New data from the National Institutes of Health-funded RECOVER-Adult Cohort study concludes that none of 25 routine clinical lab values can be reliably used to diagnose long COVID, also known as postacute sequelae of SARS-CoV-2 infection (PASC).
The findings, published today in the Annals of Internal Medicine, suggest that clinicians should continue to focus on symptoms and symptom relief rather than relying solely on lab tests, the authors said.
"Our challenge is to discover biomarkers that can help us quickly and accurately diagnose long COVID to ensure people struggling with this disease receive the most appropriate care as soon as possible," David Goff, MD, PhD, director of the Division of Cardiovascular Sciences at the National Heart, Lung, and Blood Institute (NHLBI), said in a University of Colorado Anschutz Medical Campus news release.
"Long COVID symptoms can prevent someone from returning to work or school, and may even make everyday tasks a burden, so the ability for rapid diagnosis is key," he added. Goff was not a study author.
Lack of validated PASC biomarkers
The team evaluated the standard lab test results, physical exam findings, and interview responses of 10,094 US adults in 33 states; Washington, DC; and Puerto Rico with and without a COVID-19 infection in the past 6 months from October 2021 to October 2023. Nearly 19% of participants were considered to have PASC.
Participants, who were seen at 83 enrollment sites of the Researching COVID to Enhance Recovery (RECOVER) study, completed surveys every 3 months and provided blood and urine samples at enrollment and at 6, 12, 24, 36, and 48 months postinfection if the previous result was abnormal. Of all participants, 72% were women, 17% were Hispanic, 14% were Black, and 62% were fully vaccinated by the infection date.
Although potential models of pathogenesis have been postulated, including immune dysregulation, viral persistence, organ injury, endothelial dysfunction, and gut dysbiosis, there are currently no validated clinical biomarkers of PASC.
The researchers used propensity score–weighted regression models to estimate differences in average lab values by infection status and the study-developed PASC index (score range, 12 or more [PASC] vs 0 [no PASC]).
The 25 lab values assessed were chosen based on site availability and standardized use, published literature, and clinical experience. They were used to compare adults with and without a history of COVID-19 6 months or earlier, those with and without PASC, participants with each of four PASC symptom phenotypes, and those unlikely to have PASC.
The PASC phenotypes were cluster 1 (abnormal smell and taste), cluster 2 (postexertional malaise (PEM), cluster 3 (brain fog, PEM, and fatigue), and cluster 4 (fatigue, PEM, dizziness, brain fog, gastrointestinal symptoms, and heart palpitations).
"Although potential models of pathogenesis have been postulated, including immune dysregulation, viral persistence, organ injury, endothelial dysfunction, and gut dysbiosis, there are currently no validated clinical biomarkers of PASC," the researchers wrote.
No clinically relevant differences
Of the 10,094 participants, 8,746 (average age, 46 years) had previously tested positive for COVID-19, 1,348 (average age, 52) were uninfected, 1,880 had a PASC index score of 12 or higher, and 3,351 had a score of 0.
After propensity-score adjustment, no clinically meaningful phenotypic differences were found in previously infected adults with PASC scores of greater than 12 and those with a 0 score.
Our findings suggest that even highly symptomatic PASC may have no clinically observable objective findings on routine laboratory testing.
"The difference in HbA1c levels was attenuated after participants with preexisting diabetes were excluded," the researchers wrote. "Among participants with prior infection, no meaningful differences in mean laboratory values were found between those with a PASC index of 12 or higher and those with a PASC index of zero."
The authors concluded that clinicians should continue to order routine clinical lab tests to exclude other treatable causes of PASC symptoms, but with the knowledge that the 25 routine tests assessed in the study don't appear useful in defining PASC.
"Our findings suggest that even highly symptomatic PASC may have no clinically observable objective findings on routine laboratory testing," they wrote. "Understanding the basic biological underpinnings of persistent symptoms after SARS-CoV-2 infection will likely require a rigorous focus on investigations beyond routine clinical laboratory studies (for example, transcriptomics [RNA], proteomics [proteins], metabolomics [metabolites]) to identify novel biomarkers."
Lead author Kristin Erlandson, MD, professor of medicine–infectious diseases at the University of Colorado, said the research will continue. "Future work will use RECOVER’s biobank of cohort samples such as blood and spinal fluid, to develop more novel laboratory-based tests that help us better understand the pathophysiology of long COVID," she said in an NHLBI press release.
More funding needed to continue research
In a related commentary, Annukka Antar, MD, PhD, and Paul Auwaerter, MD, both of Johns Hopkins University School of Medicine, called PASC diagnosis a "Herculean task."
"Some of the greatest unsolved challenges of the COVID-19 pandemic relate to understanding, diagnosing, and treating long COVID," they wrote.
And despite this RECOVER-Adult Cohort study, significant questions remain. "How well does this study’s definition of long COVID match what we see in clinical practice?" they asked. "Does symptom severity correlate with laboratory values? Are there sex-based differences in laboratory values in long COVID? Is there any time in the postacute period (for example, within 1 month of infection) in which results of routine laboratory tests would differ in people with versus without long COVID?"
With RECOVER’s $1.15 billion almost spent, the medical community should join patients in advocating for continued funding for long COVID research to continue making progress in understanding, diagnosing, and curing long COVID.
Antar and Auwaerter urged clinicians to consider PASC in the differential diagnosis of symptoms or illnesses with no obvious cause, acknowledge symptoms with compassion, and develop a symptom-relief plan to foster trust and hope with patients amid uncertainty.
"This first of many Herculean tasks accomplished, another one arises: What are the biomarkers of long COVID?," they concluded. "With RECOVER’s $1.15 billion almost spent, the medical community should join patients in advocating for continued funding for long COVID research to continue making progress in understanding, diagnosing, and curing long COVID."
