The questions of long COVID

Roughly a year after it became apparent that COVID-19 was not just another flu, the virus continues to wreak havoc across the planet in unexpected ways.

In the past year, we’ve seen it mutate many times over, developing variants that may even threaten the efficacy of much-vaunted vaccines.

But doctors and researchers are increasingly worried about another problem, emerging particularly in countries where acute infections are falling: a syndrome called “long COVID”, or “post-acute COVID”, which typically sets in after the acute stage of infection has passed.

So far, our understanding of this stage of COVID is very limited and fluid. While there are many studies underway across the world into the new syndrome, Professor Bruce Brew, a neurologist at St Vincent’s Hospital in Sydney, and the co-author of Australia’s most advanced study into long COVID to date, says that despite “varying levels of scientific rigour… and far larger data sets, the figures are not dissimilar to what we’ve found.”

What Brew – along with other eminent Australian researchers such as program leader Professor Gail Matthews and her fellow Kirby Institute professors Gregory Dore and Anthony Kelleher – have done is follow 78 people diagnosed with COVID-19 through St Vincent’s Hospital clinical service for a year after they were infected. The study cohort has increased over time to almost 150 patients, and it will continue beyond a year; the researchers are also seeking funding for more work in this area.

Over the course of the year, researchers have collected data on the patients’ respiratory and neuro-cognitive function and their mental health and wellbeing; they’ve taken blood tests to measure the patients’ immune responses to find out which antibodies are being produced, as well as undertaking other more complex tests designed to find out how the immune system is functioning.

So far, what they’ve found largely provides good clues and limited evidence about long COVID.

“We’ve found that out of the 78 people, 35% had persisting symptoms some months after acute infection [defined as enduring for 69 days],” Brew says. “At this stage, long COVID is almost certainly a combination of residual damage from the acute infection – such as lung damage from scarring – and an irregular immune system, which continues to be activated after the acute infection has passed.”

The reason why the immune system continues to be switched on is unclear. One theory points to COVID being a highly unusual virus that lingers, thus forcing the immune system to keep clearing up the damage it caused for longer than it usually would after other viruses; another is that (and Brew says this is far less likely) the virus has mutated and is sticking around, prompting the immune system to try and keep fighting it.

Broadly speaking, there seem to be three overlapping types of long COVID patients, according to Dr Avindra Nath, clinical director of the US National Institute of Neurological Disorders and Stroke at the National Institutes of Health (NIH), in Maryland.

The first cohort is characterised by “exercise intolerance”, meaning that even small amounts of physical activity causes patients to feel out of breath and exhausted. The second cohort is characterised by complaints of brain fog, memory complaints and mood abnormalities; and the third presents with problems of the autonomic nervous system, the nerves that control such things as heartbeat, breathing and digestion.

“Currently, it is estimated that between 10% and 20% of patients who have had COVID-19 complain of these symptoms,” Nath says, adding that about six months beyond acute infection, the number drops to 10% for those individuals in whom no other cause can be found to explain the symptoms.

At the moment there are no specific treatment options available for long COVID. Patients may benefit from symptomatic treatments, and they are also encouraged to participate in clinical trials as they become more widely available. Anecdotal evidence also suggests that some long COVID sufferers feel better after they receive a COVID-19 vaccine, something that Nath says is also evident in chronic fatigue sufferers.

“When they get the flu shot, a number of these patients will say they got better for a little while, if not forever,” he says. “What this tells you is that there is something abnormal happening to the immune system, and when you crank it up it improves their symptoms, but only temporarily – effects can last a month at most.”

Brew adds that while he has also heard such anecdotes, there is still much to understand about the effects of vaccines on long COVID: such as how often do they help, who, to what extent, and is the relief provided related to a certain type or types of vaccine.

Based on the patterns of long COVID symptoms, researchers are focusing on two hypotheses that they think may help explain the syndrome. The first is the theory that long COVID is a persistent virus that lingers in the body long after the acute phase has passed.

“We think this could be the case in long COVID patients who had milder symptoms, and because they were milder they never mounted a strong enough immune response to fight it, and as a result the virus has sat around and mutated enough to drive a chronic response,” says Nath.

The second hypothesis centres around long COVID being similar to an autoimmune disease, which holds that the virus has over-stimulated the immune response and caused it to go rogue, and to attack the body’s own tissues.

Now that there’s something to look for, Nath says he and his team are in the process of selecting 50 out of 300 potential long COVID patients to study in greater detail.

“We want to bring these patients into the NIH and keep them for a week and study them thoroughly,” he says. “This means looking at the brain with high resolution MRI scans, PET scans, conducting neurocognitive testing, undergoing psychiatric evaluation to check for depression, checking spinal fluid and blood, looking at immune cells to see if they are abnormal, gene dysregulation and more.”

Another little-known side effect of acute COVID-19 may also shine a light on the virus’s long-term impact on the brain.

Last year, Nath and his team realised that some people – usually not sick enough to seek medical attention – had died suddenly. Several were found dead in bed. Another was discovered dead on a subway, and another man died suddenly while lifting his sister. The presence of COVID-19 was revealed only at the time of autopsy. These patients had only mild infection in their lungs.

“But when we looked at their brains, most had abnormalities such as blood vessel damage in different regions, and were leaking proteins from the blood into the brain,” Nath says. “This leakiness was causing inflammation in the brain and damaging neurons in certain areas.”

The study has since been published in the February issue of the New England Journal of Medicine, and is influencing Nath’s longer study.

As to who is more likely to suffer from long COVID, the data is skewing towards women. Age is contested: while a 2020 study by King’s College London found the median age of those with self-reported long COVID to be 45, other research suggests it may be older people. Nath also believes it’s women around 40 and younger who tend to present more with long COVID, while Brew says his data suggest women may be more vulnerable.

Brew says women may be more at risk due to their having higher rates of autoimmune conditions, as well as hormonal influences: “COVID is associated with an increased risk of stroke, and women are more at risk of stroke due to hormonal replacement and taking the contraceptive pill,” he says.

Despite all the initial and ongoing global research into the condition, Associate Professor Hassan Vally, an epidemiologist with a special interest in infectious diseases at La Trobe University, says there is no “universal definition” of long COVID.

“It looks as though the percentage of people suffering from long COVID is between 10 to 19 per cent, a figure which seems to vary depending on the time frame, so how long people are being tracked for,” he says.

“If you’re looking at people four weeks after the acute infection has passed, you will end up with a larger number of sufferers than after eight months.”

An important first step towards understanding will be to isolate the symptoms experienced due to long COVID from those prompted by other conditions over a long period of time. Nath says the best patients to study are those who’ve had COVID-19 but are otherwise healthy individuals with no underlying illnesses, organ damage or other issues.

One way or the other, researchers agree that a universal definition of long COVID may prove elusive for some time yet.