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The Debilitating Puzzle Box of Long COVID

The persistence of symptoms in many people who get COVID-19 demands answers, but studying long COVID proves to be quite the scientific challenge

Imagine sitting in front of 40,000 tiny pieces that you have to assemble into a jigsaw puzzle. Except that some of these pieces may belong to a different puzzle. There is no box to tell you what the final image looks like. And in front of you is a massive hourglass, its sand slowly and inevitably flowing down, and as time goes by, more and more people suffer. You must solve the puzzle while minimizing suffering.

I am not describing an “elevated horror” sequel to the Saw movie franchise. Rather, the puzzle is long COVID, and more and more people are debilitated by it as physicians, researchers, and the very people suffering from it race to solve it.

“Long COVID” is a term coined by the very people affected by it. Meanwhile, the scientific community is still trying tortuous alternatives on for size. Post-acute sequelae of SARS-CoV-2 infection or PASC. Switch two letters and you get post-acute COVID-19 syndrome or PACS. Move the words “post,” “chronic,” “condition,” and “syndrome” around “COVID-19” and you get other suggestions that populate scientific papers.

Even its definition remains debated. Long COVID is about the presence of symptoms following the acute phase of COVID-19, like you can’t quite shake off an ever-evolving infection, but while the CDC says it starts four weeks after symptoms began, the WHO moves it to three months after the start of symptoms and defines its duration as at least two months. Like the six-foot physical distancing rule, it’s meant to helpfully delineate something that is diffuse, like nailing Jell-O to the wall.

Studying long COVID and figuring out how a tiny virus can cause so much long-term damage is proving to be very, very challenging. Again, like nailing Jell-O to the wall.

Gone fishin’

The symptoms that those who experience long COVID (known as COVID long-haulers) have to put up with are legion. When nearly 4,000 long-haulers with laboratory-confirmed or suspected COVID-19 filled out a thorough survey of their long COVID symptoms, the results were gobsmacking. It painted a portrait of a fiendishly complex disease that seemingly affects every organ system in the body. The long-haulers reported fatigue, sweats, extreme thirst, menstrual issues, loss of smell and taste, heart palpitations, tightness in the chest, joint pain, new allergic reactions, sore throat, dry eyes, shortness of breath, diarrhea, peeling skin, and a long list of other physical symptoms. On the mental health front, the inventory was no less overwhelming, including anxiety, memory loss, and brain fog.

Surveys are frontline tools in scientific research when a new phenomenon affecting people gains enough momentum. It was the first step, for example, in trying to get an idea of what ASMR was, the experience of soothing tingles when watching intimacy surrogates. These surveys can be rudimentary instruments, like very large nets meant to catch fish. In the long COVID survey I cited above, some people reported a decrease in size of their penis or testicles as a symptom. Likewise, another symptom listed was floaters, these annoying clumps of collagen fibres that start drifting inside the jelly of our eye as we get older. Noticing something after getting sick with a virus does not automatically imply that it was caused by the virus. Large nets catch fish but undesirable things as well.

As more and more surveys were published, reviews of these data sets could be done, like those of the Public Health Agency of Canada and of the United Kingdom’s Office for National Statistics, and the defining features of long COVID came into sharper focus.

A little over half of people with a laboratory-confirmed infection by SARS-CoV-2 report at least one symptom that persists, although the certainty around this estimate is low. The most common symptoms are fatigue, shortness of breath, mental health issues, and trouble remembering, learning new things and concentrating. And lest we think that “fatigue” simply means needing an additional cup of coffee to get through the day, it has been described as “crushing.” Long-haulers, as cited in a recent Canadian report, refer to their symptoms as “overwhelming,” “unmanageable,” and “unpredictable.” Many people affected by long COVID led robust and active lives before getting sick. At Stanford University’s clinic for long COVID, nearly half of their patients have more than 12 symptoms.

Is the fatigue and the constellation of symptoms tied to long COVID all due to the coronavirus? Probably not. Enmeshed in the net, academics suspect, are other causes, like the steroids used to treat hospitalized patients, the ventilator some were put on, and what doctors refer to as subclinical conditions, meaning health problems that were there before COVID but hadn’t been noticed until now. Like the true size of someone’s genitalia. Maybe, maybe not.

Trying to separate these causes from the multifarious effects of the virus itself is a real scientific challenge. Researchers who have summarized the growing literature on long COVID are not shy about listing the many, many limitations of the studies out there, chief among them the frequent lack of a control group. If you ask COVID survivors about their long-term symptoms, like fatigue and anxiety, but you don’t compare them to a similar group of people who are not known to have been infected, it becomes harder to separate long COVID from the burden of living through a pandemic. Some surveys never even ask if a person’s symptoms existed before COVID. Another issue is how problems like pain and fatigue, which we’ve never been great at measuring, are reported from one study to the next, making comparisons difficult. Long COVID has put so many of the problems of scientific research front and centre, including many researchers’ reluctance to involve actual patients in designing their projects.

Emerging from this haze, though, are indications of who is at risk for long COVID. It tends to affect women more often than men (more on that later). People who have a mild infection or do not show any symptom despite incubating the virus are not immune from long COVID, that is to say that it is not a consequence of a particularly bad infection. Reassuringly, though, recent studies indicate that the vaccine does protect against long COVID, at least in part because it protects against COVID itself. There have been reports of fully vaccinated individuals who got COVID and developed long COVID afterwards, though these cases are, so far, rare. A recent paper looking at multiple cellular and molecular markers in 309 patients reported four risk factors present when COVID-19 was initially diagnosed that anticipated the development of long COVID: type 2 diabetes, circulating bits of the virus’ RNA in the blood, reactivation of the Epstein-Barr virus, and antibodies directed against the patients’ own proteins. Independent work will be needed to validate these risk factors, although the researchers helpfully found these risk factors in one cohort of patients and then validated it in a second.

