Tag: PEM

Development and initial content validation of the Vienna post-exertional malaise questionnaire: an iterative mixed-methods study

Abstract:

Objectives: Post-exertional malaise (PEM) is a multidimensional exertion-response pattern involving diverse triggers, variable onset, and prolonged recovery. This study developed and content-validated the Vienna Post-Exertional Malaise (VPEM) Questionnaire, a patient-reported outcome measure assessing functional decline, recovery, crash-associated symptoms, and pacing adaptations in ME/CFS.

Methods: An iterative mixed-methods instrument-development study combined quantitative ratings and qualitative feedback across sequential evaluation cycles. An initial 13-item draft, informed by existing PEM, fatigue, and functional-capacity instruments and consensus literature, was evaluated by individuals with ME/CFS or Post-COVID-19 syndrome (PCS) using Likert ratings, open-ended feedback, and interviews. Quantitative data were summarised descriptively, and qualitative data were analysed using deductive-inductive structuring content analysis. Revisions were documented in revision matrices. The revised instrument was evaluated by an interdisciplinary expert panel using domain-level and item-level ratings of relevance and clarity.

Results: Twelve individuals with ME/CFS and one individual with PCS fulfilling ME/CFS criteria evaluated the questionnaire. Ratings showed high approval for length (92.3%) and terminology (76.9%), while completeness and clarity were more heterogeneous. Qualitative findings identified ambiguities in distinguishing PEM from non-specific fatigue, missing trigger domains, and insufficient representation of intra-individual variability. After revision, the expert panel (n = 11) rated PEM coverage as complete or largely complete (100%) and the multidimensional structure as suitable or very suitable (90.9%). Item-level ratings showed high relevance (S-CVI/Ave = 0.96), whereas clarity ratings were more variable (S-CVI/Ave = 0.82).

Conclusions: The VPEM Questionnaire operationalises PEM as multidimensional post-exertional deterioration. Findings support initial content and face validity, warranting further psychometric validation.

Source: Pimminger T, Ahrens-Schwabe A, Fragner T, Brandl T, Kotzian ST, Wüst RCI, Waldhoer T, Kapan A. Development and initial content validation of the Vienna post-exertional malaise questionnaire: an iterative mixed-methods study. Qual Life Res. 2026 Nov 7;35(12):327. doi: 10.1007/s11136-026-04434-2. PMID: 42998183; PMCID: PMC13744550. https://pmc.ncbi.nlm.nih.gov/articles/PMC13744550/ (Full text)

ME/CFS and the thalamus as a precision gate: what reversible thalamocortical connectivity reveals about central gain in post-infectious fatigue

Abstract:

Kim and colleagues report a finding that is easy to understate: thalamic hyperconnectivity with sensorimotor and visuo-occipital cortices, present in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) at baseline, shifts back toward the pattern seen in healthy controls after hyperbaric oxygen therapy and does so most in the patients who improve clinically. To my knowledge, this is the first treatment-coupled, apparently reversible thalamocortical signature in ME/CFS.

Viewed through predictive processing (the framework in which the brain continually predicts its own sensory and bodily inputs), the thalamus is theorised to be a gain-control gate that helps set the precision or weight assigned to ascending bodily signals. I argue that the baseline hyperconnectivity reflects deficient filtering of expected input, and that its post-treatment reduction may index restored filtering. The same failure of attenuation offers a parsimonious account of several symptoms that often co-occur in patients, including sensory hypersensitivity, pain, orthostatic intolerance, and cognitive “brain fog”, as one mechanism expressed across exteroceptive, nociceptive, autonomic, and cognitive domains.

Because hyperbaric oxygen therapy is a vascular intervention and resting-state connectivity is an indirect measure this gain interpretation remains a hypothesis and I outline how it can be tested across exertion and post-exertional malaise rather than at baseline alone.

