Millions of people worldwide continue to experience symptoms weeks, months, or even years after an initial SARS-CoV-2 infection. For more than four years, long COVID has remained one of the pandemic’s most perplexing mysteries. Yet, despite the global scale of the problem, there has been no objective way to confirm a diagnosis. Doctors have relied almost entirely on patient-reported symptoms and a process of elimination to rule out other causes.That may be about to change. A team of researchers from the Translational Genomics Research Institute (TGen), part of City of Hope, and the Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center has identified a potential biomarker that could offer the first measurable, laboratory-based confirmation of long COVID. Their findings, published in the journal Infection, point to a new way of detecting the lingering footprint of the virus in the body — and with it, the possibility of changing how long COVID is diagnosed, studied, and treated.Why Diagnosing Long COVID Is Difficult?Long COVID is not a single, uniform illness. It’s a complex, post-viral condition with more than 200 possible symptoms, ranging from crushing fatigue and brain fog to shortness of breath, chest pain, and neurological changes. According to estimates, anywhere from 15% to over 40% of people infected with COVID-19 may experience lingering symptoms, depending on which definition is used.That lack of standardization is a huge problem. A recent study analyzing definitions from five countries — the US, UK, Netherlands, Sweden, and Puerto Rico — found wildly different prevalence rates when the same patient dataset was assessed. Without an objective test, researchers struggle to identify who truly has long COVID, making large-scale studies inconsistent and slowing the development of targeted treatments.William Stringer, M.D., a senior author of the new study and a Lundquist Institute investigator, explains the gap: “If a patient arrives in clinic and describes the persistence of typical signs and symptoms of long COVID, 12 weeks or more after COVID-19 infection, I give them a presumptive diagnosis. But I don’t have any blood tests or biomarkers to confirm this diagnosis.”Traces of the Virus in Extracellular VesiclesThe new research zeroes in on extracellular vesicles (EVs) — microscopic packages released by cells to transport proteins, metabolites, and other materials throughout the body. These vesicles act like biological couriers, shuttling information from cell to cell.Researchers collected and analyzed 56 blood samples from 14 long COVID patients over 12 weeks of aerobic exercise training, as part of an ongoing clinical trial. What they found was striking- 65 distinct protein fragments from SARS-CoV-2 inside the EVs, all originating from the virus’s Pp1ab protein.This protein is an RNA replicase enzyme — crucial to the virus’s ability to copy itself and produce new viral particles — and is unique to SARS-CoV-2. It does not occur in uninfected human cells. “We thought that maybe if the virus is circulating or moving in the body, we should try to see if EVs are carrying those viral fragments,” says lead author Asghar Abbasi, Ph.D., of the Lundquist Institute.Importantly, these viral peptides were detected in every patient, though not in every individual blood draw, and were absent in a separate control group using pre-pandemic EV samples. That suggests the biomarker may be specific to long COVID.Could This Mean the Virus Lingers in the Human Body?One of the most debated questions in long COVID research is whether the virus — or pieces of it — persist in the body long after the initial infection. Evidence has been mounting that SARS-CoV-2 may remain in certain tissues, creating “viral reservoirs” that could contribute to ongoing symptoms.The new study supports this theory. The detection of Pp1ab fragments inside EVs hints that remnants of the virus might be traveling through the body, possibly reaching tissues without typical viral entry points, such as the brain. How this happens remains unknown. EVs may play a role in delivering these viral remnants to distant sites, potentially influencing symptoms.Still, co-senior author Patrick Pirrotte, Ph.D., of TGen urges caution. “The molecular signal of the viral peptides was subtle and not consistently detected at every time point,” he notes. “We don’t yet know if exercise triggers the release of these proteins, if they come from a permanent reservoir, or if they’re simply leftover molecular ‘trash’ from past viral replication.”If validated by further studies, this biomarker could be a game-changer for both clinical care and research.For patients- An objective blood test could confirm a diagnosis and give legitimacy to those whose symptoms have been dismissed or attributed to other causes. It could also guide treatment decisions, help monitor disease progression, and potentially measure response to therapy.For researchers- A biomarker could bring much-needed consistency to clinical trials. Right now, varying definitions and diagnostic criteria make it difficult to compare studies or determine which interventions truly work. With a measurable indicator, scientists could better select participants, study the underlying mechanisms, and test targeted treatments more effectively.The study leaves several unanswered questions. For one, it’s not yet clear whether these viral fragments are present in people who had COVID-19 but recovered without long-term symptoms. Without that comparison, it’s hard to know if the biomarker is unique to long COVID or simply a lingering byproduct of infection.The mechanism is also murky, are these proteins signs of ongoing viral replication somewhere in the body, or are they debris being cleared out over time? And if they are part of an active process, could targeting them improve patient outcomes?Until these issues are resolved, the biomarker is more of a promising lead than a definitive diagnostic tool.Why Have We Not Fully Understood Long COVID?Long COVID remains an evolving medical challenge. Despite years of research, we still don’t fully know what causes it, why it affects some people and not others, or how to predict recovery. Without a standardized definition, prevalence estimates vary widely, and with more than 800 million COVID cases worldwide, the potential number of patients is staggering.The National Academies of Sciences, Engineering, and Medicine in the US has proposed a definition that includes up to 200 symptoms and states that no single symptom can confirm or rule out a diagnosis. While comprehensive, some experts argue that narrowing the symptom list could make diagnosis more specific and practical for research and clinical use.The researchers behind the new study are already planning follow-up work to test whether the biomarker appears in people who had COVID-19 without developing long COVID. They also aim to investigate whether its presence changes over time or in response to treatments.If their findings hold, this biomarker could mark the start of a new chapter in the fight against long COVID — one where diagnosis is not just about listening to symptoms, but also about identifying a clear, measurable biological signal.As Dr. Stringer puts it, “This raises the question: is this just continuing to take out the trash from the COVID-infected cell, or is this really ongoing replication someplace? That’s the mechanistic issue that needs to be resolved in future studies.”