Category: Pathophysiology

Perioperative outcomes in patients with myalgic encephalomyelitis/chronic fatigue syndrome undergoing general anesthesia: a retrospective matched-pair study

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic multisystem disease characterized by profound fatigue, post-exertional malaise, cognitive impairment, and autonomic dysfunction. Despite features with potential relevance for anesthesia and perioperative care, empirical data on perioperative outcomes in patients with ME/CFS remains limited. We therefore performed a retrospective matched-pair analysis to generate clinical data on perioperative responses and identify areas for future research.

Methods: We conducted a retrospective matched-pair analysis at a single tertiary center. All patients with ME/CFS undergoing general anesthesia from 2015 to 2026 were identified using ICD-10-GM codes with additional manual verification and matched 1:1 to controls for comparison. Patients with confounding diagnoses or American Society of Anesthesiologists physical status above III were excluded. The analysis focused on intraoperative hemodynamic parameters, including baseline, post-induction, median, and lowest recorded systolic blood pressure and heart rate, as well as early postoperative outcomes in the post-anesthesia care unit (PACU), including maximum pain scores and requirement for rescue analgesia.

Results: Out of 189 individuals identified through ICD-10 codes, 15 matched pairs were included after application of exclusion criteria. Patients with ME/CFS exhibited lower minimum intraoperative systolic blood pressure (90.0 [82.5-95.0] vs. 100.0 [90.0-110.0] mmHg, p = 0.044) and lower minimum heart rate (50.0 [40.0-57.5] vs. 60.0 [50.0-65.0] bpm, p = 0.012). Vasopressor use and fluid administration did not differ, and no episodes of severe hypotension or perioperative adverse events were observed. Postoperative pain was higher in ME/CFS, with higher maximum pain scores (NRS 5.0 [4.0-6.0] vs. 1.0 [0.0-4.0], p = 0.008) and more frequent opioid rescue analgesia (80% vs. 33%, p = 0.039). Postoperative nausea or vomiting, oxygen supplementation, and PACU length of stay were similar between groups.

Conclusions: In this small exploratory cohort, general anesthesia was not associated with clinically relevant hemodynamic instability in patients with ME/CFS. Postoperative pain scores and opioid rescue requirements were higher in the ME/CFS group. Post-exertional malaise, a key disease feature with potentially delayed onset and significant impact, was not captured and remains an important target for future research. These findings should be considered hypothesis-generating and support prospective studies evaluating perioperative management and patient-relevant outcomes in ME/CFS.

Source: Steinkirchner FM, Kaufmann CK, Kraus RF, Käss M, Schieffer E, Graf BM, Lassen C, Kimmerling V, Dejaco A. Perioperative outcomes in patients with myalgic encephalomyelitis/chronic fatigue syndrome undergoing general anesthesia: a retrospective matched-pair study. BMC Anesthesiol. 2026 Jul 16;26(1):426. doi: 10.1186/s12871-026-04102-5. PMID: 42464211. https://link.springer.com/article/10.1186/s12871-026-04102-5 (Full text available as PDF file)

Metabolomic Classification of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome via Explainable Ensemble Learning and Pareto-Guided Feature Selection

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem illness characterised by post-exertional malaise, non-restorative sleep, and cognitive impairment, yet no objective diagnostic biomarkers have been established. Untargeted plasma metabolomics provides a broad view of the biochemical disturbances underlying ME/CFS; however, the high dimensionality of omics datasets and the limited interpretability of conventional classifiers nevertheless hinder translation into clinical practice. This study evaluates three ensemble classifiers-Explainable Boosting Machine (EBM), XGBoost, and LightGBM-for binary ME/CFS classification using plasma metabolomic and lipidomic profiles from 197 participants (106 ME/CFS; 91 healthy controls; 888 features).

Feature dimensionality was reduced using a Pareto-Guided Recursive Neural Network (PRNN) pipeline. Model performance was assessed via 50-repeat stratified hold-out validation. EBM achieved the highest accuracy (0.909; 95% CI: 0.868-0.949) and area under the receiver operating characteristic curve (AUC: 0.940; 95% CI: 0.909-0.983), with XGBoost and LightGBM performing comparably. Interpretability analyses revealed that pairwise metabolite interaction terms-particularly proline & indole-3-lactate, tyrosine & N-acetylornithine, and maleic acid & arachidic acid-contributed the greatest discriminative signal.

