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BiomarkerPEM-relevant

Biomarkers

258 studies in the atlas

Identifying reliable biomarkers for ME/CFS is a major research priority. Studies have explored cytokine dysregulation, altered gene expression patterns, metabolomics signatures, autoantibodies against G-protein coupled receptors, and blood-based indicators of immune and metabolic dysfunction. Multi-omics approaches — combining proteomics, transcriptomics, and metabolomics — have shown promise in identifying patient subgroups and distinguishing ME/CFS from other conditions. A reliable diagnostic biomarker would address one of the most significant clinical challenges in ME/CFS: the absence of an objective laboratory test for diagnosis.

What we know

  • Multiple candidate biomarkers have been identified, including NK cell cytotoxicity, cytokine profiles, and metabolomic signatures
  • Two-day CPET provides an objective functional measure, though it is not a blood-based biomarker
  • Several blood-based diagnostic assays are under development, including impedance-based and proteomic approaches
  • No single biomarker has yet been validated for clinical diagnostic use

What remains uncertain

  • Whether a single biomarker or a panel approach will prove most effective
  • Biomarker results may vary by disease duration, severity, and subtype
  • The Ron Davis lab impedance assay showed initial promise but awaits independent replication at scale
  • Whether Long COVID biomarker research will accelerate ME/CFS biomarker discovery

What is emerging

  • Which candidate biomarkers will survive large-scale validation
  • Whether biomarkers can predict disease trajectory or treatment response
  • The timeline to a clinically available diagnostic test
  • Whether different ME/CFS subtypes require different biomarker panels

Start here

E0 ConsensusPEM requiredPreliminary

Dysregulation of lipid metabolism, energy production, and oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War Syndrome and fibromyalgia.

Davis, Leah, Higgs, Maisy, Snaith, Ailsa et al.·Frontiers in neuroscience·2025

This review examined research showing that ME/CFS, Gulf War Syndrome, and fibromyalgia may share similar problems with how the body produces energy and handles stress at the cellular level. Scientists found that these three conditions show signs of disrupted fat metabolism, energy production difficulties, and increased cellular damage from oxidative stress. Better understanding these shared biological problems could help doctors diagnose these conditions faster and develop treatments that target the root causes rather than just treating symptoms.

Research Momentum

258 publications over 36 years. Recent trend: steady (17/year over the last 3 years).

All Studies

258 studies, sorted by review status and evidence level

E0 ConsensusPEM unclearModerate confidenceReview-NarrativeEditor reviewed

Machine learning and multi-omics in precision medicine for ME/CFS.

Huang, Katherine, Lidbury, Brett A, Thomas, Natalie et al.·Journal of translational medicine·2025

This review examines how advanced computer analysis and detailed biological testing could help doctors better understand and treat ME/CFS. Because ME/CFS affects people differently, researchers are exploring ways to look at each patient's unique genetic and molecular makeup to find personalized treatments. The study discusses how combining multiple types of biological data—genes, proteins, and metabolites—along with artificial intelligence could help identify specific patterns that distinguish ME/CFS patients and guide their care.

Biomarkers
E0 ConsensusPEM requiredModerate confidenceReview-NarrativeEditor reviewed

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.

BiomarkersImmune SystemCognitive ImpairmentPost-Exertional Malaise
E0 ConsensusPEM requiredModerate confidenceSystematic-ReviewEditor reviewed

Comparison of serum acylcarnitine levels in patients with myalgic encephalomyelitis/chronic fatigue syndrome and healthy controls: a systematic review and meta-analysis.

Jinushi, Ryuhei, Masuda, Sakue, Tanisaka, Yuki et al.·Journal of translational medicine·2023

This review combined results from seven studies comparing a chemical in the blood called acylcarnitine between people with ME/CFS and healthy people. Researchers found that people with ME/CFS have significantly lower levels of this chemical. These lower levels might one day help doctors diagnose ME/CFS, though more research is needed before it can be used as a reliable test.

BiomarkersEnergy Metabolism
E0 ConsensusPEM requiredPreliminarySystematic-ReviewEditor reviewed

Biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review.

Maksoud, Rebekah, Magawa, Chandi, Eaton-Fitch, Natalie et al.·BMC medicine·2023

Researchers reviewed 101 studies looking for biological markers (biomarkers) that could help diagnose ME/CFS. A biomarker is something measurable in your blood or body that shows a disease is present. While scientists found many potential biomarkers affecting the immune system, energy production, circulation, and other body functions, none have been proven reliable enough to use as a diagnostic test yet.

BiomarkersImmune System
E0 ConsensusPEM unclearPreliminarySystematic-ReviewEditor reviewed

A systematic review and meta-analysis of urinary biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Taccori, Asher, Maksoud, Rebekah, Eaton-Fitch, Natalie et al.·Journal of translational medicine·2023

Researchers looked at 21 studies examining urine samples from ME/CFS patients to find markers that could help diagnose the condition. They focused especially on a substance called cortisol (a stress hormone) in urine. While they found some differences in urine samples between people with ME/CFS and healthy people, the results were too inconsistent to identify a reliable single marker for diagnosis.

Biomarkers
E0 ConsensusPEM not requiredModerate confidenceEvidence-MapEditor reviewed

Frontiers in chronic fatigue syndrome research: An analysis of the top 100 most influential articles in the field.

Wang, Xingxin, Li, Xuhao, Dong, Tiantian et al.·Medicine·2023

This study analyzed the 100 most-cited scientific papers on ME/CFS to understand what researchers have been focusing on and what directions the field is moving toward. Researchers found that ME/CFS research is a global effort involving hundreds of institutions across many countries, with studies increasingly looking at cognitive behavioral therapy, how to diagnose ME/CFS better, and the biological basis of the condition. The analysis suggests future research will likely focus on finding biological markers, understanding immune system changes, and identifying genetic risk factors.

Biomarkers
E0 ConsensusPEM unclearPreliminaryReview-NarrativeEditor reviewed

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.

NeuroinflammationBiomarkers
E0 ConsensusPEM unclearModerate confidenceEditorialEditor reviewed

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 System
E0 ConsensusPEM unclearModerate confidenceReview-NarrativeEditor reviewed

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
E0 ConsensusPEM requiredModerate confidenceReview-NarrativeEditor reviewed

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Neurological Entity?

Murga Gandasegui, Iñigo, Aranburu Laka, Larraitz, Gargiulo, Pascual-Ángel et al.·Medicina (Kaunas, Lithuania)·2021

This review examines whether ME/CFS is primarily a neurological disorder by looking at brain imaging studies and tests of the autonomic nervous system (the part that controls automatic body functions like heart rate). The authors found that while brain imaging shows various changes in ME/CFS patients, these changes aren't specific enough to diagnose the condition on their own. However, specialized tests measuring heart rate variability and immune responses show promise as potential biomarkers that could help identify and monitor ME/CFS.

BiomarkersPost-Exertional Malaise
E0 ConsensusPEM unclearWeak / uncertainSystematic-ReviewEditor reviewed

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 unclearPreliminarySystematic-ReviewEditor reviewed

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 unclearPreliminarySystematic-ReviewEditor reviewed

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 System
E0 ConsensusPEM requiredModerate confidenceReview-NarrativeEditor reviewed

[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.

BiomarkersEnergy MetabolismImmune SystemPost-Exertional Malaise
E0 ConsensusPEM not requiredModerate confidenceMeta-AnalysisEditor reviewed

Inflammatory proteins are altered in chronic fatigue syndrome-A systematic review and meta-analysis.

Strawbridge, Rebecca, Sartor, Maria-Laura, Scott, Fraser et al.·Neuroscience and biobehavioral reviews·2019

This research review looked at 42 studies measuring inflammatory proteins (substances in the blood linked to inflammation) in people with ME/CFS compared to healthy people. The researchers found that people with ME/CFS had higher levels of five specific inflammatory proteins, but twelve other proteins were similar to healthy controls. This suggests that inflammation may play a role in ME/CFS for some patients, but it's likely not the main problem for everyone with the condition.

BiomarkersImmune System
E0 ConsensusPEM not requiredModerate confidenceSystematic-ReviewEditor reviewed

The clinical value of cytokines in chronic fatigue syndrome.

Yang, Tiansong, Yang, Yan, Wang, Delong et al.·Journal of translational medicine·2019

This review examined whether immune system signaling molecules called cytokines could help doctors diagnose or treat ME/CFS. While researchers found that cytokines are abnormal in ME/CFS patients' blood and fluid around the brain, the current evidence shows these markers are not reliable enough to use alone for diagnosis. The review suggests that measuring multiple cytokines together might help doctors better understand what's happening in individual patients, but cytokines are not yet proven as effective treatment targets.

BiomarkersImmune System
E0 ConsensusPEM unclearPreliminaryReview-NarrativeEditor reviewed

Metabolic abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a mini-review.

Tomas, Cara, Newton, Julia·Biochemical Society transactions·2018

This review examines research showing that people with ME/CFS have problems with how their bodies use energy at a cellular level. Scientists have found several different metabolic abnormalities—issues with immune function, mitochondria (the cell's power plants), muscle acid buildup, and other energy-related problems—that could potentially be used as biomarkers (measurable signs) to diagnose the disease. However, no single test can yet reliably identify ME/CFS.

BiomarkersImmune System
E0 ConsensusPEM unclearModerate confidenceEvidence-MapEditor reviewed

The European ME/CFS Biomarker Landscape project: an initiative of the European network EUROMENE.

Scheibenbogen, Carmen, Freitag, Helma, Blanco, Julià et al.·Journal of translational medicine·2017

Researchers across Europe are working together to find biological markers (signs in blood or body tests) that could help diagnose ME/CFS and track how treatments work. This study reviewed all the biomarker research happening in Europe and created a database of what scientists are studying. The goal is to develop reliable tests that doctors could use in the future to diagnose ME/CFS and improve clinical trials.

Biomarkers
E0 ConsensusPEM unclearModerate confidenceReview-NarrativeEditor reviewed

Myalgic Encephalomyelitis: Symptoms and Biomarkers.

Jason, Leonard A, Zinn, Marcie L, Zinn, Mark A·Current neuropharmacology·2015

This review article examines what we know about ME/CFS symptoms and biological markers that could help diagnose the disease. The authors point out that ME/CFS is often confused with other conditions like early multiple sclerosis or Parkinson's disease because they share similar symptoms. They call for better standardized ways to diagnose ME/CFS and more large-scale studies to understand what's happening in the body during this illness.

Biomarkers
E0 ConsensusPEM not requiredPreliminarySystematic-ReviewEditor reviewed

The genetics and epigenetics of fatigue.

Landmark-Høyvik, Hege, Reinertsen, Kristin V, Loge, Jon H et al.·PM & R : the journal of injury, function, and rehabilitation·2010

This study reviewed scientific literature to understand whether genetics (inherited traits) and epigenetics (chemical changes that affect how genes work) influence fatigue in people with ME/CFS and other conditions. The researchers found that while some biological systems appear to malfunction in people with persistent fatigue, no clear genetic or epigenetic markers have been reliably identified yet. The authors argue that future research needs to be larger, better-designed, and consider how genes, environment, and body systems work together.

Endocrine DisruptionBiomarkers
E0 ConsensusPEM unclearModerate confidenceSystematic-ReviewEditor reviewed

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.

NeuroinflammationBiomarkersImmune System
E0 ConsensusPEM requiredPreliminaryReview-NarrativeEditor reviewed

Dysregulation of lipid metabolism, energy production, and oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War Syndrome and fibromyalgia.

Davis, Leah, Higgs, Maisy, Snaith, Ailsa et al.·Frontiers in neuroscience·2025

This review examined research showing that ME/CFS, Gulf War Syndrome, and fibromyalgia may share similar problems with how the body produces energy and handles stress at the cellular level. Scientists found that these three conditions show signs of disrupted fat metabolism, energy production difficulties, and increased cellular damage from oxidative stress. Better understanding these shared biological problems could help doctors diagnose these conditions faster and develop treatments that target the root causes rather than just treating symptoms.

BiomarkersPost-Exertional Malaise
E0 ConsensusPEM unclearModerate confidenceReview-NarrativeEditor reviewed

Biomarkers over Time: From Visual Contrast Sensitivity to Transcriptomics in Differentiating Chronic Inflammatory Response Syndrome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Dooley, Ming·International journal of molecular sciences·2025

This review examines how doctors can better distinguish between two similar-looking illnesses: Chronic Inflammatory Response Syndrome (CIRS) and ME/CFS. The authors trace how testing methods have evolved from simple vision tests to advanced blood tests that read genetic activity. They suggest that some patients diagnosed with ME/CFS may actually have CIRS, which is treatable if properly identified.

BiomarkersImmune System
E0 ConsensusPEM unclearPreliminaryReview-NarrativeEditor reviewed

Metabolic neuroimaging of myalgic encephalomyelitis/chronic fatigue syndrome and Long-COVID.

Zhu, Yijuan, Quan, Patrick, Yamazaki, Tadahiro et al.·Immunometabolism (Cobham, Surrey)·2025

This review examines brain imaging studies that look at how the brains of people with ME/CFS and Long-COVID process energy and nutrients differently. Researchers used advanced scanning techniques to measure glucose and oxygen use in the brain, finding that both conditions show similar patterns of disrupted brain energy metabolism and inflammation. The findings suggest these brain changes might explain why patients experience persistent fatigue, thinking problems, and worsening after physical activity.

NeuroinflammationBiomarkersPost-Exertional Malaise
E0 ConsensusPEM not requiredPreliminaryReview-NarrativeEditor reviewed

Advancing research on regulatory autoantibodies targeting GPCRs: Insights from the 5th international symposium.

Cabral-Marques, Otavio, Schimke, Lena F, Moll, Guido et al.·Autoimmunity reviews·2025

Scientists at an international conference discussed autoantibodies—immune proteins that can attack the body's own cells—that target structures called GPCRs found on many cells. These autoantibodies were once thought to be harmless side effects but are now recognized as active players in diseases including ME/CFS and long COVID. The conference brought together experts to share new ways of detecting these autoantibodies and ideas for using them as diagnostic tools and treatment targets.

BiomarkersImmune System
E0 ConsensusPEM unclearPreliminaryReview-NarrativeEditor reviewed

Identifying microRNAs Possibly Implicated in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Review.

Tsamou, Maria, Kremers, Fabiënne A C, Samaritakis, Keano A et al.·International journal of molecular sciences·2024

This review examined tiny molecules called microRNAs that may play a role in ME/CFS and fibromyalgia. Researchers looked at existing studies to identify which microRNAs appear to be abnormal in these conditions and what role they might play in causing symptoms. They found that certain microRNAs may be involved in immune system problems, energy production difficulties, and increased pain sensitivity—processes that could help explain why people with these diseases experience fatigue, pain, and other symptoms.

BiomarkersImmune System
E0 ConsensusPEM not requiredPreliminaryMeta-AnalysisEditor reviewed

DNA Methylation Changes in Blood Cells of Fibromyalgia and Chronic Fatigue Syndrome Patients.

Przybylowicz, Patrycja Kamila, Sokolowska, Katarzyna Ewa, Rola, Hubert et al.·Journal of pain research·2023

This study looked at chemical changes called 'methylation' in the blood cells of people with fibromyalgia and chronic fatigue syndrome. Researchers combined data from three previous studies and found that while the specific methylation patterns differed slightly between studies, they consistently affected genes involved in body processes that could explain symptoms like pain and exhaustion. This suggests that methylation changes may play a role in how these conditions develop.

BiomarkersImmune System
E0 ConsensusPEM unclearPreliminaryReview-NarrativeEditor reviewed

Induced pluripotent stem cells as suitable sensors for fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome.

Monzón-Nomdedeu, María B, Morten, Karl J, Oltra, Elisa·World journal of stem cells·2021

This review examines whether special laboratory cells called induced pluripotent stem cells (iPSCs) could be used as 'sensors' to detect ME/CFS and fibromyalgia. The researchers found that patients with these conditions have unusual chemicals in their blood and body fluids that differ from healthy people. They propose that iPSCs could be grown in patient samples to detect these abnormal chemicals, potentially helping diagnose these diseases and predict how patients might respond to future treatments.

BiomarkersEnergy Metabolism
E1 ReplicatedPEM unclearModerate confidenceCase-ControlEditor reviewed

Cytokine signatures in chronic fatigue syndrome patients: a Case Control Study and the effect of anakinra treatment.

Roerink, Megan E, Knoop, Hans, Bronkhorst, Ewald M et al.·Journal of translational medicine·2017

Researchers compared immune signaling molecules (cytokines) in the blood of 50 women with ME/CFS to 48 healthy women and found two markers were elevated in the ME/CFS group: IL-12p40 and CSF-1. They also tested whether a drug called anakinra (which blocks inflammation) could help reduce these markers, but found it did not significantly change cytokine levels after 4 weeks of treatment.

BiomarkersImmune System
E1 ReplicatedPEM unclearModerate confidenceObservationalEditor reviewed

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.

Severe MEBiomarkersImmune System
E1 ReplicatedPEM requiredModerate confidenceObservationalEditor reviewed

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.

BiomarkersEnergy Metabolism
E1 ReplicatedPEM not requiredModerate confidenceRCTEditor reviewed

Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Trial.

Natelson, Benjamin H, Vu, Diana, Mao, Xiangling et al.·The journal of pain·2015

This study tested whether a medication called milnacipran could reduce brain inflammation and pain in fibromyalgia patients. Researchers measured a chemical called lactate in the brain using a special MRI scan and found that fibromyalgia patients had higher levels than healthy people. After 8 weeks of treatment, patients taking milnacipran showed lower lactate levels and less pain compared to those taking placebo, suggesting the medication may work by reducing brain inflammation.

NeuroinflammationBiomarkers
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Charting the circulating proteome in ME/CFS using cross-system profiling to uncover mechanistic insights.

Hoel, August, Hoel, Fredrik, Dyrstad, Sissel Elisabeth et al.·Cell reports. Medicine·2026

Researchers analyzed thousands of proteins in the blood of ME/CFS patients and compared them to healthy people. They found significant differences in protein patterns, including too much of certain immune-related proteins and too little of proteins normally made by muscles. These differences might help explain why ME/CFS causes such severe exhaustion and could eventually lead to new ways to diagnose or treat the condition.

BiomarkersImmune System
E2 ModeratePEM requiredModerate confidenceCase-ControlEditor reviewed

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.

NeuroinflammationBiomarkersImmune System
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Mapping the complexity of ME/CFS: Evidence for abnormal energy metabolism, altered immune profile, and vascular dysfunction.

Heng, Benjamin, Gunasegaran, Bavani, Krishnamurthy, Shivani et al.·Cell reports. Medicine·2025

This study examined blood samples from ME/CFS patients and healthy people to understand what goes wrong in the body. Researchers found that immune cells in ME/CFS patients are struggling to make energy (ATP), the fuel that powers our cells. The immune system also showed signs of being immature or worn out, and blood proteins related to clotting and blood vessel problems were elevated, suggesting blood vessel dysfunction may contribute to ME/CFS symptoms.

BiomarkersImmune System
E2 ModeratePEM unclearModerate confidenceObservationalEditor reviewed

Variation in Repeated Handgrip Strength Testing Indicates Submaximal Force Production in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Popkirov, Stoyan·European journal of neurology·2025

This study looked at handgrip strength tests in ME/CFS patients and healthy people to understand why grip strength varies so much in ME/CFS. Researchers found that ME/CFS patients showed more inconsistency in their grip strength measurements compared to healthy controls, suggesting their bodies aren't producing maximum force even when asked to do so. This pattern indicates the problem may be related to how the brain controls muscles rather than the muscles themselves being permanently damaged.

Biomarkers
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Cerebrospinal fluid immune phenotyping reveals distinct immunotypes of myalgic encephalomyelitis/chronic fatigue syndrome.

