A new long COVID study shows that a persistent infection could explain why some people experience long-haul symptoms, according to researchers at Brigham and Women’s Hospital.

The Brigham team found that people with wide-ranging long COVID symptoms were twice as likely to have virus proteins in their blood, compared to those without long COVID symptoms.

“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 the Brigham.

The researchers looked at 1,569 blood samples from 706 people, including 392 participants from the National Institutes of Health-supported Researching COVID to Enhance Recovery Initiative — who had previously tested positive for a COVID infection.

With a highly sensitive test they developed, 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 when the blood samples were taken.

Compared to people who didn’t report long COVID symptoms, those who reported persisting symptoms affecting heart and lung, brain, and musculoskeletal systems were twice as likely to have virus proteins circulating in their blood.

The research team was able to detect the spike protein and other components of the SARS-CoV-2 virus using Simoa, an ultrasensitive test for detecting single molecules. Commonly reported long COVID symptoms included fatigue, brain fog, muscle pain, joint pain, back pain and headache.

Specifically, 43% of those with long COVID symptoms affecting three major systems in the body tested positive for viral proteins within 1 to 14 months of their positive COVID test.

But 21% of those who didn’t report any long COVID symptoms tested positive for the virus biomarkers in this same period.

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

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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 the Brigham 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, 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 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, 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.

The SARS-CoV-2 blood test developed by Brigham researchers is also currently being used in a national study, called RECOVER-VITAL, which 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,” Swank said. She noted that animal studies have found Ebola and Zika proteins in tissues post-infection, and these viruses have also been associated with post-infection illness.