Our knowledge on the risks faced by children, however, is still muddy. A study of studies published last November appears quite reassuring, but it highlights that the majority of studies it looked at were of poor quality. An often-cited Danish study looking at 15,000 COVID-positive children and 15,000 controls and published this January was also encouraging, but it has been criticized for some methodological issues. Better studies are needed.

Surveying long COVID is important, but below the surface, scientists are asking deeper questions: what is happening to the human body after the virus has its way with it?


Long COVID is not the first biological puzzle box to drop from the sky. A disabling, post-infection fatigue lasting six months or more is known to affect a significant minority of people infected by a variety of disease-causing organisms, like dengue virus and Ebola virus (as summarized here). After SARS, which like COVID was caused by a coronavirus, two in five patients had chronic fatigue two years later. For women specifically, it was two in three.

Many of the symptoms of long COVID partly overlap with conditions like chronic fatigue syndrome (ME/CFS), fibromyalgia, mast cell activation syndrome (MCAS), postural orthostatic tachycardia syndrome (POTS), and “chemo brain,” the brain fog that a third of patients struggle with following chemotherapy for cancer. Unfortunately for long-haulers, these “cousin” conditions tend to be poorly studied. The hope is that the crisis of long COVID helps shed light on these other conditions as well.

So, what is the biology of long COVID? As scientists scan patients’ blood, genes, and entire bodies worth of proteins looking for anomalies, a number of hypotheses have been put forward. Like the symptoms of long COVID themselves, the list of speculations is imposing.

It could be that SARS-CoV-2 can go through the blood brain barrier, reach the brain, and cause local inflammation. Its RNA and proteins have been found there in some autopsy studies. It may be that the virus causes injury to certain organs, like the lungs and the kidneys, which results in symptoms long after the acute infection has resolved itself.

This coronavirus seems capable of sticking around in certain parts of our body, which is in keeping with what is known of other coronaviruses (summarized here). The virus could continue replicating or, even if it was too fragmented to do so, could trigger a persistent reaction of the immune system.

And then there’s the fact that SARS-CoV-2 does not enter into a sterile body. Many of us carry dormant viruses inside of us, like herpes viruses, Epstein-Barr, and varicella zoster virus, and a COVID infection could reactivate these sleeping viruses, which could cause long COVID symptoms.

Then there is the microbiome, the constellation of bacteria that live on and inside our body, and the virome, the totality of the viruses we harbour. We have so much to learn about them, but we do know that our immune system essentially keeps them in check. It’s possible SARS-CoV-2 upsets that truce. We know, for example, that the nose of about a third of us contains the bacterium S. aureus, and in cases where the immune system is suppressed, it can change the expression of its genes and cause disease.

It is also quite possible that COVID-19 promotes, in some people, an autoimmune condition, meaning that their immune system turns against themselves. The virus’ proteins can be similar to ours. If the antibodies we direct at the virus’ proteins start attacking similar proteins that our body makes, we have a problem.

Finally, there might be genetic variations in certain people’s DNA that predispose to long COVID, such as variations in genes that code for immune proteins that help clear invading viruses.

The theories are many, and given the diversity of long COVID symptoms, it may be that many are true. Thus, long COVID may not be just one thing, but many syndromes that superficially look the same.

As for the somewhat small prevalence of women with long COVID symptoms, it could be a reporting artefact, although there might be a biological reason for it as well. A woman’s immune system is typically a bit different than a man’s. Autoimmune conditions, for example, tend to be much more common among women than among men: 80% of autoimmune conditions reported in the U.S. affect women, in fact. Long COVID could be the latest addition to the list.

The siren’s voice

A parting warning, though. Long COVID can be horrible. Clinics that specialize in caring for this syndrome, so-called post-COVID care centres, are popping up, but there is no miracle cure in sight. As piecemeal discoveries are made, expect the usual suspects to sell unproven, all-natural remedies that capitalize on them. Cancer treatment, for example, can lead to immune cells in the brain called microglia to be always turned on, creating inflammation which some hypothesize manifests as “chemo brain.” As Dr. Michelle Monje, MD, PhD, who studies this phenomenon, told Stat, “I wouldn’t want people to think, ‘Oh, I read somewhere that x y z, you know, calms down microglia.’ I’ve seen that happen on Twitter.”

As the debilitating puzzle box of long COVID slowly lets out its secrets and red herrings alike, desperate people will be captivated by the siren song of hucksters, promoting so-called immune-modulating herbs and anti-inflammatory supplements to “help the body heal itself of long COVID.” Gwyneth Paltrow’s goop has already started singing. The temptation will be hard to resist as long as medicine fails to provide effective alternatives.

Take-home message:
-Long COVID is a poorly defined condition that follows infection by SARS-CoV-2, the virus that causes COVID-19, and that often manifests as many symptoms, including fatigue, shortness of breath, mental health issues, and trouble remembering, learning new things and concentrating.
-Many of the surveys of long COVID have important limitations, such as a lack of a control group, which makes understanding the condition more challenging.
-Multiple hypotheses have been put forward as to how SARS-CoV-2 could cause chronic symptoms, such as the virus’ persistence in certain parts of the body and the creation of an autoimmune condition in which our immune system turns against us.


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