What Covid-19's long tail is revealing about disease
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Some studies suggest one in 10 patients experience symptoms 12 weeks after their initial infection with Sars-CoV-2 (Credit: Philippe Lopez/AFP/Getty Images)
Many months after their initial infection, some Covid-19 patients are still suffering a baffling constellation of symptoms. More than a year since the pandemic began, scientists are starting to unravel what is causing long Covid and how they can treat it.

When Melissa Heightman set up the UK's first post-Covid-19 clinic at University College London Hospitals (UCLH) in May 2020, she expected that the bulk of her time would be filled helping patients recover from the after-effects of spending many weeks on a ventilator. For the majority of these patients, she hoped the road to full recovery would be swift.

"At the beginning of the pandemic, we didn't know what the long-term sequelae of a Covid infection would be," says Heightman, a consultant respiratory specialist. "We thought it would be like flu, it would all just go away, and be fine."

Little did she know that a year on, a third of the clinic's patients would still be unwell, and largely unable to work. More than half were never admitted to hospital for Covid-19.

Almost as soon as the clinic opened, Heightman began fielding calls from puzzled local GPs, confused at a sudden influx of patients – often relatively young and with no underlying health conditions – who were experiencing chronic symptoms. Their stories all followed a recurring pattern, beginning with an apparently mild infection, before a strange constellation of ailments started to emerge. Rather than subsiding, these symptoms continued to persist for weeks and even months after the virus had supposedly left their bodies.

It was a conundrum that the medical world was not expecting. "These patients were initially left behind," says Heightman. "Most hospitals weren't able to see them easily, because they didn't have the budget to open a dedicated post-Covid clinic. But they're now our main focus."

While Covid-19 is primarily thought of as a respiratory disease, the virus is capable of infecting many different tissues around the body (Credit: Naveen Sharma/Getty Images)

While Covid-19 is primarily thought of as a respiratory disease, the virus is capable of infecting many different tissues around the body (Credit: Naveen Sharma/Getty Images)

The most common symptom, which Heightman says was experienced by more than 80% of patients in her clinic, is a deadening fatigue which impairs their life, making it difficult to complete the simplest of daily tasks. Research studies have found persistent fatigue to be present in at least 62% of long Covid patients. Such cases are now known as long Covid or post-acute Covid-19 syndrome, a post-viral illness which has proven to be more prevalent than anyone initially imagined. The general scientific consensus is that around one in 10 Covid-19 patients will still have symptoms 12 weeks later.

But to fully understand the subtleties of this complex condition, it is necessary to consider long Covid as encompassing two very disparate patient groups – those who were admitted to hospital and those who weren't – each with different underlying causes.

The former group has proven far more straightforward for doctors to manage. Typically their lungs or heart have been damaged by either the acute viral infection, or the resulting cytokine storm – the severe inflammatory response that can cause a patient's immune system to attack their own tissues. Computerised tomography (CT) and Magnetic Resonance Imaging (MRI) scans swiftly reveal the extent of the damage, while drugs such as colchicine can be used to dampen down any lingering inflammation in the internal organs.

Heightman says that two thirds of the UCLH clinic's long Covid patients admitted to hospital are now recovering well, while the remaining third have seen improvements in their scans after six months.

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"We expect the vast majority of these patients will improve to the point that they shouldn't be left with damage that limits their life," she says. "We hope that less than 10%, those who were in the ICU for a long time, will be left with any permanent heart or lung abnormality."

But the non-hospital patients with long-term symptoms have proven far more perplexing.

According to Heightman, the peak age tends to be between 35 and 49, and they report a mysterious range of symptoms. Some surveys of patients have identified up to 98 different symptoms, while an international study published in July 2021 reported more than 200 symptoms across 10 organ systems including the cardiovascular system, the nervous system, the brain and the respiratory system. The most common symptoms include fatigue, brain fog, muscle and joint pain, sleep disturbances, migraines, chest pain, skin rashes, new sensitivities to smells and tastes, and dysautonomia, a normally rare condition which causes an uncomfortable and rapid increase in heartbeat when they attempt any form of activity.

