Front Pain Res (Lausanne). 2025 Mar 18:6:1527783.
Introduction: Fibromyalgia (FM) is the prototypical nociplastic pain condition, characterized by widespread pain and issues with cognition, mood, and sleep. Currently, there are limited treatment options available that effectively treat FM symptoms. Psilocybin-assisted therapy (PAT) is an emerging combined drug-therapy intervention, but no studies to-date have investigated PAT for FM.
Methods: Here, we report findings from an open-label, pilot clinical trial of PAT for FM (N = 5). In conjunction with psychotherapy (two preparatory, four integration sessions), participants received two doses of oral psilocybin (15 mg and 25 mg) delivered two weeks apart.
Results: Regarding safety (primary outcome), there were transient elevations of blood pressure or heart rate during dosing which normalized by the end of treatment, with no serious adverse events. Four of five participants reported transient headaches following dosing. Compared to baseline, participants reported clinically meaningful improvements in the following secondary outcomes one month following their second psilocybin dose (reported as Cohen's d): pain severity [d = -2.1, 95% CI(-3.7 to -0.49)], pain interference [d = -1.8, 95% CI (-3.27 to -0.24)], and sleep disturbance [d = -2.5, 95% CI (-4.21 to -0.75)]. Using the Patient Global Impression of Change, one participant reported their symptoms "very much improved," two reported "much improved," and two reported "minimally improved." We stopped recruitment early because of concerns about generalizability and changes in FDA guidance for psychedelic clinical trials that occurred data collection.
Discussion: This small open-label trial preliminarily supports that PAT is well-tolerated by people with FM, establishing a basis for larger randomized controlled trials.
Clinical trial registration: ClinicalTrials.gov, identifier, (NCT05128162).
Keywords: clinical trial; fibromyalgia; pilot; psilocybin; psilocybin-assisted therapy.
© 2025 Aday, McAfee, Conroy, Hosanagar, Tarnal, Weston, Scott, Horowitz, Geller, Harte, Pouyan, Glynos, Baker, Guss, Davis, Burgess, Mashour, Clauw and Boehnke.
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Invisible No More: Embracing Your Road to Recovery from Long Covid and Other Complex Chronic Illnesses Hardcover – June 17, 2025
by Ilene Sue Ruhoy MD PhD (Author)
A possible useful book to read:
From a neurologist who diagnosed her own brain tumor, Invisible No More empowers patients with chronic and complex illnesses to take their health into their own hands.
While Covid-19 has brought increased attention to chronic and complex illnesses, these conditions have impacted millions worldwide, long before the pandemic. Covid was not the first exposure to cause long-term disease and disability, nor will it be the last.
In Invisible No More, Dr. Ilene Sue Ruhoy aims to empower the long-term patients of chronic and complex diseases, delving into her own harrowing experience as a patient. She details her evolution as a neurologist, toxicologist, and integrative physician to work with people across the globe in treating their chronic symptoms and disabling disease, all while amplifying their own voices. This book serves as a practical guide with sections on nutrition, breathing, supplements and more. With a focus on healing and empowerment, Invisible No More will answer patients' most pressing questions and take their health into their own hands.
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Sustained illness burden over time among Australians with myalgic encephalomyelitis/chronic fatigue syndrome
Gepubliceerd op 1 januari 2026
Weigel, Eaton-Fitch, Thapaliya, Marshall-Gradisnik
Abstract
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling chronic illness. Many people with ME/CFS (pwME/CFS) are unable to continue employment and require support to complete activities of daily living. Despite this, ME/CFS remains unrecognised as a disability in Australia. The present study aimed to highlight the profound burdens experienced by pwME/CFS over time to provide evidence of permanency and necessitate reforms to Australian healthcare policies.
Methods
Data were collected for this longitudinal investigation between 1st October 2021 and 3rd October 2024. All participants were Australian residents aged between 18 and 65 years fulfilling the Canadian or International Consensus Criteria. Sociodemographic information, medical history, illness presentation and patient-reported outcomes were collected using three self-administered questionnaires distributed at approximately six-month intervals. Illness presentation and patient-reported outcomes were investigated over 12 months with Cochran’s Q, Friedman and one-way repeated measures ANOVA tests using Statistical Package for the Social Sciences version 29.0. Quality of life data were compared with Australian population norms using one-sample Wilcoxon signed-rank tests.
Results
Thirty-two pwME/CFS (n = 22/32, 68.8% female) participated at all three time points. At baseline, the mean age was 44.03 years and median illness duration was 12.50 years. Participants reported a median of 30 symptoms at each time point – the most common of which were also the most severe in presentation. Importantly, there were no significant changes in any symptom or patient-reported outcome over the 12-month study period. Overall health status, physical health and the ability to participate in daily and work life activities were the most substantially impacted. Quality of life was significantly reduced among pwME/CFS when compared with population norms at all time points.
Conclusions
PwME/CFS face substantial and sustained illness burdens. These consistent, profound impairments emphasise the need for improved access to disability and social support services for pwME/CFS in Australia through policy reform.
Source: PLOS One, open access
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Does Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Represent a Poly-Herpesvirus Post-Virus Infectious Disease?
Gepubliceerd op 7 januari 2026
Ariza, Palomo & Williams
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem illness with unknown etiology. An estimated 17–24 million people representing approximately 1% of the population are afflicted worldwide.
In over half of cases, ME/CFS onset is associated with acute “flu-like” symptoms, suggesting a role for viruses. However, no single virus has been identified as the only etiological agent. This may reflect the approach employed or more strongly the central dogma associated with herpesviruses replication, which states that a herpesvirus exists in two states, either lytic or latent.
The purpose of this review is to address the role that abortive lytic replication may have in the pathogenesis of ME/CFS and other post-acute viral infections and also to raise awareness that these syndromes might be poly-herpesviruses mediated diseases.
There is sufficient data to demonstrate that ME/CFS patients can be divided into at least two subgroups: those whose illness is not triggered by a virus infection and those whose are. The latter group should be referred to as patients with post-infective ME/CFS (PI-ME/CFS). This classification is necessary because while the symptomology exhibited by patients in these subsets might be similar, the mechanism(s) driving the disease process will be different, and thus, different therapeutic approaches might be required.
DNA viruses, including human herpesviruses, encode a wide array of proteins. These proteins have diverse effects on host cells, such as promoting cell proliferation, inhibiting apoptosis, and evading immune responses. Identifying the specific viral gene products responsible for fatigue, pain, cognitive dysfunction, and post-exertional malaise (PEM) will be essential for developing reliable biomarkers and targeted therapies. Continued research in this area is therefore critical.
Finally, if simultaneous abortive lytic replication of multiple herpesviruses is a key driver in certain ME/CFS patients, then targeted treatment protocols could be developed for this PI-ME/CFS subgroup. Such approaches might include combinations of antiviral agents (e.g., ganciclovir), cell-depleting therapies such as rituximab, checkpoint inhibitors, or agents designed to prevent viral reactivation.
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Virus-induced endothelial senescence as a cause and driving factor for ME/CFS and long COVID: mediated by a dysfunctional immune system
Gepubliceerd op 10 januari 2026
Nunes, Kell, Slaghekke, Wüst, Fielding, Kell & Pretorius
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are two post-viral diseases, which share many common symptoms and pathophysiological alterations. Yet a mechanistic explanation of disease induction and maintenance is lacking. This hinders the discovery and implementation of biomarkers and treatment options, and ultimately the establishment of effective clinical resolution.
Here, we propose that acute viral infection results in (in)direct endothelial dysfunction and senescence, which at the blood-brain barrier, cerebral arteries, gastrointestinal tract, and skeletal muscle can explain symptoms.
The endothelial senescence-associated secretory phenotype (SASP) is proinflammatory, pro-oxidative, procoagulant, primed for vasoconstriction, and characterized by impaired regulation of tissue repair, but also leads to dysregulated inflammatory processes.
Immune abnormalities in ME/CFS and long COVID can account for the persistence of endothelial senescence long past the acute infection by preventing their clearance, thereby providing a mechanism for the chronic nature of ME/CFS and long COVID.
The systemic and tissue-specific effects of endothelial senescence can thus explain the multisystem involvement in and subtypes of ME/CFS and long COVID, including dysregulated blood flow and perfusion deficits. This can occur in all tissues, but especially the brain as evidenced by findings of reduced cerebral blood flow and impaired perfusion of various brain regions, post-exertional malaise (PEM), gastrointestinal disturbances, and fatigue.
Paramount to this theory is the affected endothelium, and the bidirectional sustainment of immune abnormalities and endothelial senescence. The recognition of endothelial cell dysfunction and senescence as a core element in the aetiology of both ME/CFS and Long COVID should aid in the establishment of effective biomarkers and treatment regimens.
Source: Cell Death & Disease, open access
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Abnormal T-Cell activation and cytotoxic T-Cell frequency discriminate symptom severity in myalgic encephalomyelitis/chronic fatigue syndrome
Gepubliceerd op 22 januari 2026
Ji-Sook Lee, Eliana Lacerda, Caroline Kingdon, Ella Abken, Giada Susannini, Hazel M Dockrell, Luis Nacul , Jacqueline M Cliff
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating but poorly-understood disease. ME/CFS symptoms include immune system effects alongside incapacitating fatigue and post-exertional disease exacerbation. Symptom severity can range from mild to severe and whilst symptoms can fluctuate, few people fully recover.
Methods
Immunological profiles of people living with ME/CFS were analysed by flow cytometry, focusing on cytotoxic cells, to determine whether people with mild/moderate (n = 43) or severe ME/CFS (n = 53) expressed different immunological markers. Flow cytometry data were tested for normality and the two clinical groups were compared by t-test or Mann-Whitney U-test as appropriate.
