Tag: 2026

Vitamin D in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome After COVID-19 or Vaccination: A Randomized Controlled Trial

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) can develop as post-vaccination syndrome (PVS) or Post-Acute Sequelae of SARS-CoV-2 infection (PASC). In our prior retrospective study, most patients with PVS who developed ME/CFS had vitamin D insufficiency or deficiency. We evaluated the efficacy of vitamin D replacement therapy guidance for ME/CFS symptom improvement in patients with vitamin D insufficiency or deficiency.

Methods: This open-label randomized controlled trial enrolled 91 participants with ME/CFS as PVS or PASC and serum 25(OH) vitamin D < 30 ng/mL across five clinical sites. Participants were randomized 1:1 to intervention (active vitamin D preparation plus vitamin D replacement therapy guidance: 25 μg daily supplementation, dietary counseling, sun exposure, and exercise) or control (active vitamin D preparation alone) for 12 weeks. The primary endpoint was the change in ME/CFS symptom count from screening to Week 12.

Results: Mean symptom change was -6.7 in the intervention group versus -1.2 in the control group (between-group difference -5.6; 95% CI: -7.2, -3.9; p < 0.001). Serum 25(OH) vitamin D improved from 18.6 to 27.1 ng/mL in the intervention group, while the control group showed a decreasing trend (between-group difference 10.2 ng/mL; 95% CI: 7.9, 12.5). Achievement of <8 symptoms (i.e., no longer meeting ME/CFS diagnostic criteria) was significantly higher in the intervention group, with 16 participants achieving this threshold compared to 1 in the control group (p < 0.001). Subgroup analyses showed consistent benefit in both PVS (n = 56) and PASC (n = 29) cohorts.

Conclusions: Vitamin D replacement therapy guidance significantly reduced ME/CFS symptoms along with improvement of serum 25(OH) vitamin D levels in patients with vitamin D insufficiency or deficiency who developed ME/CFS as PVS or PASC.

Source: Kodama S, Nakata M, Konishi N, Yoshino M, Fujisawa A, Naganuma M, Kobayashi Y, Hirai Y, Kitagawa A, Miyokawa M, Mishima R, Teramukai S, Fukushima M. Vitamin D in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome After COVID-19 or Vaccination: A Randomized Controlled Trial. Nutrients. 2026 Feb 3;18(3):521. doi: 10.3390/nu18030521. PMID: 41683343. https://www.mdpi.com/2072-6643/18/3/521 (Full text)

Potential application of brain-gut axis-based treatments in Long COVID and ME/CFS: a case-based systematic review

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID share clinical features including persistent fatigue, post-exertional malaise (PEM), and gastrointestinal (GI) dysfunction. Growing evidence implicates brain-gut axis dysregulation, characterized by dysbiosis, neuroinflammation within the central nervous system (CNS), increased intestinal permeability, and microbial translocation in their pathophysiology. However, therapeutic strategies targeting these pathways remain poorly defined.

Methods: We report a case of post-COVID ME/CFS successfully treated with electroacupuncture (EA)-based deep peroneal nerve stimulation which was employed to potentiate the vagal reflex. Fatigue trajectories were assessed using the Multidimensional Fatigue Inventory over 12 weeks. Based on the case, a systematic review of randomized controlled trials (RCTs) evaluating brain-gut axis-modulating interventions in ME/CFS or Long COVID was conducted.

Results: The patient exhibited a significant reduction in total fatigue, with early improvements in motivation and mental fatigue, and delayed improvement in physical fatigue following transient systemic symptom flares. Across included RCTs (n = 8, 790 participants), four investigated gut microbiome-modulating therapies and four employed nerve stimulation. Synbiotic and herbal interventions demonstrated benefits for fatigue or PEM, accompanied by alterations in specific bacterial populations or CNS metabolisms. Regarding nerve stimulation, transcranial direct current stimulation (tDCS) combined with exercise program improved fatigue, whereas standalone tDCS, auricular or peripheral TENS showed limited efficacy.

