Long COVID: A New Perspective on Problem Solving

MedTour continues to keep you updated on medical news from Ukraine and around the world. In this meeting, leading Ukrainian doctors discussed the relevance of post-COVID syndrome and new approaches to its treatment. In particular, the issue of the effectiveness of stem cell therapy for the consequences of coronavirus infection was considered.

Oleksandr Nykonenko: Good afternoon, dear colleagues. Today we aim to discuss the issue of post-COVID syndrome. The following experts are participating in the discussion:

• Olha Holubovska is a Professor, Head of the Department of Infectious Diseases at the Bogomolets National Medical University, President of the All-Ukrainian Association of Infectious Disease Specialists, Honored Doctor of Ukraine;
• Mykola Kolesnyk is a Professor, Corresponding Member of the National Academy of Medical Sciences, President of the Association of Nephrologists, Honored Scientist and Technology Figure of Ukraine;
• Andrii Pavlov is a Ph.D., Senior Researcher at the Romodanov Neurosurgery Institute;
• Andrii Kovalchuk is a biotechnologist, Associate Professor at the Ternopil State Medical University, Director of the biotechnological company “Genom”;
• Oleksandr Nykonenko is an academician of the National Medical University, Professor at the Zaporizhzhia State Medical and Pharmaceutical University.

Today we are discussing post-COVID syndrome (Long COVID). This is a newly recognized post-COVID-19 condition that covers a wide range of symptoms and dysfunction of many organs. The seriousness of this pathology is determined by the large number of patients suffering from it. According to current data, up to 30-40% of people who have had COVID-19 experience post-COVID syndrome. For example, in the United States, today there are about 15 million people who are suffering from the consequences of coronavirus disease.

Many countries allocate significant funds for research and treatment of post-COVID syndrome. Over the past few years, the UK healthcare system has invested heavily in supporting people with long COVID. This includes the creation of special post-COVID services and medical facilities. Moreover, the UK has also developed guidelines for the treatment of post-COVID syndrome, which, among other measures, includes the use of stem cells.

Unfortunately, today there are no specific medications that could effectively treat long COVID. Instead, combination therapy is used, which in some cases involves the use of highly toxic drugs aimed at suppressing the immune system and inflammation. The search for more effective and safer treatment methods has led to growing interest in the use of mesenchymal stem cell therapy. There are many studies in world practice that have demonstrated the effectiveness of cell therapy.

Dear Professor Holubovska, you are a leading specialist in COVID. We admire your energy in speaking out and communicating to the public how to treat the acute stage of COVID. How is Ukraine handling the assistance provided to patients with post-COVID syndrome? How serious is this condition and does it require special attention?

Olha Holubovska: Good afternoon, dear colleagues. Thank you for your question. It is really very interesting to me, since, as you correctly mentioned, I am an infectious disease specialist. We focused our attention on treating seriously ill patients during the most active period of COVID. However, now I tell my colleagues and in my lectures that our time is already ending, and the period of post-COVID disorders has begun. Why? Firstly, the Omicron variant, which on the one hand reduced mortality by 90%, which is great. But on the other hand, it acts as a litmus test that reveals genetically determined or hidden problems in patients’ bodies.

Moreover, much about the COVID remains unknown. For example, influenza was discovered in 1933 and is the most studied virus after the human immunodeficiency virus (HIV). At the same time, we still often encounter new information. Today, COVID is a systemic, immune-mediated and poorly understood disease.

I recently returned from Germany, and I can say that clinics are opening in Europe specifically for the treatment of post-COVID-19 conditions. They are overcrowded. Nobody knows exactly what to do about this yet. We are just beginning to study this problem. There are people who become disabled and experience a decline in quality of life. That is why this issue must be addressed.

Practicing physicians frequently encounter undifferentiated conditions, such as nervous system damage. These conditions lead to the greatest reduction in quality of life in patients with long COVID. People experience symptoms such as brain fog and polyneuropathy. There is a surge in autoimmune disorders that cannot be precisely diagnosed.

Therefore, I believe that we must unite to study this issue and help people, based on the single principle “Do no harm!”. As you remember, COVID was not well understood initially, however, in many countries – in China, Italy, Spain, and Ukraine – developed treatment protocols based on the mechanism of disease development and laboratory changes. Even so, disputes continued, and in some cases, doctors were faced with restrictions on treating seriously ill patients.

