Tag: PEM

Total blood volume and red blood cell volume are not associated with orthostatic intolerance in adults with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Orthostatic intolerance is common in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and may worsen daily functioning. Although hypovolemia has been proposed as a contributor, its relationship to objective orthostatic abnormalities remains uncertain. We examined whether measured blood-volume abnormalities were associated with standardized lean-test outcomes.

Adults meeting the 1994 ME/CFS criteria and reporting substantial post-exertional malaise underwent a 10-min lean test with capnography, followed 8 days later by total blood volume (TBV) measurement using the Daxor BVA-100. Supine hypocapnia was defined as baseline end-tidal CO2 (eTCO2) <34 mmHg; postural orthostatic syndrome of hypocapnia (POSH) as normal supine eTCO2 with any leaning value <34 mmHg; and postural orthostatic tachycardia syndrome (POTS) as a heart-rate increase ≥30 beats/min or absolute heart rate ≥120 beats/min.

Among 49 participants, TBV was hypovolemic in 35%, normovolemic in 43%, and hypervolemic in 22%; red blood cell volume was deficient in 49%. Overall, 55.1% had at least one lean-test abnormality, most commonly POSH (40.8%). Abnormalities did not differ by TBV or red blood cell volume category. Static blood-volume categories were not associated with lean-test-defined orthostatic abnormalities in ME/CFS, suggesting contributions from autonomic, vascular, respiratory, or cerebrovascular mechanisms.

Source: Yamazaki T, Mancini DM, Blate M, Quan P, Norweg A, Cook DB, Natelson BH. Total blood volume and red blood cell volume are not associated with orthostatic intolerance in adults with myalgic encephalomyelitis/chronic fatigue syndrome. Physiol Rep. 2026 Sep;14(17):e71087. doi: 10.14814/phy2.71087. PMID: 42717554. https://physoc.onlinelibrary.wiley.com/doi/10.14814/phy2.71087 (Full text)

Impact of post-exertional malaise frequency and fatigue in Long COVID patients on health-related quality of lif

Abstract:

Purpose: The aim of this study was to investigate the impact of post-exertional malaise (PEM) frequency and PEM severity on health-related quality of life (HRQoL) among individuals with Long COVID.

Methods: We conducted a cross-sectional online survey including adults in Germany with self-reported Long COVID and PEM. Fatigue severity was assessed with the Fatigue Assessment Scale (FAS), and HRQoL was measured using the EQ-5D-3L (descriptive index and visual analogue scale [EQ-VAS]). Associations between PEM frequency, fatigue, and HRQoL were examined using correlations and non-parametric group comparisons. Multiple linear regression models were fitted to predict HRQoL while controlling for age, sex, employment status, and subjective social status.

Results: Higher PEM frequency was associated with significantly lower EQ-5D index scores (ρ = – 0.32, p<.001). PEM severity was also strongly correlated with reduced HRQoL (EQ-5D index: ρ = – 0.43, p<.001). In multivariable regression models, greater fatigue and higher PEM frequency independently predicted poorer HRQoL, even after adjustment for sociodemographic factors.

Conclusion: Both PEM frequency and PEM severity substantially impair HRQoL in individuals with Long COVID. These findings underscore the clinical relevance of PEM as a key symptom and highlight the need for targeted management strategies to mitigate its impact on daily life.

Clinical trial number: German Clinical Trials Register DRKS00026007; registration date: 9 September 2021.

Source: Thölking T, Müller F, Riester T, Lampe V, Theil LM, Hummers E, Sarpari K, Dopfer-Jablonka A, Happle C, Steffens S, Meier-Maiwald M, Mikuteit M, Schröder D. Impact of post-exertional malaise frequency and fatigue in Long COVID patients on health-related quality of life. Health Qual Life Outcomes. 2026 May 11;24(1):64. doi: 10.1186/s12955-026-02523-x. PMID: 42116095; PMCID: PMC13162394. https://pmc.ncbi.nlm.nih.gov/articles/PMC13162394/ (Full text)