For many long Covid patients who were not admitted to hospital, symptoms come and go in three separate waves

Heightman says that while 50% of UCLH's long Covid patients who were not admitted to hospital have improved over the course of a year to the point that they can manage their symptoms alone, the remaining half are still unwell.

Much of the information we have about the long-term prognosis and symptoms experienced by this group of patients has come from a handful of dedicated clinics like Heightman's around the world, along with the efforts of virtual long Covid communities such as the Patient-Led Research Collaborative (PLRC).

While half of Heightman's patients have made a good recovery, others have not been so fortunate. A recent survey from the PLRC painted a bleaker picture. Out of 3,762 long Covid patients, 77% were still experiencing fatigue after six months, 72% were struggling with post-exertional malaise, 55% were suffering from cognitive dysfunction, while 36% of female patients experienced menstrual cycle issues. "My own cycle disappeared for three months," says Hannah Wei, part of the PLRC leadership team, who herself suffered from long Covid over the past year.

The survey identified that for many long Covid patients who were not admitted to hospital, symptoms come and go in three separate waves. This pattern begins with a dry cough and fever, followed swiftly by a second wave of new symptoms such as dysautonomia, which peak after two months and then taper off. A month after the initial infection, a third wave of symptoms appears, including skin rashes, muscle pain, new allergies, and brain fog. "This is the most concerning, because this wave of symptoms just continues to get gradually worse, peaking at around four months, and then just keeps going," says Wei.

Many long Covid patients report experiencing their symptoms in waves that come and go (Credit: Matic Zorman/Getty Images)

Many long Covid patients report experiencing their symptoms in waves that come and go (Credit: Matic Zorman/Getty Images)

But why is it that Covid-19 impacts these patients in this way, and how is it that some people who were first infected a year ago are still yet to recover? One of the major challenges for doctors attempting to treat long Covid is that there are likely to be a variety of underlying triggers or causes, depending on the patient.

Recent epidemics have provided one way of gaining crucial clues about what these underlying causes might be. Far from being unique to Sars-CoV-2 – the virus that causes Covid-19 – some scientists believe almost all infectious outbreaks leave behind a proportion of patients who remain chronically unwell with symptom patterns similar to long Covid. This is known as the "long tail" of epidemics. By studying survivors of the Sars coronavirus outbreaks of the early 2000s, and the West Africa Ebola crisis of the past decade, a handful of scientists think they know why it happens.

The Long Tail

In 2004, Harvey Moldofsky, a neuroscientist at the University of Toronto, received a call from an old friend. A year earlier, Sars had briefly spread from Asia to Canada, infecting 251 people, mainly healthcare workers in the Toronto area. But more than 12 months later, 50 of them were still unwell, and John Patcai, a consultant at Toronto General Hospital, wanted to try and find out why.

"It was a mystery because even though there didn't seem to be any evidence of lingering lung inflammation, or the Sars virus, they had all these symptoms," says Moldofsky. "They felt weak, extremely fatigued, had aches and pains all over their body, and they were completely unable to work. We called it post-Sars syndrome, and because I had a history of studying fatigue, John asked me to have a look at them."

There's a huge amount of studies showing how infectious organisms can persist in tissue, and contribute to disease processes – Amy Proal

Moldofsky soon identified that those suffering from the condition were sleeping extremely poorly. He suspected this, along with the other symptoms, was a sign of widespread inflammation in the brain, but lacked the funding to investigate further.

But then came a breakthrough. Scientists in China reported discovering fragments of the Sars virus' genetic material in various brain cells in patients with post-Sars syndrome. For Moldofsky, this finding explained much of their malaise. "We know there's a direct connection from our nose to the brain, called the olfactory nerve, and this is probably how the virus got directly into the circulation of the brain," he says. "I believe these viral fragments were interfering with how their brains were functioning, which would explain the poor sleep quality and other issues."

