Assessment and Incidence Determination of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Following a SARS-CoV-2 Infection in a Prospective Cohort of Hospital Employees

Abstract:

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.

Source: Tack M, Gruber R, Betting L, Herbrandt S, Wu S, Schlößer B, Häussermann P, Maegele M, Schlang G, Mattner F. Assessment and Incidence Determination of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Following a SARS-CoV-2 Infection in a Prospective Cohort of Hospital Employees. Medicina (Kaunas). 2026 Mar 3;62(3):480. doi: 10.3390/medicina62030480. PMID: 41901562. https://www.mdpi.com/1648-9144/62/3/480 (Full study)

Expert perspectives on Myalgic encephalomyelitis/chronic fatigue syndrome – Insights from the 3rd International Conference of the Charité Fatigue Center

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multisystemic disorder mostly triggered by viral infections, with core symptoms including post-exertional malaise (PEM), fatigue, pain, and cognitive dysfunction. Its prevalence has increased significantly in the context of the coronavirus disease 2019 (COVID-19) pandemic. Despite its severity and impact on patients’ quality of life, ME/CFS remains poorly understood.

On May 12 and 13, 2025, the 3rd International Conference hosted by the Charité Fatigue Center brought together nearly 200 researchers from various disciplines on-site, and around 3,700 participants online to discuss recent advances in ME/CFS research, diagnostics, clinical care, and therapeutic trials. The program featured 33 lectures by international experts on key topics such as post-COVID syndrome (PCS), care structures, and pathophysiological mechanisms including cardiovascular dysregulation, immune dysregulation, autoimmune mechanisms, and metabolic dysfunction.

In addition, results from clinical trials addressing disease mechanisms, including those specifically targeting autoantibodies, were presented. While public awareness and funding opportunities have increased in the wake of the pandemic and the emergence of PCS, ME/CFS remains severely underresearched. Sustained and adequately funded research efforts are urgently required to advance understanding, identify diagnostic markers, and develop targeted therapeutic interventions.

Source: Fehrer A, Windzio L, Schoening S, Steiner S, Aschenbrenner AC, Babel N, Behrends U, Bellmann-Strobl J, Cammà G, Cash A, Doehner W, den Dunnen J, Fluge Ø, Franke C, Hoffmann K, Kedor C, Kim L, Löhden W, Mella O, Mihatsch LL, Peluso MJ, Puta C, Putrino D, Ramoji A, Sato W, Sawitzki B, Schlieper G, Schoenfeld Y, Seifert M, Sigurdsson F, Slaghekke A, Sommerfelt K, Sotzny F, Stein E, Steinacker JM, Stingl M, Systrom DM, Tronstad KJ, Wirth K, Wörmann B, Wüst RCI, Yamamura T, Scheibenbogen C. Expert perspectives on Myalgic encephalomyelitis/chronic fatigue syndrome – Insights from the 3rd International Conference of the Charité Fatigue Center. Autoimmun Rev. 2026 Mar 25:104043. doi: 10.1016/j.autrev.2026.104043. Epub ahead of print. PMID: 41895458. https://www.sciencedirect.com/science/article/pii/S1568997226000571 (Full text)

Putting the PASC score to the test: Clinical vs. statistical accuracy in long COVID diagnosis

Abstract:

Objective: To validate the RECOVER Post-Acute Sequelae of SARS-CoV-2 infection (PASC) score in a cohort of patients who develop long COVID (LC) or fully recover while iteratively improving the tool’s sensitivity and specificity.

Methods: A cross-sectional study in 130 LC patients followed at LC clinics in Baltimore, MD, USA, who met the National Academies of Sciences, Engineering, and Medicine (NASEM) 2024 LC definition, and 60 SARS-CoV-2 exposed but fully recovered individuals. LC participants were required to have at least one neuropsychiatric symptom. Participants completed comprehensive surveys and questionnaires assessing symptoms based on published methods to determine PASC score. Using the NASEM 2024 LC definition as the “true” condition, we compared evaluation metrics for the RECOVER PASC score cutoff (PASC > 12) and the presence of individual/multiple symptoms. Evaluation metrics (e.g., sensitivity, specificity, F1) were calculated based on these classifications for the overall PASC score and symptom combinations.

