Tag: long covid vs ME/CFS

Facility-Measured Sleep Electroencephalographic Microstructures in Long COVID

Abstract:

Study objectives: Sleep electroencephalographic (EEG) microstructures are related to brain functions, providing a window into the unrefreshing, non-restorative sleep and daytime fatigue symptoms in long COVID (LC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We aim to characterize sleep EEG microstructural differences in individuals with LC and age-sex-matched healthy controls (HC), and also ME/CFS, using overnight in-lab facility-measured polysomnography (PSG).

Methods: 28 LC and 28 HC participants came from a single-center research study. 19 ME/CFS participants came from a single clinical center. Sleep EEG was processed to extract spectral band powers, spindles, slow oscillations (SO, 0.5-1 Hz), spindle-SO coupling, brain age index (BAI), alpha-delta patterns, and infraslow oscillation relative band power (ISO, 0.005-0.03 Hz).

Results: Compared to HC, LC had higher SO power during wake before sleep and REM sleep. In N2 and N3, LC showed a faster within-spindle frequency drop (chirp) and shorter SO peak duration in the frontal region. LC showed widespread, early spindle-SO coupling phase at SO trough for both fast and slow spindles, with early fast spindle-SO coupling associated with worse sleep quality. ME/CFS shared some differences with LC but had higher SO-uncoupled slow spindle densities in frontal and central regions, more alpha-delta patterns in the first half of the night, and widespread elevated ISO power in the slow sigma band (11-13 Hz).

Conclusions: These findings suggest that LC and ME/CFS are associated with plausibly pathological sleep EEG microstructure changes, illuminating the pathobiology of post-infectious processes on brain activity.

CLINICAL TRIAL INFORMATION

Trial 1: Sleep and Inflammatory Resolution Pathway, https://clinicaltrials.gov/study/NCT03377543, NCT03377543.

Trial 2: Pain in Long COVID-19: the Role of Sleep, https://clinicaltrials.gov/study/NCT05606211, NCT05606211.

Source: Sun H, Dang R, Li P, Xiao W, Scott-Sutherland J, Sassower KC, Westover MB, Felsenstein D, Thomas RJ, Haack M, Mullington JM. Facility-Measured Sleep Electroencephalographic Microstructures in Long COVID. Sleep. 2026 Apr 22:zsag090. doi: 10.1093/sleep/zsag090. Epub ahead of print. PMID: 42017829. https://pubmed.ncbi.nlm.nih.gov/42017829/

Comparing ME/CFS following mononucleosis with Long COVID

Abstract:

Objectives: Long COVID following SARS-CoV-2 and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) following infectious mononucleosis (IM) are examples of post-infectious chronic illnesses. Behavioral and pathophysiological underpinnings of both ME/CFS following IM and Long COVID are not well understood.

Methods: We studied ME/CFS development following IM in a diverse group of college students who were enrolled before the onset of IM. We categorized those meeting either moderate or severe ME/CFS criteria. We subsequently recruited a matched sample of those infected with SARS-CoV-2, some of whom recovered and others of whom developed Long COVID. We compared and contrasted ME/CFS and Long COVID following IM and SARS-CoV-2 infection in terms of somatic symptoms, coping strategies, depression and anxiety symptoms, and functional status.

Results: In general, the Long COVID group’s symptom burden was less than that of the Severe ME/CFS group but more than that of the Moderate ME/CFS group.

Discussion: These findings may allow investigators a better understanding of these post-viral illness pathophysiologies.

Source: Jason LA, Furst J, Katz BZ. Comparing ME/CFS following mononucleosis with Long COVID. Chronic Illn. 2026 Apr 15:17423953251347108. doi: 10.1177/17423953251347108. Epub ahead of print. PMID: 41984971. https://pubmed.ncbi.nlm.nih.gov/41984971/

Testing a Personalised Dysautonomia Management Protocol in Patients with Orthostatic Intolerance and a Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Long COVID

Abstract:

Background/Objectives: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID (LC) are complex multisystem conditions with significant functional disability. Many patients experience symptoms of orthostatic intolerance, which can be captured in some cases as Orthostatic Hypotension (OH) or Postural orthostatic Tachycardia Syndrome (PoTS) on objective testing. Conservative treatments are recommended for first-line symptom management, but there is a lack of efficacy evidence. This study aims to assess the feasibility of an 8-week clinically supervised, personalised Dysautonomia Management Protocol (DMP) in a cohort of ME/CFS and LC patients with subjective and objective evidence of orthostatic intolerance (dysautonomia).

Methods: ME/CFS and LC patients with objective dysautonomia on the 10 min active Lean Test (LT) were recruited to an 8-week DMP, with interventions introduced cumulatively every two weeks. Interventions included increasing daily fluid intake to 3 litres and salt intake to 10 g, pacing to avoid crashes and calf activation. Baseline and weekly data collection included the LT, Composite Autonomic Symptom Score questionnaire (COMPASS-31) and Yorkshire Rehabilitation Scale (YRS).

Results: Sixteen participants completed the 8-week program, five discontinued during the program, and one was withdrawn following a severe crash. The COMPASS-31 improved by 7.7 points from week 1 to week 8 (p = 0.045), with a medium Cohen’s d effect size of 0.55. For the same period, there was a non-significant (p = 0.16) improvement in the YRS symptom severity score by 2 points. Comparing the final two weeks of the program with the first two weeks, mean heart rate during the LT decreased by 4.8 beats per minute (p = 0.032), with a medium Cohen’s d effect size of 0.44. Adherence to the interventions was highly variable, with none of the patients able to fully employ all four recommendations.