Targeting Bioenergetic, Redox and Prostaglandin Pathways in Long COVID-Associated Post-Exertional Malaise and Brain Fog: A Nutraceutical Translational Hypothesis

Abstract:

Post-exertional malaise (PEM) and cognitive dysfunction (hereafter “cognitive dysfunction”, including the patient-reported syndrome often described as “brain fog”) are among the most disabling features of Long COVID; yet, approved disease-modifying treatments remain lacking. Emerging evidence implicates interacting disturbances in mitochondrial bioenergetics, redox regulation and neurovascular inflammation, although much of the supporting evidence remains indirect and derives from acute COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), primary mitochondrial disease, inflammatory biology and mechanistic pharmacology rather than from direct Long COVID intervention trials.

This hypothesis-generating narrative review develops a mechanism-based translational framework: that a pathway-targeted nutraceutical programme may modulate selected elements of these three axes, subject to prior demonstration of formulation quality, pharmacokinetic feasibility, target engagement and safety. Candidate modules comprise coenzyme Q10 and alpha-lipoic acid for bioenergetic/redox support; selenium, sulforaphane and resveratrol for Nrf2-thioredoxin-related redox regulation; and Boswellia serrata, luteolin and eicosapentaenoic acid for putative prostaglandin/resolution-pathway modulation. Sonlicromanol provides a conceptual mechanistic precedent for combined redox and prostaglandin-directed pharmacology, but it is not considered pharmacologically equivalent to an eight-agent nutraceutical combination.

We summarise the mechanistic rationale, distinguish direct from indirect evidence, define qualitative evidence-grading criteria, outline safety and interaction considerations, and propose a staged translational research programme. This framework is intended to generate falsifiable hypotheses for future Long COVID studies, not to imply established clinical efficacy.

Source: Praet SFE. Targeting Bioenergetic, Redox and Prostaglandin Pathways in Long COVID-Associated Post-Exertional Malaise and Brain Fog: A Nutraceutical Translational Hypothesis. Nutrients. 2026 Aug 13;18(16):2650. doi: 10.3390/nu18162650. PMID: 42654231. https://www.mdpi.com/2072-6643/18/16/2650 (Full text)

Skeletal muscle properties in long COVID and ME/CFS differ from those induced by bed rest

Abstract:

Patients with long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suffer from post-exertional malaise. The accompanying physical inactivity may contribute to a lower aerobic capacity and may explain skeletal muscle adaptations in these patients. Here, we compare whole-body exercise responses and skeletal muscle adaptations after strict 60-day bed rest in healthy people with those in long COVID and ME/CFS patients, and healthy age- and sex-matched controls.

Bed rest alters respiratory and cardiovascular responses to maximal exercise, which are dissimilar in patients. Bed rest causes muscle atrophy without altering fiber type. Both patient groups have more glycolytic fibers, and ME/CFS patients display type I-specific atrophy. Only after bed rest is oxidative phosphorylation capacity associated with maximal oxygen uptake.

As skeletal muscle characteristics differ between patients and healthy individuals after bed rest, physical inactivity cannot solely explain the lower exercise capacity and skeletal muscle adaptations in long COVID and ME/CFS patients.

Source: Charlton BT, Slaghekke A, Appelman B, Eggelbusch M, Huijts JY, Noort W, Hendrickse PW, Bloemers FW, Posthuma JJ, van Amstel P, Goulding RP, Degens H, Jaspers RT, van Vugt M, Wüst RCI. Skeletal muscle properties in long COVID and ME/CFS differ from those induced by bed rest. Nat Commun. 2026 Jul 28;17(1):9125. doi: 10.1038/s41467-026-75725-y. PMID: 42649155. https://www.nature.com/articles/s41467-026-75725-y (Full text)

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)

Haptoglobin Phenotypes Stratify Post-Exertional Cognitive Dysfunction Associated with Altered Cerebral Oxygenation and Metabolic Signatures in Long COVID

Abstract:

Long COVID (LC) is a heterogeneous post-infectious syndrome characterized by persistent symptoms, yet the biological basis underlying its interindividual variability remains poorly understood. Given the clinical overlap between LC and myalgic encephalomyelitis (ME), and prior demonstration that haptoglobin (Hp) phenotypes modulate symptom severity in ME, we investigated whether Hp phenotypes similarly stratify post-exertional cognitive dysfunction in LC.
In this longitudinal observational study, 44 individuals with LC and 20 short-course COVID controls, who recovered rapidly from SARS-CoV-2 infection without persistent symptoms or sequelae, underwent Hp phenotyping alongside metabolomic and physiological profiling before and after a standardized 90 min passive post-exertional challenge. Hp phenotypes identified clinically distinct LC subgroups.
Compared with Hp1-1 individuals, Hp2 allele carriers exhibited greater fatigue, poorer physical function, and more severe post-exertional symptoms. Immediately following the challenge, Hp2-2 participants with LC showed significant cognitive decline, whereas Hp1-1 individuals demonstrated cognitive resilience and more favorable longitudinal cognitive trajectories.
This differential susceptibility was accompanied by higher post-exertional cerebral fractional tissue oxygen extraction in the right hemisphere in Hp1-1 individuals and by distinct metabolic signatures, with Hp2 allele carriers exhibiting lower post-exertional plasma concentrations of citric acid, isethionate, and glucosamine. Lower metabolite levels were associated with poorer cognitive performance.
These findings support Hp phenotypes as promising candidate biomarkers for biological stratification in Long COVID, pending validation in larger independent cohorts.

Source: Moezzi A, Elremaly W, Leveau C, Franco A, Nepotchatykh O, Armstrong CW, Moreau A. Haptoglobin Phenotypes Stratify Post-Exertional Cognitive Dysfunction Associated with Altered Cerebral Oxygenation and Metabolic Signatures in Long COVID. International Journal of Molecular Sciences. 2026; 27(15):7000. https://doi.org/10.3390/ijms27157000 https://www.mdpi.com/1422-0067/27/15/7000 (Full text)

Central noradrenergic deficiency in post-infectious chronic fatigue: Neurobehavioral correlates

Abstract:

Fatigue, brain fog and post-exertional malaise are major features of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome and post-acute sequelae of severe acute respiratory syndrome coronavirus 2. To date, no specific neurotransmitter abnormalities have been found in either condition. We examined the possibility of central catecholaminergic involvement and clinical correlates in post-infectious myalgic encephalomyelitis/chronic fatigue syndrome and post-acute sequelae of severe acute respiratory syndrome coronavirus 2 groups compared to healthy volunteers and, as positive controls, Parkinson’s disease patients.

In an observational, cross-sectional cohort study conducted at the National Institutes of Health Clinical Center we measured CSF levels of catecholamines and metabolites in the four groups and assessed correlations with neurobehavioral measures. CSF indices of the central Norepinephrine Pathway (norepinephrine + 3,4-dihydroxyphenylglycol + 3-methoxy-4-hydroxyphenylglycol) and Dopamine Pathway (dopamine + 3,4-dihydroxyphenylacetic acid + homovanillic acid) were measured and related to patient-recorded outcomes and physiological assessments.

Mean values for Norepinephrine Pathway activity (in pmol/mL) were lower in the post-infectious myalgic encephalomyelitis/chronic fatigue syndrome, post-acute sequelae of severe acute respiratory syndrome coronavirus 2, and Parkinson’s disease groups compared to the healthy volunteer cohort (post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (-15.9, 95% confidence interval [-26.1, -5.7], P = 0.0006); post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (-9.62, [-17.9, -1.4], P = 0.015); Parkinson’s disease (-19.4, [-27.5, -11.3], P < 0.0001)).

Post-acute sequelae of severe acute respiratory syndrome coronavirus 2 participants with post-exertional malaise had evidence of central noradrenergic deficiency compared to healthy volunteers (-18.3 [-31.3, -5.3], P = 0.0018). The post-infectious myalgic encephalomyelitis/chronic fatigue syndrome and post-acute sequelae of severe acute respiratory syndrome coronavirus 2 groups did not differ from the healthy group in values for the Dopamine Pathway index. Across all participants, Norepinephrine Pathway activity correlated positively with handgrip duration and general health and negatively with fatigue.