An ablation analysis comparing the full interaction-augmented EBM (AUC = 0.940) with a main-effects-only EBM (AUC = 0.882) confirmed that pairwise metabolite co-variation contributes additional discriminative value beyond individual metabolite levels, implicating amino acid catabolism, tryptophan-kynurenine pathway dysregulation, mitochondrial energy impairment, and lipid remodelling as central pathophysiological features. Global and instance-level explanations jointly demonstrated population-level metabolic signatures alongside individual heterogeneity, highlighting the added clinical value of explainable artificial intelligence (XAI) in metabolomics.

These findings support EBM-based metabolomic profiling as an internally validated approach for ME/CFS classification, subject to external validation, calibration assessment, and prospective testing.

Source: Yagin FH, Korkmaz Y, Colak C, Alzakari SA, Alkhalifa AK, Al-Hashem F, Aghaei M. Metabolomic Classification of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome via Explainable Ensemble Learning and Pareto-Guided Feature Selection. Int J Mol Sci. 2026 Jun 30;27(13):5920. doi: 10.3390/ijms27135920. PMID: 42450188. https://www.mdpi.com/1422-0067/27/13/5920 (Full text)

Disrupted glymphatic function and its relationship with sleep and cognitive impairment in ME/CFS assessed via DTI-ALPS

Abstract:

The glymphatic system is a recently discovered brain waste clearance system that is mostly active during sleep and disengaged during wakefulness. Impaired glymphatic function leads to the deposition of metabolic waste products in the brain potentially causing inflammation leading to various symptoms in ME/CFS. While the glymphatic function has been assessed in other neurodegenerative diseases using ‘diffusion tensor imaging along the perivascular space’ (DTI-ALPS), it has not been studied in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

This preliminary study investigates glymphatic function in 58 participants (ME/CFS = 31 and healthy controls = 27) using the DTI-ALPS index derived from DTI data acquired with 3 T MRI. The bilateral hemispheric DTI-ALPS index was estimated to assess glymphatic function, and an asymmetry index was calculated to determine interhemispheric asymmetry in glymphatic function.

We found that the global DTI-ALPS index was significantly lower in ME/CFS patients compared to healthy controls (ME/CFS: 1.44 ± 0.086; healthy controls: 1.51 ± 0.11, p = 0.014), indicating reduced glymphatic function in ME/CFS. Examining the hemispheres separately, showed the right hemisphere DTI-ALPS index was lower in ME/CFS than healthy controls (ME/CFS = 1.41 ± 0.097; healthy controls = 1.49 ± 0.12; p = 0.009) but not different on the left. Additionally, we did not find any significant difference in asymmetry index between ME/CFS and healthy controls. We observed an association between the global DTI-ALPS index and severity of ‘sleep disturbance’ (p = 0.013, r = -0.47) and “impaired concentration” (p = 0.026, r = -0.43).

This study demonstrated impaired glymphatic function in ME/CFS which may lead to symptoms such as cognitive dysfunction and sleep disturbance experienced by ME/CFS.

Source: Thapaliya K, Marshall-Gradisnik S, Inderyas M, Barnden L. Disrupted glymphatic function and its relationship with sleep and cognitive impairment in ME/CFS assessed via DTI-ALPS. Front Neurosci. 2026 Jun 19;20:1875420. doi: 10.3389/fnins.2026.1875420. PMID: 42403482; PMCID: PMC13329448. https://pmc.ncbi.nlm.nih.gov/articles/PMC13329448/ (Full text)

Association between light exposure patterns and multidimensional health outcomes in individuals with myalgic encephalomyelitis/chronic fatigue syndrome: findings from an observational cross-sectional cohort study

Abstract:

Background: Light is a major environmental factor regulating circadian rhythms, sleep- wake cycles, and mood-related behaviors. Patients with Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often experience circadian disruption and poor sleep quality, which severely compromise their quality of life; however, the relationship between light exposure and illness severity remains largely unknown.

Methods: An observational cross-sectional cohort secondary study used collected data from 100 ME/CFS patients and 56 healthy controls to explore the impact of spontaneous light exposure on multidimensional health status and circulating biochemical parameters. Demographic and clinical features were assessed using validated patient-reported outcome measures. Light intensity, wrist temperature, and physical activity were continuously monitored at home over one week using wrist-worn actigraphy. Light intensity during predefined intervals and rhythmic variables of light cycle were calculated. Principal component analysis (PCA) was applied to reduce dimensionality of light variables. Multivariable analysis was performed adjusting for age, sex, body mass index, and physical activity.

Results: Following PCA of the light patterns, two components emerged across groups with high consistency: PC1 (explaining 61.7% of the total variance) reflected higher daytime light and rhythm stability, and PC2 (explaining 16.1%) represented nocturnal/early-morning light and rhythm instability. In ME/CFS patients, light variables were more extensively associated with clinical outcomes measures (FIS-40, PSQI and SF-36) than in healthy controls (all p < 0.05). Furthermore, PC2 was associated with higher levels of VCAM-1 and triglycerides, and lower serotonin concentrations (all p < 0.05). Four distinct light patterns were identified based on PCA scores: nocturnal light, healthy, adverse, and low diurnal light. ME/CFS patients exhibiting the healthy light pattern showed significantly lower fatigue, fewer sleep complaints, reduced autonomic dysfunction, and higher quality of life compared to those with the adverse light pattern (all p < 0.05). No significant differences were observed among healthy controls.

Conclusions: Light exposure patterns show distinct associations with symptom variability in ME/CFS compared to healthy controls. More stable daytime light appears to relate to better symptom profiles, whereas irregular exposure and nocturnal light are linked to poorer health outcomes. Although causality cannot be inferred, these findings highlight light exposure as a potentially modifiable, non-invasive target for behavioral interventions aimed at improving the quality of life in ME/CFS, representing a promising emerging for future translational research.

Source: Cambras T, Domingo JC, Sanmartín-Sentañes R, Alegre-Martín J, Castro-Marrero J. Association between light exposure patterns and multidimensional health outcomes in individuals with myalgic encephalomyelitis/chronic fatigue syndrome: findings from an observational cross-sectional cohort study. J Transl Med. 2026 Jul 3. doi: 10.1186/s12967-026-08556-6. Epub ahead of print. PMID: 42399727. https://link.springer.com/article/10.1186/s12967-026-08556-6 (Full text available as PDF file)

Tryptophan Metabolism and Aryl-Hydrocarbon Receptor Agonists in the Gut Microbiome of People With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease with unknown biological basis and no cure. Microbiome dysbiosis has been reported in people with ME/CFS but its relevance to pathophysiology is unknown. Gut microbes are an important source of tryptophan metabolites that activate the aryl hydrocarbon receptor (AHR), a regulator of homeostatic and inflammatory genes. Dysregulated activation of AHR contributes to pathophysiology of several neuroimmune and chronic diseases but its role in ME/CFS has not been investigated. The purpose of this study was to investigate the production of tryptophan metabolites and AHR agonists by gut microbes of people with ME/CFS.

We found lower diversity and altered microbiome community structure in people with ME/CFS and changes in the subcommunity of microbes that correlated with tryptophan metabolites. Using targeted metabolomics we identified nine metabolites elevated in the stool of people with ME/CFS, including three AHR agonists. Stool ex vivo cultures were tested for their capacity to activate AHR in a reporter cell line and by qPCR. AHR activation did not differ between people with ME/CFS and controls, however, we detected elevated agonist activity in people with neurocognitive symptoms, regardless of underlying disease.

These findings are consistent with previous work revealing changes in the gut microbiome of people with ME/CFS and adds further support to alterations in tryptophan metabolism associated with the disease. Altered AHR activity by gut microbial metabolites may be a common mechanism contributing to neurocognitive symptoms in diseases including ME/CFS.

Source: Esteban DJ, Conrad B, Cullinan A, Luong S, Albaum J, Wilk V. Tryptophan Metabolism and Aryl-Hydrocarbon Receptor Agonists in the Gut Microbiome of People With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Microbiologyopen. 2026 Jun;15(3):e70333. doi: 10.1002/mbo3.70333. PMID: 42325052. https://onlinelibrary.wiley.com/doi/10.1002/mbo3.70333 (Full text)

Gastrointestinal symptoms correlate with core clinical features and systemic inflammation in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem illness marked by fatigue, cognitive impairment, and post-exertional malaise. Gastrointestinal (GI) symptoms are frequently reported, yet their relationship to central features of the illness and biological correlates remains poorly understood.

Objectives: We aimed to characterize GI symptom burden in ME/CFS and evaluate its associations with core clinical features and specific immune and inflammatory markers, with attention to potential gut-related contributions to disease expression.

Methods: GI symptoms and 49 additional symptoms across nine domains were assessed in 116 ME/CFS patients and 80 matched controls. Plasma C-reactive protein (CRP) and antibodies against dietary and microbial antigens were measured as indicators of systemic inflammation and putative gut-derived antigen exposure.