Results
People with mild/moderate ME/CFS had increased expression of cytotoxic effector molecules alongside enhanced proportions of early-immunosenescence cells, determined by the CD28-CD57- phenotype, indicative of persistent viral infection. In contrast, people with severe ME/CFS had higher proportions of activated circulating lymphocytes, determined by CD69+ and CD38+ expression, and expressed more pro-inflammatory cytokines, including interferon-γ, tumour necrosis factor and interleukin-17, following stimulation in vitro, indicative of prolonged non-specific inflammation.
These changes were consistent across different cell types including CD8+ T cells, mucosal associated invariant T cells and Natural Killer cells, indicating generalised altered cytotoxic responses across the innate and adaptive immune system.
Conclusions
These immunological differences likely reflect different disease pathogenesis mechanisms occurring in the two clinical groups, opening up opportunities for the development of prognostic markers and stratified treatments.
Source: Journal of Translational Medicine, open access
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Distinct functional connectivity patterns in myalgic encephalomyelitis and long COVID patients during cognitive fatigue: a 7 Tesla task-fMRI study
Gepubliceerd op 11 maart 2026 Inderyas, Thapaliya, Marshall-Gradisnik & Barnden
Abstract
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and long COVID are chronic debilitating illnesses featuring fatigue, post-exertional malaise (PEM) and neurocognitive deficits. Temporal correlation of neural activity between distinct brain regions, also referred to as functional connectivity (FC), can provide insights into how brain networks coordinate, at rest or during task. Therefore, we explored intrinsic FC correlates of cognitive fatigue in ME/CFS and long COVID patients during two Stroop-colour-word paradigms on 7 Tesla fMRI.
Methods
450 sagittal volumes were acquired from seventy-eight participants: 32 patients with MECFS (pwME/CFS); 19 long COVID (pwLC) and 27 healthy controls (HC) during performance of baseline or Pre (before/during fatigue build-up) and repeat Post (fatigue set-in) Stroop tasks. Structural and functional data were analysed using the CONN toolbox.
Results
Regions of interest (ROI-to-ROI) analysis revealed significantly increased FC in subcortical regions in HC for Pre vs Post. Relative to HC, pwLC showed significantly reduced FC between nucleus accumbens and vermis 3 (p = 0.02) in Pre and increased FC in the prefrontal cortex and hippocampus (p = 0.02) in Post. pwME/CFS showed a significantly increased FC between the left cuneiform nucleus and right medulla (p = 0.03). Compared to HC, reduced FC was significant in pwLC during Pre, and between medulla and hippocampus (p = 0.04) and between nucleus accumbens and vermis (p = 0.001) during Post. Aberrant FC was significant for pwME/CFS in core networks during Pre. Core network FC to the cerebellum, amygdala, caudate and red nucleus correlated with symptom scores for cognition in both pwME/CFS and pwLC. Hippocampus and cerebellar FC correlated with duration of illness in pwME/CFS.
Conclusions
Our findings of reduced dopaminergic hippocampal-nucleus-accumbens connectivity imply blunted motivation and cognition. Extensive FC differences in subcortical and core networks in patient cohorts were detected relative to an increased FC in HC. High regional communication indicative of greater task engagement by HC was distinctive while FC differences in ME/CFS and long COVID patients indicated reduced and dysregulated regional coordination that may serve as candidate biomarkers of symptomatology in long COVID and ME/CFS.
Source: Springer Nature Link, open access
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Charting the circulating proteome in ME/CFS using cross-system profiling to uncover mechanistic insights
Gepubliceerd op 9 maart 2026
A.Hoel, F. Hoel, Dyrstad, Chapola, Rekeland, Risa, Alme, Sørland, Brokstad, Marti, Mella, Fluge, Tronstad
Highlights
• Serum proteomics reveals widespread protein changes in ME/CFS patients
• Tissue-linked shifts show reduced intracellular and increased secreted proteins
• Immune signatures show reprogramming with reduced neutrophil-derived proteins • Regulatory networks link immune, vascular, and metabolic dysfunction
Summary
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition often triggered by infections, with unclear mechanisms and no established biomarkers or treatments.
We apply aptamer-based serum proteomics to 50 ME/CFS patients and 29 healthy controls, analyzing 7,326 protein targets. We identify 1,823 aptamers with significant differences between the groups (845 after false discovery rate [FDR] correction).
Distinct patterns of tissue- and process-specific changes are seen. There is a broad increase in secreted proteins, while intracellular proteins, e.g., from skeletal muscle, particularly show reduction.
Immune cell-associated signatures indicate immune reprogramming, including a distinct reduction in proteins secreted by activated neutrophils.
Focused secretome analysis supports intensified regulatory interactions related to immune activity, inflammation, vasculature, and metabolism.
Validation of measurements using antibody-based methods confirms findings for a selection of proteins.
The uncovered serum proteome patterns in ME/CFS patients may contribute to understanding the pathophysiology and inform future biomarker research and therapeutic development.
Source: Cell Reports Medicine, open access
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ME/CFS and Long COVID Demonstrate Similar Bioenergetic Impairment and Recovery Failure on Two-Day Cardiopulmonary Exercise Testing
Gepubliceerd op 12 maart 2026
Todd Davenport, Staci Stevens, Jared Stevens, Mark Van Ness
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long Covid are characterized by post-exertional malaise (PEM). Similarities in disease presentation suggest important commonalities in bioenergetic impairment, but this hypothesis has not been demonstrated. The metabolic underpinnings of each disease can be elucidated by two cardiopulmonary exercise tests (CPET) administered 24 hours apart.
This retrospective study examined physiological responses on two-day CPET in people with ME/CFS (63 females and 21 males), Long Covid (52 females and 27 males), and matched non-disabled control participants (51 females and 20 males). Data were analyzed within sexes using repeated measures analysis of variance.
All participants met maximal effort criteria. There were significant reductions in oxygen consumption (O₂) and workload at the ventilatory anaerobic threshold (VAT) in both patient groups compared to non-disabled controls, with larger effect sizes at VAT than at peak exertion.
Performance decrements were observed in both sexes. Females exhibited more pronounced abnormalities and significant group by test effects. No significant differences were observed between patient groups. Severe disability based on impaired
O₂ was prevalent in both patient groups. Hemodynamic and ventilatory measures were within normal ranges. ME/CFS and Long Covid both involve a functionally significant bioenergetic failure complicated by inadequate post-exertional recovery, which is similar between the conditions and unexplained by hemodynamic and ventilatory changes.
Findings support the utility of two-day CPET as an objective measure of PEM and functional impairment. Future studies may integrate mechanistic biomarkers with two-day CPET as trial endpoints and to establish likely responses to treatments for PEM.
Source: Research Square, preprint, open access
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Uncovering the genetic architecture of ME/CFS: a precision approach reveals impact of rare monogenic variation Gepubliceerd op 12 maart 2026
Birch, Wilk, Gajapathy, Hutchins, Kaur, Brown, Mamidi, Hodgin, Turgut , Younger, Worthey
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling and heterogeneous disorder lacking validated biomarkers or targeted therapies. Clinical variability and elusive pathophysiology hinder progress toward effective diagnostics and treatment. Core symptoms include persistent fatigue, post-exertional malaise, unrefreshing sleep, cognitive dysfunction, and pain. We tested whether an individualized, “n-of-1” genomic and transcriptomic framework combined with comprehensive, participant-informed phenotyping could reveal molecular signatures unique to each patient.
Methods
Clinical-grade whole-genome sequencing was conducted in 31 affected individuals from 25 families, with RNA-seq performed on a subset (16 affected, 7 unaffected) using blood samples. Machine-learning assisted variant triage, transcript-aware damage prediction, and expert review identified pathogenic or likely pathogenic variants in 8 of 25 probands (32%) and 12 of 31 affected individuals (39%).
Results
Findings revealed marked genetic heterogeneity, including large-effect rare and more common variants. Implicated pathways included ATP generation, oxidative phosphorylation, fatty acid oxidation; regulation of glycolysis, amino acid and lipid turnover; ion and solute homeostasis; synaptic signaling, excitability, oxygen transport, and muscle integrity, resilience, and post-exertional recovery; previously implicated processes. Plausible modifiers influencing disease onset, severity, and relapsing–remitting patterns and possibly explaining intrafamilial variability and inconsistent findings across studies, were also identified. Despite gene-level diversity, downstream effects converged on impaired energy production, reduced stress resilience, and vulnerability to post-exertional metabolic failure; disruptions consistent with core ME/CFS symptoms of exertional intolerance, cognitive fog, and fatigue.
Conclusions
Our findings support the hypothesis that at least a subset of ME/CFS cases represent distinct molecular disorders that converge on shared physiological pathways.
Validation in larger, more diverse cohorts will be essential to test this hypothesis and establish generalizability, but increase size alone is unlikely to resolve causation in a disorder defined by rarity, heterogeneity, and molecular complexity. We suggest that progress will require experimental designs that integrate individual-level genomic data with deep, participant-informed deep phenotyping, capturing the combined effects of rare and common variants and environmental modifiers on disease expression and progression.
We believe that an individualized precision medicine framework will uncover molecular drivers and modifiers of ME/CFS previously obscured by heterogeneity, enabling biologically informed stratification, improved trial design, biomarker discovery, and targeted interventions in this historically neglected condition.
Source: Springer Nature, open access. Preprint ahead of final publication.
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Systematic Examination of Gene Expression and Proteomic Evidence Across Tissues Supports the Role of Mitochondrial Dysregulation in ME/CFS Gepubliceerd op 11 maart 2026
Keele, Enger, Barnette, Ruiz-Esparza, Alvarado, Mathur, Stratford, Giamberardino, Brown, Webb & Carnes
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, multisystem disease characterized by post-exertional malaise and persistent fatigue. The cause of ME/CFS is not well understood, and there are no established biomarkers or FDA-approved pharmacotherapies.
The clinical heterogeneity of ME/CFS presents challenges to diagnosis and treatment and necessitates collaborative efforts to generate robust findings.
This study leveraged gene and protein expression data from the mapMECFS data repository and the DecodeME Genome-Wide Association Study (GWAS) to assess consistent gene signatures across studies.
