Medscape Medical News > Conference News > ACR 2024
Post-Exertional Malaise in Fatiguing Diseases: What to Know to Avoid Harmful Exercise Miriam E. Tucker December 20, 2024
Identifying the phenomenon of post-exertional malaise (PEM) in patients with fatiguing conditions is critical because it necessitates a far more cautious approach to exercise, experts said.
PEM is a defining feature of the condition myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and it is present in many people with long COVID. It is characterized by a worsening of fatigue and of other symptoms after previously tolerated physical or mental exertion, typically emerging 24-72 hours after the exertion and lasting days or weeks thereafter. The experience is often called a “crash.”
In a study presented at American College of Rheumatology (ACR) 2024 Annual Meeting, PEM was also identified in people with various rheumatologic conditions, ranging from 4% in those with osteoarthritis to 20% in those with fibromyalgia. The presence of PEM was also associated with worse pain, sleep, cognition, and other symptoms that are also characteristic of ME/CFS and many cases of long COVID.
“PEM assessment is becoming more important in those with long COVID, as we are assisting more of those with long durations of this condition…This is the first study we know of presenting PEM rates in a rheumatologic disease population,” Kaleb Michaud, PhD, director of FORWARD—The National Databank for Rheumatic Diseases and professor of rheumatology and immunology, University of Nebraska Medical Center, Omaha, Nebraska, said in his presentation of the data at the ACR meeting.
During the discussion period, study investigator Leonard H. Calabrese, DO, head of the Section of Clinical Immunology, Cleveland Clinic, Cleveland, commented, “PEM is seen with numerous post-acute infectious sequelae. It segregates with that population of patients who meet the diagnostic criteria for ME/CFS, of which 50%-70% of people will also meet criteria for fibromyalgia…This is a first step, but it has big ramifications regarding exercise.”
In an interview with Medscape Medical News, Calabrese said, “We recommend exercise to virtually everyone with fibromyalgia who doesn’t have ME/CFS,” but that the assessment tool used in the study, the 5-item DePaul Symptoms Questionnaire, isn’t adequate for assessing true PEM that would preclude exercise, despite being validated. “That instrument is inexact and lacks specificity…It just shows where the field is. We need better biomarkers.”
In Those With PEM, Exercise May Harm
Asked to comment, Brayden P. Yellman, MD, a rheumatologist at the Bateman Horne Center, Salt Lake City, Utah, told Medscape Medical News, “if there is an infection-associated chronic condition that meets criteria for what we would call ME/CFS or long COVID, and if there’s true post-exertional malaise, any graded exercise that ultimately leads to post-exertional malaise is harmful…There is a subset of people who have milder disease, who can sometimes do very mild exercise that does not trigger PEM, and they do see benefits over time very slowly with really carefully curated, carefully monitored exercise. But we have to be really careful.”
For the majority, however, the approach is to teach patients to pace their activities in order to avoid PEM, also referred to as staying within their “energy envelope.” Clinician resources are available on the Bateman Horne Center’s website.
This isn’t typically included in rheumatology training, Yellman noted. “Having completed an entire rheumatology fellowship and working in rheumatology, I was not taught at all about [then-termed] chronic fatigue syndrome. It was lumped under fibromyalgia. And of course, they teach about fibromyalgia because it’s a great mimic of a lot of inflammatory, rheumatological conditions, but the idea of [PEM], that pathognomonic feature that we see in infection-associated chronic conditions, was not once mentioned when I trained, in 2014 to 2016.”
Nonetheless, he added, “rheumatologists are definitely seeing this in their fibromyalgia patients and some of their other patients at a high rate, and I’m sure that they’re missing it, along with other comorbidities like orthostatic hypotension.”
Another expert asked to weigh in, Todd Davenport, PT, DPT, PhD, professor and chair of the Department of Physical Therapy at the University of the Pacific, Stockton, California, told Medscape Medical News, “Our experience is that the body’s responses to short bouts of exercise are abnormal, and graded exercise is unsuccessful and makes people worse…Clinicians should be particularly on the lookout for PEM in patients who are already reporting fatigue, such as with fibromyalgia and rheumatologic conditions that can have some diagnostic overlaps with ME/CFS, because you can get fooled into thinking that your well-meaning exercise program intended to help give them a little more juice during their daily activities actually might be harmful.”
