A question for researchers created by the pandemic is that of long covid. About 10% of Covid-19 patients, particularly those with severe cases or pre-existing conditions, will experience some form of long Covid, meaning they experience symptoms that could last for weeks or even months after initial infection. These symptoms may include fatigue, joint and muscle pain, memory, concentration, or sleep problems, depression or anxiety, and many others. The exact mechanism behind these long-lasting symptoms is an ongoing area of research, and will likely be one long after the pandemic is concluded. But Covid-19 is not the only virus that causes these types of symptoms long after the initial infection is over. So today, I will talk about post-viral syndrome, what we think it is, and how it bridges research into Covid-19 with other poorly understood chronic conditions.
Persistent Viral Infections
To start, let’s talk about what long Covid is NOT. When most people think about long-lasting viral infections, they might first think of diseases like HIV, HPV, or herpes. But the mechanism behind these types of infections is very different from that of Covid.
I’ve briefly talked before about persistent viral infections, but just to recap, viruses are protein capsules containing genetic material and enzymes. They reproduce by entering a cell, inserting their genetic material into the cell’s genome, then tricking the cell into following these new instructions. Per these instructions, all other cellular functions are switched off so the cell can focus solely on manufacturing thousands of new viruses. Finally, the cell is torn open and these new viruses go on to infect other cells. For most species of viruses, this process takes between 8 and 72 hours from initial infection to cell death. But a few species of viruses have an additional bit of instructions in their DNA which allows the infected cell to regulate itself. When the new viruses wouldn’t be able to survive long enough to spread, because of an immune response or the presence of antiviral drugs, the infected cell will simply not create any new viruses until the threat passes. These infected cells can remain indefinitely until the coast clears of immune system threats, causing a lifelong infection.
These regulatory instructions and the mechanisms to permanently insert their DNA into a cell is rather complex, so only a few families of viruses have evolved to cause these persistent infections. On top of the viruses listed above, both chickenpox and mononucleosis (mono) are persistent viral infections caused by viruses in the same family as herpes. Even after the immune system clears the virus that causes mono (Epstein-Barr) from the body, there can still be B cells infected with the virus. These cells will remain in a latent stage for the rest of the patient’s life, as the antibody response to Epstein-Barr makes it impossible for the virus to leave this latent stage without being immediately killed. That said, some persistent viruses, such as HPV, Hepatitis, and Epstein-Barr, can make latent infected cells reproduce faster in order to increase the number of infected cells, which increases the risks of these cells becoming cancerous. There are certain types of blood cancer that are exclusively seen amongst those who had severe mono earlier in life, though less than 1% of these severe mono patients get this cancer. Chickenpox is another virus that can be kept in its latent stage for a long time by a normal immune system. That said, the immune system does naturally weaken with old age, which can allow the virus to flare back up. This is how shingles occurs; one’s immune response to chickenpox weakens with age, allowing the virus to become active again.
We know that coronaviruses can’t create persistent infections. They don’t have the necessary genes or structures to incorporate themselves into an infected cell and regulate their latent stage. A cell infected with Covid-19 will always release its viruses within a day and an immune response to Covid-19 can completely remove the virus from the body. Whatever long Covid is, it is not a persistent infection.
Post-Viral Syndrome
While long Covid is getting a lot of focus and research, it is not the only disease to cause these types of symptoms. Fatigue and cognitive dysfunction lasting for weeks or months after a severe viral infection has been noticed for over a century in diseases from seasonal flu strains to severe illnesses like polio and ebola to other coronaviruses like SARS and MERS. The exact reason for why post-viral syndrome occurs is still poorly understood and there might not be a single answer that’s true for every case. But to give a rough list of hypotheses, we have;
The immune system is weakened by having to fight off the initial infection, creating room for other diseases to take hold and cause mild symptoms. This could include viruses that were already in the body but weren’t strong enough to cause symptoms due to the presence of the immune system. It might even include some of the persistent infections that we talked about before, able to cause symptoms with the immune system distracted.
Post-viral syndrome could be an autoimmune disorder. I’ve talked about this before, but the immune system being overactive from fighting an infection makes it more likely that an immune response to something naturally found in the body could start by accident.
Some have suggested that long Covid might in some cases be a psychological condition. The term ‘post-intensive care syndrome’ has been used for years to describe fatigue and cognitive problems in patients who experience long stays in intensive care. The symptoms of post-viral syndrome do have similarities to symptoms of trauma, which severe illness and intensive care can trigger.
Even though the immune system can clear the bloodstream of viruses, there are parts of the body that the immune system doesn’t have full access to. This includes the eyes, testes, uterus, and central nervous system, as these are parts that can’t work properly when inflamed or could be easily damaged by immune responses. While these tissues do have special immune cells to protect them and barriers to keep viruses out, antibodies can’t enter these tissues. If any viruses manage to enter these tissues, they can create a reservoir that persists in the body even with an immune response. It should be noted that autopsies of the brains of patients with chronic fatigue syndrome (more on that later) are often found to have evidence of viral infection.
There could be a genetic component to post-viral syndrome as well. Studies on cases of chronic fatigue syndrome have found that certain gene variants were correlated with patients having chronic fatigue after a viral infection. How these genes influence one’s susceptibility to these conditions is unknown, but it’s most likely a case of certain variants being easier to become dysregulated by certain viruses.
Current Research
Unfortunately, what causes long Covid and how to treat it is still barely understood. Covid isn’t the only virus that causes these symptoms, which means there is some pre-existing research to build on, but post-viral syndrome is also not well understood. The fact that there are multiple similar conditions of long-lasting fatigue and cognitive dysfunction only makes this more complicated. I’ve briefly mentioned chronic fatigue syndrome, also known as myalgic encephalomyelitis, a condition that can consist of severe fatigue that doesn’t go away after sleep, difficulties with memory or focus, chronic pain or soreness, all of which can last for years or be life long. Most recorded cases began shortly after a severe viral infection, often Epstein-Barr or another Herpesvirus.
The fact that post-viral syndrome and chronic fatigue syndrome are so similar has been an area of study for a while now. These conditions are not well understood, and some of that is because it involves several very complex parts of the body. But it should also be noted that research into these conditions and their treatment have historically not been a priority. A 2006 study found that of 811 surveyed general practitioners in the United Kingdom, only 72% accepted that chronic fatigue syndrome was a recognized illness and only 48% felt confident they could diagnose the condition. Chronic conditions have historically been harder for the medical community to take seriously, as have conditions with symptoms that can only be observed by the patient. The fact that chronic fatigue syndrome disproportionately affects women over men doesn’t help matters, though that is another conversation entirely. So while research into long Covid will benefit from the pre-existing research into post-viral syndrome and chronic fatigue, the research into these conditions will likely equally benefit from research into long Covid. Hopefully, it will force a degree of attention and importance to these diseases that they haven’t had in the past.
It remains important to remember that getting vaccinated and boosted has been shown to significantly reduce one’s risk of long Covid symptoms.
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