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New research shows coronavirus may have lasting impacts on cognitive ability. By Rick Morton.

Lost function: Long-term consequences of surviving coronavirus

They call themselves the Covid long-haulers.

Weeks and months after the initial infection has passed, people around the world are still reporting a strange medley of often debilitating symptoms that have caused them daily pain, confusion and deepening concern.

Those with “long Covid” are marshalling in online forums and on private social media pages to share their symptoms and new discoveries about maladies that, they believe, simply did not affect them before the virus.

On Thursday, Victoria recorded its highest day on record for coronavirus cases with 723 infections. There have now been more than 17 million cases around the world. Authorities, families and healthcare workers have been understandably preoccupied with the fatality rate. But the story of Covid-19’s impact is far more complex, and in some respects more concerning, than the death rate itself.

As early as February, testimony from people who had notionally “recovered” from Covid-19 but were still unwell began to tie in with scientific research that showed the SARS-CoV-2 virus having effects across the body.

One such study, from researchers in China and Japan, was published in the Journal of Medical Virology. “Increasing evidence shows that coronaviruses are not always confined to the respiratory tract and that they may also invade the central nervous system inducing neurological diseases,” it read.

“The infection of [the 2002 SARS virus] has been reported in the brains from both patients and experimental animals, where the brainstem was heavily infected.”

This is precisely what long-haulers such as Hannah Davis are reporting, four months after contracting Covid-19.

“I am young, and I was healthy,” Davis said this week. “Dying is not the only thing to worry about. I still have a near-daily fever, loss of cognitive function, essential tremors, GI [gastrointestinal] issues, severe headaches, heart rate of 150-plus, viral arthritis, heart palpitations, muscle aches, a feeling like my body has forgotten to breathe.”

She continued, outlining lingering problems ranging from loss of feeling in her hands to extreme back, kidney and rib pain; phantom smells, “like someone barbecuing bad meat”; difficulties with focus and comprehension; light and noise sensitivity; and increased propensity for bruising.

“I’m not alone in the cognitive issues,” she said.

Davis, an algorithmic researcher and musician, is one of a team that has established the network Patient-Led Research for Covid-19, which seeks to co-ordinate a laundry list of ailments associated with “post-Covid” and direct research to unpick the mystery of their onset.

What they and scientists have found is troubling in its scale. The SARS-CoV-2 virus appears to do its deadly work across a constellation of human systems.

The Saturday Paper has reviewed dozens of scientific papers from the Journal of the Neurological Sciences, Clinical Neurology and Neurosurgery, the American Journal of Emergency Medicine, Cell Press journals Neuron and Immunity, Pathogens and Disease, the Journal of Medical Virology, The New England Journal of Medicine, The Lancet Infectious Diseases, BMC Neurology and JAMA: The Journal of the American Medical Association, among others. The following details are drawn from those preliminary studies.

Early research suggests Covid-19 can affect the brain, though virus particles are rarely found there. The virus is unusual for its type in that it appears to travel through the bloodstream, and high amounts of it have been found in the heart.

The virus causes a “strange hypercoagulate” state in the blood, according to Dr Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases in the United States. This hypercoagulation leads to clotting, including in the carotid artery, which is an uncommon feature in viruses. The pathogen can also wreak havoc on the kidneys. It can compel the wrong type of immune response, resulting in “cytokine storms” of proteins such as interleukins, which inflame tissue and organs and can lead to multi-organ failure.

At least eight papers have been published, including in the Journal of Clinical Neuroscience, linking the incurable Guillain-Barré syndrome to Covid-19, with at least seven cases implicated so far. That condition – in which the body’s immune system attacks nerves, eventually causing paralysis – developed in patients days after infection.

Last week, the US Centers for Disease Control and Prevention (CDC) issued an early release paper regarding long-term health problems associated with the virus.

Even in symptomatic adults who had not been hospitalised, the CDC reported, “it might take weeks for resolution of symptoms and return to usual health”.

On July 9, an Italian study of 143 “recovered” Covid-19 patients, published in JAMA, found “87.4 per cent reported persistence of at least one symptom, particularly fatigue and dyspnea [shortness of breath]”.

Almost everything about this virus is new. But those still suffering from ill health months after clearing Covid-19 from their system are asking one question: how long does this last?

 

There are dozens and dozens of coronaviruses, including many common types that cause colds. The pathogen behind Covid-19 shares almost three-quarters of its genome with the original SARS virus that swept across Asia in 2002 and 2003.

It is, however, most closely related to another coronavirus called RaTG13, which was found in an intermediate horseshoe bat in China’s Yunnan province in 2013. These details could provide some clues as to how the behaviour of this latest virus may affect us in the long run.

“I’ve been trying to get the message out because I don’t want people to think that this is not a problem for young people,” Nobel prize-winning immunologist Professor Peter Doherty tells The Saturday Paper.

“We know what sort of consequences we might see from the sort of cardiac damage and respiratory damage, lung damage, we’re seeing now. But I don’t think we understand any of the neurological manifestations at this stage.

“And then what we also don’t know is what are the long-term consequences of the inflammatory-type syndrome?

“Whether you are going to see more rheumatoid arthritis in these people later or you’re going to see more chronic inflammatory, autoimmune-type diseases that could be completely novel, I don’t know. We really don’t know.”

The inflammatory symptoms to which Doherty refers appeared early in the outbreak but, in mid-May, the CDC issued a national health advisory in the US to report Covid-19 cases that meet the criteria for multisystem inflammatory syndrome in children (MIS-C).

