Tag: long covid vs ME/CFS

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)

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

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)

Autoantibody targeting therapies in post COVID syndrome and myalgic encephalomyelitis/chronic fatigue syndrome

Introduction:

Following the shift of SARS-CoV-2 from pandemic to endemic, post COVID syndrome (PCS) joins the list of already known post-acute infection syndromes (PAIS) and its most severe manifestation, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The exact pathomechanism of PCS has not yet been fully understood. Immune dysregulation with persistent inflammation, microvascular injury with endothelial dysfunction, autonomic nervous system dysfunction, mitochondrial dysfunction, gut microbiome dysbiosis and persistence of SARS-CoV-2 virus or SARS-CoV-2 viral particles have been proposed [1].

Autoimmunity could be a linking element across various mechanisms and there is indeed mounting evidence that autoantibodies (AAbs) in particular play a role in a subset of PCS and ME/CFS. In ME/CFS there are now numerous studies showing elevated levels and altered functions of G-protein coupled receptor autoantibodies (GPCR AAbs) and their correlation with severity of key symptoms [2]. First trials with AAb-targeting therapies show promising though mixed results. These include studies directly targeting AAbs by removal with immunoadsorption or their enhanced degradation with efgartigimod or neutralization with BC007 (rovunaptabin). Further B cell depletion with rituximab or plasma cell depletion with daratumumab has yielded some positive but inconsistent results.

Source: Wohlrab F, Eltity M, Ufer F, Paul F, Scheibenbogen C, Bellmann-Strobl J. Autoantibody targeting therapies in post COVID syndrome and myalgic encephalomyelitis/chronic fatigue syndrome. Expert Opin Biol Ther. 2025 Apr 10. doi: 10.1080/14712598.2025.2492774. Epub ahead of print. PMID: 40211686. https://www.tandfonline.com/doi/full/10.1080/14712598.2025.2492774#d1e211 (Full text)

Identifying commonalities and differences between EHR representations of PASC and ME/CFS in the RECOVER EHR cohort

Abstract:

Background: Shared symptoms and biological abnormalities between post-acute sequelae of SARS-CoV-2 infection (PASC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) could suggest common pathophysiological bases and would support coordinated treatment efforts. Empirical studies comparing these syndromes are needed to better understand their commonalities and differences.

Methods: We analyzed electronic health record data from 6.5 million adult patients from the National COVID Cohort Collaborative. PASC and ME/CFS diagnostic groups were defined based on recorded diagnoses, and other recorded conditions within the two groups were used to train separate machine learning-driven computable phenotypes (CPs). The most predictive conditions for each CP were examined and compared, and the overlap of patients labeled by each CP was examined. Condition records from the diagnostic groups were also used to statistically derive condition clusters. Rates of subphenotypes based on these clusters were compared between PASC and ME/CFS groups.

Results: Approximately half of patients labeled by one CP are also labeled by the other. Dyspnea, fatigue, and cognitive impairment are the most-predictive conditions shared by both CPs, whereas other most-predictive conditions are specific to one CP. Recorded conditions separate into cardiopulmonary, neurological, and comorbidity clusters, with the cardiopulmonary cluster showing partial specificity for the PASC groups.

Conclusions: Data-driven approaches indicate substantial overlap in the condition records associated with PASC and ME/CFS diagnoses. Nevertheless, cardiopulmonary conditions are somewhat more commonly associated with PASC diagnosis, whereas other conditions, such as pain and sleep disturbances, are more associated with ME/CFS diagnosis. These findings suggest that symptom management approaches to these illnesses could overlap.

Source: Powers JP, McIntee TJ, Bhatia A, Madlock-Brown CR, Seltzer J, Sekar A, Jain N, Hornig M, Seibert E, Leese PJ, Haendel M, Moffitt R, Pfaff ER; N3C Consortium and RECOVER-EHR. Identifying commonalities and differences between EHR representations of PASC and ME/CFS in the RECOVER EHR cohort. Commun Med (Lond). 2025 Apr 11;5(1):109. doi: 10.1038/s43856-025-00827-5. PMID: 40210986. https://www.nature.com/articles/s43856-025-00827-5 (Full text)

Understanding symptom clusters, diagnosis and healthcare experiences in myalgic encephalomyelitis/chronic fatigue syndrome and long COVID: a cross-sectional survey in the UK

Abstract:

Objectives: This study aims to provide an in-depth analysis of the symptoms, coexisting conditions and service utilisation among people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID. The major research questions include the clustering of symptoms, the relationship between key factors and diagnosis time, and the perceived impact of National Institute for Health and Care Excellence (NICE) guidelines on patient care.

Design: Cross-sectional survey using secondary data analysis.