There are several lines of evidence for abnormal responses to exercise in people with PEM, Davenport said. These include muscle worsening, cardiac preload failure and impaired systemic oxygen extraction, metabolic dysregulation, and abnormal immunologic and neurologic changes.
Several studies show impaired recovery after 2-day cardiopulmonary exercise testing, with the largest to date published in July 2024. Patients with PEM have also reported harm from prescribed exercise.
Yellman commented, “We think of PEM like an injury, where you need to recover. If you keep stacking injuries on top of it, that injury is never going to heal the same way again…We are still trying to understand the pathophysiology of ME/CFS in general, and of PEM. But if you think of it as a neuroinflammatory injury, and there’s some evidence suggesting neuroinflammation, you can kind of understand the approach of needing to heal and to recover.”
How Prevalent Is PEM in Rheumatologic Conditions?
For the study presented at the ACR meeting, data of people with confirmed rheumatic diseases were taken from the ongoing longitudinal US-based research database FORWARD. Participants completed biannual self-reported questionnaires during January-June 2024 that included the 5-item PEM subscale from the validated DePaul Symptoms Questionnaire.
Questions relate to frequency and severity of each of the five items: “Dead, heavy feeling after starting to exercise,” “next-day soreness or fatigue after nonstrenuous, everyday activities,” “mentally tired after the slightest effort,” “minimum exercise makes you physically tired,” and “physically drained or sick after mild activity.” Participants are asked to rate each item on a scale from 0 if not present to 1 (mild/a little of the time) up to 4 (very severe/all of the time).
A positive PEM result was defined as a frequency of at least two and simultaneous severity of at least two on any survey item. Additional questions asked about recent and previous SARS-CoV-2 infections, long COVID diagnoses, and comorbidities.
Of 1158 individuals who completed the PEM questionnaire, 7.5% overall met PEM criteria. By individual condition, the proportions were 4.4% with osteoarthritis, 7.4% with rheumatoid arthritis, 12.2% with systemic lupus erythematosus, 13.8% with fibromyalgia diagnosed by rheumatologists, and 20.3% with fibromyalgia based on the 2016 revised ACR criteria.
The overall PEM prevalence was 8.3% among those reporting ever having COVID-19 and 9.5% among those who had COVID-19 during July-December 2023. The PEM prevalence increased more dramatically with more severe COVID-19 — 17.2% among those who had been hospitalized for COVID-19, 22.0% of those ever diagnosed with long COVID, and 28.1% with a long COVID diagnosis in January 2024.
By diagnosis, 50% of individuals who met the ACR’s 2016 fibromyalgia criteria and currently had long COVID scored positively for PEM.
Measures of pain, fatigue, sleep, patient global assessment, activity score, polysymptomatic distress, disability, depression, anxiety, and other functional scores were all significantly worse among those scoring positive for PEM (P < .001), Michaud reported.
Better Tools Are Available
The developer of the DePaul questionnaire, Leonard Jason, PhD, director of the Center for Community Research and professor of psychology at DePaul College of Science and Health, Chicago, told Medscape Medical News that an updated 10-item screening tool specifically designed to screen for PEM adds some important elements missing from the 5-item version.
Here, patients are initially asked two questions: “Do you experience a worsening of your fatigue/energy related illness after engaging in minimal physical effort?” and “Do you experience a worsening of your fatigue/energy related illness after engaging in mental effort?” If they answer “yes” to either, the next question is “If you feel worse after activities, how long does this last?” Answers are coded from 0 to 6 (24 hours or more).
The fourth additional question then asks how quickly patients recover, while a fifth question asks whether the person is avoiding activity because it makes them feel worse (thereby potentially creating a false negative).
For those scoring positive on the 10-item screen, a more comprehensive measure could be used, such as this online screening tool, Jason said.