The mitochondrial genes MT-RNR1 and MT-RNR2 exhibited lower expression in ME/CFS cases in two studies. Combining this with increased expression of mitochondrial genes in platelets from another study, this supports mitochondrial dysregulation as having a role in ME/CFS.
Furthermore, ME/CFS-associated genes were mapped to compounds in drug databases as possible treatments for further investigation. In muscle gene expression data, 107 approved compounds target 26 genes with functions relevant to mitochondrial support and immunomodulators.
From the DecodeME GWAS, 83 approved compounds target 24 genes with functions related to energy metabolism and mitochondrial function. Though little consistency in specific genes was observed across studies, which highlights the need for larger studies, mitochondrial dysfunction in ME/CFS cases was evident across studies.
Source: International Journal of Molecular Sciences, open access
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A chronobiology-based protocol for multi-omic mapping of menstrual cycle and diurnal rhythms in ME/CFS and long COVID Gepubliceerd op 11 maart 2026
Thomas, Huang, Schneider-Futschik, Pollack, Caspi Tal, Fineberg, Gurvich, Pretorius, Bergquist & Armstrong
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are debilitating multisystem illnesses with overlapping symptoms and poorly understood mechanisms.
Female sex is a major risk factor, and preliminary evidence links sex hormones and other fluctuating endocrine hormones, including cortisol, aldosterone, and DHEA, to these conditions. However, existing studies have not comprehensively captured diurnal, infradian, and circadian biorhythms, leaving critical gaps in understanding.
The MELLOW study (ME/CFS + Long COVID Longitudinal Omics and Women’s Health) is a prospective, chronobiology-based study of reproductive-aged women with ME/CFS, long COVID, and healthy controls. It integrates menstrual-phase and diurnal sampling with multi-omics profiling (genomics, proteomics, metabolomics, lipidomics, steroidomics), physiological monitoring, and symptom tracking.
By accounting for natural and disrupted biorhythms, MELLOW will map temporal links between hormonal, molecular, physiological, and symptom dynamics, improving biomarker reproducibility and clarifying endocrine network disruption underlying ME/CFS, long COVID, and women’s health more broadly.
Source: mpj/women’s health, open access
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The potential causes of myasthenia and fasciculations in severely ill ME/CFS patients: the role of disturbed electrophysiology Gepubliceerd op 10 maart 2026
Klaus J. Wirth & Jürgen M. Steinacker
Abstract
Patients with severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are bedridden and suffer from hypersensitivities to light and noise, severe orthostatic intolerance reducing cerebral blood flow, and skeletal muscle symptoms, including loss of force, fatigue, pain, fasciculations, and cramps.
Because neurological investigations exclude neuronal causes of myasthenia, we hypothesize a muscular pathomechanism. In previous articles, we considered insufficient activity of the Na+/K+-ATPase to be the main cause of mitochondrial damage via high intracellular sodium that reverses the transport mode of the sodium-calcium-exchanger to import calcium, causing calcium overload.
Low Na+/K+-ATPase activity also causes sarcolemmal depolarization, leading to less effective action potential propagation and loss of force.
Depolarization brings the membrane potential closer to the threshold potential, causing hyperexcitability that explains fasciculations and cramps. These increase sodium influx during excitation to further increase the workload of Na+/K+-ATPase.
Thereby, depolarization causes further depolarization. Higher intracellular sodium favors calcium overload and mitochondrial damage, which lowers the energy supply of Na+/K+-ATPase and increases the reactive oxygen species, further inhibiting Na+/K+-ATPase. The muscle is in a state of depolarization even at rest.
Depolarization and mitochondrial damage reinforce each other. Thus, dysfunction of Na+/K+-ATPase as a single mechanism can explain the different skeletal muscle symptoms of severely ill ME/CFS patients, comprising loss of force, fatigue, and fasciculations.
Source: Frontiers in Physiology, open access
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Evidence of White Matter Neuroinflammation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Diffusion-Based Neuroinflammation Imaging Study Gepubliceerd op 16 maart 2026
Yu, Kothe, Kwiatek, Del Fante, Bonner, Calhoun, Shan
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder with suspected neuroinflammatory pathophysiology. However, previous diffusion tensor imaging (DTI) studies have reported inconsistent white matter abnormalities in ME/CFS, and specific white matter inflammatory changes remain poorly characterised.
This study employed an advanced diffusion-based neuroinflammation imaging (NII) model to investigate white matter neuroinflammation in ME/CFS. Diffusion MRI data from 67 ME/CFS patients (median age, 38; and 54 women) and 67 rigorously matched healthy controls (HCs) (median age 38; and 52 women) were analysed.
Seven NII-derived metrics were computed: hindered water ratio (NII-HR), restricted fraction (NII-RF), fibre fraction (NII-FF), axial diffusivity (NII-AD), radial diffusivity (NII-RD), mean diffusivity (NII-MD) and fractional anisotropy (NII-FA).
Conventional DTI metrics were also calculated. Tract-based spatial statistics were used to perform voxel-wise group comparisons, and multiple regression analysis was conducted to examine the relationship between NII/DTI metrics and clinical measures of mental health, physical health, sleep quality, disability, disease severity and disease duration.
Compared to HCs, ME/CFS patients exhibited widespread white matter abnormalities, including significantly lower NII-HR and NII-RF, and significantly higher NII-FF, NII-AD, NII-MD and NII-FA across association, commissural and projection fibres. Additionally, some regions showed decreased NII-AD and NII-MD in ME/CFS.
Lower NII-RF, NII-AD and NII-MD in ME/CFS were significantly associated with worse mental health, while lower NII-RF was also associated with a higher level of disability.
Among ME/CFS patients, higher NII-FF was associated with lower disease severity. Conventional DTI showed minimal group differences and no significant clinical associations.
This study provides in vivo evidence of white matter neuroinflammation in ME/CFS, characterised by cerebral edema (reduced NII-HR), cellular infiltration (reduced NII-RF) and axonal reorganisation
(increased NII-FF). This suggests NII-derived indices may serve as sensitive biomarkers for neuroinflammation in ME/CFS.
Source: Human Brain Mapping, open access
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Outcomes of ME/CFS following infectious mononucleosis: seven-year follow-up of a prospective study Gepubliceerd op 17 maart 2026 Jason, Furst, Worth & Katz
Abstract
Background
Many individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) report experiencing an infectious illness prior to disease onset. Approximately 30% of cases are linked to Epstein-Barr virus (EBV) infection resulting in Infectious Mononucleosis (IM).
Methods
We examined the progression of ME/CFS following IM among a cohort of college students who were recruited before they developed the infection. This sample represented a socioeconomically and ethnically diverse population of young adults who were monitored over a 7-year period.
Assessments of health status, psychological functioning, and blood biomarkers were conducted at four time points: (1) baseline, when participants were healthy and at least 6 weeks from IM onset; (2) within 6 weeks of IM diagnosis; (3) 6 months post-IM, when participants had either recovered or met criteria for ME/CFS; and (4) the 7-year follow-up.
Results
At follow-up, 81% of participants who had initially presented with severe ME/CFS continued to fulfill diagnostic criteria. In contrast, only about one-third of those with moderate or lingering symptoms at 6 months still had ME/CFS 7 years later.
Conclusion
These findings indicate that ME/CFS following IM tends to persist over the long term, particularly among those whose illness was more severe at onset.
Source: Frontiers in Medicine, open access
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Perioperative outcomes in patients with myalgic encephalomyelitis/chronic fatigue syndrome undergoing general anesthesia: a retrospective matched-pair study
Please note that as a preprint, it is yet to be peer reviewed.
Felix M. Steinkirchner, Christina K. Kaufmann, View ORCID ProfileRichard F. Kraus, Maximilian Käss, View ORCID ProfileElisabeth Schieffer, View ORCID ProfileBernhard M. Graf, View ORCID ProfileChristoph Lassen, View ORCID ProfileViktoria Kimmerling, View ORCID ProfileAlexander Dejaco
doi: https://doi.org/10.64898/2026.04.06.26348924
This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
Abstract
Background Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic multisystem disease characterized by profound fatigue, post-exertional malaise, cognitive impairment, and autonomic dysfunction. Its pathophysiology is incompletely understood and likely involves complex interactions between immune, autonomic, and metabolic dysregulation. Despite features with potential relevance for anesthesia and perioperative care, evidence to guide anesthetic management in individuals with ME/CFS remains limited. We therefore performed a retrospective matched-pair analysis to generate clinical data on perioperative responses and identify areas for future research.
Methods We conducted a retrospective matched-pair analysis at a single tertiary center. All patients with ME/CFS undergoing general anesthesia from 2015 to 2026 were identified using ICD-10-GM codes (G93.3 and U09.9) with additional manual verification and matched 1:1 to controls for comparison. Patients with confounding diagnoses or American Society of Anesthesiologists physical status above III were excluded. The analysis focused on intraoperative hemodynamic parameters, including baseline, post-induction, median, and lowest recorded systolic blood pressure and heart rate, as well as early postoperative outcomes in the post-anesthesia care unit (PACU), including maximum pain scores and requirement for rescue analgesia.
Results Out of 189 individuals identified through ICD-10 codes, 15 matched pairs were included after application of exclusion criteria. ME/CFS patients exhibited lower lowest recorded intraoperative systolic blood pressure (90.0 [82.5-95.0] mmHg in ME/CFS vs 100.0 [90.0-110.0] mmHg in controls, p = 0.044) as well as lower lowest heart rate (50 [40.0-57.5] bpm in ME/CFS vs 60 [50.0-65.0] bpm in controls, p = 0.012). Vasopressor use and fluid administration did not differ, and no episodes of severe hypotension or perioperative adverse events were observed. Postoperative pain was higher in ME/CFS, with higher maximum pain scores (NRS 5.0 [4.0-6.0] in ME/CFS vs 1.0 [0.0-4.0] in controls, p = 0.008) and more frequent opioid rescue analgesia (80% in ME/CFS vs 33% in controls, p = 0.039). Postoperative nausea or vomiting, oxygen supplementation, and PACU length of stay were similar between groups.
