Search Results (313)

Myalgic Encephalomyelitis (ME) is a chronic, multisystem disease characterized by systemic metabolic dysfunction and post-exertional malaise (PEM). In this study, we investigated the dysregulation of irisin, an exercise-induced myokine, and its potential antagonism by thrombospondin-1 (TSP-1). In a cross-sectional study (92 ME patients vs. 44 sedentary healthy controls), plasma irisin and TSP-1 levels were measured at baseline and after a 90 min mechanical stress challenge applied to induce PEM. ME patients exhibited significantly lower baseline irisin (p < 0.05) and a blunted exertional response (p < 0.05). Paradoxically, baseline irisin was an independent predictor of fatigue severity (β = 0.728, p = 0.018), with moderate-to-severe patients showing elevated levels of both irisin and TSP-1 (p < 0.05), suggesting a compensatory but ineffective response. Functional cellular dielectric spectroscopy indicated that TSP-1 inhibits irisin signaling in a concentration-dependent manner. Irisin signaling was markedly reduced by both αvβ5 blockade and HSP90α inhibition in this experimental system, consistent with a diminished ability to counteract TSP-1. Collectively, these findings support a model in which dysregulation of the irisin–TSP-1 axis contributes to metabolic dysfunction in ME. Elevated circulating TSP-1 levels are associated with symptom severity and are linked to impaired irisin signaling in an HSP90α- and αvβ5-dependent context. This interaction is consistent with defective metabolic adaptation and highlights a potential therapeutic target that warrants further validation to restore energy homeostasis. Full article

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a complex and debilitating disorder with limited treatment options. Camel milk (CM), known for its rich nutrients and anti-fatigue properties, may offer multi-target benefits for managing this condition. This study utilized an integrated approach combining metabolomics, network pharmacology, and animal experiments. CM metabolites were profiled and screened via ADME. Potential targets were predicted and intersected with CFS/ME-associated genes. Male BALB/c mice were subjected to chronic restraint and forced swimming to evaluate the effects of CM (1000 mg/kg) on behavioral, inflammatory, neuroendocrine, and metabolic parameters. CM administration significantly improved exhaustive swimming time and reduced immobility. It attenuated systemic inflammation (restored IL-10), normalized brain CREB and DRD2/OPRM1 mRNA, and enhanced skeletal muscle AKT/GLUT4 expression and glycogen levels. Camel milk alleviates CFS/ME symptoms through the multi-component, multi-target regulation of neuroendocrine, inflammatory, and energy metabolism pathways. These preclinical findings suggest that CM may have potential as a supportive nutritional intervention for alleviating chronic fatigue, pending validation in human studies. Full article

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID-19 syndrome (LC) show substantial clinical overlap, but direct comparative microbiome studies remain limited. Methods: In this cross-sectional study, we compared the fecal gut microbiome of patients with ME/CFS, LC, and healthy controls (HC) within a unified analytical framework using 16S rRNA profiling, differential abundance testing, and multivariate modeling. We also examined associations between microbiome variation and questionnaire-derived symptom-domain scores. Results: Alpha-diversity did not differ significantly among groups, whereas beta-diversity analyses showed small but significant disease-associated community differences with broad overlap between cohorts. Differential abundance analysis identified stronger signals in disease-versus-control contrasts than in the direct ME/CFS vs. LC contrast. Both ME/CFS and LC shared enrichment of Sutterella and depletion of Terrisporobacter and Lachnospiraceae relative to HC. Predicted functional profiling showed shared disease-versus-control changes in pathways related to anaerobic acetate/H₂ carbon flow, inositol/polyol degradation, phosphonate/C1-related metabolism, and lysine-derived fermentation. Regression analyses showed the strongest microbiome associations with fatigue-related and physiosomatic domains, while affective, cognitive, and gastrointestinal outcomes showed weaker signals. Conclusions: Overall, these findings support the presence of overlapping but non-identical gut microbiome alterations in ME/CFS and LC. The results provide a basis for future longitudinal and multi-omics studies aimed at clarifying the stability, functional relevance, and clinical utility of these microbial patterns. Full article

