Four Key Questions About Long Covid

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Feature ILLUSTRATION BY ACAPULCO STUDIO ACAPULCO BY ILLUSTRATION quite as overwhelming one year on, she says, “I’ve never had a symptom-free day since.” Hastie has what is now called long COVID: a long-lasting disorder that arises following FOUR KEY QUESTIONS infection with SARS-CoV-2, the virus that causes COVID-19. Surveys of thousands of people have revealed an extensive list of symptoms, such as fatigue, dry cough, shortness of breath, ABOUT LONG COVID headaches and muscle aches. A team led by Athena Akrami, a neuroscientist at University It is now clear that many people who become College London who has long COVID, found 205 symptoms in a study of more than 3,500 infected with SARS-CoV-2 develop a lingering people1. By month 6, the most common were disorder that can last months — but many key “fatigue, post-exertional malaise, and cognitive dysfunction”. These symptoms fluctuate, mysteries remain unsolved. By Michael Marshall and people often go through phases of feel- ing better before relapsing2. In the first months of the pandemic, the idea that the virus might cause a chronic condition was overlooked in the desperate hen Claire Hastie fell ill in March But within a week she was flattened. “I had struggle to deal with acute cases. But Hastie of last year, she reacted the way just never felt ill in this way before. I felt like I soon realized that she was not alone in having she usually would to a minor had an elephant sitting on my chest.” At times, a lingering form of the disease. In May 2020, ailment: she tried to ignore it. she became convinced she was going to die. she started a Facebook group for people with “It started off incredibly mild,” A single mother of three, Hastie “said what long COVID. Today, it has more than 40,000 she says. “I would normally I thought might be my final words to the one members and works with research groups have paid no attention to it child who happened to be walking past my studying the condition — with Hastie some- Wwhatsoever.” bedroom door”. Although her condition is not times appearing as a co-author of papers. 168 | Nature | Vol 594 | 10 June 2021 ©2021 Spri nger Nature Li mited. All ri ghts reserved. ©2021 Spri nger Nature Li mited. All ri ghts reserved.

Meanwhile, long COVID has moved from a gone on to get long COVID. If the UK preva- SARS-CoV-2 get long COVID — as the ONS data curiosity, dismissed by many, to a recognized lence is applicable elsewhere, that’s more than suggest — why those 10%? public-health problem. In January, the World 16 million people worldwide. Health Organization revised its guidelines for The condition seems to be more common What is the underlying biology of COVID-19 treatment to include a recommen- in women than in men. In another ONS anal- long COVID? dation that all patients should have access to ysis, 23% of women and 19% of men still had Although researchers have exhaustively sur- follow-up care in case of long COVID. symptoms 5 weeks after infection. That is veyed the diverse symptoms of long COVID, Funding agencies are also paying atten- “striking”, says Rachael Evans, a clinician sci- no clear explanation for them exists. “We need tion. On 23 February, the US National Insti- entist at the University of Leicester, UK, and a people to be looking at the mechanisms,” tutes of Health (NIH) announced that it would member of the Post-Hospitalisation COVID-19 says Hastie. This will not be easy: studies have spend US$1.15 billion over four years into study (PHOSP-COVID). “If you’re male and get shown that many people with long COVID have research on long COVID, which it refers to COVID, you’re more likely to go to hospital and problems with multiple organs6, suggesting as “post-acute sequelae of COVID-19 (PASC)”. you’re more likely to die. Yet if you survive, that it is a multisystem disorder. In the United Kingdom, the National Insti- actually it’s females that are much more likely It seems unlikely that the virus itself is still tute for Health Research (NIHR) announced to get the ongoing symptoms.” at work, says Evans. “Most of the studies have in February that it was investing £18.5 million There is also a distinctive age distribution. shown that after a few weeks you’ve pretty (US$25.8 million) to fund four studies of According to the ONS, long COVID is most much cleared it, so I very much doubt it’s an long COVID — and the following month, it common in middle-aged people: the preva- infective consequence.” launched another round of funding worth lence was 25.6% at 5 weeks for those between However, there is evidence that fragments of £20 million. 