Tag: long covid vs ME/CFS

Overlapping Post-COVID Conditions: A Case of Myalgic Encephalomyelitis and Postural Orthostatic Tachycardia Syndrome Triggered by Sequential Epstein-Barr Virus (EBV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infections

Abstract:

The rise in post-infectious syndromes following COVID-19, such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Postural Orthostatic Tachycardia Syndrome (POTS), has become increasingly common in clinical practice, representing an emerging clinical challenge. This case highlights a possible clinical scenario involving the interaction between sequential viral infections – such as the Epstein-Barr virus (EBV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) – in triggering overlapping chronic conditions. This report presents the case of a patient who developed ME/CFS and POTS following SARS-CoV-2 infection, with a prior history of EBV mononucleosis, and discusses the diagnostic, therapeutic, and pathophysiological implications.

A 48-year-old woman with a history of mononucleosis in childhood developed persistent and disabling symptoms after COVID-19 in January 2022. She presented with extreme fatigue, orthostatic intolerance, paresthesia, cognitive dysfunction, and multisystem symptoms. After extensive investigation, she was diagnosed with ME/CFS (early 2023) and POTS (later that year). Mast Cell Activation Syndrome (MCAS) was considered as a hypothesis during follow-up, but objective testing was not confirmatory. Management included pharmacological therapy (including low-dose naltrexone, duloxetine, and palmitoylethanolamide (PEA)), activity adjustments (pacing), and a multidisciplinary approach, with partial and fluctuating responses.

This case illustrates how viral infections such as EBV and SARS-CoV-2 may act as sequential triggers in an individual clinical trajectory compatible with the development of ME/CFS and POTS. The symptomatic overlap, the lack of readily available objective biomarkers in this patient, and the need for a predominantly clinical and functional diagnostic approach in her evaluation highlight the complexity of these conditions. This experience also underscores the importance of continued efforts in research, clinical training, and integrated care models to improve the management of patients presenting with post-COVID conditions (PCC).

Source: Mayrink Magalhães VR, Ribeiro Oliveira LA, Lourenço AJ, Ribeiro Camargos I, Da Silva LG, Filgueiras PS, De Souza Lima AE, Marques Contin SV, Costa M, Istilli P, Ferreira da Costa Gomes M, Pedretti CB, Correa PRL, Grenfell RF. Overlapping Post-COVID Conditions: A Case of Myalgic Encephalomyelitis and Postural Orthostatic Tachycardia Syndrome Triggered by Sequential Epstein-Barr Virus (EBV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infections. Cureus. 2026 Sep 24;18(9):e116844. doi: 10.7759/cureus.116844. PMID: 42927133; PMCID: PMC13695498. https://pmc.ncbi.nlm.nih.gov/articles/PMC13695498/ (Full text)

Explaining Fatigue and Post-Exertional Malaise in Long COVID and ME/CFS: From Skeletal Muscle To Exercise Immunology

Abstract:

The SARS-CoV-2 viral outbreak in 2020 resulted in a record number of global hospitalizations and deaths. Although most people recover from an initial COVID infection within 3 months, around 10% of people have symptoms that do not improve after 3 months, which is called long COVID. Other viruses and bacterial infections can also result in long-term symptoms, which is known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

One of the most common symptoms of long COVID or ME/CFS is post-exertional malaise, which is the worsening of symptoms or development of new symptoms after physical, mental or emotional stress. This can lead to patients leading less physically active lifestyles. Physical activity is known to be beneficial for overall health and wellbeing, mostly by increasing exercise capacity, which is a significant predictor in long-term health. Physical inactivity.

It is thought that many symptoms of long COVID and ME/CFS can be explained by lower physical activity of patients. However, people who are less physically active don’t experience post-exertional malaise, implying there are disease-specific changes. Many of the benefits that come from exercise come from a persons ability to adapt to an exercise session. Usually, exercise will create a short energy deficit, which then may result in small amounts of muscle damage. This then triggers a short-lived immune response, led first by neutrophils and macrophages, which result in activation of fibroadipogenic progenitor cells (FAP cells) and satellite cells (muscle stem cells). FAP cells and satellite cells communicate to repair damage to the muscle itself, while immune cells clear debris surrounding the muscle. In healthy situations, this creates a stronger, more resilient muscle. It is unknown whether these responses are still seen in long COVID or ME/CFS. The goal of this thesis then to 1) understand muscle changes in patients with long COVID and ME/CFS, 2) to better understand how these changes may relate to PEM, 3) to understand whether the muscle changes in patients are a result of physical inactivity.

