It's a question that's tantalised researchers since the first reports of "long haulers" back in 2020: what causes long COVID?
What we do know is it can be incredibly debilitating for months, even years, with people frequently experiencing fatigue, brain fog and heart palpitations.
We also know it's not uncommon. An estimated 4.7 per cent of Australian adults have had symptoms for at least three months post-infection, according to a recent survey by the Australian National University.
Some are afflicted with long COVID after a very mild or even asymptomatic bout of COVID-19, but generally the more severe the disease, the higher the chances of developing the condition.
A Swedish study published yesterday of more than 200,000 COVID-19 patients found one in 100 people who weren't hospitalised went on to be diagnosed with long COVID.
This jumped to around one in three for patients who'd been in intensive care with the disease.
And exactly how the SARS-CoV-2, the virus behind COVID-19, triggers a swag of frustratingly persistent symptoms in some individuals is something researchers are trying to unravel.
In fact, it's likely that the syndrome we know as "long COVID" potentially covers a bunch of different subtypes, each driven by different and perhaps multiple factors, says Chansavath Phetsouphanh, an immunologist at the University of New South Wales.
Clues from our immune system
While the underlying causes of long COVID remain elusive for the moment, researchers are building a list of possibilities based on how our immune system behaves in the months after the initial infection.
The easiest way to do this is via a blood test, which provides a snapshot of immune cells circulating the body and the various chemicals they secrete.
In one study, Dr Phetsouphanh and his colleagues took a series of immune snapshots in people who developed long COVID after Delta or Omicron infection, and found (among other things) sustained levels of chemicals called interferons in their blood.
Interferons are part of our initial defence against pathogens such as SARS-CoV-2. When white blood cells encounter virus-infected cells in our body, they pump out interferons, which recruit more immune cells to the site.
"It's a very early response, and [interferon levels] usually drop quite early too," Dr Phetsouphanh says.
But the long-COVID cohort had high interferon levels for at least eight months, he adds.
"It was a real surprise for us to see them still elevated that long post-infection."
What's activating an immune response?
Dr Phetsouphanh's study suggests something was triggering immune cells to churn out interferons in his long COVID cohort. Blood tests couldn't tell him precisely what was happening, or even where.
But the study participants hadn't tested positive for COVID-19 on a PCR test in the best part of a year, so the virus was no longer in their body … or was it?
One theory for long COVID is that some people may harbour pockets of SARS-CoV-2 somewhere in their body — not enough to create full-blown disease, but just enough to activate the immune system.
It may not even be the whole virus either. SARS-CoV-2 might leave behind bits of itself, or even scraps of its RNA genetic blueprint, which our cells may use to build tiny viral proteins, setting off an immune response.
Another hypothesis is that SARS-CoV-2 somehow provokes our immune system to turn against our body, causing an autoimmune reaction that persists after the virus has been expelled, Dr Phetsouphanh says.
It might also tinker with the bugs that already dwell inside us.
SARS-CoV-2 infection may reawaken latent viruses such as the Epstein-Barr virus, which causes myalgic encephalomyelitis/chronic fatigue syndrome in some people, or upset the balance of our gut microbiome, which can also have chronic effects.
Toxic side-effects of viral replication
Then there's the possibility that substances that trigger chronic inflammation and cause damage may be made while SARS-CoV-2 hijacks and replicates in our cells.
The SARS-CoV-2 RNA genome is a blueprint for around 29 proteins. Four of those are "structural proteins" — they form the virus itself.
Researchers are still discovering exactly what the 25 non-structural proteins do, but some are thought to help the virus fly under our immune system's radar, or control how the structural proteins are put together.
A couple may also contribute to neurological symptoms of long COVID.
"The virus has been found in the brain and the central nervous system of patients who've passed away with COVID-19," Nicholas Reynolds from La Trobe University says.
He was involved in a study, led by Mirren Charnley from Swinburne University, that showed fragments of two non-structural proteins, produced during SARS-CoV-2 replication, can form clumps called amyloids, which are toxic to brain cells.
"Amyloid is a molecular hallmark in some neurodegenerative diseases like Alzheimer's and Parkinson's," Dr Charnley says.
And the damage and inflammation inflicted by SARS-CoV-2 amyloid clumps may be responsible for some of the brain fog, loss of smell and taste, and cognitive issues commonly experienced in long COVID.
Why hunt for a cause?
At the moment, long COVID management focuses on alleviating symptoms, and letting the body recover on its own.
Nailing down the reason — or reasons — for long COVID will hopefully improve how the condition is treated, Dr Phetsouphanh says.
"I'm always asked, 'what do you think is driving [long COVID]? Are there any therapeutic molecules we can use to target it?'
"All I can say is we don't know yet, and we have to find out what's driving it before we can test any therapies."
