Long COVID Research Is a Bit of a Mess

Back in March 2020, as the COVID-19 pandemic descended over the world, Naïma was a busy tech worker, zipping around London, speaking to clients and jogging on the weekends.

“I was very, very busy,” she says. “I did triathlons and [was] running 10Ks all the time. I was living a normal life, a full life.”

Then, like every other person in the UK, her life came to a standstill as the country’s first lockdown began. Only, Naïma was even more sedentary than most; she was ill with COVID-19. 

“I had quite a few symptoms: headache, fever, full-body soreness, sore throat, a bit of a cough and I felt very weak,” she explains. “That lasted a couple of weeks.”

It would have been easy to panic, contracting the very virus that had just shut down the world, but Naïma was relatively calm. “Because I was so fit, I wasn’t too worried,” she says. “The only real story that was happening was the hospitalizations. The line was: ‘Unless you have underlying conditions or you’re much older, you’ll be fine’.”

And for a while she was, mostly.

“I had this niggling sensation in my chest that would pop up every couple of days, just for a few seconds. And in those few seconds, I couldn’t breathe properly. But that didn’t develop into anything else for several months.”

When it did, Naïma wasn’t just troubled with a tight chest; she was debilitated with palpitations and crippling fatigue. She could barely walk. “My world was turned upside down from that point in October, when those severe symptoms kicked in. I spoke to general practitioners; I said, ‘I can’t move at all. It feels like there are bricks on my chest and shooting pains that come whenever I get up’. They said, ‘You know, you’re so young and fit, but this sounds like a heart attack’.”

It wasn’t. It was long COVID. Naïma was part of the first batch of people in the world to develop ongoing, disabling complications following an un-hospitalized COVID-19 infection. And she’s still ill, more than three years later.

“It took me some a couple of months to realize that this wasn’t going anytime soon. I was convinced I’d just wake up and be fine. And, yeah, that obviously never materialized.”

Research required

How could a fit and healthy 26-year-old go from running triathlons to being bed-bound for months, just from a passing viral infection? Why were she and people like her left with life-altering symptoms, while others could move on from their infections, seemingly unchanged? Back in 2020, no one had answers to these questions. No one really knew how to help those struggling with the illness. Research was desperately needed.

And, as 2021 dawned, research arrived. The UK government awarded £18.5 million to four studies that set out to define long COVID. The European Union gave €27.9 million to a larger research initiative, known as ORCHESTRA, to study how COVID-19 was impacting people’s health. And in February 2021, the US National Institutes of Health (NIH) raised the bar and allocated $1.15 billion to research the causes of long COVID and its possible treatments.

So, nearly three years later, what has been learned? Perhaps more importantly, have any treatments been produced?

The short answers: a lot. And not quite.

What exactly is long COVID?

To begin with, researchers set about defining long COVID as a starting point. Many understood the condition to involve persisting symptoms after a SARS-CoV-2 infection, but that was about it. They didn’t know exactly what these symptoms were or who they were affecting. To gather insights, they began profiling patients.

“A lot of these patients were actually young and healthy, in their 20s and 30s,” says Dr. Ziyad Al-Aly, a clinical epidemiologist at Washington University. “And everybody at the time [in March 2020] was telling them that, ‘If you’re young and healthy, then SARS-CoV-2, it’s not a big deal; you’ll recover’. But weeks later, these people were not recovering. So we decided to research long COVID to try to understand what it is.”

Al-Aly and his colleagues began by looking at patient medical records. They recently published two years’ worth of observations in Nature, comparing the medical data of 138,818 individuals who had had a SARS-CoV-2 infection and 5,985,227 who hadn’t. There were some stark differences.

Among the non-hospitalized, long COVID took away 80.4 disability-adjusted life years (DALYs), a standard measure of disease burden, per 1,000 people. For comparison, others studies have estimated that chronic obstructive pulmonary disease, for instance, costs between 3.6 and 6.7 DALYs per 1,000 people.

Long COVID’s high disease burden is partly explained by its sheer number of possible symptoms; Al-Aly and his colleagues observed more than 80 within the medical records. These included atrial fibrillation, cardiac arrest, anemia, diabetes, fatigue, acute gastritis, myalgia, memory problems and peripheral neuropathy. Just over 30% of these sequalae remained “significant” in non-hospitalized patients for two years.