Amy Proal, a microbiologist who runs the PolyBio Research Foundation, which studies the causes of chronic inflammatory diseases, believes that small amounts of pathogens that linger beyond the reach of the immune system in remote pockets of the body, known as reservoirs or anatomical sanctuaries, are at least partially responsible for a whole range of post-infectious syndromes. This includes long Covid, but also a number of mysterious illnesses which have puzzled scientists for decades, such as chronic Lyme disease, and also ME/CFS, a condition which has long been speculated to have infectious origins although some scientists feel there could be a range of potential causes, and bears a number of similarities to long Covid.

"The phenomenon of people developing chronic symptoms after an infectious outbreak is not new," she says. "If the Sars-CoV-2 virus didn't do this, it would pretty much be the only documented time where a major pathogen didn't result in chronic cases. There's a huge amount of studies, which have been neglected by the mainstream medical community, showing how infectious organisms can persist in tissue, and contribute to disease processes. Some viruses are highly neurotrophic, meaning they can burrow into nerves, and hide out there, and there's evidence that Sars-CoV-2 is capable of this."

Proal says that in the past, many doctors have been quick to attribute post-infectious syndromes to psychological factors, rather than the latent effects of a pathogen still causing harm somewhere in the body. However over the past decade, outbreaks of Ebola, Zika, and now Covid-19 have all resulted in long-term chronic illness in a proportion of survivors, resulting in an increased openness to this idea.

A recent Ebola outbreak in Guinea, West Africa, originated with a man who contracted the virus during an outbreak five years earlier (Credit: Kenzo Tribouillard/AFP/Getty Images)

A recent Ebola outbreak in Guinea, West Africa, originated with a man who contracted the virus during an outbreak five years earlier (Credit: Kenzo Tribouillard/AFP/Getty Images)

In particular, Ebola has already taught scientists a lot about the capacity of viruses to linger in the body, for months and sometimes even years. Since 2013, Georgios Pollakis, a microbiologist at the University of Liverpool, has been working with hospitals across West Africa, monitoring reported cases of long Ebola, where survivors report pain, fatigue and a range of neurological symptoms including headaches and dizziness. Intrigued by research that indicates a high proportion of Ebola survivors experience a resurgence in antibody levels to the virus up to a year after their infection, Pollakis and others have detected the presence of its genetic material in a reservoirs throughout the body, from the eye to the lymph nodes, and even in body fluids like breast milk and semen.

While scientists had previously thought that these viral traces might be relatively benign, long Ebola has shown that a virus can remain active in these reservoir sites for months or even years. Earlier this year, a new genetic analysis, published as a preprint, suggested that a recent outbreak in Guinea even originated from an Ebola survivor who initially contracted the infection between 2014 and 2016. The man spread the virus by infecting a sexual partner, after it had lain dormant in his testes for at least five years.

Pollakis believes that the symptoms of both long Ebola and long Covid occur because the body fails to completely clear the virus. Instead, remnants of the viruses' genetic material hide in reservoirs where they induce local inflammation. Periodically the viruses back into the bloodstream, and trigger an immune reaction, along with other symptoms.

He points out that Sars-CoV-2 has been shown to be capable of infecting a wide range of tissues in the body, from the brain to the testes.  "With Covid-19, it's shown that the virus can be measured in semen over longer periods of time," he says. "So we already have suspicions that it can linger in these immunoprivileged sites."

Some researchers have speculated that Covid-19 could be triggering the reactivation of viruses that have lain dormant in the body for years or even decades

But rogue fragments of the Sars-CoV-2 virus are unlikely to be the sole cause of long Covid. The sudden appearances of allergies that were previously not suffered, as well as the muscle and joint pains experienced by some patients, suggest the virus may trigger an autoimmune reaction in a proportion of cases.

"We think that in some patients, something about Covid stimulates the immune system to attack the body's own tissue, in a similar manner to autoimmune diseases like lupus, rheumatoid arthritis, and multiple sclerosis," says Heightman.

This could help explain the relatively high proportion of women who suffer from long Covid. Heightman says that 66% of the UCLH clinic's patients are female, and similar gender skews have been reported in ME/CFS. Women are also known to be more vulnerable to developing autoimmune diseases. The PRLC are currently working with a number of research groups to identify long Covid patients with autoantibodies – antibodies that attack their own proteins – which could be driving some of their symptoms.

