What exactly is long COVID, and who is at risk? This NIH project may discover

Scientists with the RECOVER Initiative claim to be working as quickly as possible to find solutions.

SARS-CoV-2 infection can saddle people with persistent symptoms. An ongoing NIH effort will examine the long-term health effects of infection.  WILDPIXEL/GETTY
SARS-CoV-2 infection can saddle people with persistent symptoms. An ongoing NIH effort will examine the long-term health effects of infection.  WILDPIXEL/GETTY

You may have heard about the recent big long COVID news: According to a Scottish study, approximately half of people infected with SARS-CoV-2 have not fully recovered six to 18 months after infection. That outcome confirms what many doctors and patients have been saying for months. Long COVID is a serious issue that affects a large number of people.

However, finding treatments for a disease that is still so poorly defined is difficult (SN: 7/29/22). A major research effort in the United States is attempting to change that. And one of my colleagues, Macon Morehouse, News Director at Science News, got a sneak peek into the process.

Morehouse has donated 15 vials of blood, two urine specimens, and a saliva sample in the last two months. Technicians took her blood pressure, oxygen level, height, weight, and waist circumference, as well as how many times she could stand from sitting in 30 seconds. Morehouse is not ill, nor is she collecting health data. She's doing it for science's sake.

RECOVER has been chastised by some scientists and patients for moving too slowly. Katz, who has recovered from long periods of COVID, says he understands. "We began about a year and a half ago, and we still don't have definitive answers," he says. "I understand how disappointing it is for people who have been suffering."

But, with more than 400 doctors, scientists, and other experts involved, roughly 180 sites across the country enrolling participants, and a grant timeline that disrupted the usual order of events, Katz says the old adage about building the plane while flying fits. "We're working extremely hard to move as quickly as possible."

Looking for solutions

Other aspects of the initiative have recently begun to shine. According to an analysis of electronic health records, children under the age of five, those with certain medical conditions, and those who have had severe COVID-19 infections may be most at risk for long COVID, according to researchers who published their findings in JAMA Pediatrics in August. A separate study of health records suggests that vaccinated adults have some protection against long COVID, even if they have a breakthrough infection. This month, scientists published their findings on medRxiv.org in a study that has yet to be peer-reviewed.

These studies make use of previously collected data. The majority of the RECOVER studies will take longer because scientists will follow patients for years while analyzing data. "These are observational, long-term studies," Katz explains. "There's no intervention; we're just trying to figure out how long COVID is."

Nonetheless, Katz anticipates seeing early results later this fall. By then, scientists should have a formal, if hazy, definition of long COVID, which could aid doctors in diagnosing the disease. Katz believes that by the end of the year, RECOVER will have answers about viral persistence — whether coronavirus relics left in the body can reboot symptoms.

According to Kanecia Zimmerman, a pediatric critical care specialist at the Duke Clinical Research Institute in North Carolina, the project has recently sprouted the arm of a clinical trial, which may launch this winter. One of the first trials planned will see if an antiviral therapy that removes SARS-CoV-2 from the body helps patients who have persistent symptoms.

Though RECOVER is a significant effort to better understand long COVID, progress will necessitate research — and ideas — from a diverse group of scientists, according to Diane Griffin, a microbiologist at the Johns Hopkins Bloomberg School of Public Health in Baltimore and member of the Long COVID Research Initiative who is not involved in the project. "Just because we've invested in this one big study doesn't mean we'll get all the answers," she says.

However, data from study participants such as Morehouse and the nearly 10,000 other adults who have already enrolled in RECOVER will be useful. Meanwhile, Griffin emphasizes the importance of continuing to support long-term COVID research. "That's the only way we're ever going to figure this out."

Morehouse is involved in a long-term COVID study at Howard University in Washington, D.C. It's part of a multi-pronged project aimed at determining the long-term health effects of COVID-19. The National Institutes of Health launched the RECOVER Initiative last year with the goal of enrolling approximately 60,000 adults and children. Morehouse is volunteer No. 182 at the Howard site.

Among study participants, she is something of a unicorn: Morehouse, as far as she knows, has never had COVID-19. According to Stuart Katz, a cardiologist and RECOVER study leader at NYU Langone Health in New York City, about 10% of participants will eventually avoid the virus. Scientists are still recruiting volunteers, but "omicron made it more difficult to find uninfected people," he says.

RECOVER Scientists require participants like Morehouse so that they can compare them to people who have developed long COVID. That could reveal what the disease is and who is prone to contracting it. "Our goals are to define long COVID and to understand your risk of getting [it] after COVID infection," Katz explains. Their findings could pave the way for the development of treatments.

Timeline constraint

During the first year of the pandemic, doctors noticed that some COVID-19 patients developed long-term symptoms like brain fog, fatigue, and chronic cough. Katz and other physicians and scientists met in December 2020 to discuss what was known. The answer was, as it turned out, not much. "This is a new virus," he claims. "No one knew what it was capable of." At the same time, Congress approved $1.15 billion for the NIH to study the long-term health effects of COVID-19.

Five months later, the agency had awarded nearly $470 million to NYU Langone Health to serve as the hub for its lengthy COVID studies. "Everything was on a very, very tight timeline," Katz says. NYU then rushed to develop a study plan that included three main groups: adults, children/families, and tissue samples from people who died after being exposed to COVID-19. Katz describes the project as "not your typical research project." "We were tasked with researching a disease that had no definition."

RECOVER has now enrolled slightly more than half of its target population of 17,680 adults. Katz hopes to complete this project by the spring of 2023. The project's focus on children has yet to be completed. According to Diana Bianchi, director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and a member of RECOVER's executive committee, the goal is to enroll nearly 20,000 children; so far, they have around 1,200. 


C.E. Hastie et al. Outcomes among confirmed cases and a matched comparison group in the Long-COVID in Scotland study. Nature Communications. Vol. 13, October 23, 2022. doi: 10.1038/s41467-022-33415-5. 

M.D. Brannock et al. Long COVID risk and pre-COVID vaccination: An EHR-based cohort study from the RECOVER program. medRxiv.org. Posted October 7, 2022. doi: 10.1101/2022.10.06.22280795. 

S. Rao et al. Clinical features and burden of Postacute sequelae of SARS-CoV-2 infection in children and adolescents. JAMA Pediatrics. Vol. 176, August 22, 2022, p. 1000. doi: 10.1001/jamapediatrics.2022.2800.


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