Bastos, Victoria C, Greene, Kerrie A, Tabachnikova, Alexandra et al.·Journal of immunology (Baltimore, Md. : 1950)·2025

Researchers studied cerebrospinal fluid (the fluid around the brain and spinal cord) from people with ME/CFS and found that the immune system appears to work differently in different patients. They discovered two distinct patient groups with different immune patterns and pathogen exposure histories, even though both groups had similar symptoms. This suggests that ME/CFS may not be a single disease, but rather several related conditions with different underlying causes.

BiomarkersImmune System
E2 ModeratePEM unclearModerate confidenceLongitudinalEditor reviewed

AI-driven multi-omics modeling of myalgic encephalomyelitis/chronic fatigue syndrome.

Xiong, Ruoyun, Aiken, Elizabeth, Caldwell, Ryan et al.·Nature medicine·2025

Researchers used artificial intelligence to analyze blood, gut bacteria, immune cells, and symptoms from 249 ME/CFS patients tracked over 4 years. The AI model discovered that ME/CFS involves abnormal patterns in gut bacteria products, blood fats, and immune cells that attack infections—particularly special T cells that become overactive. These findings suggest ME/CFS isn't caused by a single problem but by multiple connected systems going wrong together.

BiomarkersGut MicrobiomeEnergy MetabolismImmune System
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Age-specific alterations of the gut mycobiome in patients with myalgic encephalomyelitis/chronic fatigue syndrome and identification of potential diagnostic biomarkers.

Gan, Yunong, Ning, Ruihong, Zhang, Wen et al.·BMC microbiology·2025

Researchers studied fungi living in the gut of ME/CFS patients compared to healthy people across different age groups. They found that people with ME/CFS have different types and amounts of gut fungi than healthy people, and these differences vary depending on age. Using these fungal patterns, they could identify ME/CFS patients with high accuracy—especially when looking at people of similar ages—suggesting gut fungi might help diagnose the condition.

Biomarkers
E2 ModeratePEM requiredModerate confidenceCase-ControlEditor reviewed

Haptoglobin phenotypes and structural variants associate with post-exertional malaise and cognitive dysfunction in myalgic encephalomyelitis.

Moezzi, Atefeh, Ushenkina, Anastasiya, Widgren, Anna et al.·Journal of translational medicine·2025

Researchers studied a protein called haptoglobin in people with ME/CFS and found it may be connected to post-exertional malaise (that worsening of symptoms after activity) and brain fog. They discovered that certain genetic variations of this protein were more common in ME/CFS patients, and those variations were linked to worse symptoms and cognitive problems. The study suggests haptoglobin could be a useful marker to help doctors understand why ME/CFS symptoms vary between patients.

BiomarkersPost-Exertional Malaise
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Circulating Levels of SMPDL3B Define Metabolic Endophenotypes and Subclinical Kidney Alterations in Myalgic Encephalomyelitis.

Rostami-Afshari, Bita, Elremaly, Wesam, McGregor, Neil R et al.·International journal of molecular sciences·2025

Researchers found that people with ME have lower levels of a kidney protein called SMPDL3B in their blood and urine compared to healthy people. This protein is important for keeping the kidney's filtering system working properly. The study also identified several metabolic imbalances in ME patients' blood that are linked to kidney problems. These findings suggest that kidney function may be affected in ME, and this protein could potentially be used as a simple blood test to help understand the disease.

BiomarkersEnergy Metabolism
E2 ModeratePEM unclearModerate confidenceCase-ControlEditor reviewed

SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis.

Rostami-Afshari, Bita, Elremaly, Wesam, Franco, Anita et al.·Journal of translational medicine·2025

Researchers identified a protein called SMPDL3B that appears to be elevated in people with ME/CFS and linked to symptom severity. This protein is found in the blood at higher levels in ME patients, particularly in women, and seems to be influenced by hormones and immune system dysfunction. The study also tested two existing diabetes medications (vildagliptin and saxagliptin) in the laboratory and found they could potentially help restore balance to this protein, suggesting a possible new treatment approach.

BiomarkersImmune System
E2 ModeratePEM not requiredPreliminaryObservationalEditor reviewed

Association between fatigue, peripheral serotonin, and L-carnitine in hypothyroidism and in chronic fatigue syndrome.

Raij, Tommi, Raij, Kari·Frontiers in endocrinology·2024

This study examined whether a supplement called L-carnitine could help reduce fatigue by increasing serotonin levels in the blood. Researchers tracked 12 people with ME/CFS and 40 people with hypothyroidism who were experiencing fatigue, measuring their serotonin and fatigue levels before and after taking L-carnitine for 7 weeks. They found that L-carnitine increased serotonin levels significantly and fatigue decreased by about half in both groups, suggesting a possible connection between low serotonin and fatigue.

BiomarkersEnergy Metabolism
E2 ModeratePEM unclearPreliminaryMechanisticEditor reviewed

Data-independent LC-MS/MS analysis of ME/CFS plasma reveals a dysregulated coagulation system, endothelial dysfunction, downregulation of complement machinery.

Nunes, Massimo, Vlok, Mare, Proal, Amy et al.·Cardiovascular diabetology·2024

Researchers analyzed blood proteins in 15 ME/CFS patients and 10 healthy controls to look for differences that might explain ME/CFS symptoms. They found that ME/CFS patients had abnormal levels of proteins involved in blood clotting, blood vessel function, and immune system regulation. These findings suggest that problems with blood clotting and blood vessel health may play a role in ME/CFS.

BiomarkersImmune System
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Sex and disease severity-based analysis of steroid hormones in ME/CFS.

Pipper, Cornelia, Bliem, Linda, León, Luis E et al.·Journal of endocrinological investigation·2024

Researchers measured hormone levels in the blood of ME/CFS patients and compared them to healthy people. They found that certain hormones—including cortisol-related compounds and progesterone—were different in people with ME/CFS, and the differences varied depending on whether patients had mild/moderate or severe disease and their sex. These hormone patterns might help doctors better identify and categorize ME/CFS in the future.

Biomarkers
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Discriminating Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and comorbid conditions using metabolomics in UK Biobank.

Huang, Katherine, G C de Sá, Alex, Thomas, Natalie et al.·Communications medicine·2024

Researchers studied blood samples from nearly 1,200 people with ME/CFS and compared them to people with other common conditions like depression, asthma, and thyroid problems. They found nine specific markers in the blood that, combined with basic health information, could identify ME/CFS patients about 70% of the time. This blood test approach could eventually help doctors diagnose ME/CFS more easily, since there is currently no definitive test for the condition.

Biomarkers
E2 ModeratePEM not requiredModerate confidenceObservationalEditor reviewed

Proteomics and cytokine analyses distinguish myalgic encephalomyelitis/chronic fatigue syndrome cases from controls.

Giloteaux, Ludovic, Li, Jiayin, Hornig, Mady et al.·Journal of translational medicine·2023

Researchers studied tiny particles called extracellular vesicles found in the blood of ME/CFS patients and compared them to healthy controls. They found that ME/CFS patients had more of these particles and they contained different levels of immune chemicals, particularly one called IL2. Using computer algorithms to analyze 20 different blood proteins, they could correctly identify ME/CFS patients about 86% of the time, suggesting that blood tests might one day help diagnose this condition.

BiomarkersImmune System
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Circulating miRNAs Expression in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Soffritti, Irene, Gravelsina, Sabine, D'Accolti, Maria et al.·International journal of molecular sciences·2023

Researchers tested whether six small molecules called microRNAs (miRNAs) in the blood could help identify people with ME/CFS. They compared blood samples from 40 ME/CFS patients with 20 healthy people and found that five miRNAs were more abundant in patients' blood while one was less abundant. Interestingly, the levels of these molecules matched how severe each patient's symptoms were, suggesting they could potentially be used as a blood test to help diagnose ME/CFS.

Biomarkers
E2 ModeratePEM requiredPreliminaryCross-SectionalEditor reviewed

Exploring the joint potential of inflammation, immunity, and receptor-based biomarkers for evaluating ME/CFS progression.

Berkis, Uldis, Svirskis, Simons, Krumina, Angelika et al.·Frontiers in immunology·2023

This study looked for blood markers that could help doctors understand how severe ME/CFS is and track disease progression. Researchers measured inflammation-related proteins, immune system components, and antibodies against nerve receptors in blood samples from healthy people and patients with mild, moderate, and severe ME/CFS. They found that certain markers—especially antibodies against beta2-adrenergic and M4 receptors, along with specific immune proteins—showed promise for distinguishing disease severity, with over 90% accuracy in identifying who has ME/CFS versus who is healthy.

BiomarkersImmune System
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Unsupervised Cluster Analysis Reveals Distinct Subtypes of ME/CFS Patients Based on Peak Oxygen Consumption and SF-36 Scores.

Lacasa, Marcos, Launois, Patricia, Prados, Ferran et al.·Clinical therapeutics·2023

This study examined whether oxygen consumption during an exercise test could help identify different types of ME/CFS patients. Researchers used questionnaire responses from 2,347 ME/CFS patients and then tested their findings in 92 patients who completed an exercise test. They found that patient responses on a quality-of-life survey directly matched up with how much oxygen their bodies could use during exercise, suggesting that low oxygen consumption may be a useful marker for identifying ME/CFS severity.

Biomarkers
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Comparative Analysis of Extracellular Vesicles in Patients with Severe and Mild Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Bonilla, Hector, Hampton, Dylan, Marques de Menezes, Erika G et al.·Frontiers in immunology·2022

Researchers looked for tiny particles called extracellular vesicles in the blood of people with ME/CFS to see if they could help diagnose or understand the disease. They found that people with severe ME/CFS had higher levels of certain vesicles that come from B cells (immune cells) and platelets (blood clotting cells) compared to healthy people. While these differences were promising, they weren't strong enough to confirm they're reliable markers yet.

BiomarkersImmune System
E2 ModeratePEM unclearPreliminaryCase-ControlEditor reviewed

Revisiting IgG Antibody Reactivity to Epstein-Barr Virus in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Its Potential Application to Disease Diagnosis.

Sepúlveda, Nuno, Malato, João, Sotzny, Franziska et al.·Frontiers in medicine·2022

This study looked at antibody responses to Epstein-Barr virus (EBV), a common virus linked to ME/CFS onset in some patients. Researchers analyzed blood samples from 92 ME/CFS patients and 50 healthy people, testing reactions to over 3,000 EBV proteins. They found that in patients whose ME/CFS started after a suspected EBV infection, two specific viral proteins triggered stronger antibody responses than in healthy controls. These antibody patterns could correctly identify about 83% of infected patients and 72% of healthy people, suggesting they might become useful diagnostic markers.

BiomarkersImmune System
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Biomarkers in the diagnostic algorithm of myalgic encephalomyelitis/chronic fatigue syndrome.

Gravelsina, Sabine, Vilmane, Anda, Svirskis, Simons et al.·Frontiers in immunology·2022

This study looked for biological markers (measurable signs in the blood) that could help doctors diagnose ME/CFS more easily. Researchers tested 134 ME/CFS patients and 33 healthy people for a virus called HHV-6 and specific antibodies that attack nerve receptors. They found that ME/CFS patients had higher levels of certain antibodies compared to healthy controls, and patients with more virus in their blood tended to have more severe symptoms.

BiomarkersImmune System
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Autoimmune gene expression profiling of fingerstick whole blood in Chronic Fatigue Syndrome.

Wang, Zheng, Waldman, Michelle F, Basavanhally, Tara J et al.·Journal of translational medicine·2022

Researchers tested blood samples from 166 ME/CFS patients and 83 healthy people to look for immune system clues that might explain the disease. They found that six specific genes related to immune function were more active in patients with severe, bedridden ME/CFS compared to those with milder disease. The study suggests these genes could potentially be used as biomarkers to identify how severe someone's ME/CFS is and might point toward new treatments.

BiomarkersImmune System
E2 ModeratePEM requiredPreliminaryProtocolEditor reviewed

Multimodal MRI of myalgic encephalomyelitis/chronic fatigue syndrome: A cross-sectional neuroimaging study toward its neuropathophysiology and diagnosis.

Shan, Zack Y, Mohamed, Abdalla Z, Andersen, Thu et al.·Frontiers in neurology·2022

This study used advanced brain imaging to investigate whether ME/CFS is caused by a problem with how the brain's blood vessels respond to neural activity. Researchers scanned the brains of 288 people—including those with ME/CFS, chronic fatigue, fibromyalgia, and healthy controls—while they performed tasks and held their breath, measuring blood flow and brain chemicals. The goal was to find distinctive brain patterns that could objectively diagnose ME/CFS and understand what goes wrong in this disease.

Biomarkers
E2 ModeratePEM not requiredPreliminaryEditor reviewed

Metabolomic Evidence for Peroxisomal Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Che, Xiaoyu, Brydges, Christopher R, Yu, Yuanzhi et al.·International journal of molecular sciences·2022

Researchers found that people with ME/CFS have abnormal levels of certain fats and chemicals in their blood compared to healthy people. Specifically, they had lower levels of protective fats called plasmalogens and phospholipids, but higher levels of compounds called dicarboxylic acids. These chemical differences were so distinctive that a computer program could identify ME/CFS patients from their blood work with reasonable accuracy.

Biomarkers
E2 ModeratePEM not requiredWeak / uncertainCross-SectionalEditor reviewed

Potential of Activin B as a Clinical Biomarker in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Gravelsina, Sabine, Nora-Krukle, Zaiga, Vilmane, Anda et al.·Biomolecules·2021

Researchers tested whether a protein called activin B could be used as a simple blood test to diagnose ME/CFS. They compared activin B levels in 134 people with ME/CFS and 54 healthy people, but found no meaningful difference between the two groups. Based on these results, activin B does not appear to be a useful diagnostic tool for ME/CFS.

Biomarkers
E2 ModeratePEM unclearModerate confidenceObservationalEditor reviewed

Evaluation of Immune Dysregulation in an Austrian Patient Cohort Suffering from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Lutz, Lena, Rohrhofer, Johanna, Zehetmayer, Sonja et al.·Biomolecules·2021

This study looked at blood test results from 262 ME/CFS patients to understand problems with their immune systems. Researchers found that nearly two-thirds of patients had low levels of certain immune proteins or cells, while about one-quarter showed signs of inflammation. These findings suggest that immune system dysfunction is a common feature of ME/CFS and could potentially be used to help diagnose or treat the condition.

BiomarkersImmune System
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Recursive ensemble feature selection provides a robust mRNA expression signature for myalgic encephalomyelitis/chronic fatigue syndrome.

Metselaar, Paula I, Mendoza-Maldonado, Lucero, Li Yim, Andrew Yung Fong et al.·Scientific reports·2021

Researchers found a set of 23 genes in blood cells that could reliably identify people with ME/CFS. By looking at both gene activity and chemical markers on genes, they developed a test that correctly identified ME/CFS patients about 92-97% of the time. This is important because there's currently no reliable blood test to diagnose ME/CFS.

BiomarkersImmune System
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Analysis of Gender Differences in HRV of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Using Mobile-Health Technology.

Capdevila, Lluis, Castro-Marrero, Jesús, Alegre, José et al.·Sensors (Basel, Switzerland)·2021

Researchers used a smartphone app connected to a heart monitor to measure heart rate variability (how much the time between heartbeats varies) in ME/CFS patients and healthy people. They found that women with ME/CFS showed different heart patterns than healthy women, but men with ME/CFS did not show the same clear difference. This suggests that ME/CFS may affect the heart's nervous system control differently in men versus women.

Biomarkers
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Are Circulating Fibroblast Growth Factor 21 and N-Terminal Prohormone of Brain Natriuretic Peptide Promising Novel Biomarkers in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?

Domingo, Joan Carles, Cordobilla, Begoña, Ferrer, Roser et al.·Antioxidants & redox signaling·2021

This study looked for new blood markers that could help identify ME/CFS by measuring two proteins called FGF21 and NT-proBNP in patients and healthy people. The researchers found that ME/CFS patients had significantly higher levels of both proteins and showed signs of increased inflammation and oxidative stress (cellular damage). These findings suggest these proteins might be useful tools for diagnosing ME/CFS or developing new treatments.

BiomarkersImmune System
E2 ModeratePEM unclearModerate confidenceObservationalEditor reviewed

Sex-specific plasma lipid profiles of ME/CFS patients and their association with pain, fatigue, and cognitive symptoms.

Nkiliza, Aurore, Parks, Megan, Cseresznye, Adam et al.·Journal of translational medicine·2021

This study analyzed fatty substances in the blood of ME/CFS patients and healthy controls to see if they differ in ways that might explain symptoms. Researchers found that men and women with ME/CFS had different patterns of these blood fats compared to healthy people. Importantly, certain blood fats were connected to the severity of fatigue, headaches, and thinking difficulties, suggesting that problems with how the body processes fats may play a role in ME/CFS symptoms.

BiomarkersEnergy MetabolismImmune System
E2 ModeratePEM not requiredModerate confidenceCross-SectionalEditor reviewed

The maintained attention assessment in patients affected by Myalgic encephalomyelitis/chronic fatigue syndrome: a reliable biomarker?

Murga, Iñigo, Aranburu, Larraitz, Gargiulo, Pascual A et al.·Journal of translational medicine·2021

This study looked at attention problems in ME/CFS patients by giving them a simple attention test (the Toulouse-Piéron test) and comparing their results to healthy people. Most ME/CFS patients had normal overall thinking skills, but 70% showed very low attention scores and complained of mental fatigue. Women with ME/CFS reported feeling more effort during the test than men did, even though their attention scores were similar.

Biomarkers
E2 ModeratePEM requiredPreliminaryCross-SectionalEditor reviewed

The role of low-grade inflammation in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) - associations with symptoms.

Jonsjö, Martin A, Olsson, Gunnar L, Wicksell, Rikard K et al.·Psychoneuroendocrinology·2020

This study looked at whether low-level inflammation in the blood is connected to ME/CFS symptoms like exhaustion after activity, brain fog, muscle pain, and flu-like illness. Researchers tested 53 ME/CFS patients for various inflammatory markers and found that several of these markers were associated with cognitive problems and pain, though they were surprisingly less connected to post-exertional fatigue. Interestingly, the connection between inflammation and symptoms was different for men and women in some cases.

BiomarkersImmune SystemCognitive ImpairmentPost-Exertional Malaise
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Properties of measurements obtained during cardiopulmonary exercise testing in individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Davenport, Todd E, Stevens, Staci R, Stevens, Jared et al.·Work (Reading, Mass.)·2020

Researchers tested whether a standard exercise test (cardiopulmonary exercise test, or CPET) could reliably measure how ME/CFS affects the body's ability to exercise. They had 51 women with ME/CFS and 10 healthy women do the same exercise test twice, 24 hours apart. The results showed that the measurements were consistent and clearly different between the two groups, suggesting that CPET could be a useful tool for assessing ME/CFS.

Biomarkers
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Identification of actin network proteins, talin-1 and filamin-A, in circulating extracellular vesicles as blood biomarkers for human myalgic encephalomyelitis/chronic fatigue syndrome.

Eguchi, Akiko, Fukuda, Sanae, Kuratsune, Hirohiko et al.·Brain, behavior, and immunity·2020

This study found that people with ME/CFS have higher levels of tiny particles called extracellular vesicles in their blood, which contain specific proteins (talin-1 and filamin-A) that appear to be unique markers of the disease. By measuring these particles and proteins in a simple blood test, researchers were able to correctly identify ME/CFS patients about 90-94% of the time, suggesting this could become a useful diagnostic tool.

BiomarkersImmune System
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Assessing diagnostic value of microRNAs from peripheral blood mononuclear cells and extracellular vesicles in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Almenar-Pérez, Eloy, Sarría, Leonor, Nathanson, Lubov et al.·Scientific reports·2020

This study looked for biological markers (tiny genetic molecules called microRNAs) in blood samples from severely ill ME/CFS patients that could help doctors diagnose the disease. Researchers found that certain microRNAs and physical characteristics of particles in the blood appeared different in ME/CFS patients compared to healthy controls. If validated in larger studies, these findings could eventually lead to a simple blood test for diagnosis.

