In a cohort study of over 10,000 participants with and without prior SARS-CoV-2 infection, a handful of routine clinical laboratory tests were unable to provide a reliable biomarker of SARS-CoV-2 infection’s post-acute sequelae (PASC), also known as “long COVID.” The researchers also showed that all 25 tests failed to provide significant differences between patients without prior infection and those who tested positive for SARS-CoV-2 several months earlier. This study emphasizes the importance of a sustained effort to understand the biological basis of long-lasting symptoms following SARS-CoV-2 infection.
What is “long COVID”
PASC is a huge problem in public health, as it has been reported in millions of people around the world. “PASC” is commonly used to describe a broad range of symptoms and health issues that continue after acute SARS-CoV-2 infection and significantly affect people’s quality of life. There are no established clinical indicators of PASC at this time, even though several models of pathogenesis have been proposed, such as immune dysregulation, viral persistence, organ injury, endothelial dysfunction, and gut dysbiosis. Researchers have used research-focused assays to identify possible biomarkers linked to PASC, but the results have been inconsistent, which may be because different PASC studies use different definitions.
As part of the National Institutes of Health’s RECOVER (Researching COVID to Enhance Recovery) Initiative, a large-scale research collaboration analyzed data from nearly 10,000 individuals in the RECOVER-Adult cohort, focusing on individuals who had and had not been infected with SARS-CoV-2. Through this analysis, the researchers identified 12 symptoms that effectively differentiate individuals with previous SARS-CoV-2 infection. This study found various clusters or subphenotypes of PASC and led to the development of the “PASC index,” with 23% of the cohort with a history of SARS-CoV-2 infection meeting this research threshold, but did not provide a framework that encompasses all people experiencing PASC.
0-for-25
The study, led by Leora Horwitz, MD, Andrea S. Foulkes, PhD, and Grace A. McComsey, MD, examined 25 routinely used and standardized laboratory tests chosen based on availability across institutions, prior literature, and clinical experience. These tests were conducted prospectively in laboratories that are certified by the Clinical Laboratory Improvement Amendments (CLIA). The samples were collected from 10,094 RECOVER-Adult participants, representing a diverse cohort from all over the U.S.
The study’s authors concluded that none of the 25 commonly used clinical laboratory values reliably indicate previous infection, PASC, or the particular cluster type of PASC. Although some minor differences in the results of specific laboratory tests attempted to differentiate between individuals with and without a history of infection, these findings were generally clinically meaningless. The authors suggest that, although clinicians should use appropriate diagnostic testing to rule out treatable causes of PASC symptoms, these findings demonstrate that routine laboratory tests are not valuable biomarkers for PASC.
Despite their insignificance in PASC diagnosis, these subtle variations may point to possible pathways in the disease’s pathophysiology or clusters of PASC. Research focusing on areas beyond standard clinical laboratory studies, such as transcriptomics, proteomics, and metabolomics, may be necessary to uncover new biomarkers if we are to understand the fundamental biological basis of symptoms that persist following SARS-CoV-2 infection.
