RECOVER study establishes working clinical definition of long COVID

In a new multisite study including the University of Kansas Medical Center, researchers have created a working definition of long COVID by identifying 12 distinguishing symptoms, with malaise after physical or mental exertion, fatigue, brain fog, dizziness and gastrointestinal problems topping the list. The results of the study were published in JAMA on May 25.

More than 200 symptoms have been associated with long COVID, but efforts to develop testing and treatments have been hindered by the lack of a standard definition of the condition, which varies in type and severity from one patient to the next and affects multiple organ systems.

A condition in which a person has new, relapsing or ongoing symptoms after the initial COVID-19 infection, long COVID affects as many as 10% of Americans who have had COVID-19 and is a major public health concern.

The study was sponsored by the National Institutes of Health and is part of the NIH Researching COVID to Enhance Recovery (RECOVER) Initiative. The goal of RECOVER is to determine why some people have long-term symptoms after contracting COVID-19 and then use that knowledge to prevent and treat long COVID. (See RECOVER Research Q&A)

“Persistent symptoms after COVID-19 infection can be quite varied. A clinical definition of the several conditions of long COVID is needed in order to understand how to best diagnose the conditions and to develop treatments,” said Mario Castro, M.D., MPH, vice chair for clinical and translational research and the principal investigator for the study site at KU Medical Center. “This study provides the information needed to move the science of long COVID forward.”

The study also found that long COVID was more common and severe in people who were infected before the Omicron variant emerged in the U.S. in December 2021 and confirmed previous findings that COVID-19 vaccinations reduce the risk of developing long COVID. Additionally, the study found that reinfections were linked to higher long COVID frequency and severity.

The research included nearly 10,000 participants, ages 18 and over. Roughly 9,000 of those participants had COVID before they joined the study, and approximately 1,000 had never been infected (as confirmed by an antibody test). Nearly 150 participants enrolled in the study were from KU Medical Center.

The researchers analyzed data from surveys given to the study participants about their symptoms. The surveys revealed 37 symptoms that participants had more often six months or longer after having COVID-19 compared with participants who were never infected. The researchers then applied statistical analyses that identified a dozen symptoms that most distinguished participants with long COVID from those without.

The 12 symptoms, listed in order of decreasing frequency, are:

• Feeling tired and unwell that gets worse after physical or mental activity (post-exertional malaise)
• Feeling weak and tired (fatigue)
• Brain fog
• Dizziness
• Gastrointestinal symptoms
• Fluttering or pounding heartbeats (palpitations)
• Loss of sexual desire or ability
• Loss of, or change in, taste or smell
• Feeling thirsty
• Long-term (chronic) cough
• Chest pain
• Unusual (abnormal) movements, such as twitching

After identifying these 12 symptoms, the researchers established a scoring system that assigned a point value to each symptom based on its likelihood to occur in participants with long COVID versus those without. These point values enabled the researchers to establish a composite-score threshold to identify long COVID.

The researchers expect this early definition to be refined as further studies are completed. Moreover, the study results do not imply that anyone who does not meet the scoring threshold does not have long COVID. Additional research is needed before a definition can be used in clinical practice.

In the meantime, the study serves as a valuable framework upon which to base further research.

“Now that this study is done, we can use this expanded working definition to test various treatments that may help patients suffering from the varied symptoms of long COVID,” said Castro.