BiomarkersImmune System
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Plasma proteomic profiling suggests an association between antigen driven clonal B cell expansion and ME/CFS.

Milivojevic, Milica, Che, Xiaoyu, Bateman, Lucinda et al.·PloS one·2020

Researchers studied blood proteins in ME/CFS patients and healthy controls to look for disease markers. They found that certain immune-related proteins, particularly immunoglobulin proteins (which are part of the immune system), were abnormal in ME/CFS patients and could help identify who has the disease. The results suggest ME/CFS involves an overactive or dysregulated immune response.

BiomarkersImmune System
E2 ModeratePEM not requiredPreliminaryObservationalEditor reviewed

A Machine Learning Approach to the Differentiation of Functional Magnetic Resonance Imaging Data of Chronic Fatigue Syndrome (CFS) From a Sedentary Control.

Provenzano, Destie, Washington, Stuart D, Baraniuk, James N·Frontiers in computational neuroscience·2020

Researchers used a computer algorithm to analyze brain scans from ME/CFS patients and healthy controls while they performed a memory task, both before and after exercise. The algorithm was able to correctly identify which scans came from ME/CFS patients 80% of the time on the first day and 76% on the second day, suggesting that ME/CFS may create a distinctive pattern of brain activity that could eventually be used as an objective diagnostic test.

Biomarkers
E2 ModeratePEM requiredPreliminaryMechanisticEditor reviewed

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 requiredModerate confidenceCross-SectionalEditor reviewed

Circulating levels of GDF15 in patients with myalgic encephalomyelitis/chronic fatigue syndrome.

Melvin, A, Lacerda, E, Dockrell, H M et al.·Journal of translational medicine·2019

This study measured a protein called GDF15 in the blood of ME/CFS patients and compared it to healthy people. GDF15 is released by cells when they are stressed or damaged. The researchers found that patients with severe ME/CFS had higher levels of GDF15 than healthy controls, and the levels of this protein were linked to how tired patients felt. The GDF15 levels stayed relatively stable over several months, suggesting it could be a useful marker for measuring cellular stress in ME/CFS.

Biomarkers
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Evidence of Clinical Pathology Abnormalities in People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) from an Analytic Cross-Sectional Study.

Nacul, Luis, de Barros, Barbara, Kingdon, Caroline C et al.·Diagnostics (Basel, Switzerland)·2019

Researchers tested blood samples from 272 people with ME/CFS and 136 healthy people to look for measurable differences that might help diagnose the condition. They found that people with severe ME/CFS had notably lower levels of an enzyme called creatine kinase (CK) in their blood compared to healthy people and those with milder ME/CFS. This is the first study to report this pattern, suggesting that CK levels might be useful for identifying who has the most severe form of the disease.

Biomarkers
E2 ModeratePEM requiredPreliminaryCross-SectionalEditor reviewed

Rethinking ME/CFS Diagnostic Reference Intervals via Machine Learning, and the Utility of Activin B for Defining Symptom Severity.

Lidbury, Brett A, Kita, Badia, Richardson, Alice M et al.·Diagnostics (Basel, Switzerland)·2019

This study looked for blood test markers that could help diagnose ME/CFS and measure how severe someone's illness is. Researchers tested a protein called activin B along with routine blood work from pathology labs in people with ME/CFS and healthy controls. They used a computer learning method to see which combinations of blood markers worked best for identifying ME/CFS and predicting symptom severity.

Biomarkers
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

A new approach to find biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) by single-cell Raman micro-spectroscopy.

Xu, Jiabao, Potter, Michelle, Tomas, Cara et al.·The Analyst·2019

Researchers used a new scanning technology called Raman spectroscopy to look at individual cells from ME/CFS patients and healthy people. They found that cells from ME/CFS patients had higher levels of a protein building block called phenylalanine, similar to cells with broken energy-producing structures (mitochondria). Using computer learning, they could identify ME/CFS patient cells with 98% accuracy based on this signature.

Biomarkers
E2 ModeratePEM not requiredPreliminaryObservationalEditor reviewed

Associations between clinical symptoms, plasma norepinephrine and deregulated immune gene networks in subgroups of adolescent with Chronic Fatigue Syndrome.

Nguyen, Chinh Bkrong, Kumar, Surendra, Zucknick, Manuela et al.·Brain, behavior, and immunity·2019

This study looked at blood samples from teenagers with ME/CFS to understand how their immune systems and stress-response chemicals differ from healthy teenagers. Researchers found two distinct subgroups of ME/CFS patients based on immune activity and a stress hormone called norepinephrine. Patients with lower norepinephrine levels had more severe fatigue, while those with higher levels showed different patterns of immune dysfunction.

BiomarkersImmune System
E2 ModeratePEM not requiredModerate confidenceObservationalEditor reviewed

Decreased Expression of the CD57 Molecule in T Lymphocytes of Patients with Chronic Fatigue Syndrome.

Espinosa, P, Urra, J M·Molecular neurobiology·2019

Researchers measured levels of a protein called CD57 on immune cells in ME/CFS patients and compared them to healthy people. They found that ME/CFS patients had significantly lower amounts of CD57 on their T cells (a type of white blood cell). This difference was large enough that measuring CD57 levels could potentially help doctors diagnose ME/CFS.

BiomarkersImmune System
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

A laboratory approach for characterizing chronic fatigue: what does metabolomics tell us?

Erasmus, Elardus, Mason, Shayne, van Reenen, Mari et al.·Metabolomics : Official journal of the Metabolomic Society·2019

This study looked at whether a simple urine test could help measure fatigue severity in ME/CFS patients. Researchers used a specialized scanning technique (NMR) to analyze urine samples from 578 women with chronic fatigue before and after a detoxification challenge, finding that the fatigue group showed different metabolite patterns compared to controls. While the study didn't identify a single reliable biomarker for fatigue, it suggests that fatigue may be connected to how the body processes toxins.

Biomarkers
E2 ModeratePEM not requiredPreliminaryCase-ControlEditor reviewed

MicroRNAs as Biomarkers of Pain Intensity in Patients With Chronic Fatigue Syndrome.

Al-Rawaf, Hadeel A, Alghadir, Ahmad H, Gabr, Sami A·Pain practice : the official journal of World Institute of Pain·2019

This study looked at tiny molecules called microRNAs in the blood of adolescents with ME/CFS to see if they could help explain why these patients experience pain. Researchers found that five specific microRNAs were lower in ME/CFS patients compared to healthy teens, and these changes were linked to higher levels of inflammatory chemicals that are known to cause pain. Interestingly, girls with ME/CFS had even lower microRNA levels and higher inflammation markers than boys with the condition.

BiomarkersImmune System
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Hand Grip Strength as a Clinical Biomarker for ME/CFS and Disease Severity.

Nacul, Luis Carlos, Mudie, Kathleen, Kingdon, Caroline C et al.·Frontiers in neurology·2018

Researchers tested whether hand grip strength could be a useful tool for diagnosing ME/CFS and measuring how severe the condition is. They found that people with ME/CFS—especially those with severe disease—have noticeably weaker grip strength compared to healthy people, and their grip strength drops more across repeated tests. This simple, objective test may help doctors better diagnose ME/CFS and track how patients are doing over time.

Biomarkers
E2 ModeratePEM unclearModerate confidenceBiobank-ResourceEditor reviewed

The UK ME/CFS Biobank: A Disease-Specific Biobank for Advancing Clinical Research Into Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Lacerda, Eliana M, Mudie, Kathleen, Kingdon, Caroline C et al.·Frontiers in neurology·2018

Researchers in the UK created a special collection of biological samples (like blood) and health information from 600 people—including those with ME/CFS, people with multiple sclerosis, and healthy volunteers. This resource, called the UK ME/CFS Biobank, was designed to help scientists study ME/CFS more effectively and find reliable ways to diagnose the disease. The biobank is being shared with researchers around the world to speed up discovery.

Biomarkers
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics.

Nagy-Szakal, Dorottya, Barupal, Dinesh K, Lee, Bohyun et al.·Scientific reports·2018

Researchers studied blood and gut bacteria samples from 50 people with ME/CFS and 50 healthy people to find biological markers of the disease. They found that people with ME/CFS have abnormal levels of certain substances in their blood called metabolites, particularly a fatty molecule called ceramide in those who also have irritable bowel syndrome. When scientists combined information about both blood metabolites and gut bacteria, they could identify ME/CFS patients more accurately than using either test alone.

Biomarkers
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Weighting of orthostatic intolerance time measurements with standing difficulty score stratifies ME/CFS symptom severity and analyte detection.

Richardson, Alice M, Lewis, Don P, Kita, Badia et al.·Journal of translational medicine·2018

This study tested a new way to measure ME/CFS severity by combining how long patients can stand with how difficult standing feels to them. Researchers found that this combined measurement (called weighted standing time) was significantly different between ME/CFS patients and healthy people, and it also related to differences in certain inflammation markers in the blood. This suggests that a simple standing test could help doctors diagnose ME/CFS and track how severe a patient's symptoms are.

Biomarkers
E2 ModeratePEM unclearPreliminaryCase-ControlEditor reviewed

Identification of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-associated DNA methylation patterns.

Trivedi, Malav S, Oltra, Elisa, Sarria, Leonor et al.·PloS one·2018

Researchers studied chemical tags on DNA (called methylation) in people with ME/CFS compared to healthy people. While the overall amount of these tags was similar between groups, they found specific locations on thousands of genes where the tags differed. Many of these differences were in genes involved in immune system function, which aligns with what doctors already know about ME/CFS affecting immunity.

BiomarkersImmune System
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Restricted Spatial Windows of Visibility in Myalgic Encephalomyelitis (ME).

Ahmed, Nadia S, Gottlob, Irene, Proudlock, Frank A et al.·Vision (Basel, Switzerland)·2018

This study looked at how ME affects vision by testing how well people can see contrast (the difference between light and dark areas). Researchers tested 19 people with ME and 19 healthy people by asking them to identify faint striped patterns. People with ME had more difficulty seeing these patterns, especially at lower levels of detail, suggesting that ME may affect how the eyes and brain process visual information.

Biomarkers
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology.

Germain, Arnaud, Ruppert, David, Levine, Susan M et al.·Metabolites·2018

Researchers studied blood samples from 32 women with ME/CFS and 19 healthy women to look for chemical differences. They found 14 metabolites (small molecules in the blood) that were different in ME/CFS patients, suggesting their bodies may have trouble managing oxidative stress—a chemical imbalance that could contribute to their symptoms. This discovery could eventually help doctors identify ME/CFS through a blood test.

Biomarkers
E2 ModeratePEM not requiredPreliminaryCross-SectionalEditor reviewed

Structural brain changes versus self-report: machine-learning classification of chronic fatigue syndrome patients.

Sevel, Landrew S, Boissoneault, Jeff, Letzen, Janelle E et al.·Experimental brain research·2018

Researchers compared two methods for identifying ME/CFS patients: looking at structural brain changes on MRI scans versus asking patients to rate their symptoms like fatigue, pain, and sleep quality. While brain imaging showed some useful differences between ME/CFS patients and healthy people, patients' own descriptions of their symptoms were actually better at identifying who had ME/CFS.

Biomarkers
E2 ModeratePEM unclearModerate confidenceBiobank-ResourceEditor reviewed

The UK ME/CFS Biobank for biomedical research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Multiple Sclerosis.

Lacerda, Eliana M, Bowman, Erinna W, Cliff, Jacqueline M et al.·Open journal of bioresources·2017

The UK ME/CFS Biobank is a collection of blood samples and health information from 284 people with ME/CFS, 60 people with multiple sclerosis, and 135 healthy volunteers. Researchers created this resource to help scientists study what causes ME/CFS and find better ways to diagnose and treat it. The samples and detailed patient information can be used by researchers worldwide to search for biological markers of the disease.

BiomarkersImmune System
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Metabolic profiling of a myalgic encephalomyelitis/chronic fatigue syndrome discovery cohort reveals disturbances in fatty acid and lipid metabolism.

Germain, Arnaud, Ruppert, David, Levine, Susan M et al.·Molecular bioSystems·2017

This study examined the chemicals in the blood of 17 ME/CFS patients and compared them to 15 healthy people. Researchers found 74 different chemicals at abnormal levels in ME/CFS patients, with 35 showing significant differences. Many of these chemicals are important for producing energy in the body, which could help explain why ME/CFS patients feel so exhausted.

BiomarkersEnergy Metabolism
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome.

Nagy-Szakal, Dorottya, Williams, Brent L, Mishra, Nischay et al.·Microbiome·2017

This study looked at the bacteria living in the gut of 50 ME/CFS patients and 50 healthy people to see if differences in gut bacteria might explain some ME/CFS symptoms. The researchers found that ME/CFS patients have unusual patterns of gut bacteria, and these patterns are different depending on whether the patient also has irritable bowel syndrome (IBS). Importantly, the type and balance of gut bacteria were linked to how severe patients' fatigue, pain, and other symptoms were.

BiomarkersEnergy Metabolism
E2 ModeratePEM not requiredPreliminaryCase-ControlEditor reviewed

Elevated brain natriuretic peptide levels in chronic fatigue syndrome associate with cardiac dysfunction: a case control study.

Tomas, Cara, Finkelmeyer, Andreas, Hodgson, Tim et al.·Open heart·2017

This study found that people with ME/CFS have higher levels of a hormone called BNP (brain natriuretic peptide) in their blood compared to healthy people without the condition. Interestingly, those with higher BNP levels had smaller heart chambers, which suggests their hearts may be working differently in ME/CFS. The researchers believe this finding is related to the condition itself, not simply from being inactive.

Biomarkers
E2 ModeratePEM unclearModerate confidenceCase-ControlEditor reviewed

Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity.

Natelson, Benjamin H, Mao, Xiangling, Stegner, Aaron J et al.·Journal of the neurological sciences·2017

This study compared brain and spinal fluid measurements in people with ME/CFS and healthy controls to understand what physical changes occur in the condition. Researchers found that ME/CFS patients had lower levels of a protective brain chemical (glutathione), reduced blood flow to the brain, higher levels of lactate (a sign of energy problems), and more abnormalities in spinal fluid compared to healthy people. Importantly, these differences were the same whether or not ME/CFS patients also had depression or anxiety, suggesting psychiatric conditions are not making the disease worse.

Biomarkers
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Reductions in circulating levels of IL-16, IL-7 and VEGF-A in myalgic encephalomyelitis/chronic fatigue syndrome.

Landi, Abdolamir, Broadhurst, David, Vernon, Suzanne D et al.·Cytokine·2016

Researchers measured 34 different immune system proteins in blood samples from 100 ME/CFS patients and 79 healthy controls. They found that three specific immune proteins—IL-16, IL-7, and VEGF-A—were significantly lower in ME/CFS patients. This pattern was different from what is seen in other chronic diseases with similar fatigue symptoms, suggesting it may be unique to ME/CFS.

BiomarkersImmune System
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Illness progression in chronic fatigue syndrome: a shifting immune baseline.

Russell, Lindsey, Broderick, Gordon, Taylor, Renee et al.·BMC immunology·2016

This study looked at three inflammatory proteins (IL-1α, IL-6, and IL-8) in the blood of people with ME/CFS at different stages of illness—newly diagnosed teenagers, people in the middle of their illness, and those who had been sick for over a decade. The researchers found that the pattern of these proteins changes as the illness progresses, suggesting that the body's immune response shifts over time. By adjusting for how long someone has been ill, doctors might be able to use these three proteins together to identify ME/CFS with 75-88% accuracy.

BiomarkersImmune System
E2 ModeratePEM not requiredPreliminaryCase-ControlEditor reviewed

A potential biomarker for fatigue: Oxidative stress and anti-oxidative activity.

Fukuda, Sanae, Nojima, Junzo, Motoki, Yukari et al.·Biological psychology·2016

This study looked at whether certain markers of cellular damage from harmful molecules (oxidative stress) and the body's ability to repair that damage (antioxidant capacity) could be used to identify ME/CFS patients and measure their fatigue levels. Researchers compared these markers in ME/CFS patients at rest versus healthy people during and after exercise, finding that ME/CFS patients had a different pattern of these markers compared to healthy controls.

Biomarkers
E2 ModeratePEM unclearModerate confidenceMechanisticEditor reviewed

Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome.

Loebel, Madlen, Grabowski, Patricia, Heidecke, Harald et al.·Brain, behavior, and immunity·2016

Researchers tested whether ME/CFS patients have unusually high levels of antibodies (immune proteins) that attack nerve signaling receptors in the body. They found that about 30% of ME/CFS patients had elevated antibodies against certain receptors involved in adrenaline and acetylcholine signaling—chemicals that control heart rate, breathing, and other automatic body functions. Importantly, patients who received rituximab (a treatment that depletes B cells) and improved showed decreases in these antibody levels, suggesting a possible link between these antibodies and disease activity.

BiomarkersImmune System
E2 ModeratePEM not requiredPreliminaryCross-SectionalEditor reviewed

Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles.

Yamano, Emi, Sugimoto, Masahiro, Hirayama, Akiyoshi et al.·Scientific reports·2016

Researchers analyzed blood samples from ME/CFS patients and healthy people to look for chemical markers that could help diagnose the disease. They found that certain metabolites—molecules involved in energy production and waste removal—were abnormal in ME/CFS patients. Two specific chemical ratios in the blood showed promise as potential diagnostic tools, correctly identifying CFS patients about 75-80% of the time.

BiomarkersEnergy Metabolism
E2 ModeratePEM requiredPreliminaryCase-ControlEditor reviewed

Submaximal exercise testing with near-infrared spectroscopy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients compared to healthy controls: a case-control study.

Miller, Ruth R, Reid, W Darlene, Mattman, Andre et al.·Journal of translational medicine·2015

This study tested whether a simple hand-squeezing exercise combined with a special infrared light tool could help identify ME/CFS in patients. Researchers compared 16 people with ME/CFS to 16 healthy people and measured how well oxygen was being used in their muscles during the test. People with ME/CFS showed different patterns of oxygen use and reported feeling more tired during the exercise, even though they were squeezing with less force.

BiomarkersPost-Exertional Malaise
E2 ModeratePEM unclearModerate confidenceObservationalEditor reviewed

Distinct plasma immune signatures in ME/CFS are present early in the course of illness.

Hornig, Mady, Montoya, José G, Klimas, Nancy G et al.·Science advances·2015

This study found that people with ME/CFS have distinctive patterns of immune system markers in their blood, but only early in the disease. Researchers compared blood samples from 52 people with early-stage ME/CFS to 348 healthy people and 246 people with long-standing ME/CFS. The early-stage group showed heightened immune activity that was not present in people who had been sick longer, suggesting the disease's immune profile changes over time.

BiomarkersImmune System
E2 ModeratePEM requiredPreliminaryCross-SectionalEditor reviewed

A new case definition of Neuro-Inflammatory and Oxidative Fatigue (NIOF), a neuroprogressive disorder, formerly known as chronic fatigue syndrome or Myalgic Encephalomyelitis: results of multivariate pattern recognition methods and external validation by neuro-immune biomarkers.

Maes, Michael·Neuro endocrinology letters·2015

This study looked at whether ME/CFS could be better understood by examining specific blood markers related to inflammation, oxidative stress, and immune activation. Researchers found two distinct groups of people with chronic fatigue—one group had significantly higher levels of problematic immune markers and inflammatory signs. The study proposes a new way to identify ME/CFS based on fatigue plus at least four of these symptoms: muscle tension, memory problems, sleep issues, digestive problems, headaches, or flu-like feelings.

BiomarkersImmune System
E2 ModeratePEM unclearPreliminaryLongitudinalEditor reviewed

Longitudinal analysis of immune abnormalities in varying severities of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients.

Hardcastle, Sharni Lee, Brenu, Ekua Weba, Johnston, Samantha et al.·Journal of translational medicine·2015

This study tracked immune system changes in 42 ME/CFS patients (divided into moderate and severe groups) and 18 healthy controls over 6 months. Researchers used blood tests to count different types of immune cells. They found that people with severe ME/CFS had noticeably different immune cell patterns than those with moderate ME/CFS or healthy controls, suggesting the immune system may work differently depending on how severe the illness is.

