Topic

Biomarkers

Domain: Biomarker

PEM-relevant research

20 studies in the atlas

Objective biological markers that may support ME/CFS diagnosis or stratification.

What We Know

Naviaux metabolomics, cytokine panels (Montoya), and the nanoelectronics immune assay (Esfandyarpour) have all shown promising discriminatory ability. No single biomarker has been validated for clinical use.

What We Think

Multi-omics integration approaches combining metabolomics, proteomics, and immune profiling may yield more robust diagnostic signatures.

What We Don't Know

None of the proposed biomarkers are yet clinically validated. Lack of standardized cohorts and assays makes cross-study comparison difficult.

Studies in this Topic

E0 ConsensusPEM ✓Moderate confidenceReviewed

Chronic Fatigue Syndrome: Diagnosis, Treatment, and Future Direction.

Graves, B Sue, Patel, Mitsu, Newgent, Hailey et al.·Cureus·2024

ME/CFS is a serious illness that causes extreme tiredness that doesn't improve with rest and often gets worse with activity. People with ME/CFS also struggle with brain fog, pain, sleep problems, and immune system issues. Right now, doctors don't have a simple blood test or scan to diagnose ME/CFS, which makes it hard to identify and treat the condition properly.

BiomarkersCognitive ImpairmentPost-Exertional MalaiseImmune Dysregulation

E0 ConsensusPEM ?Moderate confidenceReviewed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): diagnosis and management.

Fan, Jin, Jiao, Jiao, Chang, Hai-Qing et al.·Journal of translational medicine·2025

This comprehensive review examines how ME/CFS is diagnosed and treated based on current medical knowledge. The authors found that ME/CFS is caused by problems with the immune system, energy production in cells, and brain inflammation, but there are currently no definitive blood tests to confirm the disease. Treatment options include both medication approaches (targeting immune dysfunction and cell energy) and non-medication strategies like activity pacing and cognitive behavioral therapy, though doctors now recognize that exercise programs can actually harm some patients.

BiomarkersNeuroinflammationImmune Dysregulation

E0 ConsensusPEM ?PreliminaryReviewed

A systematic review of cytokines in chronic fatigue syndrome/myalgic encephalomyelitis/systemic exertion intolerance disease (CFS/ME/SEID).

Corbitt, Matthew, Eaton-Fitch, Natalie, Staines, Donald et al.·BMC neurology·2019

Researchers reviewed 15 studies that measured immune signaling molecules called cytokines in people with ME/CFS compared to healthy people. Although many studies have looked at cytokines in ME/CFS, the results were too mixed and inconsistent to show that cytokines could be used as a reliable test for the condition or to confirm a clear role in causing the disease.

BiomarkersImmune Dysregulation

E0 ConsensusPEM ✓Moderate confidenceReviewed

[Myalgic encephalomyelitis or chronic fatigue syndrome].

Brinth, Louise, Nielsen, Henrik, Varming, Kim et al.·Ugeskrift for laeger·2019

ME/CFS is a serious condition that causes extreme tiredness affecting both mind and body, along with pain, sleep problems, difficulty thinking clearly, and a symptom called post-exertional malaise where activity makes symptoms worse. Research has found changes in patients' cells, hormones, immune systems, and how their bodies process energy, which could lead to better ways to diagnose and treat this condition.

Metabolic DysfunctionBiomarkersPost-Exertional MalaiseImmune Dysregulation

E0 ConsensusPEM ?Weak / uncertainReviewed

A systematic review of metabolomic dysregulation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis/Systemic Exertion Intolerance Disease (CFS/ME/SEID).

Huth, Teilah Kathryn, Eaton-Fitch, Natalie, Staines, Donald et al.·Journal of translational medicine·2020

Researchers reviewed 11 studies that measured tiny chemical molecules (metabolites) in the blood and urine of ME/CFS patients to see if problems with these chemicals might explain the illness. While they found some patterns—especially with chemicals related to amino acids (building blocks of proteins)—the results were inconsistent across different studies. The researchers concluded that we don't yet have enough evidence that metabolite problems cause ME/CFS.

Biomarkers

E0 ConsensusPEM ?Moderate confidenceReviewed

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back!

Ariza, Maria Eugenia·Biomolecules·2021

This review examines whether certain viruses, particularly Epstein-Barr virus (EBV), may play a role in ME/CFS. Earlier research on this topic produced mixed results, leading some scientists to think viruses weren't involved. However, newer research methods have found that specific proteins made by EBV could contribute to immune system and nervous system problems in some ME/CFS patients.

BiomarkersImmune Dysregulation

E0 ConsensusPEM ?PreliminaryReviewed

A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease.