Yellman said that the Bateman Horne Center uses a “good day, bad day” questionnaire to tease out some of the same information. In addition, he noted that it’s important to capture the timeframe between the exertion and the onset of symptoms because PEM doesn’t start during or immediately after activity. “If somebody is mowing the lawn and they start feeling symptoms immediately, they’re probably, at least in ME/CFS, experiencing orthostatic intolerance. Post-exertional malaise occurs 12-72 hours later, when their function is severely reduced as compared to baseline.”
And of course, Davenport noted, listening to patients is key. “Patients will tell you wildly unusual responses to activity before you even do the work of trying to figure out what the activity was. They’ll tell you things like they can’t think as well, that they have to be in bed for 3 days to a week to 2 weeks, depending on the level of exertion.”
Yellman, Davenport, and several other colleagues are currently working on a paper that will explain the differences between pacing and graded exercise, define PEM, and provide guidelines. They aim to submit it in time for publication early next year. In the meantime, the Bateman Horne Center’s website provides numerous resources for healthcare professionals and patients.
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Machine learning and multi-omics in precision medicine for ME/CFS - Huang, Lidbury, Thomas, Gooley & Armstrong
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex and multifaceted disorder that defies simplistic characterisation.
Traditional approaches to diagnosing and treating ME/CFS have often fallen short due to the condition's heterogeneity and the lack of validated biomarkers.
The growing field of precision medicine offers a promising approach which focuses on the genetic and molecular underpinnings of individual patients.
In this review, we explore how machine learning and multi-omics (genomics, transcriptomics, proteomics, and metabolomics) can transform precision medicine in ME/CFS research and healthcare.
We provide an overview on machine learning concepts for analysing large-scale biological data, highlight key advancements in multi-omics biomarker discovery, data quality and integration strategies, while reflecting on ME/CFS case study examples.
We also highlight several priorities, including the critical need for applying robust computational tools and collaborative data-sharing initiatives in the endeavour to unravel the biological intricacies of ME/CFS.
source: Journal of Translational Medicine, Open Access
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Journal of General Internal Medicine
Incidence and Prevalence of Post-COVID-19 Myalgic Encephalomyelitis: A Report from the Observational RECOVER-Adult Study
Original Research Open access Published: 13 January 2025
Suzanne D. Vernon PhD, Tianyu Zheng MS, Hyungrok Do PhD, Vincent C. Marconi MD, Leonard A. Jason PhD,
Benjamin H. Natelson MD, Zaki A. Sherif PhD, Hector Fabio Bonilla MD, Emily Taylor MA, Janet M. Mullington PhD, Hassan Ashktorab PhD, Adeyinka O. Laiyemo MD, Hassan Brim PhD, Thomas F. Patterson MD, Teresa T. Akintonwa BA, Anisha Sekar BA, Michael J. Peluso MD, Nikita Maniar MD, Lucinda Bateman MD, Leora I. Horwitz MD & Rachel Hess MD on behalf of the NIH Researching COVID to Enhance Recovery (RECOVER) Consortium
Abstract
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may occur after infection. How often people develop ME/CFS after SARS-CoV-2 infection is unknown.
Objective
To determine the incidence and prevalence of post-COVID-19 ME/CFS among adults enrolled in the Researching COVID to Enhance Recovery (RECOVER-Adult) study.
Design, Setting, and Participants
RECOVER-Adult is a longitudinal observational cohort study conducted across the U.S. We included participants who had a study visit at least 6 months after infection and had no pre-existing ME/CFS, grouped as (1) acute infected, enrolled within 30 days of infection or enrolled as uninfected who became infected (n=4515); (2) post-acute infected, enrolled greater than 30 days after infection (n=7270); and (3) uninfected (1439).
Measurements
Incidence rate and prevalence of post-COVID-19 ME/CFS based on the 2015 Institute of Medicine ME/CFS clinical diagnostic criteria.
