Long COVID is real – and complex. A major study aims to untangle its causes.

CU researchers see RECOVER as a big step along the path to better treatments and understanding of long COVID.
April 12, 2023
Long COVID’s symptoms are diverse – and unsettlingly common: the UCHealth Post-COVID Clinic alone has seen nearly 1,200 patients so far. The University of Colorado School of Medicine site of the national RECOVER long-COVID study is working to understand the roots of long COVID and tailor treatments for it.
Long COVID’s symptoms are diverse – and unsettlingly common. The UCHealth Post-COVID Clinic alone has seen nearly 1,200 patients so far. The University of Colorado School of Medicine site of the national RECOVER long-COVID study is working to understand the roots of long COVID and tailor treatments for it. Photo: Getty Images.

Rarely has a clinical trial’s name better signaled its ultimate aims. But then, a billion-dollar study deserves a first-rate acronym, too.

RECOVER is the name. It stands for Researching COVID to Enhance Recovery. Its focus is on understanding long COVID – a wide swath of maladies whose roots lay in infection with the SARS-CoV-2 virus that swept the planet starting in late 2019 and continues to mutate and spread, if much less aggressively than during the pandemic. Each infection or reinfection opens the door to long COVID (also called post-acute sequelae SARS-CoV-2 infection, or PASC). We may have moved on from COVID, but COVID has not moved on from us.

The number of long-COVID cases is hard to nail down, but it’s big. One review, which considered 194 studies totaling 735,000 participants, found that, “on average, at least 45% of COVID-19 survivors, regardless of hospitalization status, went on to experience at least one unresolved symptom” an average of four months after infection. The U.S. Centers for Disease Control and Prevention says 19% of those who reported having COVID-19 in the past have long-COVID symptoms. Another review estimates that 10% to 30% of non-hospitalized cases, 50% to 70% of hospitalized cases, and 10% to 12% of vaccinated cases end up with long COVID. Considering that as many as 94% of U.S. residents have gotten the coronavirus at some point, these percentages yield millions of people.

The University of Colorado School of Medicine is one of 86 medical centers around the country participating in the four-year, $1.15 billion National Institutes of Health RECOVER study. It has enrolled more than 12,000 people so far. The CU School of Medicine site at UCHealth University of Colorado Hospital on the Anschutz Medical Campus (UCH) has signed up about 240 patients and counting.

Many health conditions under the long COVID umbrella

Dr. Kristine Erlandson
Dr. Kristine Erlandson, an infectious disease specialist, leads the CU School of Medicine site for the RECOVER trial at UCHealth University of Colorado Hospital.

RECOVER will probably be the largest U.S. trial of its kind, says Dr. Kristine Erlandson, the infectious disease specialist who leads the study’s Colorado site. The study’s size and its inclusion of a control group of those who never had COVID-19 are important, she says. RECOVER’s leaders have also made an effort to enroll populations that have been underrepresented in many previous COVID studies, such as Hispanic/Latino populations and rural residents. While the study is ongoing, Erlandson says it has enormous potential to help future long-COVID patients.

“I think it’s going to be very important to the field,” she said. “I think there will be, eventually, thousands of papers that leverage this RECOVER cohort to really advance our knowledge of long COVID.”

Improving the diagnosis and treatment of long COVID will be important to millions of people. The disease best known for its spread by the lungs can also impact a wide range of bodily systems over time: the immune system, the brain and neurological system, the gastrointestinal tract, the heart and circulatory system, and the reproductive system among them.

A recent, comprehensive review listed a few of the “multiple adverse outcomes” under the long COVID umbrella: cardiovascular, thrombotic (blood clot-related), and cerebrovascular (brain-related) disease, type 2 diabetes, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and dysautonomia (especially postural orthostatic tachycardia syndrome, or POTS). That’s just a small selection of a long list of documented long-COVID symptoms.

Some are easier to treat than others. Some may last for years. Some, such as ME/CFS and dysautonomia, which renders up to 75% of those with the severe form of the disease unable to work, “are expected to be lifelong,” as the authors put it.

Long COVID broke into five maladies

Critical-care medicine specialist Dr. Sarah Jolley, medical director of the UCHealth Post-COVID Clinic, is co-author of a forthcoming RECOVER-based study that assigns many of the long COVID-related maladies into five domains, she says. They include:

  • ME/CFS including post-exertional malaise (PEM).
  • Dysautonomia and POTS.
  • Neurocognitive symptoms (such as “brain fog”).
  • Cardiopulmonary exercise intolerance.
  • Persistent olfactory (related to the ability to smell) problems.

Jolley has seen them all. She has consulted with about 1,200 patients since the UCHealth Post-COVID Clinic launched in 2020.

“A lot of those same symptoms that were described early on have been solidified into discrete syndromes that come under the umbrella of long COVID,” Jolley said.

Dr. Sarah Jolley, who specializes in critical-care medicine, is medical director of the UCHealth Post-COVID Clinic.
Dr. Sarah Jolley, who specializes in critical care medicine, is the medical director of the UCHealth Post-COVID Clinic.

Goal: better treatments for people with long COVID

Some patients have just one long-COVID symptom, such as neurocognitive problems, she says. Others have several. Some recover completely over a period of weeks or months. “And then we’re seeing some people who have persistent symptoms three years out,” Jolley said.

The RECOVER trial is still recruiting at UCHealth but it’s now focusing on patients recently diagnosed with COVID-19, Erlandson says. The idea is that, by tracking patients from the time they get the disease, researchers can make connections between types of patients (in terms of demographics, prior health status, and the results of laboratory and other testing) and the long-COVID symptoms that may or may not later manifest, she says. That can help tailor treatments going forward.

There are already treatments out there, Jolley says. They depend on how cases of long COVID manifest and what the suspected causes are. In cases where there may be a lingering virus, an antiviral such as Paxlovid may come into play. If inflammation looks to be the culprit, an anti-inflammatory such as metformin (a drug best known for diabetes treatment) may be the preferred approach. Those with chronic-fatigue symptoms may benefit from low-dose naltrexone. The RECOVER study’s data should help doctors refine diagnoses and point the way to better tools to help patients, Jolley says.

“Having that biological data, paired with the trial’s data, will help us understand how to individualize treatment even more,” she said.

Some of that data may come from studies of RECOVER participants at UCH. The first follow-on study, slated to launch this summer, will involve the antiviral Paxlovid, Erlandson says.

The impact of such research could extend beyond COVID-19 survivors, she says. For one thing, long COVID’s impact on diverse systems has brought multidisciplinary care to the fore. The UCHealth Post-COVID Clinic taps into experts in virology, infectious disease, neurology, cardiology, psychiatry, and other fields, for example.

“I am hopeful that the things we learn about long COVID will help us care for patients in a more multidisciplinary manner,” Erlandson said.

She adds that the RECOVER study could help pay forward the help that long-COVID patients have gotten from treatments developed for chronic fatigue, post-Lyme, and other post-viral syndromes.

“I think what we can learn from long COVID can help people who are impacted by the chronic effects of other viruses, too,” Erlandson said.

About the author

Todd Neff has written hundreds of stories for University of Colorado Hospital and UCHealth. He covered science and the environment for the Daily Camera in Boulder, Colorado, and has taught narrative nonfiction at the University of Colorado, where he was a Ted Scripps Fellowship recipient in Environmental Journalism. He is author of “A Beard Cut Short,” a biography of a remarkable professor; “The Laser That’s Changing the World,” a history of lidar; and “From Jars to the Stars,” a history of Ball Aerospace.