How are doctors unravelling the mystery of long COVID?
1st May 2022

They call them long-haulers – people still suffering symptoms long after a bout of COVID. But what is the condition, exactly? Doctors expect the answer will change our understanding of immunity forever.

Six months after physiotherapist Scott Willis became one of Australia’s first COVID-19 patients, something strange happened in a swimming pool. One moment he was doing laps, the next he could barely move his arms and legs. “I just ran out of steam. I can pinpoint it to the second,” Willis says. “If I didn’t have the rope to grab on to, if I’d been out in the ocean, what would have happened?”

That bone-deep exhaustion, which can hit suddenly or linger all day, is the most common sign of what has become known as long COVID, in which illness strikes again or drags on months after a COVID-19 infection. But about 200 other symptoms have been linked to it too – sometimes entirely new ones such as confusion and hallucinations, heart palpitations, seizures and sexual dysfunction. So-called long-haulers have likened the condition to “a living death”. Many are too tired to work – or get out of bed.

Millions of people have been affected by long COVID – even many of the clinicians treating it, such as Willis. And that list is only expected to grow. Some researchers expect long COVID cases in Australia to hit 10,000 by the end of the year. Yet, more than two years into the pandemic (and at least 18 months into the condition for Willis), long COVID remains something of a medical mystery.

Is it a new phenomenon or a syndrome like chronic fatigue on a bigger scale? Are some people more at risk of developing the condition than others? What might be going on in the body? And what treatments are being tried?

Credit:Artwork: Monique Westermann/Getty

What is long COVID?

Not long after Willis first fell ill with COVID in Tasmania in early 2020, doctors on the other side of the world, at New York’s Mount Sinai Health Network, noticed something odd. Hospitals had been so overwhelmed during the pandemic’s first wave that Dr David Putrino had set up an app for Mount Sinai doctors to monitor less severe COVID patients remotely, including their oxygen levels. Some were still reporting symptoms months after getting sick.

Putrino says: “People would tell us, ‘Look, I don’t have these acute COVID symptoms any more, but I’m not myself. I’ve got heart palpitations. If I carry my groceries up the stairs, I’m knocked out for two days.’ That was our first inkling long COVID existed.”

Mount Sinai was then setting up a post-COVID recovery hub for patients they expected would need more time to recover – those with lung scarring and other organ damage from a particularly severe infection, or complications from long stays in intensive care. Dr Neha Dangayach, who runs neurological intensive care for Mount Sinai, says: “You can get neurological issues, delirium, or take a long time to bounce back from something like sepsis. But this was something else.”

Most of the patients, particularly those with neurological symptoms, had suffered only mild or moderate cases of COVID-19, and they hadn’t been hospitalised. Often their scans were normal.

Given the virus can affect so much of the body, it is perhaps not surprising that long COVID comes with a strange constellation of symptoms too.

As more cases emerged around the world, experts at Mount Sinai and elsewhere began looking for answers – and patients banded together online to share stories and push back against scepticism about the new condition.

Professor Gail Matthews and her colleagues at the Kirby Institute in Sydney were among the first to set up a long-COVID study, at St Vincent’s Hospital. Some patients, she says, will find themselves struggling with just one persistent COVID-19 symptom – a loss of smell and taste, for example. Others show signs their entire nervous system is affected.

COVID presents as a respiratory illness but samples of the virus behind it (SARS CoV-2) have been discovered all over the body – in the lungs, heart and other organs, including, in rare cases, the brain. It can cause clots and stroke, strange rashes, heart, kidney or liver failure, even inflamed, red “COVID toes”. Among survivors, the risk of cardiovascular disease is likely to remain high for months, even years.

Given the virus can affect so much of the body, Matthews says it is perhaps not surprising that long COVID comes with a strange constellation of symptoms too, “though I have found the neurological ones especially surprising”.

