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)

“I would love to say it’s the fatigue but honestly it’s not”: Into Adulthood with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Abstract:

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is a debilitating and poorly understood condition which interferes with adolescents’ typical development. This study aimed to explore the experience of transitioning into adulthood from the perspective of adolescents and young adults (16-25yo) with CFS/ME.

Thirteen young people recruited through a community allied health clinic in Victoria, Australia, participated in semi-structured interviews. Interviews were analysed using reflexive thematic analysis and produced the following themes: Independence: a different path or an inaccessible adulthood? Identity: who could I have been? Isolation and disconnection: being with people but not being like them.

Our analysis of these themes suggests several avenues to support young people with CFS/ME and their families. Mental health professionals may have a specific role in helping foster assertiveness and confidence, assisting identity exploration and understanding, and supporting families in helping their adolescent to continue to develop psychologically.

Source: Tenhave, A., Bognar, R., & Sidis, A. (2025). “I would love to say it’s the fatigue but honestly it’s not”: Into Adulthood with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. Psychology, Health & Medicine, 1–19. https://doi.org/10.1080/13548506.2025.2495891 https://www.tandfonline.com/doi/full/10.1080/13548506.2025.2495891 (Full text)

Awareness and Perception of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome Among Pain Specialists: A Questionnaire-Based Study

Abstract:

Background: This study aims to explore the perceptions and clinical approaches of pain management specialists toward myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a condition characterized by persistent fatigue, widespread pain, unrefreshing sleep, and autonomic dysfunction. Given the challenges in diagnosis and management, pain specialists may play a pivotal role in symptom relief. By identifying variations in evaluation and treatment practices, this study seeks to enhance the recognition of ME/CFS and improve its clinical management within pain medicine.

Material and methods: The questionnaire was distributed in printed form to 250 pain specialists in Turkey. Given the limited number of pain physicians in the country, the study aimed to encompass all actively practicing specialists. The survey included four demographic questions, eight true-false questions, 12 multiple-choice questions, and four rating-scale questions. Data were collected anonymously. Data were analyzed using Statistical Product and Service Solutions (SPSS, version 27.0; IBM SPSS Statistics for Windows, Armonk, NY), with descriptive statistics and chi-square (χ²) tests applied to examine the relationships between awareness levels and attitudinal variables.

Results: In Turkey, 106 pain medicine physicians (42.4%) participated in the study. The average age was 40.6±8.52 years. Among the participants, 39.6% had previously heard of myalgic encephalomyelitis. Physicians were inclined to first ask the question, “Do you think you get enough sleep at night?” when evaluating these patients, with a rate of 63.2%. The majority of participants (65.9%) stated that they “occasionally” or “rarely” considered the relationship between fatigue and orthostatic intolerance. Additionally, 37.7% believed that this disease is a subtype of depression. The statement, “chronic fatigue decreases with intense aerobic exercise,” was agreed upon by 50.9% of participants. This controversial statement was particularly more common among those who were unaware of ME/CFS’s alternative name (p=0.009) and those who did not take dysautonomic disorders into account (p=0.048). When considering an ME/CFS diagnosis, physicians most frequently referred patients to the physical medicine and rehabilitation department (32.1%). Those who preferred not to refer patients to any department (12.3%) tended to find it appropriate for a patient to seek consultation at a pain medicine clinic due to widespread body pain and fatigue (χ2=11.405, p=0.044).

Conclusion: This study is the first questionnaire-based research assessing pain physicians’ awareness and attitudes toward ME/CFS. By highlighting their perspectives on its evaluation and management, our findings may improve recognition and clinical approaches to ME/CFS. Future research should focus on education and standardized guidelines to enhance patient care.

Source: Uygun GG, Gözükızıl ST, Bilen A. Awareness and Perception of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome Among Pain Specialists: A Questionnaire-Based Study. Cureus. 2025 Mar 23;17(3):e81030. doi: 10.7759/cureus.81030. PMID: 40264626; PMCID: PMC12013460. https://pmc.ncbi.nlm.nih.gov/articles/PMC12013460/ (Full text)

How I treat my patients with Myalgic Encephalomyelitis, Chronic Fatigue Syndrome (ME/CVS), fibromyalgia or “long COVID”

Abstract:

Common to Myalgic encephalomyelitis, chronic fatigue syndrome and so-called long Covid is the panoply of complaints, with Post Exertional Malaise (PEM) as the most typical symptom. Added to that are permanent feeling of fatigue, decreased capacity to concentrate, so-called brain fog, non restorative sleep, diffuse pain, and – in case of long Covid – respiratory distress.

Several recent studies have confirmed my original hypothesis that poor metabolism and energy production by the mitochondria are responsible for the majority of these phenomena. I have suggested that inhibition of Pyruvate dehydrogenase (Pdh) activity is the major reason for this. Pdh inhibition is probably caused by the excess of the phosphatase: Pyruvate Dehydrogenase Kinase (PDK). The latter results from “Systemic Immune Disorder” (what I called “SID”) and inflammation.

Based on this hypothesis I have applied oral and infusion treatment modalities which were successful in approximately 80% of 130 consecutive patients. The pivotal substances are sodium dichloroacetate, that reduces PDK, Meldonium, that facilitates intracellular glucose metabolism, and low dose Nalexone, that optimises the function of microglia.

Source: Comhaire F. How I treat my patients with Myalgic Encephalomyelitis, Chronic Fatigue Syndrome (ME/CVS),
Fibromyalgia or “long COVID”. J Clin Images Med Case Rep. 2025; 6(3): 3508. https://jcimcr.org/pdfs/JCIMCR-v6-3508.pdf (Full text)