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National Institutes of Health Study Finds No Reliable Biomarkers Exist for Long COVID

Study is another example of how important clinical laboratory testing is when government officials attack a new public health issue

Long COVID—aka SARS-CoV-2 infection’s post-acute sequelae (PASC)—continues to confound researchers seeking one or more clinical laboratory biomarkers for diagnosing the condition. A new study led by the National Institutes of Health’s (NIH) RECOVER Initiative and supported by NYU Langone Health recently revealed that “routine clinical laboratory tests were unable to provide a reliable biomarker of … long COVID,” Inside Precision Medicine reported.

The NIH’s Researching COVID to Enhance Recovery (RECOVER) Initiative used a cohort study of more than 10,000 individuals with and without previous COVID-19 diagnoses and compared samples using 25 common laboratory tests in hopes a useful biomarker could be identified. They were unsuccessful.

Leora Horwitz, MD, director of the Center for Healthcare Innovation and Delivery Science and co-principal investigator for the RECOVER CSC (Clinical Science Core) at NYU Langone; Andrea S. Foulkes, ScD, director of biostatistics at Massachusetts General Hospital, Boston; and Grace A. McComsey, MD, VP of research and associate chief scientific officer at University Hospitals Health System, and professor of pediatrics and medicine at Case Western Reserve University, led the study.

Long COVID—or PASC—is an umbrella term for those with persistent post-COVID infection symptoms that negatively impact quality of life. Though it affects millions worldwide and has been called a major public health burden, the NIH/Langone study scientists noted one glaring problem: PASC is defined differently in the major tests they studied. This makes consistent diagnoses difficult.

The study brought to light possible roadblocks that prevented biomarker identification.

“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 study authors wrote in their study, “Differentiation of Prior SARS-CoV-2 Infection and Postacute Sequelae by Standard Clinical Laboratory Measurements in the RECOVER Cohort,” published in the journal Annals of Internal Medicine.

“This study is an important step toward defining long COVID beyond any one individual symptom,” said study author Leora Horwitz, MD (above), director of the Center for Healthcare Innovation and Delivery Science and co-principal investigator for the RECOVER CSC at NYU Langone, in a Langone Health news release. “This definition—which may evolve over time—will serve as a critical foundation for scientific discovery and treatment design.” In the future, clinical laboratories may be tasked with finding combinations of routine and reference tests that, together, enable a more precise and earlier diagnosis of long COVID.  (Photo copyright: Yale School of Medicine.)

NIH/Langone Study Details

“The study … 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 US,” Inside Precision Medicine reported.

However, the scientists found no clinical laboratory “value” among the 25 tests examined that “reliably indicate previous infection, PASC, or the particular cluster type of PASC,” Inside Precision Medicine noted, adding that “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.”

“In a cohort study of more than 10,000 participants with and without prior SARS-CoV-2 infection, we found no evidence that any of 25 routine clinical laboratory values provide a reliable biomarker of prior infection, PASC, or the specific type of PASC cluster. … 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 study authors wrote in Annals of Internal Medicine.

In addition to a vague definition of PASC, the NIH/Langone researchers noted a few other potential problems identifying a biomarker from the research.

“Use of only selected biomarkers, choice of comparison groups, if any (people who have recovered from PASC or healthy control participants); duration of symptoms; types of symptoms or phenotypes; and patient population features, such as sex, age, race, vaccination status, comorbidities, and severity of initial infection,” could be a cause for ambiguous results, the scientists wrote.

Future Research

“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, proteomics, metabolomics) to identify novel biomarkers,” the study authors wrote in Annals of Internal Medicine.

“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,” said David Goff, MD, PhD, director of the division of cardiovascular sciences at the NIH’s National Heart, Lung, and Blood Institute, in an NHLBI 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.”

“Approximately one in 20 US adults reported persisting symptoms after COVID-19 in June 2024, with 1.4% reporting significant limitations,” the NIH/Langone scientists wrote in their published study.

Astute clinical laboratory scientists will recognize this as possible future diagnostic testing. There is no shortage of need.

—Kristin Althea O’Connor

Related Information:

“Long COVID” Evades Common SARS-CoV-2 Clinical Lab Tests

Differentiation of Prior SARS-CoV-2 Infection and Postacute Sequelae by Standard Clinical Laboratory Measurements in the RECOVER Cohort

Long COVID Diagnostics: An Unconquered Challenge

RECOVER Study Offers Expanded Working Definition of Long COVID

Routine Lab Tests Are Not a Reliable Way to Diagnose Long COVID

Researchers at Stanford University Discover Gene Variant That Appears to Protect Individuals from Both Alzheimer’s and Parkinson’s Disease

Study findings may lead to new clinical laboratory tests, as well as vaccines and immunotherapies for neurodegenerative diseases

Research into the human genome continues to produce useful new insights. This time, a study led by researchers at Stanford University identified a genetic variation that is believed to help “slow or even stall” progression of neurodegenerative diseases, including Alzheimer’s and Parkinson’s, according to a press release. Because these genetic variations are common, it is likely that diagnostic tests can be developed for use by clinical laboratories.