In a paper published in The New England Journal of Medicine on June 29, researchers noted that “many of the pediatric patients with this hyperinflammatory syndrome have had fever and mucocutaneous [where mucous membranes and skin meet] manifestations similar to those of Kawasaki’s disease, a rare vasculitis of childhood that can cause coronary-artery aneurysms.”

They continued: “Some patients have presented with features of toxic shock syndrome … Although the cause of Kawasaki’s disease remains unknown, a preceding or active infection has been suspected.

“… The evidence from our investigations, from early reports from New York State and Europe, and from the literature on adult patients suggests that the cases of MIS-C are part of a spectrum of Covid-19–related disease with severe immune-mediated pathology.”

The virus itself is not an especially efficient “cell killer”. Instead, it can weaponise our own body against us.

The new coronavirus seems most likely to infect humans through the nose – this might explain why one of its most common features is a loss of smell and taste – but the pathogen is an accomplished traveller.

Viral RNA from the SARS-CoV-2 virus has been found in the heart after autopsies. For some people, according to the University of California San Francisco Magazine, their hearts were ruptured completely.

Professor Doherty says it is likely the virus travels through the bloodstream.

“We don’t pick up the virus in the blood, but it is clearly getting around in the blood,” he says. “And I think the reason they’re not picking it up in the blood is that it gets taken out very quickly, because of these ACE2 receptors that it binds to, which are everywhere.”

What remains under close study is the “neuroinvasive potential” of Covid-19.

So far, all indications are that the disease can lead to a “post-viral syndrome” that appears to be anchored in the brain. This disorder resembles the condition known as chronic fatigue syndrome, an enigmatic malaise that has baffled scientists for decades.

On July 9, Anthony Fauci said that, anecdotally at least, “there is no question that there are a considerable number of individuals who have a post-viral syndrome”.

“They have things that are highly suggestive of myalgic [encephalomyelitis] and chronic fatigue syndrome – brain fog, fatigue, difficulty in concentrating. So, this is something we really need to seriously look at,” he told delegates at an AIDS conference.

Online, in thriving chat groups, such stories abound.

Cathy Reed-Fink, who lives in the US state of Maryland, reports she has had some version of symptoms for 21 weeks now. Her fever has only recently gone down.

A specialist nurse named Laura says she hasn’t been at work since April 6. “I’m still fatigued, I still have pyrexia [fever] most days that fluctuates,” she said.

“I contracted Covid late March,” Jonathan Helm tells one group. “I was a fit firefighter, mountaineer, cyclist, runner always on the go. I’m now on week 19 of being off sick from work.”

In late May, Japanese researchers reported the first presumed case in a Covid-19 patient of “mild encephalitis/encephalopathy with a reversible splenial lesion”, otherwise known as MERS – not to be confused with that other disease caused by a beta coronavirus, Middle East respiratory syndrome.

The authors, writing in a letter published in the Journal of the Neurological Sciences, say their work shows one of the first symptoms of Covid-19 may be disordered movement, balance and muscle co-ordination, known as cerebellar ataxia. This condition usually occurs after damage to the brain’s cerebellum.

Similarly, a review of the virus’s neurological implications, published in May in Clinical Neurology and Neurosurgery, suggests SARS-CoV-2 may have a “higher affinity” for targets in the central nervous system than its viral forebears.

The review’s authors, led by Dr Victor C. Montalvan, propose two theories about how this might happen. The first is that the virus enters the brain through the circulatory system where, upon reaching the organ, the flow of blood is greatly reduced. Here, through receptors in the wafer-thin capillary network, the pathogen gains access to the brain itself.

An alternative posed by the researchers is that it sneaks in through something called the cribriform plate, a sieve-like structure at the back of the nasal cavity, bypassing the blood-brain barrier.

In their analysis of 67 other studies, Montalvan and other researchers from Texas Tech University and the National Autonomous University of Honduras raised the very real possibility that at least some patients who have acute respiratory distress syndrome caused by Covid-19 don’t have it solely because their lungs have been damaged.

Instead, they may experience severe cases because the virus has shut down function in the cardiovascular centre of the brain, found in the medulla oblongata.

This is the architecture that allows us to breathe without thinking about it. In the 2002-03 SARS outbreak and 2012 MERS epidemic, studies showed these beta coronaviruses presaged the “death” of neurons in this region.

The systematic review of neurological manifestations of Covid-19 by Montalvan et al assembled a frightening array of conditions linked to the current and historical coronaviruses. People with multiple sclerosis, an autoimmune condition, have had human coronavirus particles found in their systems after death. A female airline worker in her 50s developed acute necrotising haemorrhagic encephalitis, which leads to tissue death in the brain, three days after she began showing Covid-19 symptoms.

“In another case report, a 24-year-old man, after experiencing headaches, generalized fatigue and fever, presented with generalized seizures and altered mental status that progressed to impaired consciousness,” the paper says.

The likely cause? SARS-CoV-2 meningitis.

Much of the scientific literature emerging in relation to Covid-19 comes with this crucial caveat: we are only at the beginning of our understanding, and the path is long.

“The more I think about it, the more I wonder whether any asymptomatic people are totally asymptomatic,” says Peter Doherty.

“I think we will see a long-term disease burden out of this pandemic.

“This is a whole big experiment, quite frankly. A lousy experiment.”

This article was first published in the print edition of The Saturday Paper on Aug 1, 2020 as "Lost function: Long-term consequences of surviving coronavirus".

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Rick Morton is The Saturday Paper’s senior reporter.