We’re closing in on the causes of long covid and possible treatments

What causes long covid

Tens of millions of people have long covid. We are finally beginning to understand the mechanisms behind the disease – and medicines are probably less than a year away

What causes long covid

Pete Reynolds

LAUREN NICHOLS first fell ill on 10 March 2020. Her symptoms started with crushing fatigue, swiftly followed by headaches, brain fog and agonising gastrointestinal pain. “My oesophagus was incredibly painful,” she says. “Every time I took a breath of air, every time I spoke, I wanted to die.” Her doctor diagnosed bad acid reflux.

Nichols had an inkling it was covid-19, and later tested positive, but her symptoms didn’t run their course in a couple of weeks, as official advice at the time stated. Two years down the line, she is still waiting for relief.

She isn’t alone. Alongside the 5.8 million people confirmed to have died from the coronavirus, tens of millions more have long covid: a lingering condition with symptoms that last for months or years. These “long haulers” are still experiencing the ill effects of infection, often with little help from doctors. “They still aren’t listening to patients,” says Nichols, who is now vice president of Body Politic, an international advocacy group currently focusing on covid-19.

The first whispers of a lingering condition associated with covid-19 started within months of the disease emerging. Some people who had been infected with SARS-CoV-2 reported that they couldn’t get better. The multitude of symptoms varied from person to person and changed over time in unpredictable ways.

The term “long covid” was coined by archaeologist Elisa Perego in a tweet in May 2020 and was swiftly adopted by the world. What has taken much longer to agree on is a definition of what it is; how many people have it; why some get it while others don’t; and how to treat it. Today, with better definitions of the condition and a host of published papers, scientists can start to provide some answers. We now know that around 1.3 million people in the UK currently have long covid, as reported by the Office for National Statistics on 3 February. That number is likely to grow following a wave of infections with the omicron variant, which recently swept through the UK’s largely unvaccinated young people.

“My oesophagus was incredibly painful. Every time i took a breath of air, every time i spoke, I wanted to die”

The global toll is estimated to be around 100 million, according to prevalence data from a meta-analysis published in December 2021 of 81 studies, which found that 32 per cent of people diagnosed with covid-19 were still experiencing fatigue 12 weeks later, while 22 percent had cognitive impairments.

We also know that certain people are more at risk. A study published in January showed that people were more likely to develop long covid if they had type 2 diabetes; if they had certain “autoantibodies” that can attack their own tissues; if pieces of the virus’s genome were still circulating in their blood; and if they had previously been infected with the Epstein-Barr virus, which causes glandular fever. Recently, we have also discovered that people with long covid have a distinct set of bacteria in their guts, although it isn’t clear whether their gut bacteria predisposed them to the illness, or the illness triggered the change in gut bacteria.

Of over 200 known symptoms associated with long covid, the most common are shortness of breath, post-exertional malaise – in which even a tiny amount of exercise leads to exhaustion – and cognitive difficulties dubbed brain fog.

This last symptom is remarkably common, arising even in people who don’t think they have long covid. In a study published in January, Sijia Zhao at the University of Oxford and her colleagues gave cognitive tests to 53 people who didn’t report lasting symptoms after covid19 infection, alongside 83 controls who reported not having been infected. The covid-19 group mostly matched the controls, but were worse at remembering pictures they had seen and at focusing on a task. Fortunately, these difficulties eased. “There is a slow but quite obvious recovery from these deficits after about six to nine months,” says Zhao.

Others aren’t so fortunate. Nichols is still unwell, having experienced a roller coaster of symptoms including severe diarrhoea, an “utterly terrifying” mini-stroke, shingles and hair loss. Her case is severe, but not uniquely so. “A lot of us are just consistently not well, or getting worse,” she says.

Long covid isn’t unique in this respect. Many other viruses, such as those that cause Zika or pneumonia, can cause long-term symptoms. Chikungunya virus, which is common in the tropics, causes fever, but is often followed by lingering symptoms that resemble arthritis.