In late 2021, the World Health Organisation defined long COVID as occurring in people with “a history of probable or confirmed SARS CoV-2 infection, usually three months from the onset of COVID-19” with symptoms that last for at least two months and cannot be explained by anything else.

Putrino says that with so little understood about the condition, it is right for long COVID to remain a fairly broad church, ranging from those recovering from severe infections to people with sudden neurological symptoms down the road. (In rarer cases, someone may even be affected by both lingering complications and a flare-up of long COVID.)

“We don’t want anyone to fall through the gaps,” he says. “People need insurance cover, access to care. Of course, it also means people might have different treatment [paths]. Some might spontaneously get better, some might not.”

The universities of Oxford, Sheffield, Cardiff and Manchester have been collaborating to try new scanning techniques to pick up less obvious signs of lung damage in long COVID patients (right).Credit:Oxford University

Who is affected by long COVID?

More than 500 million people have now had COVID-19 but no one knows how many long-haulers are among them (some researchers estimate it’s already more than 100 million). So far, while most COVID-19 patients seem to recover, it’s thought that at least 10 to 30 per cent of cases become ongoing – and the risk is about halved if you’re vaccinated. (Recent British data tracking long COVID suggests that fewer than a third of patients fully recover within a year of catching the virus.)

Mount Sinai’s long-COVID clinic has now treated more than 2000 patients, from the bed-bound to the “milder” cases of people who can still work “but they have to lie on the couch all night to recover from the day”, says Putrino. The average age is 45. “In fact, you’re less likely to show up at the clinic if you’re over 65,” he says. “We don’t know why. And I think that there are a lot of people out there with long-COVID symptoms who don’t know it because they are, fortunately, mild. Some maybe didn’t even know they had COVID.”

“They were like, ‘Oh yeah, I am fatigued, and my heart does beat fast and that never happened before’…”

Recently, when the hospital was recruiting patients for a clinical trial of those who had fully recovered from COVID, it hit a snag. “Sixty per cent of people who said they had recovered still had symptoms,” says Putrino. “They were like, ‘Oh yeah, I am fatigued, and my heart does beat fast and that never happened before’, whereas only 1 per cent of the control group who had never had COVID failed the symptom screen.”

While you don’t need a severe case of COVID to develop the ongoing condition, one study suggests that having a high viral load (a lot of virus replicating in your system) during your initial infection can push up your risk of long COVID; as can type 2 diabetes, certain “auto-antibodies” that mistakenly attack the body instead of the virus, or a reawakened case of the usually fairly harmless Epstein-Barr virus many people catch in childhood.

There is also a skew towards women in the data. Matthews says: “That could be because women tend to go to the doctor more or because women have different immunology.”

Long COVID can emerge in children too, although as with a regular COVID infection, this is much rarer.

Researchers are not sure if long COVID rates have fluctuated as the virus mutates into different variants, but Putrino says he has found the symptoms fairly consistent between waves. “We’re still getting Delta long COVID into the clinic now,” he says. “Omicron is only starting.”

Australia, along with many countries, does not track long COVID numbers. But in data released in April by the Australian Bureau of Statistics, 42 of the more than 5000 COVID deaths then officially registered since the pandemic began were considered to be due to long COVID.

Credit:Artwork: Monique Westermann/Getty

What might be causing it?

Such a broad spectrum of symptoms and patients makes long COVID a particularly puzzling knot to unpick for scientists. “You do have to be like detectives,” says Matthews.

She and her team have already found one smoking gun of sorts – significant biological markers of inflammation in the blood of people with ongoing symptoms compared with those who have fully recovered from COVID or from other mild coronaviruses that cause colds. These markers are cytokines – proteins that command the immune system’s defences during a viral attack. You might have heard of a cytokine storm where “overzealous” immune cells damage the body as they wage war on an infection, causing inflammation and sometimes serious harm in the fallout.

“We normally see lots of cytokines during acute infection, and then they go away,” says Matthews. “So this finding really validated that these people do still have something going on. And it explains some of the symptoms, the aches and pains, the fatigue.”

When we get sick, a lot of our symptoms are not caused by the virus directly but by the body’s immune system fighting back. (That’s why the aftermath of a COVID vaccine, which also activates the immune system, can sometimes feel like a short bout of the virus.)

Putrino says there has even been evidence of cytokine storms during otherwise mild or “silent” (asymptomatic) infections. “Suddenly, patients will present with blood clots because the [cytokines] were disrupting the usual clotting mechanism in cells,” he says. And in very rare cases, infected children have presented with dangerous hyper-inflammation similar to toxic shock or Kawasaki disease.

Given COVID is a new virus to humanity, scientists say it makes sense that it stirs up such a strong immune reaction. But they are trying to determine why this appears to stay “switched on” or reawaken as it does in long COVID patients – in patterns that look remarkably similar to autoimmune conditions such as lupus and rheumatoid arthritis. Could the virus be lurking in our bodies for longer than usual?

“Am I saying antivirals will cure all long COVID? Probably not. And, really, long COVID could be 10 different things.”

If the virus is still attacking or disrupting the body, perhaps hiding out in tissue or the gut, this could itself explain some symptoms. Researchers have been able to detect SARS-CoV-2 in patients’ faeces seven months after an infection and, at times during autopsy, viral particles in patient brains. Dangayach says one hypothesis is that SARS-CoV-2 could be infiltrating the brain stem (the control centre of the autonomic nervous system), causing inflammation or disrupting regular breathing and heart rhythms. Inflammation in both the brain and spinal cord (such as the kind that affects patients with the autoimmune condition multiple sclerosis) can be difficult to spot on regular scans. Some researchers now want to trial antivirals that attack the virus directly in long-COVID patients.

Of course, any lingering virus could be dead already – and just being misinterpreted by the immune system as a threat. “You could have people who still have spike proteins floating around, perhaps in their connective tissue, which then leads to chronic inflammation,” Putrino says. “Or you could be someone who just has persistent virus in their gut, and if you take an antiviral that virus will clear. But am I saying antivirals will cure all long COVID? Probably not. And, really, long COVID could be 10 different things.”

He points to research from Africa that has found persistent micro-clots in long-COVID patients, missed by regular tests but that appear to respond to medication. Dangayach says that not only can this trap inflammatory molecules, but blood vessel changes of this kind can affect the energy and oxygen levels in our cells.

At Yale University, another leader in long-COVID research, scientists put patients with persistent breathlessness but otherwise normal scans through more intensive testing and found that oxygen was not being extracted by the cells in their muscles properly, leaving them more exhausted. Meanwhile, the Mount Sinai team has noticed that long-COVID patients tend to breathe out less carbon dioxide than usual – generally seen in people hyperventilating.

“We have all these breadcrumbs, and sometimes they come together,” says Putrino. “If the cells can’t produce enough energy, they are producing less carbon dioxide too as a byproduct, so that might explain why it’s low in their expired air.”

Meanwhile, a healthy breath into the diaphragm stimulates the vagus nerve, the backbone of the autonomic nervous system, helping regulate breathing, heart rate, blood pressure and more. “If you do breath work, many people will show improvement, but that’s just treating a symptom,” says Putrino. “All of these signs could be just symptoms. We’re still hunting for the underlying pathology.”

Credit:Artwork Monique Westermann/Getty Images

Is it like an autoimmune disease or chronic fatigue?

One concern at the back of Putrino’s mind is that the virus has tipped some people, perhaps with an underlying susceptibility, into an autoimmune condition. These conditions are still being understood by science but often involve the body producing “auto-antibodies” that disrupt the normal functioning of the immune system. Sometimes, they are accompanied by dysautonomia, where the autonomic nervous system is out of whack.

Someone with dysautonomia might get heart palpitations, dizziness and breathlessness after exerting themselves, or even standing up suddenly, as the body’s flight-or-fight response is tripped. This is common among long-COVID patients, including roughly 70 per cent of those at the Mount Sinai clinic.