Conclusions General anesthesia appears hemodynamically well tolerated in individuals with ME/CFS. In contrast, postoperative pain burden is increased and may require tailored analgesic strategies. Post-exertional malaise, a key disease feature with potentially delayed onset and significant impact, was not captured in this study and remains an important target for future research. These hypothesis-generating findings highlight the need for prospective studies to optimize perioperative management and evaluate patient-relevant outcomes in ME/CFS.
Competing Interest Statement The authors have declared no competing interest.
Funding Statement This study was supported by the German Society for ME/CFS (DGMECFS). The funder had no role in study design, data collection, analysis, interpretation, or the decision to submit for publication.
Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
This study was approved by the Ethics Committee of the University of Regensburg (reference number: 25-4271-101). The requirement for informed consent was waived in accordance with institutional and national regulations due to the retrospective design and use of routinely collected, de-identified clinical data.
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes
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Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
bioRxiv and medRxiv thank the following for their generous financial support:
The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The University of Edinburgh, University of Washington, and Vrije Universiteit Amsterdam.
Transl Med . 2025 Jul 7;23:748. doi: 10.1186/s12967-025-06829-0
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SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis
Bita Rostami-Afshari 1,2,3,4, Wesam Elremaly 1,3,4, Anita Franco 1,3,4, Mohamed Elbakry 1,3,4,5, Marie-Yvonne Akoume 1,3,4,6, Ines Boufaied 7, Atefeh Moezzi 1,2,3,4, Corinne Leveau 1,2,3,4, Pierre Rompré 8, Christian Godbout 9, Olav Mella 10, Øystein Fluge 10, Alain Moreau 1,2,3,4,11,✉
PMCID: PMC12236014 PMID: 40624584
This article has been corrected. See J Transl Med. 2025 Aug 14;23:911.
Abstract
Background
Sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B) is emerging as a potential biomarker and therapeutic target in myalgic encephalomyelitis (ME), a complex multisystem disorder characterized by immune dysfunction, metabolic disturbances, and persistent fatigue. This study investigates the role of SMPDL3B in ME pathophysiology and explores its clinical relevance.
Methods
A case–control study was conducted in two independent cohorts: a Canadian cohort (249 ME patients, 63 controls) and a Norwegian replication cohort (141 ME patients). Plasma and membrane-bound SMPDL3B levels were quantified using ELISA and flow cytometry. Gene expression of SMPDL3B and PLCXD1, encoding phosphatidylinositol-specific phospholipase C (PI-PLC), was analyzed by qPCR. The effects of dipeptidyl peptidase-4 (DPP-4) inhibitors—vildagliptin, saxagliptin, and linagliptin—on modulation of membrane-bound and soluble SMPDL3B were assessed in vitro by qPCR, flow cytometry and ELISA.
Results
ME patients exhibited significantly elevated plasma SMPDL3B levels, which correlated with symptom severity. Flow cytometry revealed a reduction in membrane-bound SMPDL3B in monocytes, accompanied by increased PLCXD1 expression and elevated plasma levels of PI-PLC and SMPDL3B. These findings suggest that immune dysregulation in ME may be linked to enhanced cleavage of membrane-bound SMPDL3B by PI-PLC. Sex-specific differences were observed, with female ME patients displaying higher plasma SMPDL3B levels, an effect influenced by estrogen. In vitro, estradiol upregulated SMPDL3B expression, indicating hormonal regulation. Vildagliptin and saxagliptin were tested for their potential to inhibit PI-PLC activity independently of their role as DPP-4 inhibitors, and restored membrane-bound SMPDL3B while reduced its soluble form.
Conclusions
SMPDL3B emerges as a key biomarker for ME severity and immune dysregulation, with its activity influenced by hormonal and PI-PLC regulation. The ability of vildagliptin and saxagliptin to preserve membrane-bound SMPDL3B and reduce its soluble form via PI-PLC inhibition suggests a novel therapeutic strategy. These findings warrant clinical trials to evaluate their potential in mitigating immune dysfunction and symptom burden in ME.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12967-025-06829-0.
Keywords: Myalgic encephalomyelitis (ME), Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3B), Phosphatidylinositol-specific phospholipase C (PI-PLC), Vildagliptin, Saxagliptin
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Health, labour market, and social service outcomes for people with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome on a health or disability related benefit: an Aotearoa | New Zealand nationwide cross-sectional study using the integrated data infrastructure
Research Open access Published: 24 April 2026 article number , (2026)
Cite this article You have full access to this open accessarticle
Nicholas Bowden, Keith McLeod, Francesca Anns, Fiona Charlton, Barry Taylor, Rosamund Vallings, Hien Vu & Warren Tate
We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.
Abstract
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating chronic condition characterised by persistent fatigue and multisystem symptoms, often leading to long-term disability and socioeconomic disadvantage. In Aotearoa New Zealand (NZ), little is known about the health, labour market, and social service outcomes of people with ME/CFS.
Methods
We conducted a nationwide cross-sectional study using the Integrated Data Infrastructure (IDI) to identify a cohort of working-age individuals (16–64 years) receiving a health or disability-related benefit with a recorded ME/CFS diagnosis. Outcomes were compared to propensity score-matched cohorts: (1) benefit recipients without ME/CFS, and (2) a general population not receiving any benefit. We examined sociodemographic characteristics, co-occurring conditions, health service utilisation, disability support use, employment and income, and benefit reliance.
Results
The study population included 1,902 individuals with ME/CFS. Compared to the general population, the ME/CFS cohort had significantly higher rates of emergency department visits (18.8% vs. 12.8%) and pharmaceutical use (32.8% vs. 14.2% for > 10 medications), and lower current employment (18.3% vs. 83.8%). Compared to other benefit recipients, those with ME/CFS had lower hospitalisation (11.2% vs. 20.9%) and disability support service use (1.6% vs. 7.2%), but higher rates of Supported Living Payment (64.7% vs. 49.0%) and long-term benefit receipt. The ME/CFS cohort was disproportionately female and European, with notable underrepresentation of Māori, Pacific, and Asian ethnic groups.
Conclusions
People with ME/CFS on a benefit in NZ, while only representative of a small fraction of those affected by ME/CFS, still face substantial health burdens, economic vulnerability, and limited access to appropriate supports. The findings highlight systemic policy exclusions that disadvantage individuals with chronic, fluctuating conditions. Improved diagnostic coding, inclusive eligibility criteria, and integrated, person-centred care models are urgently needed to address inequities and support this underserved population.
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Identification of novel reproducible combinatorial genetic risk factors for myalgic encephalomyelitis in the DecodeME patient cohort and commonalities with long COVID
J. M. Sardell, S. Das, M. Pearson, D. Kolobkov, A. R. Malinowski, L. M. Fullwood, M. Sanna, H. Baxter, K. McLellan, M. Natt, D. Lamirel, S. Chowdhury, M. A. Strivens & S. Gardner
We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.
Abstract Background
Myalgic encephalomyelitis (also known as ME/CFS or simply ME) has severely impacted the lives of tens of millions of people globally, but the disease currently has no accurate diagnostic tools or effective treatments. Identifying the biological causes of ME has proven challenging due to its wide range of symptoms and affected organs, and the lack of reproducible genetic associations across ME populations. This has prolonged misunderstanding, lack of awareness, and denial of the disease, further harming patients.
Methods
We used the PrecisionLife® combinatorial analytics platform to identify disease signatures (i.e., combinations of 1–4 SNP-genotypes) that are significantly enriched in two cohorts of ME participants from DecodeME relative to controls from UK Biobank (UKB). We tested whether the number of these signatures possessed by an individual is significantly associated with increased prevalence of ME in a third disjoint cohort of DecodeME participants. We characterized a number of drug repurposing opportunities for a set of candidate core genes whose disease signatures had the strongest association with ME and which were linked to different mechanisms. We then tested gene overlap between the ME signatures identified and previous studies in long COVID, using two independent approaches to explore these shared genetic commonalities.
Results
We identified 22,411 reproducible disease signatures, comprising combinations of 7,555 unique SNPs, that are consistently associated with increased prevalence of ME in three disjoint patient cohorts. The count of reproducible signatures was significantly associated with increased prevalence of ME (p = 4 × 10− 21), and participants with a top 10% signature count had an odds ratio of disease 1.64 times greater than participants with a bottom 10% signature count, confirming that these genetic signatures are associated with increased susceptibility for developing ME. These disease signatures map to 2,311 genes. We identified substantial overlap between the genes found by this combinatorial analysis and previous studies. We found that the 259 candidate core genes most strongly associated with ME are enriched in disease mechanisms including neurological dysregulation, inflammation, cellular stress responses and calcium signaling. We demonstrated that 76 out of 180 genes previously linked to long COVID in the UK Sano GOLD and the US All of Us cohorts are also significantly associated with ME in the DecodeME cohort. These findings allowed identification of many existing and novel drug repurposing opportunities, including candidates linked to several genes with shared etiology for long COVID.
Conclusion
These findings provide further evidence that ME is a complex multisystemic condition where the risk of developing the disease has a very clear genetic and biological basis. They give a substantially deeper level of insight into the genetic risk factors and mechanisms involved in ME. The discovery of so many multiply reproducible genetic associations implies that ME is highly polygenic, which has important consequences for its future study and the delivery of clinical care to patients. The striking overlap in genes and mechanisms between long COVID and ME suggests the potential for development of novel or repurposed drug therapies that could be used to successfully treat either condition. However, although they share significant genetic commonalities, long COVID and ME appear to be best considered as partially overlapping but different diseases.
- doi: 10.3389/fpain.2025.1527783. eCollection 2025.