Results
The incidence rate of ME/CFS in participants followed from time of SARS-CoV-2 infection was 2.66 (95% CI 2.63–2.70) per 100 person-years while the rate in matched uninfected participants was 0.93 (95% CI 0.91–10.95) per 100 person-years: a hazard ratio of 4.93 (95% CI 3.62–6.71). The proportion of all RECOVER-Adult participants that met criteria for ME/CFS following SARS-CoV-2 infection was 4.5% (531 of 11,785) compared to 0.6% (9 of 1439) in uninfected participants. Post-exertional malaise was the most common ME/CFS symptom in infected participants (24.0%, 2830 of 11,785). Most participants with post-COVID-19 ME/CFS also met RECOVER criteria for long COVID (88.7%, 471 of 531).
Limitations
The ME/CFS clinical diagnostic criteria uses self-reported symptoms. Symptoms can wax and wane.
Conclusion
ME/CFS is a diagnosable sequela that develops at an increased rate following SARS-CoV-2 infection. RECOVER provides an unprecedented opportunity to study post-COVID-19 ME/CFS.
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Articles The Lancet
Volume 49101161February 2025
Efficacy of repeated immunoadsorption in patients with post-COVID myalgic encephalomyelitis/chronic fatigue syndrome and elevated β2-adrenergic receptor autoantibodies: a prospective cohort study
Elisa Steina ∙ Cornelia Heindricha ∙ Kirsten Wittkea ∙ Claudia Kedora ∙ Rebekka Rusta,c ∙ Helma Freitaga∙ et al.
Summary
Background
Since the pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the leading trigger for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Evidence indicates that autoimmunity plays an important pathophysiological role. We aimed to evaluate the effectiveness of IA treatment in post-COVID ME/CFS patients.
Methods
This pre-post study included 20 post-coronavirus disease 2019 (COVID) ME/CFS patients found to have elevated β2 adrenergic autoantibodies (β2 AR-AB) between October 2022 and October 2023. Patients, with a median disease duration of 22 months (IQR: 15–31), were treated with five immunoadsorption sessions at Charité - Universitätsmedizin Berlin, Germany. Seven were male and 13 female, with a median age of 40 years (IQR: 36–51). The primary end point was the change in the Short Form (36) Health Survey physical functioning domain (SF36 PF) from baseline to four weeks post immunoadsorption. Key symptoms were assessed via questionnaires over six months. Handgrip strength and EndoPAT® measurements were used to evaluate muscle fatigue and vascular dysfunction. Seven patients who worsened after an initial response received a second cycle.
Findings
The treatment was generally well tolerated, reducing total immunoglobulin G by 79% (CI: 73–84%) and β2 AR-AB by 77% (CI: 58–95%). Patients demonstrated a mean increase in the SF36 PF of 17.75 points (CI: 13.41–26.16), with the greatest improvement occurring between months two and three, and significant gains maintained through month six. 14/20 (70%) patients were categorized as responders with an increase in the SF36 PF of ≥ ten points. Further lasting improvements were reported in fatigue, post-exertional malaise, pain, cognitive, autonomic, and immunological symptoms. Female patients had increased repeat handgrip strength at month six.
Interpretation
Immunoadsorption may improve symptoms in post-COVID ME/CFS patients. The beneficial effects of IgG depletion suggest a significant role for autoantibodies and disturbed B-cell function in the condition's pathophysiology.
Funding
Funded by The Federal Ministry of Education and Research and the Weidenhammer Zöbele Research Foundation.
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Women’s Immune Systems May Explain Increased Long COVID Diagnoses
Samantha Anderer
JAMA. 2025;333(3):194-195. doi:10.1001/jama.2024.25505
Women are more likely than men to experience post–COVID-19 condition, also known as long COVID, and a new study from Science Translational Medicine identified a possible explanation.
In an analysis of blood samples from 45 participants taken during and after SARS-CoV-2 infection, the authors identified sex-specific immune pathways in acute infection that were associated with subsequent development of long COVID. Females with long COVID displayed a decreased expression of transforming growth factor β1, whereas males who developed long COVID expressed more of the protein. Additionally, compared with those who recovered, women with long COVID expressed more of the RNA gene XIST, which plays a role in autoimmunity. Despite the sex-specific markers, there were some consistencies across sexes, such as increased expression of proinflammatory monocytes.