Conclusions: The results suggest that targeted conservative interventions could influence autonomic function and symptom reduction. However, the magnitude of change was limited, and statistical significance might not necessarily relate to a clinically significant improvement in symptoms.

Source: Barr J, Marsden L, Dassanayake T, Almutairi N, McKeever V, Gaber T, Tarrant R, Godfrey B, Witton S, Sivan M. Testing a Personalised Dysautonomia Management Protocol in Patients with Orthostatic Intolerance and a Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Long COVID. J Clin Med. 2026 Mar 25;15(7):2510. doi: 10.3390/jcm15072510. PMID: 41976810. https://www.mdpi.com/2077-0383/15/7/2510 (Full text)

The Role of ME/CFS Phenotype in Outpatient Post-COVID Rehabilitation

Abstract:

Post-COVID-19 syndrome (PCS) shares core clinical features with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), particularly persistent fatigue and post-exertional malaise (PEM). However, the prevalence of ME/CFS among PCS rehabilitation outpatients remains unclear.

Medical records of 216 PCS rehabilitation outpatients (57% female; age 47.7±12.5; January 2021 to April 2022) were retrospectively reviewed. During rehabilitation and at a six-month telephone follow-up, ME/CFS was diagnosed using the Canadian Consensus Criteria (CCC). Demographics, body mass index (BMI), FAS, and 6MWT were compared between phenotype and non-phenotype groups using logistic regression, repeated measures ANOVA, and chi-square tests (α=0.05). Of 216 patients, 15 (93% female; age 40.6±10.7; BMI 25.7±5.6) met ME/CFS criteria, yielding a prevalence of 6.9%.

Compared with non-ME/CFS phenotype, ME/CFS phenotype patients were significantly younger (p=0.01) and predominantly female (p=0.003). Baseline FAS was significantly higher (35.8±6.4 vs. 27.8±8.6, p=0.001) and did not improve (Δ +1.3±4.5 vs. Δ -5.1±6.2, p<0.001). Baseline 6MWT was significantly lower (479±132 m vs. 540±96.1 m, p=0.02) and both groups improved over time, but between-group change was not significant (p=0.49).

Approximately 7% of PCS in outpatient rehabilitation exhibit ME/CFS, characterized by severe, persistent fatigue, female predominance, and attenuated functional gains. While the FAS is a practical screening tool, confirmation via CCC remains essential. Future studies should validate these findings and explore tailored rehabilitation strategies for patients with ME/CFS.

Source: Kaiserseder M, Prüfer F, Untersmayer-Elsenhuber E, Zwick RH. Welche Rolle spielt der ME/CFS-Phänotyp in einer ambulanten Post-COVID-Rehabilitation? [The Role of ME/CFS Phenotype in Outpatient Post-COVID Rehabilitation]. Pneumologie. 2026 Mar 30. German. doi: 10.1055/a-2823-6976. Epub ahead of print. PMID: 41911688. https://pubmed.ncbi.nlm.nih.gov/41911688/ (Full text available in German)

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)

ICD-10 Diagnoses prior to ME/CFS diagnosis in children and young people suggest potential early diagnostic indicators

Abstract:

To identify ICD-10-GM codes recorded in the year preceding a Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) diagnosis, we conducted a 1:5 matched case–control study using statutory health insurance data of 6–27-year-olds with ME/CFS (ICD-10-GM: G93.3, 2020–2022). Cases (n = 6,077) were matched 1:5 to controls by birth year, sex, and postal code. ICD-10-GM codes from the preceding year were analyzed using multivariable conditional logistic regression, reporting odds ratios (OR) and 95% confidence intervals. Most cases were female and aged 18–27 years.

Forty-four ICD-10-GM code classes were associated with increased and four with decreased odds, spanning 13 diagnostic chapters. Most associations were in chapters F (mental/behavioral disorders), R (respiratory diseases), and M (musculoskeletal disorders). Frequent conditions included fatigue, depression, pain disorders, and somatoform disorders (≥ 10% in cases; ORs 1.11–2.19. Rare diagnoses (≤ 1% prevalence), such as fibromyalgia (OR 2.08, 95% CI: 1.20–3.59) and mild cognitive impairment (2.93, 1.21–7.10), were strongly associated. Four COVID-19 or vaccination-related code classes were identified, with post-COVID-19 condition showing the highest OR (3.84, 2.97–4.98). Several ICD-10-GM codes, including COVID-19 related codes, were associated with later ME/CFS diagnoses.

Prospective studies should clarify timing relative to ME/CFS onset, and distinguish between pre-existing conditions, comorbidities, early manifestations, or misdiagnoses.

Source:Wirth M, Haastert B, Linnenkamp U, Andrich S, Icks A, Pricoco R, Behrends U, De Bock F. ICD-10 Diagnoses prior to ME/CFS diagnosis in children and young people suggest potential early diagnostic indicators. Sci Rep. 2026 Feb 26. doi: 10.1038/s41598-026-40848-1. Epub ahead of print. PMID: 41741569. https://www.nature.com/articles/s41598-026-40848-1 (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)

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)