- Jacob S Aday 1 2, Jenna McAfee 1, Deirdre A Conroy 3, Avinash Hosanagar 3 4, Vijay Tarnal 1 2, Cody Weston 3, Katherine Scott 1, Dana Horowitz 4, Jamarie Geller 2 3, Steven E Harte 1 2 5, Niloufar Pouyan 1 2 5, Nicolas G Glynos 1 2, Anne K Baker 1 2, Jeffrey Guss 6, Alan K Davis 7 8 9, Helen J Burgess 3, George A Mashour 1 2 5, Daniel J Clauw 1, Kevin F Boehnke 1 2
- Affiliations Expand:PMID: 40171515 PMCID: PMC11958999
Introduction: Fibromyalgia (FM) is the prototypical nociplastic pain condition, characterized by widespread pain and issues with cognition, mood, and sleep. Currently, there are limited treatment options available that effectively treat FM symptoms. Psilocybin-assisted therapy (PAT) is an emerging combined drug-therapy intervention, but no studies to-date have investigated PAT for FM.
Methods: Here, we report findings from an open-label, pilot clinical trial of PAT for FM (N = 5). In conjunction with psychotherapy (two preparatory, four integration sessions), participants received two doses of oral psilocybin (15 mg and 25 mg) delivered two weeks apart.
Results: Regarding safety (primary outcome), there were transient elevations of blood pressure or heart rate during dosing which normalized by the end of treatment, with no serious adverse events. Four of five participants reported transient headaches following dosing. Compared to baseline, participants reported clinically meaningful improvements in the following secondary outcomes one month following their second psilocybin dose (reported as Cohen's d): pain severity [d = -2.1, 95% CI(-3.7 to -0.49)], pain interference [d = -1.8, 95% CI (-3.27 to -0.24)], and sleep disturbance [d = -2.5, 95% CI (-4.21 to -0.75)]. Using the Patient Global Impression of Change, one participant reported their symptoms "very much improved," two reported "much improved," and two reported "minimally improved." We stopped recruitment early because of concerns about generalizability and changes in FDA guidance for psychedelic clinical trials that occurred data collection.
Discussion: This small open-label trial preliminarily supports that PAT is well-tolerated by people with FM, establishing a basis for larger randomized controlled trials.
Clinical trial registration: ClinicalTrials.gov, identifier, (NCT05128162).
Keywords: clinical trial; fibromyalgia; pilot; psilocybin; psilocybin-assisted therapy.
© 2025 Aday, McAfee, Conroy, Hosanagar, Tarnal, Weston, Scott, Horowitz, Geller, Harte, Pouyan, Glynos, Baker, Guss, Davis, Burgess, Mashour, Clauw and Boehnke.
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Invisible No More: Embracing Your Road to Recovery from Long Covid and Other Complex Chronic Illnesses Hardcover – June 17, 2025
by Ilene Sue Ruhoy MD PhD (Author)
A possible useful book to read:
From a neurologist who diagnosed her own brain tumor, Invisible No More empowers patients with chronic and complex illnesses to take their health into their own hands.
While Covid-19 has brought increased attention to chronic and complex illnesses, these conditions have impacted millions worldwide, long before the pandemic. Covid was not the first exposure to cause long-term disease and disability, nor will it be the last.
In Invisible No More, Dr. Ilene Sue Ruhoy aims to empower the long-term patients of chronic and complex diseases, delving into her own harrowing experience as a patient. She details her evolution as a neurologist, toxicologist, and integrative physician to work with people across the globe in treating their chronic symptoms and disabling disease, all while amplifying their own voices. This book serves as a practical guide with sections on nutrition, breathing, supplements and more. With a focus on healing and empowerment, Invisible No More will answer patients' most pressing questions and take their health into their own hands.
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Sustained illness burden over time among Australians with myalgic encephalomyelitis/chronic fatigue syndrome
Gepubliceerd op 1 januari 2026
Weigel, Eaton-Fitch, Thapaliya, Marshall-Gradisnik
Abstract
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling chronic illness. Many people with ME/CFS (pwME/CFS) are unable to continue employment and require support to complete activities of daily living. Despite this, ME/CFS remains unrecognised as a disability in Australia. The present study aimed to highlight the profound burdens experienced by pwME/CFS over time to provide evidence of permanency and necessitate reforms to Australian healthcare policies.
Methods
Data were collected for this longitudinal investigation between 1st October 2021 and 3rd October 2024. All participants were Australian residents aged between 18 and 65 years fulfilling the Canadian or International Consensus Criteria. Sociodemographic information, medical history, illness presentation and patient-reported outcomes were collected using three self-administered questionnaires distributed at approximately six-month intervals. Illness presentation and patient-reported outcomes were investigated over 12 months with Cochran’s Q, Friedman and one-way repeated measures ANOVA tests using Statistical Package for the Social Sciences version 29.0. Quality of life data were compared with Australian population norms using one-sample Wilcoxon signed-rank tests.
Results
Thirty-two pwME/CFS (n = 22/32, 68.8% female) participated at all three time points. At baseline, the mean age was 44.03 years and median illness duration was 12.50 years. Participants reported a median of 30 symptoms at each time point – the most common of which were also the most severe in presentation. Importantly, there were no significant changes in any symptom or patient-reported outcome over the 12-month study period. Overall health status, physical health and the ability to participate in daily and work life activities were the most substantially impacted. Quality of life was significantly reduced among pwME/CFS when compared with population norms at all time points.
Conclusions
PwME/CFS face substantial and sustained illness burdens. These consistent, profound impairments emphasise the need for improved access to disability and social support services for pwME/CFS in Australia through policy reform.
Source: PLOS One, open access
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Does Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Represent a Poly-Herpesvirus Post-Virus Infectious Disease?
Gepubliceerd op 7 januari 2026
Ariza, Palomo & Williams
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem illness with unknown etiology. An estimated 17–24 million people representing approximately 1% of the population are afflicted worldwide.
In over half of cases, ME/CFS onset is associated with acute “flu-like” symptoms, suggesting a role for viruses. However, no single virus has been identified as the only etiological agent. This may reflect the approach employed or more strongly the central dogma associated with herpesviruses replication, which states that a herpesvirus exists in two states, either lytic or latent.
The purpose of this review is to address the role that abortive lytic replication may have in the pathogenesis of ME/CFS and other post-acute viral infections and also to raise awareness that these syndromes might be poly-herpesviruses mediated diseases.
There is sufficient data to demonstrate that ME/CFS patients can be divided into at least two subgroups: those whose illness is not triggered by a virus infection and those whose are. The latter group should be referred to as patients with post-infective ME/CFS (PI-ME/CFS). This classification is necessary because while the symptomology exhibited by patients in these subsets might be similar, the mechanism(s) driving the disease process will be different, and thus, different therapeutic approaches might be required.
DNA viruses, including human herpesviruses, encode a wide array of proteins. These proteins have diverse effects on host cells, such as promoting cell proliferation, inhibiting apoptosis, and evading immune responses. Identifying the specific viral gene products responsible for fatigue, pain, cognitive dysfunction, and post-exertional malaise (PEM) will be essential for developing reliable biomarkers and targeted therapies. Continued research in this area is therefore critical.
Finally, if simultaneous abortive lytic replication of multiple herpesviruses is a key driver in certain ME/CFS patients, then targeted treatment protocols could be developed for this PI-ME/CFS subgroup. Such approaches might include combinations of antiviral agents (e.g., ganciclovir), cell-depleting therapies such as rituximab, checkpoint inhibitors, or agents designed to prevent viral reactivation.
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Virus-induced endothelial senescence as a cause and driving factor for ME/CFS and long COVID: mediated by a dysfunctional immune system
Gepubliceerd op 10 januari 2026
Nunes, Kell, Slaghekke, Wüst, Fielding, Kell & Pretorius
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are two post-viral diseases, which share many common symptoms and pathophysiological alterations. Yet a mechanistic explanation of disease induction and maintenance is lacking. This hinders the discovery and implementation of biomarkers and treatment options, and ultimately the establishment of effective clinical resolution.
Here, we propose that acute viral infection results in (in)direct endothelial dysfunction and senescence, which at the blood-brain barrier, cerebral arteries, gastrointestinal tract, and skeletal muscle can explain symptoms.
The endothelial senescence-associated secretory phenotype (SASP) is proinflammatory, pro-oxidative, procoagulant, primed for vasoconstriction, and characterized by impaired regulation of tissue repair, but also leads to dysregulated inflammatory processes.
Immune abnormalities in ME/CFS and long COVID can account for the persistence of endothelial senescence long past the acute infection by preventing their clearance, thereby providing a mechanism for the chronic nature of ME/CFS and long COVID.
The systemic and tissue-specific effects of endothelial senescence can thus explain the multisystem involvement in and subtypes of ME/CFS and long COVID, including dysregulated blood flow and perfusion deficits. This can occur in all tissues, but especially the brain as evidenced by findings of reduced cerebral blood flow and impaired perfusion of various brain regions, post-exertional malaise (PEM), gastrointestinal disturbances, and fatigue.
Paramount to this theory is the affected endothelium, and the bidirectional sustainment of immune abnormalities and endothelial senescence. The recognition of endothelial cell dysfunction and senescence as a core element in the aetiology of both ME/CFS and Long COVID should aid in the establishment of effective biomarkers and treatment regimens.
Source: Cell Death & Disease, open access
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Abnormal T-Cell activation and cytotoxic T-Cell frequency discriminate symptom severity in myalgic encephalomyelitis/chronic fatigue syndrome
Gepubliceerd op 22 januari 2026
Ji-Sook Lee, Eliana Lacerda, Caroline Kingdon, Ella Abken, Giada Susannini, Hazel M Dockrell, Luis Nacul , Jacqueline M Cliff
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating but poorly-understood disease. ME/CFS symptoms include immune system effects alongside incapacitating fatigue and post-exertional disease exacerbation. Symptom severity can range from mild to severe and whilst symptoms can fluctuate, few people fully recover.
Methods
Immunological profiles of people living with ME/CFS were analysed by flow cytometry, focusing on cytotoxic cells, to determine whether people with mild/moderate (n = 43) or severe ME/CFS (n = 53) expressed different immunological markers. Flow cytometry data were tested for normality and the two clinical groups were compared by t-test or Mann-Whitney U-test as appropriate.
