From the earliest days of the COVID-19 pandemic, scientists have raised concerns about the potential for long-term health problems linked to SARS-CoV-2 and warned repeated infections are likely to increase the risk.
An association between COVID and cardiovascular disease emerged quickly.
And now – almost exactly four years since the first case was discovered in Wuhan – a growing body of scientific research is cautiously linking the inflammation caused by a COVID infection to diseases like Alzheimer’s and Parkinson’s as well as autoimmune conditions from bowel disease to rheumatoid arthritis.
The virus has even been suggested to impact some pregnant women, associated with double the risk of premature delivery.
As the eighth COVID wave hits Australia, experts are taking notice.
“Large epidemiological studies looking at the risk profile [suggest] an increase in the incidence of these diseases concomitant with the infection. But it is still early days and the data is still emerging,” says Professor Kevin Barnham from the Florey Institute of Neuroscience and Mental Health at the University of Melbourne.
Professor Catherine Bennett, the chair of epidemiology at Deakin University, has spent her career studying how disease impacts communities. “We know inflammation is behind a lot of disease,” she says. “And so anyone looking at diseases [like SARS-CoV-2] where that’s part of the aetiology will be watching with concern.”
Prof. Barnham stresses that current research doesn’t show SARS-CoV-2 directly causes these complications: not everyone who contracts COVID will be affected.
But the findings do suggest a COVID infection is one of “a raft of contributing factors” that can significantly increase the risk in susceptible people, perhaps those who already have a genetic predisposition to a particular disease or condition.
“Our immune systems are sometimes so well primed they can overreact,” he says. “That immune system can be activated by pollution, by a variety of viruses and bacterial infections as well. All these things add up.”
And Prof. Barnham is not surprised.
Smell is a portal to the brain
When the first wave of COVID patients began reporting loss of smell and taste, Prof. Barnham’s radar went up.
“Any time you see olfactory impairment it tells you that there’s going to be neurological impact,” he says. “Loss of smell is a cardinal, pre-clinical symptom of Parkinson’s disease and it’s been implicated in Alzheimer’s disease as well.”
The fact that COVID patients reported loss of smell not only during the active phase of the disease, but as a persistent symptom, suggested to Prof. Barnham that longer-term health consequences were likely. Loss of smell is associated with loss of brain volume.
A giant study of American military veterans published in the journal Nature Medicine last year has backed up these concerns.
It showed rates of death among veterans, as well as heart failure, diabetes, depression and Alzheimer’s disease, was higher than the general population in the three months following a COVID-19 infection.
Veterans who had been hospitalised with more serious COVID-19 infections were up to twice as likely to be diagnosed with Alzheimer’s disease and 50 per cent more likely to experience heart failure.
While the research has been criticised for sampling mostly older, white males who caught COVID early in the pandemic before vaccinations were available – meaning the research may not be easily applied to a diverse and vaccinated population that has since contracted milder variants – its findings are similar to many other large studies.
A Danish study, for example, published in 2022, compared just under one million participants who took COVID-19 tests and found the 43,375 who tested positive for the virus had a substantially increased risk of Alzheimer’s disease (3.5 times), Parkinson’s disease (2.7 times) and ischaemic stroke (2.7 times) and up to 4.8 times the risk of bleeding in the brain.
These associations have encouraged urgent follow-up investigation.
How is COVID impacting the brain?
At the University of Queensland’s School of Biomedical Sciences, Professor Trent Woodruff and his team are working on the next generation of COVID research. Their focus is on understanding potential links with neurodegenerative diseases like Parkinson’s and Alzheimer’s.
In late 2020, when the pandemic was in full swing, Prof. Woodruff and post-doctoral research fellow Eduardo Albornoz began investigating how COVID-19 was affecting the brain.
“We started out by asking the question: could the virus activate inflammatory pathways, that we’ve shown are involved in the [development of] Parkinson’s disease,” he says.
Around Prof. Woodruff’s lab sat dishes of human microglia – immune cells in the brain – that had been infected with SARS-CoV-2.
Prof. Woodruff had expected the cells would show an inflammatory reaction to the COVID virus, and they did. But what he did not expect was how strong that reaction would be.
Armed with the finding that brain cells became inflamed in the presence of COVID virus, Dr Albornoz and Prof. Woodruff began to look for a link with Parkinson’s disease.
The experiment was run again. This time some microglia were exposed to Parkinson’s disease proteins and some were infected with a low dose of COVID virus before being exposed to the Parkinson’s disease proteins.
What Dr Albornoz found was the microglia that were infected with COVID as well as the Parkinson’s proteins showed “this great, synergistic inflammatory response”, Prof. Woodruff says, suggesting Parkinson’s inflammation in the cells was supercharged by the presence of the virus.
Little doubt COVID is a risk factor
The research helps to explain why many COVID patients display Parkinson’s-like symptoms: including things like brain fog, cognitive changes and motor dysfunction. The question now is whether these associations can lead to an actual Parkinson’s diagnosis.
History suggests the answer might be ‘yes’.
“There is prior evidence that some of the concerns we have may have played out in other pandemics and with other viruses,” Prof. Woodruff says.
The Spanish flu, which broke out in 1918, coincided with significantly increased numbers of people diagnosed with Parkinson’s disease later in life, particularly those who were young when the outbreak took hold.