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long Coronavirus Disease 2019 (long COVID) are complex chronic conditions that often follow infectious triggers with overlapping clinical features but poorly defined pathophysiological relationships. This study aimed to identify disease-specific immune signatures through multiparameter immunophenotyping of monocytes, dendritic cells, and T cell subsets. A total of 207 participants were included (ME/CFS: n = 103; long COVID: n = 63; healthy controls: n = 41). Peripheral blood mononuclear cells were analyzed using multiparameter flow cytometry. Statistical analyses included non-parametric testing, age-adjusted Analysis of covariance (ANCOVA), correlation network analysis, and principal component analysis (PCA). Long COVID was characterized by increased M2-like monocyte polarization, elevated CD80 expression across monocyte subsets, expansion of dendritic cells, and reduced expression of activation markers, indicating persistent immune activation with features of immune exhaustion. In contrast, ME/CFS exhibited reduced costimulatory molecule expression, impaired C-C chemokine receptor type 7 (CCR7)-mediated immune cell trafficking, and less coordinated activation patterns, consistent with a state of immune suppression. Correlation network analysis revealed more extensive and integrated immune interactions in long COVID, while PCA identified distinct immunophenotypic components and enabled moderate discrimination between the two conditions. These findings demonstrate that ME/CFS and long COVID are characterized by distinct immune profiles, supporting the concept of divergent immunopathological mechanisms. The identified signatures may contribute to biomarker development and guide targeted therapeutic approaches. Full article

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system disease characterized by a multitude of symptoms across various organ systems. Diagnosis has relied heavily on heterogeneous clinical symptom presentation and evolving case definitions, with treatment focused on addressing presenting symptoms due to the paucity of validated biomarkers. Meanwhile, advances have been made in understanding the underlying pathophysiology through strong epidemiologic, clinical, and basic science studies. This narrative review synthesizes recent advances that are likely to drive a shift in understanding from symptom-based classification toward a molecularly defined understanding of the disease. This shift in understanding will likely provide the foundation for future research efforts focused on targeting diagnosis and treatment more effectively. Specifically, we reference the identification of rare genetic risk variants through the HEAL2 deep learning framework, the large-scale DecodeME genome-wide association study, and dynamic epigenetic markers of disease state. In addition, the findings revealed the downstream consequences of this genetic and epigenetic priming: chronic innate immune activation, CD8+ T cell exhaustion characterized by upregulation of the exhaustion-driving transcription factors Thymocyte Selection-Associated HMG Box (TOX) and Eomesodermin (EOMES), and a cellular energy crisis centered on mitochondrial dysfunction. Furthermore, results of recent studies have revealed sex-specific transcriptomic and proteomic signatures of maladaptive recovery. We also highlight the role of machine learning and artificial intelligence integrations in translating high-dimensional multi-omics data into actionable biological insights, including the identification of monocyte subsets via Positive Unlabeled Learning, circulating cell-free RNA diagnostic signatures, and integrated multi-modal disease models such as BioMapAI. The combination of these findings, which highlight multiple identifiable mechanisms of molecular activity, support the feasibility of molecular subtyping, precision diagnostics, and targeted therapeutic strategies for ME/CFS. Full article

Human endogenous retroviruses (HERVs) are potential driving forces of the pathophysiology of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), linking post-infectious immune dysfunction to chronic inflammation and immune and neurocognitive dysfunction that are hallmark features of ME/CFS. Accumulating evidence from related autoimmune diseases and cancers has shown that reactivated HERVs can contribute to disease pathogenesis by amplifying immune activation through viral protein-mediated innate sensing, long terminal repeat (LTR)-driven transcription, and disrupting epigenetic silencing. HERV signatures are therefore promising biomarkers for diagnosis, patient stratification for drug-repurposing trials, and therapy monitoring. Accumulating evidence suggests a possible correlation between HERV expression and ME/CFS symptom severity, alterations in immune phenotypes, function and inflammatory gene networks. Importantly, locus-specific HERV profiling is a promising approach for distinguishing ME/CFS from overlapping or co-morbid conditions and healthy controls. Furthermore, HERV-targeted antibodies, immune modulators, epigenetic and antiviral interventions offer promise as concomitant therapeutic strategies for ME/CFS. Additional research incorporating viromics and other-omics validation, functional assays, and HERV-stratified clinical trials is now needed to realise this potential and to transform ME/CFS from a symptom-based syndrome into a mechanism-driven, treatable condition. Full article