Results
People with mild/moderate ME/CFS had increased expression of cytotoxic effector molecules alongside enhanced proportions of early-immunosenescence cells, determined by the CD28-CD57- phenotype, indicative of persistent viral infection. In contrast, people with severe ME/CFS had higher proportions of activated circulating lymphocytes, determined by CD69+ and CD38+ expression, and expressed more pro-inflammatory cytokines, including interferon-γ, tumour necrosis factor and interleukin-17, following stimulation in vitro, indicative of prolonged non-specific inflammation.
These changes were consistent across different cell types including CD8+ T cells, mucosal associated invariant T cells and Natural Killer cells, indicating generalised altered cytotoxic responses across the innate and adaptive immune system.
Conclusions
These immunological differences likely reflect different disease pathogenesis mechanisms occurring in the two clinical groups, opening up opportunities for the development of prognostic markers and stratified treatments.
Source: Journal of Translational Medicine, open access
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Distinct functional connectivity patterns in myalgic encephalomyelitis and long COVID patients during cognitive fatigue: a 7 Tesla task-fMRI study
Gepubliceerd op 11 maart 2026 Inderyas, Thapaliya, Marshall-Gradisnik & Barnden
Abstract
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and long COVID are chronic debilitating illnesses featuring fatigue, post-exertional malaise (PEM) and neurocognitive deficits. Temporal correlation of neural activity between distinct brain regions, also referred to as functional connectivity (FC), can provide insights into how brain networks coordinate, at rest or during task. Therefore, we explored intrinsic FC correlates of cognitive fatigue in ME/CFS and long COVID patients during two Stroop-colour-word paradigms on 7 Tesla fMRI.
Methods
450 sagittal volumes were acquired from seventy-eight participants: 32 patients with MECFS (pwME/CFS); 19 long COVID (pwLC) and 27 healthy controls (HC) during performance of baseline or Pre (before/during fatigue build-up) and repeat Post (fatigue set-in) Stroop tasks. Structural and functional data were analysed using the CONN toolbox.
Results
Regions of interest (ROI-to-ROI) analysis revealed significantly increased FC in subcortical regions in HC for Pre vs Post. Relative to HC, pwLC showed significantly reduced FC between nucleus accumbens and vermis 3 (p = 0.02) in Pre and increased FC in the prefrontal cortex and hippocampus (p = 0.02) in Post. pwME/CFS showed a significantly increased FC between the left cuneiform nucleus and right medulla (p = 0.03). Compared to HC, reduced FC was significant in pwLC during Pre, and between medulla and hippocampus (p = 0.04) and between nucleus accumbens and vermis (p = 0.001) during Post. Aberrant FC was significant for pwME/CFS in core networks during Pre. Core network FC to the cerebellum, amygdala, caudate and red nucleus correlated with symptom scores for cognition in both pwME/CFS and pwLC. Hippocampus and cerebellar FC correlated with duration of illness in pwME/CFS.
Conclusions
Our findings of reduced dopaminergic hippocampal-nucleus-accumbens connectivity imply blunted motivation and cognition. Extensive FC differences in subcortical and core networks in patient cohorts were detected relative to an increased FC in HC. High regional communication indicative of greater task engagement by HC was distinctive while FC differences in ME/CFS and long COVID patients indicated reduced and dysregulated regional coordination that may serve as candidate biomarkers of symptomatology in long COVID and ME/CFS.
Source: Springer Nature Link, open access
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Charting the circulating proteome in ME/CFS using cross-system profiling to uncover mechanistic insights
Gepubliceerd op 9 maart 2026
A.Hoel, F. Hoel, Dyrstad, Chapola, Rekeland, Risa, Alme, Sørland, Brokstad, Marti, Mella, Fluge, Tronstad
Highlights
• Serum proteomics reveals widespread protein changes in ME/CFS patients
• Tissue-linked shifts show reduced intracellular and increased secreted proteins
• Immune signatures show reprogramming with reduced neutrophil-derived proteins • Regulatory networks link immune, vascular, and metabolic dysfunction
Summary
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition often triggered by infections, with unclear mechanisms and no established biomarkers or treatments.
We apply aptamer-based serum proteomics to 50 ME/CFS patients and 29 healthy controls, analyzing 7,326 protein targets. We identify 1,823 aptamers with significant differences between the groups (845 after false discovery rate [FDR] correction).
Distinct patterns of tissue- and process-specific changes are seen. There is a broad increase in secreted proteins, while intracellular proteins, e.g., from skeletal muscle, particularly show reduction.
Immune cell-associated signatures indicate immune reprogramming, including a distinct reduction in proteins secreted by activated neutrophils.
Focused secretome analysis supports intensified regulatory interactions related to immune activity, inflammation, vasculature, and metabolism.
Validation of measurements using antibody-based methods confirms findings for a selection of proteins.
The uncovered serum proteome patterns in ME/CFS patients may contribute to understanding the pathophysiology and inform future biomarker research and therapeutic development.
Source: Cell Reports Medicine, open access
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ME/CFS and Long COVID Demonstrate Similar Bioenergetic Impairment and Recovery Failure on Two-Day Cardiopulmonary Exercise Testing
Gepubliceerd op 12 maart 2026
Todd Davenport, Staci Stevens, Jared Stevens, Mark Van Ness
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long Covid are characterized by post-exertional malaise (PEM). Similarities in disease presentation suggest important commonalities in bioenergetic impairment, but this hypothesis has not been demonstrated. The metabolic underpinnings of each disease can be elucidated by two cardiopulmonary exercise tests (CPET) administered 24 hours apart.
This retrospective study examined physiological responses on two-day CPET in people with ME/CFS (63 females and 21 males), Long Covid (52 females and 27 males), and matched non-disabled control participants (51 females and 20 males). Data were analyzed within sexes using repeated measures analysis of variance.
All participants met maximal effort criteria. There were significant reductions in oxygen consumption (O₂) and workload at the ventilatory anaerobic threshold (VAT) in both patient groups compared to non-disabled controls, with larger effect sizes at VAT than at peak exertion.
Performance decrements were observed in both sexes. Females exhibited more pronounced abnormalities and significant group by test effects. No significant differences were observed between patient groups. Severe disability based on impaired
O₂ was prevalent in both patient groups. Hemodynamic and ventilatory measures were within normal ranges. ME/CFS and Long Covid both involve a functionally significant bioenergetic failure complicated by inadequate post-exertional recovery, which is similar between the conditions and unexplained by hemodynamic and ventilatory changes.
Findings support the utility of two-day CPET as an objective measure of PEM and functional impairment. Future studies may integrate mechanistic biomarkers with two-day CPET as trial endpoints and to establish likely responses to treatments for PEM.
Source: Research Square, preprint, open access
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Uncovering the genetic architecture of ME/CFS: a precision approach reveals impact of rare monogenic variation Gepubliceerd op 12 maart 2026
Birch, Wilk, Gajapathy, Hutchins, Kaur, Brown, Mamidi, Hodgin, Turgut , Younger, Worthey
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling and heterogeneous disorder lacking validated biomarkers or targeted therapies. Clinical variability and elusive pathophysiology hinder progress toward effective diagnostics and treatment. Core symptoms include persistent fatigue, post-exertional malaise, unrefreshing sleep, cognitive dysfunction, and pain. We tested whether an individualized, “n-of-1” genomic and transcriptomic framework combined with comprehensive, participant-informed phenotyping could reveal molecular signatures unique to each patient.
Methods
Clinical-grade whole-genome sequencing was conducted in 31 affected individuals from 25 families, with RNA-seq performed on a subset (16 affected, 7 unaffected) using blood samples. Machine-learning assisted variant triage, transcript-aware damage prediction, and expert review identified pathogenic or likely pathogenic variants in 8 of 25 probands (32%) and 12 of 31 affected individuals (39%).
Results
Findings revealed marked genetic heterogeneity, including large-effect rare and more common variants. Implicated pathways included ATP generation, oxidative phosphorylation, fatty acid oxidation; regulation of glycolysis, amino acid and lipid turnover; ion and solute homeostasis; synaptic signaling, excitability, oxygen transport, and muscle integrity, resilience, and post-exertional recovery; previously implicated processes. Plausible modifiers influencing disease onset, severity, and relapsing–remitting patterns and possibly explaining intrafamilial variability and inconsistent findings across studies, were also identified. Despite gene-level diversity, downstream effects converged on impaired energy production, reduced stress resilience, and vulnerability to post-exertional metabolic failure; disruptions consistent with core ME/CFS symptoms of exertional intolerance, cognitive fog, and fatigue.
Conclusions
Our findings support the hypothesis that at least a subset of ME/CFS cases represent distinct molecular disorders that converge on shared physiological pathways.
Validation in larger, more diverse cohorts will be essential to test this hypothesis and establish generalizability, but increase size alone is unlikely to resolve causation in a disorder defined by rarity, heterogeneity, and molecular complexity. We suggest that progress will require experimental designs that integrate individual-level genomic data with deep, participant-informed deep phenotyping, capturing the combined effects of rare and common variants and environmental modifiers on disease expression and progression.
We believe that an individualized precision medicine framework will uncover molecular drivers and modifiers of ME/CFS previously obscured by heterogeneity, enabling biologically informed stratification, improved trial design, biomarker discovery, and targeted interventions in this historically neglected condition.
Source: Springer Nature, open access. Preprint ahead of final publication.
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Systematic Examination of Gene Expression and Proteomic Evidence Across Tissues Supports the Role of Mitochondrial Dysregulation in ME/CFS Gepubliceerd op 11 maart 2026
Keele, Enger, Barnette, Ruiz-Esparza, Alvarado, Mathur, Stratford, Giamberardino, Brown, Webb & Carnes
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, multisystem disease characterized by post-exertional malaise and persistent fatigue. The cause of ME/CFS is not well understood, and there are no established biomarkers or FDA-approved pharmacotherapies.
