AII researchers have discovered why some patients become seriously ill after an infection with the coronavirus. These patients appear to produce many abnormal antibodies, which provoke an extreme and damaging inflammatory reaction. The researchers have a drug in mind with which they can counteract this derailed immune response, in order to help seriously ill covid patients in the ICU. This is an already approved medicine that is used for the treatment of autoimmune diseases.

Jeroen den Dunnen and Menno de Winther of Amsterdam UMC saw that seriously ill covid-19 patients produce extremely high and abnormal antibodies against the coronavirus, which greatly worsen the disease. The results were published in the scientific journal Science Translational Medicine (11 May).

Extreme inflammation reaction

Immunologist Jeroen den Dunnen explains: "During an infection your immune system makes antibodies. These protect you against viruses. This is the case with most people who are infected with the coronavirus. But in covid patients who become seriously ill, antibody production is disrupted. These patients not only produce a lot of antibodies, but also antibodies with a different structure. This causes an extreme inflammatory reaction in the lungs."

Menno de Winther, expert on immune cells: "The antibodies our body makes are shaped like a Greek Y. The top binds to the virus, while the tail binds to and activates immune cells in the lungs. We now know that the tail is different in patients who are seriously ill. To put it simply, it contains completely different sugar compounds. As a result, these antibodies activate the immune cells in the lungs far too strongly." This over-activation results in a cytokine storm. Den Dunnen: "This causes the immune system to go into overdrive and produce too many inflammatory proteins. The inflammatory reaction that was intended to attack the virus now also affects the body's own tissues. In addition, the blood vessels become leaky and the lungs fill up with fluid. The platelets also start to clot, causing blood clots everywhere. Admission to the ICU is often unavoidable and the prognosis for these patients is not too good.

Treatment

To counteract the serious consequences of a corona infection, it is not so much antiviral drugs that are needed, but drugs that suppress the immune response. That is why seriously ill patients are currently given such medicines, such as dexamethasone and tocilizumab. Den Dunnen: "These medicines do indeed have some effect, but the major disadvantage is that they flatten the entire immune system and you don't want that. A good immune response is still important." Thanks to their extensive knowledge of the immune system, the researchers were able to select drugs that specifically inhibit the inflammatory response caused by the abnormal antibodies, but leave the rest of the immune system intact. "The drug we studied, fostamatinib, prevents the immune cells in the lungs from reacting to the abnormal antibodies but still to the virus. This specificity makes this drug a promising candidate for treating seriously ill covid patients." Research into treating patients with this drug is still at the beginning. Because the drug is already registered for another disease, it does not have to go through all kinds of steps before it can be tested in humans. De Winther: "We now have the results of an initial study in which the drug was tested on 59 patients. In the group of 30 who were given the drug, fewer people died, there were fewer side effects and people recovered more quickly than the 29 patients who were given a placebo. On the basis of this study, a large follow-up study has now been started in more than 40 hospitals, which should show whether this medicine can be used to treat seriously ill covid patients".

Testing more drugs

De Winther and Den Dunnen, who work together in the Amsterdam Institute for Infection and Immunity, will not stop at this one medicine. Last year they received a grant from ZonMw to further investigate this mechanism and to test more candidate drugs. "The aim is to find drugs that work just as well as fostamatinib, or preferably better. We have several already approved drugs that we suspect may work in covid infection."