Source: Strube A. ME/CFS and the thalamus as a precision gate: what reversible thalamocortical connectivity reveals about central gain in post-infectious fatigue. J Transl Med. 2026 Jul 29;24(1):1345. doi: 10.1186/s12967-026-08718-6. PMID: 42934697. https://link.springer.com/article/10.1186/s12967-026-08718-6 (Full text)

Recognizing and managing post-exertional malaise in primary care

Abstract:

in English, French

Post-exertional malaise (PEM) is a syndrome characterized by a worsening of symptoms after physical, cognitive, or emotional exertion. It presents as increased fatigue, usually accompanied by other clinical symptoms, such as muscle pain or cognitive impairment. First described in patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), PEM is now recognized as a hallmark of post-infectious syndromes that have received increasing attention through the emergence of long COVID. PEM is a distinguishing symptom of these conditions, and its early detection and appropriate management are essential to prevent long-term functional decline of affected patients. This review describes the definition and clinical impact of PEM and summarizes current recommendations for its management.

Source: Garcia S, Tzartzas K, von Plessen C, Favrat B, Kokkinakis I. Reconnaître et gérer le malaise post-effort en médecine de premier recours [Recognizing and managing post-exertional malaise in primary care]. Rev Med Suisse. 2026 Oct;22(1):17-21. French. doi: 10.53738/REVMED.2026.22.1.e48753. PMID: 42899626. https://pubmed.ncbi.nlm.nih.gov/42899626/

Explaining Fatigue and Post-Exertional Malaise in Long COVID and ME/CFS: From Skeletal Muscle To Exercise Immunology

Abstract:

The SARS-CoV-2 viral outbreak in 2020 resulted in a record number of global hospitalizations and deaths. Although most people recover from an initial COVID infection within 3 months, around 10% of people have symptoms that do not improve after 3 months, which is called long COVID. Other viruses and bacterial infections can also result in long-term symptoms, which is known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

One of the most common symptoms of long COVID or ME/CFS is post-exertional malaise, which is the worsening of symptoms or development of new symptoms after physical, mental or emotional stress. This can lead to patients leading less physically active lifestyles. Physical activity is known to be beneficial for overall health and wellbeing, mostly by increasing exercise capacity, which is a significant predictor in long-term health. Physical inactivity.

It is thought that many symptoms of long COVID and ME/CFS can be explained by lower physical activity of patients. However, people who are less physically active don’t experience post-exertional malaise, implying there are disease-specific changes. Many of the benefits that come from exercise come from a persons ability to adapt to an exercise session. Usually, exercise will create a short energy deficit, which then may result in small amounts of muscle damage. This then triggers a short-lived immune response, led first by neutrophils and macrophages, which result in activation of fibroadipogenic progenitor cells (FAP cells) and satellite cells (muscle stem cells). FAP cells and satellite cells communicate to repair damage to the muscle itself, while immune cells clear debris surrounding the muscle. In healthy situations, this creates a stronger, more resilient muscle. It is unknown whether these responses are still seen in long COVID or ME/CFS. The goal of this thesis then to 1) understand muscle changes in patients with long COVID and ME/CFS, 2) to better understand how these changes may relate to PEM, 3) to understand whether the muscle changes in patients are a result of physical inactivity.

Within the thesis, I find that patients with long COVID and ME/CFS have specific patterns of skeletal muscle that separate them from healthy individuals. This is highlighted by more fast-twitch fibre types, slow-twitch muscle atrophy, lower mitochondrial respiration that is separate from just mitochondrial loss, less metabolites related to oxidative capacity and antioxidation, less lipids that are required for cell membrane maintenance, and lower amounts of satellite cells and FAP cells.

Beyond this, I find that ME/CFS can be distinguished from long COVID by less capillaries, less slow-twitch fibres, less local immune cells, and lower amounts of several essential amino acids. As well, I find evidence that physical inactivity alone cannot explain long COVID and ME/CFS symptoms. Where all of long COVID, ME/CFS, and physical inactivity have lower whole-body aerobic capacity, physical inactivity causes a decrease in muscle fibre size, loss of mitochondria, increases in muscle lipotoxic lipids, and decreases in metabolites related to carnitine metabolism. These changes are not seen in either long COVID nor ME/CFS, and support the idea that long COVID and ME/CFS have disease specific muscle changes.

