Tag: 2025

Post-exertional malaise in Long COVID: subjective reporting versus objective assessment

Abstract:

Background: Post-exertional malaise (PEM) is a central feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and has emerged as a prominent feature of Long COVID. The optimal clinical approach to PEM is inconclusive, and studies of the impact of exercise have yielded contradictory results.

Objective: The objective of this study was to examine PEM in Long COVID by assessing the prevalence of self-reported PEM across study cohorts and symptom responses of Long COVID patients to a standardized exercise stressor. Secondarily, Long COVID symptom responses to exercise were compared to those of ME/CFS and healthy volunteers.

Methods: Data from three registered clinical trials comprised four cohorts in this study: Long COVID Questionnaire Cohort (QC; n = 244), Long COVID Exercise Cohort (EC; n = 34), ME/CFS cohort (n = 9), and healthy volunteers (HV; n = 9). All cohorts completed questionnaires related to physical function, fatigue, and/or PEM symptoms. EC also performed a standardized exercise test (cardiopulmonary exercise test, CPET), and the PEM response to CPET was assessed using visual analog scales and qualitative interviews (QIs) administered serially over 72 h. EC PEM measures were compared to ME/CFS and HV cohorts. A secondary analysis of QI explored positive responses to CPET among EC, ME/CFS and HV.

Results: Self-reported PEM was 67% in QC and estimated at 27% in EC. Only 2 of 34 EC patients (5.9%) were observed to develop PEM after a CPET. In addition, PEM responses after CPET in Long COVID were not as severe and prolonged as those assessed in ME/CFS. Twenty-two of 34 EC patients (64.7%) expressed at least one of 7 positive themes after the CPET.

Conclusion: Self-report of PEM is common in Long COVID. However, observable PEM following an exercise stressor was not frequent in this small cohort. When present, PEM descriptions during QI were less severe in Long COVID than in ME/CFS. Positive responses after an exercise stressor were common in Long COVID. Exercise testing to determine the presence of PEM may have utility for guiding clinical management of Long COVID.

Source: Stussman B, Camarillo N, McCrossin G, Stockman M, Norato G, Vetter CS, Ferrufino A, Adedamola A, Grayson N, Nath A, Chan L, Walitt B, Chin LMK. Post-exertional malaise in Long COVID: subjective reporting versus objective assessment. Front Neurol. 2025 Apr 23;16:1534352. doi: 10.3389/fneur.2025.1534352. PMID: 40337174; PMCID: PMC12055772. https://pmc.ncbi.nlm.nih.gov/articles/PMC12055772/ (Full text)

Case Report: The intersection of psychiatry and medicine: diagnostic and ethical insights from case studies

Abstract:

The intersection of psychiatry and medicine presents unique diagnostic and ethical challenges, particularly for conditions involving significant brain-body interactions, such as psychosomatic, somatopsychic, and complex systemic disorders. This article explores the historical and contemporary issues in diagnosing such conditions, emphasizing the fragmentation of medical and psychiatric knowledge, biases in clinical guidelines, and the mismanagement of complex illnesses.

Diagnostic errors often arise from insufficient integration between general medicine and psychiatry, compounded by the reliance on population-based guidelines that neglect individual patient needs. Misclassification of conditions like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Lyme disease, and fibromyalgia as psychosomatic or psychogenic has led to stigmatization and delayed care. While these conditions are referenced as emblematic examples of misclassified and poorly understood disorders, the five clinical cases discussed in this article do not directly illustrate these diseases. Instead, they exemplify shared diagnostic and ethical dilemmas at the medicine–psychiatry interface, including uncertainty, fragmentation, and the risk of epistemic injustice.

The article critically examines terms like medically unexplained symptoms and functional disorders, highlighting their limitations and potential for misuse. Case examples underscore the consequences of diagnostic inaccuracies and the urgent need for improved approaches. Ethical considerations are also explored, emphasizing respecting patient experiences, promoting individualized care, and acknowledging the inherent uncertainties in medical diagnosis.

Advances in technologies such as brain imaging and molecular diagnostics offer hope for bridging the gap between psychiatry and medicine, enabling more accurate assessments and better patient outcomes. The article concludes by advocating comprehensive training at the medicine-psychiatry interface and a patient-centered approach that integrates clinical observation, research insights, and a nuanced understanding of mind-body dynamics.

