Scientists are getting closer to explaining the mystery of the so-called long COVID. The syndrome of prolonged symptoms, affecting people who have undergone infection with the SARS-CoV-2 virus, can concern up to almost half of all infected people. However, there is still no answer to the question of what causes many of the symptoms that are part of the post-COVID syndrome. Prof. dr hab. Katarzyna Piwocka from the Nencki Institute of Experimental Biology, Polish Academy of Sciences in Warsaw is looking for answers. Her research is funded by European Funds from the Intelligent Development Operational Programme within the TEAM-TECH Core Facility programme of the Foundation for Polish Science.
Even patients who have undergone COVID-19 asymptomatically or very mildly are at risk of serious long-term effects of the infection. Lasting for more than a few months, the symptoms of post-COVID syndrome affect virtually all systems and organs of our body. They can include respiratory and circulatory problems, chronic fatigue unrelated to exercise, neurological symptoms including taste, smell, concentration and memory disorders, headaches and dizziness, blood clotting disorders and thromboembolic complications, and even anxiety and depression.
Such a wide range of possible symptoms, which can occur singly or in various combinations in patients, leads researchers to believe that not one mechanism, but multiple biological consequences of virus infection are responsible for post-COVID syndrome. Importantly, recent studies show that a huge percentage of all infected patients may be affected.
“Recently, there have been results analysing numerous studies, involving cohorts of several hundred thousand people in total, which have collected very medically relevant information”, says prof. dr hab. Katarzyna Piwocka. “Just as our initial observations indicated, post-COVID syndrome, or “long COVID”, affects not only people who have undergone “acute” COVID, i.e. the severe form of the disease, but also those who have undergone it minimally symptomatic or even asymptomatic. Post-COVID syndrome has been found to affect 43 per cent of all people who have undergone the infection, and among those who have undergone the severe form of the disease, this percentage exceeds 60 per cent”.
This means that the long-term consequences of COVID-19 will affect hundreds of millions of people worldwide. The importance of this phenomenon is evidenced by the fact that the World Health Organisation (WHO) has already defined clear criteria for this post-COVID syndrome and presented a list of 33 symptoms that could be a sign of its occurrence, but more are still being added to this list. Recent studies indicate that the previously mentioned symptoms may be joined by symptoms such as hair loss and decreased libido. Metabolic disorders, inflammation of organs related to glucose and insulin metabolism and so-called “post-COVID diabetes” have also emerged among the symptoms.
Prof. Piwocka’s team is investigating what effects the undergoing of COVID-19, in its various forms, has on the long-term “remodelling” of patients’ immune systems and the functioning of their bodies. The researchers asked whether people who are even six months after undergoing a Sars-CoV-2 infection, or so-called convalescents, are “immunologically healthy”, what their immune status looks like depending on the severity of the disease, and how these changes correlate with the symptoms of long COVID. To do this, they are using advanced flow cytometry, a technique that allows very precise determination of the properties of cells determined by simultaneous measurement of several dozen parameters labelled with fluorescent dyes.
Used by prof. Piwocka’s team, the first 5-laser spectral cytometer in Poland allows the simultaneous assessment of 30 or more parameters of each blood cell. Such multi-parameter analyses of protein markers at the single cell level allow the dynamic state and function of immune cells to be examined.
“This provided capabilities incomparable to those of classical cytometry and was of great importance to our research. We then subjected the data obtained to advanced bioinformatics analysis, which allowed us to identify new subpopulations of immune cells, even unique and rare ones, specifically found in the different groups of convalescent patients examined. Importantly, our research was conducted over six months, so we were able to see how the polarity of immune system cell status and function changes over time”, explains the researcher.
The team found that in patients who underwent COVID-19, a very high level of immune system activity persists for months afterwards, ultimately leading to the appearance of markers associated with ageing and the so-called exhaustion state, along with elements of chronic inflammation. This is a very serious and unfavourable disturbance of bodily functions. It particularly affects patients with a moderate to severe course of infection. However, long-term symptoms can affect all convalescents.
“We also observed abnormalities in immune function and status in people who underwent COVID-19 in the mild form, although these were quite different. We certainly cannot treat all of these people as immunologically healthy”, explains the researcher. “Some parameters concerning the functioning of the immune system were altered even six months after the infection, which means that for a very long time the body is not able to return to the pre-infection baseline, if such a return is possible at all. Interestingly, we also observed long-lasting changes in people who had undergone COVID-19 very mildly, and our advanced follow-up research indicates the presence of an immune signature specific to this group. This clearly indicates that research, diagnosis and potential treatment should be extended to all people with symptoms of post-COVID syndrome, not just those who have undergone a severe form of the disease.”
“While cardiopulmonary symptoms tend to correlate with severe COVID, i.e. the more severely patients went through the infection, the higher the proportion of them had shortness of breath or breathing difficulties, symptoms related to neurological symptoms and chronic fatigue do not correlate with how severely COVID was experienced”, warns prof. Piwocka.
Similarly, recent data also do not show a clear correlation between thromboembolic disorders and the acute form of the disease course. This means that a completely different mechanism functions in these cases. And there is a particular danger associated with this, because patients who go through the disease lightly can also expect long-term effects of the infection. We still do not know what the long-term consequences of the pandemic will be for our health and the functioning of society. However, many experts and doctors believe that the long-term effects of experiencing COVID-19 could be on such a scale as to exceed healthcare capacity, and many countries are launching entire healthcare programmes dedicated to these patients.
The key task now is to develop methods to rapidly identify those suffering from long COVID/post-COVID syndrome and to identify the mechanisms leading to specific symptoms, especially the neurological and thromboembolic ones, which remain the most mysterious for the time being. Such a direction is already evident in many countries.
“Today, there is no longer any doubt that vaccination and subsequent doses of it greatly reduce the risk of death and severe COVID, hence it is extremely important that we vaccinate. Analyses around the world are still in progress, but they indicate that vaccination only partially protects against the occurrence of long COVID, which relates to our observations that long COVID also affects people who have undergone the disease mildly and reaffirms the importance and validity of our research. Our current research is focused on this very group – we want to better understand the changes that occur in people who have undergone a mild form of COVID-19 and suffered a post-COVID syndrome, and perhaps identify specific predictive immune signatures that would allow earlier diagnosis and treatment of this group,” prof. Piwocka states.
The results of prof. Piwocka’s team’s work were published on 10 June 2022 in the journal Frontiers in Immunology. Source: Wiech M, Chroscicki P, Swatler J, Stepnik D, De Biasi S, Hampel M, Brewinska-Olchowik M, Maliszewska A, Sklinda K, Durlik M, Wierzba W, Cossarizza A, Piwocka K. Remodeling of T Cell Dynamics During Long COVID Is Dependent on Severity of SARS-CoV-2 Infection. Front Immunol. 2022 Jun 10;13:886431. doi: 10.3389/fimmu.2022.886431.
The TEAM-TECH Core Facility programme is implemented by the Foundation for Polish Science with EU funds from the European Regional Development Fund under the Intelligent Development Operational Programme, Axis IV: Increasing the scientific and research potential, Measure 4.4 Increasing the personnel potential of the R&D sector.