Setting: Community-based primary care level across the UK, incorporating online survey participation.

Participants: A total of 10 458 individuals responded to the survey, of which 8804 confirmed that they or a close friend/family member had ME/CFS or long COVID. The majority of respondents were female (83.4%), with participants from diverse regions of the UK.

Primary and secondary outcome measures: Primary outcomes included prevalence and clustering of symptoms, time to diagnosis, and participant satisfaction with National Health Service (NHS) care, while secondary outcomes focused on symptom management strategies and the perceived effect of NICE guidelines.

Results: Fatigue (88.2%), postexertional malaise (78.2%), cognitive dysfunction (88.4%), pain (87.6%) and sleep disturbances (88.2%) were the most commonly reported symptoms among participants with ME/CFS, with similar patterns observed in long COVID. Time to diagnosis for ME/CFS ranged widely, with 22.1% diagnosed within 1-2 years of symptom onset and 12.9% taking more than 10 years. Despite updated NICE guidelines, only 10.1% of participants reported a positive impact on care, and satisfaction with NHS services remained low (6.9% for ME/CFS and 14.4% for long COVID).

Conclusions: ME/CFS and long COVID share overlapping but distinct symptom clusters, indicating common challenges in management. The findings highlight significant delays in diagnosis and low satisfaction with specialist services, suggesting a need for improved self-management resources and better-coordinated care across the NHS.

Source: Mansoubi M, Richards T, Ainsworth-Wells M, Fleming R, Leveridge P, Shepherd C, Dawes H. Understanding symptom clusters, diagnosis and healthcare experiences in myalgic encephalomyelitis/chronic fatigue syndrome and long COVID: a cross-sectional survey in the UK. BMJ Open. 2025 Apr 2;15(4):e094658. doi: 10.1136/bmjopen-2024-094658. PMID: 40180399. https://bmjopen.bmj.com/content/15/4/e094658 (Full text)

An In-Depth Exploration of the Autoantibody Immune Profile in ME/CFS Using Novel Antigen Profiling Techniques

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder characterized by serious physical and cognitive impairments. Recent research underscores the role of immune dysfunction, including the role of autoantibodies, in ME/CFS pathophysiology.

Expanding on previous studies, we analyzed 7542 antibody-antigen interactions in ME/CFS patients using two advanced platforms: a 1134 autoantibody Luminex panel from Oncimmune and Augmenta Bioworks, along with Rapid Extracellular Antigen Profiling (REAP), a validated high-throughput method that measures autoantibody reactivity against 6183 extracellular human proteins and 225 human viral pathogen proteins.

Unlike earlier reports, our analysis of 172 participants revealed no significant differences in autoantibody reactivities between ME/CFS patients and controls, including against GPCRs such as β-adrenergic receptors. However, subtle trends in autoantibody ratios between male and female ME/CFS subgroups, along with patterns of herpesvirus reactivation, suggest the need for broader and more detailed exploration.

Source: Germain A, Jaycox JR, Emig CJ, Ring AM, Hanson MR. An In-Depth Exploration of the Autoantibody Immune Profile in ME/CFS Using Novel Antigen Profiling Techniques. Int J Mol Sci. 2025 Mar 20;26(6):2799. doi: 10.3390/ijms26062799. PMID: 40141440; PMCID: PMC11943395. https://pmc.ncbi.nlm.nih.gov/articles/PMC11943395/ (Full text)

Cognitive Impairments in Two Samples of Individuals with ME/CFS and Long COVID: A Comparative Analysis

Abstract:

Cognitive impairments, including memory and concentration difficulties, are common in individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID. These conditions frequently co-occur, but it remains unclear how cognitive difficulties differ between individuals with ME/CFS, long COVID, both, or neither. The purpose of this study was to examine cognitive impairment presence and type for individuals with and without these conditions.

Data from the 2022 and 2023 National Health Interview Survey were analyzed. Participants included 27,512 and 29,404 U.S. adults in 2022 and 2023, respectively. Survey weights and variance estimation variables were utilized and multivariate logistic regression models assessed the likelihood of cognitive difficulty, accounting for sociodemographics and shared variance. Participants from both cohorts were primarily female, white, and non-Hispanic/Latine, with an average age of 48.1 years in both cohorts.

ME/CFS (aOR 6.18; 95% CI 4.82-7.93; aOR 5.33; 95% CI 4.04-7.05) and long COVID (aOR 2.01; 95% CI 1.67-2.44; aOR 2.16; 95% CI 1.82-2.56) were significantly associated with reported cognitive difficulties, after controlling for the other condition and sociodemographic factors. Individuals with ME/CFS, particularly those with comorbid long COVID, are especially prone to memory and concentration difficulties.