Holden, Sean, Maksoud, Rebekah, Eaton-Fitch, Natalie et al.·Journal of translational medicine·2020

This review looked at 19 studies examining whether the power-generating structures in our cells (called mitochondria) work differently in people with ME/CFS compared to healthy people. While many studies found some differences in how these cellular power plants function, the results were inconsistent across different research groups, making it hard to draw clear conclusions about whether mitochondrial problems actually cause ME/CFS.

Biomarkers

E0 ConsensusPEM ?PreliminaryMachine draft

Could the kynurenine pathway be the key missing piece of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) complex puzzle?

Kavyani, Bahar, Lidbury, Brett A, Schloeffel, Richard et al.·Cellular and molecular life sciences : CMLS·2022

This review explores whether problems with how your body processes an amino acid called tryptophan might explain ME/CFS symptoms. The kynurenine pathway is a biochemical process that helps your cells make energy and affects immune function and brain inflammation. The authors suggest that abnormalities in this pathway could be a missing piece in understanding why ME/CFS develops.

BiomarkersNeuroinflammation

E0 ConsensusPEM ?Moderate confidenceMachine draft

Insights into Metabolite Diagnostic Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Yamano, Emi, Watanabe, Yasuyoshi, Kataoka, Yosky·International journal of molecular sciences·2021

ME/CFS is a serious condition that causes extreme exhaustion and is difficult to diagnose because we don't have reliable tests for it. This review examined research on how the chemicals in patients' bodies differ from healthy people, looking for patterns that could help doctors identify ME/CFS with a simple blood test. Scientists reviewed studies that measured these body chemicals and tested them in animal models to understand what goes wrong in ME/CFS.

Biomarkers

E1 ReplicatedPEM ✓Moderate confidenceReviewed

Metabolic features of chronic fatigue syndrome

Robert K. Naviaux, Jane C. Naviaux, Kefeng Li et al.·Proceedings of the National Academy of Sciences (PNAS)·2016·n=84

This study analyzed blood metabolites from 84 ME/CFS patients and 45 healthy controls using untargeted metabolomics. Researchers found 80% of the abnormal metabolites were decreased in ME/CFS patients, suggesting a hypometabolic state — the body running in energy conservation mode. The pattern resembled a 'dauer-like' state seen in organisms under stress.

Metabolic DysfunctionBiomarkers

E1 ReplicatedPEM ?Moderate confidenceReviewed

Cytokine signature associated with disease severity in chronic fatigue syndrome patients

Jose G. Montoya, Tyson H. Holmes, Jill N. Anderson et al.·Proceedings of the National Academy of Sciences (PNAS)·2017·n=192

Stanford researchers measured 51 cytokines in 192 ME/CFS patients and 392 healthy controls. Seventeen cytokines were significantly elevated in ME/CFS, with TGF-beta most strongly associated with disease severity. More severe patients had higher cytokine levels, suggesting immune activation scales with illness burden.

Immune DysregulationBiomarkers

E2 ModeratePEM ✓PreliminaryReviewed

A nanoelectronics-blood-based diagnostic biomarker for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Rahim Esfandyarpour, Aref Kashi, Maya Nemat-Gorgani et al.·Proceedings of the National Academy of Sciences (PNAS)·2019·n=40

Stanford researchers developed a nanoelectronics device that detects immune cell changes using a tiny electrical sensor. When salt stress was applied to blood samples, ME/CFS patient samples showed a distinctly different electrical response compared to healthy controls. This 'nano-needle' assay could potentially serve as an objective diagnostic test.

BiomarkersDiagnostics

E2 ModeratePEM ✓Moderate confidenceMachine draft

Development and validation of blood-based diagnostic biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using EpiSwitch® 3-dimensional genomic regulatory immuno-genetic profiling.

Hunter, Ewan, Alshaker, Heba, Bundock, Oliver et al.·Journal of translational medicine·2025

Researchers developed a new blood test called EpiSwitch®CFS that may help diagnose ME/CFS by detecting specific patterns in how DNA is organized in blood cells. When tested on stored blood samples from 47 ME/CFS patients and 61 healthy people, the test correctly identified 92% of ME/CFS patients and correctly ruled out 98% of healthy controls. This could potentially help doctors diagnose ME/CFS more reliably, since there is currently no standard blood test for the condition.

BiomarkersNeuroinflammationImmune Dysregulation

E2 ModeratePEM ✓Moderate confidenceMachine draft

One-year follow-up of young people with ME/CFS following infectious mononucleosis by Epstein-Barr virus.

