Tag: long covid vs ME/CFS

Evidence for transcriptomic changes impacting muscle contraction in patients with post-acute COVID-19 syndrome

Abstract:

Post-acute COVID-19 syndrome (PACS) overlaps with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) but, due to frequent muscle pain and exertional intolerance, neuromuscular disorders are often suspected. We report the results of a comprehensive neuromuscular evaluation in 27 PACS patients (22F/5M; median age 41 ys).

All patients developed chronic fatigue (>6 months), post-exertional malaise, and cognitive impairment, with muscle pain in 88% but no neuromuscular deficits at clinical examination. 18/27 patients were unable to work. All patients fulfilled established ME/CFS diagnostic criteria (CDC 1994, ICC 2011, Inst Medicine 2015, NICE 2021). Electrophysiological studies and CK levels were normal.

Brain 18FDG-PET/MRI (14/27) showed posterior hypometabolism in 8/14. Muscle biopsy (7/27) showed moderate dysimmune changes in 2/7. Exploratory transcriptomic analyses performed in muscle biopsies from PACS patients and pre-COVID controls unveiled in PACS differentially expressed genes in the cytokine and autophagy pathways.

Interestingly, other genes were also differentially expressed in pathways affecting actin, the cytoskeleton, and contraction. Indeed, we found upregulated genes involved in the troponin-tropomyosin complex, a key regulator of muscle contraction through calcium binding. We also found downregulated genes involved in the formation and stabilization of actin bundles at sarcomere Z discs and in mechanical signaling.

These findings indicate that PACS patients with prominent muscular symptoms do not exhibit overt neuromuscular involvement on standard investigations but may show subtle myopathic or dysimmune changes and central metabolic alterations. At the transcriptomic level, the data show an impact on key pathways involved in contraction. The overlap with ME/CFS highlights the importance of careful differential diagnosis and suggests a complex pathophysiology beyond a basic muscle disease.

Source: Gianmarco Severa, Rakel Altabe-Mellul, Alessio Rotini, Peggy Lafuste, Sarah Souvannanorath, Edoardo Malfatti, Emmanuel Itti, Hakim Ahmed-Belkacem, Fred Relaix, Francois Jerome Authier, 3.14P Evidence for transcriptomic changes impacting muscle contraction in patients with post-acute COVID-19 syndrome, Neuromuscular Disorders, Volume 67, Supplement 1, 2026, 106984, ISSN 0960-8966, https://doi.org/10.1016/j.nmd.2026.106984. https://www.sciencedirect.com/science/article/abs/pii/S0960896626006528

FreeSurfer-based amygdala subfield volumetry in long COVID and ME/CFS: clinical and immunological correlations

Abstract:

Background: Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) share debilitating symptoms and have been associated with limbic-system dysfunction. We investigated amygdala subfield volumes to identify disease-specific neuroanatomical features and their clinical and immunological correlates.

Methods: We prospectively examined 27 patients with long COVID, 38 patients with ME/CFS, and 47 healthy controls (HCs). Amygdala subfields were segmented using high-resolution 3-T MRI and FreeSurfer software. Group comparisons were performed using analysis of covariance, and partial correlations with clinical and immunological indices, including autoantibodies, plasmablasts, regulatory T cells (Tregs), and Eomesodermin-positive helper T cells (Eomes+ Th cells), were assessed.

Results: Patients with long COVID had nominally larger right cortical nucleus volumes than HCs (raw p = 0.040; Bonferroni-adjusted p = 0.119), whereas patients with ME/CFS had a nominally larger left paralaminar nucleus (raw p = 0.048; Bonferroni-adjusted p = 0.145). In long COVID, G-protein-coupled receptor (GPCR) autoantibodies were nominally negatively associated with right medial nucleus volume. In ME/CFS, performance status was nominally positively associated with the right basal nucleus, right paralaminar nucleus, and right whole amygdala, and plasmablasts were nominally positively associated with the right corticoamygdaloid transition area. No group difference or partial correlation remained significant after correction for multiple testing.