Conclusion: Brain-gut axis-based interventions may alleviate fatigue in ME/CFS and Long COVID by potentially modulating neuroinflammation, restoring microbiome balance, and improving epithelial barrier function. EA-based vagal stimulation represents a feasible option for patients with severe or treatment-resistant symptoms. Larger mechanistic studies and rigorously designed RCTs are needed to establish therapeutic targets and optimize intervention strategies.

Source: Kim DY, Youn J, Kang N, Cho SI, Ha IH. Potential application of brain-gut axis-based treatments in Long COVID and ME/CFS: a case-based systematic review. J Transl Med. 2026 Feb 10. doi: 10.1186/s12967-026-07807-w. Epub ahead of print. PMID: 41668172. https://link.springer.com/article/10.1186/s12967-026-07807-w (Full text available as PDF file)

Activation of the Lectin Pathway Drives Persistent Complement Dysregulation in Long COVID

Abstract:

Long COVID affects a substantial proportion of survivors of acute infection with severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2), who suffer a variety of symptoms that limit their quality of life and economic activity. Although the aetiology of long COVID is obscure, it appears to be a chronic inflammatory condition. Complement dysregulation is a prevalent feature of long COVID. Specifically, markers of classical, alternative, and terminal pathway activation are often elevated in patients with this condition.

Here, we used a sensitive assay for mannan-binding lectin-associated serine protease-2 (MASP-2)/C1Inh complexes to analyse lectin pathway activation in a previously characterised cohort of patients with long COVID (n = 159) and healthy convalescent individuals with no persistent symptoms after infection with SARS-CoV-2 (n = 76). The data were combined with those from the most predictive complement analytes identified previously to delineate potential biomarkers of long COVID. MASP-2/C1Inh complexes were significantly elevated in patients with long COVID (p = 0.0003). Generalised linear modelling further identified an optimal set of four markers, namely iC3b (alternative pathway), TCC (terminal pathway), MASP-2/C1Inh (lectin pathway), and the complement regulator properdin, which had a receiver operating characteristic predictive power of 0.796 (95% confidence interval = 0.664-0.905). Combinations of the classical pathway markers C4, C1q, and C1s/C1Inh were poorly predictive of long COVID.

These findings demonstrate that activation of the lectin complement pathway, which occurs upstream of the alternative and terminal pathways and can be inhibited therapeutically, is a salient feature of long COVID.

Source: Keat SBK, Khatri P, Ali YM, Arachchilage CH, Demopulos G, Baillie K, Miners KL, Ladell K, Jones SA, Davies HE, Price DA, Zelek WM, Morgan BP, Schwaeble WJ, Lynch NJ. Activation of the Lectin Pathway Drives Persistent Complement Dysregulation in Long COVID. Immunology. 2026 Jan 25. doi: 10.1111/imm.70110. Epub ahead of print. PMID: 41581925. https://onlinelibrary.wiley.com/doi/10.1111/imm.70110?af=R (Full text)

Indistinguishable mitochondrial phenotypes after exposure of healthy myoblasts to myalgic encephalomyelitis/chronic fatigue syndrome or control serum

Abstract:

Myalgic Encephalomyelitis (ME) / Chronic Fatigue Syndrome is a disease of uncertain aetiology that affects up to 400,000 individuals in the UK. Exposure of cultured cells to the sera of people with ME has been proposed to cause phenotypic changes in these cells in vitro when compared to sera from healthy controls. ME serum factors causing these changes could inform the development of diagnostic tests.

In this study, we performed a large-scale, pre-registered replication of an experiment from Fluge et al (2016) that reported an increase in maximal respiratory capacity in healthy myoblasts after treatment with serum from people with ME compared to serum from healthy controls.

We replicated the original experiment with a larger sample size, using sera from 67 people with ME and 53 controls to treat healthy cultured myoblasts, and generated results from over 1,700 mitochondrial stress tests performed with a Seahorse Bioanalyser. We observed no significant differences between treatment with ME or healthy control sera for our primary outcome of interest, oxygen consumption rate at maximal respiratory capacity.

