For many people, the covid-19 pandemic feels like a thing of the past. But for those with long covid, it is far from over. Five years on from when covid-19 turned up, those with lingering symptoms still can鈥檛 live their lives as they did before.
The emergence of long covid in the first few months of the pandemic sparked an explosion of research into why some people develop persistent symptoms after being infected with the SARS-CoV-2 virus. Half a decade later, there is growing clarity about how common long covid is and its underlying mechanisms. What is less clear is how many people recover and how best to treat it.
The World Health Organization defines long covid as after the initial infection, or that develop after that point with no alternative explanation. The symptoms of long covid are diverse, the most common being fatigue, headaches, brain fog and post-exertional malaise 鈥� meaning even small amounts of physical activity can cause severe exhaustion.
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Initially, there was a lot of debate about how common long covid is, but now a rough consensus has formed. Around 5 to 6 per cent of people who are infected with SARS-CoV-2 develop long covid, says at the VA St Louis Health Care System in Missouri. While this is lower than some early estimates, 鈥渋t鈥檚 not an insignificant number鈥�, he says. Some people are also more vulnerable, notably women and people .
The risk doesn鈥檛 disappear after the first infection, says at the University of Southampton, UK. The first time you catch covid-19 poses the biggest risk, but it still mounts up with subsequent infections, as Alwan and her colleagues of more than 100,000 UK cases.
On the plus side, newer variants of SARS-CoV-2 are less likely to trigger long covid than the ones that circulated earlier in the pandemic. 鈥淚t鈥檚 not the same virus that it was three, four years ago,鈥� says Al-Aly.
In a study published in July last year, he and his colleagues found that the in unvaccinated people from when the early alpha variant was circulating to when it was replaced by delta and omicron. 鈥淭here鈥檚 a clear decline in the risk and burden of long covid as a function of the changes in SARS-CoV-2 itself,鈥� says Al-Aly.
It is also clear that covid-19 vaccines lower the risk. There is some debate about the scale of this reduction, says Al-Aly. But, 鈥淚 haven鈥檛 seen a credible study that suggests that the vaccines don鈥檛 reduce the risk of long covid鈥�, he says.
What is less clear is how many people recover from long covid or how long it takes. 鈥淚 don鈥檛 really think we have a proper definition [of recovery],鈥� says Alwan. Does it mean having no symptoms at all, and if so for how long, or does it mean being able to return to your previous lifestyle even if you still have mild symptoms? Some researchers have attempted to , but used conflicting definitions of recovery. 鈥淚t鈥檚 a mess,鈥� says Al-Aly.
Crucially, many people with long covid report that their symptoms ease, sometimes for weeks or months, then return. This must be factored in, says Alwan. 鈥淲e could possibly talk about it more in terms of remission.鈥�
To learn more about recovery, we need much more clarity about the underlying causes of long covid. 鈥淭here are multiple mechanisms at play,鈥� says Al-Aly, which helps explain why long covid鈥檚 symptoms are .
In at least some cases, SARS-CoV-2 persists in the body. Early in the pandemic, this was widely believed to be unlikely. However, at the Icahn School of Medicine at Mount Sinai in New York says there have now been many well-conducted studies showing that entire viruses, or , can remain in various .
In a study published in October last year, Putrino and his colleagues found that molecules called antigens from the virus could be detected in people鈥檚 blood up to 14 months , and this was more common in those with long covid. The question now is why this leads to symptoms 鈥� and why some people are unaffected.
Additional infections may also contribute to the risk. Viruses like and linger in the body , 鈥渘ot really causing much trouble鈥�, says Putrino, but covid-19 somehow . 鈥淎ll of a sudden, you鈥檝e got symptoms,鈥� he says. 鈥淧reviously latent pathogens are reactivating.鈥�
Other mechanisms see the body . One much-discussed finding is that people with long covid appear to be , often having tiny microclots in their bloodstream that could block smaller blood vessels, causing or damaging vessel walls. This could be due to the immune system misfiring in some way or it may be a consequence of the virus persisting in the body. If the latter, treating clotting may ease some symptoms, but won鈥檛 eradicate the virus or cure long covid.
Long covid is also strongly associated with disruptions of the immune system. Evidence has accumulated around the importance of autoantibodies, which cause the immune system to attack the body.
Last year, in a study that wasn鈥檛 peer-reviewed, Putrino and his colleagues found that people with long covid had higher levels of autoantibodies, and those with neurological symptoms had nervous system proteins. When the team transferred immune proteins from these people into mice, the animals became less able to balance or coordinate their movements, mirroring the dizziness experienced by the participants.
A group that included Rob W眉st at VU Amsterdam in the Netherlands reported in a preliminary study in May. 鈥淢ost likely, one of the pathological drivers there is a functional autoantibody,鈥� says聽Putrino.
Some of the fatigue that marks long covid may be due to a literal energy shortage. Our cells contain mitochondria, which supply energy. 鈥淭here is some form of mitochondrial dysfunction happening in people with long covid,鈥� says Al-Aly. Last year, W眉st鈥檚 team reported in people with long covid-related post-exertional fatigue, which indicated that their mitochondria weren鈥檛 working properly.
Like with many conditions, the gut microbiome could also play a role. The idea is that when we get sick with covid-19, so do the microorganisms in our gut, says Al-Aly. 鈥淢aybe they don鈥檛 fully recover, and then when they don鈥檛 recover, we don鈥檛 really recover.鈥� He calls it 鈥渁 less-accepted hypothesis鈥�, but points out that a 2023 randomised controlled trial found that a daily cocktail of symptoms. 鈥淪o there may be something to it,鈥� he says.
What does all this mean for people who have long covid? If they have access to healthcare, they should be offered treatments that tackle their symptoms. For instance, people with heart palpitations may be given beta blockers. They could also be recommended lifestyle interventions. 鈥淧acing is widely recommended for long covid 鈥� doing what you can within your energy level,鈥� says Alwan.
However, there is no treatment that tackles the root cause or causes. Not a single medication has been approved in either the US or the European Union, which Al-Aly calls 鈥渁 major collective failure鈥�.
Part of the problem is that the US National Institutes of Health allocated most of its long covid funding to observational studies, holding little back for randomised-controlled trials, says Al-Aly. 鈥淣ow they鈥檙e trying to play catch-up.鈥�
Many treatments are being tested, with Al-Aly, Putrino and Alwan all being involved in such trials. However, Al-Aly and Putrino both say that long covid requires a different approach to testing.
Traditional trials that focus inflexibly on one treatment will take too long, because there are so many potential therapies to sort through and long covid is so diverse. If researchers stick to the traditional paradigm, we will be in the same position on the 10th anniversary of covid-19, says Al-Aly.
Instead, he and Putrino want to do adaptive trials, in which multiple treatments are offered and people can change therapies during the study, which has been done in cancer and cardiology research. 鈥淭he concept is not new,鈥� says Al-Aly.
Healthcare and public health systems also to better handle conditions like long covid. 鈥淲e need to have proper frameworks for these infection-induced non-communicable diseases,鈥� says Alwan. This could include rules around ventilation to reduce transmission and introducing care teams that provide a range of treatments and support.
鈥淭here鈥檚 going to be another pandemic,鈥� says Al-Aly. 鈥淲e just don鈥檛 know when and what.鈥� Like with covid-19, that infection could also cause lingering symptoms. To understand the causes of post-infection complications, and avoid widespread ill health, Al-Aly wants to see more focus on long covid, not just SARS-CoV-2 itself: 鈥淗ow do we best optimise our response to 鈥榣ong virus 2030鈥�?鈥�
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