FOR many of us, the covid-19 pandemic is fading into memory. But for millions of people, that isn’t possible as they are still unwell. An illness that is often brief and mild is, for some, the start of a rollercoaster of symptoms that can last years. Today, around 65 million people may have long covid.
That is the bad news. But around four years since the first cases emerged, evidence of the causes of long covid is rapidly accumulating, paving the way for treatments. Multiple trials of therapies are under way and several have already shown promising results. It is now also clear that people experience wide differences in their long covid symptoms, so treating this condition is an exercise in personalised medicine: no single approach will work for everyone.
Many questions remain, however. Can the plummeting levels of certain hormones explain the fatigue and brain fog, and is the persistence of the virus really key to understanding what is going on? And what should we do – and not do – to avoid developing long covid in the first place?
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Long covid symptoms
The SARS-CoV-2 coronavirus started spreading around the world in early 2020. Within months, reports began emerging that some people were experiencing lingering symptoms. The and widely adopted. The most common symptoms include headaches, brain fog and fatigue, or post-exertional malaise, in which even small amounts of activity cause exhaustion. Altogether, more than 200 symptoms have been reported, ranging from depression to gastrointestinal problems.
Since that time many things about this once mysterious condition have become clearer, but there is still a long way to go. For a start, the exact prevalence of long covid among people who have been infected with the virus remains uncertain. “The loose consensus would be roughly around 10 per cent,” says at the Icahn School of Medicine at Mount Sinai in New York. In a led by at Imperial College London that followed more than 242,000 adults, the median duration of symptoms of covid-19 infection was 1.3 weeks – in line with many previous analyses indicating that most people recover within a few weeks. However, 7.5 per cent still had symptoms after 12 weeks, and 5.2 per cent had them after a year.
On the other hand, a Swiss study that tracked 1106 unvaccinated adults who caught SARS-CoV-2 , and 17.2 per cent still had them after two years.
Meanwhile, the cumulative burden of long covid continues to rise. , comparable with the number who currently have heart disease. However, the risk of long covid depends on the virus variant. Around 11 per cent of people infected with the older delta variant ended up with long covid, compared with .
It is now also clear that women are at greater risk of developing long covid than men, as are people who are unvaccinated (see “Reducing the risk”) and . There is evidence of a genetic element too. For instance, variations in one region of the genome, close to a gene called FOXP4 that is known to be important for lung function, were .
In short, it is a messy picture. And our understanding of the causes of long covid isn’t much clearer. “There’s no unifying theory yet,” says Putrino. Instead, there are several working hypotheses, each with at least some evidence to support it, and it seems likely that different sets of mechanisms are at work in different people, perhaps with some overlap.
Causes of long covid
One of the most prominent, and controversial, ideas is that long covid is the result of abnormal particles in the blood, dubbed microclots. This hypothesis has been advocated by at Stellenbosch University in South Africa and her colleagues, who have described and characterising their biochemical make-up. Furthermore, in a , which doesn’t seem to have been published in a peer-reviewed journal, her team described using a set of three drugs to destroy the particles, resulting in a reduction of symptoms. As a result, people with long covid began . Some received apheresis, which involves inserting large needles into veins to filter the blood. Others were given cocktails of drugs.
This caught the attention of at the Liverpool School of Tropical Medicine in the UK and her colleagues. Fox specialises in producing systematic reviews for the Cochrane Collaboration, often considered the gold standard of evidence-based medicine. “We couldn’t really see where the evidence had come from to justify this treatment,” says Fox.
The result was a , and of the microclots hypothesis as a whole, published in July. “We first looked for any trials to see whether there was any evidence for the effectiveness and the safety of that treatment,” says Fox. They couldn’t find any controlled trials of apheresis for long covid. “That’s not completely unheard of,” she says, particularly for emerging therapies.
A second issue concerned the microclots themselves. “They weren’t true clots,” says co-author , also at the Liverpool School of Tropical Medicine. In medical terms, a clot isn’t any old particle in the blood, but rather a specific kind containing cells called platelets and proteins called fibrin or fibrinogen. The microclots had these proteins, but not the platelets: instead, they had another protein called amyloid. This means treatments that target traditional clots wouldn’t necessarily work.
However, other long covid researchers are following up on Pretorius’s work. For instance, Putrino has seen many people with long covid with microclots, and says that treatments targeting them seem to bring improvements. His team is now working on a rigorous analysis of the particles. The upshot is that a firm answer on microclots will only be had when studies have been repeated and validated.
Meanwhile, there is a large body of evidence showing . One possibility is that some people’s immune systems don’t respond correctly when first infected. In some studies, people with lower levels of antibodies against the coronavirus at an early stage of infection were more likely to develop long covid later. There is also evidence that some people with long covid have ongoing activation of their immune system. Other studies indicate that certain parts of the immune system remain overactive in people with long covid, while other parts are underactive. There is also some evidence of autoimmunity, in which the immune system attacks the body.
The difficulty is figuring out which of these immune disruptions are specific to long covid, what the causal mechanisms are and how they are linked to the various symptoms. Putrino and his colleagues took a step towards this in a study published in September. They with and without long covid, then used a machine-learning algorithm to look for a “signature” of long covid. The team found a host of differences, from changes to populations of white blood cells to altered antibody responses. Patterns of two particular immune chemicals indicate “that the body is fighting something persistently”, says Putrino.
However, the biggest change in those with long covid was hormonal. These individuals had low levels of the hormone cortisol in the mornings. Cortisol has many functions, notably as a modulator of immune response, suppressing some immune functions and boosting others. It is also responsible for waking us up. “You expect to see peaking levels of cortisol in the morning, and what we saw were very flat levels of cortisol in this particular long covid cohort,” says Putrino.
The following month, by a team led by at the University Medical Center Rotterdam in the Netherlands. The researchers studied the immune systems of 37 people with long covid with fatigue and 36 with it but without fatigue, plus 42 people who had never had the condition. Those with long covid had more signs of inflammation and evidence that some of their white blood cells weren’t functioning correctly. In addition, those with more severe fatigue showed signs of chronic activation of white blood cells.
Co-author , also at the University Medical Center Rotterdam, says there is growing evidence that immune system disturbances can disrupt other bodily systems, including hormones and the brain – sometimes contributing to conditions like depression. “I see patients with severe depression after the infection and it fits completely with the idea that we had that there is a disturbed immune system in depression,” he says. If inflammation is at work in those with long covid, anti-inflammatory drugs could help, says Berentschot. Some such medications are being tested: for example, a German trial is investigating whether the anti-inflammatory methylprednisolone can .
Many of these studies of the immune system have uncovered signs of chronic overactivation, as if people with long covid are still fighting an infection. This has led many researchers to suspect that the explanation for the condition is disarmingly simple: the SARS-CoV-2 virus is still in their bodies.
Early in the pandemic, this idea was widely dismissed because the virus doesn’t show up in blood samples after the first few weeks. However, many now view that as a mistake. In a review published in September, at PolyBio Research Foundation in Massachusetts and her colleagues summarised that the virus can persist in many tissues and organs, including the gut lining, skin and lungs. She says similar viral persistence has been seen in other post-infection conditions, such as post-Ebola syndrome. An added complication is that many people carry latent viruses anyway, notably herpesviruses that excel at hiding in our bodies. There is evidence that reactivation of these latent viruses can , as well as in other chronic conditions such as myalgic encephalomyelitis, also known as chronic fatigue syndrome.
Viral persistence
For Proal, viral persistence may be the key to long covid. “I see it as the upstream driver of most of those other things,” she says. For example, a reservoir of virus could explain the chronic immune activation seen in some people. Furthermore, the virus’s spike protein has been shown to cause clotting, so if this leaks out of the virus reservoir into the blood, it could explain microclots. Proal says that 30 to 60 per cent of people with long covid show the spike or other SARS-CoV-2 proteins in their blood.
Persistence of the virus can have widespread consequences. This was highlighted in a study from October led by at the University of Pennsylvania showing that , a neurotransmitter and hormone. The researchers then identified a complex chain of events behind this. Persistent virus led to chronic inflammation, which reduced serotonin levels by impairing the gut’s ability to take up a crucial precursor found in food, reducing serotonin storage and increasing its turnover. The low levels of serotonin, in turn, affected the central nervous system – potentially explaining some of the cognitive symptoms in long covid.
For these people, a key part of treatment will be to suppress or eliminate the virus. Putrino and his colleagues are starting a trial in people with long covid of Paxlovid, an antiviral that blocks the action of one of the coronavirus’s proteins. “It doesn’t eradicate the virus, it just stops the virus from replicating,” he says. Meanwhile, a study by at the University of California, San Francisco, will using a cloned, lab-made antibody.
“There are many clinical trials on the horizon,” says Putrino. Notably, two medications have shown promise for preventing long covid when given soon after infection. A study from June showed that metformin, a drug used to treat type 2 diabetes, . Similarly, a March study showed that Paxlovid also made long covid less likely.
Long covid researchers agree that a mix of treatments will be needed. “There’s not going to be one single blockbuster long covid treatment,” says Proal. What is needed, according to Peluso and others, is a and other post-infection conditions.
Such syndromes may be more common than suspected. Lingering symptoms have been seen in the wake of other diseases, including the 1918 influenza pandemic and many Ebola outbreaks. And according to a , even common respiratory infections can cause long-term symptoms: in other words, some people experience “long colds”.
All this highlights how far we have come in understanding the long-term aftereffects of viral infections. And while the complex picture of long covid that has emerged means that treatment pathways are likely to be complex too, researchers are cautiously optimistic. “I think the interventional landscape is certainly a lot more exciting and interesting than it was a year ago,” says Putrino.
Reducing the risk
, as is in the first two weeks of the initial infection. But most crucial is preventing infection in the first place and several things can help with this. Improved ventilation and purification reduce the number of pathogens around. When we do become sick, wearing face masks and staying at home can reduce the risk of passing on the disease.
Long covid in kids
Early in the pandemic, it became clear that children were generally at lower risk from covid-19 than adults. This is also true for long covid – but there are still many children with the condition. A recent study found that , experiencing many of the same symptoms as adults, with older children at greater risk of this. Fortunately, many recovered: after 18 months, only around 1 per cent were still symptomatic.