Given the variety of long covid symptoms, finding one mechanism behind it or a single treatment is unlikely. “I would caution anybody who tells you they have one answer to long covid,” says Mark Toshner at the University of Cambridge. He says we probably aren’t dealing with a single disease pathway. Instead, we are getting a number of overlapping answers, some of which describe mechanisms we already knew about from other viruses, some of which may be heightened in covid-19 and some of which may be specific to it.

Promising paths
As research progresses, a long list of possible mechanisms is slowly being cut down to the most promising candidates. These include the idea that the virus may cause severe tissue damage that the body can’t repair. This is particularly likely in people who require intensive care, says Iwasaki. Other possible explanations suggest the virus may leave the immune system permanently disrupted, or even trigger an autoimmune disease in which the immune system attacks healthy tissue. In some cases, the virus may linger in the body, causing ever more harm.

The idea that SARS-CoV-2 might stick around in the body was initially rejected by many experts because the virus stopped showing up in blood tests within weeks of infection. It was a mistake to dismiss the idea, says Michael VanElzakker at Massachusetts General Hospital in Boston. He says the problem was that it was easier to identify abnormal immune cell activity from a blood test than to identify fragments of virus that may be hiding out anywhere in the body.

In January 2021, a key study published by Michel Nussenzweig at the Rockefeller University in New York and his colleagues reignited the idea. They showed that memory B-cells, part of the immune system, become increasingly attuned to the virus between 1.3 and 6.2 months after infection – suggesting that the virus was still present, and that B-cells were adapting to it, well after it stopped showing up in blood tests.

“We will throw the full immunologist toolkit at them to work out what has happened”

Then, in December, Daniel Chertow at the National Institutes of Health in Bethesda, Maryland, and his team reported in a preprint, a study yet to be peer reviewed, that the virus was “widely distributed” around the bodies and brains of 44 covid-19 patients who had died. “It’s evidence that the virus is sticking around for months and months,” says VanElzakker. An earlier study supported this finding by showing the virus lingering in people’s guts.

The implication is simple. Many people with long covid may still have SARS-CoV-2 in their bodies, and a crucial step in helping them recover will be to destroy the virus. Monoclonal antibodies would be worth trying, says Iwasaki. Vaccination could also help. A review published this month by the UK Health Security Agency showed that it helps cut the risk of developing long covid, over and above helping you avoid infection in the first place.

It also showed that some unvaccinated people with long covid who were subsequently vaccinated had reduced symptoms. One theory is that the vaccination may help clear lingering fragments of the virus from the body.

However, it is crucial to differentiate between long haulers who are still fighting the virus and those whose illness is caused by their own immune system. The evidence for immune disruptions in long covid is overwhelming. Many studies show that immune chemicals are overproduced in long covid. These have widespread knock-on effects, including disrupting brain chemicals.

This chemical chaos might explain long covid brain fog, if Iwasaki’s experiments are anything to go by. In one, mice infected with SARS-CoV-2 had elevated levels of an immune chemical called CCL11, which was also found in long covid patients with cognitive symptoms, but not in those with long covid and no cognitive symptoms. In the mice, brain cells called microglia were also inflamed. We know from studies of “chemo brain”, the brain fog that sometimes follows chemotherapy, that inflamed microglia can damage neurons, causing cognitive disturbances. The suggestion is that long covid brain fog may be caused by inflammation of the microglia.

To get a clearer picture of which immune system alterations pertain to which long covid symptoms, Danny Altmann at Imperial College London and his team are now grouping people with long covid by their symptoms, with, he says, the intention of “throwing the full molecular immunologist toolkit at them”, to pick apart what has happened to their bodies.

Blood vessels might also be involved, an idea that has grabbed the imaginations of many long haulers. This is the notion that the primary cause of long covid is tiny blood clots, which restrict the flow of blood to the organs and damage the walls of blood vessels. Such is the enthusiasm for this idea that #TeamClots has become a popular hashtag on Twitter.

The hypothesis is the brainchild of researchers co-led by Resia Pretorius at Stellenbosch University in South Africa. She has previously argued that bacteria in blood can disrupt clotting, which occurs to stop bleeding, and that this malign clotting plays a role in many conditions, including Alzheimer’s. Could the same be true for a virus?

