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People walk past a COVID-19 assessment centre outside a hospital in Toronto on April 4.Nathan Denette/The Canadian Press

When it comes to long COVID, there are many questions – but answers are in short supply. It’s unclear who will go on to develop any of the many baffling symptoms that linger after a COVID-19 infection; how, beyond avoiding infection, the condition can be prevented; or what patients can do to get better. But researchers and clinicians aren’t without ideas about how and why it occurs.

Angela Cheung, a professor of medicine at the University of Toronto and a senior physician scientist at the University Health Network, participates in weekly discussions with other researchers from around the world to share data on long COVID and to discuss ways to treat it.

“The science has actually moved very fast,” Dr. Cheung said. While researchers now have some evidence for various pieces of the puzzle, “I don’t think we have the whole picture yet.”

Even so, several leading hypotheses have emerged about the mechanisms behind long COVID, also known as post-COVID condition, according to Akiko Iwasaki, an immunologist and virologist at the Yale School of Medicine.

Any one of them alone may not explain the vast array of symptoms patients experience, from shortness of breath to heart palpitations, fatigue, brain fog, diarrhea, muscle pain and rashes, Dr. Iwasaki said. Instead, long COVID could be the result of multiple mechanisms or a sequence of mechanisms.

“You may start off with one mechanism, but that leads to another and another,” she said.

Researchers studying the condition explained four top hypotheses.

The ‘viral reservoirs’ of long COVID

Even when an individual no longer tests positive for COVID-19, it’s possible the virus continues to replicate somewhere in the body that can’t be accessed by nasal or saliva swabs, Dr. Iwasaki said. Several studies, for instance, have shown that viral proteins and RNA can be detected in the lining tissue of the intestines. Other studies have found viral proteins and RNA in other organs, including the brain and kidneys of people who had severe COVID-19, she said.

Additionally, a recent pilot study, published in the journal Frontiers in Medicine, found that dogs trained to sniff out infected individuals were able to distinguish between long COVID patients and healthy ones.

As the authors explained in their study, their findings suggest that the odours specific to acute COVID-19 infection, in the form of volatile organic compounds, remain in most people with long COVID. They added that the dogs may have also been able to detect viral proteins, lending support to the idea that the virus still replicates, at least to a limited extent, after individuals test negative.

Whether the virus continues to be infectious is unknown, Dr. Iwasaki said. But these viral reservoirs, which go undetected by oral and nasal swabs, may be one explanation for what’s causing damage and stimulating an immune response for a long time, she said.

How the immune system could be involved

A COVID-19 infection could trigger autoreactivity, activating the immune system to attack one’s own cells and tissues by mistake, Dr. Iwasaki said.

She is proposing to study the link between these autoantibodies, involved in the autoimmune disease lupus, and the development of long COVID. Some early research correlates the presence of lupus autoantibodies in patients who go on to develop long COVID, Dr. Iwasaki said, noting that both conditions seem to disproportionately affect women.

Dr. Cheung likened the various cells and antibodies of the immune system to “untrained soldiers” in the fight against SARS-CoV-2; since they’re inexperienced with the virus, they can cause collateral damage.

“It’s your own body sort of wreaking havoc on normal, good cells and causing issues,” she said.

But she said researchers still have a lot to figure out. Even healthy people can possess autoantibodies, but that doesn’t mean these autoantibodies will go on to cause health problems, she said.

Chronic symptoms could be linked to latent viruses

A COVID-19 infection may reactivate viruses that exist in the body, Dr. Iwasaki said. For example, it’s estimated most adults have been infected with the Epstein-Barr virus (EBV) at some point, and after the initial infection, the virus – a member of the herpes family and the cause of mononucleosis – remains inactive in the body.

“The idea is that COVID-19 triggers activation of these latent viruses and that could lead to the chronic consequences we’re seeing,” Dr. Iwasaki said.

A large study, published last year in eClinical Medicine, a Lancet journal, indicated that at least a portion of long COVID patients had other infections. The study, which examined survey responses from more than 3,700 international participants, found that 2.8 per cent experienced shingles, a reactivation of the varicella-zoster virus that causes chickenpox; almost 7 per cent had a current or recent EBV infection; and 1.4 per cent had a current or recent cytomegalovirus infection, a common virus that usually stays dormant in healthy people. Some 1.7 per cent of respondents had a current or recent Lyme disease infection, caused by bacteria that can remain latent for a long time.

Dr. Cheung, however, cautioned that not everything may be attributable to COVID-19. For example, people can experience a recurrence of shingles when they are stressed or tired. So it’s possible these factors, not COVID-19 itself, can activate latent viruses, she said.

Potential long-term effects

Inflammation and tissue damage from a COVID-19 infection that can’t be repaired can cause chronic changes in the tissue, Dr. Iwasaki said.

In a new study, published in the journal Cell, she and her team found that even when a COVID-19 infection was mild and contained within the lungs of mice, long-term changes and damage to the brain could occur. They associated these brain changes with elevated levels of inflammatory cytokines, proteins involved in the immune response, in the central nervous system.

Meanwhile, researchers at the University of Western Ontario, led by professor Grace Parraga, who holds a Tier 1 Canada research chair in lung imaging, used functional magnetic resonance imaging to find that people with lingering symptoms after a COVID-19 infection had microscopic abnormalities that affect the transfer of oxygen from the alveolar sacs of the lungs into red blood cells.

In their study, published in the journal Radiology, Dr. Parraga and her team suggested the obstruction of small capillaries and other vascular changes, such as vascular injury, could potentially explain these abnormalities.

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