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Why Long COVID Is Still Such A Mystery To Researchers

Both long and post-COVID are still misunderstood by the general public and the scientific community. This can cause even more suffering for those affected, who already fear their symptoms being dismissed as psychosomatic.

Why Long COVID Is Still Such A Mystery To Researchers

Patients are fighting for their symptoms to be recognized

Edda Grabar

Christoph Kleinschnitz chooses his words very carefully. He knows that he can’t afford to put a foot wrong, otherwise he’s going to cause all sorts of trouble. So his first sentence is unequivocal: “Long COVID and post-COVID both exist. There is no doubt about that.”

Kleinschnitz has good reason to be cautious. The director of neurology at Essen University Hospital recently appeared as an expert in a controversial documentary by doctor and TV presenter Eckart von Hirschhausen, where he pointed out that for some patients who are apparently suffering from long COVID, their symptoms may be intensified – or even fully explained – by psychological causes. Since that appearance, sufferers have branded him a long COVID and post-COVID denier.

Nothing could be further from the truth, says Kleinschnitz. The only thing he questions is the apparent frequency of long COVID and post-COVID cases – and a colleague’s claim to have cured herself with a highly controversial treatment: flushing antibodies, which she believed were causing her symptoms, out of her blood. Depending on the number of treatments required, this can cost up to €10,000.

Kleinschnitz’s appearance in Hirschhausen’s film only lasted two minutes. But it was enough to spark attacks against not only him but also his family.

“This case shows how emotionally charged this topic is,” says Harald Prüß, director of the experimental neurology department at Berlin-based research institute the German Centre for Neurodegenerative Diseases. The first conference on long COVID, which is currently being held in Jena in central Germany, will do nothing to change that.

Key risk factor

Scientists, doctors and patients are deeply divided over the issue. Patients are fighting for their symptoms to be recognized, while doctors are seeking to establish how they can reliably diagnose the syndrome – or rule it out. And scientists are trying to determine the causes of patients’ symptoms.

There is still a lot of uncertainty around the long-term symptoms experienced by COVID patients. Are depression and anxiety after a COVID infection caused by processes in the brain sparked by the virus? Or are they the result of increased stress after the pandemic? There is evidence for both explanations: studies suggest the virus does cause changes in the brain.

However, other studies show that these changes disappear after the patient recovers from the infection. At the same time, scientists have identified the most important risk factors for developing post-COVID. Alongside the severity of the infection, one of the main factors is psychological problems.

There are still many areas of uncertainty – even the definition of the illness is unclear. Doctors speak of long COVID when symptoms persist for four weeks after infection, and post-COVID when patients have not recovered or have got worse after three months. But this rough delineation doesn’t adequately describe the syndromes.

What's the dfference between long-COVID and post-COVID?

Peter Berlit, general secretary of the German Neurological Society, says doctors need to differentiate more clearly between the syndromes. There are some patients who have to be on ventilators in intensive care for long periods. That puts a lot of stress on the body, says Berlit, and patients often need months of rehab to recover. “But they are not really suffering from post-COVID. They are suffering from Post-Intensive-Care Syndrome (PICS),” he explains, a long-recognized syndrome.

He estimates that between 15 and 20% of cases could be explained by PICS — “which most people recover from through targeted neurological rehabilitation,” he says.

Doctors believe that even long COVID may not necessarily be a COVID-specific problem. Similar symptoms appear in patients after other severe infections, such as flu. In a Danish study, scientists compared the severity of COVID patients’ symptoms with those of patients who’d suffered from other respiratory diseases, and saw that the majority of complaints experienced by COVID patients were also found in the other group.

Except for two: changes to the sense of smell and taste, and a reduced ability to plan ahead. “The good news is that this also gets better over time,” says Berlit.

Then there is post-COVID. According to some international studies, roughly 30 to 40% of COVID patients suffer from long-term symptoms, although many doctors dispute this. Data from five health insurance providers, which provide around half of health insurance policies in Germany, recently showed that physical and mental illness both increased significantly after a COVID infection.

“These are very interesting results, but they don’t necessarily imply causality,” says Berlit. It’s difficult to determine whether a headache three months after a COVID infection is related.

Are depression and anxiety after a COVID infection caused by processes in the brain sparked by the virus? Or are they the result of increased stress after the pandemic?

Christian Erfurt

An umbrella term for a range of symptoms

Clara Lehmann, director of the working group on outpatient treatment at Cologne University Hospital, believes that the number of people suffering from long COVID or post-COVID is vastly overestimated. “The umbrella term is hiding a whole range of different syndromes,” she said in an interview with the Science Media Center.

More than 200 symptoms have been linked to the syndrome – from headaches and difficulty concentrating to kidney and liver damage, heart attacks, strokes and fatigue.

Immunologist Akiko Iwasaki from the Yale School of Medicine, who is also taking part in the conference in Jena, is looking into the causes. There are a range of theories: from vascular inflammation, which increases the risk of heart attack and stroke, to the immune system trying to fight off coronavirus particles that are still in the body, to autoimmune reactions, as described in the controversial Hirschhausen documentary. “We are looking into all these possibilities,” Iwasaki said.

Symptoms dismissed as psychosomatic

Scientists believe it is plausible that COVID increases the risk of stroke and heart attack over a specific time period: the virus can attack vascular cells. In a study recently posted for peer review, Iwasaki compared post-COVID patients to a control group and found that they showed more instances of reactivated Epstein-Barr virus and other latent viruses.

That could explain a whole host of symptoms. Iwasaki was surprised not to find “significantly raised levels of autoantibodies, which target the body’s own cell proteins,” she says. But what about cases where these autoantibodies were found in patients’ blood or spinal fluid? “The fact that they are present doesn’t necessarily mean they are causing damage,” says Prüß.

Any doctor who neglects that side is not caring for the patient holistically

But what about all the other patients and their symptoms, which cardiologists and neurologists are struggling to explain? “Many people are suffering from post-traumatic stress disorder after the pandemic,” says infection expert Lehmann. Studies from France and Great Britain support this view: scientists there compared people who’d tested positive for COVID with those who simply believed they’d been infected, and found that many people in the latter group experienced similar levels of exhaustion.

But that is exactly what many sufferers are afraid of: their symptoms being dismissed as psychosomatic. “That doesn’t mean that these patients are imagining their symptoms,” says Kleinschnitz. “It just means that the treatments we would usually use for post-viral fatigue won’t be effective for them.”

Harald Prüß believes that between 20 and 30% of his neurological patients suffer from psychosomatic problems. And neurologist Berlit points to a range of other illnesses where doctors treat psychosomatic symptoms: cancer, multiple sclerosis and fatigue. “Any doctor who neglects that side is not caring for the patient holistically,” he says. “And why should the approach we take for other serious neurological diseases be considered wrong in this case?”

What causes long COVID?

It’s unclear which factors cause people to suffer from long COVID or post-COVID – although it seems to be related to the severity of their illness and the specific variant. The Omicron variant seems to have fewer long-term health effects than the Alpha or Beta variants.

Studies that rely on data from the early days of the pandemic assumed a very high number of COVID patients would suffer long-term effects, but a recent study concluded that only 6% of patients experience at least one symptom three months after they were infected. After a year, that rate drops to 1%.

Long COVID doesn’t affect everyone equally. Some people seem particularly vulnerable to long-term effects. According to a U.S. study, around two thirds of those affected were middle-aged women. Important risk factors include being overweight and having pre-existing chronic or psychological conditions — such as anxiety and depression. A latent Epstein-Barr virus infection and diabetes also increase the risk of suffering from long COVID.

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