Conclusion: Although no finding survived correction for multiple testing, the exploratory results suggest that amygdala-related structural variation may be relevant to both long COVID and ME/CFS. The nominal, uncorrected within-group patterns centered on olfactory-related amygdala nuclei and GPCR autoantibodies in long COVID, and on amygdala structure, functional severity, and plasmablasts in ME/CFS; however, these patterns do not support a conclusion of between-group differences. These observations are hypothesis-generating and do not establish disease-specific mechanisms. Prespecified validation in larger longitudinal and independent cohorts is required.

Source: Kimura Y, Sato W, Shigemoto Y, Kagaya R, Hayakawa A, Kumazawa Y, Shin I, Amano K, Yamamura T, Sato N. FreeSurfer-based amygdala subfield volumetry in long COVID and ME/CFS: clinical and immunological correlations. Front Neurol. 2026 Sep 16;17:1913553. doi: 10.3389/fneur.2026.1913553. PMID: 42819213; PMCID: PMC13623709. https://pmc.ncbi.nlm.nih.gov/articles/PMC13623709/ (Full text)

A cardiometabolic perspective on post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID

Abstract:

Post-exertional malaise (PEM), the defining feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is increasingly recognized in individuals with Long COVID. Although traditionally viewed as symptom exacerbation and/or emergence of new symptoms following exertion, PEM may reflect disrupted coordination across interconnected physiological systems operating over distinct post-exertional timescales. Such disruption may result in altered post-exertional physiological trajectories that contribute to multisystem manifestations and potential cardiometabolic consequences.

This perspective outlines a conceptual approach for investigating PEM through longitudinal assessment of post-exertional physiological trajectories while considering disease severity and underlying cardiometabolic health, including obesity and type 2 diabetes. Integrating these dimensions may help contextualize post-exertional responses, inform future longitudinal cardiometabolic profiling, facilitate patient stratification, and provide a framework for future mechanistic and interventional studies in ME/CFS and Long COVID.

Source: Westermeier F, Pretorius E, Untersmayr E, Bertinat R, Sepúlveda N, Fisman E. A cardiometabolic perspective on post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID. Cardiovasc Diabetol. 2026 Aug 20;25(1):250. doi: 10.1186/s12933-026-03316-8. PMID: 42625219. https://link.springer.com/article/10.1186/s12933-026-03316-8 (Full text)

Microstructural alterations in brain tissue of ME/CFS and long COVID using diffusion tensor imaging and diffusion kurtosis imaging

Abstract:

Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and long COVID have overlapping symptoms, such as profound fatigue, cognitive impairment, post-exertional malaise, pain and sleep disturbances that are debilitating and reduce quality of life. While Magnetic Resonance Imaging (MRI) techniques, specifically Diffusion Tensor Imaging (DTI) and Diffusion Kurtosis Imaging (DKI), have been used to investigate brain tissue microstructure in ME/CFS or long COVID, no study has yet combined these modalities to directly compare tissue microstructural differences between people living with ME/CFS and long COVID.

Methods: We recruited 37 ME/CFS participants (Age: 43.56 ± 12.5), 19 long COVID participants (Age: 47.92 ± 13.3), and 27 healthy controls (Age: 37.9 ± 10.4). Data were acquired using a 3 Tesla (3T) Prisma MRI scanner. DTI and DKI metrics were determined using MRtrix v3.0.7 and Designer V2.0 software, respectively. Voxel-based statistical analysis of cohort differences was performed using the Statistical Parametric Mapping (SPM12) toolbox in MATLAB. Correlation analysis was performed between DTI, DKI metrics and clinical measures such as duration of illness, fatigue severity, SF36 domains and WHODAS domains.

Results: Compared with healthy controls, individuals with ME/CFS showed microstructural alterations in the cingulum, supplementary motor areas, and parts of the corpus callosum (all p < 0.05). Long COVID participants demonstrated microstructural alterations in regions including the fusiform and precentral gyrus and in major white matter tracks (all p < 0.05). Direct comparisons between ME/CFS and long COVID revealed difference in the left corona radiata (p = 0.001).

