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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 in Boston Find COVID-19 Spike Protein Lingers in Long COVID-19 Patients

Viral reservoir could be behind persistence, says study, which also suggests a blood biomarker could be found for clinical laboratory testing

Microbiologists and virologists working closely with physicians treating long COVID-19 patients will gain new insights in a study that found coronavirus spike protein in COVID-19 patients’ blood up to 12 months after diagnosis. The researchers believe their findings could be used to develop a clinical laboratory biomarker for long COVID-19.

Researchers at Brigham and Women’s Hospital and Massachusetts General Hospital said medical experts are not sure why some people have unwelcome symptoms weeks and months after a positive COVID-19 diagnosis, while others clear the infection without lingering effects.

The scientists believe if this work is validated, clinical laboratories might gain an assay to use in the diagnosis of long COVID-19.

“The diagnosis and management of post-acute sequelae of COVID-19 (PASC) poses an ongoing medical challenge. … Strikingly, we detect SARS-CoV-2 spike antigen in a majority of PASC patients up to 12 months post-diagnosis, suggesting the presence of an active persistent SARS-CoV-2 viral reservoir,” the researchers wrote in their published study, which can be found on the preprint server medRxiv, titled, “Persistent Circulating SARS-CoV-2 Spike Is Associated with Post-Acute COVID-19 Sequelae.”

David Walt, PhD

“The half-life of spike protein in the body is pretty short, so its presence indicates that there must be some kind of active viral reservoir,” said David Walt, PhD (above), Professor of Pathology, Brigham and Women’s Hospital, and lead author of the study that found coronavirus spike protein in long COVID patients. The study findings indicate a potential clinical laboratory biomarker for long COVID-19. (Photo copyright: Brigham and Women’s Hospital.)

Viral Reservoir Possibly Behind Long COVID-19

The study suggests that SARS-CoV-2 finds a home in the body, particularly the gastrointestinal tract, “through viral reservoirs, where it continues to release spike protein and trigger inflammation,” Medical News Today reported.

Lead author of the study David Walt, PhD, Professor of Pathology, Brigham and Women’s Hospital and the Hansjörg Wyss Professor Biologically Inspired Engineering at Harvard Medical School, told The Guardian he “was motivated to carry out the study after earlier research by his colleagues detected genetic material from the COVID virus (viral RNA) in stool samples from children with multisystem inflammatory syndrome (a rare but serious condition that often strikes around four weeks after catching COVID) as well as spike protein and a marker of gut leakiness in their blood.”

Long COVID—also known as long-haul COVID, post-COVID-19, or its technical name, post-acute sequelae of COVID-19 or PASC—can involve health problems continuing weeks, months, or even years after a positive diagnosis, according to the federal Centers for Disease Control and Prevention (CDC).

Symptoms of long COVID, according to the researchers, include:

  • fatigue,
  • loss of smell,
  • memory loss,
  • gastrointestinal distress, and
  • shortness of breath. 

“If someone could somehow get to that viral load and eliminate it, it might lead to resolution of symptoms,” Walt told the Boston Globe, which noted that the researchers may explore a clinical trial involving antiviral drugs for treatment of long COVID-19.

Clues from Earlier Studies on Long COVID-19

Medical conditions that persisted following a COVID-19 infection have been studied for some time. In fact, in an earlier study, Walt and others found children who developed a multisystem inflammation syndrome weeks after being infected by SARS-CoV-2, according to their 2021 paper published in The Journal of Clinical Investigation, titled, “Multisystem Inflammatory Syndrome in Children Is Driven by Zonulin-Dependent Loss of Gut Mucosal Barrier.”

Although these earlier studies provided clues, the cause of PASC remains unclear, the researchers noted. They planned to take a more precise look at PASC biology by using appropriate sampling and patient recruitment.

“Disentangling the complex biology of PASC will rely on the identification of biomarkers that enable classification of patient phenotypes. Here, we analyze plasma samples collected from PASC and COVID-19 patients to determine the levels of SARS-CoV-2 antigens and cytokines and identify a blood biomarker that appears in the majority of PASC patients,” the researchers wrote.

Finding a Marker of a Persistent Infection

The researchers used plasma samples from 63 people with a previous SARS-CoV-2 diagnosis (37 also had PASC), Medical News Today reported. Over a 12-month period, the researchers’ findings included:

  • Detection in 65% of PASC samples of full-length spike, S1 spike, and nucleocapsid throughout the year of testing.
  • Spike detected in 60% of PASC patient samples, and not found in the COVID-19 samples.

In an interview with Scientific American, bioengineer Zoe Swank PhD, post-doctoral researcher, Brigham and Women’s Hospital, and co-author of the study, said, “Our main hypothesis is that the spike protein is not causing the symptoms, but it’s just a marker that is released because you still have infection of some cells with SARS-CoV-2.” 

In that article, Swank shared the scientists’ intent to do more research involving hundreds of samples over the course of the COVID-19 pandemic from many hospitals and people.

COVID-19 Not the Only Virus That Hangs On

Having a long-haul COVID-19 marker is a “game-changer,” according to an infectious disease expert who was not involved in the study.

“There has not so far been a clear, objective marker that is measurable in the blood of people experiencing long COVID-19,” Michael Peluso, MD, Assistant Professor, Medicine, University of California San Francisco, told Scientific American. “I hope their findings will hold up. It really would make a difference for a lot of people if a marker like this could be validated,” he added.

However, COVID-19 is not the only virus that could persist. Ebola also may linger in areas that skirt the immune system, such as the eye interior and central nervous system, according to a World Health Organization fact sheet.

Thus, medical laboratory leaders may want to follow the Brigham and Women’s Hospital research to see if the scientists validate their finding, discover a biomarker for long-haul COVID-19, and pursue a clinical trial for antiviral drugs. Such discoveries could have implications for how diagnostic professionals work with physicians to care for long COVID patients.   

Donna Marie Pocius

Related Information:

Persistent Circulating SARS-CoV-2 Spike Is Associated with Post-Acute COVID-19 Sequelae

Long COVID: “Viral Reservoir” of Spike Protein May Explain Long-Term Symptoms

Are Pockets of COVID in the Gut Causing Long-Term Symptoms?

CDC: COVID-19: Long-Term Effects

Boston Researchers May Have Found Biomarker for Long COVID

Multisystem Inflammatory Syndrome in Children Is Driven by Zonulin-Dependent Loss of Gut Mucosal Barrier

People with Long COVID May Still Have Spike Proteins in Their Blood

WHO: Ebola Virus Disease

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