On October 3, 2024, an extensive review article appeared in the scientific journal Cell on the mechanisms of Long COVID and the path to possible treatment. This article could be seen as a follow-up to the article that appeared in mid-January 2023 in Nature Reviews Microbiology, about which C-support previously posted an extensive summary.
Below is a summary of this new paper by Michael Peluso and Steven G. Deeks of the University of California, San Francisco, and how it ties in with the earlier piece.
Definitions of Long COVID
In the article, the authors start by outlining the definitions used for Long COVID in 2024. It is characterized by a wide range of symptoms that persist for weeks to months after infection. The World Health Organization (WHO) uses a cut-off of two months of persistent symptoms that are not explained by another diagnosis. Other organizations use, for example, 3 months as a lower limit. Health organizations use different terms such as post-COVID, post-COVID syndrome and post-acute sequelae of SARS-CoV-2 (PASC), but, the authors write, internationally most patient organizations seem to prefer the most well-known term: Long COVID.
How much it occurs
The estimates of how much Long COVID occurs depend heavily on the definition used. If you only look at 'one or more new symptoms developed since the illness', it can be as high as thirty percent of people who have had COVID-19. But that also includes people who only lost their sense of smell for a few months and people who already had something before their corona infection, which only came to light afterwards, whether or not 'unmasked' by the virus.
The coronavirus is certainly not the only virus that can cause long-term complaints, but the virus relatively often leads to more serious complaints. A stricter definition of Long COVID, 'multiple long-term complaints several months after the corona infection', is met by 3 to 6 percent of people who have had COVID-19. The social impact team in the Netherlands made a calculation and arrived at 100.000 serious cases of Long COVID in the Netherlands. The percentage is significantly higher in women than in men.
Overlap with other post-infectious conditions
There is a lot of overlap between Long COVID and other infection-related chronic conditions such as ME/CFS and Lyme*. ME/CFS also occurs in many cases after a viral infection and sixty percent of Long COVID patients also meet the diagnostic criteria for this. The hope is that knowledge about Long COVID will also be of benefit to patients with these other chronic post-infectious conditions.
These diseases also usually involve so-called 'post-exertional malaise' (PEM), a severe relapse after exertion that makes it very difficult, if not impossible, to build up resilience through training. The authors write that for this reason patient representatives are very critical of interventions aimed at 'gradual build-up' of physical activities. Such interventions are not recommended for patients with PEM, they write, but patients without PEM could benefit from them, according to the authors.
Also, an overlapping feature is “postural orthostatic tachycardia syndrome” (POTS) – severe heart palpitations and dizziness when standing or sitting. POTS is a key sign of dysregulation of the autonomic nervous system, which causes these automated processes to malfunction. Other common symptoms include brain fog, fatigue, shortness of breath, muscle and joint pain.
A systemic disease
There is still some scepticism among the general public and also in the medical world as to whether Long COVID is 'real', the authors write. The fact that there is still no blood test or other diagnostic test based on so-called 'biomarkers' does not help either.
And this while it has become clear from various scientific research that the disease causes serious damage in various places and in various organ systems in the body. The article shows in various illustrations that Long COVID is a systemic disease that causes fundamental damage with consequences in various places in the body. Almost all organs can be affected: the genitals, blood vessels, kidneys, liver, intestines, lungs, pancreas and, not to forget, the brain.
Increasing insight into mechanisms
Slowly but surely, it is becoming clearer how Long COVID develops after the virus infection and what malfunctions often occur afterwards. According to the authors, these mechanisms can be divided into two categories: the underlying mechanisms that explain the disruption of all kinds of bodily processes ('upstream'), such as dysregulation of the immune system. And the mechanisms that explain how these disruptions lead to various symptoms ('downstream'), such as organ damage, disturbances in the nervous system (neuropathy), disturbed signaling between the intestines and the brain, and a disturbed function of the energy factories in the body cells, the mitochondria.
The fundamental disruptive mechanisms ('upstream') include, for example, persistent inflammatory processes, dysregulation of the immune system (with and without autoimmunity, where the immune system attacks the body itself) and in some cases possibly the persistence of the virus or parts of it. This could involve the well-known 'spike protein', which the virus uses to attach to cells so that it can enter them to multiply itself.
When the first cases of Long COVID emerged, most scientists believed that 'the coronavirus' (SARS-CoV-2) could not remain in the body for long periods of time. Other (cold-causing) coronaviruses did not do this either, as far as was known. However, more and more studies provide strong evidence that virus particles or fragments of them can still be present in the intestines for months. This could explain why many patients continue to suffer from inflammation, which in turn causes damage to the rest of the body.
The virus, or the body's response to it, also appears to be able to disrupt blood clotting for a long time, causing so-called 'microclots or very small blood clots' to form in the smallest blood vessels of our body, the capillaries. These clots would cause various organs, including the lungs, to function less well, because the blood supply is disrupted. This could explain, among other things, why many Long COVID patients remain very short of breath without their lungs being visibly affected.