BiomarkersImmune System
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Increased Vulnerability to Pattern-Related Visual Stress in Myalgic Encephalomyelitis.

Wilson, Rachel L, Paterson, Kevin B, Hutchinson, Claire V·Perception·2015

This study tested whether people with ME/CFS experience more visual discomfort when looking at certain patterns compared to healthy people. Forty participants (20 with ME/CFS and 20 without) viewed three different striped patterns and reported how distorted or uncomfortable they looked. People with ME/CFS reported significantly more visual distortion, especially when viewing medium-frequency patterns, suggesting their eyes and brains may process visual information differently.

Pain and SensitizationBiomarkers
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Use of single-nucleotide polymorphisms (SNPs) to distinguish gene expression subtypes of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).

Shimosako, Nana, Kerr, Jonathan R·Journal of clinical pathology·2014

This study looked at small variations in DNA (called SNPs) from people with ME/CFS to see if these genetic differences could help identify different subtypes of the condition. Researchers compared DNA from 108 ME/CFS patients with 17 people with depression and 68 healthy people. They found that certain genetic variations were more common in ME/CFS patients and that different combinations of these variations appeared to match different subtypes of the illness.

Biomarkers
E2 ModeratePEM not requiredPreliminaryCross-SectionalEditor reviewed

Multiscale analysis of heart rate variability in non-stationary environments.

Gao, Jianbo, Gurbaxani, Brian M, Hu, Jing et al.·Frontiers in physiology·2013

This study looked at how the heart rate patterns of people with ME/CFS differ from healthy people, especially when they're under stress. Researchers used advanced computer methods to analyze heart rate data collected during a social stress test. They found that before the stress test, people with ME/CFS had noticeably different heart rate patterns than healthy controls, but these differences became smaller during the stress test itself.

Biomarkers
E2 ModeratePEM requiredModerate confidenceCross-SectionalEditor reviewed

Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), and Chronic Fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data.

Maes, Michael, Twisk, Frank N M, Johnson, Cort·Psychiatry research·2012

This study looked at whether ME, CFS, and chronic fatigue are truly different conditions or if they overlap too much to distinguish. Researchers tested 144 patients and found that post-exertional malaise (PEM)—where symptoms worsen after activity—is a key feature that separates ME from CFS. They also found that ME and CFS patients had higher levels of certain inflammatory markers in their blood compared to people with simple chronic fatigue.

BiomarkersImmune SystemPost-Exertional Malaise
E2 ModeratePEM not requiredPreliminaryCross-SectionalEditor reviewed

NMR metabolic profiling of serum identifies amino acid disturbances in chronic fatigue syndrome.

Armstrong, Christopher W, McGregor, Neil R, Sheedy, John R et al.·Clinica chimica acta; international journal of clinical chemistry·2012

Researchers used a specialized blood test called NMR to compare the levels of different chemicals in the blood of 11 people with ME/CFS and 10 healthy people. They found that people with ME/CFS had significantly lower levels of two amino acids (building blocks of protein): glutamine and ornithine. These findings suggest that people with ME/CFS may have problems with how their bodies process certain proteins and manage nitrogen, which are important for energy and cell function.

Biomarkers
E2 ModeratePEM not requiredPreliminaryCross-SectionalEditor reviewed

Visible and near-infrared spectra collected from the thumbs of patients with chronic fatigue syndrome for diagnosis.

Sakudo, Akikazu, Kuratsune, Hirohiko, Kato, Yukiko Hakariya et al.·Clinica chimica acta; international journal of clinical chemistry·2012

Researchers used a special light-based scanner on patients' thumbs to see if they could tell the difference between people with ME/CFS and healthy people. The scanner detected subtle changes in how light passes through the skin in a specific wavelength range. When they analyzed the results using computer models, they were able to correctly identify about 70% of ME/CFS patients and 83% of healthy people, suggesting this method might someday help doctors diagnose ME/CFS more objectively.

Biomarkers
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Increased plasma peroxides as a marker of oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Maes, Michael, Kubera, Marta, Uytterhoeven, Marc et al.·Medical science monitor : international medical journal of experimental and clinical research·2011

This study measured two markers of oxidative stress (damage caused by harmful molecules in the body) in people with ME/CFS compared to healthy people. Researchers found that ME/CFS patients had significantly higher levels of plasma peroxides—harmful molecules that damage cells. These findings suggest that oxidative stress may play a role in ME/CFS, which could help explain some of the illness's symptoms.

Biomarkers
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.

Brenu, Ekua W, van Driel, Mieke L, Staines, Don R et al.·Journal of translational medicine·2011

This study examined immune system markers in 95 ME/CFS patients compared to 50 healthy people to see if certain blood tests could help diagnose the condition. Researchers found that ME/CFS patients had imbalanced immune responses, including higher levels of certain inflammatory proteins and lower activity of immune cells that normally fight infections. These immune differences might one day be used as reliable diagnostic markers to help doctors identify ME/CFS.

BiomarkersImmune System
E2 ModeratePEM not requiredModerate confidenceCross-SectionalEditor reviewed

Failure to Detect XMRV-Specific Antibodies in the Plasma of CFS Patients Using Highly Sensitive Chemiluminescence Immunoassays.

Oakes, Brendan, Qiu, Xiaoxing, Levine, Susan et al.·Advances in virology·2011

In 2009, researchers claimed they found a virus called XMRV in most ME/CFS patients' blood. This study tested whether that finding was real by looking for antibodies (immune system markers) to XMRV in blood samples from ME/CFS patients and healthy people. The researchers found no evidence of XMRV antibodies in any of the samples, suggesting the original finding may not have been accurate.

Biomarkers
E2 ModeratePEM not requiredPreliminaryCross-SectionalEditor reviewed

Assessment of a 44 gene classifier for the evaluation of chronic fatigue syndrome from peripheral blood mononuclear cell gene expression.

Frampton, Daniel, Kerr, Jonathan, Harrison, Tim J et al.·PloS one·2011

Researchers tested whether 44 genes could be used together to diagnose ME/CFS by measuring their activity in blood samples from patients and healthy people. While the combination of genes worked well when tested on the original group, it failed when applied to a new group of patients, correctly identifying only about two-thirds of cases. This suggests that a simple blood test using these genes is not yet ready for diagnosing ME/CFS in everyday medical practice.

Biomarkers
E2 ModeratePEM not requiredModerate confidenceCase-ControlEditor reviewed

Nitric oxide concentrations are normal and unrelated to activity level in chronic fatigue syndrome: a case-control study.

Meeus, Mira, VAN Eupen, Inge, Hondequin, Jasmien et al.·In vivo (Athens, Greece)·2010

This study examined whether a chemical messenger in the blood called nitric oxide (NO) is related to how active people are in ME/CFS. Researchers measured activity levels and blood NO in 30 ME/CFS patients and 29 healthy but inactive people over one week. While ME/CFS patients were indeed much less active than controls, the amount of NO in their blood was normal and had no connection to their activity levels.

Biomarkers
E2 ModeratePEM not requiredModerate confidenceCross-SectionalEditor reviewed

Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder.

Murrough, James W, Mao, Xiangling, Collins, Katherine A et al.·NMR in biomedicine·2010

This study used a special type of brain imaging called MRI to measure a substance called lactate in the fluid around the brain of people with ME/CFS. The researchers found that people with ME/CFS had significantly higher lactate levels compared to healthy people and people with depression. Interestingly, people with depression had normal lactate levels, suggesting this finding may be specific to ME/CFS and not just a symptom of mental illness.

Biomarkers
E2 ModeratePEM not requiredModerate confidenceLongitudinalEditor reviewed

Longitudinal MRI shows no cerebral abnormality in chronic fatigue syndrome.

Perrin, R, Embleton, K, Pentreath, V W et al.·The British journal of radiology·2010

This study used MRI brain scans to look for physical abnormalities in people with ME/CFS compared to healthy people. Eighteen patients with ME/CFS and nine healthy volunteers were scanned twice, one year apart. The researchers found no significant differences between the two groups in brain size, fluid levels, blood flow, or white matter lesions, and these measurements remained stable over the year.

Biomarkers
E2 ModeratePEM not requiredModerate confidenceLongitudinalEditor reviewed

Fluctuation of serum vitamin E (alpha-tocopherol) concentrations during exacerbation and remission phases in patients with chronic fatigue syndrome.

Miwa, Kunihisa, Fujita, Masatoshi·Heart and vessels·2010

This study examined whether people with ME/CFS have lower levels of vitamin E, an important antioxidant that protects cells from damage. Researchers found that ME/CFS patients had significantly lower vitamin E levels than healthy controls, and these levels improved when patients went into remission, suggesting that oxidative stress (cellular damage from chemical imbalances) may play a role in ME/CFS.

Biomarkers
E2 ModeratePEM not requiredPreliminaryCross-SectionalEditor reviewed

The increase of alpha-melanocyte-stimulating hormone in the plasma of chronic fatigue syndrome patients.

Shishioh-Ikejima, Nobue, Ogawa, Tokiko, Yamaguti, Kouzi et al.·BMC neurology·2010

Researchers measured a hormone called alpha-MSH in the blood of 55 ME/CFS patients and compared it to 30 healthy people. They found that patients diagnosed within the last 5 years had significantly higher alpha-MSH levels than healthy controls, but this difference disappeared in patients who had been ill longer. This suggests alpha-MSH might be a useful blood test for identifying ME/CFS in newly diagnosed patients.

Biomarkers
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Plasma neuropeptide Y: a biomarker for symptom severity in chronic fatigue syndrome.

Fletcher, Mary A, Rosenthal, Martin, Antoni, Michael et al.·Behavioral and brain functions : BBF·2010

This study measured a stress-related substance called neuropeptide Y (NPY) in the blood of ME/CFS patients and compared it to healthy people and people with Gulf War Illness. The researchers found that ME/CFS patients had significantly higher NPY levels, and these levels correlated with how severe their symptoms were—including stress, depression, fatigue, and cognitive problems. This suggests NPY could be a useful blood test to help identify ME/CFS and track symptom severity.

Biomarkers
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Vitamin D metabolites as clinical markers in autoimmune and chronic disease.

Blaney, Greg P, Albert, Paul J, Proal, Amy D·Annals of the New York Academy of Sciences·2009

This study measured two types of vitamin D in the blood of patients with autoimmune and chronic diseases, including ME/CFS. The researchers found that a specific form of vitamin D (1,25-D) at high levels was associated with these conditions, but the commonly-tested form of vitamin D (25-D) was not. This suggests doctors may need to test for the right type of vitamin D to properly assess autoimmune disease.

BiomarkersImmune System
E2 ModeratePEM not requiredModerate confidenceCase-ControlEditor reviewed

Gene expression in peripheral blood leukocytes in monozygotic twins discordant for chronic fatigue: no evidence of a biomarker.

Byrnes, Andrea, Jacks, Andreas, Dahlman-Wright, Karin et al.·PloS one·2009

Researchers compared blood cells from 44 people with ME/CFS to their identical twins who do not have the illness, looking for genetic differences that might explain the disease. Despite careful testing using advanced technology, they found no differences in how genes were expressed between the two groups. This suggests that if previous studies claimed to find biomarkers (biological signs) of ME/CFS in blood, those findings may have been due to errors in how the studies were conducted rather than real biological differences.

Biomarkers
E2 ModeratePEM not requiredModerate confidenceCase-ControlEditor reviewed

Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: an in vivo 3.0 T (1)H MRS imaging study.

Mathew, Sanjay J, Mao, Xiangling, Keegan, Kathryn A et al.·NMR in biomedicine·2009

Researchers used a specialized brain scan to measure a substance called lactate in the fluid surrounding the brain in people with ME/CFS, people with anxiety disorder, and healthy people. They found that people with ME/CFS had about three times more lactate in their brain fluid than the other groups, suggesting their brain cells may not be using energy efficiently.

Biomarkers
E2 ModeratePEM not requiredModerate confidenceCross-SectionalEditor reviewed

Hypocapnia is a biological marker for orthostatic intolerance in some patients with chronic fatigue syndrome.

Natelson, Benjamin H, Intriligator, Roxann, Cherniack, Neil S et al.·Dynamic medicine : DM·2007

This study compared how ME/CFS patients and healthy volunteers responded to standing up for 8 minutes. Researchers measured blood pressure, heart rate, breathing rate, and carbon dioxide levels in the blood. ME/CFS patients were more likely than healthy people to have abnormal responses, particularly low carbon dioxide levels (hypocapnia), which was linked to feeling more ill and short of breath.

Biomarkers
E2 ModeratePEM not requiredPreliminaryCross-SectionalEditor reviewed

Spectroscopic diagnosis of chronic fatigue syndrome by visible and near-infrared spectroscopy in serum samples.

Sakudo, Akikazu, Kuratsune, Hirohiko, Kobayashi, Takanori et al.·Biochemical and biophysical research communications·2006

Researchers used a special light-based scanning technique to analyze blood samples from ME/CFS patients and healthy people. The scans could correctly identify which samples came from ME/CFS patients about 93% of the time. This suggests that a simple blood test using this technology might one day help doctors diagnose ME/CFS objectively, rather than relying only on symptoms and other tests.

Biomarkers
E2 ModeratePEM not requiredPreliminaryObservationalEditor reviewed

Evaluation of autoantibodies to common and neuronal cell antigens in Chronic Fatigue Syndrome.

Vernon, Suzanne D, Reeves, William C·Journal of autoimmune diseases·2005

Researchers tested blood samples from people with ME/CFS and healthy controls to look for autoantibodies—proteins the immune system makes that can attack the body's own cells. They found that some people with ME/CFS had higher levels of antibodies against two specific targets: a brain protein called MAP2 and a component of DNA. However, most common autoantibodies were not elevated in ME/CFS patients.

BiomarkersImmune System
E2 ModeratePEM not requiredModerate confidenceCase-ControlEditor reviewed

Oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms.

Kennedy, Gwen, Spence, Vance A, McLaren, Margaret et al.·Free radical biology & medicine·2005

This study measured harmful molecules called free radicals in the blood of ME/CFS patients and compared them to healthy people. Researchers found that ME/CFS patients had higher levels of these damaging molecules, and in patients without heart disease risk factors, the amount of free radicals correlated with how severe their symptoms were, particularly fatigue after exertion and joint pain.

BiomarkersPost-Exertional Malaise
E2 ModeratePEM not requiredModerate confidenceObservationalEditor reviewed

Salivary cortisol as a predictor of postoperative fatigue.

Rubin, G James, Hotopf, Matthew, Papadopoulos, Andrew et al.·Psychosomatic medicine·2005

This study tested whether low cortisol (a stress hormone) causes or predicts chronic fatigue by following 161 patients before and after surgery. The researchers measured cortisol levels and fatigue at multiple time points, but found that low cortisol before or after surgery did not predict who would develop fatigue. This suggests that if low cortisol is connected to chronic fatigue, it develops after symptoms begin rather than causing them.

Biomarkers
E2 ModeratePEM not requiredPreliminaryObservationalEditor reviewed

Elevated levels of some neuroactive progesterone metabolites, particularly isopregnanolone, in women with chronic fatigue syndrome.

Murphy, B E Pearson, Abbott, F V, Allison, C M et al.·Psychoneuroendocrinology·2004

Researchers measured hormone breakdown products in the blood of women with ME/CFS and compared them to healthy women. They found that women with ME/CFS had significantly higher levels of a specific progesterone metabolite called isopregnanolone—more than twice as high as controls. This suggests that abnormal hormone metabolism may be involved in ME/CFS, and that depression alone cannot explain these chemical differences.

Biomarkers
E2 ModeratePEM not requiredPreliminaryCross-SectionalEditor reviewed

Diagnostic evaluation of 2', 5'-oligoadenylate synthetase activities and antibodies against Epstein-Barr virus and Coxiella burnetii in patients with chronic fatigue syndrome in Japan.

Ikuta, Kazufumi, Yamada, Takeshi, Shimomura, Tokio et al.·Microbes and infection·2003

This study tested whether certain viral infections and immune system markers are linked to ME/CFS. Researchers measured a protein called 2-5AS in blood cells from ME/CFS patients in Japan and compared it to healthy people. They found that ME/CFS patients had higher levels of this immune marker than healthy controls, and some patients showed signs of past infections with Epstein-Barr virus or another bacteria.

BiomarkersImmune System
E2 ModeratePEM not requiredPreliminaryCase-ControlEditor reviewed

Utility of the blood for gene expression profiling and biomarker discovery in chronic fatigue syndrome.

Vernon, Suzanne D, Unger, Elizabeth R, Dimulescu, Irina M et al.·Disease markers·2002

Researchers examined blood cells from people with ME/CFS and healthy volunteers to see if they could find differences in how genes are turned on or off. They found that blood cells from ME/CFS patients showed different gene activity patterns compared to healthy people, and some of these differences involved immune system genes. This suggests that ME/CFS involves problems with how the immune system is functioning.

BiomarkersImmune System
E2 ModeratePEM not requiredPreliminaryCross-SectionalEditor reviewed

Physical performance and prediction of 2-5A synthetase/RNase L antiviral pathway activity in patients with chronic fatigue syndrome.

Snell, Christopher R, Vanness, J Mark, Strayer, David R et al.·In vivo (Athens, Greece)·2002

This study looked at whether exercise test results could predict high levels of RNase L, an enzyme that may be involved in ME/CFS. Researchers asked 73 patients to exercise until they were exhausted, and found that those with elevated RNase L had lower exercise capacity than those with normal levels. The findings suggest that simple exercise tests might help doctors identify which ME/CFS patients have this particular biological abnormality.

BiomarkersImmune System
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Autoantibodies to a 68/48 kDa protein in chronic fatigue syndrome and primary fibromyalgia: a possible marker for hypersomnia and cognitive disorders.

Nishikai, M, Tomomatsu, S, Hankins, R W et al.·Rheumatology (Oxford, England)·2001

Researchers tested blood samples from ME/CFS and fibromyalgia patients to look for specific antibodies (immune proteins) that might be unique to these conditions. They found that about 13% of ME/CFS patients and 16% of fibromyalgia patients had antibodies against a protein called 68/48 kDa. Importantly, patients with these antibodies were more likely to experience severe sleep problems, memory issues, and trouble concentrating.

Biomarkers
E2 ModeratePEM not requiredPreliminaryCase-ControlEditor reviewed

Blood parameters indicative of oxidative stress are associated with symptom expression in chronic fatigue syndrome.

Richards, R S, Roberts, T K, McGregor, N R et al.·Redox report : communications in free radical research·2000

Researchers compared blood samples from 33 people with ME/CFS and 27 healthy people, looking for signs of oxidative stress—a type of cellular damage caused by unstable molecules called free radicals. They found that people with ME/CFS had higher levels of certain markers of this damage, particularly a substance called methaemoglobin. The levels of these damage markers were strongly linked to how severe patients' symptoms were, including fatigue, pain, sleep problems, and cognitive difficulties.

Biomarkers
E2 ModeratePEM unclearPreliminaryCase-ControlEditor reviewed

A 37 kDa 2-5A binding protein as a potential biochemical marker for chronic fatigue syndrome.

De Meirleir, K, Bisbal, C, Campine, I et al.·The American journal of medicine·2000

Researchers found a specific protein (37 kDa) in the blood cells of 88% of ME/CFS patients, compared to only 28% of control subjects. This protein was present in much higher amounts in ME/CFS patients, suggesting it could potentially be used as a blood test to help identify the condition.

BiomarkersImmune System
E2 ModeratePEM not requiredPreliminaryCross-SectionalEditor reviewed

Low levels of serum acylcarnitine in chronic fatigue syndrome and chronic hepatitis type C, but not seen in other diseases.

