The Pathophysiology of Long COVID

Why is long COVID, well, long?

The Pathophysiology of Long COVID
3D rendered illustration of a mutating virus that causes COVID-19. (James Thew/Adobe Stock)
Yuhong Dong

One of the most devastating aspects of COVID is that it can continue to affect patients for months—and even years—after infection.

Ask Carrie Anna McGinn. After a year of fighting off symptoms, Maclean’s Magazine reports that she continues to battle a cough, cognitive dysfunction, and pain.
While most patients successfully fight off the symptoms of COVID within a few days, some continue to experience symptoms long after infection. When symptoms last longer than two months, persistent symptoms are diagnosed as post-COVID condition, also called long COVID.
We’ve discussed the prevalence of long COVID from the new Omicron variant in a previous article, and we’ve also published advice on how to ameliorate long COVID symptoms using a holistic approach.

But one aspect of long COVID that is still developing is its pathophysiology—the why behind how long COVID symptoms occur. This may actually be the most interesting piece: what is COVID doing to the body that makes symptoms last for months or years?

In this article, we present several current theories for why long COVID occurs and how the symptoms persist in some people while they disappear in others.

Potential Mechanism of Long COVID

So what causes the “long” in long COVID? There are a few theories.
One recent review of the research, which was published in Nature, identified the three most likely reasons that COVID hangs around in some people more than others: Inflammation, autoimmune responses, and “reservoirs” of the virus.
Here’s how these would work.

Long COVID Could Be Caused by a Persistent Inflammatory Response

You might not realize how serious inflammation can be.

Inflammation is a natural bodily response when something goes wrong in the body. Basically, your body sends white blood cells, cytokines, and other immune cells to try to fight off infection or repair tissue. When those cells take effect, they start to repair tissue and get rid of toxins.

It is this “fight” between your body’s protective cells and the harmful ones that causes inflammation.

Acute inflammation lasts just a little while. For example, imagine you twist your ankle. Your body sends out repair cells, to the area. As the tissue is being repaired, there is some inflammation in the ankle. Once the tissue is repaired, the inflammation dissipates.

Chronic inflammation happens when an inflammatory response lasts for a long time. It occurs because the cytokines and white blood cells, which contribute to inflammation, don’t dissipate. When inflammation becomes chronic, white blood cells can end up attacking both bad cells and good, healthy cells from your own body. It’s kind of like “friendly fire.”

One theory of long COVID is that it causes a kind of chronic inflammatory response. That inflammation is then partly responsible for a person’s ongoing symptoms.

Some evidence for this theory comes from one small study of 31 individuals with long COVID, matched with 31 others who had COVID, but who recovered normally (and also 46 healthy controls). The researchers found that the individuals with long COVID had persistent increases in several cells that are associated with inflammatory responses to acute diseases: activated CD14+CD16+ monocytes, plasmacytoid dendritic cells, and both type I (IFNβ) and type III (IFNλ1) interferons.

The authors conclude, “These analytes have been associated with acute severe disease, suggesting a delayed or defective resolution of inflammation in long-haul COVID individuals.”

Another study of 207 COVID-19 patients similarly found defective immune recovery drive ongoing diseases .A pronounced early immune response and no evidence of systemic inflammation is seen in patients with mild diseases, meanwhile. a number of inflammatory markers and pathways including serum C reactive protein (CRP),  TNF-α and IL-6 are prominent in hospitalized patients with more severe diseases. The most prominent are associations with genes involved in the type I interferon pathway, known to be the key driver of bystander T cell activation helping to clear the virus. Increasing age and comorbidity such as diabetes and chronic inflammatory disease are known to suppress early CD8+ T and B cell responses contributing to persistent diseases.
The persistent elevation of inflammation-causing immune cells could be causing some of the common long COVID symptoms: neuroinflammation, injury to the kidneys, insulin resistance, and others.

Autoimmune Responses Could Also Contribute to Long COVID

A second possible cause of long COVID is an autoimmune response that persists even after the virus is eliminated.

The body’s immune system is set up to protect itself against infections. But sometimes, immune cells mistakenly begin targeting our own body instead of infections. That’s called an autoimmune response.