Conclusion: This study identifies distinct tissue microstructural alterations in ME/CFS and long COVID and offers a vital insight into the neuropathological basis of shared symptoms in both conditions.

Source: Singh TB, Marshall-Gradisnik S, Barnden L, Eaton-Fitch N, Huynh TH, Inderyas M, Thapaliya K. Microstructural alterations in brain tissue of ME/CFS and long COVID using diffusion tensor imaging and diffusion kurtosis imaging. Front Med (Lausanne). 2026 Jul 17;13:1824498. doi: 10.3389/fmed.2026.1824498. PMID: 42539798; PMCID: PMC13424405. https://pmc.ncbi.nlm.nih.gov/articles/PMC13424405/ (Full text)

Two-timepoint multidomain follow-up of post-COVID condition and ME/CFS: overlapping autonomic, small-fiber, and cognitive changes

Abstract:

Background: Post-COVID condition (PCC) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) show marked clinical overlap, suggesting a shared post-infectious pathophysiology. This study aims to characterize the longitudinal change of autonomic function, small-fiber integrity, cognitive performance, and clinical symptoms in PCC and ME/CFS, and to determine whether trajectories differ between diagnostic groups.

Methods: Thirty-eight participants (21 PCC, 17 ME/CFS) underwent two standardized evaluations separated by a median of 31 months. Assessments included comprehensive autonomic testing, small-fiber evaluation, and an extensive neuropsychological battery.

Results: ME/CFS showed longer disease duration than PCC at baseline (median 42 vs. 12 months), while the interval between evaluations was comparable (31 vs. 30 months). Baseline profiles were largely overlapping, although ME/CFS showed nominally higher QST warm detection thresholds (p = 0.034), greater autonomic symptom burden (p = 0.038), and lower hemodynamic scores (p = 0.019), none surviving FDR correction. Cross-domain analyses linked small-fiber symptoms with autonomic symptom burden (Rho = 0.65, pFDR = 0.002) and fatigue (Rho = 0.55, pFDR = 0.018), while fatigue was negatively associated with processing speed (Rho = – 0.57, pFDR = 0.004), attention (Rho = – 0.49, pFDR = 0.018), and executive function (Rho = – 0.44, pFDR = 0.047). Rank-transformed mixed-effects models identified FDR-corrected Time effects, with increases in CHEPs (pFDR < 0.001) and verbal memory (pFDR = 0.010), and decreases in processing speed (pFDR = 0.006) and QST cold thresholds (pFDR = 0.038).

Conclusions: PCC and ME/CFS showed broadly overlapping multidomain profiles, with particularly similar profiles at follow-up. This suggests that, among individuals with persistent symptoms, PCC may increasingly resemble longer-standing ME/CFS across autonomic, small-fiber/sensory, and cognitive domains. These findings are consistent with overlapping post-infectious mechanisms, but do not establish identical disease trajectories or definitive disease convergence.

Source: Azcue N, Barranco C, Tijero-Merino B, Acera M, Fernández-Valle T, Lafuente JV, Gabilondo I, Ruiz-Lopez M, Del Pino R, Gómez-Esteban JC. Two-timepoint multidomain follow-up of post-COVID condition and ME/CFS: overlapping autonomic, small-fiber, and cognitive changes. J Transl Med. 2026 Jun 12. doi: 10.1186/s12967-026-08321-9. Epub ahead of print. PMID: 42286686. https://link.springer.com/article/10.1186/s12967-026-08321-9 (Full study available as PDF file)

Dynamic microclot profiling: thromboelastography advances precision management in long COVID and myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) share overlapping symptoms, and emerging evidence implicates persistent fibrinoid microclots in their pathophysiology, contributing to impaired microcirculation. This review explores the role of microclots and evaluates thromboelastography (TEG) as a potential diagnostic tool.