Kuratsune, H, Yamaguti, K, Lindh, G et al.·International journal of molecular medicine·1998

Researchers measured a substance called acylcarnitine in the blood of people with ME/CFS and compared it to healthy people and those with other diseases. They found that people with ME/CFS had significantly lower levels of this substance, and this same pattern appeared in both Japanese and Swedish patients. Importantly, this low level was only seen in ME/CFS and one other condition (chronic hepatitis C), not in other common diseases like diabetes or high blood pressure.

BiomarkersEnergy Metabolism
E2 ModeratePEM not requiredPreliminaryCross-SectionalEditor reviewed

[31P-mr spectroscopy of peripheral skeletal musculature under load: demonstration of normal energy metabolites compared with metabolic muscle diseases].

Block, W, Träber, F, Kuhl, C K et al.·RoFo : Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin·1998

Researchers used a special MRI scanner to measure how muscles use energy during exercise by looking at chemical changes in the calf. They found that healthy people used two different types of energy pathways during exercise, while people with ME/CFS showed unusual resting energy levels but normal recovery after exercise—unlike patients with genetic metabolic disorders, whose muscles recovered very slowly.

Biomarkers
E2 ModeratePEM unclearPreliminaryObservationalEditor reviewed

Magnesium deficit in a sample of the Belgian population presenting with chronic fatigue.

Moorkens, G, Manuel y Keenoy, B, Vertommen, J et al.·Magnesium research·1997

This study tested whether people with chronic fatigue have low magnesium levels. Researchers gave 97 patients a special magnesium test and found that 44 had magnesium deficiency. After magnesium supplements, their bodies retained less magnesium, suggesting the treatment may have helped. However, the researchers did not find a clear link between low magnesium and chronic fatigue syndrome itself.

Biomarkers
E2 ModeratePEM not requiredPreliminaryCross-SectionalEditor reviewed

Preliminary determination of a molecular basis of chronic fatigue syndrome.

McGregor, N R, Dunstan, R H, Zerbes, M et al.·Biochemical and molecular medicine·1996

Researchers tested the urine of 20 ME/CFS patients and 45 healthy controls to look for chemical differences. They found that ME/CFS patients had different levels of several substances in their urine, particularly one called CFSUM1 and beta-alanine, which were higher in patients with more severe symptoms. These findings suggest ME/CFS may have measurable biological markers that could help identify the condition.

BiomarkersEnergy Metabolism
E2 ModeratePEM not requiredModerate confidenceCase-ControlEditor reviewed

Clinical laboratory test findings in patients with chronic fatigue syndrome.

Bates, D W, Buchwald, D, Lee, J et al.·Archives of internal medicine·1995

Researchers compared blood test results from 579 ME/CFS patients with results from 147 healthy people. They found that ME/CFS patients were much more likely to have certain abnormal results, particularly immune-related changes like unusual white blood cells and immune complexes. However, no single test was abnormal enough in all patients to serve as a reliable diagnostic tool on its own.

BiomarkersImmune System
E2 ModeratePEM not requiredModerate confidenceCase-ControlEditor reviewed

Investigation of retroviral involvement in chronic fatigue syndrome.

Folks, T M, Heneine, W, Khan, A et al.·Ciba Foundation symposium·1993

Researchers tested whether certain viruses called retroviruses might be a biological marker that could help diagnose ME/CFS. They looked for five different retroviruses in people with ME/CFS and compared them to healthy controls. None of these viruses were found in either group, meaning they cannot be used to identify who has ME/CFS.

Biomarkers
E2 ModeratePEM not requiredPreliminaryObservationalEditor reviewed

[Chronic fatigue syndrome--cases in the Kanebo Memorial Hospital].

Ogawa, R, Toyama, S, Matsumoto, H·Nihon rinsho. Japanese journal of clinical medicine·1992

This study looked at 134 ME/CFS patients seen at one hospital in Japan and found that many had immune system abnormalities, including weakened natural killer cells and reactions to common substances like dust and pollen. Researchers also discovered some patients had low levels of certain fatty acids in their blood. When treated with a traditional Chinese herbal medicine called Ren-Shen-Yang-Rong-Tang, about 73% of patients were able to return to work or school.

BiomarkersImmune System
E2 ModeratePEM unclearPreliminaryObservationalEditor reviewed

Nondiscocytic erythrocytes in myalgic encephalomyelitis.

Simpson, L O·The New Zealand medical journal·1989

Researchers looked at red blood cells from 102 people with ME/CFS using a powerful microscope and compared them to healthy people and those with multiple sclerosis. They found that people with ME/CFS had fewer normal-shaped red blood cells and more cup-shaped red blood cells than the other groups. This suggests ME/CFS may have a physical cause that could potentially be detected through a blood test.

Biomarkers
E2 ModeratePEM unclearModerate confidenceLongitudinalEditor reviewed

Post-Acute Sequelae of COVID-19 Persist Over 3 Years in Acute Lung Injury/Acute Respiratory Distress Syndrome Survivors But Are Not Associated With Persistent Thromboinflammation or Endothelial Dysfunction.

Jones, Ansley E, Khan, Zain, McGroder, Claire F et al.·Critical care explorations·2026

This study followed people who were hospitalized with severe COVID-19 for 3 years after they left the hospital. About one-quarter of them continued to experience long COVID symptoms like fatigue, brain fog, and difficulty with physical activity. Surprisingly, when researchers measured inflammation and blood vessel markers in their blood, these markers were not elevated and did not explain why some people had ongoing symptoms.

BiomarkersImmune SystemPost-Exertional Malaise
E2 ModeratePEM unclearModerate confidenceLongitudinalEditor reviewed

Exploring DNA methylation, telomere length, mitochondrial DNA, and immune function in patients with Long-COVID.

Polli, Andrea, Godderis, Lode, Martens, Dries S et al.·BMC medicine·2025

This study followed 358 people who had COVID-19 to understand why some develop Long-COVID with symptoms like extreme fatigue, sleep problems, and post-exertional malaise (feeling much worse after activity). Researchers measured biological markers in blood and found that two factors—elevated troponin T (a heart protein) and shortened telomeres (the protective caps on DNA)—were most strongly linked to Long-COVID, particularly the fatigue cluster. The study shows that Long-COVID is not a single illness but has different symptom patterns, suggesting different underlying causes may be at play.

BiomarkersPost-Exertional Malaise
E2 ModeratePEM not requiredModerate confidenceCase-ControlEditor reviewed

No reduced serum serotonin levels in patients with post-acute sequelae of COVID-19.

Mathé, Philipp, Götz, Veronika, Stete, Katarina et al.·Infection·2025

Researchers compared serotonin levels in the blood of 34 people with long COVID (PASC) and 14 healthy people. Serotonin is a chemical in the body that affects mood and fatigue. The study found no meaningful difference in serotonin levels between the two groups, suggesting that low serotonin is probably not the main cause of long COVID symptoms.

Biomarkers
E2 ModeratePEM not requiredModerate confidenceCross-SectionalEditor reviewed

Distinguishing features of long COVID identified through immune profiling.

Klein, Jon, Wood, Jamie, Jaycox, Jillian R et al.·Nature·2023

Researchers studied 275 people with and without long COVID to understand what happens in the immune system. They found that people with long COVID have different patterns of immune cells and antibodies, including stronger responses to past viral infections like Epstein-Barr virus, and lower levels of the stress hormone cortisol. Using computer analysis, they identified specific immune markers that could help identify who has long COVID.

BiomarkersImmune System
E2 ModeratePEM not requiredModerate confidenceCross-SectionalEditor reviewed

Post-COVID-19 Syndrome: Retinal Microcirculation as a Potential Marker for Chronic Fatigue.

Schlick, Sarah, Lucio, Marianna, Wallukat, Gerd et al.·International journal of molecular sciences·2022

Researchers studied whether tiny blood vessels in the eye could be a measurable sign of fatigue in people with long COVID. Using a special imaging technique to look at blood vessels in the retina (back of the eye), they found that people with long COVID—especially women—had reduced blood flow in these tiny vessels compared to healthy people. Those with long COVID who reported severe fatigue had even lower blood vessel density than those with milder fatigue, suggesting the eye scan might objectively confirm what patients report feeling.

Biomarkers
E2 ModeratePEM not requiredPreliminaryObservationalEditor reviewed

HERV-W ENV antigenemia and correlation of increased anti-SARS-CoV-2 immunoglobulin levels with post-COVID-19 symptoms.

Giménez-Orenga, Karen, Pierquin, Justine, Brunel, Joanna et al.·Frontiers in immunology·2022

This study found that a dormant virus-like element called HERV-W, which exists naturally in our DNA, may reactivate and remain active long after COVID-19 infection has cleared in people with long COVID. The researchers also discovered that people with higher levels of certain immune proteins (antibodies) against SARS-CoV-2, especially IgE antibodies, tended to have worse physical function. These findings suggest that HERV-W activation and lingering antibody responses might help explain why some people develop long-lasting COVID symptoms.

BiomarkersImmune System
E2 ModeratePEM unclearModerate confidenceCase-ControlEditor reviewed

Urinary Peptidomic Profiling In Post-Acute Sequelae of SARS-CoV-2 Infection: A Case-Control Study.

Gülmez, Dilara, Siwy, Justyna, Kurz, Katharina et al.·Proteomics·2026

Researchers found a simple urine test that can accurately identify people with long COVID (PASC) by measuring tiny protein fragments in the urine. The test correctly identified long COVID patients 96% of the time compared to healthy people and those with ME/CFS. The urine signatures suggest that long COVID involves ongoing inflammation and changes in how the body breaks down and rebuilds connective tissue.

BiomarkersImmune System
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

HERV activation segregates ME/CFS from fibromyalgia while defining a novel nosologic entity.

Giménez-Orenga, Karen, Martín-Martínez, Eva, Nathanson, Lubov et al.·eLife·2025

This study looked at special genetic materials called human endogenous retroviruses (HERVs) in the blood cells of women with ME/CFS, fibromyalgia, both conditions, or neither. The researchers found that the pattern of which HERVs were active could perfectly distinguish between these four groups—suggesting this could become a reliable blood test to diagnose these conditions. The study also found that ME/CFS patients had specific changes in immune cells that matched how severe their symptoms were.

BiomarkersImmune System
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Association of circulating biomarkers with illness severity measures differentiates myalgic encephalomyelitis/chronic fatigue syndrome and post-COVID-19 condition: a prospective pilot cohort study.

Domingo, Joan Carles, Battistini, Federica, Cordobilla, Begoña et al.·Journal of translational medicine·2024

This study compared blood markers and body responses between people with ME/CFS, people with long COVID, and healthy controls. Researchers found that people with ME/CFS had distinct patterns of inflammation and blood vessel dysfunction compared to long COVID patients, suggesting these are different conditions with different underlying problems. By measuring specific proteins in the blood and testing how the body responds to positional changes, researchers could tell the two patient groups apart.

BiomarkersImmune System
E2 ModeratePEM requiredModerate confidenceLongitudinalEditor reviewed

Long-term symptom severity and clinical biomarkers in post-COVID-19/chronic fatigue syndrome: results from a prospective observational cohort.

Legler, Franziska, Meyer-Arndt, Lil, Mödl, Lukas et al.·EClinicalMedicine·2023

This study followed 106 people with long-term fatigue after COVID-19 for up to 20 months to see how they recovered over time. Researchers found that some patients met the diagnostic criteria for ME/CFS and had persistent, severe symptoms including fatigue and post-exertional malaise (worsening after activity), while others improved more substantially. Lower muscle strength at the start of illness was linked to ongoing symptoms, especially in those with ME/CFS.

BiomarkersImmune SystemPost-Exertional Malaise
E2 ModeratePEM unclearPreliminaryObservationalEditor reviewed

Utility of Serum Ferritin for Predicting Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Patients with Long COVID.

Yamamoto, Yukichika, Otsuka, Yuki, Tokumasu, Kazuki et al.·Journal of clinical medicine·2023

This study looked at 234 people with long COVID to understand why some developed ME/CFS (a severe fatigue condition) while others didn't. Researchers found that people who developed ME/CFS had significantly higher levels of ferritin, a protein that stores iron, in their blood compared to those with long COVID fatigue alone or no fatigue. The finding was especially strong in women, suggesting that a simple blood test measuring ferritin might help predict who is at risk of developing ME/CFS after COVID-19.

Biomarkers
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Evidence of a Novel Mitochondrial Signature in Systemic Sclerosis Patients with Chronic Fatigue Syndrome.

van Eeden, Charmaine, Redmond, Desiree, Mohazab, Naima et al.·International journal of molecular sciences·2023

This study looked at people with a connective tissue disease called systemic sclerosis who also experience severe fatigue (ME/CFS symptoms). Researchers found that fatigued patients had different patterns in how their cells' energy-producing structures (mitochondria) work compared to non-fatigued patients. These differences involved specific genes related to energy production, suggesting that measuring these genes might help doctors identify which systemic sclerosis patients have ME/CFS.

Biomarkers
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Circulating microRNA expression signatures accurately discriminate myalgic encephalomyelitis from fibromyalgia and comorbid conditions.

Nepotchatykh, Evguenia, Caraus, Iurie, Elremaly, Wesam et al.·Scientific reports·2023

Researchers studied tiny molecules called microRNAs in the blood to see if they could tell the difference between ME/CFS, fibromyalgia, and people who have both conditions. They found that each condition has a unique pattern of these microRNAs, like a biological fingerprint. Using these patterns, they created a computer model that could accurately identify which condition a person has, which could help with proper diagnosis.

Biomarkers
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Sex-Based Differences in Plasma Autoantibodies to Central Nervous System Proteins in Gulf War Veterans versus Healthy and Symptomatic Controls.

Abou-Donia, Mohamed B, Krengel, Maxine H, Lapadula, Elizabeth S et al.·Brain sciences·2021

Researchers found that Gulf War veterans with Gulf War illness have abnormal immune proteins in their blood that attack brain cells, and these patterns differ between men and women. The study also found that these same immune markers can help distinguish Gulf War illness from other similar conditions like ME/CFS and IBS. This discovery is important because it offers a possible objective blood test that doctors could use to identify and diagnose these difficult-to-recognize illnesses.

BiomarkersImmune System
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Exercise modifies glutamate and other metabolic biomarkers in cerebrospinal fluid from Gulf War Illness and Myalgic encephalomyelitis / Chronic Fatigue Syndrome.

Baraniuk, James N, Kern, Grant, Narayan, Vaishnavi et al.·PloS one·2021

Researchers studied the fluid around the brain and spinal cord in people with ME/CFS and Gulf War Illness to see how exercise affects certain chemicals in the body. They found that glutamate (a brain chemical) levels changed differently depending on whether someone had exercised and how their body responded, and that some fat-related molecules were different between the two conditions. This suggests that ME/CFS and Gulf War Illness may involve different problems with how the body uses energy and processes fats.

NeuroinflammationBiomarkersPost-Exertional Malaise
E2 ModeratePEM unclearPreliminaryCase-ControlEditor reviewed

Using Plasma Autoantibodies of Central Nervous System Proteins to Distinguish Veterans with Gulf War Illness from Healthy and Symptomatic Controls.

Abou-Donia, Mohamed B, Lapadula, Elizabeth S, Krengel, Maxine H et al.·Brain sciences·2020

Researchers tested blood samples from Gulf War veterans with Gulf War Illness (GWI) and compared them to healthy veterans and people with ME/CFS or irritable bowel syndrome. They found that GWI veterans had higher levels of autoantibodies—proteins the immune system makes that mistakenly attack the brain and nervous system—compared to all three control groups. This suggests that a blood test measuring these autoantibodies could potentially help doctors diagnose Gulf War Illness objectively.

NeuroinflammationBiomarkers
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Patients with Fibromyalgia and Chronic Fatigue Syndrome show increased hsCRP compared to healthy controls.

Groven, Nina, Fors, Egil A, Reitan, Solveig Klæbo·Brain, behavior, and immunity·2019

This study measured inflammation markers in the blood of people with ME/CFS and fibromyalgia, compared to healthy people. Both patient groups had higher levels of a marker called hsCRP (a sign of inflammation) than healthy controls. The two conditions showed similar inflammation levels, suggesting they may share some biological similarities.

BiomarkersImmune System
E2 ModeratePEM not requiredPreliminaryCross-SectionalEditor reviewed

Artificial intelligence based discovery of the association between depression and chronic fatigue syndrome.

Zhang, Feilong, Wu, Chuanhong, Jia, Caixia et al.·Journal of affective disorders·2019

This study looked at whether depression and chronic fatigue syndrome (CFS) share common biological markers in the blood and urine. Researchers used advanced chemical testing and artificial intelligence to analyze samples from 295 people and found that depression and CFS have some overlapping chemical signatures, though they also have distinct differences. The findings suggest these two conditions may be more closely related than previously thought.

Biomarkers
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Gene Expression Factor Analysis to Differentiate Pathways Linked to Fibromyalgia, Chronic Fatigue Syndrome, and Depression in a Diverse Patient Sample.

Iacob, Eli, Light, Alan R, Donaldson, Gary W et al.·Arthritis care & research·2016

Researchers studied blood cell genes from 261 people—including those with ME/CFS, fibromyalgia, depression, and healthy controls—to see if certain genes work together in patterns tied to these conditions. They found four distinct gene clusters, and two of these clusters showed opposite patterns in ME/CFS patients compared to those with depression, suggesting these conditions may involve different biological pathways even when they overlap.

BiomarkersImmune System
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Cytokine expression provides clues to the pathophysiology of Gulf War illness and myalgic encephalomyelitis.

Khaiboullina, Svetlana F, DeMeirleir, Kenny L, Rawat, Shanti et al.·Cytokine·2015

This study looked at chemical messengers in the blood called cytokines to understand Gulf War illness (GWI) and ME/CFS better. Researchers found that certain cytokines could identify ME/CFS patients very well, but were less reliable for GWI patients. The findings suggest that while GWI and ME/CFS share many similar symptoms, they may have different underlying immune system problems.

BiomarkersImmune System
E2 ModeratePEM not requiredModerate confidenceLongitudinalEditor reviewed

The MAPP research network: design, patient characterization and operations.

Landis, J Richard, Williams, David A, Lucia, M Scott et al.·BMC urology·2014

The MAPP Research Network is a large study designed to understand chronic pelvic pain conditions and related illnesses like fibromyalgia, chronic fatigue syndrome, and irritable bowel syndrome. Researchers followed over 1,000 patients at six sites across the United States, collecting detailed information about their symptoms, blood samples, and brain imaging to identify what causes these conditions and how they connect to each other.

Biomarkers
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Extracellular Vesicle Protein and MiRNA Signatures as Biomarkers for Post-Infectious ME/CFS Patients.

Seifert, Martina, Schäfers, Johannes, Douglas, Fiona F et al.·International journal of molecular sciences·2026

Researchers examined tiny packages of proteins and molecules (called extracellular vesicles) found in the blood of ME/CFS patients to see if they contain unique signatures that could help diagnose the disease. They found that certain proteins and a specific small molecule called hsa-let-7b-5p were different in ME/CFS patients compared to healthy people, and these differences were linked to worse fatigue, pain, and immune problems. This discovery suggests that blood tests measuring these substances could eventually help doctors diagnose ME/CFS and better understand who has the disease.

Biomarkers
E2 ModeratePEM unclearModerate confidenceLongitudinalEditor reviewed

Chronic Reactivation of Persistent Human Herpesviruses EBV, HHV-6 and VZV and Heightened Anti-dUTPase IgG Antibodies Are a Recurrent Hallmark in Post-Infectious ME/CFS and is Associated With Fatigue.

Palomo, Irene Mena, Cox, Brandon, Williams, Marshall V et al.·Journal of medical virology·2026

This study found that people with ME/CFS have higher levels of immune responses to three common viruses (EBV, HHV-6, and VZV) compared to healthy people. About 72% of ME/CFS patients showed antibodies to multiple viruses at the same time, versus only 31% of healthy controls. The antibody levels were higher in patients with moderate to severe fatigue, suggesting a possible connection between these viral reactivations and symptom severity.