35 and 49 years old. It is less common in the virus, such as protein molecules, can persist As the number of confirmed COVID cases younger people and older people — although for months7, in which case they might disrupt tops 170 million across the globe, millions Evans says the latter finding is probably due the body in some way even if they cannot infect of people might be experiencing persistent to ‘survivor bias’, because so many old people cells. symptoms and searching for answers about who have had COVID-19 have died. A further possibility is that long COVID is their future health. Here, Nature looks at four And although long COVID is rarer in younger caused by the immune system going haywire of the biggest questions that scientists are people, that does not mean it is absent. Even and attacking the rest of the body. In other investigating about the mysterious condition for children aged 2–11, the ONS estimates that words, long COVID could be an autoimmune known as long COVID. 9.8% of those who test positive for the virus disease. “SARS-CoV-2 is like a nuclear bomb still have symptoms after at least 5 weeks, in terms of the immune system,” says Steven How many people get long COVID reinforcing the suggestion from other stud- Deeks, a physician and infectious-disease and who is most at risk? ies that children can get long COVID4. Yet researcher at the University of California, San There is increasing clarity on the overall prev- some medical professionals play down the Francisco. “It just blows everything up.” Some of alence of long COVID, thanks to a series of sur- idea, says Sammie Mcfarland, who founded those changes might linger — as has been seen veys — but it is less certain who is most at risk, the UK-based support group Long Covid Kids. in the aftermath of other viral infections (see and why it affects only some. “Long COVID in children isn’t believed. The ‘What is the relationship between long COVID Most of the early prevalence studies looked symptoms are minimized.” and other post-infection syndromes?’). only at people who had been hospitalized with Nevertheless, age and sex are surprisingly Still, it is too early to say which hypothesis acute COVID-19. Ani Nalbandian, a cardiologist powerful for identifying people at risk. A is correct, and it might be that each is true in at Columbia University Irving Medical Center paper published in March presented a model different people: preliminary data suggest that in New York, and her colleagues collated that successfully predicted whether a per- long COVID could be several disorders lumped nine such studies for a review published on son would get long COVID using only their into one. 22 March3. They found that between 32.6% and age, their sex and the number of symptoms Some researchers are taking that next step, 87.4% of patients reported at least one symp- reported in the first week5. hoping to unpick the biology. PHOSP-COVID tom persisting after several months. Still, many uncertainties remain. In par- has recruited more than 1,000 UK patients But most people with COVID-19 are never ticular, if about 10% of people infected with and taken blood samples to look for evidence ill enough to be hospitalized. The best way of inflammation, cardiovascular problems and to assess the prevalence of long COVID is to UNCERTAIN ENDPOINT other changes. Similarly, Deeks has helped to follow a representative group of people who The UK Oice for National Statistics (ONS) tracked recruit almost 300 COVID-19 patients who have have tested positive for the virus. The UK more than 20,000 people following a positive since been followed up every 4 months and COVID-19 test, to determine how long their symptoms Office of National Statistics (ONS) has done lasted. The ONS considers ‘long COVID’ to be the have given blood and saliva samples. “We have just that, by following more than 20,000 peo- persistence of symptoms for more than four weeks. a massive specimen bank,” says Deeks. “We’re ple who have tested positive since April 2020 25 looking at inflammatory outcomes, changes in (see ‘Uncertain endpoint’). In its most recent the coagulation system, evidence that the virus analyses, published on 1 April, the ONS found persists.” The team has found altered levels of 20 that 13.7% still reported symptoms after at cytokines — molecules that help to regulate least 12 weeks (there is no widely agreed defi- immune responses — in the blood of people nition of long COVID, but the ONS considers it 15 who have had COVID-19, suggesting that the to be COVID-19 symptoms that last more than immune system is indeed out of balance, as 4 weeks). 10 well as protein markers suggesting neuronal “I think that’s the best estimate so far,” says dysfunction8. Akrami, who now splits her research time 5 A better understanding of the underlying between her original focus, neuroscience, biology will point the way to treatments and

and work on long COVID. (%) symptoms reporting Participants medications, says Evans. But it seems unlikely 0 In other words, more than one in 10 people 5 6 7 8 9 10 11 12 13 14 15 16 17 18 that there is a single, neat explanation for long

UK OFFICE FOR NATIONAL STATISTICS NATIONAL UK OFFICE FOR who became infected with SARS-CoV-2 have Weeks COVID. “There is a story emerging,” says Deeks.

