In the early days of the COVID-19 pandemic, urologist and clinical epidemiologist Kari Tikkinen found his schedule full of cancelled surgeries, so he had some time to kill. “Do whatever you feel is most useful,” his boss at the University of Helsinki advised him. So Tikkinen threw himself into running clinical trials for COVID-19 therapies.
From the start — before the world learnt of long COVID — Tikkinen saw a need to follow study participants for months after their recovery. He wanted to monitor long-term side effects of the medicines. “Very soon, it became clear: it’s not only about safety,” he says.
Now, Tikkinen and a handful of others are hoping to learn more about whether treatments given during the acute phase of COVID-19 can reduce the risk of experiencing symptoms months later. “It’s an urgent and pressing health need that people need to start focusing on,” says intensive-care specialist Charlotte Summers, at the University of Cambridge, UK.
Research into long COVID — which is also known as post-acute sequelae of COVID-19, and is usually defined as COVID-19 symptoms that last longer than three months — has lagged behind studies of the acute phase of infection. People who experience long COVID live with a wide array of symptoms, ranging from mild to severely debilitating. Researchers have proposed a variety of causes for the condition — from lingering viral reservoirs, to autoimmunity, to tiny blood clots. Many think that a mix of these factors is to blame. “It took a while to get going on any serious mechanistic long-COVID research,” says immunologist Danny Altmann at Imperial College London. “It’s hard to piece the big picture together.”
Thus far, vaccines are the best way to prevent long COVID. COVID-19 vaccines reduce the risk of SARS-CoV-2 infection, and they might lessen the risk of long COVID after a breakthrough infection in someone who has been vaccinated.
Several studies have looked at this question: although they have yielded divergent results, the overall trend suggests that vaccination could reduce the risk of long COVID by about half among those who become infected after vaccination. For example, one study1 that has not yet been peer reviewed found that vaccination reduced the chances of developing long-COVID symptoms by about 41% in more than 3,000 double-vaccinated participants who were later infected with SARS-CoV-2.
But that still leaves too many people at risk of getting long COVID, says Altmann. “Half is not as good as I thought it would be,” he says. “I was thinking and hoping that long COVID would be a thing of the past.”
Beyond vaccination, it’s unclear whether any existing COVID-19 therapy has an effect on long-COVID risk. In theory, a drug that reduces disease severity might reduce the severity of long-term symptoms, says Altmann. But long COVID is not always associated with serious acute illness. “There are loads of people out there who are really destroyed by long COVID and had asymptomatic or near asymptomatic infections,” he says. “It’s really hard to grapple with.”
Nevertheless, some studies plan to look at the impact of early treatment with antiviral drugs on long COVID. A clinical trial called PANORAMIC has been testing the effects of the oral antiviral molnupiravir, developed by Merck in Kenilworth, New Jersey, and Ridgeback Biotherapeutics in Miami, Florida, on COVID-19 severity. Although it is not the primary goal of the study, researchers will gather data from participants at three and six months after treatment — which could determine whether the drug affects long-COVID risk. Similarly, two trials of Paxlovid, an antiviral drug developed by Pfizer in New York City, will include a six-month follow-up of participants.
These antiviral drugs are typically used to treat people with relatively mild COVID symptoms. Tikkinen and his colleagues hope to learn more about the long-term impact of treatments received by those who were hospitalized with COVID-19. His team is following up with participants in the University of Helsinki’s arm of the World Health Organization’s international COVID-19 treatment trial, called SOLIDARITY. In the next few weeks, he hopes to have the results of a one-year follow-up study of participants who were hospitalized with COVID-19 and treated with the antiviral drug remdesivir.
His team will also follow up with participants in two other arms of the SOLIDARITY trial, one that tested an immune-suppressing drug called infliximab and another that tested imatinib, a drug that could help to reduce inflammation in blood vessels.
But, Tikkinen cautions, none of these studies had enough participants to give clear-cut answers on long COVID. His team went to extraordinary measures to contact participants months after their remdesivir treatment and to encourage them to fill out a survey about their symptoms. The team hired graphic designers to make the surveys easier to fill out, had the questions translated into ten languages and offered to hand-deliver the paperwork to participants’ homes. The result was a 95% response rate, which Tikkinen says is unusually high for such long-term studies. But because the original study included only about 350 people, it is probably still too small to provide a definitive conclusion.
Researchers are hoping to find out whether more treatments can reduce the risk of long COVID. A large UK-based trial called HEAL-COVID is testing two drugs that target the cardiovascular system in people who have been hospitalized with COVID-19. One, called apixaban, is an anticoagulant. The other, atorvastatin, is a cholesterol-lowering medication thought to reduce inflammation in blood vessels.
The study will investigate whether either treatment reduces hospitalizations and deaths in the year after people are first discharged from hospital. Nearly one-third of people who are discharged after treatment for COVID-19 are re-admitted within six months, and 12% die within six months of their initial discharge. “And when we looked at what was most plausibly leading to death after hospitalization, it was probably the cardiopulmonary effects,” says Summers, who is leading the study.
At the University of Chicago in Illinois, pulmonologist and critical-care physician Ayodeji Adegunsoye has observed a possible increase in the accumulation of scar tissue, called fibrosis, in the lungs well after the acute infection in people who were hospitalized with COVID-19 and required supplemental oxygen. He is now testing a drug called sirolimus — an immune-suppressing drug that is sometimes given to organ-transplant recipients — in such people, in the hope that it will prevent the migration of cells that promote fibrosis in the lung.
By their nature, long-COVID studies require patience: one commonly accepted definition of long COVID is the persistence of certain symptoms for more than 12 weeks after the acute infection. Altmann is optimistic that this year will yield advances, but cautions against reading too much into small trials that might not yield statistically meaningful results. “There’s such pressure,” he says. “There’s this incredibly pressing and desperate need — we all feel that anxiety.”