Tag: 2026

A cardiometabolic perspective on post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID

Abstract:

Post-exertional malaise (PEM), the defining feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is increasingly recognized in individuals with Long COVID. Although traditionally viewed as symptom exacerbation and/or emergence of new symptoms following exertion, PEM may reflect disrupted coordination across interconnected physiological systems operating over distinct post-exertional timescales. Such disruption may result in altered post-exertional physiological trajectories that contribute to multisystem manifestations and potential cardiometabolic consequences.

This perspective outlines a conceptual approach for investigating PEM through longitudinal assessment of post-exertional physiological trajectories while considering disease severity and underlying cardiometabolic health, including obesity and type 2 diabetes. Integrating these dimensions may help contextualize post-exertional responses, inform future longitudinal cardiometabolic profiling, facilitate patient stratification, and provide a framework for future mechanistic and interventional studies in ME/CFS and Long COVID.

Source: Westermeier F, Pretorius E, Untersmayr E, Bertinat R, Sepúlveda N, Fisman E. A cardiometabolic perspective on post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID. Cardiovasc Diabetol. 2026 Aug 20;25(1):250. doi: 10.1186/s12933-026-03316-8. PMID: 42625219. https://link.springer.com/article/10.1186/s12933-026-03316-8 (Full text)

Microvascular remodeling and endothelial dysfunction across the post-COVID-19 spectrum: a prospective observational case-control 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: The “All Eyes on PCS” is a prospective observational study assessing the microcirculation using retinal vessel analysis (RVA). Both dynamic and static parameters (DVA and SVA) were compared across never SARS-CoV-2 infected individuals (NI, n = 96), SARS-CoV-2 recovered individuals (n = 102), and PCS patients (n = 102), including a subgroup fulfilling ME/CFS criteria (n = 62). Analyses were complemented by propensity score-based weighting and multivariable adjustment. Associations with symptom severity and circulating biomarkers of endothelial dysfunction and inflammation were examined.

Results: PCS patients showed reduced venular flicker-induced dilation compared with recovered individuals (3.7% ± 2.2 vs. 4.8% ± 3.0, p = 0.006) and narrower retinal arterioles (CRAE) compared with both recovered (178.3 ± 15.5 μm vs. 186.1 ± 15.7 μm, p = 0.001) and NI individuals (184.4 ± 14.3 μm, p = 0.009). Arteriolar-to-venular ratio (AVR) was lower in PCS compared with NI (0.83 ± 0.06 vs. 0.87 ± 0.06, p < 0.001) and recovered participants (0.86 ± 0.07, p = 0.034). Findings remained largely consistent after age and sex balancing and adjustment for CV risk factors, although the association for AVR was attenuated. PCS patients fulfilling ME/CFS criteria showed the most pronounced retinal microvascular alterations, and a combined model discriminated ME/CFS patients with good accuracy (AUC = 0.79). Higher symptom burden was associated with lower AVR (r = – 0.21, p = 0.037), particularly for neurocognitive symptoms. IL-6, ICAM-1, and VCAM-1 were elevated in PCS and ME/CFS, and lower AVR was associated with inflammatory and iron-related markers (all adjusted p < 0.01).

Conclusions: PCS is associated with persistent endothelial dysfunction, most pronounced in ME/CFS patients and linked to symptom severity and ongoing inflammation. These findings support the potential use of RVA as a non-invasive tool for assessing and monitoring endothelial health in post-viral syndromes, with implications for cardiovascular risk stratification.

Trial registration: The All Eyes on PCS Study has previously been registered at ClinicalTrials.gov (NCT05635552).

Source: Wallraven T, Günthner R, Lethen I, Ribeiro A, Lech M, Oertel FC, Reeß LG, Haller B, Streese L, Hanssen H, Basta-Wunderle M, Schmaderer C. Microvascular remodeling and endothelial dysfunction across the post-COVID-19 spectrum: a prospective observational case-control study. BMC Med. 2026 Aug 19;24(1):456. doi: 10.1186/s12916-026-05144-9. PMID: 42625188. https://link.springer.com/article/10.1186/s12916-026-05144-9 (Full text)

Experimental hypoxia to probe neuro-metabolic and vascular dysregulation in ME/CFS: a multimodal proof-of-concept MRI study

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a poorly understood, debilitating multisystem condition. Converging evidence implicates impaired cellular bioenergetics, neuroinflammation and defective neurovascular coupling that may manifest as “virtual hypoxia” only under physiological stress.

