A study of nearly 10,000 Americans has uncovered new details about long COVID, the post-infection set of conditions that can affect nearly every tissue and organ in the body.

Clinical symptoms of long COVID vary and include fatigue, brain fog and dizziness that last for months or years after a person is initially infected with the virus. The study, conducted by a research team funded by the National Institutes of Health, found that long COVID was more common and severe in study participants infected before the 2021 omicron variant.

The study, published in the Journal of the American Medical Association, was coordinated through the NIH's RECOVER, initiative, which stands for Researching COVID to Enhance Recovery. The nationwide effort is dedicated to understanding why some people develop long-term symptoms following COVID-19 and how to detect, treat and prevent long COVID. University of Arizona Health Sciences researchers led one of 15 adult cohorts that contributed to the research.

"This is a very important first glimpse into the clinical complexities of long COVID. We now have an initial roadmap on how to better diagnose it, and we need to validate it in ongoing studies," said Dr. Janko Nikolich, a principal investigator for the Arizona cohort, director of the Aegis Consortium at UArizona Health Sciences and professor and head of the Department of Immunobiology at the UArizona College of Medicine – Tucson.

RECOVER researchers hope this study is the next step toward potential treatments for long COVID, which affects millions of Americans. 

"Americans living with long COVID want to understand what is happening with their bodies," said Rachel L. Levine, assistant secretary for health in the U.S. Department of Health and Human Services. "RECOVER, as part of a broader government response, in collaboration with academia, industry, public health institutions, advocacy organizations and patients, is making great strides toward improving our understanding of long COVID and its associated conditions."

"Arizona residents suffer from long COVID at a rate that is approximately 3% higher than the national rate of long COVID," said Dr. Sairam Parthasarathy, another principal investigator for the Arizona cohort and professor of medicine and chief of the Division of Pulmonary, Allergy, Critical Care and Sleep Medicine in the Department of Medicine at the UArizona College of Medicine – Tucson. "More research needs to be done to further refine and polish this definition using clinical diagnostic tests and research tools. Such additional work will help us better understand why an individual develops long COVID and how we can better treat them."

Researchers examined data from 9,764 adults, including 8,646 who had COVID-19 and 1,118 who did not have COVID-19. They assessed more than 30 symptoms across multiple body areas and organs and 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.

They then established a scoring system based on patient-reported symptoms. By assigning points to each of the 12 symptoms, the team gave each patient a score based on symptom combinations. With these scores in hand, researchers identified a meaningful threshold for identifying participants with long COVID. They also found that certain symptoms occurred together and defined four subgroups or "clusters" with a range of impacts on health. 

"One of the big takeaways from this study is the heterogeneity of long COVID," said Andrea Foulkes, principal investigator of the RECOVER Data Resource Core, a professor at Harvard Medical School, and director of Biostatistics at Massachusetts General Hospital. "Long COVID is not just one syndrome; it's a syndrome of syndromes."

Of the 2,231 patients in the study who had a first COVID-19 infection on or after Dec. 1, 2021, when the omicron variant was circulating, about 10% experienced long-term symptoms or long COVID after six months. The results are based on a survey of a highly diverse set of patients and are not final. Survey results will next be compared for accuracy against an array of lab tests and imaging. 

To date, more than 100 million Americans have been infected with SARS-CoV-2, the virus that causes COVID-19. As of April, the federal government's Household Pulse survey estimates that about 6% of those infected with the virus continue to experience and suffer from the many symptoms termed together as long COVID. Patients and researchers have identified more than 200 symptoms associated with long COVID.

"This study is an important step toward defining long COVID beyond any one individual symptom," said study author Dr. Leora Horwitz, director of the Center for Healthcare Innovation and Delivery Science and co-principal investigator for the RECOVER Clinical Science Core at NYU Langone Health. "This research definition — which may evolve over time — will serve as a foundation for scientific discovery and treatment design."

The researchers say studying the underlying biological mechanisms of long COVID is central to advancing informed interventions and identifying effective treatment strategies.
In addition to establishing the scoring system, the researchers found that participants who were unvaccinated, had COVID-19 for the first time before the 2021 omicron strain or had reinfections were more likely to have long COVID and more severe cases of long COVID. 

"While the score developed in this study is an important research tool and early step toward diagnosing and monitoring patients with long COVID, we recognize its limitations," said Dr. David C. Goff, director of the Division of Cardiovascular Sciences at the National Heart, Lung, and Blood Institute, part of NIH. Goff serves as an epidemiology lead for NIH RECOVER. "All patients suffering from long COVID deserve the attention and respect of the medical field, as well as care and treatment driven by their experiences. As treatments are developed, it will be important to consider the complete symptom profile." 

The ongoing RECOVER research serves as the foundation for planned clinical trials, which are expected to begin enrolling patient participants this year. 

This research was funded by NIH agreements OT2HL161841, OT2HL161847, and OT2HL156812. Additional support came from grant R01 HL162373.

A version of this article originally appeared on the UArizona Health Sciences website.