“Long COVID is literally the long-lasting legacy of this pandemic,” Al-Aly says.

Al-Aly’s study documented, in unprecedented detail, just how wide-ranging the effects of long COVID-19 can be. But what exactly is causing these symptoms? Parallel research has shed some light.

One study found that long COVID patients had 100 times the levels of SARS-CoV-2-specific T cells normally seen in people who recovered from the virus – a finding that suggests the virus is still active in the bodies of people with long COVID, surviving in reservoirs, plaguing sufferers for months. Tiny blood clots have been found in patients – clots that could be blocking oxygen from reaching cells, starving patients of their energy. The brains of people with long COVID are also more active in certain areas than the brains of those without the post-viral illness – an observation that could explain the memory loss and confusion experienced by many with the condition.

There’s a lot going on under the skin of long COVID patients, multiple etiologies affecting multiple organ systems.

And this is where the field of long COVID research gets sticky, because highly variable diseases are difficult to study further. What kind of clinical researcher is best suited to the job? A cardiologist? A neurologist? An infectious disease specialist? Based off the mounting data, it seems like long COVID is a job for all three.

This issue is partly why, more than three years on from when the illness was identified, long COVID research is still stuck in its characterization phase. Have a Google of “long COVID research” these days and one will still come across new papers decrying how blurry the definition of the disease is and arguing for more thorough studies to detail it better.

But people with this condition can’t wait any longer for such preliminary studies. They’re desperate for interventional clinical trials now. “People are hanging their hopes on these trials,” says Al-Aly. “They want them to be done yesterday. And yet we’re moving forward at a turtle’s pace.”

Ironically, it’s the same kind of characterization research that demonstrates this desperation best. Almost one in five UK doctors responding to a recent BMJ survey said that they had lost their ability to work due to their post-COVID ill-health. A US study, published last year, estimated that long COVID potentially accounted for 15% of the country’s whole labor shortage.

Even those who have managed to keep working through their illness report life-altering levels of fatigue (the most common symptom of long COVID), enough to rob them of their prior quality of life. One survey of patients at a long COVID clinic, published in BMJ Open this year, found that, on average, the patients’ fatigue scores were worse or similar to those of people with severe kidney disease. The respondents’ quality of life scores were also lower than those of people with stage four lung cancer.

Most concerning of all, due to the toll of the illness, people with long COVID seem to be at a higher risk of suicide. One US patient-led survey found that 45% of respondents had experienced recent suicidal thoughts – more than 11 times the national average (4%). Sadly, these data are supported by a growing number of anecdotal reports within the long COVID patient community from grieving loved ones.

So, with no approved treatments for the illness or standardized care plan – and a disease duration that can span over three years in certain cases – it’s perhaps no wonder people with long COVID are crying out for trials. Fortunately, a few have been greenlit.

What’s being trialed?

In August 2023, there were 386 trials underway around the world relating to long COVID, according to the ClinicalTrials.gov database. A promising figure, one might think. Only 94 of those studies, however, were classed as interventional and were recruiting, and only 12 trials were testing pharmacological interventions; the rest were testing the effects of food supplements, psychological support, acupuncture and other non-drugs.

What are the 12 drug trials testing, though? Well, one – led by Yale University – is studying whether Paxlovid (a COVID-19 antiviral made by Pfizer) could benefit people with long COVID, perhaps by eliminating any rogue remnants of SARS-CoV-2 that may still be lingering in their bodies. Another – led by a private US company – is seeing whether a novel drug designed to remove pro-inflammatory nucleic acids could reduce the levels of vascular inflammation observed in long COVID patients, thereby reducing their fatigue.

But perhaps the most highly anticipated trial within the long COVID community is that undertaken by the relatively small biotech company Berlin Cures. The German start-up made headlines back in 2021 when it announced that it had effectively treated four people with long COVID with just a single infusion (per person) of its proprietary drug, BC 007. Encouraged by these initial results, the company has since launched a Phase 2 clinical trial of its neutralizing functional auto-antibody formula, which recently completed a Phase 2 open study for heart failure.

“We know, and others have shown, that these functional auto-antibodies play a key role in the pathogenesis of various debilitating diseases,” says Oliver von Stein, Berlin Cures’ CEO. “Long COVID, we believe, is one of them, heart failure is potentially another.”