Methods: We performed a single-session multimodal 3T MRI study combining brain volumetry, arterial spin labelling (ASL) and multivoxel proton magnetic resonance spectroscopy under normoxia and two controlled hypoxic challenges (oxygen saturation 87 ± 3%) in 26 ME/CFS patients and 27 age- and sex-matched healthy controls.

Results: After intracranial-volume normalization, patients showed a reduced brainstem volume (1.46 ± 0.14 vs. 1.55 ± 0.18 % of eTIV; p = 0.013, FDR-p = 0.039), whereas deep grey matter and whole-brain parenchymal fraction did not differ between groups. Whole-brain cerebral blood flow (CBF) rose under hypoxia in both groups (controls +4.8 ± 13.0%, patients +3.7 ± 11.7%), with greater initial inter-individual variability in patients (patient-to-control variance ratio up to 6.94; FDR-p = 0.001). Thalamic lactate-to-creatine (Lac/tCr) ratios increased with hypoxia in controls (FDR-p = 0.028) but were already elevated at normoxia in patients (0.171 vs. 0.135; FDR-p = 0.021) and did not rise further (FDR-p = 0.38). In exploratory analyses, patients showed exaggerated inverse coupling between thalamic total N-acetylaspartate (tNAA/tCr) and white-matter CBF.

Conclusions: These findings provide in vivo evidence of impaired neuro-metabolic and vascular adaptive capacity in ME/CFS, supporting the virtual hypoxia hypothesis and highlighting candidate imaging markers for stratification that warrant validation.

Source:  Viola Bader, Katharina Estermann, Eva Niess, Tobias Zrzavy, Florian Fischmeister, Teresa Haider, Birgit Ludwig, Frederik Barkof, Henk JMM Mutsaerts, Gregor Kasprian, Fabian Niess, Wolfgang Bogner, Kathrin Kollndorfer, Lukas Haider. Experimental hypoxia to probe neuro-metabolic and vascular dysregulation in ME/CFS: a multimodal proof-of-concept MRI study. medRxiv 2026.08.10.26359935; doi: https://doi.org/10.64898/2026.08.10.26359935 https://www.medrxiv.org/content/10.64898/2026.08.10.26359935v1.full-text (Full text)

Cerebrospinal fluid opening pressure in relation to symptomatology and craniocervical anatomy in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease that affects millions worldwide. Its cause remains unknown, although many physiological mechanisms are impaired. Structural abnormalities in the craniocervical region seem to be more prevalent in patients with ME/CFS, with a possible impact on intracranial pressure (ICP) and lumbar puncture (LP) measurements. This study aimed to quantify the occurrence of elevated cerebrospinal fluid (CSF) opening pressure and a possible association with clinical symptoms and radiological variables in craniocervical segments in a cohort of patients with ME/CFS.

Methods: This study included 34 patients previously diagnosed with ME/CFS as part of a larger case-control study, for whom LP was performed only in the case group. Key measurements included age, sex, opening pressure from LP, symptomatic relief post-LP, and radiological variables with potential influence on CSF dynamics. Individuals were stratified into two groups according to opening pressure (OP) measurements using 20 cmH2O as the cutoff value, with subsequent statistical comparisons.

Results: Overall, the majority of participants reported moderate disease severity (65%) and concomitant self-reported low quality of life. The median CSF opening pressure was 18 (IQR 8) cmH2O, ranging from 11 to 29.5. Opening pressure stratification showed that 21 of the 34 cases (62%) had an OP measurement of <20 cmH2O (low-OP group) and 13 cases (38%) had an OP measurement of ≥20 cmH2O (high-OP group). The two OP groups did not differ significantly in baseline characteristics, including disease severity and quality of life. However, for certain radiological measurements, the high-OP group presented with measures reflecting a wider spinal canal, including a significantly larger foramen magnum diameter (33.9 mm), which was higher than the measures in the low-OP group (31.7 mm). Estimates of symptom relief 1-4 days post-LP were significantly higher among patients in the high-OP group (80%) than among those in the low-OP group (19%).

Conclusion: This study suggests that a proportion of patients with ME/CFS have elevated CSF opening pressures and may experience symptom relief following CSF subtraction. Our data indicate that some anatomical structures in the craniocervical area may be related to CSF pressure, although interpretation is challenging and merits further investigation.