Researchers at Stanford Medicine led the study which discovered that approximately one in five individuals carry the gene variant, a protective allele identified as DR4 (aka, HLA-DR4). It’s one of a large number of alleles found in a gene known as DRB1.

DRB1 is part of a family of genes collectively known as the human lymphocyte antigen complex or HLA. The HLA-DRB1 gene plays a crucial role in the ability of the immune system to see a cell’s inner contents.

The Stanford scientists published their findings in the journal PNAS titled, “Multiancestry Analysis of the HLA Locus in Alzheimer’s and Parkinson’s Diseases Uncovers a Shared Adaptive Immune Response Mediated by HLA-DRB1*04 Subtypes.” Approximately 160 researchers from roughly 25 countries contributed to the work. 

Emmanuel Mignot, MD, PhD

“In an earlier study, we’d found that carrying the DR4 allele seemed to protect against Parkinson’s disease,” said Emmanuel Mignot, MD, PhD (above), Director of the Stanford Center for Narcolepsy, in a Stanford press release. “Now, we’ve found a similar impact of DR4 on Alzheimer’s disease.” Clinical laboratories may soon have new vaccines for both neurodegenerative diseases. (Photo copyright: Stanford University.)


DR4 Found to Impact Both Parkinson’s and Alzheimer’s Diseases

To perform their research, the team examined a large collection of medical and genetic databases from 176,000 people who had either Alzheimer’s or Parkinson’s disease. The people involved in the study were from numerous countries located in East Asia, Europe, the Middle East and South America. Their genomes were then compared with people who did not have the diseases, focusing on the incidence and age of onset.

“In an earlier study we’d found that carrying the DR4 allele seemed to protect against Parkinson’s disease,” said Mignot in the Stanford press release. “Now, we’ve found a similar impact of DR4 on Alzheimer’s disease.”

The team found that about 20% to 30% of people carry DR4, and that they have around a 10% risk reduction for developing the two diseases. 

“That this protective factor for Parkinson’s wound up having the same protective effect with respect to Alzheimer’s floored me,” said Emmanuel Mignot, MD, PhD, the Craig Reynolds Professor of Sleep Medicine in the Department of Psychiatry and Behavioral Sciences at Stanford University and the Director of the Stanford Center for Narcolepsy, in the Stanford Medicine press release. “The night after we found that out, I couldn’t sleep.”

The scientists also analyzed data from autopsied brains of more than 7,000 Alzheimer’s patients and discovered that individuals who carry DR4 had fewer neurofibrillary tangles and that those tangles are composed mainly of modified tau proteins, a common biomarker for Alzheimer’s.

The presence of these tangles corresponds with the severity of Alzheimer’s disease. They are not typically seen in Parkinson’s patients, but the Stanford team found that Parkinson’s patients who did carry DR4 experienced later onset of symptoms.

Mignot stated that tau, which is essential in Alzheimer’s, may also play a role in Parkinson’s, but that further research is required to prove its function.

Both diseases are characterized by the progressive loss of certain nerve cells or neurons in the brain and are linked to an accumulation of abnormal proteins. The Stanford researchers suggested that the DR4 gene variant may help protect individuals from Alzheimer’s and Parkinson’s by preventing the buildup of tau proteins.

“This is a very interesting study, providing additional evidence of the involvement of the immune system in the pathogenesis of Alzheimer’s and Parkinson’s,” neurologist Wassim Elyaman, PhD, Assistant Professor of Neurological Sciences in Neurology, the Taub Institute and the Institute for Genomic Medicine at Columbia University, told Live Science.

New Vaccines and Immunotherapies

According to the Alzheimer’s Association, more than six million Americans are currently living with Alzheimer’s disease and approximately one in three Americans die with Alzheimer’s or another dementia. 

The Parkinson’s Foundation states that nearly one million Americans are currently living with Parkinson’s disease, and that number is expected to rise to 1.2 million by 2030. Parkinson’s is the second-most common neurodegenerative disease after Alzheimer’s disease.

Even though the genetic analysis of the Stanford research is strong, more immune cell and blood-based research is needed to definitively establish how tau is connected to the two diseases.

This research could have implications for clinical laboratories by giving them biomarkers for a useful new diagnostic test, particularly for diagnosing Alzheimer’s and Parkinson’s.

Further, Mignot suggested that an effective vaccine could delay the onset or slow the progression of both diseases. He hopes to test his hypothesis on genetically modified mice and eventually human subjects.

—JP Schlingman

Related Information:

Stanford Medicine-led Study Finds Genetic Factor Fends Off Alzheimer’s and Parkinson’s

Gene Variant Carried by One in Five People May Guard Against Alzheimer’s and Parkinson’s, Massive Study Finds

Multiancestry Analysis of the HLA Locus in Alzheimer’s and Parkinson’s Diseases Uncovers a Shared Adaptive Immune Response Mediated by HLA-DRB1*04 Subtypes

Alzheimer’s Disease: Tau Biology and Pathology

Tau Protein and Alzheimer’s Disease: What’s the Connection?

C₂N Diagnostics Releases PrecivityAD, the First Clinical Laboratory Blood Test for Alzheimer’s Disease

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