BiomarkersImmune System
E2 ModeratePEM requiredModerate confidenceLongitudinalEditor reviewed

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.

Severe MEBiomarkersPost-Exertional Malaise
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

No difference in serum levels of B-cell activating receptor and antibodies against cytolethal distending toxin B and flagellin in post-infectious irritable bowel syndrome and chronic fatigue syndrome after Giardia infection.

Hanevik, Kurt, Saghaug, Christina, Aaland, Maren et al.·JGH open : an open access journal of gastroenterology and hepatology·2022

This study looked for three potential biological markers (BAFF, anti-CdtB, and anti-flagellin antibodies) in the blood of people who developed ME/CFS and/or IBS after a Giardia infection. Researchers compared these markers in patients to healthy controls but found no significant differences between the groups. The findings suggest these three markers are not useful for diagnosing ME/CFS or IBS.

BiomarkersImmune System
E2 ModeratePEM not requiredModerate confidenceLongitudinalEditor reviewed

Predictors of chronic fatigue in adolescents six months after acute Epstein-Barr virus infection: A prospective cohort study.

Pedersen, Maria, Asprusten, Tarjei Tørre, Godang, Kristin et al.·Brain, behavior, and immunity·2019

This study followed 200 teenagers who had an acute Epstein-Barr virus (EBV) infection to see which factors predicted who would develop lasting fatigue six months later. Researchers measured many baseline characteristics including pain sensitivity, mood, memory, physical activity level, and blood markers like vitamin B12 and inflammation levels. They found that fatigue six months after EBV was most strongly predicted by things like sensory sensitivity, pain, anxiety, and how active the teenager was—rather than by immune system markers alone.

Biomarkers
E2 ModeratePEM not requiredPreliminaryLongitudinalEditor reviewed

Tracking post-infectious fatigue in clinic using routine Lab tests.

Harvey, Jeanna M, Broderick, Gordon, Bowie, Alanna et al.·BMC pediatrics·2016

Researchers followed 301 teenagers who had infectious mononucleosis to see who would develop chronic fatigue syndrome (ME/CFS). They found that measuring common blood tests over 2 years—including stress hormones, sex hormones, and immune cell counts—might help doctors identify which patients are at risk and confirm the diagnosis. Only 4% of the teens developed CFS, but specific blood markers showed different patterns in those who did compared to those who recovered normally.

Biomarkers
E2 ModeratePEM not requiredPreliminaryMechanisticEditor reviewed

Manual Therapy Improves Fibromyalgia Symptoms by Downregulating SIK1.

Bonastre-Férez, Javier, Giménez-Orenga, Karen, Falaguera-Vera, Francisco Javier et al.·International journal of molecular sciences·2024

This study tested whether a specialized hands-on therapy treatment could help fibromyalgia patients and discovered why it might work. Researchers found that the treatment lowered levels of a specific gene called SIK1 in patients' blood cells, and this change was linked to improvements in pain, fatigue, and quality of life. Importantly, this gene change only happened in fibromyalgia patients who received the treatment—not in healthy people who got the same therapy.

Biomarkers
E2 ModeratePEM not requiredPreliminaryCross-SectionalEditor reviewed

A Causal-Pathway Phenotype of Chronic Fatigue Syndrome due to Hemodialysis in Patients with End-Stage Renal Disease.

Asad, Halah Nori, Al-Hakeim, Hussein Kadhem, Moustafa, Shatha Rouf et al.·CNS & neurological disorders drug targets·2023

This study looked at patients with severe kidney disease who need dialysis (a machine that cleans their blood) and found they often experience extreme fatigue and other symptoms similar to ME/CFS, such as muscle pain, sleep problems, and brain fog. Researchers measured various substances in the blood and found that fatigue was linked to anemia (low blood iron), poor nutrition, and certain protein imbalances caused by the dialysis treatment itself. The more dialysis sessions patients needed, the worse their fatigue tended to be.

Biomarkers
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Machine Learning Detects Pattern of Differences in Functional Magnetic Resonance Imaging (fMRI) Data between Chronic Fatigue Syndrome (CFS) and Gulf War Illness (GWI).

Provenzano, Destie, Washington, Stuart D, Rao, Yuan J et al.·Brain sciences·2020

This study used brain imaging (fMRI) and computer learning programs to see if people with ME/CFS and Gulf War Illness have different patterns of brain activity during memory tasks, both before and after exercise. Researchers found that computer programs could correctly distinguish between the two conditions about 75-82% of the time, and identified about 30-33 brain regions that showed different activation patterns between the two groups. This suggests that ME/CFS and Gulf War Illness may have measurable biological differences in how the brain works during cognitive tasks and recovery from exertion.

BiomarkersPost-Exertional Malaise
E2 ModeratePEM not requiredModerate confidenceCross-SectionalEditor reviewed

Metabolic analysis of amino acids and vitamin B6 pathways in lymphoma survivors with cancer related chronic fatigue.

Fosså, Alexander, Smeland, Knut Halvor, Fluge, Øystein et al.·PloS one·2020

This study looked at blood chemicals called amino acids and B vitamins in lymphoma survivors who experienced lasting fatigue after cancer treatment. Researchers found that people with this fatigue had lower tryptophan (an amino acid) and signs of ongoing low-level immune activation and inflammation. The study suggests that persistent tiredness after lymphoma treatment may be caused by the body's immune system staying activated longer than expected.

BiomarkersImmune System
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Metabolic features of Gulf War illness.

Naviaux, Robert K, Naviaux, Jane C, Li, Kefeng et al.·PloS one·2019

Researchers studied blood samples from Gulf War veterans with chronic illness and compared them to healthy controls. They found that veterans with Gulf War illness had abnormal levels of certain fats in their blood, particularly a type called ceramides and sphingomyelins. Interestingly, while Gulf War illness and ME/CFS share some similar symptom patterns, the chemical changes in the blood are largely opposite between the two conditions.

BiomarkersEnergy Metabolism
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Multidimensional Comparison of Cancer-Related Fatigue and Chronic Fatigue Syndrome: The Role of Psychophysiological Markers.

Park, Hye Youn, Jeon, Hong Jun, Bang, Young Rong et al.·Psychiatry investigation·2019

This study compared fatigue in people with cancer (CRF) and people with ME/CFS to see if these conditions are similar or different. Researchers measured fatigue levels, mood, stress, sleep quality, and specific biological markers like inflammation and brain activity. While both groups reported similar amounts of fatigue, they showed different underlying biological patterns, suggesting the two conditions may have different causes.

BiomarkersImmune System
E2 ModeratePEM not requiredModerate confidenceCross-SectionalEditor reviewed

Superiority of 18F-FDG PET compared to 111In-labelled leucocyte scintigraphy in the evaluation of fever of unknown origin.

Seshadri, N, Sonoda, L I, Lever, A M et al.·The Journal of infection·2012

This study compared two imaging tests for finding the cause of fever that doctors can't explain. One test (PET) was much better at detecting problems—finding a cause in 86% of patients—compared to the other test (leucocyte scintigraphy), which only found a cause in 20% of patients. PET scans successfully identified infections, inflammation, and other conditions causing unexplained fevers.

Biomarkers
E2 ModeratePEM not requiredPreliminaryCross-SectionalEditor reviewed

Lower whole blood glutathione peroxidase (GPX) activity in depression, but not in myalgic encephalomyelitis / chronic fatigue syndrome: another pathway that may be associated with coronary artery disease and neuroprogression in depression.

Maes, Michael, Mihaylova, Ivanka, Kubera, Marta et al.·Neuro endocrinology letters·2011

This study looked at a protective enzyme called GPX that helps defend cells from damage in people with depression and ME/CFS. The researchers found that people with depression had lower levels of this enzyme compared to healthy people, but people with ME/CFS had normal levels. Both groups showed connections between low enzyme levels and symptoms like mood problems and autonomic nervous system dysfunction.

Biomarkers
E2 ModeratePEM not requiredPreliminaryCross-SectionalEditor reviewed

Use of dynamic tests of muscle function and histomorphometry of quadriceps muscle biopsies in the investigation of patients with chronic alcohol misuse and chronic fatigue syndrome.

Wassif, W S, Sherman, D, Salisbury, J R et al.·Annals of clinical biochemistry·1994

Researchers tested muscle function and examined muscle samples from people with ME/CFS and people with chronic alcohol problems to see if their muscle problems were similar or different. They found that while some people initially thought to have ME/CFS actually had other conditions (like a rare enzyme deficiency or inflammation), the muscle changes in alcohol misuse were quite distinct and recognizable through muscle biopsies.

Biomarkers
E3 PreliminaryPEM unclearModerate confidenceMechanisticEditor reviewed

Indistinguishable mitochondrial phenotypes after exposure of healthy myoblasts to myalgic encephalomyelitis/chronic fatigue syndrome or control serum.

Ryback, Audrey A, Hillier, Charles B, Loureiro, Camila M et al.·PloS one·2026

Researchers wanted to test whether something in the blood of people with ME/CFS could damage the energy-producing parts of cells (mitochondria) when added to healthy cells in the lab. They tested blood from 67 people with ME/CFS and 53 healthy people on cultured muscle cells and measured how well the cells could use oxygen. Unlike a previous smaller study, they found no difference between the ME/CFS blood and healthy blood samples.

BiomarkersEnergy Metabolism
E3 PreliminaryPEM not requiredModerate confidenceMethods-PaperEditor reviewed

Pipeline-optimized machine learning for chronic fatigue syndrome diagnosis: A lightweight, interpretable model using blood biochemical and metabolomic data.

Li, Junrong, Cao, Hanyu, Zhu, Zirun et al.·Computational biology and chemistry·2026

Researchers developed a computer program that uses blood tests to help diagnose ME/CFS more accurately and quickly. The program was trained on data from over 1,100 people with ME/CFS and nearly 67,000 control participants, and it correctly identified ME/CFS in about 94% of cases. This tool could help doctors catch the condition earlier and tailor treatment to individual patients.

Biomarkers
E3 PreliminaryPEM requiredPreliminaryReview-NarrativeEditor reviewed

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 requiredPreliminaryPreprintPreprintEditor reviewed

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.

BiomarkersImmune SystemCognitive ImpairmentPost-Exertional Malaise
E3 PreliminaryPEM requiredPreliminaryMechanisticEditor reviewed

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.

BiomarkersImmune SystemPost-Exertional Malaise
E3 PreliminaryPEM requiredPreliminaryMechanisticEditor reviewed

Extracellular vesicle proteomics uncovers energy metabolism, complement system, and endoplasmic reticulum stress response dysregulation postexercise in males with myalgic encephalomyelitis/chronic fatigue syndrome.

Glass, Katherine A, Giloteaux, Ludovic, Zhang, Sheng et al.·Clinical and translational medicine·2025

Researchers studied tiny particles called extracellular vesicles in the blood of ME/CFS patients before and after exercise. They found that in people with ME/CFS, these particles show signs of energy problems, immune overactivity, and cellular stress after exertion—changes that were linked to post-exertional malaise (the worsening of symptoms after activity). These findings suggest new targets for treatment that could help improve recovery and energy in ME/CFS.

BiomarkersPost-Exertional Malaise
E3 PreliminaryPEM unclearPreliminaryMethods-PaperEditor reviewed

Application of DNA Methylome Analysis to Patients with ME/CFS.

Peppercorn, Katie, Edgar, Christina D, Al Momani, Suzan et al.·Methods in molecular biology (Clifton, N.J.)·2025

This study describes a technique called RRBS that examines how chemical tags on our DNA (called methylation) are different in ME/CFS patients compared to healthy people. These tags act like switches that turn genes on or off, and abnormal patterns might help explain why ME/CFS causes such severe symptoms. The researchers show how this method can be used to identify patterns that could eventually lead to better diagnostic tests or ways to track how the illness changes over time.

Biomarkers
E3 PreliminaryPEM requiredPreliminaryMethods-PaperEditor reviewed

Measuring Biomarkers of Oxidative Stress in ME/CFS Patients.

Walker, Max·Methods in molecular biology (Clifton, N.J.)·2025

This study looked at whether certain molecules in the blood and immune cells could show signs of oxidative stress (cellular damage from harmful molecules called free radicals) in ME/CFS patients. The researchers tested two different markers before and after exercise: one test successfully measured protein damage, while another test designed to measure DNA damage was not sensitive enough to detect changes in this patient group.

BiomarkersPost-Exertional Malaise
E3 PreliminaryPEM not requiredPreliminaryCross-SectionalEditor reviewed

Histone phosphorylation analysis of two main TCM syndromes of chronic fatigue syndrome.

Xu, Tingting, Gao, Shuo, Cheng, Xinxin et al.·Journal of translational medicine·2025

Researchers studied blood cells from 20 ME/CFS patients (divided into two Traditional Chinese Medicine symptom patterns) and 10 healthy controls. They found differences in how proteins were modified in the blood cells of ME/CFS patients compared to healthy people. These differences involved processes that affect how cells communicate with each other and organize their internal structures.

BiomarkersImmune System
E3 PreliminaryPEM unclearPreliminaryCross-SectionalEditor reviewed

Dysregulation of the Kynurenine Pathway, Cytokine Expression Pattern, and Proteomics Profile Link to Symptomology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Kavyani, Bahar, Ahn, Seong Beom, Missailidis, Daniel et al.·Molecular neurobiology·2024

This study found that ME/CFS patients have imbalances in a particular chemical pathway in their body (the kynurenine pathway) that appears connected to inflammation and symptom severity. The researchers discovered that higher levels of one early chemical in this pathway correlated with worse symptoms, while lower levels of later chemicals in the pathway might affect how cells produce energy. Interestingly, they also found that five of the most significantly changed proteins in ME/CFS patients are involved in gut health, suggesting the gut microbiome may play an important role in the disease.

BiomarkersGut MicrobiomeEnergy MetabolismImmune System
E3 PreliminaryPEM requiredPreliminaryCross-SectionalEditor reviewed

Dysregulation of extracellular vesicle protein cargo in female myalgic encephalomyelitis/chronic fatigue syndrome cases and sedentary controls in response to maximal exercise.

Giloteaux, Ludovic, Glass, Katherine A, Germain, Arnaud et al.·Journal of extracellular vesicles·2024

When people without ME/CFS exercise, their bodies release tiny particles called extracellular vesicles that help cells communicate and recover. This study found that in people with ME/CFS, these particles carry different proteins after exercise compared to healthy people, and these differences match how severe a person's symptoms are. This suggests that ME/CFS patients' bodies may have a distinct biological response to exercise that could explain why exertion makes their symptoms worse.

BiomarkersPost-Exertional Malaise
E3 PreliminaryPEM unclearPreliminaryMechanisticEditor reviewed

Immunometabolic changes and potential biomarkers in CFS peripheral immune cells revealed by single-cell RNA sequencing.

Sun, Yujing, Zhang, Zhenhua, Qiao, Qincheng et al.·Journal of translational medicine·2024

Researchers used advanced cell analysis to examine immune cells from the blood of 4 ME/CFS patients and 4 healthy people. They found that ME/CFS patients have an unusual mix of immune cells, with too many T cells but too few natural killer cells and other immune cells that normally fight infections. Some of their immune cells also show signs of overactivity while others seem weakened, and the researchers identified a potential blood test marker that could help diagnose ME/CFS.

BiomarkersImmune System
E3 PreliminaryPEM unclearPreliminaryMethods-PaperEditor reviewed

Development of an expert system for the classification of myalgic encephalomyelitis/chronic fatigue syndrome.

Yagin, Fatma Hilal, Shateri, Ahmadreza, Nasiri, Hamid et al.·PeerJ. Computer science·2024

Researchers used artificial intelligence to analyze blood samples from 32 women with ME/CFS and 19 healthy controls, examining 832 different substances in their blood. The AI model identified just 50 key substances that could distinguish ME/CFS patients from healthy people with 98.85% accuracy. The study found that ME/CFS patients had different levels of five specific metabolites in their blood, which could potentially be used as biomarkers for diagnosis.

Biomarkers
E3 PreliminaryPEM unclearPreliminaryCross-SectionalEditor reviewed

An Explainable Artificial Intelligence Model Proposed for the Prediction of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and the Identification of Distinctive Metabolites.

Yagin, Fatma Hilal, Alkhateeb, Abedalrhman, Raza, Ali et al.·Diagnostics (Basel, Switzerland)·2023

Researchers used artificial intelligence and a type of blood analysis called metabolomics to find chemical markers that could help identify ME/CFS patients. They studied 26 people with ME/CFS and 26 healthy people, testing 768 different chemicals in their blood. The AI model identified four key chemicals (C-glycosyltryptophan, oleoylcholine, cortisone, and 3-hydroxydecanoate) that were different between the two groups and could help diagnose ME/CFS with high accuracy.

Biomarkers
E3 PreliminaryPEM unclearPreliminaryCross-SectionalEditor reviewed

Detection of Elevated Level of Tetrahydrobiopterin in Serum Samples of ME/CFS Patients with Orthostatic Intolerance: A Pilot Study.

Gottschalk, Carl Gunnar, Whelan, Ryan, Peterson, Daniel et al.·International journal of molecular sciences·2023

This study looked at a molecule called BH4 in the blood of ME/CFS patients, particularly those who experience dizziness when standing up. The researchers found that ME/CFS patients have higher levels of BH4 than healthy people, and this may be connected to oxidative stress (harmful chemical reactions in the body). This finding could help explain why some ME/CFS patients struggle with dizziness and blood flow problems.

Biomarkers
E3 PreliminaryPEM unclearModerate confidenceMethods-PaperEditor reviewed

Bayesian Statistics Improves Biological Interpretability of Metabolomics Data from Human Cohorts.

Brydges, Christopher, Che, Xiaoyu, Lipkin, Walter Ian et al.·Metabolites·2023

This study compared blood chemistry samples from three different groups of ME/CFS patients and healthy people to find differences in metabolites—small molecules in the blood. Instead of using the traditional statistical method, researchers used a newer approach called Bayesian statistics that allows them to combine results from multiple studies to find patterns that traditional methods missed. They discovered several important differences in blood metabolites between ME/CFS patients and healthy controls, including abnormal fat molecules and reduced levels of prostaglandin F2alpha.

Biomarkers
E3 PreliminaryPEM requiredPreliminaryCross-SectionalEditor reviewed

Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome With Partial Least Squares Discriminant Analysis: Relevance of Blood Extracellular Vesicles.

González-Cebrián, Alba, Almenar-Pérez, Eloy, Xu, Jiabao et al.·Frontiers in medicine·2022

Researchers tested whether tiny particles called extracellular vesicles in blood could help diagnose ME/CFS. They analyzed various substances in blood from patients and healthy controls using a computer analysis method. The study found that certain features of these blood particles, combined with other markers, could potentially identify ME/CFS, though more testing is needed to confirm this works reliably in larger groups.

Biomarkers
E3 PreliminaryPEM requiredModerate confidenceReview-NarrativeEditor reviewed

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 unclearWeak / uncertainEditorialEditor reviewed

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
E3 PreliminaryPEM unclearModerate confidenceRegistry-ResourceEditor reviewed

mapMECFS: a portal to enhance data discovery across biological disciplines and collaborative sites.

Mathur, Ravi, Carnes, Megan U, Harding, Alexander et al.·Journal of translational medicine·2021

Researchers created mapMECFS, an online database that brings together research information about ME/CFS from scientists around the world. Instead of having data scattered across different locations and websites, this portal allows researchers to easily find, share, and compare information about the disease in one place. This tool is designed to help scientists discover patterns and connections that might reveal new ways to diagnose and treat ME/CFS.

Biomarkers
E3 PreliminaryPEM unclearPreliminaryCross-SectionalEditor reviewed

Altered endothelial dysfunction-related miRs in plasma from ME/CFS patients.

