On January 13, 2023, a summary of the worldwide available literature (review) on Long COVID was published in the leading journal Nature Reviews, written by Hannah E. Davis, Lisa McCorkell, Julia Moore Vogel & Eric J.Topol. (Long COVID: major findings, mechanisms and recommendations). The authors discuss the most important findings to date based on five different hypotheses that may underlie the development of complaints in Long COVID.
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After a corona infection
Long COVID is a multisystem disease that often includes severe symptoms following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
Biomedical research has made significant progress in characterizing disease processes and identifying potential risk factors. Similarities between ME/CFS (Chronic Fatigue Syndrome) and Long COVID have laid the foundation for scientific research in this area. Approximately 10% of people who have had a corona infection develop the disease Long COVID. It is estimated that at least 65 million people worldwide now have a Long COVID symptom pattern. Long COVID is a multisystem disease in which more than 200 symptoms have been identified with traceable effects on multiple organ systems. Symptoms can persist for years in some cases. Long COVID can occur in all age groups and is not always related to the severity of the acute phase of this disease. The diagnosis is most often made in the age group between 36 and 50 years and women. Long COVID also occurs most often in patients who have not been hospitalized and who have experienced a mild course of the infection. About vaccination 1 study showed no significant difference in the development of Long COVID between vaccinated and unvaccinated individuals. Other studies indicate that vaccines provide partial protection, with a reduced risk of Long COVID between 15% and 41%, with Long COVID continuing to affect 9% of people with COVID-19.
Children and Long COVID
Like adults, children with Long COVID also experience symptoms of extreme fatigue, post-exertional malaise (PEM: worsening of symptoms that occurs after all forms of exertion – physical, cognitive, social and psychological), cognitive dysfunction, memory loss, headache, orthostatic intolerance (POTS), sleep problems and shortness of breath. Several studies have shown that children infected with SARS-CoV-2 (corona) are significantly less likely to have a positive PCR test result than adults. This makes diagnosis more difficult. In children, this can lead to a situation where up to 90% of cases of the infection are therefore missed. Long COVID can affect all ages in children, including very young children.
Possible risk factors
Possible risk factors have now been defined that give a higher chance of developing Long COVID symptoms. These are the following possible risk factors:
- Female gender
- People with an autoimmune disease
- People with previous Pfeiffer's
- People with Q fever
- People with ADHD
- People with type 2 diabetes
- People with chronic hives
- People with connective tissue disorders such as rheumatism
- People with allergic rhinitis (chronically inflamed nasal mucosa)
- People of Hispanic or Latino descent
- Returning to work too soon after a COVID-19 infection may also be a risk factor due to insufficient recovery and balance.
A third of people with Long COVID appear to be healthy and not suffering from chronic conditions prior to infection.
Hypotheses about Long COVID
Several hypotheses have been described about the mechanism of how Long COVID develops in the human body. These have been broken down into five independent profiles that indicate what could be going on in a body (see Fig. 1 for graphical representation).
1 - Viral persistence: the theory that virus particles remain present for a long time or perhaps permanently in various organs such as the abdomen, intestines, lungs, brain, kidneys, reproductive organs, etc.
2 - Dysbiosis in the intestines: the permanent disruption of the balance between good and bad bacteria (including viruses) in the intestinal tract. A viral infection can disrupt the delicate balance between the various types of intestinal bacteria (colonies), which causes an inflammation process. In some cases, this inflammation remains active in the intestinal tissue. The white blood cells are then no longer able to protect the body against a new infection or have reduced function. This ultimately results in a weakening of the immune system. Restoring the balance in the bacterial colonies is the only way for a healthy intestinal immune system.
3 - Hyperimmunity: dysregulation of the immune system. With or without reactivation of underlying diseases, including previously experienced (often harmless) infections with, for example, a herpes virus (chickenpox virus) and the common Epstein-Barr virus (cause of Pfeiffer). According to this theory, the immune system is confused and immune cells in the body are incorrectly programmed and attack the body's own cells (autoimmunity).