Source: Jolley C, Bragée B, Soinne L, Huhmar H, Billing H, Bertilson B, Sjogren P. Cerebrospinal fluid opening pressure in relation to symptomatology and craniocervical anatomy in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Front Med (Lausanne). 2026 Aug 4;13:1869714. doi: 10.3389/fmed.2026.1869714. PMID: 42614190; PMCID: PMC13481257. https://pmc.ncbi.nlm.nih.gov/articles/PMC13481257/ (Full text)

Subclinical neurovascular and immune correlates of post-COVID-19 syndrome detected by retinal imaging

Abstract:

Background: Post-COVID-19 Syndrome (PCS) encompasses a range of persistent symptoms, including cognitive and autonomic disturbances, potentially linked to microvascular or neuroinflammatory mechanisms. Retinal imaging provides a non-invasive window into the central nervous system and vascular integrity. This study aimed to assess retinal structural and microvascular alterations in PCS patients and explore their relationship with symptom severity.

Methods: In this monocentric, cross-sectional, exploratory study, we performed Optical Coherence Tomography (OCT) and OCT Angiography (OCTA) in patients with PCS and a group of COVID-19 recovered individuals. Multiple circulating biomarkers reflecting endothelial dysfunction and chronic inflammation were measured. Associations with validated symptom scores (PCS Score, C19-YRS, PHQ-9, GAD-7) were evaluated.

Results: After adjusting for age and gender, no significant differences were observed in OCTA-derived vessel density (VD) or foveolar avascular zone (FAZ) between PCS patients and COVID-19-recovered controls. However, PCS patients exhibited significant thinning of the peripapillary retinal nerve fibre layer (pRNFL), ganglion cell inner plexiform layer (GCIP), and total macular volume (TMV). Lower values of these structural parameters were consistently observed in patients with higher symptom severity. Vascular parameters (VD and FAZ) were not related to clinical scores. Higher MCP-1 levels, a chemokine associated with chronic inflammation, were linked to lower inner nuclear layer and GCIP thickness.

Conclusion: Structural retinal alterations in PCS were associated with symptom burden and may reflect underlying neuroinflammatory or neurodegenerative processes. OCT parameters could serve as potential non-invasive biomarkers, warranting further investigation in longitudinal, multicenter studies.

Source: Wunderle M, Wicklein R, Ribeiro A, Carbajo-Lozoya J, Wöhnl A, Negele J, Kesseler V, Wild A, Niedermayer S, Lethen I, Lech M, Menten MJ, Kreitner L, Schmaderer C, Wallraven T. Subclinical neurovascular and immune correlates of post-COVID-19 syndrome detected by retinal imaging. Brain Behav Immun Health. 2026 Jul 25;56:101315. doi: 10.1016/j.bbih.2026.101315. PMID: 42571220; PMCID: PMC13451791. https://pmc.ncbi.nlm.nih.gov/articles/PMC13451791/ (Full text)

Recovery trajectories and predictors of symptom resolution in post-COVID-19 condition: a population-based cohort study

Abstract:

Background: SARS-CoV-2 infection can lead to persistent symptoms, known as Post-COVID-19 Condition (PCC). Previous studies on PCC prognosis mainly looked at severe cases in rehabilitation settings and without knowledge about pre-infection symptom levels. Uncertainty remains about recovery trajectory in the general population, its predictors, and whether recovery differs by symptom.

Methods: We analysed data from Lifelines, a prospective population-based observational cohort. Adults completed 31 COVID-19 questionnaires between March 2020 and October 2022 providing longitudinal symptom data to assess PCC status, and recovery. PCC was defined as at least one moderately severe symptom, among 12 identified as PCC-specific, that worsened 90-150 days after infection. Cox-proportional hazard models estimated recovery, defined as symptom decline to an individual’s pre-infection baseline, adjusted for symptoms present at PCC diagnosis, age, sex, BMI, smoking, hospitalization, vaccination, and comorbidities.

Findings: We analysed time series of 809 cases (mean age 55.0; [SD 11.0]; 590 [73%] female; mean follow up 368 days; [SD 200]). Symptom decline to pre-infection baseline or below was observed in 558 participants; the Kaplan-Meier 24-month symptom decline estimate was 92%. Greater symptom burden was associated with a lower likelihood of recovery (HR per additional symptom 0.69, 95% CI 0.63-0.76), whereas younger age had a higher likelihood of recovery compared with middle adulthood (HR 1.52, 95% CI 1.06-2.18). Median time to symptom decline was 226 days (IQR 182-372), with most improvement within the first 235 days before slowing and plateauing.