Overall, I find that the reduced whole-body capacity of long COVID and ME/CFS patients is not cause by physical inactivity, and is defined by reduced muscle oxidative ability. The lower amounts of local cells that would normally support exercise and damage responses are lower in both long COVID and ME/CFS, which partially explains the occurrence of PEM. This also suggests that patients experiencing PEM should not undertake normal rehabilitation, however it might be that more individually tailored, and severely monitored approaches may still be beneficial.
Source: Charlton, B. T. (2026). Explaining Fatigue and Post-Exertional Malaise in Long COVID and ME/CFS: From Skeletal Muscle To Exercise Immunology. [PhD-Thesis – Research and graduation internal, Vrije Universiteit Amsterdam]. https://doi.org/10.5463/thesis.1979 https://research.vu.nl/en/publications/explaining-fatigue-and-post-exertional-malaise-in-long-covid-and-/ https://research.vu.nl/ws/portalfiles/portal/517511531/aio01877%20braeden%20charltonfinal%20-%206acf4153820e1.pdf (Full text)

Measures of Overall Illness Severity and Burden for ME/CFS: A Scoping Review

Abstract:

Background and objectives: Consensus has not been established on measures of illness severity and burden for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), which is characterized by a wide range of symptoms including post-exertional malaise, unrefreshing sleep, and cognitive impairment. A scoping review was conducted to systematically evaluate the measurement of illness severity and burden in individuals with ME/CFS.

Methods: A literature search was conducted following PRISMA-ScR guidelines across five academic databases and one patient-organization-led website (with no restrictions on publication date; restricted to English language studies, and excluding review articles). Records were imported into Covidence, a systematic and scoping review data management tool, with studies retained if they evaluated an ME/CFS population and explicitly measured illness severity or illness burden. Information from each source was extracted and relevant measures were evaluated.

Results: From the reviewed literature, 190 full-text articles met the final inclusion criteria and were retained for analysis. The most frequently utilized tools for evaluating illness severity and burden in individuals with ME/CFS were the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the Sickness Impact Profile (SIP). Additional prominent instruments identified across the literature include disease-specific measures such as the DePaul Symptom Questionnaire (DSQ) and generic health-related quality of life indices like the EuroQoL 5-Dimension (EQ-5D-5L).

Conclusions: Significant discrepancies persist in how illness severity and illness burden are operationalized in ME/CFS research. The reliance on generic instruments often obscures core symptom domains like post-exertional malaise (PEM), while inconsistent standards limit cross-comparability. Establishing standardized, disease-specifici illness metrics is critical to accurately capturing the true burden of illness and advancing rigorous clinical research.

Source: Cripe J, Ravichandran S, Deditz S, Jason LA. Measures of Overall Illness Severity and Burden for ME/CFS: A Scoping Review. Patient. 2026 Oct 15. doi: 10.1007/s40271-026-00849-8. Epub ahead of print. PMID: 42879116. https://pubmed.ncbi.nlm.nih.gov/42879116/

Comprehensive review of myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, debilitating disease that is unexplained and is characterised by persistent unexplained fatigue, Post Exertional Malaise (PEM), cognitive impairment, unrefreshing sleep and multisystem impairment. Despite the high burden of symptoms and the worldwide prevalence, ME/CFS has been poorly understood, underdiagnosed and underfunded. This large-scale review summarises the available evidence regarding the epidemiology, diagnostic progress, main clinical characteristics, pathophysiological theories and therapeutic approaches for ME/CFS.

Despite problems with diagnostic consistency, the lack of validated biomarkers, and historical linkage to psychiatric illness, the recognition of this condition has been delayed and has led to patient marginalisation. The review highlights PEM as a cardinal symptom and reviews the weaknesses in earlier diagnostic criteria, as well as current changes in treatment guidelines, including the formal withdrawal of Graded Exercise Therapy, which has evidence of harm.