Feature “There’s not one clinical phenotype. There’s dif- 12% reported persistent symptoms including anti-inflammatory agent that it has devel- ferent flavours, different clusters. They all may “disabling fatigue, musculoskeletal pain, neuro- oped. Results are expected in the second half have different mechanisms.” His group plans to cognitive difficulties, and mood disturbance”10. of 2021. In the United Kingdom, intensive-care use machine learning to work out how many That percentage is strikingly similar to the long specialist Charlotte Summers at the Univer- types there are and how they differ. COVID prevalence observed in the United King- sity of Cambridge and her colleagues have Evans and her PHOSP-COVID colleagues dom by the ONS. launched a study called HEAL-COVID, which have taken a stab at this, in a preprint posted Some people with long COVID will proba- aims to prevent long COVID from taking hold. on 25 March9. They studied 1,077 COVID-19 bly meet the diagnostic criteria for ME/CFS, Participants who have been hospitalized with patients, recording symptoms including phys- according to Komaroff and his colleague COVID-19 will be given one of two drugs after ical impairments, mental-health difficulties Lucinda Bateman, founder of the Bateman being discharged: apixaban, an anticoagulant such as anxiety, and cognitive impairments Horne Center in Salt Lake City, Utah, which spe- that might reduce the risk of dangerous blood in areas such as memory and language. The cializes in treating ME/CFS11. But there do seem clots; and atorvastatin, an anti-inflammatory. researchers also recorded basic information to be differences: for instance, people with long In the United States, the NIH is funding a trial of such as age and sex, and biochemical data such COVID are more likely to report shortness of existing drugs that people with mild COVID-19 as levels of C-reactive protein — a measure of breath than are those with ME/CFS, Komaroff can administer at home. Participants will be inflammation. The team then used a mathemat- says. Furthermore, if long COVID does end up followed for 90 days to test the drugs’ impact ical tool called cluster analysis to see whether being subdivided into multiple syndromes, that on longer-term symptoms. there were identifiable groups of patients with will further complicate comparisons between Finally, there is the question of what part similar profiles. it and ME/CFS. COVID-19 vaccines might play. Although many “We would think if you had a terrible acute “I’ve so far resisted saying long COVID is of them prevent death and severe illness, lung injury and multi-organ failure, those would ME/CFS, because I really think it is an umbrella scientists do not yet know whether they pre- be the people that would have the ongoing term and there are multiple things happening vent long COVID. pathology,” says Evans. But the study found What about the impact of vaccines in people little relationship between the severity of the “SARS-CoV-2 is like a who already have long COVID? A UK survey of acute phase, or levels of organ damage, and the more than 800 people with long COVID, which severity of long COVID. nuclear bomb in terms of has not been peer reviewed, reported in May The reality was more complicated. The the immune system.” that 57% saw an overall improvement in their analysis identified four clusters of long COVID symptoms, 24% no change and 19% a deteriora- patients whose symptoms were distinct. Three tion after their first dose of vaccine12. In April, of the groups had mental-health and physical in this long COVID umbrella,” says Nisreen Akrami’s team launched a systematic survey impairments to varying degrees, but few or Alwan, a public-health researcher at the Uni- to shed more light. “People need to get vac- no cognitive difficulties. The fourth cluster versity of Southampton, UK. What many do cinated to come out of the pandemic, but we showed only moderate mental-health and agree on, however, is that the two conditions need to first address their concern of whether physical