Pricoco, Rafael, Meidel, Paulina, Hofberger, Tim et al.·Frontiers in pediatrics·2023

This study followed 25 young people (12 teenagers and 13 young adults) who developed ME/CFS after having infectious mononucleosis caused by Epstein-Barr virus. Researchers checked on their symptoms and quality of life at the start, 6 months, and 12 months later. Teenagers showed better improvement over the year, with more than half no longer meeting ME/CFS criteria, while young adults continued to have severe symptoms with little improvement.

BiomarkersPost-Exertional Malaise

E3 PreliminaryPEM ✓Moderate confidenceReviewed

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): An Overview.

Deumer, Undine-Sophie, Varesi, Angelica, Floris, Valentina et al.·Journal of clinical medicine·2021

ME/CFS is a long-term illness that causes extreme tiredness, worsening of symptoms after activity, and difficulty thinking clearly. Patients experience these symptoms very differently from one another, and currently there are no blood tests or physical exams that can definitively diagnose the condition. This review examines several potential causes, including past infections, genetic factors, hormone imbalances, and changes in gut bacteria, while exploring whether a simple blood test might someday help diagnose ME/CFS.

BiomarkersPost-Exertional Malaise

E3 PreliminaryPEM ✓PreliminaryReviewed

Attenuating post-exertional malaise in Myalgic encephalomyelitis/chronic fatigue syndrome and long-COVID: Is blood lactate monitoring the answer?

Faghy, Professor Mark A, Ashton, Dr Ruth Em, McNelis, Mr Robin et al.·Current problems in cardiology·2024

This editorial discusses whether measuring blood lactate levels could help manage post-exertional malaise (PEM)—the debilitating fatigue that occurs after physical activity in ME/CFS and long-COVID patients. The authors suggest that blood lactate monitoring might help identify safe exercise limits and prevent PEM crashes. However, this is an opinion piece rather than a research study with new data.

BiomarkersPost-Exertional Malaise

E3 PreliminaryPEM ✓PreliminaryReviewed

Tetrahydrobiopterin in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Friend or Foe?

Rahman, A F M Towheedur, Benko, Anna, Bulbule, Sarojini et al.·Biomolecules·2025

This review article examines a molecule called tetrahydrobiopterin (BH4) and its possible role in ME/CFS, particularly in patients who experience orthostatic intolerance (dizziness or fainting when standing up). The researchers found that BH4 metabolism—the way the body processes this molecule—is not working properly in ME/CFS patients with these symptoms. By understanding how BH4 goes wrong, scientists hope to explain why ME/CFS patients have problems with blood flow to the brain.

BiomarkersPost-Exertional Malaise

E3 PreliminaryPEM ✓PreliminaryReviewed

Dissecting the genetic complexity of myalgic encephalomyelitis/chronic fatigue syndrome via deep learning-powered genome analysis.

Zhang, Sai, Jahanbani, Fereshteh, Chander, Varuna et al.·medRxiv : the preprint server for health sciences·2025

Researchers used advanced artificial intelligence to analyze the genes of ME/CFS patients and discovered 115 genes that may contribute to the disease. They found that people with ME/CFS have lower levels of these risk genes active in their immune cells and nervous system. This genetic analysis could eventually help doctors diagnose ME/CFS more accurately and identify new treatment targets.

BiomarkersCognitive ImpairmentPost-Exertional MalaiseImmune Dysregulation

E3 PreliminaryPEM ✓PreliminaryReviewed

Precision Medicine Study of Post-Exertional Malaise Epigenetic Changes in Myalgic Encephalomyelitis/Chronic Fatigue Patients During Exercise.

Sharma, Sayan, Hodges, Lynette D, Peppercorn, Katie et al.·International journal of molecular sciences·2025

This study looked at how exercise affects the chemical switches on our genes (epigenetics) in ME/CFS patients, particularly during post-exertional malaise (PEM)—the exhaustion that worsens after physical activity. Researchers took blood samples from five ME/CFS patients before, immediately after, and 24-48 hours after an exercise test, and found distinct patterns of genetic changes that were specific to ME/CFS patients and not seen in healthy controls. These changes affected genes related to immune function, inflammation, and blood vessel health, suggesting the body's response to exercise in ME/CFS is fundamentally different at the molecular level.

BiomarkersPost-Exertional MalaiseImmune Dysregulation

E3 PreliminaryPEM ?Weak / uncertainMachine draft

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: When Suffering Is Multiplied.

Komaroff, Anthony L·Healthcare (Basel, Switzerland)·2021

ME/CFS is a real illness with measurable biological problems in the body, even though standard blood tests often appear normal. Over the past 20 years, advanced research tools have found objective abnormalities in people with ME/CFS. Unfortunately, many doctors aren't aware of this evidence, which can lead them to dismiss patients' symptoms and wrongly suggest there's nothing physically wrong—adding emotional harm on top of the already serious illness.

Biomarkers