RECOVER’s mid-year milestones: A look at 2025 progress

During the first half of 2025, the RECOVER Initiative continued to advance our understanding of Long COVID across its 5 different types of studies. The continued progress of this ongoing work is due to the dedication of the many people who are part of RECOVER—including research teams, study site staff, and members of the Long COVID community—who carry forward the initiative’s mission to understand, diagnose, prevent, and treat Long COVID.

This year, RECOVER has met or approached enrollment goals for several of its clinical trials, launched new pathobiology studies, and continued seeking participants for additional clinical trials and its tissue pathology (autopsy) study. Researchers and biostatisticians are collaborating on plans to analyze study data and make more important discoveries about Long COVID. These discoveries have resulted in publications in leading scientific journals like the Journal of the American Medical Association (JAMA) Pediatrics and Nature Communications, with additional results and publications expected during the coming months.

Observational studies provide insight into risk of Long COVID and other chronic conditions

After completing enrollment for its pediatric study group late last year, researchers across RECOVER’s observational studies spent the first half of this year continuing various analyses of study data from adult, pregnant, and pediatric participants. Findings from these studies provide deeper insight into who is affected by Long COVID and the wide range of Long COVID symptoms that different groups of people experience.

In the first 6 months of 2025, RECOVER researchers published 15 research papers in scientific journals to report findings from observational studies and electronic health record (EHR) studies. Some key discoveries from the RECOVER observational studies include:

• Females were more likely to have Long COVID symptoms than males. Researchers discovered that the risk of getting Long COVID was higher in females aged 40 to 54 and females who had not gone through menopause. Watch the Discover RECOVER videos that summarize this research, available in English and Spanish.
• Adults who had COVID-19 were more likely to develop a chronic condition called myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) compared to those who didn’t have COVID-19. ME/CFS symptoms can be very severe and are often similar to forms of Long COVID. The study found that new cases of ME/CFS were 15 times higher than before the COVID-19 pandemic. Watch the Discover RECOVER videos on this research, available in English and Spanish.
• The most common Long COVID symptoms experienced by children 0 to 5 years old can be different from those experienced by older children and adults. Additionally, infants (aged 0 to 2) were likely to experience different Long COVID symptoms than preschool-aged children (aged 3 to 5). Watch the Discover RECOVER video that provides an overview of this research.

This spring, RECOVER closed its Digital Health Program, which collected data from observational study participants through FitBits (devices that people can wear on their wrists that monitor different measures of health). Although this portion of the study is now complete, RECOVER’s observational studies are ongoing. Participants continue to attend regular study visits and complete surveys to help RECOVER better understand, diagnose, prevent, and treat Long COVID.

3 clinical trials closed enrollment while additional trials continue to seek study participants

• Both the RECOVER-VITAL and RECOVER-NEURO trials have officially closed. Data from these trials are currently under review, with results expected later this year. RECOVER-VITAL is studying whether antiviral medication Paxlovid can be used to treat Long COVID. RECOVER-NEURO focuses on how the virus that causes COVID-19 affects the brain and is testing possible treatments to improve brain function for people with Long COVID.
• The RECOVER-AUTONOMIC Severe POTS (IVIG) and RECOVER-AUTONOMIC Moderate POTS (Ivabradine) trials have exceeded monthly enrollment goals for 5 consecutive months. Both trials are on track to complete enrollment this summer. RECOVER-AUTONOMIC is studying possible treatments for adults who have a Long COVID-related autonomic nervous system disorder called postural orthostatic tachycardia syndrome (POTS). POTS can cause a range of symptoms, including dizziness, fatigue (extreme tiredness), or a fast heart rate. See the RECOVER-AUTONOMIC study record on ClinicalTrials.gov.
• The RECOVER-ENERGIZE Post-Exertional Malaise (Structured Pacing) trial completed enrollment of 300 participants in May—2 months ahead of schedule. The RECOVER-ENERGIZE Exercise Intolerance (Personalized Cardiopulmonary Rehabilitation) trial continues to actively recruit participants at more than 40 sites across the country. RECOVER-ENERGIZE is focused on understanding exercise intolerance and post-exertional malaise (PEM), or symptoms that get worse after physical, mental, or emotional activity. The trials are testing possible treatments to improve quality of life and daily functioning for people who experience these conditions. See the RECOVER-ENERGIZE study record on ClinicalTrials.gov.
• RECOVER-SLEEP Hypersomnia (Modafinil/Solriamfetol) and RECOVER-SLEEP Complex Sleep Disturbances (Melatonin + Light Therapy)—the 2 largest RECOVER clinical trials—are making steady progress with enrolling participants at more than 45 sites in the US. The RECOVER-SLEEP trials are focused on sleep disturbances related to Long COVID, including problems falling and staying asleep, feeling very sleepy or tired during the day, or an irregular sleep-wake schedule. See the RECOVER-SLEEP study record on ClinicalTrials.gov.

