Getting to the bottom of long COVID

Researchers found people with wide-ranging long COVID symptoms were twice as likely to have SARS-CoV-2 proteins in their blood, compared to those without long COVID symptoms, according to a study out of Harvard-affiliated Brigham and Women’s Hospital.

Commonly reported long COVID symptoms included fatigue, brain fog, muscle pain, joint pain, back pain, headache, sleep disturbance, loss of smell or taste, and gastrointestinal symptoms.

Results are published in Clinical Microbiology and Infection.

Specifically,  the team found that 43 percent of those with long COVID symptoms affecting three major systems in the body, including cardiopulmonary, musculoskeletal, and neurologic systems, tested positive for viral proteins within 1 to 14 months of their positive COVID test. But only 21 percent of those who didn’t report any long COVID symptoms tested positive for the SARS-CoV-2 biomarkers in this same period.

“If we can identify a subset of people who have persistent viral symptoms because of a reservoir of virus in the body, we may be able to treat them with antivirals to alleviate their symptoms,” said lead author Zoe Swank, a postdoctoral research fellow in the Department of Pathology at BWH.

The study analyzed 1,569 blood samples collected from 706 people, including 392 participants from the National Institutes of Health-supported Researching COVID to Enhance Recovery (RECOVER) Initiative,  who had previously tested positive for a COVID infection. Using Simoa, an ultrasensitive test for detecting single molecules, researchers looked for whole and partial proteins from the SARS-CoV-2 virus. They also analyzed data from the participants’ long COVID symptoms, using electronic medical chart information or surveys that were gathered at the same time as the blood samples were taken.

It’s possible that a persistent infection explains some — but not all — of the long COVID sufferers’ symptoms. If this is the case, testing and treatment could aid in identifying patients who may benefit from treatments such as antiviral medications.

A condition with more than one cause

One of the questions raised by the study is why more than half of patients with wide-ranging long COVID symptoms tested negative for persistent viral proteins.

“This finding suggests there is likely more than one cause of long COVID,” said David Walt, a professor of pathology at BWH and principal investigator on the study. “For example, another possible cause of long-COVID symptoms could be that the virus harms the immune system, causing immune dysfunction to continue after the virus is cleared.”

To better understand whether an ongoing infection is behind some people’s long COVID symptoms, Swank, Walt, and other researchers are currently conducting follow-up studies. They’re analyzing blood samples and symptom data in larger groups of patients, including people of wide age ranges and those with compromised immune symptoms. This way, they can also see if some people are more likely to have persistent virus in the body.

“There is still a lot that we don’t know about how this virus affects people,” said David C. Goff, a senior scientific program director for the RECOVER Observational Consortium Steering Committee and director of the Division of Cardiovascular Sciences at the National Heart, Lung, and Blood Institute (NHLBI), part of NIH. “These types of studies are critical to help investigators better understand the mechanisms underlying long COVID — which will help bring us closer to identifying the right targets for treatment.”

Goff added that these results also support ongoing efforts to study antiviral treatments.  

The SARS-CoV-2 blood test developed by Brigham and Women’s researchers is also currently being used in a national study, called RECOVER-VITAL, that is testing whether an antiviral drug helps patients recover from long COVID. The RECOVER-VITAL trial will test the patients’ blood before and after treatment with an antiviral to see if treatment eliminates persistent viral proteins in the blood.

The idea that a virus can stay in the body and cause ongoing symptoms months after an infection isn’t unique to COVID.

“Other viruses are associated with similar post-acute syndromes,” said Swank. She noted animal studies have found Ebola and Zika proteins in tissues post-infection, and these viruses have also been associated with post-infection illness.

Funding for this work came from the National Institutes of Health (NIH) and Barbara and Amos Hostetter.