Oleksandr Nykonenko: Professor Holubovska, so it seems that a person might think they’ve recovered from COVID, believing that everything is fine, but in reality, the problems are just beginning?

Olha Holubovska: Yes, and for some people, it is not entirely clear why. Interestingly, the severity of post-COVID disorders does not always correlate with the severity of the acute period of COVID itself. Women are disproportionately affected, as they experience long COVID more often than men.

Oleksandr Nykonenko: How do you determine the appropriate treatment when data suggest that patients can present up to 60 different symptoms?

Olha Holubovska: More than that. To date, there are more than 287 post-COVID-19 conditions.

Oleksandr Nykonenko: How is the treatment carried out? You’ve been to Germany, how do they handle it there?

Olha Holubovska: Treatment is carried out by a multidisciplinary team of specialists. However, I must emphasize again that therapy is very challenging because patients are symptomatic, yet all the standard tests we are accustomed to using often appear normal. Only recently have they started talking about the fact that certain deviations are observed in immunograms. Regarding treatment, I would like to give an example. Paul E. Marik is a man who literally saved half the globe. He released his protocol, which included hormones that were banned globally for another year. And now Paul Marik has a protocol from the Front Line COVID-19 Critical Care Alliance (FLCCC), which he leads, for treating long COVID. It involves the use of low doses of glucocorticosteroids.

However, there are nuances here as well. For instance, we prescribe glucocorticosteroids when C-reactive protein levels are elevated. I asked the head of a clinic specializing in post-COVID disorders if they rely on this protein level when prescribing medications. The answer was no.

Oleksandr Nykonenko: Professor Holubovska, we again return to the fact that current treatments focus on suppressing the immune system.

Olha Holubovska: Yes, unfortunately, that is the case for now.

Oleksandr Nykonenko: There is a lot of data in the literature that many patients who have had COVID suffer from kidney disease. Professor Kolesnyk, have you observed such cases?

Mykola Kolesnyk: First of all, I would like to sincerely thank you for the opportunity to communicate with colleagues whom I have known for a long time, and who are true professionals in their fields. I would also like to highlight several important aspects of this issue. A brief preamble: all kidney damages currently are divided into three main groups: acute kidney injury, acute kidney disease, and chronic kidney disease.

Why is this important? It is crucial, first of all, because COVID-19 infection can trigger any of these conditions, the first two of which are life-threatening and extremely serious. On the other hand, patients who suffer from these conditions may become ill with COVID, which contributes to their accelerated progression, and in this case also becomes life-threatening.

It is important to emphasize that acute kidney injury lasts for up to 7 days, while 7 to 90 days corresponds to acute kidney disease. If the patient survives (either in the case of combined COVID with kidney disease or in the case of kidney disease caused by COVID), they develop chronic kidney disease, which subsequently can progress to the need for hemodialysis, peritoneal dialysis, or kidney transplantation. This makes the issue extremely significant, especially considering that it is currently poorly managed.

Oleksandr Nykonenko: It seems difficult to control, doesn’t it?

Mykola Kolesnyk: Not at all. First, a urine test is needed (to determine the level of albumin and proteinuria), and secondly, kidney function should be evaluated (to determine the concentration of creatinine and calculate the glomerular filtration rate).

Returning to post-COVID syndrome, this term is currently very vague and undefined. And, as is usually the case, it is very difficult to conduct research. Nevertheless, we recently completed a three-year fundamental study on the mechanisms of post-COVID syndrome in patients treated with hemodialysis and the identification of therapeutic targets. This is just a partial answer to the question: what, how, and when to address.

Long COVID is observed in approximately 80% of patients undergoing hemodialysis. Its incidence is much higher than in the general population, which confirms the fact that this category of patients is the most vulnerable. Now, regarding the mechanisms of post-COVID syndrome, there are three of them: immune, metabolic, and endothelial (it is somehow connected with the first two mechanisms and is characterized by damage to the microvascular basins of various organs and systems with corresponding clinical symptoms and laboratory manifestations).

Based on this, how should post-COVID syndrome be managed in this patient group? First, it is the definition of life-threatening conditions, understand their mechanisms, and determine appropriate therapeutic targets. Second, identifying conditions that impair quality of life and longevity in the medium and long term.