In early 2021, Pretorius started collecting blood samples from long covid patients. She focused on the plasma, the liquid part in which red and white blood cells are carried. Under the microscope, she saw lots of what she calls “microclots”: tiny lumps of material resembling blood clots. The microclots were unusually difficult to break down, compared with normal clots. They didn’t show up in the blood of people who had never been infected with SARSCoV-2.

In a second study, Pretorius’s team showed that the spike protein from the virus can, on its own, disrupt the normal clotting process. Clots form when a protein called fibrinogen is converted into a second protein called fibrin. The researchers discovered that the spike 6/8 protein altered the three-dimensional structure of the fibrinogen – a finding that has since been backed up by other work.

It is unlikely that the spike protein used in covid-19 vaccines would have the same effect because the volume given is too small and localised to generate a significant interaction with fibrinogen circulating in the blood, says Robert Ariёns at the University of Leeds, UK.

The Pretorius group’s most dramatic discovery comes from a preprint published in late December 2021. The researchers examined the blood of 70 people with long covid and found microclots in all participants. Then they gave 24 of them three medications to stop clots from either forming or being maintained. Two were antiplatelet agents – clopidogrel and aspirin – and the third was an anticoagulant called apixaban. Afterwards, the number of microclots fell. According to the 24 recipients of the drugs, their main symptoms – shortness of breath, fatigue and brain fog – were relieved.

There was no control group, so the findings are preliminary, but it could be that the clots are interfering with oxygen delivery, leading to these symptoms. The idea was backed up by another preprint last month. Fergus Gleeson at the University of Oxford and his colleagues pumped the noble gas xenon into the lungs of 11 people with long covid who were never 7/8 hospitalised, 12 people who were hospitalised with covid-19 but didn’t have long covid, and 13 people without covid-19. The xenon made it into the lungs, but struggled to cross into blood vessels and then into red blood cells in those with long covid.

Cardiovascular specialists say the microclot hypothesis is intriguing but unproven. “It is possible that this is something really interesting going on here, but the evidence as yet makes me cautious,” says Ariёns. He points out that the microclots have only been seen by the Pretorius group. “I’d like to see it confirmed in other labs.” Pretorius and her group are currently applying for a full clinical trial to test their triple therapy in more patients. “We need that desperately,” she says

A resolution to the microclot debate may be months away, but meanwhile, millions of people still experiencing long-term symptoms from covid-19 infection are desperate for treatments and many are willing to try anything.

Global effort

For Toshner, the solution is to emulate the international RECOVERY trial, which offered experimental treatments to people hospitalised with acute covid-19 and led to key discoveries, including the usefulness of dexamethasone, a steroid that significantly reduces death in people with severe covid-19. “Right now, all around the world, long covid clinics are being set up,” he says. He wants everyone who attends to be invited to take part in randomised trials of potential therapies. That will give participants the opportunity to try things under the supervision of a doctor, and at the same time create large sample sizes and robust results. “There needs to be international collaboration,” he says. “I’d be surprised if we didn’t have some pretty good answers and a shelf of therapeutics a year from now”

There is one more path that holds promise – a medicine that can stop people getting long covid in the first place. Two strong candidates for this are apixaban, the anticoagulant used in Pretorius’s trial, and atorvastatin, an anti-inflammatory that could help dampen an overactive immune system. To test these drugs, Toshner and his colleagues have set up a clinical trial called HEAL-COVID that will send hospitalised patients home with these extra medications, in the hope of preventing long-term complications. Early results may be available within the year.

Altmann says he is optimistic that there is light at the end of the long-hauler tunnel. “I’d be surprised if we didn’t have some pretty good answers and a shelf of therapeutics a year from now.”

Source: https://www.newscientist.com/article/mg25333751-500-were-closing-in-on-the-causes-of-long-covid-and-possible-treatments/

Image Source: https://www.freepik.com/free-photo/senior-male-patient-getting-vaccinated-coronavirus_19245693.htm#query=covid&position=35&from_view=search

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