An autoimmune response to the initial viral infection could also be linked to another prevailing theory, which might explain some of the odder long Covid symptoms such as the dysautonomia and blood clots. Some scientists perceive Covid-19 as an endothelial disease, where the inflammation generated against the virus ends up damaging the vascular endothelium, a fragile layer which acts as an interface between the blood and the body's tissues. Earlier this year, scientists at the University of Copenhagen proposed that in some Long Covid patients, the body might end up attacking its own vascular structures.    

But in another sub-group of patients, something even stranger may be happening. A number of studies have reported reactivation of the herpes zoster virus – most commonly known as the cause of chickenpox – as well as the Epstein-Barr virus, and cytomegalovirus in acute Covid-19 patients. These are all viruses that are known to be retained in the body for life as they can remain inactive inside cells.

Some researchers have speculated that Covid-19 could be triggering the reactivation of viruses that have lain dormant in the body for years or even decades, leading to the development of chronic symptoms.

"One of the things that the Sars-CoV-2 virus does, is it blunts interferon signaling, and interferons are part of the immune system which keeps viruses in check," says Proal. "So, if you already had the Epstein-Barr virus lying dormant in your body, it might then reactivate, and infect a new nerve or new tissue, maybe get into the central nervous system, and that could result in these chronic symptoms."

Exercise based therapies like at this clinic in Poland are being used to help rehabilitate patients suffering from long Covid (Credit: Bartosz Siedlik/AFP/Getty Images)

Exercise based therapies like at this clinic in Poland are being used to help rehabilitate patients suffering from long Covid (Credit: Bartosz Siedlik/AFP/Getty Images)

But this very complexity of long Covid, with its numerous symptoms and multiple possible causes, creates a major challenge for clinicians as they try to work out how to treat patients. While governments have been scrambling to dedicate funding to further our understanding of the disease – in February, the National Institute for Health Research and UK Research and Innovation awarded scientists at the University of Birmingham £2.2 million to study long Covid – clinical trials examining different treatment possibilities are still yet to get underway.

For doctors and patients alike, this delay is proving difficult to accept. "You feel a bit helpless because for both long Covid clinicians and patients, we don't have time, we need answers now," Heightman says. "You have patients out there who are trying all kinds of things in desperation."

Examples of the alternative medicines being tried range from quercetin – a plant pigment found in green tea, onions and various berries – to niacin, a form of vitamin B with antioxidant properties. The evidence base for either of these therapies remains negligible, but as Heightman points out, patients are turning to them because doctors can offer few alternatives.

Because of this some specialists believe that patients should be treated based on what we know from other, comparable illnesses.

The road to treatment

For long Covid, and other post-infectious syndromes, the fatigue, pain and brain fog are some of the most persistent and troubling symptoms. "When I was really struggling with long Covid last summer, there were days where I just didn't know what I was doing," remembers Wei. "I struggled to think clearly, and I had a moment in September where I realised I couldn't remember much at all from the summer. For me that was quite scary, as I normally have very vivid memories."

This kind of memory loss and confusion is often seen in ME/CFS, and over the past eight years scientists researching the illness have come to the conclusion that one of the key underlying causes is neuroinflammation, driven by immune cells in the brain called microglia. In healthy individuals, microglia play a key role in keeping the brain's neurons functioning normally, but they are vulnerable to disruption. Surges of inflammation in the bloodstream, either from an autoimmune reaction triggered by an infection, or the lingering presence of a virus, can cause these cells to pump out their own inflammatory molecules, which then disperse rapidly through the brain.

Many long Covid patients simply get better over the course of time, as their body recovers and heals

Imaging studies conducted by Japanese scientists have revealed chronic neuroinflammation in a number of ME/CFS patients, while similar microglial disruption is thought to occur in a number of psychiatric disorders like depression and schizophrenia.

As a result, Valeria Mondelli, an immunologist at Kings College London, is advocating trials of anti-inflammatory medications for long Covid patients.