Interpretation: Most individuals with PCC recover, but older adults and those with multiple symptoms are at higher risk of prolonged illness, underscoring the need for ongoing support.

Source: Brunet JL, van Ockenburg SL, Leyli-Abadi M, Lunter G, Rosmalen JGM. Recovery trajectories and predictors of symptom resolution in post-COVID-19 condition: a population-based cohort study. Lancet Reg Health Eur. 2026 Aug 8;69:101802. doi: 10.1016/j.lanepe.2026.101802. PMID: 42604070; PMCID: PMC13476563. https://pmc.ncbi.nlm.nih.gov/articles/PMC13476563/ (Full text)

Transforming biomedical uncertainty: the sociohistorical origins of myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS)

Abstract:

Myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) are serious and disabling long-term conditions characterised by uncertainty surrounding their aetiology, diagnosis and treatment. People with ME/CFS struggle to be understood, taken seriously and supported with their illness. At least since the 1990s, ME and CFS have been considered by many to be related, overlapping or synonymous with one another. However, the concepts originated from different sociohistorical contexts. This article disentangles the histories of ME and CFS, roots them in the UK and the USA respectively, and compares how they emerged as medical and scientific objects.

Drawing on a critical literature analysis of medical texts between 1950 and 1990, I explore how both ME and CFS materialised through the regulation of uncertainty within biomedical systems. In both cases, uncertainty was transformed into knowledge by systematically obscuring certain aspects of illness. These transformations shaped what could be known about these conditions in the decades to come and may be at the root of the epistemic injustices experienced by patients.

Those who campaign for more scientific research into ME/CFS should be wary of the propensity for biomedicine to generate ignorance in the face of these complex conditions. This analysis contributes to a growing body of research on the medical sociology of ignorance, further illustrating the value of uncertainty and ignorance as heuristic tools for understanding the politics of knowledge production within biomedical systems.

Source: Cross S. Transforming biomedical uncertainty: the sociohistorical origins of myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). Med Humanit. 2026 Aug 14:medhum-2025-013657. doi: 10.1136/medhum-2025-013657. Epub ahead of print. PMID: 42601195. https://pubmed.ncbi.nlm.nih.gov/42601195/

REenergizeME: intermittent hypoxia-hyperoxia treatment for myalgic encephalomyelitis/chronic fatigue syndrome-protocol for a randomised, placebo-controlled trial

Abstract:

Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, disabling condition characterised by post-exertional malaise (PEM), autonomic dysfunction and markedly reduced quality of life. Its prevalence has increased following the COVID-19 pandemic, yet no effective disease-modifying treatments are available and underlying mechanisms remain unclear. Evidence implicates immune-metabolic dysregulation, impaired energy metabolism, vascular dysfunction and altered oxygen handling. Intermittent hypoxia-hyperoxia treatment (IHHT) is a non-pharmacological intervention proposed to induce adaptive physiological and cellular responses via hypoxia- and redox-sensitive pathways. This trial evaluates the clinical efficacy of IHHT in ME/CFS and explores associated mechanisms.

Methods and analysis: This randomised, placebo-controlled, participant- and assessor-blinded clinical trial will enrol 104 female patients aged 20-59 years who meet the International Consensus Criteria for ME/CFS along with a healthy control group for mechanistic comparisons. Participants will be randomised 1:1 to IHHT or placebo following baseline assessments. The intervention will be delivered over 8 weeks. The primary endpoint is change in quality of life measured by the vitality domain of the Short Form-36 Health Survey. Secondary endpoints include PEM severity, fatigue severity, cognitive severity, functional capacity and autonomic symptoms assessed using validated patient-reported outcome measures and objective tests. Exploratory endpoints include pain phenotyping, autonomic, sudomotor and neurophysiological assessments, tissue oxygenation by near-infrared spectroscopy, peripheral small-fibre nerve assessments using corneal confocal microscopy and skin biopsy and immune-metabolic and oxidative stress biomarkers. Assessments will be conducted at baseline; post-treatment; and at 3, 6 and 12 months follow-up.

Ethics and dissemination: The trial is conducted in accordance with the Declaration of Helsinki and International Council for Harmonisation – Good Clinical Practice guidelines and was approved by the Danish Scientific Ethical Committees (De Videnskabsetiske Medicinske Komitéer, VMK; approval no. 2500959). Written informed consent will be obtained from all participants. Results will be disseminated through peer-reviewed publications and scientific conferences.