Source: Monaco F, Vignapiano A, D’Angelo M, Raffone F, Di Stefano V, Boccia A, Longobardi A, Gruttola BD, Fornaro M, Corrivetti G, Martino I, Steardo L, Steardo L Jr. Case Report: The intersection of psychiatry and medicine: diagnostic and ethical insights from case studies. Front Psychiatry. 2025 Apr 22;16:1576179. doi: 10.3389/fpsyt.2025.1576179. PMID: 40330647; PMCID: PMC12053010. https://pmc.ncbi.nlm.nih.gov/articles/PMC12053010/ (Full text)

Dissecting the genetic complexity of myalgic encephalomyelitis/chronic fatigue syndrome via deep learning-powered genome analysis

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, heterogeneous, and systemic disease defined by a suite of symptoms, including unexplained persistent fatigue, post-exertional malaise (PEM), cognitive impairment, myalgia, orthostatic intolerance, and unrefreshing sleep. The disease mechanism of ME/CFS is unknown, with no effective curative treatments.

In this study, we present a multi-site ME/CFS whole-genome analysis, which is powered by a novel deep learning framework, HEAL2. We show that HEAL2 not only has predictive value for ME/CFS based on personal rare variants, but also links genetic risk to various ME/CFS-associated symptoms. Model interpretation of HEAL2 identifies 115 ME/CFS-risk genes that exhibit significant intolerance to loss-of-function (LoF) mutations. Transcriptome and network analyses highlight the functional importance of these genes across a wide range of tissues and cell types, including the central nervous system (CNS) and immune cells.

Patient-derived multi-omics data implicate reduced expression of ME/CFS risk genes within ME/CFS patients, including in the plasma proteome, and the transcriptomes of B and T cells, especially cytotoxic CD4 T cells, supporting their disease relevance. Pan-phenotype analysis of ME/CFS genes further reveals the genetic correlation between ME/CFS and other complex diseases and traits, including depression and long COVID-19.

Overall, HEAL2 provides a candidate genetic-based diagnostic tool for ME/CFS, and our findings contribute to a comprehensive understanding of the genetic, molecular, and cellular basis of ME/CFS, yielding novel insights into therapeutic targets. Our deep learning model also offers a potent, broadly applicable framework for parallel rare variant analysis and genetic prediction for other complex diseases and traits.

Source: Zhang S, Jahanbani F, Chander V, Kjellberg M, Liu M, Glass KA, Iu DS, Ahmed F, Li H, Maynard RD, Chou T, Cooper-Knock J, Zhang MJ, Thota D, Zeineh M, Grenier JK, Grimson A, Hanson MR, Snyder MP. Dissecting the genetic complexity of myalgic encephalomyelitis/chronic fatigue syndrome via deep learning-powered genome analysis. medRxiv [Preprint]. 2025 Apr 16:2025.04.15.25325899. doi: 10.1101/2025.04.15.25325899. PMID: 40321247; PMCID: PMC12047926. https://pmc.ncbi.nlm.nih.gov/articles/PMC12047926/ (Full text available as PDF file)

Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID: Commonalities Detected by Invasive Cardiopulmonary Exercise Testing

Abstract:

Rationale: There is substantial overlap of exertional symptoms in Long COVID (LC) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) including intractable fatigue, post-exertional malaise (PEM), and orthostatic intolerance, but very little objective data liking the two. This study compares exercise pathophysiology in the two disorders and normal controls using invasive cardiopulmonary exercise testing (iCPET).

Methods: Between January 2019 and December 2024, 1,518 patients underwent a clinical iCPET at Brigham and Women’s Hospital. Exclusion criteria included morbid obesity (BMI>40 kg/m2), severe anemia ([Hb]<9.0 g/dL), elite athletes (peak VO2 (pVO2)>120% predicted), sub-maximum effort (RER<1.05), a primary pulmonary mechanical limit (VE @ AT/MVV>0.7), and comorbidities such as active/treated cancer, interstitial lung disease, or other respiratory related diseases. iCPET results from 438 ME/CFS patients, 73 LC patients, and 43 symptomatic but otherwise normal controls were analyzed. pV02, peak cardiac output (pQc), peak right atrial pressure (pRAP), peak systemic oxygen extraction (pSOE; Ca-vO2/[Hb]), and ventilatory inefficiency (VE/VCO2 slope) were compared among groups. Statistical significance was determined using Kruskal-Wallis tests for global comparisons, with post-hoc Dunn tests for pairwise group comparisons. Holm-Bonferroni adjustments were applied to control for multiple comparisons.