Oleksandr Nykonenko: I would also like to raise the very serious issue of COVID in individuals with transplanted organs. They are at high risk both during acute COVID and during long COVID. We have treated kidney transplant patients who have had COVID. Among this category of patients, approximately 10-15% lose their transplanted kidneys. This highlights the need for a serious approach both during the acute phase of COVID and afterwards when the function of the transplanted organ gradually begins to decline.

We have used cell therapy with these patients and have seen positive results. Stem cell therapy in this area is still in its early stages of development. I remember how we started organ transplantation in our country. We were very far from those people who supported cell therapy. The situation is similar now. Stem cells have found many areas of application, including in the treatment of acute COVID and post-COVID-19 conditions. However, cell therapy has not yet reached the level where we could say that it should be used in all cases. So I believe someone should start integrating this procedure into everyday practice.

When discussing long Covid, the most prominent symptom is brain fog. This indicates the significance of the problem of brain damage. Today there is even an opinion that COVID is a neurological disease. Dr. Pavlov, you are well-versed in this issue. Could you explain how it can be addressed?

Andrii Pavlov: First, I would like to thank you for organizing this meeting, as a lot of clinical experience has been accumulated, but there is no solution to the problem of long Covid yet. We need to meet as often as possible to discuss these issues.

Neurological practice has changed significantly due to COVID and the so-called long COVID. Now, when patients undergo examination, they also take a test to determine the antibody levels. We know that during the acute period of the disease, a cytokine storm occurs – hyperactive immune system response. However, even during the prolonged period (one and a half to two years), regardless of vaccination, antibody levels can exceed 10,000, which already leads to immune-mediated processes affecting the nervous system.

From the perspective of the nervous system, COVID consequences can be broadly categorized into neurological, psychological, and even psychiatric conditions. Today, in psychiatry, I can say that only schizophrenia cannot be provoked or worsened by COVID. All other conditions, including adjustment disorders and any deterioration in psychological deterioration, can be associated with long COVID.

It is also essential to discuss how the coronavirus damages neurons. The virus freely crosses the blood-brain barrier and, in addition to its direct effects, can cause immune inflammation and damage to healthy cells over the long term. This leads to impaired neuron function, irreversible damage, and even disruption of neurogenesis – the process of neuronal repair and renewal. This can provoke the development of a separate disease or worsen existing ones, such as Alzheimer’s disease, Parkinson’s disease, or amyotrophic lateral sclerosis.

Oleksandr Nykonenko: Dr. Pavlov, do you have any experience using stem cells?

Andrii Pavlov: Unfortunately, this procedure is not yet regulated in our country, and there are no international approved protocols for its use. However, in some cases, at the request of patients, we have used mesenchymal stem cells for immunomodulation. In our practice, we treated patients of a relatively young age (50-60 years old) who already had cognitive deficits that allowed us to diagnose Alzheimer’s disease. All patients were vaccinated, and after the administration of mesenchymal stem cells, their test results improved to levels typically observed in healthy individuals. The tests were performed approximately two months after cell therapy.

Oleksandr Nykonenko: What was the cell dosage used?

Andrii Pavlov: For intravenous administration, it was 1 million mesenchymal stem cells per kilogram of the patient’s weight. If intrathecal administration, the initial dose was no more than 20–25 million cells in total.

Oleksandr Nykonenko: Do you use the intranasal method?

Andrii Pavlov: Yes, we do. In my opinion, it is slightly less effective than intrathecal administration, but on the other hand, it is associated with a much lower risk of inflammatory complications in the central nervous system. Additionally, it is relatively simple, so any doctor can perform it.

Oleksandr Nykonenko: Does the dosage change in this case?

Andrii Pavlov: Since the nasal mucosa has limited capacity, we use no more than 5 million cells for intranasal administration.

Oleksandr Nykonenko: Is this method also applicable for treating other brain diseases?

Andrii Pavlov: Absolutely correct. There is an opinion that the brain is an instrument that adapts to a changing external environment.