A comprehensive literature review was conducted using major biomedical databases. Studies indicate microclots are prevalent in both conditions. Long COVID patients demonstrate a TEG profile of increased clot strength (maximum amplitude) and reduced fibrinolysis (LY30), suggesting a persistent hypercoagulable state. Despite its advantages in real-time assessment, TEG interpretation faces challenges from preanalytical variability and a lack of standardized protocols. Promising therapeutic trials, including anticoagulants (e.g., apixaban) and fibrinolytics (e.g., lumbrokinase), require further validation. Technological advancements like AI-driven TEG analysis and portable devices could improve diagnostic precision.

In conclusion, persistent microclots are a key pathophysiological feature. TEG provides a promising, novel approach for detecting coagulation abnormalities and could guide treatment, but requires standardization in future clinical trials. Future research should integrate multiomics biomarkers for precision therapeutics to improve patient outcomes.

Source: Saleem S, Hussain A, Haroon M, Raza A, Afzal U, Anwar MF, Imran S, Iqbal MU, Hajj F. Dynamic microclot profiling: thromboelastography advances precision management in long COVID and myalgic encephalomyelitis/chronic fatigue syndrome. Blood Coagul Fibrinolysis. 2026 Jun 11. doi: 10.1097/MBC.0000000000001439. Epub ahead of print. PMID: 42274123. https://pubmed.ncbi.nlm.nih.gov/42274123/

Comparative Gut Microbiome Alterations in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome & Long COVID-19 Syndrome

Abstract:

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.
Source: Donchev D, Nikolova R, Vaseva K, Taskov H, Murdjeva M, Maes M, Ivanov IN. Comparative Gut Microbiome Alterations in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID-19 Syndrome. Biomedicines. 2026; 14(6):1183. https://doi.org/10.3390/biomedicines14061183 https://www.mdpi.com/2227-9059/14/6/1183 (Full text available as PDF file)

Comprehensive Immunophenotyping of Monocytes and Dendritic Cells Suggests Distinct Pathophysiology in Chronic Fatigue Syndrome and Long COVID

Abstract:

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.

Source: Petrov S, Bozhkova M, Ivanovska M, Kalfova T, Dudova D, Todorova Y, Dimitrova R, Murdjeva M, Taskov H, Nikolova M, Maes M. Comprehensive Immunophenotyping of Monocytes and Dendritic Cells Suggests Distinct Pathophysiology in Chronic Fatigue Syndrome and Long COVID. Int J Mol Sci. 2026 May 17;27(10):4488. doi: 10.3390/ijms27104488. PMID: 42196466; PMCID: PMC13206834. https://pmc.ncbi.nlm.nih.gov/articles/PMC13206834/ (Full text)

Plasma Extracellular Vesicle Surface Marker Profiling Reveals Immune Cell-Associated Mitochondrial Membrane Potential Alterations in Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Long COVID (LC) is characterized by symptoms persisting at least 3 months after SARS-CoV-2 infection and affecting multiple organ systems. Diagnosis relies on subjective criteria without established biomarkers. Immune dysregulation and mitochondrial dysfunction are implicated in LC pathophysiology. Given clinical overlap with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), we investigated whether plasma extracellular vesicles (EVs) capture shared molecular signatures.

Methods: Plasma EVs from 125 individuals across pandemic-era and prepandemic cohorts were analyzed. The pandemic-era cohort included COVID-Recovered, LC with ME/CFS phenotype (LC-ME/CFS), and ME/CFS without infection (pan-ME/CFS). The prepandemic cohort included ME/CFS and matched controls. Extracellular vesicles were isolated using size-exclusion chromatography. Concentration and size were assessed by nanoparticle tracking analysis, and surface markers and mitochondrial membrane potential were evaluated by flow cytometry.