We conclude that post-infectious myalgic encephalomyelitis/chronic fatigue syndrome and post-acute sequelae of severe acute respiratory syndrome coronavirus 2 feature a specific central neurotransmitter pattern involving noradrenergic but not dopaminergic deficiency. The noradrenergic abnormality is associated with major symptoms such as post-exertional malaise.

Source: Aregawi L, Walitt B, Sullivan P, Norato G, Benjamin RN, Goldstein DS. Central noradrenergic deficiency in post-infectious chronic fatigue: neurobehavioral correlates. Brain Commun. 2026 May 13;8(3):fcag173. doi: 10.1093/braincomms/fcag173. PMID: 42205163; PMCID: PMC13202209. https://pmc.ncbi.nlm.nih.gov/articles/PMC13202209/ (Full text)

Pacing and energy management with digital tools for conditions with chronic fatigue: What we know so far in ME/CFS and Long COVID

Introduction:

Why pacing matters in conditions with post‑exertional symptom exacerbation

‘Pacing’, or ‘energy management’, is a structured approach to regulating one’s physical, cognitive, and emotional activities to remain within limits imposed by chronic illnesses such as fibromyalgia, cancer, ME/CFS, and Long COVID [1,2]. Pacing ostensibly prevents post‑exertional symptom exacerbation, notably post‑exertional malaise (PEM), the worsening of fatigue, pain, cognitive dysfunction, and other symptoms following even modest activity. Across the literature, pacing is heterogeneously described as strategies that include activity planning, routine‑setting, pre‑emptive rest, breaking tasks into smaller components, monitoring energy fluctuations, and intentionally avoiding activity “push‑crash” cycles that commonly drive clinical deterioration [3]. In addition to heterogenous implementation, evidence of efficacy is also varied [3–9]. In this article, we will focus on ME/CFS and Long COVID as use case examples.

Historically, pacing emerged as an energy management method encouraging individuals to do as much as they can within their limits, rather than pushing through symptoms or following externally prescribed exercise. The central principle is that of the “energy envelope” [1], which asks individuals to identify the threshold at which activity begins to provoke symptoms and then remain inside that envelope as consistently as possible.

While definitions vary across clinicians, researchers, and patient groups, a consistent theme in both our systematic review and the scoping review is that pacing is individualised and requires ongoing adjustment as symptoms fluctuate [3,7]. Importantly, pacing is now the only management strategy recommended by the 2021 NICE guidelines for ME/CFS [10], underscoring its centrality in clinical care despite the concerning lack of evidence for efficacy. As Long COVID research evolved, pacing increasingly became recognised as a pragmatic, do no harm approach for a condition characterised by varied symptomology, unpredictable recovery patterns, and vulnerability to overexertion [8,11].

Source: Sanal-Hayes NEM, Hayes LD, Mclaughlin M, Sculthorpe NF (2026) Pacing and energy management with digital tools for conditions with chronic fatigue: What we know so far in ME/CFS and Long COVID. PLOS Digit Health 5(7): e0001586. https://doi.org/10.1371/journal.pdig.0001586 https://journals.plos.org/digitalhealth/article?id=10.1371/journal.pdig.0001586 (Full text)

Multimodal approach to identify neuropsychophysiological subgroups in myalgic encephalomyelitis/chronic fatigue syndrome and their relevance for rehabilitation: protocol for a mechanistic cross-sectional and longitudinal study

Abstract:

Introduction: Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) is a debilitating condition characterized by severe fatigue and post-exertional malaise (PEM). Reported neuropsychophysiological abnormalities suggest ME/CFS is multifactorial, but current knowledge remains fragmented. This study protocol outlines a multimodal investigation designed to (1) compare neuropsychophysiological mechanisms between ME/CFS patients and healthy participants, (2) test an integrative model of ME/CFS, (3) identify neuropsychophysiological subgroups within the patient population, and (4) identify predictors of symptom response during rehabilitation.