Trial registration number: ClinicalTrials.gov Identifier: NCT07317401.

Source: Nochi M, Kristensen SK, Mehrani N, Guerreiro I, Nørholm IMD, Chandra S, Olufsen M, Gudbergsen LR, Brinth LS, Stokholm R, Karlsson P, Tankisi H, Mehlsen J, Foldager CB, Olsen RKJ. REenergizeME: intermittent hypoxia-hyperoxia treatment for myalgic encephalomyelitis/chronic fatigue syndrome-protocol for a randomised, placebo-controlled trial. BMJ Open. 2026 Aug 14;16(8):e117729. doi: 10.1136/bmjopen-2026-117729. PMID: 42601095. https://bmjopen.bmj.com/content/16/8/e117729 (Full text)

ME/CFS and the emotional toll of persistent disbelief: from epistemic to affective injustice

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating chronic illness whose sufferers are frequently met with disbelief, stigmatization, and psychologization in both clinical and social contexts. Recent work has used the concept of “epistemic injustice” to illuminate important dimensions of this problem, especially the ways in which ME/CFS patients are discredited as knowers and denied adequate interpretive resources.

This paper argues that the harms associated with persistent disbelief in ME/CFS are not exhausted by this epistemic dimension. Drawing on recent philosophical work on affective injustice, I argue that persistent disbelief can also impair patients’ affective lives in distinctive and socially patterned ways.

More specifically, I argue that individuals with ME/CFS are burdened by unjust affective expectations, pressured into norm-conforming forms of emotional self-presentation, exposed to pathologizing and gaslighting interpretations of their affective experience, denied uptake for apt emotional responses, and exploited through forms of emotional labor and affective appropriation. Conceptualizing these harms in terms of affective injustice, I argue, helps to capture dimensions of marginalization that a focus on testimony and understanding alone leaves obscure.

The paper concludes by considering objections and drawing out implications for healthcare and philosophy of medicine.

Source: Walter S. ME/CFS and the emotional toll of persistent disbelief: from epistemic to affective injustice. Med Health Care Philos. 2026 Aug 14. doi: 10.1007/s11019-026-10388-6. Epub ahead of print. PMID: 42599643. https://link.springer.com/article/10.1007/s11019-026-10388-6 (Full text)

Orthostatic intolerance with small heart and/or disequilibrium in patients with myalgic encephalomyelitis/chronic fatigue syndrome: clinical update and paradigm shift

Abstract:

Orthostatic intolerance (OI) is characterized by the inability to maintain an upright posture without experiencing severe signs and symptoms, including hypotension, palpitations, light-headedness, pallor, fatigue, weakness, dizziness, impaired concentration, tremulousness, and nausea. The majority of patients with myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) exhibit OI, which is the primary factor restricting daily functional capacity.

During an upright posture, approximately 800 mL of blood is translocated from the intrathoracic venous compartment to the veins of the buttocks, pelvis, and legs. Under normal conditions, compensatory cardiovascular responses to this orthostatic stress include activation of the muscle pump through calf muscle contraction and a neurogenically mediated increase in heart rate and in systemic vascular resistance. The majority of the symptoms of OI are believed to be cardiovascular and related to reduced cerebral blood flow and excessive activation of the sympathetic nervous system.

However, compensatory sympathetic activation is essential for maintaining orthostasis. Many patients have a small left ventricle and associated low cardiac output. In addition, both the renin-aldosterone and antidiuretic hormone systems that regulate circulatory blood volume were downregulated.

Postural stability is necessary for maintaining the static balance critical for performing many daily activities. Recently studies have reported that postural instability or disequilibrium, potentially associated with central vestibular dysfunction, should be considered to be involved in the pathogenesis of OI among patients with ME/CFS. Disequilibrium should be recognized as an important cause of OI in those patients.

Source: Miwa K. Orthostatic intolerance with small heart and/or disequilibrium in patients with myalgic encephalomyelitis/chronic fatigue syndrome: clinical update and paradigm shift. Front Med (Lausanne). 2026 Jul 29;13:1744154. doi: 10.3389/fmed.2026.1744154. PMID: 42591853; PMCID: PMC13463185.  https://pmc.ncbi.nlm.nih.gov/articles/PMC13463185/ (Full text)