4 -Blood vessels: The blood vessel walls can be damaged by the virus. An inflammatory process can then occur, particularly in the very small blood vessels. These small capillaries can become blocked by the inflammation due to so-called microclots. These in turn can cause poor blood flow. Reduced blood flow ensures less transport of nutrients and oxygen, which in turn causes damage to nerves and muscles. This can be an explanation for the often heard complaint: severe pain in the body.
5 - Dysfunctional signal processing in the brainstem and/or vagus nerve: the neurological signal transmission in the nervous system ensures a balance in dampening and activating organs and regulatory systems. Due to the toxicity (direct harm) of the virus on the nerve tissue, this system in the body is considerably disrupted. Often, neurological complaint patterns emerge over time, such as persistent headaches and POTS (dizziness when standing up). These complaints generally persist for a longer period of time.
Figure 1
Key findings
It was previously known in science that multiple viral and bacterial infections can cause a typical post-infectious clinical picture, such as that found in patients with ME/CFS (and Q fever). There are indications that Long COVID shares characteristics of these diseases. The basis of Long COVID seems to be primarily a multi-system disease that causes disruptions in various regulatory systems of the body. Due to the virus attack and the damage to various organ systems, abnormalities occur in blood vessels and possibly local clotting processes, but above all an altered immune system. The later and possibly permanent damage that is demonstrated in various tissues can mainly be attributed to an altered immune system that fights against the body's own cells. Due to a much higher activity than normal, this causes a reaction that we know as a persistent inflammatory process. Instead of a direct infection of cells by the virus.
The effects of Long COVID (damage) can manifest in many organs and there is a wide variety of symptoms (see fig. 2). These symptoms can sometimes overlap. In symptoms such as MCAS, ME/CFS, POTS, problems within the body can reinforce each other. Approximately half of patients with Long COVID are estimated to meet the criteria for the diagnosis of ME/CFS and a majority of patients with Long COVID experience post-exertional malaise (PEM).
Figure 2
Treatment
It is important to realize that there is a high urgency for the development and validation of biomarkers that can be used to confirm or deny the diagnosis of Long COVID. If suitable biomarkers become available, one or more mechanisms as outlined above as hypotheses can be tested in a patient. This targeted diagnostics can then also confirm that the hypotheses are indeed correct and underlie the difficult clinical picture called Long COVID. Although diagnostic tools exist for some components of Long COVID, these are generally still in development and not yet usable for use in regular clinical practice. There is certainly a relationship between the availability of biomarkers and the testing of new treatment methods. At the moment, there are no good biomarkers and no validated effective treatments for Long COVID. However, treatments for certain components of this disease have proven to be effective in selected patients. Many treatment strategies for ME/CFS are also effective for patients with Long COVID. Adapted training programs with the pacing technique (preventing physical and/or mental relapse after training by physiotherapists) are currently being used more and more and that was certainly not the case in recovery care after the first corona wave. Many new treatment options are currently still underexposed, often also due to a lack of funding for good and properly designed scientific research.
Incorrect diagnosis and treatment
Physicians unfamiliar with ME/CFS and dysautonomia sometimes misdiagnose patients with a psychiatric disorder; four in five patients with POTS are diagnosed with a psychiatric or psychological condition before receiving a POTS diagnosis, with only 37% retaining their psychiatric or psychological diagnosis after receiving their POTS diagnosis.
Exercise is detrimental to patients with Long COVID who have ME/CFS or post-exertional malaise. It should not be used as a treatment. Exercise worsened the condition of 75% of Long COVID patients, and less than 1% saw improvement.
Research
A research agenda for Long COVID is needed that builds on existing knowledge of conditions such as ME/CFS, dysautonomia and other conditions caused by viruses. Long COVID research should also be broadened with the scientific insights gained from research into patients with post-infectious diseases other than corona. In order to put the puzzle pieces together and better understand the mechanism behind the disease processes (pathophysiology) in post-infectious diseases. The next step is to improve diagnostic tools (targeted blood and stool examinations, new scanning techniques to map lung and brain function). Diagnostic and treatment options are currently insufficiently available. Multiple clinical studies are therefore urgently needed to thoroughly test new treatments based on the above-mentioned (hypothetical) biological mechanisms.