Results from our study provide strong evidence against the hypothesis that ME blood factors differentially affect healthy myoblast mitochondrial phenotypes in vitro.

Source: Ryback AA, Hillier CB, Loureiro CM, Ponting CP, Dalton CF. Indistinguishable mitochondrial phenotypes after exposure of healthy myoblasts to myalgic encephalomyelitis/chronic fatigue syndrome or control serum. PLoS One. 2026 Feb 3;21(2):e0341334. doi: 10.1371/journal.pone.0341334. PMID: 41632778; PMCID: PMC12867253. https://pmc.ncbi.nlm.nih.gov/articles/PMC12867253/ (Full text)

Immunoglobulin G complexes from post-infectious ME/CFS, including post-COVID ME/CFS disrupt cellular energetics and alter inflammatory marker secretion

Highlights:

  • This study addresses a critical gap in understanding the role of autoimmunity in ME/CFS and PASC, two debilitating conditions with overlapping features and few effective treatments.
  • By demonstrating that IgG antibodies from ME/CFS patients can directly alter mitochondrial structure and function in human endothelial cells, specifically inducing mitochondrial fragmentation and metabolic reprogramming, this study provides a mechanistic link between autoantibodies and endothelial cell dysfunction.
  • Furthermore, proteomic analyses reveal unique immune complex signatures in ME/CFS and PASC, highlighting disease-specific IgG activity and supporting the idea of antibody-mediated metabolic dysregulation.
  • These insights are especially important because they establish a foundation for novel, targeted therapies that modulate antibody activity or protect mitochondrial function.

Abstract:

Background: Autoimmunity is a key clinical feature in both post-infectious Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Post-Acute Sequelae of COVID (PASC). Passive transfer of immunoglobulins from patients’ sera into mice induces some clinical features of PASC. However, the physiological effects of immunoglobulins on cellular alterations remain elusive. In this study, we tested the potential effects of immunoglobulins from ME/CFS patients on endothelial cell dysfunction.

Methods: We have isolated immunoglobulins from 106 individuals, including ME/CFS (n = 39), PCS-CFS (n = 15), MS (n = 20) patients, and healthy controls (n = 41). Protein composition of the isolated immune complexes was studied using mass spectrometry. The effect of isolated immune complexes on mitochondria was evaluated using confocal microscopy and a Seahorse XFe96 Extracellular Flux Analyzer, and the impact on inflammatory cytokine secretion was studied using a multiplex bead-based assay.

Results: Here, we demonstrate that IgG isolated from post-infectious ME/CFS patients selectively induces mitochondrial fragmentation in human endothelial cells and alters cellular energetics. This effect is lost upon cleavage of IgG into its Fab and Fc fragments. The digested Fab fragment from ME/CFS alone was able to alter the cellular energetics, resembling the effect of intact IgG. IgG from post-infectious ME/CFS, including post-COVID ME/CFS patients, induced distinct but separate cytokine secretion profiles in healthy PBMCs. Proteomics analysis of IgG-bound immune complexes revealed significant changes in immune complexes from ME/CFS patients, affecting extracellular matrix organization, whereas those from post-COVID ME/CFS patients pointed to alterations in hemostasis and blood clot regulation.

Conclusions: We demonstrate that IgGs from ME/CFS patients carry a chronic protective stress response that promotes mitochondrial adaptation via fragmentation, without altering mitochondrial ATP generation capacity in endothelial cells. Together, these results highlight a potential pathogenic role of IgG in post-infectious ME/CFS and point to novel therapeutic strategies targeting antibody-mediated metabolic dysregulation.