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and post-COVID-19 syndrome share a symptom profile, including severe fatigue, cognitive dysfunction, exertional intolerance, sleep disturbances, hypervigilance, and the paradoxical state of being “wired but tired.” A well-established finding is sympathetic hyperactivity with reduced vagal tone, typically interpreted as autonomic nervous system dysfunction. Emerging evidence, however, suggests a broader disturbance across multiple neurotransmitter systems. This paper reviews current knowledge on neurotransmitter systems implicated in ME/CFS and Long COVID, focusing on potential mechanisms of dysregulation and their roles in disease pathology and symptom generation, as well as implications for treatment. In addition to abnormalities of the noradrenergic system, disturbances in serotonergic, GABAergic, and glutamatergic signaling have been reported. Contributing factors may include autoimmunity, neuroinflammation, gut dysbiosis, epigenetic influences, and stressors such as orthostatic intolerance, metabolic strain, and pain. A shift favoring excitatory over inhibitory neurotransmission can lead to excessive neural activation, autonomic dysfunction, sensory hypersensitivities, sleep disturbances, and cognitive impairment. Reduced GABAergic tone combined with increased glutamatergic and noradrenergic activity may elevate skeletal muscle tone, contributing to calcium overload, mitochondrial dysfunction, exertional intolerance, and post-exertional malaise. Various pharmacological treatments may partially rebalance these neurotransmitter systems, but limited efficacy highlights the need for systematic investigation and individualized strategies. Full article

Background: Post-exertional malaise (PEM), which is the cardinal feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is also reported in a proportion of patients with post-COVID-19 syndrome (PCS). Our objective was to identify determinants that may be linked to the emergence of PEM in PCS patients. Methods: Patients fulfilling the World Health Organization definition for PCS who attended the post-COVID unit of the Internal Medicine Department of Angers University Hospital, France, between June 2020 and December 2023 were included retrospectively. Their medical records were reviewed to extract information on COVID-19 infection history, characteristics of post-exertional malaise (PEM), fatigue severity, and relevant epidemiological variables. Results: The study included 220 patients, grouped according to whether post-exertional malaise was present (PCS/PEM+) or absent (PCS/PEM–). PEM was observed in 26.4% of patients and was significantly linked to earlier COVID onset in 2020/2021 (OR 5.68 (95% CI: 1.66–19.45), p = 0.006), as well as higher fatigue levels (OR 2.07 (95% CI: 1.22–3.50), p = 0.007). Conclusions: Patients who contracted COVID-19 during the pre-Omicron period reported PEM more frequently than those infected in later waves. This observation could reflect differences in viral characteristics following the emergence of the Omicron variant; however, alternative explanations—such as increasing vaccination coverage, accumulating post-infectious immunity, or other unmeasured factors—cannot be ruled out. Based on the observed link between PEM and symptom severity, PCS patients should be systematically assessed for the presence of PEM. Full article

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder, characterized by symptoms such as post-exertional malaise (PEM) and cognitive impairments. This study assessed reaction time (RT) metrics in three-dimensional (3D) visual tasks with the aim of objectively quantifying the cognitive impairments in ME/CFS patients compared to controls. Methods: A total of 120 participants (60 ME/CFS patients and 60 controls) were recruited at the Department of Ophthalmology, Universität of Erlangen-Nürnberg. RT was assessed using a virtual reality–oculomotor test system, presenting 3D stimuli at three disparity levels (275″, 550″, and 1100″) within three gaming repetitions (R1, R2, and R3). Mixed-effects models were used to evaluate group differences, with age and gender as covariates. Pairwise contrasts were calculated to assess changes across repetitions. Fatigue self-assessments were recorded by validated questionnaires, (FACIT Fatigue Scale, Chalder Fatigue Scale, Bell Score and Health Assessment Questionnaire), and their correlation with RT metrics was portrayed using a Spearman correlation matrix. Results: Estimated means (EM-means) for RT were significantly prolonged in ME/CFS patients compared to controls at disparity 275″ (1969 ms vs. 1384 ms; p = 0.0001), 550″ (1409 vs. 1071 ms; p = 0.0012) and 1100″ (1126 ms vs. 891 ms; p = 0.00223). Age was a significant covariate (p < 0.001), while gender showed no effect. Both groups demonstrated improvements in RT over repetitions; however, ME/CFS patients showed a significantly lower improvement compared to controls, reaching significance in R3 (p = 0.0042). RT metrics did not correlate with patients’ self-assessment scores. Conclusions: ME/CFS patients showed consistently slower RTs compared to controls, particularly in later, easier gaming repetitions, potentially reflecting the impact of fatigue. Full article

