Many People with Long COVID Have Signs of Persistent SARS-CoV-2 Proteins, New Findings Show

Credit: Donny Bliss/NIH

In 2021, NIH launched the Researching COVID to Enhance Recovery (RECOVER) Initiative, a nationwide research program, to fully understand, diagnose, and treat Long COVID. We continue to learn more about this condition, in which some people experience a variety of symptoms for weeks, months, or even years after infection with SARS-CoV-2, the virus that causes COVID-19. But we’re still working to understand the underlying reasons why people develop Long COVID, who is most likely to get it, and how best to treat or prevent it.

Studies have shown that for some people, SARS-CoV-2 doesn’t completely clear out after acute infection. Scientists have observed signs that the virus may persist in various parts of the body, and many suspect that this lingering virus, or remnants consisting of SARS-CoV-2 protein, may be causing Long COVID symptoms in some individuals. Now, in a new study supported by RECOVER, scientists found that people with Long COVID were twice as likely to have these viral remnants in their blood as people with no lingering symptoms. The findings, reported in Clinical Microbiology and Infection, add to evidence that Long COVID may sometimes stem from persistent infection or SARS-CoV-2 protein remnants.

The study team, led by David Walt and Zoe Swank at Brigham and Women’s Hospital in Boston, had earlier found preliminary evidence in a small pilot study that a SARS-CoV-2 protein could often be detected in the bloodstreams of people with Long COVID up to a year after the initial infection. In the new study, they wanted to better quantify this in a much larger group of people with Long COVID. The researchers developed a highly sensitive test to look for whole and partial proteins from the SARS-CoV-2 virus. They analyzed 1,569 blood samples collected from 706 people at various times after SARS-CoV-2 infection.

Overall, 21% of those in the study had detectable levels of a SARS-CoV-2 protein between 4 and 7 months after infection. In total, 82% of the study’s participants (578 people) had at least one symptom of Long COVID more than a month after their infections. Commonly reported symptoms included fatigue, brain fog, muscle pain, joint pain, back pain, headache, sleep disturbance, loss of smell or taste, and gastrointestinal symptoms. More than half of participants in this group (378 people) reported experiencing ongoing cardiopulmonary, musculoskeletal, or neurologic symptoms, and among those participants, 43% (165 people) had detectable virus protein. Also of note, of the asymptomatic people, about 20% had detectable virus protein.

While the researchers can’t definitively show that persistent infections are the cause of some Long COVID symptoms, the findings add to growing evidence that low levels of viral protein being present may explain some but not all cases of Long COVID. The authors and many other researchers suspect that Long COVID likely has multiple underlying causes. For instance, it’s possible that the virus may lead to harmful changes in the immune system that play a role in some cases of Long COVID.

Scientists also want to see if there is a subset of people with Long COVID or persistent symptoms who may benefit from antiviral treatment. To this end, RECOVER is supporting a clinical trial evaluating whether the antiviral drug Paxlovid (a combination of nirmatrelvir and ritonavir), which is used to treat COVID-19, could also be used to improve Long COVID symptoms. The trial is using the SARS-CoV-2 blood test developed by the Brigham and Women’s study team to evaluate whether Paxlovid can eliminate viral proteins from participants’ blood.

More study is needed to understand the causes of Long COVID symptoms in people who test negative for persistent infection, the researchers note. They are conducting follow-up studies in even more people with Long COVID, including those with compromised immune systems. They hope to learn more about what causes some people to be at higher risk for retaining some SARS-CoV-2 protein remnants and Long COVID.

Reference:

Swank Z, et al; RECOVER consortium authors. Measurement of circulating viral antigens post-SARS-CoV-2 infection in a multicohort study. Clinical Microbiology and Infection. DOI: 10.1016/j.cmi.2024.09.001 (2024).

NIH Support: RECOVER Initiative; National Institute of Allergy and Infectious Diseases; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute