Evidence of White Matter Neuroinflammation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Diffusion-Based Neuroinflammation Imaging Study

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: Yu, Q., K.Kothe, R. A.Kwiatek, et al. 2026. “Evidence of White Matter Neuroinflammation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Diffusion-Based Neuroinflammation Imaging Study.” Human Brain Mapping47, no. 4: e70505. https://doi.org/10.1002/hbm.70505. https://onlinelibrary.wiley.com/doi/full/10.1002/hbm.70505 (Full text)

Prevalence of Post-COVID Symptoms Across Variants of Concern and Follow-up Periods: A Systematic Review and Meta-Analysis

Abstract:

Objectives: The interaction between SARS-CoV-2 variants of concern (VoC) and post-COVID symptom duration remains unexplored. This is the first study to evaluate post-COVID prevalence stratified by VoC and follow-up periods.

Methods: Six databases were searched (12/2019-12/2024) for studies of adults with laboratory-confirmed SARS-CoV-2 and symptoms lasting ≥3 months. Data were stratified by VoC (Alpha through Omicron) and follow-up (<6 vs. ≥6 months) to estimate pooled prevalence using random-effects models.

Results: Pooled prevalence across 35 studies (n=159,000) was 28.5% (95% CI: 21.6-36.0), higher in pre-Omicron (35.5%) than Omicron (22.8%) eras (p=0.04). Symptoms persisted beyond six months in 29.9% of cases. Fatigue was the most prevalent symptom across all VoCs and follow-ups followed by brain fog, dyspnea, and sleep impairment. Pre-Omicron variants were linked to dyspnea and anosmia, while Omicron was associated with brain fog and paresthesia. Most symptoms showed no significant reduction beyond six months. Sleep problems were higher in early pre-Omicron cohorts but improved over time; conversely, palpitations and ocular manifestations increased in later pre-Omicron follow-ups.

Conclusions: Post-COVID condition remains a burden despite vaccination. Distinct symptomatology patterns across VoC and timelines highlight the need for tailored management strategies to mitigate long-term global impacts.

Source: Lugtu EJ, Iv DYP, Cabunoc MH, Bautista JL, Pleta FM, Ng JA, Shahid F, Carandang THDC, Lippi G, Henry BM, Fernández-de-Las-Peñas C, Notarte KI. Prevalence of Post-COVID Symptoms Across Variants of Concern and Follow-up Periods: A Systematic Review and Meta-Analysis. Int J Infect Dis. 2026 Mar 10:108522. doi: 10.1016/j.ijid.2026.108522. Epub ahead of print. PMID: 41819160. https://www.ijidonline.com/article/S1201-9712(26)00157-8/fulltext (Full text)

Molecular hydrogen as a treatment for ME/CFS: a mini-review of clinical evidence and mechanistic rationale

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem illness characterized by profound fatigue, post-exertional malaise, cognitive impairment, and autonomic dysfunction, yet it currently lacks FDA-approved treatments. Molecular hydrogen (H2), administered primarily as hydrogen-rich water (HRW), has emerged as a potential therapeutic candidate due to its selective antioxidant effects, anti-inflammatory activity, and support of mitochondrial and cellular homeostasis. These mechanisms align with several biological abnormalities implicated in ME/CFS, including oxidative stress, chronic inflammation, and impaired energy metabolism. This narrative mini-review summarizes mechanistic evidence relevant to ME/CFS and evaluates three developmental clinical studies of HRW in this population.

Although early trials are small and methodologically limited, moderate-dose HRW consumed over extended durations has demonstrated feasibility and preliminary benefits in reducing fatigue and improving physical function, with generally mild side effects. Overlapping findings in Long COVID further suggest potential applicability across related post-viral fatigue conditions. Key limitations include small sample sizes, reliance on self-report outcomes, and the absence of objective biomarkers.

Future research should prioritize larger, rigorously controlled trials incorporating remote biometric and biochemical assessments to clarify mechanisms of action and identify responsive subgroups. Overall, molecular hydrogen represents a promising, low-burden adjunctive therapy warranting further investigation in ME/CFS.