Methods and analysis: This study will enroll 115 ME/CFS patients and 55 healthy participants. Groups will be comparable in age, sex, and education level, with a larger patient sample enabling subgroup and longitudinal analyses. A cross-sectional assessment at baseline will be carried out in both groups. Patients will then be evaluated longitudinally throughout a standardized cognitive-behavioral therapy rehabilitation program delivered as routine care.

Baseline measures include systemic inflammation and general health biomarkers, measures of autonomic and central nervous system function, neuroinflammation (magnetic resonance spectroscopy, [18F]DPA714 PET in a subsample), serum short-chain fatty acid levels, gut microbiota composition and function, and neuroendocrine and self-reported responses to psychosocial stress. Fatigue severity (physical and cognitive) and PEM will be assessed through validated questionnaires, ecological momentary assessment, and laboratory tasks.

These will be re-evaluated during therapy, and all non-neuroimaging measures will be repeated after the rehabilitation program. Statistical analyses will comprise multivariate analysis of variance, general linear models, classification algorithms, structural equation models, least absolute shrinkage selection operator principal component regression (LASSO-PCR), cluster analysis and latent class growth analysis (LCGA).

Source: Dooms Y, Qiu L, Coppieters I, Vergaelen E, Claes S, Dupont P, Hehl M, Cuypers K, Engler H, Dombrowski K, Verbeke K, Van den Bergh O, Raes J, Van Oudenhove L, Van Den Houte M, Bogaerts K. Multimodal approach to identify neuropsychophysiological subgroups in myalgic encephalomyelitis/chronic fatigue syndrome and their relevance for rehabilitation: protocol for a mechanistic cross-sectional and longitudinal study. Brain Behav Immun Health. 2026 Jul 6;56:101299. doi: 10.1016/j.bbih.2026.101299. PMID: 42472232; PMCID: PMC13380062. https://pmc.ncbi.nlm.nih.gov/articles/PMC13380062/ (Full text)

Raman Spectroscopy Combined with Machine Learning Reveals Myalgic Encephalomyelitis–Associated Biomolecular Signatures at Rest and After Standardized Stress

Abstract:

Myalgic encephalomyelitis (ME) is characterized by profound fatigue, post-exertional malaise (PEM), and cognitive dysfunction. Despite its clinical significance, the pathophysiology of PEM and disease heterogeneity remain unclear, and no validated biomarkers are available for rapid diagnosis or monitoring. We aimed to develop a screening approach combining label-free Raman spectroscopy (RS) and machine learning modeling (ML) to detect biomolecular changes in blood plasma and differentiate patients with ME from sedentary healthy controls.
Blood plasma was collected from 115 patients with ME and 45 controls at rest (T0) and 90 min after a standardized, non-invasive stress test designed to induce PEM. Plasma samples were analyzed by RS, and ML models were developed independently at each time point to differentiate patients with ME and controls.
The RS-ML models identified spectral features consistent with contributions from proteins, lipids, and low-molecular-weight metabolites. At T0 and T90, the area under the receiver operating characteristic curve, accuracy, specificity and sensitivity were 0.85 and 0.83, 79% and 84%, 82% and 90%, and 73% and 69%, respectively. RS-ML provides a rapid, low-cost approach to detect ME-associated biomolecular signatures in plasma and capture biochemical alterations associated with standardized stress.
Source: Heidarifard M, Moezzi A, Dallaire F, Ember K, Elremaly W, Caraus I, Franco A, Leblond F, Moreau A, Dehaes M. Raman Spectroscopy Combined with Machine Learning Reveals Myalgic Encephalomyelitis–Associated Biomolecular Signatures at Rest and After Standardized Stress. International Journal of Molecular Sciences. 2026; 27(11):4937. https://doi.org/10.3390/ijms27114937 https://www.mdpi.com/1422-0067/27/11/4937 (Full text)