process.
High Concentrations of the Messenger Substance Are Crucial
The researchers found clear evidence that a reactivation of the Epstein-Barr virus (EBV) could be related to the development of multisystem inflammatory syndrome.
In children with MIS-C, researchers found traces of the Epstein-Barr virus in the blood significantly more often than in children without multisystem inflammatory syndrome.
Additionally, MIS-C patients had elevated levels of specific antibodies and T-cells against EBV, indicating an active fight against the virus (immune response). T-cells are specialized immune cells that actively recognize foreign structures once they are presented on the body’s own cells. They also actively defend the body against pathogens and undergo strict control during their development in the thymus. This ensures that they do not attack the body’s own structures–an important mechanism for preventing autoimmune diseases.3
Crucial was the discovery of unusually high concentrations of the messenger substance TGFβ. This inhibited the function of immune cells and could have prevented them from effectively destroying the infected cells. This could lead to a vicious cycle: The Epstein-Barr virus multiplies uncontrollably, the immune system responds with more and more pro-inflammatory cells–but these are blocked in their function by the messenger substance TGFβ. The result is an extreme inflammatory reaction that can damage organs. However, it remains unclear whether TGFβ is directly responsible for the excessive inflammation or if it is merely a side effect of the immune response.
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What Is the Significance of the Results?
The study reveals possible new connections in the development of MIS-C. It provides evidence that COVID-19 may promote a reactivation of the Epstein-Barr virus and subsequently trigger an uncontrolled inflammatory reaction. It also showed that the messenger substance TGFβ may play a crucial role in this process. These findings represent an important advancement in the research of MIS-C and could impact future treatment strategies.
So far, affected children are treated with cortisone and immunoglobulins to dampen the excessive immune reaction. The new findings suggest that a targeted blockade of TGFβ could be a promising therapeutic approach–however, further studies are needed to confirm this.
Furthermore, the findings could also be relevant for other COVID-associated diseases such as Long COVID. There is evidence that a reactivation of viruses may also play a role in Long COVID–possibly also influenced by TGFβ. However, further research is needed to verify this hypothesis.
Classification of the Study and Possible Limitations
The study provides strong evidence of a connection between Epstein-Barr virus reactivation and MIS-C. The methodology can be considered solid, as both blood analyses and immunological examinations were conducted.
However, there are limitations:
- The study shows a correlation between EBV reactivation and MIS-C, but no definitive proof of a causal relationship.
- It remains unclear why some children are affected by MIS-C and others are not, even though they carry the Epstein-Barr virus.
- The hypothesis that blocking TGFβ could be an effective therapy needs to be further tested in clinical studies.