The results could help inform tailored therapeutic interventions for long COVID, the authors stated.
Published Online: December 20, 2024. doi:10.1001/jama.2024.25505
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Original Investigation Infectious Diseases January 22, 2025
Sex Differences in Long COVID
Dimpy P. Shah, MD, PhD1; Tanayott Thaweethai, PhD2,3; Elizabeth W. Karlson, MD, MS4; et al for the RECOVER Consortium
JAMA Netw Open. 2025;8(1):e2455430. doi:10.1001/jamanetworkopen.2024.55430
Key Points
Question Does the risk of long COVID, or post-COVID condition, differ by sex?
Findings In this cohort study of 12 276 individuals, females had a significantly higher risk of long COVID compared with males after adjusting for sociodemographic and clinical risk factors. The sex-based difference in long COVID risk was age, pregnancy, and menopause dependent, with the highest risk among females aged 40 to 55 years.
Meaning These findings highlight the importance of evaluating differences in risk of long COVID after SARS-CoV-2 infection in males and females and of comparing biological mechanisms that may underlie sexually dimorphic long COVID trajectories.
Abstract
Importance A substantial number of individuals worldwide experience long COVID, or post-COVID condition. Other postviral and autoimmune conditions have a female predominance, but whether the same is true for long COVID, especially within different subgroups, is uncertain.
Objective To evaluate sex differences in the risk of developing long COVID among adults with SARS-CoV-2 infection.
Design, Setting, and Participants This cohort study used data from the National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER)–Adult cohort, which consists of individuals enrolled in and prospectively followed up at 83 sites in 33 US states plus Washington, DC, and Puerto Rico. Data were examined from all participants enrolled between October 29, 2021, and July 5, 2024, who had a qualifying study visit 6 months or more after their initial SARS-CoV-2 infection.
Exposure Self-reported sex (male, female) assigned at birth.
Main Outcomes and Measures Development of long COVID, measured using a self-reported symptom-based questionnaire and scoring guideline at the first study visit that occurred at least 6 months after infection. Propensity score matching was used to estimate risk ratios (RRs) and risk differences (95% CIs). The full model included demographic and clinical characteristics and social determinants of health, and the reduced model included only age, race, and ethnicity.
Results Among 12 276 participants who had experienced SARS-CoV-2 infection (8969 [73%] female; mean [SD] age at infection, 46 [15] years), female sex was associated with higher risk of long COVID in the primary full (RR, 1.31; 95% CI, 1.06-1.62) and reduced (RR, 1.44; 95% CI, 1.17-1.77) models. This finding was observed across all age groups except 18 to 39 years (RR, 1.04; 95% CI, 0.72-1.49). Female sex was associated with significantly higher overall long COVID risk when the analysis was restricted to nonpregnant participants (RR, 1.50; 95%: CI, 1.27-1.77). Among participants aged 40 to 54 years, the risk ratio was 1.42 (95% CI, 0.99-2.03) in menopausal female participants and 1.45 (95% CI, 1.15-1.83) in nonmenopausal female participants compared with male participants.
Conclusions and Relevance In this prospective cohort study of the NIH RECOVER-Adult cohort, female sex was associated with an increased risk of long COVID compared with male sex, and this association was age, pregnancy, and menopausal status dependent. These findings highlight the need to identify biological mechanisms contributing to sex specificity to facilitate risk stratification, targeted drug development, and improved management of long COVID.
