The scars of Long Covid

What scientists are discovering about the mysterious long-term effects of coronavirus.

(Photo By Brian Stauffer)

Loss of muscular energy was one of the earliest symptoms,” wrote Dr Jamieson, “and convalescents have been more struck by their astonishing lack of strength than by anything else.” He noted sluggish pulses and instances of “mental aberration” persisting far into convalescence. For some the aberration took the form of delirium, for others apathy and depression.

Jamieson was working in a hospital on New Zealand’s South Island during the 1918 flu pandemic. His testimony was one of many compiled by historian Geoffrey Rice in That Terrible Time: Eye-witness Accounts of the 1918 Influenza Pandemic in New Zealand, published on the centenary of that disaster. As I read them now, ten months into a new pandemic, there are recurring themes that leap out: “The men get down and very weak and don’t appear able to rally”; “My mother recovered but she had angina and died some years later from a heart attack”; “She was never the same girl again”; “I never regained my usual health”.

The lingering symptoms were not confined to New Zealand. They were reported globally, just as they are today in the context of a different disease, Covid-19. In 2020, they have been bundled together under the label “Long Covid”. Though the symptoms differ, there are eerie echoes of the Spanish flu, and in both cases the symptoms are bewilderingly diverse. In the case of Long Covid, says Birmingham-based sufferer Claire Hastie, they include such oddities as arthritic-like pains, phantom smells and bodily vibrations. She knows because in early May she set up the Long Covid Support Group on Facebook – one of many such online groups – so that fellow sufferers could share their symptoms at a time when the medical world had little to say about them. “Groups like ours can validate that you’re not going completely mental and that other people are also living this,” she says.

There is little hard data on the “Long Flu” of 1918, but only a minority of those who caught Spanish flu seem to have been affected. Though it’s too early to say, the same is presumed to be true of Long Covid. Still, given the many millions who have already been infected by Sars-CoV-2 – the virus that causes Covid-19 – even a small minority could amount to substantial misery, not to mention social and economic fallout. “My hypothesis is that there is a subset of the human population that will unfortunately be wrecked by Covid-19,” says Carlos Bustamante, who studies population genomics at Stanford University in California, and is one of many scientists trying to tease out the who, what and why of Long Covid.

One definition of Long Covid is “not recovering [for] several weeks or months following the start of symptoms that were suggestive of Covid, whether you were tested or not”. Some medics have complained that this is too vague to be useful. Others point to the importance of labelling the condition – first so that those suffering from it can be taken seriously and treated, and second so that it can be studied and, eventually, parsed into the different post-Covid-19 syndromes that it almost certainly comprises.

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Long Covid outlasts the presence of Sars-CoV-2 in the body, at least at detectable levels. Probably its most common manifestation is fatigue and breathlessness. “I used to cycle 13 miles a day on my commute and now I use a wheelchair if I need to leave the house,” says Hastie. The fatigue may last for weeks or months, but in most cases it improves eventually. When it doesn’t, a patient’s condition may come to resemble chronic fatigue syndrome (CFS) – itself regarded as a suite of conditions whose causes are unclear. No one yet knows how long Long Covid can last, or whether there are forms of it that will only emerge years or decades from now. One thing does seem clear, however: “The virus affects the whole body,” says Michael Zandi, a neurologist at University College London (UCL) who is studying Covid’s effects on the brain.

This comes as no surprise to Debby van Riel, a virologist at Erasmus University in Rotterdam, the Netherlands. For years, in human cells grown in petri dishes, in animal models and in patients, she has observed the ravages flu causes beyond the respiratory tract. She has seen them with the aggressive H5N1 “bird” flu that until last year was considered a leading candidate for the cause of the next pandemic; with the H1N1 “swine” flu that caused the mini pandemic of 2009; and – alongside her colleague Emmie de Wit, who works in a high-level biosafety lab in Montana – with the virus that caused the mother of all pandemics, in 1918. Earlier this year, Van Riel switched her attention to Sars-CoV-2, and saw that – though it behaves differently from flu – it, too, has effects beyond the respiratory tract. “At least in its severe form, we should consider Covid-19 a systemic disease,” she says.

It’s early days for understanding exactly what it does in the rest of the body, however. As Zandi notes, many patients with apparently non-Covid-19-related conditions such as stroke and heart attacks tended to stay away from hospitals in the spring, so the full clinical picture is only emerging gradually. Nevertheless, a preliminary survey he and others conducted of neurological patients over five weeks in April indicated that Covid-19 infection was associated with a range of conditions, including stroke and various forms of brain inflammation. One particularly common condition was acute disseminated encephalomyelitis, which damages white matter in the brain and spinal cord and can lead to symptoms including impaired vision and muscle weakness – even paralysis. There was no correlation between this complication and the severity of respiratory symptoms.

Evidence is accumulating that, in an unknown but probably small proportion of cases, infection with Sars-CoV-2 can cause damage to the lungs, heart, blood vessels, intestine and kidneys too. How it does so is not clear. Van Riel is testing two hypotheses: that the virus itself spreads to other tissues, and that it triggers a damaging inflammatory response that reaches those tissues via the blood. Others are exploring different theories, for example that it causes blood to become “stickier” and that circulating clots do the damage (interestingly, anecdotal reports from 1918 highlighted the unusually thick, dark blood of flu patients). It’s not yet possible to choose between these theories – though there are tantalising clues in favour of each – and there may be more than one mechanism at work. There is another outstanding question, Van Riel says: “Is [the generalised damage] virus specific, or is it a consequence of any very severe respiratory disease?”