Some long-haulers speak of an “exertion threshold” beyond which they are engulfed by a storm of symptoms – fatigue, brain fog, breathlessness. Willis hit it in that swimming pool 18 months ago. He now helps train his physiotherapy patients to find their own long-COVID limits and gradually extend or manage them. “Sometimes, I feel like my legs will just give way,” he says. “I can’t walk. I’ve played sport all my life and I’ve never had this before.”

“We could be staring down the barrel of [more widespread] autoimmunity, people who had maybe felt off but always had normal blood work, until now.”

In the absence of clear data, many doctors are trying to learn more by seeing how patients respond to treatment. Putrino says autonomic nervous system rehab has given many of his long-COVID patients at least partial symptomatic relief – not only breathing exercises but wearing compression tights on the lower body to help regulate blood pressure, or sometimes taking salt to increase blood volume. “Still, it’s not a cure. We could be staring down the barrel of [more widespread] autoimmunity, people who had maybe felt off but always had normal blood work, until now.”

Of course, even before COVID-19, an unlucky few were known to develop mysterious conditions, including fatigue, after viral infections – from Ebola to the flu. There are even reports of this kind of “post-viral syndrome” after the world’s last great pandemic, Spanish flu in 1918. In the past year, scientists have found multiple sclerosis is probably caused not just by genetic predisposition but by this kind of rare immune response to a virus too – in this case Epstein-Barr, which most people catch but do not have such a reaction to. In those rare cases of people who do, it morphs into a degenerative autoimmune disease, shredding neurons, but, as long COVID appears to, it can also subside and then flare up again.

Meanwhile, many long COVID symptoms, including dysautonomia, mirror those seen in people with chronic fatigue syndrome, an under-researched area of medicine, according to many in the field. Chronic fatigue, which mostly affects women, is usually thought to be triggered by a viral infection (glandular fever, for example) and is characterised by debilitating fatigue that lasts for at least six months.

Many experts believe unravelling the mystery of long COVID will help unlock the underlying mechanisms behind many of these other disorders – not to mention overhaul our understanding of the immune system itself. Dangayash is not surprised that many chronic-fatigue sufferers feel vindicated by the focus on long COVID – never has a post-viral condition been studied on this scale. “Perhaps there is something going on that makes people susceptible to this kind of [autoimmunity]?”

Or it may be that COVID is especially good at stimulating post-viral conditions, Matthews says. “There may be something about the shape of the virus, the way it’s crumpled up and presents itself to the immune system, that really sets this off.”

Putrino agrees there is probably something about this SARS-CoV-2, whether it is its penchant for binding so well to ACE2 receptors (found throughout the body) or just “because it is so novel”. He says that “it seems to be affecting the immune system in a way that other viruses don’t necessarily do, or do far less frequently. We keep finding abnormal lab findings in people with long COVID, even if they’re not always the same signs.”

Does long COVID affect the brain?

At the Royal Melbourne Hospital, when COVID patients started returning with fresh neurological complaints – difficulty concentrating, memory concerns, insomnia and headaches – many found themselves at the door of neuropsychologist Associate Professor Charles Malpas. He has long worked with brain inflammation conditions such as MS, and is now among doctors trying to determine whether neurological symptoms of long COVID are caused by physical inflammation or damage in the brain itself or are flow-on effects of the condition elsewhere in the body.

So far, for the patients with milder long COVID who Malpas treats, it doesn’t look like direct damage – those who complain of memory lapses and brain fog can still pass cognitive impairment tests (although in Mount Sinai, Putrino says, many of his more severe cases cannot).