Despite the increasing prevalence and median severity of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), medical education on the disease is scant, leading to a diagnostic crisis in which the majority of people with ME/CFS are undiagnosed. We created a care process algorithm in AskMayoExpert accessible to all Mayo Clinic medical providers as a source for information on diagnosis and management of ME/CFS. To evaluate whether the algorithm was associated with improved diagnostic accuracy, we compared concordance before versus after the algorithm was introduced, where concordance was defined as agreement between an appropriately coded referral to Mayo Clinic’s Chronic Fatigue Specialty Clinic and the specialty clinic with an expert diagnosis of ME/CFS. Referrals to the Chronic Fatigue Specialty Clinic increased overall and were more likely to show concordance between specialist diagnosis and referral after the introduction of the ME/CFS AskMayoExpert algorithm. Particularly in diseases that are prevalent and poorly understood, a point-of-care clinical tool may offer just-in-time opportunities to improve diagnosis and management. Full article

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a high-burden, under-researched condition characterized by heterogeneous and fluctuating symptoms, including cognitive dysfunction commonly described by patients as “brain fog”. Despite growing interest in digital health technologies for symptom monitoring and personalized care, their application to the assessment and management of cognitive dysfunction in ME/CFS remains unclear. This descriptive review aimed to examine the current scientific evidence on digital approaches related to brain fog in ME/CFS. A structured literature search following PRISMA guidance was conducted to identify relevant studies. The available literature remains limited in scope and methodological maturity. During synthesizing across studies, three main functional domains of digital application become apparent: (1) digital tools for cognitive assessment, which have the strongest evidence base; (2) digital platforms for longitudinal monitoring; and (3) digitally mediated interventions or rehabilitation approaches, both of which are less well studied. Simultaneously, the findings suggest that patient-reported brain fog may represent a visible component of the broader ME/CFS disease spectrum and could serve as an early clinical indicator guiding diagnosis and management. Interpreting these symptoms within a biopsychosocial framework may facilitate understanding of the complex nature of the disease and optimize the use of digital technologies for monitoring cognitive dysfunction and supporting patient-centered care in ME/CFS. Full article

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, multisystemic disorder characterized by severe, persistent fatigue not alleviated by rest and worsened by minimal exertion, often accompanied by post-exertional malaise (PEM), unrefreshing sleep, cognitive dysfunction, and autonomic disturbances. Despite decades of research, its pathophysiology remains incompletely understood, and skeletal muscle involvement has only recently gained attention. This review aims to provide a historical and pathophysiological synthesis of ME/CFS, emphasizing the pivotal role of skeletal muscle in the onset and persistence of symptoms, and to integrate molecular, cellular, and pathophysiological evidence into a coherent explanatory framework. This is a narrative review of published literature (1990–2025) with critical integration of clinical, biochemical, and experimental data on oxidative stress, mitochondrial dysfunction, Excitation–Contraction (E-C coupling) dysregulation, and muscle secretome alterations in ME/CFS also in relation to post-viral syndromes (e.g., Long COVID). Evidence consistently points to mitochondrial oxidative stress, redox imbalance, impaired Ca²⁺ handling, and altered signaling pathways in skeletal muscle of patients with ME/CFS. Historical milestones show an evolution from psychogenic interpretations toward recognition of ME/CFS as a biological disorder with neuromuscular and metabolic underpinnings. ME/CFS can be interpreted as a skeletal muscle–metabolic disorder characterized by oxidative distress, mitochondrial dysfunction, and impaired energy regulation, leading to the clinical picture of exercise intolerance and post-exertional malaise. Integrating basic and clinical research through a translational approach provides the foundation for new diagnostic tools, targeted therapies, and biomarkers. Full article