Results: The LC cohort (n = 130) had a mean age of 47.2 years and was predominantly female (72%), White (79%), and well-educated (77% > 16 years). Controls (n = 60) were similar demographically. LC diagnosis and PASC scores were significantly associated (χ2 = 102.99, P < 0.001). The PASC score showed excellent specificity (100%) and positive predictive value (PPV; 100%) albeit limited sensitivity (80%), missing 20% of participants with LC. We found that loss of smell/taste, post-exertional malaise, or lack of sexual desire or capacity demonstrated 94% sensitivity, 92% specificity, and 96% PPV, 87% NPV, and an F1 score of 0.949.

Conclusion: Validation of the RECOVER PASC supports its utility and highlights the need for ongoing refinement of the LC definition. We call for national efforts to develop readily implementable clinical tools for LC diagnosis.

Source: Azola A, Dastgheyb RM, Easter R, Parker H, Della Penna C, Santiuste I, Schultz H, Ehrenspeck A, Veenhuis R, Rubin LH. Putting the PASC Score to the Test: Clinical vs. Statistical Accuracy in Long COVID Diagnosis. J Gen Intern Med. 2025 Nov 17. doi: 10.1007/s11606-025-10042-6. Epub ahead of print. PMID: 41249654. https://link.springer.com/article/10.1007/s11606-025-10042-6 (Full text)

Postural Orthostatic Tachycardia Syndrome, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID as Neuroimmune Disorders

Abstract:

Postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID are heterogeneous disorders with overlapping complex, multi-factorial and multi-systemic pathophysiology. POTS and ME/CFS are the most common phenotypes of Long COVID that can lead to significant disability and functional impairment.

The exact pathophysiologic mechanisms of these disorders alone or in combination are still being investigated, but important mechanistic factors have been identified, such as autonomic dysfunction, immune dysregulation, autoimmunity, mitochondrial dysfunction, cerebral hypoperfusion, and neuroinflammation.

To this end, we believe that these conditions should be viewed as neuroimmune disorders and should be included in the field of neuroimmunology, with its educational curriculum, training, and clinical care pathways. Including these disorders as part of neuroimmunology subspecialty is the key to advancing the science and clinical care of this underserved patient population with these complex and disabling conditions.

Source: Blitshteyn S, Doherty TA, Steinman L. Postural Orthostatic Tachycardia Syndrome, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID as Neuroimmune Disorders. Immunotargets Ther. 2026 Feb 2;15:581262. doi: 10.2147/ITT.S581262. PMID: 41859298; PMCID: PMC12998959. https://pmc.ncbi.nlm.nih.gov/articles/PMC12998959/ (Full text)

Incidence age is bimodal for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, with higher severity burden for early onset disease

Abstract:

Myalgic Encephalomyelitis, or Chronic Fatigue Syndrome (ME/CFS), is a disease of uncertain origin. Studies of Norwegian health records have suggested that ME/CFS incidence across age groups is bimodal–a characteristic that could provide insight into the aetiology of the disease. Here, we analysed survey data from over 9,000 respondents with ME/CFS from 10 European countries, and observe an early onset peak with a mean of 16.0 years old (standard deviation [sd]: 4.3) and a late onset peak at 36.6 years old (sd: 10.5).

Statistical support for multimodal onset age was evident in 7 of the 10 countries examined. Infection as a trigger for ME/CFS is 10 percentage points higher among early compared to late onset disease (P = 2.1 × 10−13). Early onset ME/CFS was associated with greater odds of being severely or very severely affected (OR = 2.15, 95% CI [1.84—2.51], p < 2 × 10−16). Those with first degree relatives with ME/CFS had greater odds of early than late onset ME/CFS (OR = 1.43, 95% CI [1.25—1.63], P = 4.4 × 10−07). We further validated our findings in a UK dataset where we replicated bimodal onset age and observed significantly greater odds of glandular fever/infectious mononucleosis as a trigger in early onset cases (OR = 2.32, 95% CI [1.99—2.71], P = 2.4 × 10−24).

Our findings suggest that incidence of ME/CFS peaks in adolescence and in early middle-age and that early onset ME/CFS is more common in those with affected relatives, more often triggered by infection, and associated with more severe disease.

Source: Simon J Mcgrath, Charles B Hillier, Joshua J Dibble, Trude Schei, Arild Angelsen, Audrey A Ryback, Incidence age is bimodal for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, with higher severity burden for early onset disease, Oxford Open Immunology, 2026;, iqag007, https://doi.org/10.1093/oxfimm/iqag007 https://academic.oup.com/ooim/advance-article/doi/10.1093/oxfimm/iqag007/8527015

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)