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Nature: Published: 17 January 2025
Association between chronic fatigue syndrome/myalgic encephalomyelitis and cardiovascular disease
Mawulorm K. I. Denu, Ritika Revoori, Cherita Eghan, Fredrick Larbi Kwapong, Andrew Hillman, Cornelius A. Normeshie, Kofi Poku Berko, Emily L. Aidoo & Maame Araba E. Buadu
Scientific Reports volume 15, Article number: 2294 (2025) 101 Altmetric
Abstract
Chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is a medical condition characterized by severe and prolonged fatigue that is not relieved by rest or attributed to any underlying medical or psychological condition. Individuals with CFS/ME are considered to have an increased risk of a wide range of comorbid conditions, including cardiovascular disease (CVD). The association between CFS/ME and CVD is not fully understood. To determine the prevalence of CFS/ME in a sample population and examine its association with CVD. Weighted sample size data of 114,834 was analyzed from the 2021–2022 national health interview survey (NHIS). Information on sociodemographic factors, CVD risk factors, and history of CFS/ME and CVD were collected. Multivariable logistic regression model was used to determine the association between CFS/ME and CVD, adjusting for traditional CVD risk factors (age, sex, race, hypertension, diabetes, dyslipidemia, smoking, and body mass index (BMI). Median age of participants was 53 years, and majority of participants were female (53.9%). Prevalence of CFS/ME was 1.2%. A history of CFS/ME was significantly associated with CVD (aOR 3.26, 95%CI 2.85, 3.72, p-value: <0.001) after adjusting for traditional CVD risk factors. A history of CFS/ME was independently associated with CVD after adjusting for traditional CVD risk factors. Patients with CFS/ME need close evaluation for CVD. Further studies are needed to better understand the relationship between CFS/ME and CVD.
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Recovery from Exercise in Persons with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
March 2023 Medicina 59(3):571 DOI:10.3390/medicina59030571 License CC BY 4.0
Authors:
Geoffrey E. Moore Betsy A Keller Ithaca College Jared Stevens Xiangling Mao Weill Cornell Medicine
Abstract and Figures
Background and Objectives:
Post-exertional malaise (PEM) is the hallmark of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but there has been little effort to quantitate the duration of PEM symptoms following a known exertional stressor. Using a Symptom Severity Scale (SSS) that includes nine common symptoms of ME/CFS, we sought to characterize the duration and severity of PEM symptoms following two cardiopulmonary exercise tests separated by 24 h (2-day CPET).
Materials and Methods: Eighty persons with ME/CFS and 64 controls (CTL) underwent a 2-day CPET. ME/CFS subjects met the Canadian Clinical Criteria for diagnosis of ME/CFS; controls were healthy but not participating in regular physical activity. All subjects who met maximal effort criteria on both CPETs were included. SSS scores were obtained at baseline, immediately prior to both CPETs, the day after the second CPET, and every two days after the CPET-1 for 10 days. Results: There was a highly significant difference in judged recovery time (ME/CFS = 12.7 ± 1.2 d; CTL = 2.1 ± 0.2 d, mean ± s.e.m., Chi2 = 90.1, p < 0.0001). The range of ME/CFS patient recovery was 1–64 days, while the range in CTL was 1–10 days; one subject with ME/CFS had not recovered after one year and was not included in the analysis. Less than 10% of subjects with ME/CFS took more than three weeks to recover. There was no difference in recovery time based on the level of pre-test symptoms prior to CPET-1 (F = 1.12, p = 0.33). Mean SSS scores at baseline were significantly higher than at pre-CPET-1 (5.70 ± 0.16 vs. 4.02 ± 0.18, p < 0.0001). Pharmacokinetic models showed an extremely prolonged decay of the PEM response (Chi2 > 22, p < 0.0001) to the 2-day CPET.
Conclusions: ME/CFS subjects took an average of about two weeks to recover from a 2-day CPET, whereas sedentary controls needed only two days. These data quantitate the prolonged recovery time in ME/CFS and improve the ability to obtain well-informed consent prior to doing exercise testing in persons with ME/CFS. Quantitative monitoring of PEM symptoms may provide a method to help manage PEM.