Source:Friedberg F and LeBaron TW (2026) Molecular hydrogen as a treatment for ME/CFS: a mini-review of clinical evidence and mechanistic rationale. Front. Med. 13:1760210. doi: 10.3389/fmed.2026.1760210 https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2026.1760210/full (Full text)

Dysregulated NK-cell gene expression defines the enduring symptoms of long COVID-19

Abstract:

Introduction: Long-term COVID-19 syndrome (LTCS) or “long COVID” is a debilitating post-viral condition affecting approximately 2%–8% of individuals after SARS-CoV-2 infection. It manifests typically ≥3 months post-infection with symptoms persisting for at least 2 months, including fatigue, pulmonary dysfunction, and cognitive impairment, in the absence of alternative diagnoses. The biological mechanisms underlying LTCS remain poorly defined, yet emerging evidence implicates immune dysregulation.

Methods: We profiled plasma antibodies and cytokines from healthy controls (HC, N = 66), convalescents (CONV, N = 24), and LTCS patients (N = 94), followed by multiparametric 14-color flow cytometry of PBMCs from HC (N = 9), CONV (N = 6), and LTCS (N = 23) participants. To gain mechanistic insight, we performed single-cell transcriptomic profiling (scRNA-seq) on PBMCs from HC (N = 8), CONV (N = 6), and LTCS (N = 32) individuals.

Results: LTCS patients exhibited elevated anti-SARS-CoV-2 IgG (spike S1/RBD/N) titers compared with HC, but displayed significantly reduced systemic cytokine levels, including IFN-γ, TNF-α, IL-6, and IL-10. Flow cytometry revealed marked depletion of CD56+CD16+ NK cells and CD56+CD3+ NKT cells, accompanied by altered T-cell activation states. scRNA-seq confirmed NK type I cell loss and uncovered broad transcriptional reprogramming with upregulation of PDCD4, CHD1, CXCR4, and SLC7A5 and downregulation of TGFBR3, RIPOR2, and MBNL1. Gene set enrichment analyses indicated activation of circadian and translational programs and suppression of olfactory receptor, neurotransmitter receptor, and GABA-gated ion-channel pathways. Functional assays validated reduced NK-cell inflammatory capacity in LTCS participants.

Discussion: LTCS is characterized by systemic cytokine attenuation and a quantitative and functional NK-cell deficit coupled to neurosensory pathway suppression. These findings identify NK cells as key sentinels of LTCS pathophysiology and highlight an NK-centric neuroimmune axis as a promising target for biomarker discovery and therapeutic intervention.

Source: Ray U, Schulze Selting A, Perera RP, Yang Z, Lysenkov V, Göpel S, Bitzer M, Salker MS, Ossowski S, Riess O, Casadei N and Singh Y (2026) Dysregulated NK-cell gene expression defines the enduring symptoms of long COVID-19. Front. Immunol. 17:1720551. doi: 10.3389/fimmu.2026.1720551 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1720551/full?media_id=3855960893360206425_63872469980&media_author_id=63872469980&ranking_info_token=GCBhMjBlODkzODk5NGI0NWIwYjM3MmUwYjkyNDUyYmY5YyWmsvQCJoKX3psNGBMzODU1OTYwODkzMzYwMjA2NDI1KANndG4A&utm_source=ig_text_feed_timeline (Full text)

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

Abstract:

Post-infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic disease with unresolved pathophysiology and limited diagnostic options. Extracellular vesicles (EVs) carry disease-specific protein and miRNA signatures and may enable improved disease profiling. We aimed to identify novel protein and miRNA markers as potential biomarkers in plasma EVs from female ME/CFS patients, including post-COVID-19 ME/CFS and post-infectious ME/CFS of other origins, compared with healthy controls.

EVs were isolated from plasma by size-exclusion chromatography and characterized for number, size, morphology, and surface marker expression. Flow cytometry showed that small EVs strongly expressed tetraspanins, with only minor differences between ME/CFS patients and healthy donors. Proteomic profiling of EVs from ME/CFS patients identified altered cargo proteins, including hemoglobin subunit alpha and insulin-like growth factor-binding protein acid labile subunit compared with healthy controls (n ≤ 10/cohort). Small RNA sequencing followed by qPCR revealed significant downregulation of hsa-let-7b-5p in EVs from post-COVID-19 ME/CFS patients (n = 12) versus healthy controls (n = 15). Reduced hsa-let-7b-5p expression correlated with impaired physical functioning and increased fatigue, pain, and immune activation.

These findings indicate that EV cargo differences, particularly hemoglobin subunit alpha and insulin-like growth factor-binding protein acid labile subunit, as well as hsa-let-7b-5p, represent promising candidates for ME/CFS diagnosis and patient stratification.

Source: Seifert M, Schäfers J, Douglas FF, Schwarzburg C, Boristowski D, Birke A, Klein O, Sotzny F, Rubarth K, Windzio L, Beez CM, Peters CK, Wittke K, Scheibenbogen C, Greco A. Extracellular Vesicle Protein and MiRNA Signatures as Biomarkers for Post-Infectious ME/CFS Patients. Int J Mol Sci. 2026 Feb 28;27(5):2314. doi: 10.3390/ijms27052314. PMID: 41828537. https://www.mdpi.com/1422-0067/27/5/2314 (Full text)

Clinical relevance of circulating blood microaggregates and reactivation of Epstein Barr Virus in long-term Post-CoVID syndrome patients

Abstract:

Chronic persistence of systemic symptoms after recovery from active CoVID-19 has become a significant disease burden, named post-CoVID syndrome. Among many pathophysiological hypotheses we focus on impaired hemostasis as well as reactivation of latent Epstein-Barr virus.

We now introduce a novel diagnostic morphological approach for visualizing microaggregates circulating in peripheral venous blood, which are large enough to impede capillary blood flow. In addition, secretion of interferon gamma by mononuclear leukocytes in response to peptides of Epstein-Barr virus is increased in these patients.

As a promising therapeutic approach, we provide retrospective data on the effect of anti-thrombotic and virostatic drugs, respectively. In a large number of patients, clinical improvement was observed after platelet inhibition, particularly when EBV was also treated with antiviral therapy.

Source: Wick N, Hermann M, Lisch C, Gerth R, Wick G, Untersmayr E, Marth T, Bachler M, Fries D. Clinical relevance of circulating blood microaggregates and reactivation of Epstein Barr Virus in long-term Post-CoVID syndrome patients. Sci Rep. 2026 Mar 8. doi: 10.1038/s41598-026-42952-8. Epub ahead of print. PMID: 41796205. https://www.nature.com/articles/s41598-026-42952-8 (Full text available as PDF file)

Outcomes of ME/CFS following infectious mononucleosis: seven-year follow-up of a prospective study

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: Jason LA, Furst J, Worth R and Katz BZ (2026) Outcomes of ME/CFS following infectious mononucleosis: seven-year follow-up of a prospective study. Front. Med. 13:1676628. doi: 10.3389/fmed.2026.1676628 https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2026.1676628/full (Full text)

ACHTSAM study protocol: outreach diagnostics and assessment of tolerability in severe ME/CFS-a pilot study

Abstract:

Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe, multisystem condition that often emerges after viral infections and affects physical and cognitive function. Severely affected patients are underrepresented in research due to immobility and exertional intolerance.

Methods: This is a prospective, non-interventional observational study investigating the feasibility and tolerability of home-based diagnostics in patients with severe and very severe ME/CFS. Phase 1 includes remote identification using validated questionnaires. Phase 2 involves home visits for physiological, cognitive and biological assessments. The primary outcome is feasibility; secondary outcomes include tolerability and methodological barriers.

Ethics/dissemination: The study protocol was approved by the Ethics Committee of the University of Freiburg (No. 25-1031-S1). Written informed consent is obtained from all participants. Results will be disseminated via peer-reviewed publications and patient support groups.

Trial registration number: DRKS00035231; FRKS005506.