Results: LC and ME/CFS displayed reduced pVO2 % predicted compared to controls (LC: 78.4 ± 18%, ME/CFS: 78.1 ± 17%, Controls: 97.5 ± 10%, P≤0.0001). Reduced pQc % predicted was also observed compared to controls (LC: 91.1 ± 18%, ME/CFS: 96.3%, Controls: 101 ± 11%, P≤0.001). pRAP were significantly less compared to controls (LC: 1.1 ± 3.1 mmHg, ME/CFS: 1.3 ± 2.8 mmHg, Controls: 3.6 ± 3.4 mmHg, P≤0.001). Significant reductions in pSOE were seen for LC and ME/CFS (LC: 0.81 ± 0.1, ME/CFS: 0.81 ± 0.1, Controls, 0.91 ± 0.1, P≤0.0001). The only measure with no significant difference between disease and control was VE/VCO2 slope (LC: 31.4 ± 8.4, ME/CFS: 31.6 ± 6.9, Controls: 32.0 ± 6.7, P≥0.261). Most interestingly, no significant differences were seen between the two diseases for any of the analyzed measures (P≥0.245).

Conclusions: We report the largest cohort of ME/CFS and LC investigated with iCPET to date. ME/CFS and LC share symptomatic, reduced aerobic capacity at peak exercise, which is driven by preload insufficiency and impaired systemic O2 extraction, the latter compatible with peripheral left-to-right shunting and/or limb skeletal muscle dysfunction. These findings should drive future diagnostics and personalized medicine in both diseases. We hope these data inform the pending prospective NIH RECOVER iCPET study of LC.

Source: J. Squires, S. Palwayi, P. Li, W. Xiao, K. LeWine, S.W. Johnson, D. Felsenstein, A.B. Waxman, and D.M. Systrom. Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID: Commonalities Detected by Invasive Cardiopulmonary Exercise Testing [abstract]. Am J Respir Crit Care Med 2025;211:A7881. https://www.atsjournals.org/doi/​10.1164/ajrccm.2025.211.Abstracts.A7881

Research Supports the Integration of Acupuncture in Mainstream Health Care for the Management of Chronic Diseases

Abstract:

Purpose: To address the role of acupuncture in mainstream health care for symptom relief, condition outcome, pain management, and shared therapy in resolving chronic diseases. This article explores how acupuncture education can adapt to meet the standards required for inclusion in conventional health care.

Objectives: To discuss the future of acupuncture education and its part in training providers for inclusion in a comprehensive health care system that involves physician acupuncturists and licensed acupuncturists for treating and managing specific chronic diseases. To strategize the future of acupuncture education at an advanced clinical level that fosters incorporating acupuncture therapy into selected allopathic settings. To encourage the recognition of translational research for promoting the acceptance of acupuncture by providers and insurers.

Conclusion: Translational research employs clinical evidence to support acupuncture therapy when incorporated into selected areas of allopathic practices, including pain management, palliative care for patients with end-stage cancer, sleep disorders, anxiety disorders, post-traumatic stress, female hormonal conditions such as premenstrual syndrome and menopausal syndrome, as well as chronic fatigue syndromes including Myalgic encephalomyeltitis/chronic fatigue syndrome (ME/CFS) and Long COVID. Advanced clinical training in acupuncture schools and postgraduate certification courses are required to prepare acupuncturists to safely and effectively provide the specialized integrative acupuncture services needed in these clinical areas.

Source: Williams JE, Kim Y, Moramarco J. Research Supports the Integration of Acupuncture in Mainstream Health Care for the Management of Chronic Diseases. Med Acupunct. 2025 Apr 17;37(2):106-111. doi: 10.1089/acu.2024.0108. PMID: 40308724; PMCID: PMC12038303. https://pubmed.ncbi.nlm.nih.gov/40308724/

Recovery from Myalgic Encephalomyelitis/Chronic Fatigue syndrome developed after severe acute respiratory syndrome coronavirus 2 vaccination: A case report

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a neurological adverse effect after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinations. However, clinicians do not recognize the condition well, and no case report has shown a full recovery.

Case presentation: We present a 65-year-old Japanese female who experienced severe fatigue, postexertional malaise, orthostatic intolerance, and various symptoms after her third SARS-CoV-2 vaccination. Following thorough examinations and excluding other potential diagnoses, she met the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The symptoms persisted for 30 months and improved ultimately with comprehensive treatment and a self-management strategy, including pacing management, pharmacological treatments, and psychiatric interventions to support those struggling with the despair over the devastating symptoms.

Conclusion: This case report describes ME/CFS following the SARS-CoV-2 vaccination and its full recovery. It illustrates the importance of considering the differential diagnosis of psychiatric disorders and addressing the condition through psychiatric interventions. Our findings provide new insights into treating ME/CFS and the vaccination-related adverse effects.

