The millions of people impacted by the chronic aftereffects of COVID-19 following infection with SARS-CoV-2 present a significant public health challenge.

A recent study in the Annals of Internal Medicine examined whether current tests were adequate to identify post-acute sequelae of SARS-CoV-2 (PASC).

PASC, or long COVID, encompasses a broad range of symptoms that can significantly impact quality of life. Depending on the specific manifestations, the symptoms can vary from moderate to severe. Despite its widespread effects, no validated biomarkers exist for this condition.

Study: Differentiation of Prior SARS-CoV-2 Infection and Postacute Sequelae by Standard Clinical Laboratory Measurements in the RECOVER Cohort. Image Credit: Pressmaster/Shutterstock.com

About the study

Clinical laboratory tests were evaluated as potential biomarkers for PASC. Using a newly developed PASC index, the likelihood of these tests identifying PASC rather than a prior SARS-CoV-2 infection was calculated.

The study involved 10,094 participants across 83 sites as part of the National Institutes of Health’s RECOVER (Researching COVID to Enhance Recovery) Adult cohort. Participants included those with a history of SARS-CoV-2 infection, but none had been reinfected within 30 days of the study visit.

Researchers used prospectively obtained data to create the PASC index based on 12 symptoms with the highest discriminative value for differentiating between SARS-CoV-2 infection and non-infection. This index was validated in 23% of infected participants.

While the PASC index does not claim to identify all patients with PASC, it offers insight into the laboratory profiles of a subset of patients who meet these criteria. This could aid in diagnosing, treating, and preventing the condition, as well as providing a sound prognosis.

The study analyzed 25 standardized routine tests that are widely available and supported by prior literature and clinical experience. The goal was to determine if chronic alterations in these tests could enhance the accuracy of symptom-based PASC diagnosis and identify any characteristic changes in symptomatic PASC patients.

What did the study show?

Of the participants, 72% were female, with a median age of 47 years. Among them, 8,746 had a history of SARS-CoV-2 infection, while 1,348 did not. The PASC index was 12 or higher for 1,880 participants and zero for 3,351 participants.

 

Adjusted analysis revealed that participants with prior infection had a slightly lower mean platelet count but higher mean glycated hemoglobin (HbA1c) and urinary albumin-creatinine ratios (uACR) compared to uninfected participants. However, these differences were not clinically significant, although they do suggest damage to the vascular system, including the kidneys.

When participants with pre-existing diabetes were excluded from the analysis, no significant difference in HbA1c levels was observed between the two groups.

Additionally, participants with a PASC index of 12 or higher showed no significant differences in laboratory results compared to those with an index of zero. The lack of difference in HbA1c relative to the index may indicate a virus-induced shift in glucose metabolism, independent of symptoms.

The researchers could not determine whether the infection caused the observed changes in laboratory parameters or whether they predisposed individuals to it.

Sub-analyses revealed different SARS-CoV-2 phenotypes among those with prior infection. For example, high-sensitivity C-reactive protein (hsCRP) levels were higher on average among patients with taste or smell impairments and those experiencing fatigue, dizziness, brain fog, and gut symptoms. In contrast, decreased sodium levels but increased calcium levels were more common among those with fatigue.

These findings suggest an ongoing inflammatory state in patients with symptomatic PASC, supporting earlier studies. This condition appears to involve platelet dysfunction and clotting defects beyond reduced platelet counts.

Previous research has suggested reduced inflammation among those with sensory impairments, which conflicts with the present findings. It is possible that the current study included later viral variants that caused disturbances in taste and smell alongside greater disease severity, unlike earlier strains.

Conclusions

“No evidence was found that any of the 25 routine clinical laboratory values assessed in this study could serve as a clinically useful biomarker of PASC.”

Even severe cases of PASC may not be linked to significant laboratory abnormalities. The minor associations observed between certain lab tests and PASC phenotypes were largely negligible and may have been coincidental.

The researchers concluded that these laboratory tests are not useful for diagnosing or predicting PASC, although they are important for ruling out other potential causes of the symptoms.

Additionally, these tests could help illuminate the underlying mechanisms of PASC when combined with more detailed investigations such as transcriptomics, proteomics, and metabolomics.