Charité study provides evidence for long-held assumption

It has been suspected since the beginning of the pandemic that SARS-CoV-2 can cause chronic fatigue syndrome ME/CFS. A research group from the Charité - Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) is now showing in a well-controlled study that some of the COVID-19 sufferers actually have the full picture even after a mild course developed ME/CFS disease. The researchers also describe a second group of post-COVID sufferers with similar symptoms. Different laboratory values ​​indicate possibly different development mechanisms of the two clinical pictures. The study results are published in the journal Nature Communications*.

"Already in the first wave of the pandemic, the suspicion arose that COVID-19 could be a trigger for ME/CFS," says Prof. Dr. Carmen Scheibenbogen, Acting Director of the Institute for Medical Immunology at the Charité Campus Virchow-Klinikum. She heads the Charité Fatigue Center, which specializes in diagnosing ME/CFS (myalgic encephalomyelitis / chronic fatigue syndrome) - a complex disease characterized, among other things, by physical weakness. The center was visited by the first patients after a SARS-CoV-2 infection in the summer of 2020. Since then, there has been increasing evidence of a causal link between COVID-19 and the disease ME/CFS, which often leads to a high degree of physical impairment.

"However, it is not trivial to prove this assumption scientifically," explains Prof. Scheibenbogen. “This is also due to the fact that ME/CFS has not yet been researched very well and there are no uniform diagnostic criteria. However, through a very thorough diagnosis and a comprehensive comparison with ME/CFS sufferers who were ill after other infections, we have now been able to prove that ME/CFS can be triggered by COVID-19.”

For the study, experts from the Charité post-COVID network examined 42 people who had contacted the Charité Fatigue Center at least 6 months after their SARS-CoV-2 infection because they were still suffering from severe fatigue, i.e. one suffered from morbid exhaustion and limited resilience in their everyday lives. Most of them could only do light work for two to four hours a day, some were unable to work and could hardly support themselves. During the acute SARS-CoV-2 infection, only three of the 42 patients went to a hospital but did not require oxygen. 32 of them had experienced a mild COVID-19 course according to the WHO classification, i.e. they had not developed pneumonia, but usually experienced severe symptoms such as fever, cough, muscle and body aches for one to two weeks.

Because the SARS-CoV-2 infection occurred in the first wave of the pandemic, none of the people included in the study had been previously vaccinated. At the Charité, all those affected were examined by an interdisciplinary team from the departments of neurology, immunology, rheumatology, cardiology, endocrinology and pneumology with many years of experience in diagnosing ME/CFS. For comparison, the researchers used 19 people with a similar age and gender profile and a comparable disease duration who had developed ME/CFS after another infection.

For the diagnosis, the researchers took into account the so-called Canadian consensus criteria. "This list of criteria was scientifically developed and has proven itself in everyday clinical practice to clearly diagnose chronic fatigue syndrome," explains Dr. Judith Bellmann-Strobl, head of the multidisciplinary university outpatient clinic at the Experimental and Clinical Research Center (ECRC), a joint institution of the Charité and the MDC. She led the study together with Prof. Scheibenbogen. According to the criteria, almost half of the patients examined had full ME/CFS disease after their SARS-CoV-2 infection. The other half had comparable symptoms, but their symptoms after physical exertion, the so-called post-exertional malaise, were usually not as severe and only lasted for a few hours. In contrast, the worsening of symptoms in ME/CFS patients continued the next day. "So we can distinguish two groups of post-COVID sufferers with greatly reduced resilience," summarizes Dr. Bellmann-Strobl.

In addition to recording the symptoms, the researchers determined various laboratory values ​​and related them to the hand strength of the sufferers, which was reduced in most of them. "One of the things we found in people with less pronounced exercise intolerance was that they had less strength in their hands if they had an increased level of the immune messenger substance interleukin-8. In these cases, the reduced strength of the muscles may be due to an ongoing inflammatory reaction,” says Prof. Scheibenbogen. “In those affected with ME/CFS, on the other hand, hand strength correlated with the hormone NT-proBNP, which can be released by muscle cells when the oxygen supply is poor. This could indicate that reduced blood flow is responsible for muscle weakness in them.” According to preliminary observations by the scientists, the distinction between the two groups could also be reflected in the course of the disease. "For many people who have ME/CFS-like symptoms but do not develop the full picture of the disease, the symptoms appear to improve over the long term," explains Prof. Scheibenbogen.

The new findings could contribute to the development of specific therapies for post-COVID syndrome and ME/CFS. "However, our data also provide further evidence that ME/CFS is not a psychosomatic disease, but a serious physical disease that can be detected using objective examination methods," emphasizes Prof. Scheibenbogen. “Unfortunately, we can currently only treat ME/CFS symptomatically. That's why I can only recommend young people to protect themselves from SARS-CoV-2 infection by getting vaccinated and wearing FFP2 masks."

*Kedor C et al. Post COVID-19 Chronic Fatigue Syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity results from a prospective observational study. Nat Comm 2022 Aug 30. doi: 10.1038/s41467-022-32507-6

About ME/CFS
ME/CFS (Myalgic Encephalomyelitis / Chronic Fatigue Syndrome) is a serious disease that is usually triggered by an infection and often becomes chronic. The main feature is the "post-exertional malaise", a pronounced increase in symptoms after minor physical or mental stress, which only sets in after several hours or on the following day and lasts at least until the next day, but often also for several days or longer. It is associated with physical weakness, often headache or muscle pain, and neurocognitive, autonomic, and immunological symptoms. The incidence of ME/CFS in the global population was estimated at around 0.3 percent even before the pandemic. Experts assume that the number of people affected by the COVID-19 pandemic will increase significantly. Pathogens such as Epstein-Barr virus, dengue virus and enteroviruses have been known to trigger ME/CFS. ME/CFS cases have also been observed among people who contracted the first SARS coronavirus in 2002/2003. What is known as post-infectious fatigue, which can last for weeks to months in the context of many infectious diseases, must be differentiated from ME/CFS disease. Prof. Scheibenbogen has summarized the current state of knowledge on ME/CFS after COVID-19 in a current German-language publication.

Treatment of ME/CFS at the Charité
For the diagnosis and treatment of people with long-lasting symptoms after a SARS-CoV-2 infection, the Charité operates eleven special outpatient clinics at various clinics and institutes, which work together in the post-COVID network and care for different patients depending on their main symptoms. This also includes the Charité Fatigue Centrum, which is the contact point for people who have persistent severe fatigue, poor concentration and exercise intolerance at least six months after their COVID-19 illness and whose symptoms increase after exertion. As part of the CFS_CARE project, there is an interdisciplinary range of care for patients with ME/CFS, which includes a specially developed rehabilitation program.

To the study
The basis for the data now published was the study platform Pa-COVID-19. Pa-COVID-19 is the central longitudinal register study for COVID-19 patients at the Charité. It aims to examine those affected by COVID-19 quickly and comprehensively, both clinically and molecularly, in order to identify individual risk factors for severe forms as well as prognostic biomarkers and therapeutic approaches.

Photo: Handkraftmesser ©Charité/Anja Hagemann