Studies have found inflammation and reduced blood flow in the brain of some long-COVID patients, which has also been seen in cases of chronic fatigue. But Malpas warns that we must be cautious when interpreting some studies published overseas that link COVID-19 to brain damage such as brain mass shrinkage and lower IQ scores, or even anecdotal cases of altered personality. Some patients recovering from severe COVID probably do have a form of brain damage caused by clots, neural inflammation or other complications of the infection, he says. But in most long-COVID patients there seem to be explanations elsewhere. “And

we’re not really seeing things like impaired vision or weak limbs,” he says.

“I find it comes on if I exercise too much, I can’t even tell my wife what I want for dinner.”

Brain fog, which Malpas describes as “the feeling of walking through mud while trying to think through a problem”, is common but can be intermittent, often brought on by exertion. (Willis says: “I find it comes on if I exercise too much; I can’t even tell my wife what I want for dinner.”)

The onset of insomnia or migraines post-COVID may also be to blame. “And when that’s treated, or the fatigue is managed then, typically, brain fog resolves as well,” Malpas says. “Still, that doesn’t mean other symptoms we’re seeing like anxiety don’t need treatment too.”

The brain is usually “the final frontier” for medicine, he says, and neurological symptoms often the hardest to pin to a root cause. “It’s a cognitive act to assess your own cognition,” he says. “When people are bad, like with Alzheimer’s, they sometimes don’t report them at all. But there is a real danger too of dismissing symptoms as psychosomatic when they’re not.”

If there are structural or chemical changes happening in the brain (and elsewhere), it’s too early to say if they will be permanent. The brain is remarkably resilient in its ability to rewire and heal, after all. But Dangayach says even short-term signs of brain shrinkage underscore the urgent need for more research into long COVID. “Clearly, it’s not all in your head, right? In the 1970s, people thought MS was a psychiatric problem – it took decades to get where we are with treatments today. We shouldn’t make the same mistake.”

What is the treatment outlook?

In the 19th century, patients were expected to take a long time to recover from an illness and strict bed rest was often the tedious prescription of the day. In the modern era, doctors generally encourage us to get active again early into recovery, to ward off any other problems from staying put too long. But, in the case of COVID-19 – and particularly long COVID – exercise can have the opposite effect.

Willis, who is president of the Australian Physiotherapist Association, teaches fellow long-COVID sufferers to manage their energy budget wisely and scale up slowly, “things like vacuuming half a room at a time or not exercising on days you need to do the shopping”. His clients don’t fit one mould, although many were fit, healthy people before long COVID-19 hit. “This isn’t about fitness,” he says. Now, if they push themselves too hard, they’re often wiped out with a fresh surge of symptoms for days. “It can be one step forward, two steps back,” Willis says. “I, at least, can work and exercise. I can now swim 1½ to two kilometres before I hit my wall, [less than half] of what I used to. But I can’t get past that. Every time I think I can, I’m on my arse.”

Vaccination cuts the risk significantly. And some researchers are already testing or planning to test specific medications for long COVID.

Putrino reports only 10 to 15 per cent of his long-COVID patients feel they are now fully recovered but most have at least shown improvement, especially from autonomic nervous system rehabilitation (above). Since long COVID affects so many systems in the body, often in different ways, patients need support across disciplines, he says. Vaccination cuts the risk significantly. And some researchers are already testing or planning to test specific medications for long COVID, say, to break up microclots, reduce viral reservoirs or inflammation in blood vessels, or to dampen the body’s immune reaction.

“When you don’t have a definitive answer, you treat the symptoms,” says Dangayach.

While the speed at which science developed safe, effective vaccines and treatments for the virus may have been extraordinary, Dangayach and Putrino say this new golden era of research funding has not flowed through into long COVID in the same way. And most countries are not tracking cases or ensuring insurers cover the condition. “It’s going to be a huge economic burden, not just a healthcare one,” Willis says.

“There was so much urgency and collaboration at the start,” Dangayach says. “But now is not the time to say, ‘We’ve had enough.’ Now, we’re in a survivorship crisis and the advances we make will decide health policy and outcomes for so many people hit by long COVID. We can’t step off the gas.”

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