Background/Objectives: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID (LC) are complex multisystem conditions with significant functional disability. Many patients experience symptoms of orthostatic intolerance, which can be captured in some cases as Orthostatic Hypotension (OH) or Postural orthostatic Tachycardia Syndrome (PoTS) on objective testing. Conservative treatments are recommended for first-line symptom management, but there is a lack of efficacy evidence. This study aims to assess the feasibility of an 8-week clinically supervised, personalised Dysautonomia Management Protocol (DMP) in a cohort of ME/CFS and LC patients with subjective and objective evidence of orthostatic intolerance (dysautonomia). Methods: ME/CFS and LC patients with objective dysautonomia on the 10 min active Lean Test (LT) were recruited to an 8-week DMP, with interventions introduced cumulatively every two weeks. Interventions included increasing daily fluid intake to 3 litres and salt intake to 10 g, pacing to avoid crashes and calf activation. Baseline and weekly data collection included the LT, Composite Autonomic Symptom Score questionnaire (COMPASS-31) and Yorkshire Rehabilitation Scale (YRS). Results: Sixteen participants completed the 8-week program, five discontinued during the program, and one was withdrawn following a severe crash. The COMPASS-31 improved by 7.7 points from week 1 to week 8 (p = 0.045), with a medium Cohen’s d effect size of 0.55. For the same period, there was a non-significant (p = 0.16) improvement in the YRS symptom severity score by 2 points. Comparing the final two weeks of the program with the first two weeks, mean heart rate during the LT decreased by 4.8 beats per minute (p = 0.032), with a medium Cohen’s d effect size of 0.44. Adherence to the interventions was highly variable, with none of the patients able to fully employ all four recommendations. Conclusions: The results suggest that targeted conservative interventions could influence autonomic function and symptom reduction. However, the magnitude of change was limited, and statistical significance might not necessarily relate to a clinically significant improvement in symptoms. Full article

Background: Orthostatic intolerance (OI) is an important factor affecting daily functional capacity in patients with long COVID. Traditionally, most OI symptoms have been attributed to exaggerated sympathetic nervous system activation associated with postural orthostatic tachycardia syndrome (POTS). Disequilibrium, also referred to as postural instability, may contribute to the development of OI in patients with long COVID. Methods: This study evaluated 32 patients with long COVID using neurological examinations and the active 10-min standing test. Disequilibrium was assessed using the Romberg and tandem gait tests. OI was defined as the inability to complete the active 10-min standing test. Results: Seven patients (22%) were diagnosed with OI. None of them had POTS, whereas six (86%) demonstrated disequilibrium, as detected by the Romberg and/or tandem gait test. POTS was observed in eight patients (25%), none of whom had OI. Disequilibrium was observed in nine patients (28%), six of whom (67%) had OI. Multiple regression analysis revealed that disequilibrium was positively associated with OI (r = 0.64, p < 0.001), whereas POTS was inversely associated (r = −0.38, p < 0.05). After 6 weeks of oral minocycline treatment in six patients and 2 weeks of repetitive transcranial magnetic stimulation therapy following minocycline in the other one patient, symptom amelioration was reported in six patients with OI. OI concomitant with disequilibrium recovered in five of the six patients treated and tested, although one patient who experienced symptom recovery failed to undergo the repeated standing test. Conclusions: Disequilibrium, rather than POTS, was the primary determinant of OI in patients with long COVID. Full article

Background and Objectives: Post-COVID-19 syndrome (PCS), characterized by persistent fatigue, can develop after a SARS-CoV-2 infection. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, post-infectious condition marked by severe fatigue and post-exertional malaise. This study aimed to determine the incidence and characteristics of PCS and ME/CFS in a cohort of hospital employees (HEs) with SARS-CoV-2 infections. Materials and Methods: All HEs who tested SARS-CoV-2-positive between March 2020 and May 2021 who later reported persistent fatigue were invited for an assessment from July to December 2022. Canadian Consensus Criteria were used for the diagnosis of ME/CFS. Assessments included the Montreal Cognitive Assessment (MoCA), and determination of coagulation factors, Epstein–Barr virus (EBV) antibodies and autoantibodies (AABs) against G-protein-coupled receptors (GPCRs). Results: Of the 221 HEs, 11.8% (95% confidence interval (CI95%) 7.8–16.8, 26/221) still reported persistent fatigue and 3.2% (CI95% 1.3–6.4, 7/221) were diagnosed with ME/CFS. In total, 19 HEs (median age 51.0 years, 89.4% female, 63.1% possible or confirmed nosocomial infection) participated in our assessment. In 42.1% (8/19) MoCA results were below normal. Laboratory values showed increased GPCR AABs in 66.6% (12/18), possible EBV reactivation in 86.7% (13/15) and coagulation parameters suggesting inflammatory processes in 38.9% (7/18). Conclusions: Our study was able to determine lower-bound incidences of PCS with fatigue and ME/CFS and demonstrated a diagnostic pathway for HEs following SARS-CoV-2 infections. Possible EBV reactivation, increased GPCR AABs and potential coagulation cascade activation may play a pathogenic role. Full article