Source: Zheng Liu, Claudia Hollmann, Sharada Kalanidhi, Stephanie Lamer, Andreas Schlosser, Emils Edgars Basens, Georgy Nikolayshvili, Liba Sokolovska, Gabriela Riemekasten, Rebekka Rust, Judith Bellmann-Strobl, Friedemann Paul, Robert K. Naviaux, Zaiga Nora-Krukle, Franziska Sotzny, Carmen Scheibenbogen, Bhupesh K. Prusty. Immunoglobulin G complexes from post-infectious ME/CFS, including post-COVID ME/CFS disrupt cellular energetics and alter inflammatory marker secretion. Brain, Behavior, & Immunity – Health, Volume 52, 2026, 101187 ISSN 2666-3546,
https://doi.org/10.1016/j.bbih.2026.101187. https://www.sciencedirect.com/science/article/pii/S2666354626000207 (Full text)

From tradition to healing: the promise of acupuncture in managing chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a global public health problem affecting more than 65 million patients worldwide. The combined prevalence rate of CFS was 45.2% after 4 weeks in patients with novel coronavirus. Women, people over 40 years of age, and low-income people are susceptible groups, which have a significant impact on immune, nervous, endocrine, and other system functions.

First, from the perspective of epidemiology, this paper reviews the global epidemic trend of CFS, the differences in incidence and prevalence in different regions and populations, and risk factors such as heredity, infection, and childhood trauma. Second, the development of diagnostic techniques for CFS, including the evolution of clinical diagnostic criteria, research progress on immune and metabolic biomarkers, and the application of MRI and other imaging techniques in the diagnosis of CFS, is described, followed by an in-depth discussion of the genetics of CFS, including genetic susceptibility, genomic association, and familial aggregation. The pathophysiological mechanism of CFS was also analyzed, revealing abnormalities in NK cell function and immune factors in the immune system, dysfunction of the hypothalamic-pituitary-adrenal axis in the neuroendocrine system, and disorders of energy and lipid metabolism in the metabolic system.

This paper focuses on the study of acupuncture and moxibustion treatment of CFS, traces back to the historical application of acupuncture and moxibustion treatment of CFS, analyzes the relationship between the pathological mechanism of CFS and acupuncture and moxibustion intervention, expounds the theoretical basis of traditional Chinese medicine and modern mechanism of action of acupuncture and moxibustion treatment, and introduces the results of clinical trials, efficacy evaluation methods, and individualized treatment strategies for acupuncture and moxibustion treatment of CFS.

The innovative application of acupuncture techniques, such as electroacupuncture and acupoint catgut embedding, as well as the synergistic effect of acupuncture combined with traditional Chinese medicine and psychotherapy, are shown. At the same time, disputes and challenges in the efficacy, safety, and ethics of acupuncture treatment for CFS were pointed out, and future research directions, potential breakthroughs, and international cooperation opportunities of acupuncture treatment for CFS are discussed. This study provides a comprehensive reference for clinical treatment and research on CFS.

Source: Wang D, Yang T, Cui Y, Qu Y, Feng C, Sun Z, Zhang M. From tradition to healing: the promise of acupuncture in managing chronic fatigue syndrome. Front Med (Lausanne). 2026 Jan 20;12:1724290. doi: 10.3389/fmed.2025.1724290. PMID: 41641244; PMCID: PMC12865710. https://pmc.ncbi.nlm.nih.gov/articles/PMC12865710/ (Full text)

The fatigue spectrum in a community-based long haul COVID cohort

Abstract:

Introduction: In a Long Haul COVID referral clinic we describe the primary presentations of fatigue according to the CDC 2015 criteria for myalgic encephalitis/chronic fatigue syndrome (ME/CFS).

Methods: Between September 2021 and April 2022, 277 patients (61% women, 54 yrs: range 18-90 yrs) presented an average of 10 months after an acute COVID-19 infection (22% hospitalized). The clinical data were analyzed to conpare those with or without a primary or co-primary complaint of fatigue, subdivided as meeting ME/CFS criteria or not.