Blauensteiner, J, Bertinat, R, León, L E et al.·Scientific reports·2021

This study looked at tiny molecules called microRNAs in the blood of ME/CFS patients to understand what might be going wrong with their blood vessels. The researchers found that five specific microRNAs were higher in ME/CFS patients compared to healthy people, and these molecules are known to affect how blood vessels function. This discovery suggests that blood vessel problems might be part of what causes ME/CFS symptoms.

BiomarkersImmune System
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

Broadband electrical impedance as a novel characterization of oxidative stress in single L6 skeletal muscle cells.

Ferguson, Caroline, Pini, Niccolo, Du, Xiaotian et al.·Analytica chimica acta·2021

This study tested whether a special electrical measurement could detect damage from oxidative stress (harmful chemical reactions) in muscle cells. Researchers treated rat muscle cells with hydrogen peroxide to create oxidative stress, then measured how these stressed cells behaved electrically compared to healthy cells. The stressed cells showed distinctly different electrical patterns, suggesting this technology might one day help diagnose ME/CFS by detecting oxidative stress in patients' muscle cells.

Biomarkers
E3 PreliminaryPEM unclearPreliminaryMethods-PaperEditor reviewed

Evaluation of natural killer cell assay performance on shipped blood specimens.

Querec, Troy D, Abrams, Joseph, Stewart, Jennifer J et al.·Journal of immunological methods·2021

This study tested different laboratory methods for measuring natural killer (NK) cell function—an immune system measurement that may be important for ME/CFS—using blood samples that were shipped overnight instead of tested immediately. Researchers compared three different testing approaches and found that two of them (CRCA and FCCA) gave similar results when blood samples were processed a day after collection, suggesting these tests could work for clinical settings where samples need to be shipped.

BiomarkersImmune System
E3 PreliminaryPEM requiredPreliminaryMechanisticEditor reviewed

Profile of circulating microRNAs in myalgic encephalomyelitis and their relation to symptom severity, and disease pathophysiology.

Nepotchatykh, Evguenia, Elremaly, Wesam, Caraus, Iurie et al.·Scientific reports·2020

This study looked at tiny molecules called microRNAs in the blood of severely ill ME/CFS patients before and after a stress challenge designed to trigger post-exertional malaise (the worsening of symptoms after activity). The researchers found that eleven different microRNAs changed in response to this challenge, with patterns that varied depending on symptom severity. These microRNA signatures could potentially be used one day as blood tests to help diagnose ME/CFS.

BiomarkersPost-Exertional Malaise
E3 PreliminaryPEM unclearPreliminaryMechanisticEditor reviewed

Changes in circulating microRNA after recumbent isometric yoga practice by patients with myalgic encephalomyelitis/chronic fatigue syndrome: an explorative pilot study.

Takakura, Shu, Oka, Takakazu, Sudo, Nobuyuki·BioPsychoSocial medicine·2019

This small study tested whether a gentle form of yoga (practiced lying down with adjustable resistance) could help ME/CFS patients feel less tired. Nine patients with ME/CFS who hadn't improved with standard treatment practiced this yoga for 3 months. Their fatigue scores improved significantly, and their blood showed changes in tiny molecules called microRNAs that may be related to how the yoga helped reduce their tiredness.

Biomarkers
E3 PreliminaryPEM unclearPreliminaryObservationalEditor reviewed

Epstein-Barr Virus Induced Gene-2 Upregulation Identifies a Particular Subtype of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.

Kerr, Jonathan R·Frontiers in pediatrics·2019

This study found that about 38-55% of ME/CFS patients have higher levels of a specific gene called EBI2 turned on in their immune cells. Patients with this EBI2 pattern appear to have more severe symptoms and different antibody levels compared to other ME/CFS patients. Because EBI2 is known to affect both immune function and brain function, finding this subtype could help explain why ME/CFS patients experience such different symptoms and may lead to new treatments.

BiomarkersImmune System
E3 PreliminaryPEM unclearModerate confidenceMethods-PaperEditor reviewed

Assessing cellular energy dysfunction in CFS/ME using a commercially available laboratory test.

Tomas, Cara, Lodge, Tiffany A, Potter, Michelle et al.·Scientific reports·2019

This study tested a blood test called the Mitochondrial Energy Score (MES) that is marketed to diagnose ME/CFS by measuring how well cells produce energy. Researchers repeated the test in both ME/CFS patients and healthy people and found no difference between the two groups. They also discovered that waiting even 24 hours before processing blood samples changed the test results significantly, suggesting the test is not reliable enough to use for diagnosis.

Biomarkers
E3 PreliminaryPEM unclearPreliminaryObservationalEditor reviewed

[Neuroinflammation in the Brain of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome].

Nakatomi, Yasuhito, Kuratsune, Hirohiko, Watanabe, Yasuyoshi·Brain and nerve = Shinkei kenkyu no shinpo·2018

Researchers used a special imaging scan called PET to look at the brains of people with ME/CFS and found signs of inflammation (immune system activation) throughout several brain regions. This inflammation was connected to how severe patients' symptoms were, including problems with thinking and memory, as well as widespread pain. This discovery suggests that ME/CFS involves measurable changes in the brain that could eventually lead to better ways to diagnose and treat the condition.

NeuroinflammationBiomarkers
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

[History of Researches on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome].

Watanabe, Yasuyoshi, Kuratsune, Hirohiko·Brain and nerve = Shinkei kenkyu no shinpo·2018

This review summarizes research on ME/CFS conducted in Japan since the disease was first identified there in 1990. Scientists have been searching for objective biological markers to help diagnose ME/CFS and understand what causes it. Recent brain imaging studies found evidence of immune cell activation in the brains of ME/CFS patients, which may be linked to the severity of their symptoms.

NeuroinflammationBiomarkers
E3 PreliminaryPEM unclearPreliminaryObservationalEditor reviewed

The expression signature of very long non-coding RNA in myalgic encephalomyelitis/chronic fatigue syndrome.

Yang, Chin-An, Bauer, Sandra, Ho, Yu-Chen et al.·Journal of translational medicine·2018

Researchers looked at special molecules called very long non-coding RNAs in the blood of ME/CFS patients to see if they might be disease markers. They found that three of these RNA molecules (NTT, MIAT, and EmX2OS) were present at higher levels in ME/CFS patients compared to healthy people, and two of them (NTT and EmX2OS) increased with disease severity. When they tested these findings in lab cells exposed to oxidative stress and viral signals, the RNA levels increased, suggesting these molecules respond to the kinds of biological stresses that may occur in ME/CFS.

BiomarkersImmune System
E3 PreliminaryPEM requiredModerate confidenceReview-NarrativeEditor reviewed

Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods.

VanElzakker, Michael B, Brumfield, Sydney A, Lara Mejia, Paula S·Frontiers in neurology·2018

This review examines different methods scientists use to look for signs of brain inflammation in ME/CFS, including specialized brain scans and blood tests. The authors found that while these techniques show promise, many studies have used inconsistent methods that make it hard to compare results across different research teams. They argue that scientists need better techniques and more careful standardization if we want to find reliable biological markers that could help diagnose ME/CFS.

NeuroinflammationBiomarkers
E3 PreliminaryPEM not requiredPreliminaryCross-SectionalEditor reviewed

[New Diagnostic Biomarkers for Chronic Fatigue Syndrome].

Yamano, Emi, Kataoka, Yosky·Brain and nerve = Shinkei kenkyu no shinpo·2018

This study looked at the chemicals and compounds in the blood of people with ME/CFS compared to healthy people to find objective markers that could help doctors diagnose the condition. Researchers used advanced testing methods to examine how the body's metabolism, immune system, and hormones differ in people with ME/CFS. The goal was to develop a simple blood test that could definitively identify ME/CFS, since there is currently no reliable diagnostic test.

Biomarkers
E3 PreliminaryPEM unclearPreliminaryCross-SectionalEditor reviewed

Circulating extracellular vesicles as potential biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis: an exploratory pilot study.

Castro-Marrero, Jesús, Serrano-Pertierra, Esther, Oliveira-Rodríguez, Myriam et al.·Journal of extracellular vesicles·2018

This small pilot study looked at tiny particles called extracellular vesicles (EVs) in the blood of ME/CFS patients compared to healthy people. The researchers found that ME/CFS patients had higher amounts of these particles, and the particles were smaller than in healthy controls. This suggests that blood tests measuring these particles might one day help doctors identify ME/CFS.

Biomarkers
E3 PreliminaryPEM not requiredPreliminaryMethods-PaperEditor reviewed

A robust, single-injection method for targeted, broad-spectrum plasma metabolomics.

Li, Kefeng, Naviaux, Jane C, Bright, A Taylor et al.·Metabolomics : Official journal of the Metabolomic Society·2017

Researchers developed a new, efficient blood test that can measure over 600 different molecules (metabolites) in a single sample to help diagnose ME/CFS. The test was validated by showing it could correctly identify ME/CFS patients with 95% accuracy compared to healthy controls, even when tested again more than a year later by different researchers.

Biomarkers
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

MicroRNAs hsa-miR-99b, hsa-miR-330, hsa-miR-126 and hsa-miR-30c: Potential Diagnostic Biomarkers in Natural Killer (NK) Cells of Patients with Chronic Fatigue Syndrome (CFS)/ Myalgic Encephalomyelitis (ME).

Petty, Robert D, McCarthy, Neil E, Le Dieu, Rifca et al.·PloS one·2016

This study examined tiny molecules called microRNAs in immune cells from ME/CFS patients and healthy people. Researchers found that four specific microRNAs were abnormally high in patients' blood, particularly in natural killer (NK) immune cells. When they tested these microRNAs in the lab, they found they affected how NK cells work, suggesting this might contribute to ME/CFS symptoms.

BiomarkersImmune System
E3 PreliminaryPEM not requiredPreliminaryReview-NarrativeEditor reviewed

Potential use of visible and near-infrared spectroscopy for the analysis and diagnosis of chronic fatigue syndrome (Review).

Sakudo, Akikazu·Molecular medicine reports·2016

This review examines whether a special type of light-based scanning called visible and near-infrared spectroscopy could help diagnose ME/CFS objectively. Currently, doctors diagnose ME/CFS only by listening to patient symptoms, with no blood test or physical measurement available. Researchers found that this light-scanning technique can detect differences in blood samples and thumb tissue between people with ME/CFS and healthy people, suggesting it might identify biological markers of the disease.

Biomarkers
E3 PreliminaryPEM not requiredPreliminaryCase-ControlEditor reviewed

Bottom-up proteomics suggests an association between differential expression of mitochondrial proteins and chronic fatigue syndrome.

Ciregia, F, Kollipara, L, Giusti, L et al.·Translational psychiatry·2016

This study looked at proteins in the mitochondria—the energy-producing structures in cells—to see if they differ in people with ME/CFS compared to healthy people. Researchers found that two specific proteins (ATPB and ACON) were higher in people with ME/CFS, suggesting these could potentially be useful markers to help identify the condition. The findings also hint that different subgroups of ME/CFS patients may have different protein patterns, which could eventually lead to more personalized treatments.

Biomarkers
E3 PreliminaryPEM not requiredPreliminaryMethods-PaperEditor reviewed

Integrating Cell Phone Imaging with Magnetic Levitation (i-LEV) for Label-Free Blood Analysis at the Point-of-Living.

Baday, Murat, Calamak, Semih, Durmus, Naside Gozde et al.·Small (Weinheim an der Bergstrasse, Germany)·2016

Researchers developed a new technology that uses smartphones and magnetic fields to analyze blood cells without needing special dyes or labels. The system can identify and count white and red blood cells quickly and affordably, and it works in clinics, hospitals, and homes. This portable device could help doctors monitor patients with rare diseases, including ME/CFS, more easily and at lower cost.

Biomarkers
E3 PreliminaryPEM unclearPreliminaryObservationalEditor reviewed

High-throughput sequencing of plasma microRNA in chronic fatigue syndrome/myalgic encephalomyelitis.

Brenu, Ekua W, Ashton, Kevin J, Batovska, Jana et al.·PloS one·2014

This study looked for tiny molecular messages called microRNAs in the blood of ME/CFS patients to see if they might work as a diagnostic tool. Researchers compared blood samples from ME/CFS patients and healthy people, and found three microRNAs that were higher in ME/CFS patients. This is an early-stage discovery that could eventually help doctors identify ME/CFS more easily through a simple blood test.

Biomarkers
E3 PreliminaryPEM not requiredPreliminaryReview-NarrativeEditor reviewed

Chronic Fatigue Syndrome: The Current Status and Future Potentials of Emerging Biomarkers.

Fischer, David Benjamin, William, Arsani Hany, Strauss, Adam Campbell et al.·Fatigue : biomedicine, health & behavior·2014

This review examines potential blood tests and biological markers that could help doctors better understand and diagnose ME/CFS. Currently, ME/CFS is diagnosed mainly based on symptoms because we lack clear objective tests. The authors suggest that identifying specific biomarkers—measurable biological signs—could help identify different subtypes of ME/CFS, which might respond better to different treatments.

BiomarkersImmune System
E3 PreliminaryPEM unclearPreliminaryCase-ControlEditor reviewed

A multidisciplinary approach to study a couple of monozygotic twins discordant for the chronic fatigue syndrome: a focus on potential salivary biomarkers.

Ciregia, Federica, Giusti, Laura, Da Valle, Ylenia et al.·Journal of translational medicine·2013

Researchers studied saliva samples from identical twins—one with ME/CFS and one healthy—to look for protein differences that might help diagnose the disease. They found 13 proteins that were expressed differently in the sick twin compared to the healthy twin, with many of these proteins linked to inflammation and immune system function. This suggests that a simple saliva test might one day help doctors diagnose ME/CFS more reliably.

BiomarkersImmune System
E3 PreliminaryPEM unclearPreliminaryCross-SectionalEditor reviewed

Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome.

Light, A R, Bateman, L, Jo, D et al.·Journal of internal medicine·2012

This study looked at how genes are turned on and off in people with ME/CFS before and after moderate exercise. Researchers found that about 71% of ME/CFS patients showed increased activity in genes related to nerve signaling and stress response after exercise, which correlated with their fatigue and pain levels. A smaller subgroup (29%) showed a different pattern, with decreased activity in one specific gene, and these patients were more likely to have orthostatic intolerance (dizziness when standing).

BiomarkersPost-Exertional Malaise
E3 PreliminaryPEM not requiredPreliminaryReview-NarrativeEditor reviewed

[Biomarkers of stress and fatigue].

Tanaka, Yoshihide·Nihon rinsho. Japanese journal of clinical medicine·2012

This paper reviews different ways to measure stress and fatigue in the body. Instead of just asking patients how stressed they feel, researchers are looking for physical markers—like stress hormones in saliva or hair—that show whether someone is experiencing chronic stress. The authors explain how chronic stress affects the nervous system, hormones, and immune system, and discuss which biological markers might be useful for understanding chronic fatigue syndrome.

BiomarkersImmune System
E3 PreliminaryPEM not requiredPreliminaryObservationalEditor reviewed

Supervised selection of single nucleotide polymorphisms in chronic fatigue syndrome.

Cifuentes, Ricardo A, Barreto, Emiliano·Biomedica : revista del Instituto Nacional de Salud·2011

This study examined whether specific genetic variations (single nucleotide polymorphisms or SNPs) could help predict who has ME/CFS. Researchers used a mathematical approach to identify the most useful genetic markers and found a combination of two genetic variants that correctly identified ME/CFS in about 73% of cases. When this genetic profile was combined with specific symptoms like muscle pain or sinus problems, the accuracy improved to over 87%.

Biomarkers
E3 PreliminaryPEM not requiredModerate confidenceMethods-PaperEditor reviewed

Identification of Phosphoglycerate Kinase 1 (PGK1) as a reference gene for quantitative gene expression measurements in human blood RNA.

Falkenberg, Virginia R, Whistler, Toni, Murray, Janna' R et al.·BMC research notes·2011

Researchers studying ME/CFS need reliable ways to measure gene activity in blood samples. This study found that a gene called PGK1 is a stable and reliable 'reference point' for comparing gene measurements across different blood collection methods and sample types. Using a single stable reference gene like PGK1 makes it easier for scientists to get accurate, comparable results when searching for blood-based biomarkers of ME/CFS.

Biomarkers
E3 PreliminaryPEM not requiredPreliminaryCross-SectionalEditor reviewed

Secondary structural changes of proteins in fingernails of chronic fatigue syndrome patients from Fourier-transform infrared spectra.

Sakudo, Akikazu, Kuratsune, Hirohiko, Kato, Yukiko Hakariya et al.·Clinica chimica acta; international journal of clinical chemistry·2009

Researchers used a special infrared scanner to examine fingernails from people with ME/CFS and compared them to healthy people's nails. They found that the proteins in ME/CFS patients' nails had different structures—specifically, the nails showed less of a protein structure called alpha-helix and more of a structure called beta-sheet. This suggests that ME/CFS may cause measurable changes in nail composition that could potentially be detected with this scanning technology.

Biomarkers
E3 PreliminaryPEM not requiredPreliminaryCross-SectionalEditor reviewed

Identification of marker genes for differential diagnosis of chronic fatigue syndrome.

Saiki, Takuya, Kawai, Tomoko, Morita, Kyoko et al.·Molecular medicine (Cambridge, Mass.)·2008

This study looked at blood samples from ME/CFS patients and compared the activity of genes between patients and healthy people. Researchers found 9 genes that showed different activity patterns in ME/CFS patients—genes involved in energy production, immune cell function, and protein breakdown. These 9 genes were able to correctly identify ME/CFS patients about 94% of the time, suggesting they could potentially be useful as a biological test to diagnose the condition.

Biomarkers
E3 PreliminaryPEM not requiredPreliminaryCross-SectionalEditor reviewed

[Identification and application of marker genes for differential diagnosis of chronic fatigue syndrome].

Kawai, Tomoko, Rokutan, Kazuhito·Nihon rinsho. Japanese journal of clinical medicine·2007

This study looked for genetic markers (differences in how genes are expressed) that could help doctors diagnose ME/CFS with a blood test. The researchers identified 9 genes that were expressed differently in ME/CFS patients compared to healthy people, and showed these genes could potentially be used to distinguish ME/CFS from other conditions.

Biomarkers
E3 PreliminaryPEM not requiredPreliminaryObservationalEditor reviewed

[Chronic fatigue syndrome and herpesvirus reactivation].

Kondo, Kazuhiro·Nihon rinsho. Japanese journal of clinical medicine·2007

This study looked at whether two common viruses that hide dormant in our bodies (HHV-6 and HHV-7) wake up and become active during fatigue. Researchers found that healthy people shed more HHV-6 in their saliva when tired from work, but ME/CFS patients did not show this pattern. However, HHV-7 did increase in both groups, suggesting these viruses might be useful markers to measure fatigue objectively.

BiomarkersImmune System
E3 PreliminaryPEM not requiredPreliminaryCross-SectionalEditor reviewed

[Spectroscopic diagnosis of chronic fatigue syndrome by multivariate analysis of visible and near-infrared spectra].

Sakudo, Akikazu, Kuratsune, Hirohiko, Hakariya, Yukiko et al.·Nihon rinsho. Japanese journal of clinical medicine·2007

Researchers tested whether a special light-based technology called visible and near-infrared spectroscopy could help diagnose ME/CFS by analyzing blood samples and skin. The technique uses different wavelengths of light to detect patterns that might differ between people with ME/CFS and healthy people. Early results showed the method could correctly identify about 70-80% of cases, suggesting this approach might one day offer a quick, non-invasive way to help diagnose the condition.

Biomarkers
E3 PreliminaryPEM unclearHigher confidenceMethods-PaperEditor reviewed

CFSUM1 and CFSUM2 in urine from patients with chronic fatigue syndrome are methodological artefacts.

Chalmers, Ronald A, Jones, Mark G, Goodwin, C Stewart et al.·Clinica chimica acta; international journal of clinical chemistry·2006

An earlier study claimed to find two special markers in the urine of ME/CFS patients that could help diagnose the condition. This study re-examined those findings and discovered that these supposed markers were actually just artifacts—unintended byproducts created by the way the urine samples were prepared in the lab, not real biological differences between patients and healthy people.