To be included as a participant in the company’s trial, potential patients have to test positive for these pernicious auto-antibodies, so the Berlin Cures team can later test if a reduction in auto-antibody levels correlates with a reduction in fatigue (the prime symptom assessed by the study).

Thanks to this level of rigor built into the trial, and the early results of BC 007, von Stein and his colleagues are expecting promising results by the second half of next year – results that they hope will attract a new wave of investment for a Phase 3 trial and, beyond that, other trials for other maladies.

“We are optimistic and expect good data from our ongoing Phase 2 study,” von Stein says. “And, if this is the case, this will provide a lot of momentum to tackle other diseases, similar conditions – for example, chronic fatigue syndrome.”

The ME in the room

Chronic fatigue syndrome – or myalgic encephalomyelitis (ME) – is the elephant in the long COVID room. For the past three years, much of the media and discussion around long COVID has treated the post-viral condition as an entirely new illness, a view that has been reflected in its research; scientists from around the world have scrambled to study the disease from scratch.

But if ME had been studied more thoroughly – or even just believed – years ago, much of the foundational work of long COVID research may already have been achieved. That’s certainly the belief of many of those suffering from ME, who often live exceptionally stationary lives due to their condition. Some are bed-bound, quite literally, for decades.

“Half of long COVID symptoms are basically equivalent to ME symptoms,” says Chris Ponting, a professor at the University of Edinburgh’s Medical Research Council Human Genetics Unit and lead investigator of its Decode ME project.

If anyone is compensating for these “lost years of ME research”, it’s Ponting; he and his colleagues are currently conducting the largest study of ME ever undertaken. By analyzing the DNA samples of 25,000 patients, they hope to identify genetic markers that could underpin a person’s susceptibility to the disease. With that information in hand, they could then both validate the existence of the malady and identify targets for future drugs to treat it. 

“We anticipate that we’ll be able to find a bunch of places in our genomes that scream at us: immunology, or mitochondria or some neurological phenotype in the genome,” says Ponting. “Then, through joining up the dots, we can make an evidence-based, cogent explanation for what is going wrong.”

It all sounds quite promising. But there’s an obstacle to follow-up studies, the same one that prevented ME research for decades: funding. “Our study was funded prior to the COVID-19 pandemic,” Ponting says. “There has not been further funding since then.”

Contrary to the hopes of many in the ME community, the relative surge of interest in long COVID has not translated into a research boon for other fatigue-inducing, likely post-viral conditions, according to Ponting. “There has been a shift in the dial in acceptance of ME,” he notes, “which has not translated to substantial research funding that this disease deserves.”

And unfortunately, at the tail end of 2023, it’s not just ME that’s being starved of vital research. The funding well for long COVID is drying up, too.

Goodbye, pandemic. Goodbye, research grants

“All of these scientists, they’re back in the usual hurdles that scientists go through to try and get research up and running in this country. There is no sense of urgency at all,” says Margaret O’Hara, founder trustee of Long Covid Support, a UK-based charity supporting people with long COVID.

O’Hara liaises with researchers on behalf of the charity. Two years ago, many of the scientists she spoke to were getting their funding from the UK’s National Institute for Health and Care Research (NIHR), which launched rounds of commissioned calls that were worth millions in 2021. Now those funding rounds are a distant memory.

“Then NIHR said, ‘Right, no more commission calls’,” says O’Hara. “’Long COVID’s not special anymore, and if you want money to research it, you [must] go through the usual channels – for example, RFPB [Research for Patient Benefit] – and you compete with all the other diseases.' So, what we find now is that [research grant applications] are just getting knocked back.”

The situation seems much the same across the Atlantic. Remember that $1.15 billion the US NIH allocated to long COVID research? Well, it’s pretty much all been spent, largely on observational, characterization research, according to an analysis by STAT, and there’s been no announcement of any follow-up funding, despite calls from US researchers. Some long COVID studies in the country have since relied on charitable donations to keep going.

Why has the money dried up? Fittingly, one could blame fatigue. There is a bitter feeling within the long COVID community that the rest of the world has grown tired of all things COVID and no longer wants to hear from – or fund studies affecting – those damaged by the virus.