Results: 209 (73.5%) people (64% women) presented with fatigue. The Fatigue Severity Score was 5.33 (out 7) in those with 5.31 (SD1.54) vs. without 4.43 (SD1.65) a primary fatigue complaint (p > 0.001). Anxiety (58% vs. 38%, p < 0.02) and any psychiatric diagnosis (66% vs. 44%%, p < 0.01), but not depression itself, were overrepresented in those with Fatigue and ME/CFS. Those with prior managed sleep conditions did not increase risk for fatigue presentation. Of those with fatigue and an elevated FSS, 45/209 (21.9%) met criteria for ME/CFS. In those not meeting these criteria, associated ME/CFS symptoms were less consistent. Physical functioning by ECOG (1.88 (0.78) and 26% >2) did correlate with fatigue status. Depression was present (PHQ9 12.34 (5.95) with 63% >10) to a moderate or higher degree and was different with fatigue complaints. Brain fog (51.9%) was similar among the three categories, and correlated with FSS > 4, ECOG, and depression.

Conclusions: The fatigue phenotype in those presenting with it as a primary complaint comprises 21% meeting ME/CFS criteria and 79% which do not. In all the Long Haul COVID presentations. brain fog had separate, distinguishing features. Post-COVID fatigue is a spectrum which will confound clinical trials.

Source: Carter IV, May A, Hsieh IC, Torer J, Rosenberg D, Strohl KP. The fatigue spectrum in a community-based long haul COVID cohort. Sleep Breath. 2026 Jan 31;30(1):27. doi: 10.1007/s11325-025-03512-y. PMID: 41620575. https://link.springer.com/article/10.1007/s11325-025-03512-y (Full text)

ME/CFS and Long COVID Demonstrate Similar Bioenergetic Impairment and Recovery Failure on Two-Day Cardiopulmonary Exercise Testing

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long Covid are characterized by post-exertional malaise (PEM). Similarities in disease presentation suggest important commonalities in bioenergetic impairment, but this hypothesis has not been demonstrated. The metabolic underpinnings of each disease can be elucidated by two cardiopulmonary exercise tests (CPET) administered 24 hours apart. This retrospective study examined physiological responses on two-day CPET in people with ME/CFS (63 females and 21 males), Long Covid (52 females and 27 males), and matched non-disabled control participants (51 females and 20 males).

Data were analyzed within sexes using repeated measures analysis of variance. All participants met maximal effort criteria. There were significant reductions in oxygen consumption (O₂) and workload at the ventilatory anaerobic threshold (VAT) in both patient groups compared to non-disabled controls, with larger effect sizes at VAT than at peak exertion. Performance decrements were observed in both sexes.

Females exhibited more pronounced abnormalities and significant group by test effects. No significant differences were observed between patient groups. Severe disability based on impaired O₂ was prevalent in both patient groups. Hemodynamic and ventilatory measures were within normal ranges. ME/CFS and Long Covid both involve a functionally significant bioenergetic failure complicated by inadequate post-exertional recovery, which is similar between the conditions and unexplained by hemodynamic and ventilatory changes.

Findings support the utility of two-day CPET as an objective measure of PEM and functional impairment. Future studies may integrate mechanistic biomarkers with two-day CPET as trial endpoints and to establish likely responses to treatments for PEM.

Source: Todd Davenport, Staci Stevens, Jared Stevens et al. ME/CFS and Long COVID Demonstrate Similar Bioenergetic Impairment and Recovery Failure on Two-Day Cardiopulmonary Exercise Testing, 22 January 2026, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-8606329/v1] https://www.researchsquare.com/article/rs-8606329/v1 (Full text available as PDF file)

Microvascular Remodeling and Endothelial Dysfunction Across Post-COVID-19 and ME/CFS: Insights from the All Eyes on PCS Study

Abstract:

Background Post-viral diseases, including post-COVID-19 syndrome (PCS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), cause substantial long-term morbidity. Persistent cardiovascular (CV) risk after acute infection highlights the need for accessible tools to quantify microvascular health.

Methods All Eyes on PCS is a prospective, observational study investigating the retinal microcirculation using retinal vessel analysis (RVA). We compared RVA parameters in 102 PCS patients with 204 age- and sex-matched healthy controls (HC, matched from n = 303). Secondary matched analyses included never infected controls (NI, n = 96), recovered individuals (n = 102), PCS patients, and ME/CFS patients (n = 62). Laboratory variables, circulating markers of endothelial dysfunction (ED) and inflammation were compared between cohorts and their associations with RVA parameters were examined.