Source: Kurotori I, Sasao W, Abe M. Recovery from Myalgic Encephalomyelitis/Chronic Fatigue syndrome developed after severe acute respiratory syndrome coronavirus 2 vaccination: A case report. PCN Rep. 2025 Apr 27;4(2):e70111. doi: 10.1002/pcn5.70111. PMID: 40291166; PMCID: PMC12034265. https://pmc.ncbi.nlm.nih.gov/articles/PMC12034265/ (Full text)

The PACE Trial’s GET Manual for Therapists Exposes the Fixed Incremental Nature of Graded Exercise Therapy for ME/CFS

Abstract:

The British National Institute for Health and Care Excellence (NICE) published its updated guidelines for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in October 2021. NICE concluded, after an extensive review of the literature, that graded exercise therapy (GET) is harmful and should not be used, and that cognitive behavioural therapy (CBT) is only an adjunctive and not a curative treatment. An article by White et al., which is written by 51 researchers, claims that there are eight anomalies in the review process and the interpretation of the evidence by NICE. In this article, we reviewed the evidence they used to support their claims.

Their three most important claims are that NICE redefined the disease, that CBT and GET are effective, and that fixed incremental increases are not part of GET. However, our analysis shows that the disease was not redefined by NICE. Instead, it was redefined in the 1990s by a group of doctors, including a number of authors of White et al., when they erased the main characteristic of the disease (an abnormally delayed muscle recovery after trivial exertion, which, over the years, has evolved into post-exertional malaise) and replaced it with chronic disabling severe fatigue. Their own studies show that CBT and GET do not lead to a substantial improvement of the quality-of-life scores or a reduction in CFS symptom count, nor do they lead to objective improvement.

Also, both treatments have a negative instead of a positive effect on work and disability status. Moreover, a recent systematic review, which included one of the authors of White et al., showed that ME/CFS patients remain severely disabled after treatment with CBT. Our analysis of, for example, the PACE trial’s GET manual for therapists exposes the fixed incremental nature of GET.

Why the authors are not aware of that is unclear because eight of them were involved in the PACE trial. Three of them were centre leaders and its principal investigators, four others were also centre leaders, and another one was one of the three independent safety assessors of the trial. Moreover, many of these eight authors wrote, or were involved in writing, this manual.

In conclusion, our analysis shows that the arguments that are used to claim that there are eight anomalies in the review process and the interpretation of the evidence by NICE are anomalous and highlight the absence of evidence for the claims that are made. Furthermore, our analysis not only exposes the fixed incremental nature of GET, but also of CBT for ME/CFS.

Source:Vink M, Partyka-Vink K. The PACE Trial’s GET Manual for Therapists Exposes the Fixed Incremental Nature of Graded Exercise Therapy for ME/CFS. Life (Basel). 2025 Apr 2;15(4):584. doi: 10.3390/life15040584. PMID: 40283139. https://www.mdpi.com/2075-1729/15/4/584 (Full text)

Mixed methods study of views and experience of non-hospitalised individuals with long COVID of using pacing interventions

Abstract:

Long COVID is highly prevalent and debilitating, with key symptoms including fatigue, breathlessness, and brain fog. Pacing is an approach to energy conservation used to help people with chronic conditions like ME/CFS manage the impact of their condition, and could be a useful strategy for people with Long COVID. The aim of this study was to explore the views and experiences of non-hospitalised adults with Long COVID of pacing as an intervention.

This mixed methods study is part of the Therapies for Long COVID (TLC) Feasibility trial. A feasibility questionnaire was developed for participants. In addition, semi-structured interviews were conducted with a sub-sample of participants at the end of the study and these interviews were analysed using the reflexive thematic analysis approach. 28 participants completed the feasibility questionnaire and 19 participants took part in a qualitative interview.

found that pacing helped improve motivation and activity planning. Concerns included challenges due to time constraints, complexity of the intervention, and limited instructions. Pacing for Long COVID may offer potential benefits and is feasible but further research is required to demonstrate its benefits. Overall, research on pacing in the context of Long COVID has the potential to enhance our understanding of symptom management and rehabilitation strategies for this emerging population.

