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The public submissions to Australia’s long COVID parliamentary inquiry make for tough but important reading.

Most are anonymous, but Mary Klestadt, 65, wanted to tell her story. She was working out five times a week and managing the family company; after a mild bout of COVID she now has “crushing and immovable fatigue” that sleep and rest can’t touch. Reading is exhausting; holding a conversation almost impossible.

“I’m so tired all the time,” reads another submission, “and no one can help me.“

A patient works with a physiotherapist at NSW’s first long COVID clinic.Credit:Louise Kennerley

A third submission comes from a person trying to push through headaches, nausea and brain fog, while watching her sick leave slowly dwindle. She has an appointment at a long COVID clinic – in 90 days. “I worry about being out of the house for more than a couple of hours. Some days the whole thing just makes me cry. I hope it is going to start getting better soon.”

We’ve looked before at the evidence on risk and prevalence of long COVID – suffice to say I don’t think the question of how likely anyone is to get it is settled. Australia needs high-quality prevalence studies, particularly because our risk will be different to other countries: most people infected with COVID in Australia were already vaccinated.

But even if the true risk is very small, the absolute number of people with long COVID is going to be large because so many people have been infected. Arguing about prevalence, as Burnet Institute deputy director Professor Margaret Hellard pointed out to the parliamentary inquiry committee, probably misses the point.

Submissions to the inquiry paint a picture of baffled GPs and disbelieving friends and family.

Associate Professor Louis Irving from the Royal Melbourne Hospital’s post-COVID clinic told the inquiry his neuropsychologists had been doing cognitive testing on young people with brain fog; they could find no abnormality, he said, other than “hypervigilance”.

“They are aware of the minor mistakes we all make in daily life, but they are blowing those mistakes out and becoming paralysed by their occurrence.”

The Kirby Institute’s Professor Greg Dore, part of a study on the long-term effects of COVID-19, disagreed, pointing to lung tests that showed loss of function, and cognitive tests showing clear deficits. “There are objective, measurable deficits,” he said.

Lingering symptoms following infection are documented for many viruses: scientists call them post-acute infection syndrome, or PAIS. But we don’t yet have a handle on what is going on with long COVID. I asked Dr Nick Reynolds, who has been researching long COVID at La Trobe University, to rate the science on a spectrum of one to 10, with one being “we know nothing” and 10 being “we know everything”. “Probably a four or a five,” he said.

Long COVID’s symptoms are often described as a “constellation”: unremitting fatigue, brain impairment and nervous system dysfunction are common, as well as nausea and shortness of breath. These symptoms fluctuate.

That wide range of symptoms may be a sign that what we think of as long COVID could have several linked causes, possibly interacting with each other. Unpicking these different types of long COVID is going to be a key step towards finding effective solutions.

Larger, in-depth studies looking at biomarkers are now starting to arrive.

One large study (not yet peer reviewed) of 99 people with long COVID found elevated levels of white blood cells typically involved in antiviral responses, as well as higher levels of exhausted T cells.

Compared to healthy individuals, they also had roughly half the levels of cortisol – a hormone that controls the body’s stress response and can reduce inflammation. When the researchers ran their data through artificial intelligence, it concluded the strongest predictor of long COVID was a low cortisol level. Low cortisol levels have also been linked to chronic fatigue syndrome. Other studies on long COVID have come to similar findings.

The long COVID sufferers also displayed higher levels of antibodies to viruses known to lie dormant in our bodies and then spontaneously reactivate, including Epstein-Barr.

Some studies also detected antibodies that attack our own crucial proteins.

And a highly-detailed Australian study noted persistent levels of immune activation months after infection.

Together, these studies point to a range of hypotheses that tend to circle back to a key culprit: the immune system.

“We’re getting closer to an understanding that this is a hyperactive immune system-driven illness,” Dore told the inquiry. “But what exactly is triggering that?”

One theory: COVID-19 itself, or fragments of its genetic material, are persistently hanging around in the body, causing inflammation. Some studies showing fragments of the virus – researchers refer to them as “ghosts” – can be found in the gut months after the infection has cleared; other research has found these ghosts in all sorts of other hidey-holes throughout the body.

A second theory: other viruses lying dormant inside the body, such as the one that causes chickenpox and shingles, are reactivated by the COVID-19 infection.

Treatment for long COVID remains frustratingly out of reach. Perhaps cortisol replacement therapy could be tried, some studies suggest; perhaps antivirals could root out reservoirs of the virus?

I wonder if we need more focus on this area locally because the picture for long COVID treatment trials in Australia is not encouraging.

By my count, there are just four Australian-led clinical trials trying to treat COVID-19 – and one of them is run through the National Institute of Integrative Medicine which is testing out “neutraceutical therapies”.

One scientist suggested to me the paucity of studies was due to a lack of government funding. If that’s the case, it’s not good enough. Existing Australian studies, such as ADAPT at the Kirby Institute, are being run on “the smell of an oily rag”, the inquiry was told.

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