Results: ME/CFS patients reported significantly elevated GI symptom frequency and severity compared with controls, with 53% of ME/CFS patients versus 8% of controls reporting a prior diagnosis of irritable bowel syndrome. GI symptom burden correlated with fatigue, cognitive difficulties, flu-like symptoms, pain, sleep disturbances, neurological complaints, and sensory sensitivities, independent of illness duration. CRP levels were higher in patients with greater GI symptoms and correlated with GI, fatigue, musculoskeletal pain, and flu-like symptom burden. Patients with greater flu-like symptom expression exhibited higher IgM responses to dietary gliadin and bacterial lipopolysaccharide. These associations were not detected in controls.

Conclusions: GI symptoms are a prominent, clinically relevant dimension of ME/CFS, associated with broader symptom burden and inflammatory heterogeneity. These findings highlight the relevance of gut-related and immune processes in ME/CFS and underscore the value of incorporating GI symptom assessment in translational studies to help refine mechanistic understanding and improve therapeutic stratification. https://link.springer.com/article/10.1186/s12967-026-08442-1 (Full text available as PDF file)

Systems neuroendocrinology in ME/CFS and long COVID: a chronobiological framework for hormone-based research

Abstract:

Hormonal dysregulation is increasingly reported in ME/CFS and Long COVID, yet the broader role of neuroendocrine disruption in these conditions remains underexplored. While changes in steroid, peptide, and neuropeptide hormones have been identified, these findings are often considered in isolation and without attention to their timing or integration within broader physiological systems. The hypothalamic-pituitary axes regulate endocrine, immune, autonomic, nervous, and metabolic functions, systems commonly affected in both conditions, yet their circadian and menstrual dynamics are rarely investigated.

In this review, we examine the evidence for neuroendocrine dysfunction in ME/CFS and Long COVID, focusing on hormone output, functional assays, receptor expression, and the coordination of endocrine biorhythms. Sex hormone signalling emerges as a key area of vulnerability, particularly given the female predominance in both conditions and the complexity of reproductive hormone regulation.

We argue that accurate hormone measurement and time-structured sampling, including circadian and menstrual rhythms, are essential for detecting meaningful biological differences. By embedding chronobiology-aware, dense-sampling strategies and integrating multi-omic analyses into multi-system study designs, we outline a framework for investigating dynamic endocrine mechanisms underlying symptom variability and multisystem dysfunction, which may ultimately support the development of more targeted, personalised interventions.

Source: Thomas N, Huang K, Schneider-Futschik EK, Pollack B, Tal MC, Fineberg D, Wang X, Gurvich C, Pretorius R, Bergquist J, Armstrong CW. Systems neuroendocrinology in ME/CFS and long COVID: a chronobiological framework for hormone-based research. Front Neuroendocrinol. 2026 Jun 19:101268. doi: 10.1016/j.yfrne.2026.101268. Epub ahead of print. PMID: 42320559. https://www.sciencedirect.com/science/article/abs/pii/S0091302226000385 (Full text)

Irisin Signaling Resistance in Myalgic Encephalomyelitis: A Proposed Mechanistic Framework for Post-Exertional Malaise Involving the TSP-1-HSP90α-αvβ5 Axis

Abstract:

Myalgic Encephalomyelitis (ME) is a chronic, multisystem disease characterized by systemic metabolic dysfunction and post-exertional malaise (PEM). In this study, we investigated the dysregulation of irisin, an exercise-induced myokine, and its potential antagonism by thrombospondin-1 (TSP-1).

In a cross-sectional study (92 ME patients vs. 44 sedentary healthy controls), plasma irisin and TSP-1 levels were measured at baseline and after a 90 min mechanical stress challenge applied to induce PEM. ME patients exhibited significantly lower baseline irisin (p < 0.05) and a blunted exertional response (p < 0.05). Paradoxically, baseline irisin was an independent predictor of fatigue severity (β = 0.728, p = 0.018), with moderate-to-severe patients showing elevated levels of both irisin and TSP-1 (p < 0.05), suggesting a compensatory but ineffective response. Functional cellular dielectric spectroscopy indicated that TSP-1 inhibits irisin signaling in a concentration-dependent manner. Irisin signaling was markedly reduced by both αvβ5 blockade and HSP90α inhibition in this experimental system, consistent with a diminished ability to counteract TSP-1.

Collectively, these findings support a model in which dysregulation of the irisin-TSP-1 axis contributes to metabolic dysfunction in ME. Elevated circulating TSP-1 levels are associated with symptom severity and are linked to impaired irisin signaling in an HSP90α- and αvβ5-dependent context. This interaction is consistent with defective metabolic adaptation and highlights a potential therapeutic target that warrants further validation to restore energy homeostasis.

