Can drugs and vaccines reduce the sequelae of COVID-19 infection?

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Nature: Can drugs and vaccines reduce the sequelae of COVID-19 infection?

Early in the COVID-19 pandemic, urologist and clinical epidemiologist Kari Tikkinen found that all the surgeries on his surgical schedule had been canceled, so he took some time off. Tikkinen’s mentor at the University of Helsinki advises: “Do what you think will work best.” Tikkinen is therefore involved in clinical trials for COVID-19.

Before the public learns about long COVID, Tikkinen sees a need to follow study participants for months after they recover. He wants to monitor the long-term side effects of these drugs. “Soon, it will become clear that this research is not just about safety,” Tikkinen said.

Now, Tikkinen and others want to learn more about whether emergency treatment for COVID-19 can reduce the risk of developing symptoms in the coming months. Charlotte Summers, an intensive care specialist at the University of Cambridge, UK, said: “This is an urgent health problem that needs attention.”

The diversity of coronavirus in a single host is underestimated

Debilitating symptoms

Long COVID, also known as acute sequelae of COVID-19, usually refers to symptoms of COVID-19 lasting more than three months. Research on this lags behind studies in the acute infection phase.

Long COVID ranges from mild reactions to severe debility. Researchers have proposed different reasons for this, ranging from lingering viral hosts, autoimmunity, to tiny blood clots. Many believe this is the result of a combination of factors. Danny Altmann, an immunologist at Imperial College London, said: “All research into the mechanisms of long COVID takes a while. It’s hard to piece together the big picture.”

Vaccines are by far the best way to prevent long COVID symptoms. The COVID-19 vaccine reduces the risk of contracting SARS COV-2 and may reduce the risk of later infection in recipients. Several studies have focused on this issue: while their results vary, overall trends suggest that vaccination reduces the risk of reinfection by about half.

For example, one study, which has not yet been peer-reviewed, found that vaccination reduced the odds of developing long COVID by about 41%. The study included more than 3,000 participants who had previously completed two doses of the COVID-19 vaccine but were still infected with SARS-CoV-2.

But Altmann said that still left too many people at risk of long COVID. “Half the situation is not optimistic. I have been hoping that the COVID-19 epidemic will turn the page,” he said.

Early treatment

Beyond vaccination, it’s unclear whether existing COVID-19 treatments will work for long COVID. In theory, a drug that reduces the severity of the disease would also reduce the severity of long-term symptoms, Altmann said. But SARS-CoV-2 is not always associated with acute and severe illness. “There are a lot of people who are infected with SARS-CoV-2, and they’re going to be asymptomatic or near-asymptomatic. It’s really tough to deal with,” he said.

Still, some studies are planned to look at the effects of early treatment with antiviral drugs on long COVID. A clinical trial called PANORAMIC has been testing the efficacy of the oral antiviral drug molnupiravir, co-developed by Merck and Ridgeback, in treating the severity of COVID-19. While that wasn’t the study’s primary goal, the researchers collected data from participants three and six months after treatment to determine whether the drug would reduce the risk of long COVID.

Likewise, Pfizer conducted two trials of its antiviral drug Paxlovid, which included six-month follow-up.

These antiviral drugs are often used to treat COVID-19 patients with relatively mild symptoms. Tikkinen and his colleagues wanted to learn more about the long-term effects of the treatment in those hospitalized patients.

His team is following up with participants in a trial at the University of Helsinki as part of the WHO-led SOLIDARITY study. In the coming weeks, Tikkinen hopes to deliver results from a one-year follow-up study of participants hospitalized with COVID-19 who were treated with remdesivir.

Tikkinen’s team will also follow up with participants in two other studies of the SOLIDARITY study, one testing the immunosuppressive drug infliximab and the other imatinib, a drug that helps reduce inflammation in blood vessels.

However, Tikkinen cautioned that none of these studies had enough participants to provide clear data on the impact of long COVID. His team took the extraordinary step of contacting participants months after they received remdesivir to fill out a survey about their condition.

The team simplified how to fill out the survey, translated the questions into 10 languages, and delivered them to participants’ homes. 95% of participants provided feedback. That percentage of feedback is already very high for such a long-term study, Tikkinen said. But since the original study only enrolled about 350 people, the data was too sparse to provide a firm conclusion.

Small scale test

Researchers hope to find more treatments to reduce long COVID risk.

A large UK trial called ‘HEAL-COVID’ is testing two drugs targeting the cardiovascular system of patients hospitalized with COVID-19. One of these drugs is called apixaban, which is an anticoagulant. Another is atorvastatin, a cholesterol-lowering drug that can also be used to treat inflammation of blood vessels.

The study will examine whether the two treatments reduce hospitalization and mortality one year after the patient’s first discharge. Of those discharged after treatment, nearly a third were readmitted within 6 months, and 12% died within 6 months of their initial discharge.

“The most likely cause of death after hospitalization was a problem with cardiorespiratory fitness,” said Summers, who led the study.

Ayodeji Adegunsoye, a pulmonologist and intensivist at the University of Chicago in Illinois, observed that critically ill patients who were hospitalized with COVID-19 and needed oxygen had an increased likelihood of scar tissue hyperplasia, known as fibrosis, in the lungs after they recovered.

He is testing an immunosuppressive drug called sirolimus in these people, which is also sometimes used in organ transplant recipients. Ayodeji Adegunsoye hopes the drug will block the migration of cells that promote lung fibrosis.

By nature, research on long COVID requires patience, a common definition of which is that some symptoms that develop after an acute infection persist for more than 12 weeks.

Altmann is optimistic that the research will progress this year. But he also cautioned against overinterpreting small trials that might not produce statistically significant results.