Allergic reactions are autoimmune responses. Autoimmune responses are also behind a number of other conditions including Lupus and rheumatoid arthritis.

Autoimmune responses are actually common after viral infections. It happens when some of the proteins of the virus resemble the proteins in normal human cells. The resemblance makes it easy for immune cells to get “confused” between the virus and the body’s own cells.

This is what some believe happens with long COVID: the COVID virus may trigger an autoimmune response and that response may be responsible for the long-lasting symptoms of long COVID.

How exactly would that work?

Well, it could have to do with autoantibodies.

Autoantibodies are proteins in your immune system that mistakenly target your body’s own tissues. Autoantibodies can be caused by a number of viruses, including Epstein-Barr virus, herpes virus 6, hepatitis A and C, and rubella virus.

So one possibility is that SARS-CoV-2, the COVID virus, also creates autoantibodies. Those autoantibodies, in turn, may continue to plague the body long after the virus itself is gone.

One recent study screened 147 people hospitalized with COVID and 41 healthy controls for a range of autoantibodies. The researchers found that about half of the hospitalized people had these autoantibodies in their blood, whereas only 15 percent of the healthy controls did. In other words, long COVID patients had more autoantibodies than the COVID patients without long COVID.

The researchers also screened the blood of patients several times a day. They found that about 20 percent of the patients didn’t have autoantibodies when they were first admitted to the hospital, but developed them over their stay. So some people with long COVID developed autoantibodies over their recovery.

That study was a small one, but several other studies have also found the heightened presence of autoantibodies in patients with COVID.
These autoantibodies may also explain why several autoimmune syndromes have been associated with COVID. These include Guillain–Barré syndrome, Miller Fisher syndrome, and multisystem inflammatory syndrome in children.

Long COVID May Be Caused by Hidden Reservoirs of the Virus in the Body

A third theory for the cause of long COVID is that the virus was never properly eliminated from the body in the first place. In other words, there’s a “reservoir” of the virus that continues to cause symptoms long after most people are back to normal.

There are a few pieces of evidence for this theory.

Some research has also found that while the SARS-CoV-2 replicates in the lungs, nose, and throat, it can also replicate in cells in the small intestine. Multiple studies have reported that SARS-CoV-2 viral RNA has been detected in stool samples even after the virus is cleared from the nasopharynx.
Viruses can also find their way into the brain, and live there relatively safely. Part of the reason for that is that the brain isn’t as easily accessed by the immune cells that would fight off the virus. Some research has found the SARS-CoV-2 in brain tissue—it may be that it is able to live there and continue to cause symptoms.
Another piece of evidence for virus reservoirs is that the immune cells continue to adapt and become more potent over time in individuals with long COVID. This continual mutation of the immune cells is consistent with persistence of an antigen.
It’s therefore possible that in some people, COVID can continue to survive in some people—perhaps in the digestive system—in sufficient numbers to continue to cause long-term symptoms.

Damage to Mitochondria

One further potential mechanism for persistent COVID symptoms in some individuals is through damage to mitochondria.
It has been found that the S protein of SARS-CoV-2 can damage mitochondrial structure and function.
Mitochondria are little organs within tissue cells. They are commonly referred to as the “powerhouse” of cells because their main job is to produce energy. Most cells in our body have mitochondria, but cells that require more energy—like those in the retina, heart, muscles, and brain—have substantially more mitochondria.

Since mitochondria are so important to providing cells with energy, damaging them may help explain symptoms like fatigue, muscle weakness, and some of the mental deficits like brain fog.

The SARS-CoV-2 virus also seems to interfere with the way that cells break down lipids (fats) within cells, which may cause heart, kidney, and liver damage. Damage to these organs is one more way that COVID may end up causing long-lasting symptoms of fatigue

Can COVID Cause Myalgic Encephalitis?