Source: McMullan C, Haroon S, Turner G, Aiyegbusi OL, Hughes SE, Flanagan S, Subramanian A, Nirantharakumar K, Davies EH, Frost C, Jackson L, Guan N, Alder Y, Chong A, Buckland L, Jeyes F, Stanton D, Calvert M. Mixed methods study of views and experience of non-hospitalised individuals with long COVID of using pacing interventions. Sci Rep. 2025 Apr 25;15(1):14467. doi: 10.1038/s41598-025-96319-6. PMID: 40280997. https://www.nature.com/articles/s41598-025-96319-6 (Full text)

Assessing the Relationship in Symptomology of Myalgic Encephalitis/Chronic Fatigue Syndrome and Long COVID

Abstract:

The symptomology of Myalgic Encephalitis/Chronic Fatigue Syndrome (ME/CFS) shares many commonalities with Long COVID (LC). This study aimed to clearly define the comparison between ME/CFS and LC in terms of symptomology.

A cross-sectional analysis of 27,651 interviewees from a National Health Interview Survey 2022 adult dataset was conducted. The data was controlled for subject’s sex, race/ethnicity, age, life satisfaction, insurance coverage, poverty ratio, and comorbidities. A logistic regression was used to compare four groups: (1) LC individuals, (2) ME/CFS individuals, (3) LC with ME/CFS individuals, and (4) controls by symptoms of depression, anxiety, physical activity, fatigue, and memory.

The results showed that subjects with both ME/CFS and LC were more likely to report memory issues, anxiety, depression, fatigue, and difficulty with physical activity followed by subjects with ME/CFS only, LC only, and the controls (P < .01).

Our study suggests a synergistic mechanism between ME/CFS and LC in developing issues with anxiety, depression, fatigue, and physically activity in patients. The study’s conclusions highlight the need to elucidate the possible overlap in pathophysiological mechanisms of ME/CFS and LC in the symptomology of patients.

Source: Garapaty N, Reyes KM, Tehrani L, Mendoza MB, Hardigan P. Assessing the Relationship in Symptomology of Myalgic Encephalitis/Chronic Fatigue Syndrome and Long COVID. Am J Med Open. 2025 Feb 1;13:100085. doi: 10.1016/j.ajmo.2024.100085. PMID: 40271015; PMCID: PMC12017839. https://pmc.ncbi.nlm.nih.gov/articles/PMC12017839/ (Full text)

Anti-central fatigue effects of myelophil in 5-HTergic hyperactivity mice model

Abstract:

Background: Myelophil is a standardized ethanol extract of Astragali Radix and Salviae Miltiorrhizae Radix, which has been developed based on clinical experience in traditional Korean medicine practices for patients with unexplained chronic fatigue, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Our previous studies demonstrated Myelophil’s clinical efficacy in ME/CFS, as well as its brain-related activities in animal models. However, the underlying pharmacological mechanisms remain unclear. Recently, we identified serotonergic hyperactivity as a key pathophysiological factor in central fatigue, such as ME/CFS. Therefore, in the present study, we aimed to investigate the mechanisms by which Myelophil exerts its effects, particularly in the context of a 5-HTergic hyperactivity model.

Method: To verify the action mechanisms of Myelophil on serotonergic hyperactivity condition, we herein assessed its anti-central fatigue properties using a fluoxetine-treated mice model. Male C57BL/6 N mice (9 weeks old) were subjected to periodic intraperitoneal (IP) injections of fluoxetine for 4 weeks and the mice were simultaneously oral administered Myelophil (0, 50, or 100 mg/kg) or ascorbic acid (100 mg/kg).

Result: Four-week injection of fluoxetine notably increased serotonin (5-hydroxytryptamine, 5-HT) activity, as evidenced by immunofluorescence staining and Western blot assays in the raphe nuclei (RN), and induced central fatigue-like behaviors in the nest building test, wheel running test, rota-rod test, plantar test, and open field test. Meanwhile, Myelophil (100 mg/kg) administration significantly ameliorated those fatigue-related behaviors including pain sensitivity. Furthermore, the anti-fatigue effects of Myelophil were corroborated by changes in serotonin-related parameters (serotonin transporter; 5-HTT and vesicular monoamine transporter 2; VMAT2), as well as neurotrophic markers including c-Fos and brain-derived neurotrophic factor (BDNF) in the RN.

Conclusion: These results provide experimental evidence suggesting the potential mechanisms by which Myelophil may alleviate central fatigue associated with hyper-5-HTergic activity.

Source: Kang JY, Baek DC, Lee JS, Son CG. Anti-central fatigue effects of myelophil in 5-HTergic hyperactivity mice model. BMC Complement Med Ther. 2025 Apr 23;25(1):153. doi: 10.1186/s12906-025-04882-2. PMID: 40269903; PMCID: PMC12020330. https://pmc.ncbi.nlm.nih.gov/articles/PMC12020330/ (Full text)