New pathophysiological evidence suggests mitochondrial dysfunction, immune dysregulation, autonomic imbalance, neuroinflammation, and alterations in gut microbiome. New diagnostic and therapeutic strategies, such as metabolomic and electrophysiological assays, mTOR inhibitors, and decentralised clinical trial designs, are being studied. This intersection with Long COVID offers a chance to rapidly advance studies of post-infectious chronic diseases. The paper also argues for stringent subtyping, uniform data collection, and ongoing patient participation in research as strategies to surmount challenges of heterogeneity.

Finally, it underscores the critical need for fair funding of research, so biomarker discovery and development of disease-modifying treatments can be achieved. The care of people with ME/CFS is not only a clinical obligation, but also a public health one.

Source: Jeyaraman, M., Jeyaraman, N., Ramasubramanian, S. et al. Comprehensive review of myalgic encephalomyelitis/chronic fatigue syndrome. J Transl Med (2026). https://doi.org/10.1186/s12967-026-08833-4 https://link.springer.com/article/10.1186/s12967-026-08833-4 (Full text)

Epigenome-wide profiling identifies distinct DNA methylation architecture underlying ME/CFS and fibromyalgia symptom burden

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia are overlapping chronic disorders characterized by fatigue, pain, cognitive dysfunction, sleep disturbance, and multisystem symptoms. Whether peripheral blood DNA methylation reflects diagnostic categories, quantitative symptom burden, or both remains unclear. We aimed to identify DNA methylation axes associated with diagnosis, symptom dimensions, and clinical differences between these conditions.

Methods: This cross-sectional study included 188 women: 73 healthy controls, 71 with ME/CFS, and 44 with fibromyalgia. DNA methylation was profiled in peripheral blood mononuclear cells using the Illumina MethylationEPIC v2 array. Principal component analysis identified latent methylation axes. Linear models adjusted for age, body mass index, and estimated immune-cell composition tested associations with diagnostic group and clinical measures. Region-level methylation analyses, functional enrichment, bootstrap resampling, permutation testing, leave-one-out analyses, and medication/comorbidity sensitivity analyses were performed.

Results: Both patient groups had greater symptom burden than healthy controls but differed clinically. Fibromyalgia showed greater widespread pain, pain catastrophizing, central sensitization inventory scores, and temporal summation, whereas ME/CFS showed greater post-exertional malaise, cognitive symptoms, and lower physical activity. Two methylation axes showed clinically relevant associations. PC5 differentiated ME/CFS from fibromyalgia and healthy controls and was associated mainly with post-exertional malaise and cognitive symptoms. PC6 separated both patient groups from healthy controls but not from each other, and was associated with broader symptom burden, including widespread pain, pain impact, sleep disturbance, visceral symptoms, and temporal summation. The temporal summation association, together with higher widespread pain and temporal summation in fibromyalgia, suggests that PC6 includes a pain-related component extending to experimentally assessed nociceptive summation. Region-level analyses identified 591 PC5-associated and 54 PC6-associated high-confidence differentially methylated regions. Enrichment implicated neuroimmune, metabolic, cytokine, NF-κB, JAK-STAT, TGF-β, and immune-regulatory pathways. Sensitivity analyses supported the stability of the main associations.

Conclusions: Peripheral blood DNA methylation profiles identified partly distinct but overlapping DNA methylation axes in ME/CFS and fibromyalgia. PC5 was aligned with post-exertional malaise and cognitive symptoms, whereas PC6 was aligned with broader pain-related multisystem burden. Independent replication and longitudinal studies are needed to establish clinical utility.

Source: Polli A, Hendrix J, Wyns A, Van Campenhout J, Allard S, Aerts JL, Laeremans T, Xiong H, Buntinx Y, Michiels J, Ben Amar J, Godderis L, Thienpont B, Nijs J. Epigenome-wide profiling identifies distinct DNA methylation architecture underlying ME/CFS and fibromyalgia symptom burden. J Transl Med. 2026 Aug 22;24(1):1222. doi: 10.1186/s12967-026-08824-5. PMID: 42811334. https://link.springer.com/article/10.1186/s12967-026-08824-5 (Full text)

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)