Since recovery from damage to the brain and heart, in particular, can take months, many researchers view Covid-19 as an opportunity to study the long-term effects of viruses prospectively, and possibly shed light on refractory mysteries such as CFS in the process. Contact-tracing apps, if they ever hit their stride, could help – but only if the data they gather can be linked to primary care records, which poses privacy problems. “The population cohorts in which this country is a world leader will also be like gold dust,” says the psychiatrist Simon Wessely of King’s College London. The Covid-19 Symptom Study that King’s is coordinating is an example of these, but to date Wessely feels cohort studies have focused too much on hospitalised patients. Patients who never go to hospital – including many Long Covid sufferers – need more studies of their own.

The NHS and other socialised healthcare systems are ideally placed to mount such studies, because of their federated record-keeping, but US researchers aren’t sitting idle. Carlos Bustamante is involved in research that will follow 10,000 Covid-19-positive individuals – both adults and children – over two years. One question he hopes it will answer is how a person’s genetic make-up shapes their experience of the disease, including whether it is short or long. He is particularly interested in multisystem inflammatory syndrome in children (MIS-C), a rare paediatric complication of Covid-19 that involves inflammation in many tissues, the symptoms of which include headache, vomiting, abdominal pain and fatigue. “MIS-C is the canary in the coal mine to teach us about Long Covid,” he says.

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For the best part of a decade, researchers at Stanford have been following hundreds of children with a mysterious condition called paediatric acute-onset neuropsychiatric syndrome (Pans), in which they suddenly – sometimes from one day to the next – develop neuropsychiatric symptoms including obsessive-compulsive behaviour and eating disorders. The cause of Pans is unknown, but one theory is that it is triggered by a transient infection in children who are genetically predisposed to it. One line of evidence for this is the relatively high prevalence of Pans-like syndromes in countries such as Venezuela that also have high rates of infectious diseases such as dengue and Zika. Another is the similarities that Bustamante is seeing in the genetic profiles of children with MIS-C and Pans: “Covid-19 is a once-in-a-lifetime opportunity to study post-infectious sudden onset neuropsychiatric disease,” he says.

One of the enduring mysteries of the 1918 flu is whether it was the cause of a subsequent pandemic of encephalitis lethargica (EL), a form of brain inflammation that is thought to have affected a million people worldwide in the early 1920s. Of those, roughly a third died, a third recovered and a third went on – years later – to develop a form of Parkinsonism. (It was some of these latter patients that the neurologist Oliver Sacks wrote about in his 1973 bestseller Awakenings.) Genetic material from the flu virus has never been found in tissue taken from the brains of EL patients post-mortem, but that doesn’t mean it wasn’t there. Modern methods of detection may simply not be sensitive enough to detect it. And as Van Riel points out, the virus itself may not have to invade the brain to damage it (it could just trigger a damaging immune response there).

The historical example of EL has prompted some scientists to ask if Sars-CoV-2 could also have very long-term effects on the brain. Though he admits it will be tough to get the funding, John Hardy, a geneticist who studies neurodegenerative disease at UCL, would like the cohort studies now under way to address that question by following Covid-19 patients for several decades. He thinks that if they did they might shed light on a theory that he and others are pursuing: that chronic, low-level inflammation pushes a brain protein called tau to form the abnormal tangles inside brain cells that are associated with neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

Collectively called tauopathies, these diseases include some rare ones that have caused generations of neurologists to scratch their heads because of their inexplicable localisation in space. One is Guam disease, which has all but vanished from the eponymous Micronesian island after causing more than half a century of misery there; another is nodding syndrome in east Africa. Guam disease resembles amyotrophic lateral sclerosis, the disease that afflicted physicist Stephen Hawking, while nodding syndrome is described as a form of epilepsy, but both have much in common with post-encephalitic Parkinsonism.

Could they have been triggered by geographically circumscribed epidemics of infectious disease in the past, that might themselves have gone unreported? Hardy thinks it’s possible, and that Covid-19 is a chance to investigate the infection-as-trigger hypothesis. “We need to look out for Covid tangle disease in about 30 years’ time,” he says.

Others warn against drawing too many historical parallels with what is, after all, a novel disease. “We have to tread carefully,” says Wessely, “and not assume that previous knowledge, either from other post-viral or post infective syndromes, automatically applies to Covid-19.”

While research attempts to elucidate which historical parallels do hold, if any, he believes that the care of Long Covid patients – like that of CFS patients – should remain broad. Doctors need to provide general advice and symptomatic relief where possible, and above all listen and show kindness.

For her part, Claire Hastie would like to see public health messaging around Covid-19 change to acknowledge a category of sufferers who have remained for too long in the shadows – and who potentially cover a much broader demographic than those who end up in intensive care. “People don’t realise that you are not immune no matter how healthy or fit or young you are,” she says. “None of those are protections against this.”