NIH Study: Routine Lab Tests Ineffective for Diagnosing Long COVID

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A recent study, “Differentiation of Prior SARS-CoV-2 Infection and Postacute Sequelae by Standard Clinical Laboratory Measurements in the RECOVER Cohort,” published today in Annals of Internal Medicine, supported by the National Institutes of Health (NIH) has revealed that routine laboratory tests are not effective in diagnosing long COVID, a condition characterized by a wide range of symptoms that persist long after the initial COVID-19 infection.

The study, part of the NIH’s Researching COVID[-19] to Enhance Recovery (RECOVER) Initiative, underscores the need for novel biomarkers to distinguish long COVID from other ailments and ensure that patients receive timely and appropriate care.

Long COVID is a multifaceted condition that varies in its impact on individuals, with symptoms persisting for months or even years. These can include fatigue, brain fog, shortness of breath, and other debilitating issues that severely affect quality of life. Diagnosing long COVID has been difficult due to the lack of validated clinical biomarkers, making the diagnosis dependent on a thorough medical history, physical examination, and lab tests to exclude other possible causes.

“Accordingly, we conducted a study to determine whether SARS-CoV-2 infection led to persistent changes in results of common clinical laboratory tests, regardless of symptoms, in people with prior infection compared with those without prior infection,” the authors wrote in the study. “If so, laboratory studies could be used to augment symptom-based definitions of postacute sequelae of SARS-CoV-2 infection (PASC).”

The NIH study’s authors sought to determine whether a previous SARS-CoV-2 infection caused changes in specific biomarkers, such as platelet counts or protein levels in urine, that could help differentiate individuals with long COVID from those without it. The study included 10,094 adults from diverse demographic backgrounds, recruited from 83 sites across the United States between October 2021 and October 2023. Among the participants, 8,746 had a history of SARS-CoV-2 infection, while 1,348 had never been infected. The test had 7240 females, 2824 males, 4 intersex, and 26 missing the information as assigned at birth.

For the study, participants underwent a baseline set of surveys, physical examinations, and 25 standard laboratory tests, including complete blood count panels, metabolic panels, hemoglobin A1c (HbA1c) levels, and urinalysis. These tests were repeated at 6-, 12-, 24-, 36-, and 48-month intervals. The researchers found that routine lab tests detected few meaningful differences in biomarkers between individuals with a prior SARS-CoV-2 infection and those without. For instance, while there were modest increases in HbA1c levels among those with a history of infection, these differences disappeared after excluding individuals with preexisting diabetes.

The study also observed slight increases in the urine albumin to creatinine ratio (uACR), a measure of kidney function, among participants with prior infection. However, these increases were only seen in a minority of individuals and may have been influenced by the severity of the initial infection rather than long COVID itself.

As explained in the study, after adjusting for propensity scores, participants with prior infection had a lower mean platelet count (265.9 × 10^9 cells/L [95% CI, 264.5 to 267.4 × 10^9 cells/L]) compared to those without known prior infection (275.2 × 10^9 cells/L [CI, 268.5 to 282.0 × 10^9 cells/L]). They also showed higher mean hemoglobin A1c (HbA1c) levels (5.58% [CI, 5.56% to 5.60%] vs. 5.46% [CI, 5.40% to 5.51%]) and urinary albumin–creatinine ratio (81.9 mg/g [CI, 67.5 to 96.2 mg/g] vs. 43.0 mg/g [CI, 25.4 to 60.6 mg/g]). However, these differences were of modest clinical significance, and the HbA1c difference diminished after excluding participants with preexisting diabetes. Among those previously infected, no significant differences in mean lab values were observed between participants with a PASC index of 12 or higher and those with a PASC index of zero.

A secondary analysis focused on the differences between participants who developed long COVID and those who did not. Using a long COVID index identifying 12 key symptoms, the researchers found no significant differences in lab test results between the two groups. This finding suggests that routine laboratory tests are unreliable for diagnosing long COVID, highlighting the urgent need for novel biomarkers.

“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,” said Kristine Erlandson, MD, a professor of medicine-infectious disease at the University of Colorado Anschutz Medical Campus in the press release. The study’s findings underscore the importance of developing new diagnostic tools to more accurately identify long COVID, ensuring that patients receive the care they need as quickly as possible.

The NIH RECOVER Initiative is one of the largest and most diverse research efforts focused on understanding, diagnosing, and treating long COVID. It brings together clinicians, scientists, caregivers, patients, and community members to address the challenges posed by this condition. The initiative also includes clinical trials testing potential interventions across five symptom focus areas.

The study's results align with the broader goals of the US Department of Health and Human Services (HHS) National Research Action Plan, a government-wide effort to respond to long COVID under the direction of Assistant Secretary for Health Admiral Rachel Levine. The plan aims to advance progress in preventing, diagnosing, treating, and providing services for individuals experiencing long COVID.

In conclusion, while routine lab tests are crucial in diagnosing many conditions, they fall short in accurately identifying long COVID. “Overall, 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.”

The NIH study emphasizes the need for novel biomarkers that can distinguish long COVID from other health issues. This would ultimately lead to better patient outcomes and more targeted treatments. As research continues, developing these new diagnostic tools will be essential in addressing the ongoing challenges of long COVID.

Reference

Erlandson KM, Geng LN, Selvaggi CA, et al. Standard Clinical Laboratory Measurements Do Not Differentiate Prior SARS CoV-2 Infection and Post-Acute Sequelae among Adults in the RECOVER Cohort. Annals of Internal Medicine. 2024. DOI: 10.7326/M24-0737