Source: Fricke C, Deibert P, Maier P, Kern W, Krumnau O, Barsch F. ACHTSAM study protocol: outreach diagnostics and assessment of tolerability in severe ME/CFS-a pilot study. BMJ Open. 2026 Mar 6;16(3):e113095. doi: 10.1136/bmjopen-2025-113095. PMID: 41791789. https://bmjopen.bmj.com/content/16/3/e113095 (Full text)

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

Abstract:

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: Hoel A, Hoel F, Dyrstad SE, Chapola H, Rekeland IG, Risa K, Alme K, Sørland K, Brokstad KA, Marti HP, Mella O, Fluge Ø, Tronstad KJ. Charting the circulating proteome in ME/CFS using cross-system profiling to uncover mechanistic insights. Cell Rep Med. 2026 Mar 4:102647. doi: 10.1016/j.xcrm.2026.102647. Epub ahead of print. PMID: 41785863. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(26)00064-9?rss=yes (Full text)

A multiomics recovery factor predicts long COVID in the IMPACC study

Abstract:

BACKGROUND: Following SARS-CoV-2 infection, approximately 10%–35% of patients with COVID-19 experience long COVID (LC), in which debilitating symptoms persist for at least 3 months. Elucidating the biologic underpinnings of LC could identify therapeutic opportunities.

METHODS: We utilized machine learning methods on biologic analytes provided over 12 months after hospital discharge from more than 500 patients with COVID-19 in the IMPACC cohort to identify a multiomics “recovery factor,” trained on patient-reported physical function survey scores. Immune profiling data included PBMC transcriptomics, serum O-link and plasma proteomics, plasma metabolomics, and blood mass cytometry by time of flight (CyTOF) protein levels. Recovery factor scores were tested for association with LC, disease severity, clinical parameters, and immune subset frequencies. Enrichment analyses identified biologic pathways associated with recovery factor scores.

RESULTS: Participants with LC had lower recovery factor scores compared with recovered participants. Recovery factor scores predicted LC as early as hospital admission, irrespective of acute COVID-19 severity. Biologic characterization revealed increased inflammatory mediators, elevated signatures of heme metabolism, and decreased androgenic steroids as predictive and ongoing biomarkers of LC. Lower recovery factor scores were associated with reduced lymphocyte and increased myeloid cell frequencies. The observed signatures are consistent with persistent inflammation driving anemia and stress erythropoiesis as major biologic underpinnings of LC.

CONCLUSION: The multiomics recovery factor identifies patients at risk of LC early after SARS-CoV-2 infection and reveals LC biomarkers and potential treatment targets.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04378777.

FUNDING:

National Institute of Allergy and Infectious Diseases (NIAID), NIH (3U01AI167892-03S2, 3U01AI167892-01S2, 5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI057229-18, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07S1, 3U19AI089992-09, 3U19AI128913-03, and 5T32DA018926-1, 3U19AI1289130, U19AI128913-04S1, R01AI122220); NIH (UM1TR004528); and National Science Foundation (NSF) (DMS2310836).

Source: Gabernet G, Maciuch J, Gygi JP, Moore JF, Hoch A, Syphurs C, Chu T, Doni Jayavelu N, Corry DB, Kheradmand F, Baden LR, Sekaly RP, McComsey GA, Haddad EK, Cairns CB, Rouphael N, Fernandez-Sesma A, Simon V, Metcalf JP, Agudelo Higuita NI, Hough CL, Messer WB, Davis MM, Nadeau KC, Pulendran B, Kraft M, Bime C, Reed EF, Schaenman J, Erle DJ, Calfee CS, Atkinson MA, Brakenridge SC, Melamed E, Shaw AC, Hafler DA, Augustine AD, Becker PM, Ozonoff A, Bosinger SE, Eckalbar W, Maecker HT, Kim-Schulze S, Steen H, Krammer F, Westendorf K; IMPACC Network; Peters B, Fourati S, Altman MC, Levy O, Smolen KK, Montgomery RR, Diray-Arce J, Kleinstein SH, Guan L, Ehrlich LI. A multiomics recovery factor predicts long COVID in the IMPACC study. J Clin Invest. 2025 Sep 9;135(21):e193698. doi: 10.1172/JCI193698. PMID: 40924481; PMCID: PMC12582403. https://pmc.ncbi.nlm.nih.gov/articles/PMC12582403/ (Full text)