Olha Holubovska: May I add something? Currently, the mechanisms of pathogenesis are being actively studied. The first is the possibility of virus persistence, though this has not yet been proven. Viral particles found in the brain, as well as in other organs and tissues, do not have a cytopathogenic effect, and are therefore considered components of a non-viable virus. However, antiviral therapy is still prescribed to treat long COVID. I don’t find it particularly effective. Most authors believe that a smoldering immune inflammation occurs in the body. This inflammation may be induced both by the virus itself and by its components.

At this point, most people have recovered from COVID. Many people are vaccinated. These processes overlap, especially when considering the differing mechanisms of action among vaccines. This mechanism has a specific significance and is still being studied. Therefore, when the administration of any immunomodulators, including glucocorticosteroids, or antioxidant therapy, even inhalation-based, has shown positive effects.

Oleksandr Nykonenko: I think everyone would agree that the initial damage occurs in the lungs, which suffer greatly. Approximately 20% of patients subsequently develop severe pulmonary fibrosis, which requires special therapy using expensive, but unfortunately ineffective, drugs. The treatment is poorly tolerated by patients, and fibrosis itself is a life-threatening condition. Professor Kovalchuk has experience in treating this condition with stem cells. Could you tell us about it?

Andrii Kovalchuk: Thank you to everyone present for today’s meeting. First of all, I would like to discuss the possibility of using cell preparations for the treatment of both long COVID pneumonia and for suppressing the immunological cytokine storm.

During the peak of the pandemic, more than 20 clinical cases were registered concerning the use of stem cells for the treatment of COVID-19 pneumonia. At that time, everyone was interested, first of all, in the treatment of the acute period. Various cellular preparations were used for this purpose, including hematopoietic stem cells, umbilical cord blood cells. The methods of administration were also different: inhalation, intravenous, and combined. Many different protocols were proposed. To this day, only the most effective of them remain. Currently, the use of mesenchymal stem cells, especially donor ones, is considered optimal. The cells’ origins can vary: bone marrow, perivascular space of the umbilical cord, etc.

Previously, when the Coordination Center for Transplantation of Human Organs, Tissues and Cells was operating, clinical studies were conducted there to evaluate the effectiveness of mesenchymal stem cell therapy in the treatment of COVID pneumonia. The first institution in Ukraine to apply such treatment was the Institute of Cell Therapy. Certain clinical studies were conducted and developments were made. However, the Coordination Center was later disbanded, and some of its functions were transferred to the State Expert Center. Today, it is much more difficult to conduct such clinical studies.

Oleksandr Nykonenko: The organizational aspect is certainly very important, and I am sure it will be resolved. I would like to learn more about the results of stem cell treatment for fibrosis. You are the only person in Ukraine who knows this technique and has applied it in practice.

Andrii Kovalchuk: Yes, patients come to me with pneumofibrosis at different stages and, accordingly, with different degrees of respiratory failure. There are problematic patients whom we treat today with stem cell preparations of donor origin with appropriate informed consent. This treatment is usually performed in private clinics.

Most often, the protocol involves the administration of large doses of mesenchymal stem cells. For example, in one course of therapy, a patient weighing from 75 to 100 kg receives up to 500 million cells.

Oleksandr Nykonenko: Does the technique involve three injections?

Andrii Kovalchuk: This involves administering between 3 to 5 intravenous doses, depending on the clinical situation.

Oleksandr Nykonenko: Do you use the inhalation method?

Andrii Kovalchuk: Such a technique does exist. It is registered in the United Arab Emirates. A group of scientists has proven the effectiveness of hematopoietic stem cells. They developed a special nebulizer to deliver cellular medications directly to the lungs.

Olha Holubovska: I would like to highlight one more issue. It was observed during the treatment of acute COVID, especially in severe cases, and it remains relevant today. What I mean is that in infectious pathology and in medicine in general, doctors need to intervene before the patient’s body is completely exhausted. Treatment often begins when the lungs are almost destroyed. Some specialists even say that COVID is similar to acute respiratory distress syndrome because the lung damage resembles a chemical burn. Therefore, it is vital to start treatment as early as possible. Delaying until the affected organ and immune system are exhausted is not acceptable. Specialists need to convene to develop effective therapeutic protocols. In the US, there are examples of successful treatment of long COVID with stem cells.