Within the thesis, I find that patients with long COVID and ME/CFS have specific patterns of skeletal muscle that separate them from healthy individuals. This is highlighted by more fast-twitch fibre types, slow-twitch muscle atrophy, lower mitochondrial respiration that is separate from just mitochondrial loss, less metabolites related to oxidative capacity and antioxidation, less lipids that are required for cell membrane maintenance, and lower amounts of satellite cells and FAP cells.

Beyond this, I find that ME/CFS can be distinguished from long COVID by less capillaries, less slow-twitch fibres, less local immune cells, and lower amounts of several essential amino acids. As well, I find evidence that physical inactivity alone cannot explain long COVID and ME/CFS symptoms. Where all of long COVID, ME/CFS, and physical inactivity have lower whole-body aerobic capacity, physical inactivity causes a decrease in muscle fibre size, loss of mitochondria, increases in muscle lipotoxic lipids, and decreases in metabolites related to carnitine metabolism. These changes are not seen in either long COVID nor ME/CFS, and support the idea that long COVID and ME/CFS have disease specific muscle changes.

Overall, I find that the reduced whole-body capacity of long COVID and ME/CFS patients is not cause by physical inactivity, and is defined by reduced muscle oxidative ability. The lower amounts of local cells that would normally support exercise and damage responses are lower in both long COVID and ME/CFS, which partially explains the occurrence of PEM. This also suggests that patients experiencing PEM should not undertake normal rehabilitation, however it might be that more individually tailored, and severely monitored approaches may still be beneficial.
Source: Charlton, B. T. (2026). Explaining Fatigue and Post-Exertional Malaise in Long COVID and ME/CFS: From Skeletal Muscle To Exercise Immunology. [PhD-Thesis – Research and graduation internal, Vrije Universiteit Amsterdam]. https://doi.org/10.5463/thesis.1979 https://research.vu.nl/en/publications/explaining-fatigue-and-post-exertional-malaise-in-long-covid-and-/ https://research.vu.nl/ws/portalfiles/portal/517511531/aio01877%20braeden%20charltonfinal%20-%206acf4153820e1.pdf (Full text)

The Glymphatic–Meningeal Lymphatic System and Autophagy in ME/CFS and Long COVID: A Mechanistic Perspective

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Post-Acute Sequelae of SARS-CoV-2 infection (Long COVID) are complex multisystem disorders affecting 60–400 million individuals globally. They are considered post-infectious illnesses and share similar biological mechanisms, including immune dysregulation, orthostatic intolerance and cognitive dysfunction, highlighting a substantial overlap between the two conditions. Persistent fatigue, sleep dysfunction, post-exertional malaise and brain fog are among some of their most common and debilitating symptoms.
Despite extensive research, they remain incurable, with no effective treatments, or simple diagnostic tests. They are increasingly understood as heterogeneous, multisystem diseases, involving neurological symptoms, with varying severities and diverse underlying biological abnormalities. More recently, the possibility of glymphatic dysfunction and autophagy impairment have been proposed as parts of the mechanistic features of the pathophysiology of these conditions, which are discussed more fully in the present perspective.
With the glymphatic and meningeal lymphatic systems being operationally integrated, we will try to delineate how the metabolic waste removal mechanism afforded by this system may work together with autophagy to maintain brain homeostasis. We will provide some of the established mechanistic features of toxicity of misfolded proteins, explore their role in causing glymphatic dysfunction and impairing autophagy, and discuss the potential for therapeutic interventions.
Source: Nemat-Gorgani M, Jensen MA, Davis RW. The Glymphatic–Meningeal Lymphatic System and Autophagy in ME/CFS and Long COVID: A Mechanistic Perspective. International Journal of Molecular Sciences. 2026; 27(20):9351. https://doi.org/10.3390/ijms27209351 https://www.mdpi.com/1422-0067/27/20/9351 (Full text)

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)