impairments, but had pronounced could productively be studied in tandem. the vaccine is going to help, or not harm, or cognitive problems. “There should be a coalition,” says Alwan. Some [be] harmful.” “Cognition was really quite separate, and researchers are already planning to collaborate. Similarly, Akiko Iwasaki, an immunobiologist we weren’t expecting that,” says Evans. She For instance, a major study called DecodeME at Yale University in New Haven, Connecticut, emphasizes that the study does not unpick the aims to recruit 20,000 people to find genetic is recruiting people with long COVID who have underlying mechanisms. “But it is definitely a factors that contribute to ME/CFS — and Evans not been vaccinated, so she and her colleagues first step.” says PHOSP-COVID will be sharing data with it. can track how their bodies react to the vac- “I’m really hopeful that the silver lining will cine. She hypothesizes that the vaccine might What is the relationship be, at the end of the day, we gain better insight improve symptoms by eliminating any virus or between long COVID and other into other post-viral problems,” says Akrami. viral remnants left in the body, or by rebalanc- post-infection syndromes? Hastie puts it more bluntly: “Let’s not waste ing the immune system. Some scientists weren’t surprised by long a good crisis.” People with long COVID just want some- COVID. Illnesses that linger after an infection thing that works. “How can we get better?” have been reported in the scientific literature What can be done to help people asks Hastie. “That’s what we want to know.” for 100 years, says Anthony Komaroff, an with long COVID? internal-medicine physician at Harvard Med- Right now, the options are fairly limited, Michael Marshall is a science writer based in ical School in Boston, Massachusetts. because the disorder is so poorly understood. Devon, UK. He noted that fact in March, during a webinar Some countries are opening clinics for peo- 1. Davis, H. E. et al. Preprint at medRxiv organised by MEAction, an organization based ple with long COVID. In Germany, a company https://doi.org/10.1101/2020.12.24.20248802 (2021). in Santa Monica, California, that works to raise called MEDIAN has begun accepting people 2. Ziauddeen, N. et al. Preprint at medRxiv awareness of myalgic encephalitis, also known with long COVID at some of its private rehabil- https://doi.org/10.1101/2021.03.21.21253968 (2021). 3. Nalbandian, A. et al. Nature Med. 27, 601–615 (2021). as chronic fatigue syndrome (ME/CFS). People itation clinics. In England, the National Health 4. Buonsenso, D. et al. Acta Paediatr. https://doi.org/10.1111/ with this debilitating illness become exhausted Service has provided £10 million for a network apa.15870 (2021). after even mild activity, alongside experiencing of 69 clinics: these have started to assess and 5. Sudre, C. H. et al. Nature Med. 27, 626–631 (2021). 6. Ayoubkhani, D. et al. Preprint at medRxiv other symptoms such as headaches. Long dis- help people with the condition. https://doi.org/10.1101/2021.01.15.21249885 (2021). missed by some medical professionals because That is a welcome first step, says Hastie, but 7. Gaebler, C. et al. Nature 591, 639–644 (2021). it had no clear biological underpinning, ME/CFS few evidence-based treatments exist. 8. Sun, B. et al. Cells 10, 386 (2021). 9. PHOSP-COVID Collaborative Group et al. Preprint at is often post-viral. In terms of medicines, a handful are being medRxiv https://doi.org/10.1101/2021.03.22.21254057 It isn’t uncommon for an infection to trig- tested. Biotechnology company PureTech (2021). ger long-lasting symptoms. One study of Health in Boston, Massachusetts, announced 10. Hickie, I. et al. Br. Med. J. 333, 575 (2006). 11. Komaroff, A. L. & Bateman, L. Front. Med. 7, 606824 (2021). 253 people diagnosed with certain viral or in December that it was starting a clinical 12. LongCOVIDSOS vaccine report. Available at bacterial infections found that after 6 months, trial of deupirfenidone, an anti-fibrotic and go.nature.com/3yfqem2 (2021).