Source: Sirotiak Z, Adamowicz JL, Thomas EBK. Cognitive Impairments in Two Samples of Individuals with ME/CFS and Long COVID: A Comparative Analysis. J Clin Psychol Med Settings. 2025 Mar 22. doi: 10.1007/s10880-025-10074-4. Epub ahead of print. PMID: 40120036. https://pubmed.ncbi.nlm.nih.gov/40120036/

Predisposing and Precipitating Factors in Epstein–Barr Virus-Caused Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Long COVID following SARS-CoV-2 and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) following infectious mononucleosis (IM) are two examples of post-viral syndromes. The identification of risk factors predisposing patients to developing and maintaining post-infectious syndromes may help uncover their underlying mechanisms.
The majority of patients with ME/CFS report infectious illnesses before the onset of ME/CFS, with 30% of cases of ME/CFS due to IM caused by the Epstein–Barr virus. After developing IM, one study found 11% of adults had ME/CFS at 6 months and 9% had ME/CFS at 1 year. Another study of adolescents found 13% and 7% with ME/CFS at 6 and 12 months following IM, respectively. However, it is unclear which variables are potential risk factors contributing to the development and maintenance of ME/CFS following IM, because few prospective studies have collected baseline data before the onset of the triggering illness.
The current article provides an overview of a study that included pre-illness predictors of ME/CFS development following IM in a diverse group of college students who were enrolled before the onset of IM. Our data set included an ethnically and sociodemographically diverse group of young adult students, and we were able to longitudinally follow these youths over time to better understand the risk factors associated with the pathophysiology of ME/CFS.
General screens of health and psychological well-being, as well as blood samples, were obtained at three stages of the study (Stage 1—Baseline—when the students were well, at least 6 weeks before the student developed IM; Stage 2—within 6 weeks following the diagnosis of IM, and Stage 3—six months after IM, when they had either developed ME/CFS or recovered). We focused on the risk factors for new cases of ME/CFS following IM and found factors both at baseline (Stage 1) and at the time of IM (Stage 2) that predicted nonrecovery. We are now collecting seven-year follow-up data on this sample, as well as including cases of long COVID. The lessons learned in this prospective study are reviewed.
Source: Jason LA, Katz BZ. Predisposing and Precipitating Factors in Epstein–Barr Virus-Caused Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Microorganisms. 2025; 13(4):702. https://doi.org/10.3390/microorganisms13040702 https://www.mdpi.com/2076-2607/13/4/702 (Full text)

Efficacy of vitamin D replacement therapy on 28 cases of myalgic encephalomyelitis/chronic fatigue syndrome after COVID-19 vaccination

Abstract:

Background: Prolonged symptoms have been reported following both COVID-19 infection and vaccination, with some cases leading to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Of 80 patients presenting to our hospital with postvaccination syndrome, 28 met the diagnostic criteria for ME/CFS. We conducted a retrospective study on these 28 patients.

Methods: We measured serum 25-hydroxyvitamin D levels in 28 patients who developed ME/CFS after COVID-19 vaccination between August 2022 and February 2024. Vitamin D replacement therapy included dietary counseling, sun exposure recommendations, and oral vitamin D supplementation. We evaluated changes in blood vitamin D levels and symptom improvement.

Results: At initial visit, 27 of 28 patients diagnosed with ME/CFS had insufficient or deficient serum 25-hydroxyvitamin D levels (16 ± 4 ng/mL, mean ± SD). Following vitamin D replacement therapy, we observed an increase in blood vitamin D levels (28 ± 5 ng/mL) associated with a decrease in ME/CFS diagnostic symptoms (from 10.3 ± 2.1 to 3.3 ± 2.0). Notably, 23 of 28 patients (82%) no longer met ME/CFS diagnostic criteria after the therapy. Among the symptoms, sleep problems showed the most improvement (71%), followed by autonomic symptoms (68%).

Conclusions: For patients developing ME/CFS after COVID-19 vaccination with insufficient or deficient vitamin D levels, appropriate vitamin D replacement therapy under medical guidance may lead to symptomatic relief. We are preparing a randomized controlled trial to evaluate the efficacy of vitamin D replacement therapy in individuals with ME/CFS who have developed vitamin D deficiency following COVID-19 infection or vaccination.

Source: Kodama S, Konishi N, Hirai Y, Fujisawa A, Nakata M, Teramukai S, Fukushima M. Efficacy of vitamin D replacement therapy on 28 cases of myalgic encephalomyelitis/chronic fatigue syndrome after COVID-19 vaccination. Nutrition. 2025 Feb 18;134:112718. doi: 10.1016/j.nut.2025.112718. Epub ahead of print. PMID: 40090177. https://www.sciencedirect.com/science/article/pii/S089990072500036X (Full text)