Three years after their initial bouts with COVID-19, patients who’d once been hospitalized with the virus remained at “significantly elevated” risk of death or worsening health from long COVID complications, according to a paper published May 30 in Nature Medicine.

Even among those whose initial cases didn’t require a hospital stay, the threat of long COVID and several of its associated issues remained real, the researchers found. And cumulatively, at three years, long COVID results in 91 disability-adjusted life years (DALY) per 1,000 people— being a measure of years lost to poor health or premature death. That is a higher incidence than either heart disease or cancer.

“People are developing new-onset disease as the result of an infection that they had three years ago,” says Dr. Ziyad Al-Aly, a clinical epidemiologist at Washington University in St. Louis and lead author of the study. “It challenges the notion that these viruses are sort of self-contained or that after the acute first phase, they become inconsequential.”

With more than 130,000 patients, the study is by far the largest so far to track the progress of the virus over a full three-year period. It expands on work by Al-Aly and others at the two-year mark that found patients had elevated risk for long-COVID-related conditions that included diabetes, lung problems, fatigue, blood clots, and gastrointestinal and musculoskeletal disorders.

At three years, Al-Aly tells Fortune, the primary complications among those with mild initial COVID cases were found in the neurological, GI, and pulmonary systems. The persistent risk among those who’d been hospitalized, meanwhile, extended to seven organ systems and included severe conditions such as strokes, heart attacks, heart failure, and even Alzheimer’s disease.

The study included nationally recognized researchers Al-Aly and coauthor Dr. Eric Topol, executive vice president and professor of molecular medicine at Scripps Research. It drew from patients within the Veterans Affairs St. Louis Health Care system. As such, the scientists note, the demography skews more male, white, and slightly older than other patient studies might.

“The data are encouraging in that there were no new-onset adverse health problems found in the third year 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, cautioned that some post-acute infection illnesses can turn up years later: “We will need to keep this type of long-term follow-up studies for extended periods.”

More health challenges for hospitalized patients

Perhaps unsurprisingly, those whose initial COVID cases required hospitalization faced the greatest challenges over the course of the three-year study, a grim reminder that interventions like vaccinations and antivirals are critical, Al-Aly says. (Those in the study were all enrolled during 2020, meaning they were infected largely before vaccines and antivirals were available.)

“The story in hospitalized people is more stark,” the researcher says. “They have greater risk and longer risk horizon, with a burden of disease that is astronomically higher than non-infected people and higher than non-hospitalized individuals. Preventing hospitalization is very important.”

The risk of new long COVID complications declined over time for both hospitalized and non-hospitalized patients, the study found. “That’s the good news story,” says Al-Aly. The risk of death, meanwhile, became “insignificant” after the first year among those who didn’t have to go to a hospital—that is, most of us who’ve ever been infected by COVID.

For those whose cases required hospitalization, though, the threat of death “remained persistently elevated even in the third year,” the researchers said. That group also faced far greater burden of health—about 90 DALYs per 1,000 people, compared to about 10 DALYs per 1,000 for the non-hospitalized group. (For context, both heart disease and cancer cause about 50 DALYs per 1,000 people.)

“The difference in DALYs between the two groups should not be interpreted to mean that people with long COVID from less severe acute disease are not suffering greatly as a result of their long COVID symptoms,” says Dr. David Putrino, director of the Cohen Center for Recovery from Complex Chronic Illness at Mt. Sinai School of Medicine. “It only means that at three years out, they’re experiencing less overtly life-threatening sequelae” than those who initially required hospitalization.

The stubborn presence of long COVID reinforces the notion that this is no ordinary virus. Viral persistence, chronic inflammation, and immune system dysfunction are all thought by scientists to come into play, though more study is needed.

What is the outlook for tackling long COVID?

As for the question of what the term long COVID actually means—that is, how long it lasts—the science is still developing, Al-Aly says. He describes long COVID as “this sort of complex web of 80 or more different health problems,” some of which, like stroke or heart disease, could negatively affect patients for the rest of their lives.

“We don’t know what we don’t know,” says Al-Aly. “This is only at three years… We don’t know what’s going to happen at 10 years.” The research group is hoping to persuade its funders to continue following the patient cohort for at least that long, he said.

For these and other reasons, researchers have led the charge to accelerate the pace of trials for long COVID treatments, the early efforts at which have been criticized for wasting money and critical time. Appearing before a U.S. Senate committee in January, Al-Aly told committee members that at least 20 million people in the country have been hit with long COVID. Globally, that number is estimated to be at least 65 million.

That meeting was noteworthy in part because it represented the first Congressional hearing on long COVID since the start of the pandemic. Researchers hope that this latest study will again focus attention on a disease with a long tail and an unknowable future, and perhaps prod the National Institutes of Health to take a bigger swing at the issue.

“We need to be much bolder and much more ambitious with our trials,” Al-Aly says. “At the glacial pace that they’re going, we’re unlikely to get any definitive answers for decades to come.”