Prof Korte, what exactly is long COVID?
There is no exact definition of the term long COVID, neither in the professional literature nor in public perception. I understand it in the broadest sense to mean signs, symptoms and sequelae that persist or develop after an acute SARS-CoV-2 infection over a period of at least six weeks up to months and years. These may include, for example, memory and concentration problems, difficulty speaking, loss of smell, palpitations and dizziness, as well as shortness of breath. Symptoms are usually multi-systemic, can manifest in the form of a relapsing-recurrent pattern and exacerbate over time, with persistent, severe symptoms being possible even months or years after the actual infection. It is worth noting in this context that long COVID not only occurs after severe courses of COVID-19, but also in about six to ten percent of individuals who experienced no more than a mild course of this disease.
What specifically does the coronavirus do to the brain of those infected that leads to such long-lasting symptoms?
The following mechanisms might contribute to COVID-19-related cognitive impairment: The strong immune response to the SARS-CoV-2 virus causes neuroinflammation in the brain through systemic chemokines (signalling molecules of the immune system) and activated immune cells that migrate into the brain.
Cytokines of the central nervous system (another type of messenger molecules), chemokines and subsequently reactive microglia - a type of immune effector cells - dysregulate several types of nerve cells. They also disturb the myelin sheets, which are important for the speed of transmission of nerve impulses and for synaptic plasticity. They impair neurogenesis in the hippocampus, i.e. the formation of new nerve cells, and possibly trigger neurotoxic reactivity in astrocytes (a subtype of glia cells), each of which could impair the function of neuronal circuits and thus the performance of the brain. SARS-CoV-2 infection can reactivate latent herpesvirus infections, especially Epstein-Barr virus (EBV), which in turn can trigger further inflammation. Autoantibodies and T cells can also cause autoimmune-induced inflammation of the brain in patients and could contribute to sustained immune-mediated damage. Direct neuroinvasive infection, although rarely seen, can also lead to neuroinflammation and disrupt the energy metabolism of nerve cells, which can further trigger inflammation. Thrombus formation and narrowing of blood vessels can cause the oxygen supply to the brain to suffer, because the brain is particularly rich in small blood capillaries and is very dependent on the blood supply, as it does not store energy itself and metabolises only oxygen and glucose.
Are certain groups of people afflicted more commonly by long COVID?
Two-thirds of all afflicted individuals are women, most of them under 60 years of age and, remarkably, often after experiencing a comparatively mild course of COVID-19. Also people with diabetes, atopy and other autoimmune diseases make up risk groups. What is particularly remarkable is that, unlike life-threatening courses of acute COVID-19 disease, which manifest preferentially in men over 60 years of age, long COVID manifests twice as often in women as in men. This is exactly equivalent to the increased risk of women to suffer from autoimmune diseases.
What is the best way to protect oneself against long COVID and are there any treatment options if one gets it?
A triple vaccination against SARS-CoV-2 reduces the risk by 15 to 50 percent; the precise data are still unclear. What is certain though is that a vaccination means a reduction of the risk, although the vaccination alone cannot prevent long COVID. So basically, the most important thing would be to prevent infection altogether. In this context, I still recommend wearing an FFP2 mask in indoor spaces that are poorly ventilated and where you cannot comply with the distancing rules.
At this time, there are no established therapies directed at the cause yet. Some tests are ongoing to see if immuno-suppressant drugs effective against autoimmune diseases might also help long COVID patients. In this context, it is also being investigated whether antihistamines, which are normally used for hay fever, might also reduce long COVID symptoms. As another side aspect antihistamines may indirectly help to eliminate residual viruses in the intestine by changing the microbiome.
There are also initial promising studies of "hyperbaric oxygen therapy": In these studies, 100 per cent oxygen is used in a hyperbaric chamber, aiming to not only increase the oxygen saturation of the blood, but also to stimulate the formation of new vessels (angiogenesis), which can then replace vessels that are clogged due to the virus. This has also been shown to improve the adaptability (plasticity) of the nervous system to different stressors. However, the efficacy of these therapeutic attempts has not yet been conclusively proven in clinical studies. Therefore, they should not be carried out on one's own, as serious side effects cannot be ruled out in certain patient groups.
Interestingly, vaccination during an affliction by long COVID has also been shown to reduce symptoms in a subgroup of patients, as has the administration of the antiviral drug PaxlovidR. This may be due to the renewed stimulation of the immune system through the vaccination or medication against SARS-CoV-2 finally eliminating residual virus from the body.
A promising option for people with blood clots forming in narrowed blood vessels after SARS-CoV-2 infection is a treatment with anticoagulant drugs that dissolve these thrombi. Early clinical trials in this area are ongoing.
Which insights from your previous research have you found to be applicable to COVID-19 and are there any pertinent projects currently underway in your research group?
In a publication in 2018, my research group at the HZI, "Neuroinflammation and Neurodegeneration" (NIND), was able to show that, at least in mouse models, viral infections - even if they do not directly infect the brain - can lead to neuroinflammation, that the microglial cells are activated for a long period of time (three months in young animals, even longer in old animals) and that learning ability was impaired (Hosseini et al., JNS, 2018). Currently, in collaboration with the research groups of Andrea Kröger and Luka Cicin-Sain at the HZI, we aim to search for early biomarkers for long COVID and possible options for therapy. This work focusses on an activation complex in microglial cells, like the one we successfully used in a mouse Alzheimer's model in a publication a couple of years ago (Lonnemann et al., PNAS, 2020). This would prevent the onset of neuroinflammation. Alternatively, we are also investigating whether or not stopping ongoing neuroinflammation might be a therapeutic pathway. We have already collected some initial data on this in various mouse models, and published them (Lonnemann et al., elife, 2022). This must now be applied to the SARS-CoV-2 scenario, certainly also in collaboration with clinical groups and the German Center for Neurodegenerative Diseases (DZNE).
Interview: Andreas Fischer
Published: October 2022