“We think there’s a bit of a message coming from the top to say, ‘Yeah, let’s downplay long COVID because, you know, COVID’s over,’” says O’Hara.

Whether accurate or not, this sentiment that “the top” has lost interest in long COVID is a doubly frustrating one for those researching the disease because, right now, the field could really do with some leadership.

Long coordination

“[There is] no coherent approach to studying long COVID. No coherent strategy,” says Al-Aly. “I liken it to if you have a bunch of musicians, and everybody is singing their own tune, and there’s no conductor harmonizing all of this.”

Al-Aly’s exasperation is shared by many of his fellow researchers. At a time of disappearing grants, many say the field needs a conductor – some governing body with a comprehensive, coordinated plan of action.

“We think there should be a coordinated effort by UKRI [UK Research and Innovation] to say, ‘OK, long COVID is a disease of great interest and we need to coordinate responses,’” says O’Hara.

“We need to put these scientists together so that they’re not all repeating the same thing.”

O’Hara and her colleagues at Long Covid Support have been calling for this kind of managed response since 2020. The charity recently wrote to the UK government, recommending that it declare long COVID a public health emergency and prioritize research into treatments. These pleas have so far gone unheeded, which may be unsurprising given recent political revelations. In October 2020, when presented with the health department’s first guidance on long COVID, the then prime minister Boris Johnson scrawled “bo***cks,” in capitals, on the document.

But this offensive dismissiveness from “the top” doesn’t mean a top-down research strategy, if coordinated by health departments and research funders, is an impractical suggestion, researchers insist.

“The funders will say that’s up to the scientists to coordinate,” says Ponting. “And they would have a point; it has to be from the ground-up mostly rather than from the top-down. But top-down does work.”

“The response to mad cow disease did come from the top,” he adds. “There have been international efforts on many different diseases going back decades, including polio. So, the answer that it is up to the scientists to organize ourselves in a competitive world, where we compete for funding because there’s so little of it, is missing part of what should happen, which is that we need coordination.”

Stuck in COVID limbo

While all this disarray between researchers, funders and governments plays out, long COVID patients watch on, many despondent. Some are relatively new to the illness. Some have been coping with it for over three years with little improvement. Others have improved over time, gaining back enough physical capability to return to work. But this remission is fragile. According to a Long Covid Support survey of people who had recovered from the illness, 60% got long COVID again following a reinfection of COVID-19. This happened to Naïma, twice.

“It’s very much a relapsing and remitting story,” she says. “I’ve had periods where I can work part-time, nearly full time. And then I’ve had periods where, right now, I can’t work at all because of a reinfection.”

To protect herself from worsening symptoms, Naïma still practices strict infection protocols. She restricts her socializing. She wears a mask on public transport. She routinely tests for COVID-19 and asks others she sees to do the same. She’s still behaving like many people did in 2020. Without long COVID treatments, she can’t afford to change her habits.

“I’ve been lucky in terms of my life beforehand,” she says. “I no longer feel that way. I live with fear every day of reinfection.”

What does she make of the state of long COVID research, then? Does it give her hope for a return to a normal, fear-free future? Not quite. While she is part of a characterization study being conducted at Imperial College London, and is optimistic that such research will one day bear useful results, she says those who have been struggling with their long COVID for years need better outcomes now.

“A lot of studies are moving on to: ‘who is getting this?’ I’m part of a study now with Imperial taking blood samples. It’s just [about] understanding: why are we so greatly impacted by this? Is there a specific gene that we have? I think that [answer] would really go a long way to understanding this.  And then, of course, treatments for people who have been suffering now for years…”

She pauses.

“It’s been three years. This is a really long time to go without any hope.”

“I think, because I’ve had improvement,” she adds. “I have more hope because I know that I do have better points and worse points. But some people have not had any good moments; they’ve been around for three years and had no improvement. I think we really need to be able to offer something to those people, to all of us.”

Those interested in following Naïma’s journey of long COVID recovery can subscribe to her Substack journal.

For those living with long COVID, links to support groups and symptom management guides can be found at Long Covid Support.

Those with ME can find similar support resources at ME Association.

For those struggling with suicidal ideation in the UK, Papyrus and Samaritans offer 24/7 support. Those living in the US can call the 988 Suicide & Crisis Lifeline.