I would also like to touch on the topic of liver transplantation. Currently, we perform transplantations for patients with moderate and severe conditions, and these surgeries require a waiting period. Therefore, timely detection of compensated liver cirrhosis is a crucial challenge. I have examples of cases where patients who underwent stem cell therapy at this stage abroad have lived for decades.

Oleksandr Nykonenko: Professor Holubovska, we must honestly say that most patients who suffer from post-COVID-19 conditions fall into the category of severe chronic illness. Perhaps all of them need stem cell therapy to reprogram their immune systems. Our task is to identify the group of patients who require this treatment. However, the government funding program does not mention long COVID.

Olha Holubovska: Unfortunately, after what we witnessed with COVID treatment, I doubt we can expect anything positive regarding the development of therapy for long COVID. However, it is important to inform patients. We need to explain what types of stem cells exist and how they work, emphasizing that the treatment is safe.

Oleksandr Nykonenko: Yes, millions of studies have proven that mesenchymal stem cells are absolutely safe.

Olha Holubovska: Today, there is a severe lack of information in society, and this treatment is also quite expensive.

Andrii Pavlov: I have a question. As Professor Holubovska mentioned, patients often undergo ineffective drug treatment for a long time. Could the amount they spend on these treatments exceed the cost of stem cell therapy?

Olha Holubovska: Yes, I wrote about this in my monograph. If immunosuppressive treatment is prescribed, the response should be within 24 hours, maximum 48 hours. If there isn’t, the therapy should be changed! What often happens, however, is that after 10 days of dexamethasone treatment, the therapeutic response is zero. If a patient does not respond to treatment, the treatment must be changed. This principle applies not only to COVID, but to any other infectious disease.

Oleksandr Nykonenko: Professor Kolesnyk, could you tell us if the number of patients on dialysis increased during the coronavirus period?

Mykola Kolesnyk: If you mean whether the number of patients increased specifically due to COVID, it is hard to say. No such statistical studies were conducted. However, it is absolutely certain that post-COVID mortality among patients undergoing hemodialysis is higher than in the general population.

Returning to the issue of informing the general medical community, at the recent World Congress of Nephrology, the three of us (Mykola Kolesnyk, Oleksandr Nykonenko, and Andrii Kovalchuk – MedTour note) delivered presentations to the nephrology community, which sparked significant interest among nephrologists.

I believe the time is approaching when mesenchymal stem cell transplantation will begin its history of use in Ukraine for patients with kidney diseases. This is crucial, since the average effectiveness of current treatment is 40%, according to various sources. That means that 60% of treated patients move towards the use of dialysis therapy and transplantation. Importantly, only 3.5% of patients with non-diabetic kidney damage and 1.5% with diabetic kidney damage survive long enough to access these treatments. While waiting for this treatment, many patients die, mainly due to cardiovascular complications. That highlights the vascular mechanism of damage to organs and systems that lead to fatal outcomes.

Let us consider the question of when it might be appropriate to use mesenchymal stem cells in patients with kidney damage. I absolutely agree with Professor Holubovska that the timing of treatment is key, both for its effectiveness and to prevent discrediting the treatment method itself. Because if cell therapy is applied where it is not needed, the result will be corresponding.

In conclusion, I would like to emphasize that the search for new, unconventional treatments for kidney diseases is ongoing. Mesenchymal stem cell transplantation has already been accepted as a viable approach by both the practical and scientific communities in nephrology. The positive results observed in the treatment of acute kidney injury, diabetic nephropathy, and other diseases require intensification of this type of research. Such studies are necessary, especially since the annual mortality rate from kidney diseases now surpasses that of cancer and is the seventh leading cause of death worldwide. By 2030, it is projected to rank third.

Oleksandr Nykonenko: Dear colleagues, I believe we have addressed very important issues for our country and our population, since a large number of practicing doctors are not yet familiar with the complexities of the conditions they are currently facing. As a result, most patients with specific symptoms end up with a specialist who treats the symptom but not the underlying disease causing it. Let us set the following tasks: firstly, we will implement the mesenchymal stem cell treatment method, since it is quite effective, and secondly, we will elevate the discussion of organizing care for patients with post-COVID syndrome to a higher level. It is necessary for healthcare leaders to pay attention to this serious issue, which may soon become global.

Thank you all very much, and special thanks to MedTour for using its resources to help organize this very important meeting.

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