The clinical heterogeneity of ME/CFS presents challenges to diagnosis and treatment and necessitates collaborative efforts to generate robust findings.
This study leveraged gene and protein expression data from the mapMECFS data repository and the DecodeME Genome-Wide Association Study (GWAS) to assess consistent gene signatures across studies.
The mitochondrial genes MT-RNR1 and MT-RNR2 exhibited lower expression in ME/CFS cases in two studies. Combining this with increased expression of mitochondrial genes in platelets from another study, this supports mitochondrial dysregulation as having a role in ME/CFS.
Furthermore, ME/CFS-associated genes were mapped to compounds in drug databases as possible treatments for further investigation. In muscle gene expression data, 107 approved compounds target 26 genes with functions relevant to mitochondrial support and immunomodulators.
From the DecodeME GWAS, 83 approved compounds target 24 genes with functions related to energy metabolism and mitochondrial function. Though little consistency in specific genes was observed across studies, which highlights the need for larger studies, mitochondrial dysfunction in ME/CFS cases was evident across studies.
Source: International Journal of Molecular Sciences, open access
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A chronobiology-based protocol for multi-omic mapping of menstrual cycle and diurnal rhythms in ME/CFS and long COVID Gepubliceerd op 11 maart 2026
Thomas, Huang, Schneider-Futschik, Pollack, Caspi Tal, Fineberg, Gurvich, Pretorius, Bergquist & Armstrong
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are debilitating multisystem illnesses with overlapping symptoms and poorly understood mechanisms.
Female sex is a major risk factor, and preliminary evidence links sex hormones and other fluctuating endocrine hormones, including cortisol, aldosterone, and DHEA, to these conditions. However, existing studies have not comprehensively captured diurnal, infradian, and circadian biorhythms, leaving critical gaps in understanding.
The MELLOW study (ME/CFS + Long COVID Longitudinal Omics and Women’s Health) is a prospective, chronobiology-based study of reproductive-aged women with ME/CFS, long COVID, and healthy controls. It integrates menstrual-phase and diurnal sampling with multi-omics profiling (genomics, proteomics, metabolomics, lipidomics, steroidomics), physiological monitoring, and symptom tracking.
By accounting for natural and disrupted biorhythms, MELLOW will map temporal links between hormonal, molecular, physiological, and symptom dynamics, improving biomarker reproducibility and clarifying endocrine network disruption underlying ME/CFS, long COVID, and women’s health more broadly.
Source: mpj/women’s health, open access
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The potential causes of myasthenia and fasciculations in severely ill ME/CFS patients: the role of disturbed electrophysiology Gepubliceerd op 10 maart 2026
Klaus J. Wirth & Jürgen M. Steinacker
Abstract
Patients with severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are bedridden and suffer from hypersensitivities to light and noise, severe orthostatic intolerance reducing cerebral blood flow, and skeletal muscle symptoms, including loss of force, fatigue, pain, fasciculations, and cramps.
Because neurological investigations exclude neuronal causes of myasthenia, we hypothesize a muscular pathomechanism. In previous articles, we considered insufficient activity of the Na+/K+-ATPase to be the main cause of mitochondrial damage via high intracellular sodium that reverses the transport mode of the sodium-calcium-exchanger to import calcium, causing calcium overload.
Low Na+/K+-ATPase activity also causes sarcolemmal depolarization, leading to less effective action potential propagation and loss of force.
Depolarization brings the membrane potential closer to the threshold potential, causing hyperexcitability that explains fasciculations and cramps. These increase sodium influx during excitation to further increase the workload of Na+/K+-ATPase.
Thereby, depolarization causes further depolarization. Higher intracellular sodium favors calcium overload and mitochondrial damage, which lowers the energy supply of Na+/K+-ATPase and increases the reactive oxygen species, further inhibiting Na+/K+-ATPase. The muscle is in a state of depolarization even at rest.
Depolarization and mitochondrial damage reinforce each other. Thus, dysfunction of Na+/K+-ATPase as a single mechanism can explain the different skeletal muscle symptoms of severely ill ME/CFS patients, comprising loss of force, fatigue, and fasciculations.
Source: Frontiers in Physiology, open access
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Evidence of White Matter Neuroinflammation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Diffusion-Based Neuroinflammation Imaging Study Gepubliceerd op 16 maart 2026
Yu, Kothe, Kwiatek, Del Fante, Bonner, Calhoun, Shan
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder with suspected neuroinflammatory pathophysiology. However, previous diffusion tensor imaging (DTI) studies have reported inconsistent white matter abnormalities in ME/CFS, and specific white matter inflammatory changes remain poorly characterised.
This study employed an advanced diffusion-based neuroinflammation imaging (NII) model to investigate white matter neuroinflammation in ME/CFS. Diffusion MRI data from 67 ME/CFS patients (median age, 38; and 54 women) and 67 rigorously matched healthy controls (HCs) (median age 38; and 52 women) were analysed.
Seven NII-derived metrics were computed: hindered water ratio (NII-HR), restricted fraction (NII-RF), fibre fraction (NII-FF), axial diffusivity (NII-AD), radial diffusivity (NII-RD), mean diffusivity (NII-MD) and fractional anisotropy (NII-FA).
Conventional DTI metrics were also calculated. Tract-based spatial statistics were used to perform voxel-wise group comparisons, and multiple regression analysis was conducted to examine the relationship between NII/DTI metrics and clinical measures of mental health, physical health, sleep quality, disability, disease severity and disease duration.
Compared to HCs, ME/CFS patients exhibited widespread white matter abnormalities, including significantly lower NII-HR and NII-RF, and significantly higher NII-FF, NII-AD, NII-MD and NII-FA across association, commissural and projection fibres. Additionally, some regions showed decreased NII-AD and NII-MD in ME/CFS.
Lower NII-RF, NII-AD and NII-MD in ME/CFS were significantly associated with worse mental health, while lower NII-RF was also associated with a higher level of disability.
Among ME/CFS patients, higher NII-FF was associated with lower disease severity. Conventional DTI showed minimal group differences and no significant clinical associations.
This study provides in vivo evidence of white matter neuroinflammation in ME/CFS, characterised by cerebral edema (reduced NII-HR), cellular infiltration (reduced NII-RF) and axonal reorganisation
(increased NII-FF). This suggests NII-derived indices may serve as sensitive biomarkers for neuroinflammation in ME/CFS.
Source: Human Brain Mapping, open access
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Outcomes of ME/CFS following infectious mononucleosis: seven-year follow-up of a prospective study Gepubliceerd op 17 maart 2026 Jason, Furst, Worth & Katz
Abstract
Background
Many individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) report experiencing an infectious illness prior to disease onset. Approximately 30% of cases are linked to Epstein-Barr virus (EBV) infection resulting in Infectious Mononucleosis (IM).
Methods
We examined the progression of ME/CFS following IM among a cohort of college students who were recruited before they developed the infection. This sample represented a socioeconomically and ethnically diverse population of young adults who were monitored over a 7-year period.
Assessments of health status, psychological functioning, and blood biomarkers were conducted at four time points: (1) baseline, when participants were healthy and at least 6 weeks from IM onset; (2) within 6 weeks of IM diagnosis; (3) 6 months post-IM, when participants had either recovered or met criteria for ME/CFS; and (4) the 7-year follow-up.
Results
At follow-up, 81% of participants who had initially presented with severe ME/CFS continued to fulfill diagnostic criteria. In contrast, only about one-third of those with moderate or lingering symptoms at 6 months still had ME/CFS 7 years later.
Conclusion
These findings indicate that ME/CFS following IM tends to persist over the long term, particularly among those whose illness was more severe at onset.
Source: Frontiers in Medicine, open access
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Perioperative outcomes in patients with myalgic encephalomyelitis/chronic fatigue syndrome undergoing general anesthesia: a retrospective matched-pair study
Please note that as a preprint, it is yet to be peer reviewed.
Felix M. Steinkirchner, Christina K. Kaufmann, View ORCID ProfileRichard F. Kraus, Maximilian Käss, View ORCID ProfileElisabeth Schieffer, View ORCID ProfileBernhard M. Graf, View ORCID ProfileChristoph Lassen, View ORCID ProfileViktoria Kimmerling, View ORCID ProfileAlexander Dejaco
doi: https://doi.org/10.64898/2026.04.06.26348924
This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
Abstract
Background Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic multisystem disease characterized by profound fatigue, post-exertional malaise, cognitive impairment, and autonomic dysfunction. Its pathophysiology is incompletely understood and likely involves complex interactions between immune, autonomic, and metabolic dysregulation. Despite features with potential relevance for anesthesia and perioperative care, evidence to guide anesthetic management in individuals with ME/CFS remains limited. We therefore performed a retrospective matched-pair analysis to generate clinical data on perioperative responses and identify areas for future research.
Methods We conducted a retrospective matched-pair analysis at a single tertiary center. All patients with ME/CFS undergoing general anesthesia from 2015 to 2026 were identified using ICD-10-GM codes (G93.3 and U09.9) with additional manual verification and matched 1:1 to controls for comparison. Patients with confounding diagnoses or American Society of Anesthesiologists physical status above III were excluded. The analysis focused on intraoperative hemodynamic parameters, including baseline, post-induction, median, and lowest recorded systolic blood pressure and heart rate, as well as early postoperative outcomes in the post-anesthesia care unit (PACU), including maximum pain scores and requirement for rescue analgesia.
Results Out of 189 individuals identified through ICD-10 codes, 15 matched pairs were included after application of exclusion criteria. ME/CFS patients exhibited lower lowest recorded intraoperative systolic blood pressure (90.0 [82.5-95.0] mmHg in ME/CFS vs 100.0 [90.0-110.0] mmHg in controls, p = 0.044) as well as lower lowest heart rate (50 [40.0-57.5] bpm in ME/CFS vs 60 [50.0-65.0] bpm in controls, p = 0.012). Vasopressor use and fluid administration did not differ, and no episodes of severe hypotension or perioperative adverse events were observed. Postoperative pain was higher in ME/CFS, with higher maximum pain scores (NRS 5.0 [4.0-6.0] in ME/CFS vs 1.0 [0.0-4.0] in controls, p = 0.008) and more frequent opioid rescue analgesia (80% in ME/CFS vs 33% in controls, p = 0.039). Postoperative nausea or vomiting, oxygen supplementation, and PACU length of stay were similar between groups.