If you would like to be considered to participate in one of these RECOVER clinical trials, please contact study sites listed on each trial’s study record on ClinicalTrials.gov (linked above) or email RECOVERresearch@duke.edu.

Tissue pathology (autopsy) study enables researchers to assess changes inside the body

The RECOVER tissue pathology (autopsy) study continues to enroll people who died after having COVID-19, with 252 study participants enrolled as of late June. People are enrolled in this study after they die when their families or caregivers give permission for them to participate in the study. The study will continue enrolling participants until January 2026.

The tissue pathology (autopsy) study examines the pathology of Long COVID, or the causes, nature, and effects of the condition. This work, which is still in early stages, can provide insights into the origins of Long COVID and how SARS-CoV-2 (the virus that causes COVID-19) can change different parts of the body. 

As part of this research, participating RECOVER study sites are expected to gain access to the new Digital Slide Archive this month. The Digital Slide Archive is a database of slides that contain biosamples, or tissues contributed by study participants. Researchers will be able to view and analyze these slides online.

The initial slides were stained with special chemical dyes, enabling investigators to examine changes such as swelling, breakdown of tissue, and blood clots. The first unstained slides, which will enable researchers to make special stains to view different parts of the tissues, will be distributed to investigators in August.

Pathobiology launches newly funded studies

NIH awarded funding for 20 new Long COVID pathobiology studies through Research Opportunity Announcements (ROAs). Pathobiology is the study of the biological mechanisms—or processes that take place inside the body and its cells—to understand how Long COVID and various symptoms may develop. These one-year studies, which began in March, will use data and biosamples, such as saliva, blood, and urine, collected from RECOVER’s observational studies. The newly funded studies will continue to expand and build upon the existing RECOVER samples and data analyses. These studies provide important insights into how to treat Long COVID.

Review the full list of funded studies.

Researchers continue to analyze electronic health records to learn more about Long COVID

RECOVER researchers have access to over 60 million patient records through collaborations with national electronic health record (EHR) networks. About 40 health systems in the National Patient-Centered Clinical Research Network (PCORnet®) collaborate to learn more about Long COVID by analyzing EHRs from 2 groups of children and adults, with each group being 20 million people strong. Together with another EHR network, the National COVID-19 Cohort Collaborative (N3C), these researchers collectively continue to make strides in understanding Long COVID.

PCORnet® Adult and Pediatric EHRs

This year, as results emerge from RECOVER’s observational studies, EHR researchers have had the opportunity to compare these findings with earlier findings from EHR research. “It’s been gratifying to see many of our results confirmed in this different population,” said Dr. Charles Bailey, co-principal investigator of the PCORnet® pediatric cohort. “We now have 2 lines of evidence that show us many important things about Long COVID.”

Currently, pediatric EHR researchers are using data from health records to better understand which groups of children may be more likely to develop specific types of Long COVID. For example, an early study showed how multisystem inflammatory syndrome in children (MIS-C)—a serious complication of COVID-19)—more often appeared in children who had specific variants of COVID-19. Ongoing research is also exploring whether having COVID-19 affects children’s risk for developing other health conditions, such as certain types of cancer, heart problems, or slowing of growth.