Another mechanism that is receiving a lot of attention from scientists is the reactivation of other viruses in the body. These viruses have gone into hiding in the body after a previous infection, often years earlier, and are resurfacing due to the COVID-19 infection. This may be 'simply' because this infection puts a heavy burden on the immune system, or there may be another mechanism at play, such as the previously mentioned autoimmunity. The Epstein-Barr virus in particular has been reactivated in relatively many Long COVID patients. This virus is known from Pfeiffer's disease and can also cause Multiple Sclerosis (MS).
Populations of microorganisms in the intestines, which together form the so-called 'gut microbiome', can also be disrupted for a long time by the coronavirus. They can therefore cause intestinal complaints, but because the gut microbiome also influences other functions in the body, this disruption can also cause or worsen other complaints. And finally, the energy factories of our body cells, the mitochondria, can be disrupted, which can have a major impact on the energy level of patients. Research from the Netherlands, among others, suggests that this mechanism plays a role in the occurrence of damage in muscle cells and serious complaints after physical exertion.
The virus appears to be able to damage the heart, lungs and brain via these mechanisms, which can explain cognitive complaints (brain fog), heart complaints and respiratory complaints. Much research focuses on distinguishing between different subtypes of Long COVID based on a combination of symptoms. An example of this is a division into: heart and kidney problems, 'respiratory, sleep and anxiety complaints, neurological complaints, complaints of the musculoskeletal system and a combination of digestive and respiratory complaints. None of these classifications are ideal yet, but they can help in finding more targeted treatments for (a combination of) symptoms.
As knowledge about these mechanisms increases, the search for so-called 'biomarkers' is also progressing, i.e. specific tests based on substances in the blood, for example, to be able to detect Long COVID or even a subform thereof. This is not only important for patients who want clarity about their complaints, but also for measuring the effect of potential medicines in scientific research.
Treatment perspective
Research into effective treatments for Long COVID is still in its infancy. The most promising drugs target the mechanisms that (partly) explain the symptoms and hopefully reverse or at least reduce the dysregulation – in the aforementioned explanation 'upstream'. There are all kinds of studies into potential drugs. The authors list these drugs that are currently being studied.
According to the authors, so-called 'immune modulators' such as the anti-rheumatic drug baricitinib and anti-inflammatory drugs such as the monoclonal antibody tocilizumab could possibly work against the dysregulation of the immune system.
Existing antiviral drugs, such as Paxlovid, used against acute COVID, could possibly be effective against the survival and persistence of the virus. However, no studies have yet been published that demonstrate an effect on Long COVID. Anticoagulants such as aspirin and copidogrel may be effective against coagulation disorders. Corticosteroids and more modern anti-inflammatory drugs could be of some use against chronic inflammation. Scientific studies are currently underway with Long COVID patients using various drugs.
Downstream, the new insights offer opportunities to counteract the ultimate damage, even if the underlying dysregulation remains. For example, blood pressure medications such as beta blockers, compression stockings and salt pills can reduce symptoms of orthostatic intolerance, such as POTS. In addition, probiotics and prebiotics may improve gut health, and agents such as N-acetylcysteine may help restore mitochondria.
Partly this is a matter of treating symptoms, but until underlying mechanisms can be addressed, this can provide relief for many patients. Furthermore, this medication does not first have to go through a very complicated approval process, because such agents are already available and can be used. Sometimes this could be on the indication of a specific complaint for which the drug is already prescribed, sometimes off-label.
New insights
What new insights and perspectives have emerged since the previous major overview study at the beginning of 2023? The hypotheses from that time, which explain the symptoms, still stand, although they are now seen less as hypotheses and more as partial explanations - more evidence has now emerged. More scientists agree that in most patients, it is not one, but a combination of these different mechanisms that seems to cause the complaints. What is also new is that the researchers now distinguish between the underlying disturbances at a fundamental level in the body and how they cause the damage that explains the disease symptoms. The biggest difference from the beginning of 2023 is the number of larger and smaller clinical studies that have been started. These can help doctors and patients determine which agents benefit a substantial proportion of patients and which do not.
Step by step, we are gaining more insight into how the body can be disrupted in the long term by the coronavirus, which not only leads to broader recognition of the seriousness of the disease, but also brings targeted treatment of symptoms and perhaps even reversing the disruption itself closer. Scientists around the world are working hard to develop and test such treatments, so that the disease that is disabling for many people can hopefully be combated.
*The original article describes ME/CFS and Lyme and does not explicitly mention QFS and other PAIS. However, 'among others' is used, which refers to multiple PAIS that also include persistent complaints after Q fever, as shown in the literature used for the realization of this article.