Results Compared with HC, PCS patients showed reduced venular flicker-induced dilation (3.7 ± 2.2% vs. 4.5 ± 2.7%, p = 0.005), narrow retinal arterioles (CRAE, 178.3 ± 15.5 µm vs. 183.3 ± 15.9 µm, p = 0.009), and lower arteriolar-to-venular ratio (0.83 ± 0.06 vs. 0.86 ± 0.07, p = 0.004). Findings persisted after adjustment for CV factors and remained evident in an extended secondary matched analysis across NI, recovered, and PCS patients. ME/CFS patients showed the most pronounced alterations. PCS severity correlated with lower AVR (r = -0.21, p = 0.037) and reduced arteriolar FID (r = -0.21, p = 0.039), particularly for neurocognitive symptoms. IL-6, ICAM-1 and VCAM-1 were elevated in PCS and ME/CFS and lower AVR correlated with inflammatory and iron-related markers (all adjusted p < 0.01). A combined model discriminated ME/CFS patients with good accuracy (AUC = 0.80).

Conclusions PCS is associated with persistent ED, most pronounced in ME/CFS patients and linked to symptom severity and ongoing inflammation. RVA may provide a noninvasive, readout of ED in post-viral syndromes.

Source: Timon Wallraven, Roman Günthner, Isabelle Lethen, Andrea Ribeiro, Maciej Lech, Frederike Cosima Oertel, Lukas G. Reeß, Bernhard Haller, Lukas Streese, Henner Hanssen, Michael Wunderle, Christoph Schmaderer. Microvascular Remodeling and Endothelial Dysfunction Across Post-COVID-19 and ME/CFS: Insights from the All Eyes on PCS Study. medRxiv 2026.01.22.26344661; doi: https://doi.org/10.64898/2026.01.22.26344661 https://www.medrxiv.org/content/10.64898/2026.01.22.26344661v1.full-text (Full text)

Associations between heart rate and physical activity in people with post-COVID-19 condition accounting for myalgic encephalomyelitis/chronic fatigue syndrome symptoms

Abstract:

Background: Tachycardia after mild activity or during rest is a common complaint among people with post-COVID-19 condition (PCC). Understanding the relationships between heart rate (HR) and physical activity (PA) in this population is crucial for developing appropriate rehabilitation protocols.

Objective: To investigate the associations between HR and PA in individuals with PCC, accounting for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) symptoms.

Design: Observational study.

Subjects: Sixteen adults with PCC (81% females, mean age 51 ± 12 years).

Methods: Participants were instructed to use 2 wearable devices (Garmin smartwatch and ActiGraph accelerometer) during waking hours over 4 days while performing daily activities. Average HR, percentage of time in tachycardia (time with HR > 100 bpm), and daily step count were assessed. The accelerometer counts per minute was used to categorize daily PA as sedentary, light intensity, and moderate-to-vigorous (MVPA).

Results: Participants wore the watches and accelerometers for a mean of 11.36 ± 2.60 and 12.51 ± 1.94 h per day, respectively. Average daily HR increased with increasing PA levels from sedentary to MVPA. However, the percentage of time in tachycardia was significantly lower during periods of MVPA compared with sedentary periods, even after adjusting for ME/CFS symptoms.

Conclusion: Individuals with PCC in our study experienced more tachycardia during periods of minimal physical activity compared with periods categorized as MVPA.

Source: Adodo R, Sarmento Da Nobrega A, Villar R, Webber SC, Sanchez-Ramirez DC. Associations between heart rate and physical activity in people with post-COVID-19 condition accounting for myalgic encephalomyelitis/chronic fatigue syndrome symptoms. J Rehabil Med. 2026 Jan 27;58:jrm43340. doi: 10.2340/jrm.v58.43340. PMID: 41601198. https://medicaljournalssweden.se/jrm/article/view/43340 (Full study available as PDF file)