Another area of research enables investigators to examine how specific medications may influence the risks of developing Long COVID in children. In these studies, called target trial emulations, investigators use real-world data from EHRs to conduct research that is similar to a clinical trial but without the cost and time associated with conducting an actual trial. Researchers can study health records from children who have taken certain medications and understand whether those children later developed Long COVID less often than similarly healthy children who did not. This approach can help researchers pinpoint promising medications that could be tested in future clinical trials like RECOVER-Treating Long COVID (TLC).

View the list of recent publications using data from the pediatric EHR cohort.

National COVID Cohort Collaborative (N3C)

The scientific journal Lancet Digital Health accepted a manuscript detailing major updates to N3C’s Long COVID computable phenotype. A computable phenotype is a product powered by a computer program called a machine learning algorithm. The algorithm can define and identify cases of Long COVID based on symptoms and other patterns within the EHR.

The study team created its original algorithm to identify Long COVID symptoms and symptom patterns early in the pandemic, when there was less understanding that people can be reinfected with COVID-19 multiple times. As a result, the original model focused its “search” for Long COVID in EHRs only on a person’s first instance of COVID-19. The new algorithm aligns more closely with evolving understandings of COVID-19. Researchers also wanted to prevent the model from mistaking COVID-19 reinfections for Long COVID. The study team redesigned their model to correctly account for reinfections in 2023.

In collaboration with researchers from adult and pediatric groups from PCORnet®, the N3C team is working on target trial emulations to understand whether taking certain medications had an impact on which people developed Long COVID. Thus far, researchers have focused on medications for attention deficit and hyperactivity disorder (ADHD), as well as naltrexone, a medication commonly used to manage alcohol and opioid use disorders. These studies explore whether these medications could help prevent Long COVID, and final results will soon be publicly available. The research team plans to start work on 2 additional TTEs between now and the end of the year.

N3C is working on 4 joint analyses with investigators from PCORnet® and other RECOVER studies. Final results are expected to be available this year. The topics under examination include:

• Heart-related complications after COVID vaccination.
• Major negative heart events following SARS-CoV-2 infection (the virus that causes COVID-19).
• How Long COVID affects the health of pregnant women and their babies.
• How often people develop rare cancers following COVID-19 infection. 

Network of Biostatisticians for RECOVER develops plans to analyze study data

At the beginning of 2025, biostatisticians and researchers from the 8 Network of Biostatisticians for RECOVER (NBR) nodes completed an extensive training course on RECOVER study design and best practices for analyzing RECOVER data. Since completing the training, NBR researchers have worked closely with RECOVER study investigators to develop plans for analyzing the study data. These plans represent a critical step in answering important questions about Long COVID.

In May, RECOVER biostatisticians at Massachusetts General Hospital and Harvard Medical School hosted a forum and met with NBR investigators to collaborate on their study analysis plans and discuss statistical challenges in Long COVID research.

RECOVER Representatives continue to contribute to the initiative

In late 2024 and early this year, RECOVER welcomed 38 new Representatives. Representatives include Long COVID patients, caregivers, and advocates, as well as members of the Long COVID community. RECOVER Representatives contribute valuable perspectives and expertise to guide RECOVER research.

This year, Representatives have continued to support the development of important RECOVER manuscripts and have attended trainings on best practices for communicating in a community-centered way. They have also helped to share findings with the community by participating in a RECOVER Research Review (R3) Seminar on ethical considerations in research. Representatives will also be part of the panel for the upcoming R3 Seminar on July 8 and will offer family and caregiver perspectives on pediatric Long COVID.

Stay tuned to the RECOVER Report e-newsletter for future updates

This year, RECOVER researchers will continue to publish results from the initiative’s studies that deepen our understanding of Long COVID, its risk factors, and its symptoms. These milestones—reflecting the ongoing research across RECOVER’s different types of research studies—lay the foundation for the work ahead.

To keep up to date on the latest Long COVID research, subscribe to RECOVER’s monthly public e-newsletter, the RECOVER Report. Each issue features a variety of content about the progress RECOVER is making to understand, diagnose, prevent, and treat Long COVID.