Like Prof. Barnham, Prof. Woodruff is careful not to claim COVID is a straightforward cause of diseases like Parkinson’s.
“We’re being a bit careful to not say that COVID [causes] people to get Parkinson’s disease … but a whole range of neurological symptoms occur in people who have had COVID,” he says. “It’s not like everyone who has had COVID will get it, but we are suggesting maybe these viruses are another risk factor,” he says.
Taking into account genes and environmental causes – including things like toxins, unhealthy weight or lack of cognitive reserve – the SARS-CoV-2 virus looks like another important trigger.
The next phase
With so many questions outstanding, answering them requires significant funding to carry out the necessary research. Finding out exactly how COVID is likely to impact populations in the years ahead will rely on predictions made from studies carried out now.
But funding is hard to come by in Australia. “Our GDP spent in Australia on research is the lowest its ever been and falling rapidly,” Prof. Woodruff says. Research from Universities Australia showed investment in R&D fell from 1.8 per cent of GDP in 2019-20 to 1.68 per cent in 2021-22.
It’s little wonder researchers like Prof. Woodruff are looking abroad to fund follow-up COVID research.
The Michael J Fox Foundation in the US, named after the Hollywood actor who was diagnosed with Parkinson’s at age 29, is in discussion with Prof. Woodruff’s team to potentially fund the next phase of research. This study would use mouse models to investigate whether being infected with COVID early in life makes them more susceptible to Parkinson’s disease later in life – just as the Spanish flu did a century ago.
“Our argument would probably be that this might accelerate something that’s already happening in certain individuals,” he says. “It might be that you get early onset of a disease you would normally get in your 70s that might actually occur in your 60s because of this acceleration effect.”
The study would also treat the mice with new drugs developed for Parkinson’s disease to “see what the best interventions might be”, Prof. Woodruff says.
Prof. Barnham offers a similar theory, arguing that if COVID is confirmed to trigger diseases including Parkinson’s – which can take up to 30 years to manifest symptoms and is now diagnosed at an average age of 61 – then someone who contracts COVID as a child or adolescent may be diagnosed in their 40s, generating a significant disease burden. Parkinson’s would cease to be only a disease of the elderly, he says.
For those worried that a COVID vaccination might trigger the same risk factors as a full-blown infection – Prof. Woodruff has this to say: “Being exposed to the virus itself would enable that replication of the virus in your body that allows it to have effects on the brain. By contrast, the vaccine has a very localised immune response. There’s no way that vaccine is able to affect the brain in the same way as the live virus.”
Priming the body through vaccination to identify and attack the virus, however, can reduce the likelihood it will replicate, thereby minimising its impact on the brain.
COVID can trigger autoimmune disease and even premature birth
It’s not just flu viruses that are known to predict the risk of future disease.
Infection with the human papilloma virus increases cervical cancer risk – and the vaccine reduces that risk to almost zero. The Epstein-Barr virus, which causes glandular fever, increases the development of multiple sclerosis 30-fold. A vaccine for EBV does not currently exist.
As well as Parkinson’s and Alzheimer’s, the development of autoimmune diseases are also increasingly being linked to COVID infection.
Giant global datasets have shown COVID-19 is associated with the development of rheumatoid arthritis, lupus, vasculitis, inflammatory bowel disease and type 1 diabetes as well as Graves disease, which causes the thyroid gland to produce too much hormone.
In the three-to-15 months following a COVID-19 diagnosis, participants had a 42.6 per cent higher risk of acquiring an autoimmune condition, according to one study published this year in Nature Reviews Rheumatology.
A waiting game
Understanding exactly how the pandemic will impact our health in the years ahead is now a waiting game.
In medical terms, COVID is still in its infancy, not old enough for early research to be completed, nor to witness how the disease may affect a population across the average life span.
“We are the sum of our histories in some ways,” says Prof. Bennett. “We know a lot of human health issues are associated with our past but it takes a long time to piece together.”
It is Prof. Bennett’s job to understand how illness moves through populations but to date she says insufficient time has passed for diseases like Parkinson’s to be confidently linked to COVID.
What has been linked is the shorter-term impact of inflammation on the cardiovascular system. And of course development of long COVID – which leads to a range of symptoms that could be considered Parkinson’s-like or similar to a post-viral syndrome – is also well-established.
Part of the puzzle is that it is no longer possible to be confident about who has and who has not contracted COVID, with evidence suggesting it has spread to an overwhelming majority of the population. That makes it difficult to know what conditions can be firmly tied to COVID inflammation and which would have emerged regardless, Prof. Bennett says.
Prof. Barnham says a great deal of research is focused on short-term health implications rather than long-term impact that would capture the risk for diseases like Alzheimer’s and Parkinson’s.
“I think the problem we’ve got here is [disease onset] is likely to have multiple factors,” Prof. Barnham says. “You’ve got the short-term inflammatory response, the initial response to the infection, and then there are longer-term effects built on top of that. It is multifactorial, heterogeneous, and that really gets to the heart of our struggles to get our teeth into this problem.”
He is anxious for more research to be done, using the COVID era as a definitive starting point to begin screening and analysing data. “At the moment I’m extremely frustrated,” he says. “We don’t have the resources to do what I think we need to do.”
Without this research we must wait for the disease to emerge in human populations over time. Until then, the true cost of COVID-19 remains to be calculated.
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