RECOVER study: An important step toward defining long COVID

A study led by the National Institutes of Health's RECOVER Initiative and supported by NYU Langone Health, home to the effort's Clinical Science Core (CSC), provides an expanded working definition of long COVID.

This study is an important step toward defining long COVID beyond any one individual symptom. This definition—which may evolve over time—will serve as a critical foundation for scientific discovery and treatment design."

Leora Horwitz, MD, study author, director of the Center for Healthcare Innovation and Delivery Science and co-principal investigator for the RECOVER CSC at NYU Langone

The study, which involved RECOVER researchers from across the country, establishes a scoring system based on the symptoms that most clearly set apart patients that had been previously infected from those not reporting a prior infection. Researchers used those symptoms to identify patients with long COVID. The results are based on a survey of 9,764 patients' self-reported symptoms and will be undergoing validation, according to the authors. Survey results will next be compared against lab tests and imaging.

As of May 2023, more than 100 million Americans have been infected with SARS-CoV-2, the virus that causes COVID-19, with experts estimating that approximately 6 percent of those infected with the virus continue to experience the many symptoms termed together as long COVID. More than 200 symptoms affecting all of the body's organ systems are associated with post-COVID conditions.

Published online May 25 in the Journal of the American Medical Association, the study examined 37 symptoms across multiple body areas and organs. Researchers applied statistical analyses that identified 12 symptoms that most set apart those with and without long COVID: post-exertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, heart palpitations, issues with sexual desire or capacity, loss of smell or taste, thirst, chronic cough, chest pain, and abnormal movements.

By assigning points to each of the 12 symptoms, the team gave each participant a score based on symptom combinations, and found that 23 percent of participants with a prior COVID infection crossed the study threshold for long COVID. With these scores in hand, researchers found that certain symptoms occurred at higher rates in certain patient groups, and defined four clusters based on these symptom patterns.

"Now that we're able to identify people with long COVID, we can begin doing more in-depth studies to understand the mechanisms at play," said corresponding author Andrea Foulkes, ScD, principal investigator of the RECOVER Data Resource Core (DRC), professor at Harvard Medical School, and director of biostatistics at Massachusetts General Hospital. "These findings set the stage for identifying effective treatment strategies for people with long COVID—understanding the biological underpinnings is going to be critical to that endeavor."

RECOVER—Researching COVID to Enhance Recovery—is a nationwide initiative dedicated to understanding why some people develop long-term symptoms following a COVID-19 infection, and how to detect, treat, and prevent long COVID. As the CSC, NYU Langone is charged with integrating the research activities of nearly 200 clinical sites around the country.

A complicated disease

This study also found that long COVID was more common and severe in study participants infected before the Omicron strain emerged in late 2021, and in participants who were unvaccinated. Further, reinfections were also linked to a higher frequency and severity of long COVID.

With the 12-symptom scoring system in place, researchers were able to identify 4 subgroups of patients with different symptom clusters. Several of these clusters span multiple body systems, suggesting that a body-wide reaction to the virus may be present in some people with long COVID.

The ongoing research being conducted by RECOVER serves as the foundation for planned clinical trials, whose interventions are rooted in many of the symptoms outlined in this study, including brain fog and nerve damage, also known as autonomic dysfunction. RECOVER clinical trials are expected to begin enrolling patients in 2023.

Along with Dr. Horwitz and Dr. Foulkes, the writing committee for the study included first author Tanayott Thaweethai, PhD, of Massachusetts General Hospital and Harvard Medical School. Additional authors are Caitlin Selvaggi, MS, Daniel Shinnick, MS, and Carolin Schulte, PhD, of Massachusetts General Hospital; Elizabeth Karlson, MD, MS, Bruce Levy, MD, and Rachel Atchley, PhD, of Brigham and Women's Hospital; Sairam Parthasarathy, MD, of the University of Arizona College of Medicine-Tucson; Upinder Singh, MD, of Stanford University School of Medicine; Sarah Jolley, MD, MS, of the University of Colorado Anschutz Medical Campus; Tiffany Walker, MD, of Emory University; Emily Levitan, ScD, of the University of Alabama at Birmingham; Lisa McCorkell, MPP, of the Patient-Led Research Collaborative; Grace McComsey, MD, of Case Western Reserve University; and Girish Nadkarni, MD, of Icahn School of Medicine at Mount Sinai.

This research was funded by NIH agreements OT2HL161841, OT2HL161847, and OT2HL156812. Learn more about the RECOVER Initiative. In addition to Dr. Horwitz, the CSC at NYU Langone is co-led by RECOVER co-principal investigators Stuart D. Katz, MD, founding director of NYU Langone's heart failure program and the Helen L. and Martin S. Kimmel Professor of Advanced Cardiac Therapeutics in the Department of Medicine, Andrea B. Troxel, ScD, director of the Division of Biostatistics and professor in the Department of Population Health, and Rachel S. Gross, MD, director of pediatric research for RECOVER CSC and assistant professor in the Department of Pediatrics at the NYU Grossman School of Medicine.