One remarkable feature of long COVID is that many of the symptoms are strikingly similar to another debilitating condition called myalgic encephalomyelitis (ME), more commonly known as chronic fatigue syndrome (CFS).
Patients with this disorder experience significant functional impairment. For some, even sitting up in bed is too difficult to accomplish without help.
The most common symptoms experienced by patients with long COVID are fatigue, post-exertional malaise, and cognitive dysfunction. These three symptoms also happen to be to primary symptoms of ME/CFS. Post-exertional malaise is considered the hallmark symptom of ME/CFS. It occurs when symptoms of fatigue worsen after physical or mental exertion.
Dr. Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases, has said in interviews that people who are not recovering after contracting COVID-19 are showing symptoms “that are highly suggestive of myalgic encephalomyelitis and chronic fatigue syndrome.”
Some now believe that COVID may actually cause ME/CFS. In a webinar hosted by the Canadian Institutes for Health Research, Dr. Nina Muirhead, a British specialist in dermatology who has myalgic encephalomyelitis, comments that “ME clinicians who have been seeing ME patients for a long time can see the similarities in the long COVID patients coming in” and that “we do expect a subset of long COVID patients to develop post-viral ME.”
This makes sense, given that about 77 percent of ME cases originate from viruses or bacterial infections. These include Epstein Barr, West Nile, or Influenza. The SARS-CoV-2 may simply be just one more virus to add to the list of those that may potentially cause ME.
While perhaps not surprising, the effects of COVID on the number of ME patients could be massive. Past research on post-epidemic and post-infection recovery suggests that 10 percent to 30 percent of COVID patients could develop ME/CFS. Some estimates suggest that COVID could double the incidence of ME/CFS to between 1.6 and 5 million Americans.

Treating Long COVID Requires a Holistic Approach

Given that millions of people have been infected with COVID and that it can have dramatic effects on health, what can we do?
So far, there’s no cure for long COVID. But researchers are suggesting that a holistic approach to health can help overcome some of the symptoms of long COVID. Here are some aspects of a holistic approach that appear promising.
Healthy lifestyles. One critical aspect is to continue to pursue a lifestyle that we know supports and nurtures health. That includes:
  • Limiting alcohol consumption and smoking
  • Cultivating healthy sleep hygiene habits
  • Eating a nutritious and balanced diet
Natural experiences. Spending time in nature also helps cultivate both mental and physical health. A systematic research has found that it can reduce the risk of developing chronic illnesses like diabetes and cardiovascular disease.
Spirituality. Connection to spiritual practices may also help people cope with symptoms of COVID. One study of 427 young adults in Turkey found that those spirituality and meaning-based coping behaviors help to mitigate the negative effects of COVID on subjective well-being. In other words, connecting to spirituality may help protect one’s mental health.
Similarly, a survey of 246 Indigenous peoples in Canada found that 76 percent of Indigenous participants agreed that spirituality was important to them pre-pandemic, and 56 percent agreed that it had become more important since the pandemic began. Compared to Indigenous participants with a strong sense of community belonging, those with weak community belonging had 2.42-times greater odds of reporting symptoms of anxiety, and 4.40-times greater odds of reporting symptoms of depression. Connection to community seemed to help buffer against the negative emotional aspects of COVID.
Positive thinking. How you think about long COVID may also affect how you recover from it. While there are not yet any high-quality studies directly evaluating the extent to which positive thinking can impact recovery, other previous research suggests that a positive outlook may help recover from other types of illness.
For example, in one of the first studies on the benefits of optimism, men who underwent a coronary artery bypass graft surgery were less likely to have a heart attack during surgery when they were optimistic than when they were pessimistic. Optimists were also faster to recover from the surgery than pessimists.

These findings are corroborated by larger reviews of the research: optimists tend to have better health than pessimists.

Meditation. Meditation may also have significant impacts on the body’s ability to battle infection and recover from illness.
In one large-scale genomic study, researchers found that advanced meditation seemed to activate the immune system. The authors found that, “Strikingly, 220 genes directly associated with immune response, including 68 genes related to interferon signaling, were up-regulated, with no significant expression changes in the inflammatory genes.”

In other words, the immune system got stronger without activating inflammation.

Long COVID can be a serious and debilitating illness. It’s not yet fully clear what leads some people to continue to fight the disease months and years after it clears away in others.

But whether it is caused by inflammation, an autoimmune reaction, latent reservoirs of the virus, or damage to cells and organs, it appears that long COVID could affect many of us.

Until a suitable cure is found, a holistic approach may be our best path to wellness and recovery.

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