Conclusions General anesthesia appears hemodynamically well tolerated in individuals with ME/CFS. In contrast, postoperative pain burden is increased and may require tailored analgesic strategies. Post-exertional malaise, a key disease feature with potentially delayed onset and significant impact, was not captured in this study and remains an important target for future research. These hypothesis-generating findings highlight the need for prospective studies to optimize perioperative management and evaluate patient-relevant outcomes in ME/CFS.
Competing Interest Statement The authors have declared no competing interest.
Funding Statement This study was supported by the German Society for ME/CFS (DGMECFS). The funder had no role in study design, data collection, analysis, interpretation, or the decision to submit for publication.
Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
This study was approved by the Ethics Committee of the University of Regensburg (reference number: 25-4271-101). The requirement for informed consent was waived in accordance with institutional and national regulations due to the retrospective design and use of routinely collected, de-identified clinical data.
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes
I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes
Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
bioRxiv and medRxiv thank the following for their generous financial support:
The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The University of Edinburgh, University of Washington, and Vrije Universiteit Amsterdam.
Transl Med . 2025 Jul 7;23:748. doi: 10.1186/s12967-025-06829-0
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SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis
Bita Rostami-Afshari 1,2,3,4, Wesam Elremaly 1,3,4, Anita Franco 1,3,4, Mohamed Elbakry 1,3,4,5, Marie-Yvonne Akoume 1,3,4,6, Ines Boufaied 7, Atefeh Moezzi 1,2,3,4, Corinne Leveau 1,2,3,4, Pierre Rompré 8, Christian Godbout 9, Olav Mella 10, Øystein Fluge 10, Alain Moreau 1,2,3,4,11,✉
PMCID: PMC12236014 PMID: 40624584
This article has been corrected. See J Transl Med. 2025 Aug 14;23:911.
Abstract
Background
Sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B) is emerging as a potential biomarker and therapeutic target in myalgic encephalomyelitis (ME), a complex multisystem disorder characterized by immune dysfunction, metabolic disturbances, and persistent fatigue. This study investigates the role of SMPDL3B in ME pathophysiology and explores its clinical relevance.
Methods
A case–control study was conducted in two independent cohorts: a Canadian cohort (249 ME patients, 63 controls) and a Norwegian replication cohort (141 ME patients). Plasma and membrane-bound SMPDL3B levels were quantified using ELISA and flow cytometry. Gene expression of SMPDL3B and PLCXD1, encoding phosphatidylinositol-specific phospholipase C (PI-PLC), was analyzed by qPCR. The effects of dipeptidyl peptidase-4 (DPP-4) inhibitors—vildagliptin, saxagliptin, and linagliptin—on modulation of membrane-bound and soluble SMPDL3B were assessed in vitro by qPCR, flow cytometry and ELISA.
Results
ME patients exhibited significantly elevated plasma SMPDL3B levels, which correlated with symptom severity. Flow cytometry revealed a reduction in membrane-bound SMPDL3B in monocytes, accompanied by increased PLCXD1 expression and elevated plasma levels of PI-PLC and SMPDL3B. These findings suggest that immune dysregulation in ME may be linked to enhanced cleavage of membrane-bound SMPDL3B by PI-PLC. Sex-specific differences were observed, with female ME patients displaying higher plasma SMPDL3B levels, an effect influenced by estrogen. In vitro, estradiol upregulated SMPDL3B expression, indicating hormonal regulation. Vildagliptin and saxagliptin were tested for their potential to inhibit PI-PLC activity independently of their role as DPP-4 inhibitors, and restored membrane-bound SMPDL3B while reduced its soluble form.
Conclusions
SMPDL3B emerges as a key biomarker for ME severity and immune dysregulation, with its activity influenced by hormonal and PI-PLC regulation. The ability of vildagliptin and saxagliptin to preserve membrane-bound SMPDL3B and reduce its soluble form via PI-PLC inhibition suggests a novel therapeutic strategy. These findings warrant clinical trials to evaluate their potential in mitigating immune dysfunction and symptom burden in ME.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12967-025-06829-0.
Keywords: Myalgic encephalomyelitis (ME), Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3B), Phosphatidylinositol-specific phospholipase C (PI-PLC), Vildagliptin, Saxagliptin
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Health, labour market, and social service outcomes for people with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome on a health or disability related benefit: an Aotearoa | New Zealand nationwide cross-sectional study using the integrated data infrastructure
Research Open access Published: 24 April 2026 article number , (2026)
Cite this article You have full access to this open accessarticle
Nicholas Bowden, Keith McLeod, Francesca Anns, Fiona Charlton, Barry Taylor, Rosamund Vallings, Hien Vu & Warren Tate
We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.
Abstract
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating chronic condition characterised by persistent fatigue and multisystem symptoms, often leading to long-term disability and socioeconomic disadvantage. In Aotearoa New Zealand (NZ), little is known about the health, labour market, and social service outcomes of people with ME/CFS.
Methods
We conducted a nationwide cross-sectional study using the Integrated Data Infrastructure (IDI) to identify a cohort of working-age individuals (16–64 years) receiving a health or disability-related benefit with a recorded ME/CFS diagnosis. Outcomes were compared to propensity score-matched cohorts: (1) benefit recipients without ME/CFS, and (2) a general population not receiving any benefit. We examined sociodemographic characteristics, co-occurring conditions, health service utilisation, disability support use, employment and income, and benefit reliance.
Results
The study population included 1,902 individuals with ME/CFS. Compared to the general population, the ME/CFS cohort had significantly higher rates of emergency department visits (18.8% vs. 12.8%) and pharmaceutical use (32.8% vs. 14.2% for > 10 medications), and lower current employment (18.3% vs. 83.8%). Compared to other benefit recipients, those with ME/CFS had lower hospitalisation (11.2% vs. 20.9%) and disability support service use (1.6% vs. 7.2%), but higher rates of Supported Living Payment (64.7% vs. 49.0%) and long-term benefit receipt. The ME/CFS cohort was disproportionately female and European, with notable underrepresentation of Māori, Pacific, and Asian ethnic groups.
Conclusions
People with ME/CFS on a benefit in NZ, while only representative of a small fraction of those affected by ME/CFS, still face substantial health burdens, economic vulnerability, and limited access to appropriate supports. The findings highlight systemic policy exclusions that disadvantage individuals with chronic, fluctuating conditions. Improved diagnostic coding, inclusive eligibility criteria, and integrated, person-centred care models are urgently needed to address inequities and support this underserved population.
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Identification of novel reproducible combinatorial genetic risk factors for myalgic encephalomyelitis in the DecodeME patient cohort and commonalities with long COVID
J. M. Sardell, S. Das, M. Pearson, D. Kolobkov, A. R. Malinowski, L. M. Fullwood, M. Sanna, H. Baxter, K. McLellan, M. Natt, D. Lamirel, S. Chowdhury, M. A. Strivens & S. Gardner
We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.
Abstract Background
Myalgic encephalomyelitis (also known as ME/CFS or simply ME) has severely impacted the lives of tens of millions of people globally, but the disease currently has no accurate diagnostic tools or effective treatments. Identifying the biological causes of ME has proven challenging due to its wide range of symptoms and affected organs, and the lack of reproducible genetic associations across ME populations. This has prolonged misunderstanding, lack of awareness, and denial of the disease, further harming patients.
Methods
We used the PrecisionLife® combinatorial analytics platform to identify disease signatures (i.e., combinations of 1–4 SNP-genotypes) that are significantly enriched in two cohorts of ME participants from DecodeME relative to controls from UK Biobank (UKB). We tested whether the number of these signatures possessed by an individual is significantly associated with increased prevalence of ME in a third disjoint cohort of DecodeME participants. We characterized a number of drug repurposing opportunities for a set of candidate core genes whose disease signatures had the strongest association with ME and which were linked to different mechanisms. We then tested gene overlap between the ME signatures identified and previous studies in long COVID, using two independent approaches to explore these shared genetic commonalities.
Results
We identified 22,411 reproducible disease signatures, comprising combinations of 7,555 unique SNPs, that are consistently associated with increased prevalence of ME in three disjoint patient cohorts. The count of reproducible signatures was significantly associated with increased prevalence of ME (p = 4 × 10− 21), and participants with a top 10% signature count had an odds ratio of disease 1.64 times greater than participants with a bottom 10% signature count, confirming that these genetic signatures are associated with increased susceptibility for developing ME. These disease signatures map to 2,311 genes. We identified substantial overlap between the genes found by this combinatorial analysis and previous studies. We found that the 259 candidate core genes most strongly associated with ME are enriched in disease mechanisms including neurological dysregulation, inflammation, cellular stress responses and calcium signaling. We demonstrated that 76 out of 180 genes previously linked to long COVID in the UK Sano GOLD and the US All of Us cohorts are also significantly associated with ME in the DecodeME cohort. These findings allowed identification of many existing and novel drug repurposing opportunities, including candidates linked to several genes with shared etiology for long COVID.
Conclusion
These findings provide further evidence that ME is a complex multisystemic condition where the risk of developing the disease has a very clear genetic and biological basis. They give a substantially deeper level of insight into the genetic risk factors and mechanisms involved in ME. The discovery of so many multiply reproducible genetic associations implies that ME is highly polygenic, which has important consequences for its future study and the delivery of clinical care to patients. The striking overlap in genes and mechanisms between long COVID and ME suggests the potential for development of novel or repurposed drug therapies that could be used to successfully treat either condition. However, although they share significant genetic commonalities, long COVID and ME appear to be best considered as partially overlapping but different diseases.
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