Source: Souma B, Elremaly W, Akoume MY, Elbakry M, Godbout C, Moreau A. Irisin Signaling Resistance in Myalgic Encephalomyelitis: A Proposed Mechanistic Framework for Post-Exertional Malaise Involving the TSP-1-HSP90α-αvβ5 Axis. Int J Mol Sci. 2026 May 26;27(11):4770. doi: 10.3390/ijms27114770. PMID: 42278300. https://www.mdpi.com/1422-0067/27/11/4770 (Full text)

Dynamic microclot profiling: thromboelastography advances precision management in long COVID and myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) share overlapping symptoms, and emerging evidence implicates persistent fibrinoid microclots in their pathophysiology, contributing to impaired microcirculation. This review explores the role of microclots and evaluates thromboelastography (TEG) as a potential diagnostic tool.

A comprehensive literature review was conducted using major biomedical databases. Studies indicate microclots are prevalent in both conditions. Long COVID patients demonstrate a TEG profile of increased clot strength (maximum amplitude) and reduced fibrinolysis (LY30), suggesting a persistent hypercoagulable state. Despite its advantages in real-time assessment, TEG interpretation faces challenges from preanalytical variability and a lack of standardized protocols. Promising therapeutic trials, including anticoagulants (e.g., apixaban) and fibrinolytics (e.g., lumbrokinase), require further validation. Technological advancements like AI-driven TEG analysis and portable devices could improve diagnostic precision.

In conclusion, persistent microclots are a key pathophysiological feature. TEG provides a promising, novel approach for detecting coagulation abnormalities and could guide treatment, but requires standardization in future clinical trials. Future research should integrate multiomics biomarkers for precision therapeutics to improve patient outcomes.

Source: Saleem S, Hussain A, Haroon M, Raza A, Afzal U, Anwar MF, Imran S, Iqbal MU, Hajj F. Dynamic microclot profiling: thromboelastography advances precision management in long COVID and myalgic encephalomyelitis/chronic fatigue syndrome. Blood Coagul Fibrinolysis. 2026 Jun 11. doi: 10.1097/MBC.0000000000001439. Epub ahead of print. PMID: 42274123. https://pubmed.ncbi.nlm.nih.gov/42274123/

Immune remodeling and metabolic reprogramming in chronic fatigue: insights into GPCR signaling and epigenetic regulation

Abstract:

Inflammation-driven fatigue is a clinically significant feature of several chronic inflammatory conditions, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), post-COVID condition, autoimmune disease, and cancer-related fatigue. Across these conditions, partially overlapping disturbances in immune regulation, cellular metabolism, and neuroimmune signaling may contribute to persistent fatigue, despite important differences in initiating context and biological substrate. Current evidence implicates mitochondrial dysfunction, altered glycolysis and fatty acid utilization, lactate- and succinate-associated signaling, metabolite-sensing G protein-coupled receptor (GPCR) pathways, epigenetic acylation, and immune remodeling in the maintenance of fatigue.

This narrative review synthesizes both shared and disease-context-specific mechanisms underlying inflammation-associated fatigue, with particular emphasis on immunometabolism, peripheral-central neuroimmune crosstalk, metabolite-GPCR signaling, and epigenetic regulation.

We highlight GPCR signaling as a potentially important regulatory interface in inflammatory and metabolic pathways relevant to fatigue, while recognizing that direct causal evidence in human fatigue syndromes remains limited.

The review also examines how metabolite-mediated epigenetic acylation may influence immune cell function and fatigue-related biology, although this association remains incompletely validated in fatigue-specific settings. By integrating metabolic dysregulation, neuroimmune signaling, and immune dysfunction, this review consolidates current knowledge on candidate biomarkers, mechanistic pathways, and emerging therapeutic targets in chronic inflammation-driven fatigue.

Overall, this review provides a multidimensional framework for understanding fatigue across inflammatory disorders and for guiding future mechanistic and translational research.

Source: Hu Z, Wang J, Ma S, Zhuang J, Shi J, Zhu Y. Immune remodeling and metabolic reprogramming in chronic fatigue: insights into GPCR signaling and epigenetic regulation. Front Immunol. 2026 May 15;17:1806420. doi: 10.3389/fimmu.2026.1806420. PMID: 42220511; PMCID: PMC13218923. https://pmc.ncbi.nlm.nih.gov/articles/PMC13218923/ (Full text)