
Berlin, 03.07.2024
Dexamethasone is one of the most important drugs in the treatment of severe COVID-19, but patients respond very differently to it. Researchers at Charité – Universitätsmedizin Berlin and the German Centre for Neurodegenerative Diseases (DZNE) have now discovered how the cortisone preparation influences the impaired inflammatory response and which patients benefit from it. Their method uses so-called single-cell analyses and gives hope for a precise prediction tool for other therapies and diseases. The results have been published in the scientific journal Cell*.
It has long been a mystery to medicine why certain drugs work so well for some people – and not at all for others. Researchers at Charité and the DZNE have now trialled a method that allows the molecular mechanisms to be uncovered more precisely than before. For their study, they investigated the molecular effect of dexamethasone in patients with severe COVID-19 who responded differently to the administration of the drug.
Thanks to so-called single-cell analyses, they discovered that a certain type of cell in the immune system is responsible for the completely contrasting reactions. They also discovered a way of predicting early on in the treatment whether it will work for the person in question. The approach tested here could also be useful in the treatment of other diseases.
Monocytes indicate course of therapy
At the beginning of the coronavirus pandemic, it became apparent that the immune system of people with a severe course of the disease often reacts excessively strongly to the virus. They were therefore given dexamethasone, a cortisone preparation that is administered for numerous diseases in order to influence the immune system. For many of those affected, treatment with dexamethasone brought a rapid improvement. In others, however, the condition remained critical, sometimes even worsening and people died. The current study results now provide information about what the drug does in the body when the therapy is effective.
“Our data show that the life-saving effect of dexamethasone is linked to the reaction of so-called monocytes,” says Dr Anna Aschenbrenner from the DZNE, who led the study together with Prof Florian Kurth from Charité and other colleagues. Monocytes belong to the white blood cells and form a central component of the immune system. “Some of the monocytes showed a response to the treatment – but only in those people in whom the therapy also brought about an improvement in their condition and who ultimately survived the infection,” says Anna Aschenbrenner. “Why the monocytes show this reaction in some patients and not in others is a mystery. However, it is also known from other diseases that dexamethasone does not work equally well in all people.”
Altered signature
Back in 2020, in one of the first studies on the immune response in people with severe COVID-19, researchers from Berlin and Bonn found an altered, pathological “signature” in monocytes – in simple terms, this is a kind of molecular fingerprint that reflects the characteristics of these immune cells. As the current study shows, dexamethasone treatment reversed these changes when the therapy was effective.
The special feature: “The response of the monocytes precedes the improvement in health status by several days,” says Florian Kurth from the Department of Infectious Diseases and Intensive Care Medicine at Charité. “If the immune cells respond early to dexamethasone, we can assume that the treatment will work. If they don’t, i.e. the therapy is not effective, we can use additional drugs to help those affected.” However, further research is still needed before the new method can be used in clinical practice.
The researchers were able to elucidate these processes with the help of single-cell sequencing. “This method allows each individual cell to be characterised individually. Such a detailed analysis of cell signatures allows insights into the body that were not possible just a few years ago,” says Prof Joachim Schultze, Director of Systems Medicine at the DZNE and also one of the lead authors of the study.
Using single-cell sequencing, the researchers analysed blood samples from people who were treated with dexamethasone at Charité for severe COVID-19 disease. The samples were systematically taken early on in the pandemic at different times during the course of the disease. When analysed, the reaction of the monocytes proved to be an indicator of the future course of treatment.
New approach for targeted drug development
“The significance of our results goes far beyond COVID-19,” emphasises Prof. Leif Erik Sander, also one of the study leaders. He is Director of the Department of Infectious Diseases and Intensive Care Medicine at Charité and head of a research group at the Berlin Institute of Health at Charité (BIH). “The combination of cleverly designed clinical trials with high-resolution molecular analysis can provide crucial insights into the mode of action of drugs. This approach could identify characteristics that predict the response to therapies in the early study phases of testing new drugs.” This could speed up drug development in the future and enable personalised therapies.
“I assume that this approach can also be transferred to other diseases,” says Florian Kurth. “Depending on the specific disease and therapy, different cells will be able to serve as indicators. As soon as they are identified using single-cell sequencing, established, simpler laboratory methods will also be sufficient to determine the meaningful cell changes.”
In research, this approach is known as “companion diagnostics” – the simultaneous accompaniment of a therapy through molecular analyses. Anna Aschenbrenner sees the application of the method in infectious diseases in particular: “Immune cells play a key role here and are easily accessible via blood samples. But there is also potential for non-infectious diseases with systemic effects, which ultimately affect the entire organism. This is because diseases such as cancer or even Alzheimer’s can also be reflected in the immune cells of the blood.”
*Knoll R et al. The life-saving benefit of dexamethasone in severe COVID-19 is linked to a reversal of monocyte dysregulation. Cell 2024 Jul 3. doi: 10.1016/j.cell.2024.06.014
Image: Thanks to single-cell analysis of blood samples, it is clear that dexamethasone can save the lives of people with severe COVID-19 by acting on certain immune cells, the monocytes © Charité | Arne Sattler