Biomarkers
E3 PreliminaryPEM not requiredPreliminaryObservationalEditor reviewed

Exploration of the gene expression correlates of chronic unexplained fatigue using factor analysis.

Fostel, Jennifer, Boneva, Roumiana, Lloyd, Andrew·Pharmacogenomics·2006

Researchers used blood tests and symptom questionnaires to look for biological markers that could help identify ME/CFS. They found that ME/CFS involves multiple symptom patterns (fatigue and mood changes being most prominent) and identified 57 genes whose activity differed between people with severe symptoms and those with mild symptoms. However, no single gene or blood test on its own clearly identifies the disease.

Biomarkers
E3 PreliminaryPEM not requiredPreliminaryCross-SectionalEditor reviewed

Chronic fatigue syndrome is accompanied by an IgM-related immune response directed against neopitopes formed by oxidative or nitrosative damage to lipids and proteins.

Maes, Michael, Mihaylova, Ivana, Leunis, Jean-Claude·Neuro endocrinology letters·2006

This study found that people with ME/CFS have higher levels of immune antibodies (IgM) attacking damaged fats and proteins in their bodies. These antibodies target substances created when cells are damaged by oxidative stress—a harmful process where the body's natural defenses become imbalanced. The more severe someone's ME/CFS symptoms were, the higher their antibody levels tended to be.

BiomarkersImmune System
E3 PreliminaryPEM not requiredPreliminaryMethods-PaperEditor reviewed

Interpreter of maladies: redescription mining applied to biomedical data analysis.

Waltman, Peter, Pearlman, Alex, Mishra, Bud·Pharmacogenomics·2006

This paper describes a new computational method for analyzing complex medical data to better understand disease causes. The authors explain how combining genetic, protein, and clinical information from patients and healthy people can reveal hidden patterns that explain why diseases like ME/CFS occur and progress. They demonstrate this approach using a large CDC dataset from patients with ME/CFS.

Biomarkers
E3 PreliminaryPEM not requiredPreliminaryCross-SectionalEditor reviewed

Gene expression profile of empirically delineated classes of unexplained chronic fatigue.

Carmel, Liran, Efroni, Sol, White, Peter D et al.·Pharmacogenomics·2006

Researchers examined genes in blood samples from 111 women with unexplained chronic fatigue to see if different types of fatigue had different gene patterns. They used computer analysis to identify specific genes that were active or inactive in different fatigue groups. They found that certain genes were consistently different between fatigued and healthy people, while other genes only differed in specific fatigue subgroups.

Biomarkers
E3 PreliminaryPEM not requiredPreliminaryCross-SectionalEditor reviewed

Chronic phase lipids in sera of chronic fatigue syndrome (CFS), chronic ciguatera fish poisoning (CCFP), hepatitis B, and cancer with antigenic epitope resembling ciguatoxin, as assessed with MAb-CTX.

Hokama, Y, Uto, G A, Palafox, N A et al.·Journal of clinical laboratory analysis·2003

Researchers found that people with ME/CFS have unusual lipids (fatty substances) in their blood that react similarly to toxins found in certain poisoned fish. The study tested blood samples from ME/CFS patients and compared them to healthy people and patients with other diseases. About 96% of ME/CFS patients showed high levels of these lipids, suggesting they may be a distinctive feature of the condition.

Biomarkers
E3 PreliminaryPEM not requiredModerate confidenceReview-NarrativeEditor reviewed

Neuroimaging in chronic fatigue syndrome.

Lange, G, Wang, S, DeLuca, J et al.·The American journal of medicine·1998

This review examines how brain imaging scans can help understand ME/CFS. Researchers looked at two main types of scans: MRI scans that show the structure of the brain, and SPECT scans that show blood flow in the brain. The article discusses what these imaging techniques have revealed so far and what challenges doctors face in using them to diagnose ME/CFS.

Biomarkers
E3 PreliminaryPEM not requiredPreliminaryCross-SectionalEditor reviewed

["Prolonged" decay test and auditory brainstem responses in the clinical diagnosis of the chronic fatigue syndrome].

Neri, G, Bianchedi, M, Croce, A et al.·Acta otorhinolaryngologica Italica : organo ufficiale della Societa italiana di otorinolaringologia e chirurgia cervico-facciale·1996

This study tested whether two hearing-related tests could help diagnose ME/CFS. Researchers examined 21 people with suspected ME/CFS using specialized hearing tests that measure how the brainstem processes sound and how the ear muscles respond to loud noises. When both tests were combined, they correctly identified about 82% of people with ME/CFS, suggesting these tests might be useful diagnostic tools.

Biomarkers
E3 PreliminaryPEM not requiredPreliminaryObservationalEditor reviewed

Acylcarnitine deficiency in chronic fatigue syndrome.

Kuratsune, H, Yamaguti, K, Takahashi, M et al.·Clinical infectious diseases : an official publication of the Infectious Diseases Society of America·1994

This study found that people with ME/CFS have lower levels of acylcarnitine, a substance that helps muscles produce energy, in their blood. Because acylcarnitine plays an important role in how muscles use energy, this deficiency might explain why ME/CFS patients experience fatigue, muscle pain, and weakness. Importantly, acylcarnitine levels tended to improve as patients recovered, suggesting it could be useful for tracking disease severity.

BiomarkersPost-Exertional Malaise
E3 PreliminaryPEM not requiredPreliminaryCross-SectionalEditor reviewed

Skeletal muscle bioenergetics in the chronic fatigue syndrome.

Barnes, P R, Taylor, D J, Kemp, G J et al.·Journal of neurology, neurosurgery, and psychiatry·1993

Researchers used a special type of MRI scan to measure how muscles use energy in ME/CFS patients compared to healthy people. They found that most patients had normal muscle energy use, but about a quarter showed unusual patterns in how their muscles handled acid buildup during exercise. This suggests muscle metabolism problems may exist in some, but not all, ME/CFS patients.

Biomarkers
E3 PreliminaryPEM unclearPreliminaryCross-SectionalEditor reviewed

[Symptoms, signs and laboratory findings in patients with chronic fatigue syndrome].

Kuratsune, H, Yamaguti, K, Hattori, H et al.·Nihon rinsho. Japanese journal of clinical medicine·1992

This study examined 59 patients with ME/CFS to identify common symptoms and laboratory abnormalities. The main findings were that patients experienced prolonged fatigue after exercise, headaches, sleep problems, and mild fevers. Researchers found that ME/CFS patients had low levels of a substance called acylcarnitine in their muscles, which may help explain why their bodies struggle to produce energy and why they experience muscle pain and worsening symptoms after activity.

BiomarkersPost-Exertional Malaise
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Fatigue syndromes: new thoughts and reinterpretation of previous data.

Downey, D C·Medical hypotheses·1992

This study examined 19 patients with severe fatigue who showed unusual reactions to copper-containing bracelets or necklaces. The researchers found that 8 of these patients had deficiencies in enzymes related to heme (a component of blood), and suggested that problems with copper metabolism and heme processing might explain fatigue in conditions like ME/CFS, multiple sclerosis, and other disorders.

Biomarkers
E3 PreliminaryPEM unclearPreliminaryCross-SectionalEditor reviewed

Upregulation of olfactory receptors and neuronal-associated genes highlights complex immune and neuronal dysregulation in Long COVID patients.

Shahbaz, Shima, Rezaeifar, Maryam, Syed, Hussein et al.·Brain, behavior, and immunity·2025

Researchers studied blood samples from Long COVID patients with ME/CFS-like symptoms and compared them to healthy controls. They found that certain genes related to immune function and brain health were turned on in the patients, while others were turned off. The study also discovered unusual activation of smell-related genes and changes in immune cell types, suggesting the body remains in a state of ongoing inflammation and stress.

NeuroinflammationBiomarkersImmune System
E3 PreliminaryPEM not requiredPreliminaryReview-NarrativeEditor reviewed

Role of Tau protein in long COVID and potential therapeutic targets.

Marwaha, Bharat·Frontiers in cellular and infection microbiology·2023

Long COVID causes ongoing fatigue, breathing problems, brain fog, and other symptoms that can last months or years. This review suggests that a protein called tau—which is known to damage the brain in other diseases—may also be involved in Long COVID. The authors propose that future research should look for tau damage in Long COVID patients and that treatments designed to stop tau buildup might help.

NeuroinflammationBiomarkers
E3 PreliminaryPEM unclearPreliminaryCross-SectionalEditor reviewed

Metabolomics-Based Machine Learning Diagnostics of Post-Acute Sequelae of SARS-CoV-2 Infection.

Cai, Ethan, Kouznetsova, Valentina L, Tsigelny, Igor F·Metabolites·2025

Researchers developed a computer program that can identify Long COVID (PASC) by analyzing chemical markers in the blood called metabolites. The program successfully distinguished Long COVID from several similar conditions like Lyme disease and POTS, but had difficulty telling Long COVID apart from fibromyalgia, suggesting these two conditions may share similar chemical patterns in the body.

Biomarkers
E3 PreliminaryPEM unclearPreliminaryMethods-PaperEditor reviewed

Multifaceted evolution focused on maximal exploitation of domain knowledge for the consensus inference of Gene Regulatory Networks.

Segura-Ortiz, Adrián, Giménez-Orenga, Karen, García-Nieto, José et al.·Computers in biology and medicine·2025

Researchers created a new computer tool called BIO-INSIGHT that helps scientists better understand which genes control other genes by analyzing genetic data from patients. They tested this tool on data from people with fibromyalgia, ME/CFS, and both conditions together, and found it could identify different gene patterns specific to each illness. This could help doctors find better ways to diagnose and treat these conditions in the future.

Biomarkers
E3 PreliminaryPEM requiredPreliminaryEditorialEditor reviewed

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 unclearPreliminaryMethods-PaperEditor reviewed

Machine learning algorithms for detection of visuomotor neural control differences in individuals with PASC and ME.

Ahuja, Harit, Badhwar, Smriti, Edgell, Heather et al.·Frontiers in human neuroscience·2024

Researchers developed a new method using a simple headband that reads brain activity (EEG) to help identify people with long COVID or ME/CFS. The study used artificial intelligence to analyze brain patterns, and when trained on computer-generated synthetic data, the system was able to correctly identify these conditions 93% of the time. This approach could eventually help doctors diagnose and monitor these conditions more quickly.

Biomarkers
E3 PreliminaryPEM requiredPreliminaryCase-ControlEditor reviewed

A case of post-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome characterized by post-exertional malaise and low serum acylcarnitine level.

Jinushi, Ryuhei, Nishiguchi, Sho, Masuda, Sakue et al.·Clinical case reports·2023

This study describes a patient who developed ME/CFS after recovering from COVID-19. The researchers found that this patient had lower-than-normal levels of acylcarnitine, a substance the body uses to produce energy. The study reviews existing research on how COVID-19 can lead to ME/CFS, a condition that causes severe fatigue and symptoms that worsen after physical activity.

BiomarkersPost-Exertional Malaise
E3 PreliminaryPEM not requiredPreliminaryObservationalEditor reviewed

Plasma miR-195-5p predicts the severity of Covid-19 in hospitalized patients.

Moatar, Alexandra Ioana, Chis, Aimee Rodica, Romanescu, Mirabela et al.·Scientific reports·2023

Researchers studied a tiny molecule in the blood called miR-195 in COVID-19 patients to see if it could predict who would get sicker. They found that miR-195 levels measured in the first two days after hospital admission were very good at telling the difference between patients with mild and severe COVID-19. Interestingly, their analysis suggests this molecule may affect how heart cells produce energy, which could be relevant to long COVID and chronic fatigue syndrome.

Biomarkers
E3 PreliminaryPEM not requiredPreliminaryCross-SectionalEditor reviewed

No Signs of Neuroinflammation in Women With Chronic Fatigue Syndrome or Q Fever Fatigue Syndrome Using the TSPO Ligand [11C]-PK11195.

Raijmakers, Ruud, Roerink, Megan, Keijmel, Stephan et al.·Neurology(R) neuroimmunology & neuroinflammation·2022

Researchers used a specialized brain scan to look for signs of inflammation in the brains of women with ME/CFS and Q fever fatigue syndrome, compared to healthy women. The scan didn't find evidence of the type of brain inflammation they were looking for, which contradicts some earlier research suggesting inflammation might play a role in these conditions.

NeuroinflammationBiomarkersImmune System
E3 PreliminaryPEM unclearPreliminaryCase-ControlEditor reviewed

A Chronic Fatigue Syndrome - related proteome in human cerebrospinal fluid.

Baraniuk, James N, Casado, Begona, Maibach, Hilda et al.·BMC neurology·2005

Researchers examined fluid from around the spine (cerebrospinal fluid) in people with ME/CFS and found specific proteins that were present in patients but absent in healthy people. Using advanced laboratory techniques, they identified a set of 5 key proteins that could correctly identify ME/CFS in 80% of cases. These findings suggest ME/CFS may involve immune system and brain inflammation, offering hope for an objective test in the future.

NeuroinflammationBiomarkers
E3 PreliminaryPEM not requiredPreliminaryCase-ControlEditor reviewed

Interferon-induced proteins are elevated in blood samples of patients with chemically or virally induced chronic fatigue syndrome.

Vojdani, A, Lapp, C W·Immunopharmacology and immunotoxicology·1999

This study found that certain immune proteins called 2-5A and PKR are elevated in the blood of ME/CFS patients, whether their illness was triggered by a viral infection or chemical exposure. The researchers discovered that these two triggers activate these proteins through different biological pathways—viruses primarily use an immune signaling molecule called interferon-beta, while chemicals activate them mainly through heat shock proteins.

BiomarkersImmune System
E3 PreliminaryPEM requiredPreliminaryMechanisticEditor reviewed

Gulf War Illness Induced Sex-Specific Transcriptional Differences Under Stressful Conditions.

Frank, Joshua, Tehrani, Lily, Gamer, Jackson et al.·International journal of molecular sciences·2025

Researchers studied how the immune system responds to physical stress in Gulf War veterans with Gulf War Illness (GWI), a condition similar to ME/CFS with fatigue, brain fog, and exhaustion. They found that men and women with GWI have different patterns of immune system activation during and after exercise, suggesting their bodies handle stress differently. These differences could help doctors develop better tests and treatments tailored to each person's sex.

BiomarkersImmune SystemPost-Exertional Malaise
E3 PreliminaryPEM unclearPreliminaryMethods-PaperEditor reviewed

Establishment and evaluation of prediction model for multiple disease classification based on gut microbial data.

Bang, Sohyun, Yoo, DongAhn, Kim, Soo-Jin et al.·Scientific reports·2019

Researchers used artificial intelligence to analyze bacteria in the gut of patients with six different diseases, including ME/CFS, to see if gut bacteria patterns could help identify which disease a person has. They tested different computer learning methods and found that looking at bacteria at the genus level (a specific classification of microorganisms) worked best, and they identified certain bacterial groups that might serve as disease markers.

BiomarkersGut Microbiome
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

Human herpesvirus 6 and 7 are biomarkers for fatigue, which distinguish between physiological fatigue and pathological fatigue.

Aoki, Ryo, Kobayashi, Nobuyuki, Suzuki, Go et al.·Biochemical and biophysical research communications·2016

This study looked at whether two common viruses (HHV-6 and HHV-7) in saliva could help doctors tell the difference between normal tiredness and the severe, long-lasting fatigue seen in conditions like ME/CFS. The researchers found that these viruses increased in saliva when people were physically stressed or tired from work, then quickly decreased with rest. Importantly, these viruses did NOT increase in people with ME/CFS, sleep apnea, or depression, suggesting they might be useful markers for normal fatigue but not pathological fatigue.

Biomarkers
E3 PreliminaryPEM not requiredWeak / uncertainCase-ControlEditor reviewed

Chronic Fatigue Syndrome (CFS) in 15 dogs and cats with specific biochemical and microbiological anomalies.

Tarello, W·Comparative immunology, microbiology and infectious diseases·2001

This study looked at 15 dogs and cats that had fatigue symptoms similar to ME/CFS and tested their blood for bacterial infections. Nine out of 15 animals had a type of bacteria called Staphylococcus in their blood. When these animals were treated with an antibiotic drug, all of them got completely better and the bacteria disappeared from their blood.

Biomarkers
E0 ConsensusPEM unclearModerate confidenceMachine-drafted

Pathomechanisms and possible interventions in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Fluge, Øystein, Tronstad, Karl J, Mella, Olav·The Journal of clinical investigation·2021

This review article examines what we know about how ME/CFS damages the body and discusses possible treatments. Researchers looked at existing scientific evidence to understand the disease mechanisms—the biological processes that cause ME/CFS symptoms—and evaluated various interventions that might help patients. The goal was to create a comprehensive overview of current scientific understanding to guide future research and treatment development.

BiomarkersImmune System
E2 ModeratePEM not requiredModerate confidenceCross-SectionalMachine-drafted

The physio-affective phenome of major depression is strongly associated with biomarkers of astroglial and neuronal projection toxicity which in turn are associated with peripheral inflammation, insulin resistance and lowered calcium.

Al-Hakeim, Hussein Kadhem, Al-Naqeeb, Tabarek Hadi, Almulla, Abbas F et al.·Journal of affective disorders·2023

This study examined whether brain and nerve damage markers in the blood are connected to depression symptoms and other physical complaints. Researchers measured several proteins in the blood of people with depression and compared them to healthy controls, finding that markers of brain cell and nerve damage—along with inflammation and insulin resistance—together explained about 61% of the severity of depression, anxiety, fatigue, and physical symptoms.

NeuroinflammationBiomarkers
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeMachine-drafted

Radiation exposure and mitochondrial insufficiency in chronic fatigue and immune dysfunction syndrome.

Rusin, Andrej, Li, Megan, Cocchetto, Alan et al.·Medical hypotheses·2021

This paper explores the idea that ME/CFS may be caused by damage to mitochondria—the energy-producing parts of cells—possibly triggered by radiation exposure or other environmental stressors like viruses or toxins. When mitochondria cannot produce enough energy, cells throughout the body struggle, and neighboring tissues try to compensate, which may explain why ME/CFS patients experience widespread symptoms like fatigue and immune problems.

Biomarkers
E3 PreliminaryPEM unclearPreliminaryMachine-drafted

Long-COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Potential neurophysiological biomarkers for these enigmatic entities.

Versace, Viviana, Tankisi, Hatice·Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology·2023

This editorial discusses potential nerve-based tests that might help identify and distinguish Long-COVID and ME/CFS—two conditions that share similar exhaustion and brain symptoms but are still poorly understood. The authors review existing neurophysiological tools (tests that measure nerve and muscle function) that could potentially serve as objective biomarkers to help doctors diagnose these conditions more reliably. They highlight the need for further research to validate these tests and better understand what's happening in patients' nervous systems.

Biomarkers
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeMachine-drafted

Chronic fatigue syndrome and fibromyalgia: a status report in 2010.

Natelson, Benjamin H·MD advisor : a journal for New Jersey medical community·2010

This 2010 report by Dr. Benjamin Natelson reviews the current understanding of ME/CFS and fibromyalgia, two conditions that cause persistent fatigue and pain. The report summarizes what doctors and researchers knew at that time about how these conditions develop, how they affect the body, and how they are treated. It provides an overview of the scientific evidence available in 2010 to help explain why people with these conditions experience their symptoms.

Biomarkers
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeMachine-drafted

Assessment of intracellular cytokines and regulatory cells in patients with autoimmune diseases and primary immunodeficiencies - novel tool for diagnostics and patient follow-up.

Osnes, Liv T, Nakken, Britt, Bodolay, Edit et al.·Autoimmunity reviews·2013

This article reviews how scientists measure specific immune system molecules called cytokines and immune cells to help diagnose and monitor autoimmune diseases and immune deficiencies. By measuring both inflammatory and anti-inflammatory markers together, doctors can better understand what's happening in a patient's immune system and track whether treatments are working.

BiomarkersImmune System

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