NIAID Study Searches for Answers in Mystery of Long COVID

NIAID Now | June 07, 2022

Colorized scanning electron micrograph of an apoptotic cell (tan) heavily infected with SARS-COV-2 virus particles (orange), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland

Credit: NIAID

NIAID investigators recently published initial results from a study seeking to characterize and better understand persistent symptoms some people experience after having COVID. These persistent symptoms, often referred to as “long COVID,” can sometimes be debilitating, and their cause is currently unknown.

In contrast to other reports describing persistent post-COVID-19 symptoms, this study was designed using pre-specified diagnostic evaluations conducted on all participants. Between June 2020 and July 2021, the study enrolled 189 volunteers with a spectrum of initial COVID-19 disease severity and without regard for the presence of persistent symptoms. In addition, the study enrolled a control group of 120 people who were similar to the COVID-19 group in age and demographics with no clinical history or serologic evidence of prior SARS-CoV-2 infection. This allowed the investigators to compare findings in individuals with long COVID symptoms to both a control group of people without evidence of SARS-CoV-2 infection, as well as a group of volunteers who recovered from COVID-19 without persistent symptoms. Study participants completed physical examinations, cognitive function testing, cardiopulmonary evaluation and questionnaires. Blood was collected at the initial enrollment visit and was examined for SARS-CoV-2 antibodies, chemical analysis, hematologic assessment, multiple biomarkers of inflammation and tissue injury, autoantibodies, and research evaluations of immunologic parameters.

The initial findings from the study, published in the Annals of Internal Medicine, found about half of previously infected patients experienced persistent COVID-19 symptoms. However, the authors caution that it is probable that their study overestimates the true prevalence of long COVID as individuals with persistent post-COVID-19 symptoms were likely more motivated to enroll in the study. Most of the COVID-19 patients had experienced mild-to-moderate COVID-19 symptoms during the acute stage of infection with 12% requiring hospitalization. The study found an increased risk of long COVID in female participants and in participants with a pre-COVID-19 history of anxiety disorder. Extensive diagnostic evaluations failed to reveal a cause for reported symptoms in most participants. Abnormal findings on physical examination and routine laboratory evaluation were uncommon and occurred with similar frequency in the COVID-19 and control groups.  

Despite the largely normal findings on objective testing, the persistent symptoms reported by participants with long COVID had a significant impact on self-reported physical and mental health. Participants with long-COVID reported lower quality of life than participants in the COVID-19 group without persistent symptoms and the control group, as measured by several validated mental and physical health surveys.

Plasma and blood samples from a subgroup of participants were analyzed by scientists for levels of various inflammatory biomarkers, as well as markers of lymphocyte activation. These studies did not find evidence of abnormal activation of the immune system in people with long COVID. 

Researchers also looked for persistent viral infection in plasma and in nasopharyngeal specimens but were not able to find evidence of viral persistence. The study did note the negative results do not rule out possible viral infection in deep tissues that cannot be easily sampled. Taken together, these findings do not support the theory that aberrant immune activation triggered by persistent SARS-CoV-2 infection is the cause of long COVID, according to the study authors. 

The ongoing study, which is being led by principal investigator Michael C. Sneller, M.D., in NIAID’s Laboratory of Immunoregulation, continues to enroll participants from a 100-mile radius of the NIH Clinical Center in Bethesda, Maryland, where the study is being conducted. After their initial protocol visit, participants return every six months for three years and undergo follow-up medical evaluations to monitor their health. In addition, researchers will continue to evaluate immunological and virologic findings from the study in search for the cause of persistent symptoms such as fatigue, brain fog, and breathing problems, that many people experience following infection with the SARS-CoV-2 virus.

“The suffering described by long COVID patients is debilitating and real,” said Dr. Sneller. “There remains a lack of clarity about the distinct cause of long COVID in each individual patient and there may be multiple causes, stretching from the virologic and immunologic to the psychosocial. Every long COVID patient deserves careful, empathetic evaluation and appropriate treatment and referrals.”

This single-site study is part of a larger research effort across multiple institutes at NIH and NIH-funded institutions to understand, prevent, and treat long-term health effects related to COVID-19. NIH-supported RECOVER studies are actively enrolling adults and children, specifically those who have tested positive in the last 30 days, at sites across the country. Investigators are also working to recruit people from racial and ethnic minority groups and people who live in rural communities. Interested volunteers can visit to find more information and study sites.

Reference: M. Sneller, et al. A Longitudinal Study of COVID-19 Sequelae and Immunity: Baseline Findings. Annals of Internal Medicine DOI: 10.7326/M21-4905 (2022).



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