"Either anti-inflammatories like minocycline – an antibiotic which seems to work for patients with higher levels of inflammation in the blood – or cytokine inhibitors, could be potential treatment options," she says.

David Kaufman, a ME/CFS doctor who has treated around 1,000 patients in Mountain View, California, over the last eight years, feels that long Covid clinicians should also look for evidence of dysfunction in the microbiome, which could be making these patients more vulnerable to suffering long-term problems from the SARS-CoV-2 virus.

While ME/CFS is often regarded as an illness where sufferers rarely get better, Kaufman has an unusually high success rate, declaring that 15-20% of his patients have made a full recovery, although this claim is purely anecdotal. He says that this is in part this is due to his persistence in looking for and treating signs of a leaky gut an increased permeability of the intestinal lining, which is thought to make genetically susceptible people more prone to developing autoimmune conditions in response to an external trigger, such as a viral infection. This is because the gut is allowing toxins and bacteria to enter the bloodstream, causing a range of underlying issues from chronic inflammation to mast cell activation syndrome – a condition which typically occurs during an allergic reaction. These can be further exacerbated by a subsequent infection.

"80% of the ME/CFS patients I've tested have small intestinal bacteria overgrowth, otherwise as a leaky gut," Kaufman says. "Because the gut is a major immune organ, this leads them down a road to autoimmune problems."

There is currently little research on whether Covid-19 vaccines will help to ease the suffering caused by long Covid (Credit: Micheal Dantas/AFP/Getty Images)

There is currently little research on whether Covid-19 vaccines will help to ease the suffering caused by long Covid (Credit: Micheal Dantas/AFP/Getty Images)

Some preliminary studies have already suggested that imbalances in the microbiome of long Covid patients could be contributing towards their persistent inflammatory symptoms. But while more research is likely to be needed before medications like prebiotics or anti-inflammatories are recommended for long Covid patients as part of general clinical practice, some individual symptoms are already proving more treatable than others.

Heightman says that long Covid patients displaying allergic-type reactions tend to respond well to anti-histamines, while Amy Kontorovich, a cardiologist at Mount Sinai who specialises in treating dysautonomia, has developed a novel physical therapy programme known as Autonomic Conditioning Therapy (ACT) which has shown the ability to reduce fatigue symptoms in some long Covid patients, and has since been adopted by 53 physical therapy centres across the New York area. Kontorovich explains that ACT begins with range of motion exercises, before progressing to different aerobic exercises which slowly increase in intensity, but never allow the patient to exceed 85% of their maximum heart rate. This is inspired by a similar reconditioning programme, which has been shown to be effective in treating a form of dysautonomia, known as POTS.

"It seems to program the autonomic nervous system to kind of rewire things," she says. "One of the interesting trends I've seen in many of the long Covid patients I've treated, is that they were previously very active, and during the time of their acute illness, they were either laid up in bed or mainly sedentary. That period of inactivity may be a contributing factor for the post Covid dysautonomia pattern, because we know that that can happen with deconditioning."

ACT is not a complete panacea – Kontorovich points out that some patients with particularly severe dysautonomia are often unable to complete the programme, because they feel too unwell – but her early results show that it can benefit patients who are able to finish it.

Heightman adds many long Covid patients also simply get better over the course of time, as their body recovers and heals. As SARS-CoV-2 has still only been around for a little over a year and a half, it remains too early to say how long chronic symptoms may last. "I don't want anyone who's got long Covid symptoms to feel really frightened that this is never going away, because a very significant proportion of people do get better within the first year," she says.

For those who continue to struggle, however, the hope is that the millions of dollars of research grants being handed out will yield some viable treatment possibilities, otherwise long Covid may leave indelible social and economic consequences on society. "If we don't find answers, you could be talking millions of people who are not going to be able to work the same way," says Kaufman. "A very significant proportion of long Covid patients are healthcare workers. These are educated, active, highly productive people who now can't function. The impact of that is going to be huge."

* This article was updated on 23 August 2021 to include details of an international study published in the Lancet's EclinicalMedicine journal detailing 200 symptoms associated with long Covid.


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