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What we know—and don't know—about long Covid

Nearly 10% of Covid-19 patients are estimated to experience long-term symptoms, a condition called "long Covid"—but there is still much experts don't know about the condition. Reporting for Nature, Michael Marshall rounds up the four biggest questions experts still have about long Covid.

Recovery clinics for Covid-19 long-haulers

1. How many people have long Covid, and who's at high risk for the condition?

No one knows exactly how many people have long Covid, but recent research is finding how prevalent the condition might be and which segments of the population may be more at risk than others.

For instance, one study in March found that between 32.6% and 87.4% of patients hospitalized with acute Covid-19 reported at least one symptom remaining after several months. And another analysis, published by the UK Office of National Statistics (ONS) in April, found that of more than 20,000 people who tested positive for the coronavirus since April 2020, 13.7% reported symptoms persisting after at least 12 weeks. Athena Akrami, a neuroscientist at University College London, says is that is "the best estimate so far" since it is not limited to hospitalized patients.

Another ONS analysis found that five weeks after initial Covid-19 infection, 23% of women and 19% of men still had Covid-19 symptoms—a finding that Rachael Evans, a clinician scientist at the University of Leicester, found "striking."

"If you're male and get Covid, you're more likely to go to hospital[s] and you're more likely to die," she said. "Yet if you survive, actually it's females that are much more likely to get the ongoing symptoms."

In addition, ONS has observed that long Covid is more common in middle-aged people, finding that 25.6% of people between the ages of 35 and 49 who tested positive for Covid-19 reported symptoms five weeks post-infection. But ONS also estimates that 9.8% of children ages 2 to 11 who test positive will have symptoms persisting beyond five weeks of infection.

According to Marshall, these findings suggest that while many uncertainties remain about long Covid, we know that age and sex are "surprisingly powerful" indicators of long Covid risk.

2. What causes long Covid?

Experts aren't yet certain about what causes long Covid. However, Evans doesn't believe long Covid is caused by a continuing coronavirus infection. "Most of the studies have shown that after a few weeks you've pretty much cleared it, so I very much doubt it's an infective consequence," she said.

However, parts of the virus, such as protein molecules, could persist in the body for months, which could disrupt the body, Marshall reports.

It's also possible that long Covid is caused by the immune system attacking the body, which—if true—could suggest long Covid is an autoimmune disease. The coronavirus "is like a nuclear bomb in terms of the immune system," Steven Deeks, a physician and infectious disease researcher at the University of California-San Francisco, said. "It just blows everything up."

And although it's still too early to tell which hypothesis, if any, is correct, Marshall writes that it's also possible that "each is true in different people: preliminary data suggest[s] that long Covid could be several disorders lumped into one." In fact, he says most experts believe there are a variety of factors at work in causing long Covid.

As a result, one person's experience of long Covid may be entirely different from someone else's. "There is a story emerging," Deeks said. "There's not one clinical phenotype … They all may have different mechanisms."

To research this possibility further, experts are investigating different potential "types" of long Covid and how they differ, Marshall writes.

For instance, a study by Evans and colleagues of 1,077 Covid-19 patients found that of four long Covid patient groups, three groups presented with mental and physical health problems to varying degrees but had few cognitive problems. However, the fourth group had only moderate mental health and physical problems but significant cognitive difficulties.

"Cognition was really quite separate, and we weren't expecting that," Evans said. She added that, while the study doesn't identify the underlying mechanics of long Covid, "it is definitely a first step."

3. Is long Covid related to other post-infection conditions?

Although experts have much to learn about long Covid, they were not surprised that some symptoms lingered. According to Anthony Komaroff, an internal medicine physician at Harvard Medical School, post-infection illnesses have been reported in research for a century.

One common post-infection illness is myalgic encephalitis, or chronic fatigue syndrome (ME/CFS), Komaroff said. And in fact, he and Lucina Bateman, founder of the Bateman Horne Center, said although there may be some variations, some long Covid patients likely meet the criteria for ME/CFS.

"I've so far resisted saying long Covid is ME/CFS, because I really think it is an umbrella term and there are multiple things happening in this long Covid umbrella," said Nisreen Alwan, a public health researcher at the University of Southampton.

That said, many experts—including Alwan and Akrami—believe it could be valuable to study the two conditions in tandem. Akrami hopes that “at the end of the day, we gain better insight into other post-viral problems," Akrami said.

4. What treatments are effective for long Covid patients?

As of now, treatment options for long Covid are limited because the condition hasn't been sufficiently researched, Marshall reports, and because of the multidisciplinary expertise such a wide-ranging condition requires.

That said, some countries, including Germany and the United Kingdom, have taken the initial step of opening clinics for long Covid patients, and various therapies and medicines are being tested.

PureTech Health for example, announced in December that it is starting a clinical trial of deupirfenidone, an anti-fibrotic and anti-inflammatory drug, as a long Covid treatment. The trial results are expected in the second half of 2021, Marshall reports.

Meanwhile, researchers at the University of Cambridge have begun a study looking at how two drugs—apixaban, an anticoagulant, and atorvastatin, an anti-inflammatory—could help prevent long Covid in Covid-19 patients. And in the United States, NIH is funding a trial looking at existing drugs that can be administered by patients with mild Covid-19 at home to see how the drugs impact long-term symptoms.

Researchers have also found that Covid-19 vaccines may have an effect on long Covid. For instance, one preprint survey in the U.K. found that, among 800 people with long Covid, 57% reported an overall improvement in their condition after their first dose of a Covid-19 vaccine.

But even as these various clinic and trials seek to find answers, long Covid patients ultimately "just want something that works," Marshal writes. Quoting one long Covid patient, Claire Hastie, he said, "How can we get better? That's what we want to know" (Marshall, Nature, 6/9).

Recovery clinics for Covid-19 long-haulers

Download the case study

Recovery Clinics for Covid-19 Long-haulers

Several health systems have set up dedicated recovery clinics to help treat and coordinate care for long-haulers. This resource provides an overview of Covid-19 recovery clinic models pioneered by two early adopters—The University of Iowa Hospitals and Clinics and the University of Pennsylvania Medicine—and considerations for assessing whether it is a model you should pursue.






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