As institutions around the world struggle to coordinate meaningful trials of potential long-term COVID-19 treatments, researchers continue to tally the toll, and new findings suggest the disease's reach isn't just longer, it's continuing to grow.
Three years after first being infected with COVID-19, patients who have been hospitalized with the virus remain at “significantly elevated” risk of death or deterioration from long-term COVID-19 complications, according to a study published May 30 in the journal Nature Medicine.
The researchers found that the threat of Long COVID and some of its associated problems remain real, even among people whose early cases did not require hospitalization. And cumulatively, over three years, Long COVID results in 91 Disability-Adjusted Life Years (DALYs) per 1,000 people. DALYs are a measure of years lost due to poor health or premature death, a higher incidence than heart disease or cancer.
“People are developing new illnesses because of infections they had three years ago,” said Dr. Ziyad Al Ali, a clinical epidemiologist at Washington University in St. Louis and lead author of the study. “This research calls into question the idea that these viruses are self-contained or that they become unimportant after the initial acute phase.”
The study, which involved more than 130,000 patients, is the largest to date to track the progression of the virus over three years. It builds on Al Ali and his colleagues' work in the second year, which found that patients were at increased risk of symptoms associated with long COVID-19, including diabetes, lung disease, fatigue, blood clots, gastrointestinal problems and musculoskeletal disorders.
Al Ali told Fortune that three years later, the main complications for people who experienced mild initial COVID-19 symptoms were in the neurological, gastrointestinal and respiratory systems, while among those who had been hospitalized, the persistent risk was spread across seven organ systems and included more severe conditions such as stroke, heart attack, heart failure and even Alzheimer's disease.
The study included nationally renowned researcher Al Ali and co-author Dr. Eric Topol, vice president and professor of molecular medicine at the Scripps Research Institute. The study was conducted among patients at the VA St. Louis Healthcare System, which means the demographics skewed toward males, whites and slightly older patients than other patient studies, scientists noted.
“The data is encouraging that no new health problems were found even three years after infection,” says Akiko Iwasaki, director of the Center for Infection and Immunity at the Yale University School of Medicine. But Iwasaki, who was not involved in the study, cautions that illnesses following acute infection can sometimes not show up for years. “This kind of long-term follow-up study will need to continue for a longer period of time,” she says.
Hospitalized patients face increasing health challenges
Perhaps unsurprisingly, early COVID-19 patients who required hospitalization faced the greatest difficulties over the three-year study period, a stark reminder of the importance of interventions such as vaccinations and antiviral drugs, Al Ali said. (All study participants were enrolled in 2020, meaning most were infected before vaccines and antiviral drugs were available.)
“The situation is much more severe for hospitalized patients,” the researchers say. “They are at greater risk and have a longer period of risk, and their disease burden is astronomically higher than in uninfected and non-hospitalized people. Preventing hospitalization is crucial.”
The study found that the risk of new long-COVID complications declined over time in both hospitalized and non-hospitalized patients, “which is good news,” Al-Ali said. Meanwhile, for people who didn’t need to go to the hospital—most people who had COVID—the risk of death was “negligible” after a year.
But for patients who required hospitalization, the threat of death “remained elevated even at the third year,” the researchers say. Patients who required hospitalization faced a much greater health burden, about 90 DALYs per 1,000 people, compared with about 10 DALYs per 1,000 people for non-hospitalized patients. (For comparison, heart disease and cancer both cause about 50 DALYs per 1,000 people.)
“The difference in DALYs between the two groups should not be interpreted to mean that people who developed long COVID from a less severe acute illness are not suffering significantly as a result of their long COVID symptoms,” said Dr. David Putrino, director of the Cohen Complex Chronic Disease Recovery Center at the Mount Sinai School of Medicine. “It just means that three years later they are experiencing significantly less life-threatening sequelae than those who initially required hospitalization.”
The persistent presence of long COVID-19 strengthens the idea that this is no ordinary virus: Scientists believe that viral persistence, chronic inflammation and a dysfunctional immune system are all involved, but more research is needed.
What are the prospects for tackling Long COVID?
As for the question of what Long COVID actually means — how long it lasts — Al-Ali said the science is still evolving, describing it as “a complex web of more than 80 health problems,” some of which can have lifelong negative effects on patients, like stroke and heart disease.
“We don't know what we don't know,” Al Ali said. “This is three years out. We don't know what's going to happen in 10 years.” The group hopes to convince funders to continue following the patient cohort for at least that long, he said.
For these and other reasons, researchers have led a drive to accelerate trials of long-term COVID-19 treatments, though earlier efforts have been criticized as wasting money and precious time. Appearing before a U.S. Senate committee in January, Al Ali told committee members that at least 20 million people in the country are on long-term COVID-19 treatments. Globally, the number is estimated to be at least 65 million.
The meeting was notable because it was the first congressional hearing on Long COVID since the pandemic began, and researchers hope their latest work will bring renewed attention to the disease, which has a long, unpredictable future, and prompt the National Institutes of Health to put more effort into the issue.
“We need to be bolder and more ambitious in our experiments,” Al Ali said. “If we continue at our current slow pace, we are unlikely to have definitive answers for decades to come.”
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