Results: Both pan-ME/CFS and LC-ME/CFS exhibited elevated EV concentrations compared with COVID-recovered controls after false discovery rate (FDR) correction (q = 0.0042 and 0.0024). Leukocyte-, monocyte/macrophage-, and platelet-derived EVs were increased, whereas B cell-derived EVs were reduced in both groups. Compared with controls, pan-ME/CFS demonstrated increased mitochondrial membrane potential in B cell-, monocyte/macrophage-, and NK cell-derived subsets after FDR correction, whereas no significant differences were observed in LC-ME/CFS. Prepandemic ME/CFS showed a nominal increase in leukocyte-derived EVs that did not persist after correction, whereas elevated mitochondrial membrane potential in B cell-derived EV subsets remained significant.

Conclusions: ME/CFS and LC-ME/CFS demonstrate partially overlapping immune cell-associated EV alterations. Mitochondrial membrane potential alterations within selected immune-derived EV subsets, particularly B cell-associated EVs, suggest immune-metabolic involvement. Plasma EV profiling may inform future biomarker development.

Source: Ikeda G, Koike-Ieki M, Inoue H, Dadhania AV, El Kamari V, Jagannathan P, Geng LN, Miglis MG, Shafer RW, Yang PC, Bonilla HF. Plasma Extracellular Vesicle Surface Marker Profiling Reveals Immune Cell-Associated Mitochondrial Membrane Potential Alterations in Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Open Forum Infect Dis. 2026 May 12;13(5):ofag209. doi: 10.1093/ofid/ofag209. PMID: 42131622; PMCID: PMC13166156. https://pmc.ncbi.nlm.nih.gov/articles/PMC13166156/ (Full text)

Involvement of autoantibodies against G protein-coupled receptors in post-COVID condition and Chronic Fatigue Syndrome

Abstract:

Post-COVID condition (PCC) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are chronic disorders marked by fatigue, autonomic dysfunction, and cognitive impairment. Autoantibodies (AAbs) targeting adrenergic and muscarinic receptors have been implicated in their pathophysiology. This study aimed to investigate the association between these AAbs, autonomic nervous system (ANS) function, and cognitive performance in PCC and ME/CFS.

We included 96 PCC patients, 59 ME/CFS patients, and 36 healthy controls (HCs). Plasma AAbs against α1, β1, β2 adrenergic and M1-M4 muscarinic receptors were measured via ELISA. ANS function was evaluated using COMPASS-31, Sudoscan, hemodynamic tests (deep breathing, Valsalva, tilt test), and heart rate variability. Cognitive domains assessed included attention, fluency, processing speed, memory, visuoconstruction, perception, and executive functions.

ME/CFS patients had significantly higher β2 adrenergic AAb titers than PCC and HCs (F₂,₁₈₆ = 3.15, p = 0.046). PCC patients showed more borderline/pathological M3 muscarinic AAb results compared to HCs. β2 AAb levels correlated with increased autonomic symptoms in PCC (r = 0.27, p = 0.048) and sympathovagal imbalance in ME/CFS (r = 0.45, p = 0.001). In ME/CFS, M1, M3, and M4 AAb titers positively correlated with verbal and working memory performance.

Distinct AAb profiles in PCC and ME/CFS suggest potential differences in immunological mechanisms. β2 adrenergic receptor AAbs were associated with measures of autonomic dysfunction in PCC patients, and with sympathovagal parameters in ME/CFS patients. Muscarinic AAbs were correlated with cognitive performance in ME/CFS, supporting a potential role of these autoantibodies in autonomic and cognitive dysfunction. These findings support further investigation of AAbs as biomarkers and therapeutic targets.

Source: Azcue N, Prada A, Del Pino R, Acera M, Fernández-Valle T, Ayo-Mentxakatorre N, Pérez-Concha T, Murueta-Goyena A, Lafuente JV, López de Munain A, Ruiz Irastorza G, Ribacoba L, Gabilondo I, Tijero-Merino B, Gómez-Esteban JC. Involvement of autoantibodies against G protein-coupled receptors in post-COVID condition and Chronic Fatigue Syndrome. Sci Rep. 2026 May 5. doi: 10.1038/s41598-026-49131-9. Epub ahead of print. PMID: 42082542. https://www.nature.com/articles/s41598-026-49131-9 (Full text available as PDF file)