The long-term effects of Covid-19 infection

For Julie Helms, it started with a handful of patients admitted to her intensive care unit at Strasbourg University Hospital in northeast France in early March 2020. Within days, every single patient in the ICU had Covid-19 – and it was not just their breathing difficulties that alarmed her.

“They were extremely agitated, and many had neurological problems – mainly confusion and delirium,” she says. “We are used to having some patients in the ICU who are agitated and require sedation, but this was completely abnormal. It has been very scary, especially because many of the people we treated were very young – many in their 30s and 40s, even an 18-year-old.”

Helms and her colleagues published a small study in the New England Journal of Medicine documenting the neurological symptoms in their Covid-19 patients, ranging from cognitive difficulties to confusion. All are signs of “encephalopathy” (the general term for damage to the brain) – a trend that researchers in Wuhan had noticed in coronavirus patients there in February.

Estimates of exact prevalence vary, but it seems that roughly 50% of patients diagnosed with Sars-CoV-2 – the virus responsible for causing the illness Covid-19 – have experienced neurological problems.

The extent and severity of these neurological issues has flown largely under the radar. Most people, including physicians, may not recognise neurological abnormalities for what they are when they appear – someone experiencing a seizure may simply look dazed, without any trembling or shaking. With its beeping machinery, sedative drugs and bed-bound isolation, an ICU environment can exacerbate and induce delirium, confounding our ability to link any symptom to the virus.

Since the start of the pandemic, it has become increasingly clear that Sars-CoV-2 is not just a turbo-charged version of the virus that causes the common cold: it has a number of quirky, unusual and sometimes terrifying traits.

For example, most viral pandemics (including influenza) have a “U shaped” mortality curve, killing the very young and the very old. But Sars-CoV-2 typically only causes mild symptoms in children. The novel coronavirus also disproportionately affects men: up to 70% of people admitted to ICUs worldwide have been male, though men and women have been infected at equal rates. (Read more about how Covid-19 affects men and women differently).

“Happy hypoxia” is another mystery. Our blood normally features “oxygen saturation” levels of around 98%. Anything below 85% should lead to a loss of consciousness, coma or even death. But a large number of Covid-19 patients have been found to have oxygen saturation levels below 70%, even below 60%, yet remained fully conscious and cognitively functional.

Then there’s the fact that an enormous percentage of people who carry the virus have no symptoms. Estimates vary, but one mass-testing report from Iceland found that fully 50% of the population who carried the virus expressed no symptoms whatsoever.

There are other quirks that Stevens has noticed but cannot explain. “Covid-19 patients seem to have a lack of sensitivity to the drugs we normally use – we’ve had to use five to 10 times the amount of drugs for sedation that we would normally use,” he says.  

Virologists will spend years trying to understand the biomechanics of this invader. And though researchers have scrutinised the virus and its victims for six months, publishing scientific studies at a rate never before seen with any disease, we still have more questions than answers. The newest to be added is: can the virus infect the brain?

Most researchers believe the neurological effect of the virus are an indirect result of either oxygen starvation to the brain (the “happy hypoxia” exhibited by many patients), or the byproduct of the body’s inflammatory response (the famed “cytokine storm”). Both Fory and Helms believe the neurological effects are “cytokine-mediated”.

Others aren’t so certain: evidence is starting to accumulate demonstrating that the virus can actually invade the brain itself.

David Nutt, professor of neuropsychopharmacology at Imperial College London, says he himself treated many patients in the 1970s and 1980s who had suffered from severe clinical depression ever since the 1957 influenza pandemic in the UK.

“Their depression was enduring and it was solid – it was if their emotional circuits had all been switched off,” he says, warning that we could see the very same thing happen again, but on a much larger scale. “People who are discharged from the ICU with Covid-19 need to be monitored systematically long-term for any evidence of neurological damage – and then given interventionist treatments if necessary.”

Patients who exhibit symptoms should be moved into interventional trials, such as of selective serotonin reuptake inhibitors (SSRI) anti-depressants or beta interferons (naturally-occurring proteins often administered as drugs for conditions such as multiple sclerosis) to mitigate the damage and prevent further long-term effects. But this simply isn’t being done, he says: “What really bugs me is that every health trust in the UK is looking at the symptoms of Covid – but nobody is looking at the neurological mechanisms, such as the amount of serotonin in the brain.”

Nutt plans to enroll 20 Covid-19 patients who developed depression or another neuro-psychiatric condition into a study that will use Imperial’s state-of-the-art PET scanners to look for signs of brain inflammation or abnormalities in neurotransmitter levels.

In Baltimore, Stevens is also planning a long-term study on Covid-19 patients discharged from the ICU, which will also conduct brain scans as well as detailed cognitive tests on functions such as memory capacity.

And in Pittsburgh, through the Global Consortium Study of Neurological Dysfunction in Covid-19, Sherry Chou, a neurologist at the University of Pittsburgh, has coordinated scientists from 17 countries to collectively monitor the neurological symptoms of the pandemic, including through brain scans.

Although the virus’s impact on the lungs is the most immediate and terrifying threat, the lasting impact on the nervous system be far larger and far more devastating, says Chou.

“Even though neurological symptoms are less common in Covid-19 than lung problems, recovery from neurological injuries is often incomplete and can take much longer compared to other organ systems (for example, lung), and therefore result in much greater overall disability, and possibly more death,” she says.

In France, Helms knows better than almost anyone how intense the neurological impacts can be. We needed to delay her interview with the BBC after one of her Covid-19 patients – who was discharged from the hospital two months ago, but is still suffering from viral fatigue and severe depression – required urgent consultation for suicidal risk. And that patient is not unique – she has seen many people in similar states of distress.

“She is confused, she cannot walk, and she just wants to die, it’s really awful,” says Helms. “She’s only 60, but she has said to me ‘Covid has killed me’ – meaning it has killed her brain. She just doesn’t want anything more in life.

“This has been especially difficult because we don’t know how to prevent this damage in the first place. We just don’t have any treatments that will prevent any damage to the brain.”

Patients experiencing lung failure can be put on a respirator, and kidneys can be rescued with a dialysis machine – and, with some luck, both organs will bounce back. But there is no dialysis machine for the brain.