The Search for Long Covid Treatments Takes a Promising Turn

Scientists believe lasting symptoms following a coronavirus infection are not a single disorder. So new clinical trials are hunting for a range of solutions.

Three years in, the pandemic mania has settled to a rumbling hum. We’re back to sweating on each other in nightclubs, spluttering out birthday candles, and sharing firm handshakes. Covid-19, while still very much alive, has for most people diminished to an everyday threat, thanks to vaccines and treatments.

The same can’t be said of long Covid, the mysterious, life-limiting ailment that lingers on after an initial Covid infection. For the millions besieged by it, their situation has remained much the same. “We still have no established tools to help treat patients,” says Linda Geng, codirector of the Post-Acute Covid-19 Syndrome Clinic at Stanford University. Estimates of how many people have long Covid vary, but it’s been put as high as around 65 million—about the same as the population of France.

It’s only now, over three years into the pandemic, that a consensus on what long Covid is has started to solidify. And what it is, it turns out, is a whole bunch of things. Rather than a single disorder, it’s more likely a smorgasbord of diseases that fall under one big umbrella. That means there likely won’t be a one-size-fits-all treatment either.

What triggers long Covid for you may not be what sets it off for another. Perhaps your long Covid is caused by your immune system turning on you, attacking your body—a phenomenon called autoimmunity. So goes one theory. Or maybe it’s that splinters of the virus are hanging around your body long after the initial infection, keeping your immune system’s engine revved up to the point of exhaustion. Another theory is that SARS-CoV-2 causes long-lasting damage to certain organs or tissues. Maybe it’s that a Covid infection reawakens latent viruses your body has encountered before, such as the Epstein-Barr virus, which causes mononucleosis.

All these theories have some evidence to support them, and they may not be mutually exclusive; for some people, these things could be happening at the same time. The idea that long Covid has different causes could go some way toward explaining the sheer diversity of symptoms, which number up to 200.

Working off this basis, researchers are trying to hit two birds with one stone: trialing treatments that could alleviate long Covid while at the same time lending weight to certain hypotheses—and beginning to defog the mystifying condition. “The reality is that there’s such an urgency, we need to do these things in parallel,” says Geng. “It’s building the ship as we sail it—but we have to sail it because people need help.”

But the jumble of symptoms makes designing clinical trials much trickier. Not every person experiences every symptom, and those may vary in severity and duration. Plus, there’s no consensus on how to define long Covid, says Steven Deeks, a physician and infectious disease specialist at the University of California, San Francisco. “There’s no magic biomarker, there’s no x-ray, there’s no test.” Because of that, it’s tough to figure out who to put into a clinical trial. Right now, long Covid diagnoses work by exclusion: determining that symptoms can’t be explained away by another cause. Regardless, researchers are plowing ahead.

Akiko Iwasaki, an immunologist at Yale University, is running a randomized controlled trial of 100 long Covid patients to investigate whether Pfizer’s antiviral drug, Paxlovid, designed to treat symptomatic Covid, could actually help treat long Covid—a theory that has anecdotal backing from patients. The rationale behind the trial is based on the viral reservoir hypothesis: that Paxlovid could eradicate any lingering remnants of SARS-CoV-2 that have managed to persist despite the body’s immune response.

Iwasaki already knows Paxlovid won’t help everyone, but the trial will shed light on who it could help. Because the trial is randomized, the team is hoping it will naturally include people whose long Covid is triggered by different biological mechanisms. Patients will be divided into groups, with one group receiving Paxlovid for 15 days and the other getting a placebo.

The researchers will be keeping an eye out for immune signatures that people with long Covid have been found to carry, like exhausted T cells or circulating SARS-CoV-2 spike proteins. Iwasaki and her team plan to measure immunological biomarkers before, during, and after the treatment and look at which biomarkers were common between the people who ended up feeling better from the treatment. “It’s not just about what percentage of the people are going to benefit,” says Iwasaki. “It’s about finding out who benefits and why they might have benefited by doing some detective work.”

Other ongoing trials target alternative mechanisms. Some researchers are looking at low-dose naltrexone, a drug normally used to treat opioid addiction, which could treat long Covid by hampering inflammation in the body. In the UK, a trial called Stimulate-ICP is looking at using a blood thinner called rivaroxaban to treat microclots in the blood, as some contend that these cause long Covid by blocking oxygen delivery to tissues in the body.

According to Amitava Banerjee, a professor of clinical data science at University College London who is leading the Stimulate-ICP trial, the study is ongoing and has recruited about 500 people, although the researchers hope to recruit at least a couple of thousand. Banerjee says the drugs being tested are probably not tackling the underlying mechanisms of long Covid, but rather the mechanisms of the major symptoms—they’re treating the microclots, not what causes them.

Iwasaki is hopeful that if her team is successful, their research could shed light on other long-overlooked chronic illnesses. “If we can figure out something about long Covid, we might be able to help people with ME/CFS [chronic fatigue syndrome], and other diseases that are related,” says Iwasaki. It could be that they share mechanisms.

What’s crucial is that long Covid doesn’t meet the fate of many other chronic illnesses and end up being grossly neglected—often due in part to the sheer complexity of figuring out their root causes. While many people are returning to their normal lives, we can’t forget about long Covid, says Geng. “There’s still many, many, many people suffering, not able to work, not able to live their normal lives.”

The Search for Long Covid Treatments Takes a Promising Turn

(May require free registration to view)