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Nnature scientific reports Published: 28 January 2025
Novel brain SPECT imaging unravels abnormal cerebral perfusion in patients with postural orthostatic tachycardia syndrome and cognitive dysfunction
Marie-Claire Seeley, Howard O’Brien, Gemma Wilson, Clair Coat, Tess Smith, Kevin Hickson, Reynold Casse, Amanda J. Page, Celine Gallagher & Dennis H. Lau
Scientific Reports volume 15, Article number: 3487 (2025)
Abstract
Cognitive dysfunction is frequently reported in individuals with postural orthostatic tachycardia syndrome (POTS), possibly resulting from reduced cerebral blood flow (CBF). We used brain SPECT, an accessible imaging modality that has not been systematically evaluated in this patient group. Retrospective review of participants from our registry was undertaken to identify those who had a brain SPECT performed for investigation of cognitive dysfunction. Abnormal CBF was taken as z-score > 2 standard deviations of healthy control reference values. Patient reported outcome measures (PROMs) such as autonomic, gastric and quality of life symptom scores were analyzed. From a total of 56 participants (mean 34.8 ± 10.7 years, 88% females), PROMs indicate: moderate to severe autonomic dysfunction in 75%; at least mild to moderate gastroparesis in 23%; low global health rating and utility scores. Abnormal CBF was seen in 61% but did not differ by POTS triggers. The regions with the lowest mean z-scores were the lateral prefrontal and sensorimotor cortices. Hierarchal regression analyses found number of brain regions with abnormal CBF, autonomic and gastric symptoms to account for 51% of variances in health utility. Cerebral hypoperfusion is prevalent in those with POTS and cognitive dysfunction even whilst supine, contributing to reduced quality of life.
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The search for a blood-based biomarker for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS): from biochemistry to electrophysiology
Krista S. P. Clarke, Caroline C. Kingdon, Michael Pycraft Hughes, Eliana Mattos Lacerda, Rebecca Lewis, Emily J. Kruchek, Robert A. Dorey & Fatima H. Labeed
Journal of Translational Medicine volume 23, Article number: 149 (2025) Cite this article
Abstract
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease of unknown aetiology characterised by symptoms of post-exertional malaise (PEM) and fatigue leading to substantial impairment in functioning. Other key symptoms include cognitive impairment and unrefreshing sleep, with many experiencing pain. To date there is no complete understanding of the triggering pathomechanisms of disease, and no quantitative biomarker available with sufficient sensitivity, specificity, and adoptability to provide conclusive diagnosis. Clinicians thus eliminate differential diagnoses, and rely on subjective, unspecific, and disputed clinical diagnostic criteria—a process that often takes years with patients being misdiagnosed and receiving inappropriate and sometimes detrimental care. Without a quantitative biomarker, trivialisation, scepticism, marginalisation, and misunderstanding of ME/CFS continues despite the significant disability for many. One in four individuals are bed-bound for long periods of time, others have difficulties maintaining a job/attending school, incurring individual income losses of thousands, while few participate in social activities.
Main body
Recent studies have reported promising quantifiable differences in the biochemical and electrophysiological properties of blood cells, which separate ME/CFS and non-ME/CFS participants with high sensitivities and specificities—demonstrating potential development of an accessible and relatively non-invasive diagnostic biomarker. This includes profiling immune cells using Raman spectroscopy, measuring the electrical impedance of blood samples during hyperosmotic challenge using a nano-electronic assay, use of metabolomic assays, and certain techniques which assess mitochondrial dysfunction. However, for clinical application, the specificity of these biomarkers to ME/CFS needs to be explored in more disease controls, and their practicality/logistics considered. Differences in cytokine profiles in ME/CFS are also well documented, but finding a consistent, stable, and replicable cytokine profile may not be possible. Increasing evidence demonstrates acetylcholine receptor and transient receptor potential ion channel dysfunction in ME/CFS, though how these findings could translate to a diagnostic biomarker are yet to be explored.
Conclusion
Different biochemical and electrophysiological properties which differentiate ME/CFS have been identified across studies, holding promise as potential blood-based quantitative diagnostic biomarkers for ME/CFS. However, further research is required to determine their specificity to ME/CFS and adoptability for clinical use.
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Original Investigation Infectious Diseases January 22, 2025
Sex Differences in Long COVID
Dimpy P. Shah, MD, PhD1; et al ; for the RECOVER Consortium
JAMA Netw Open. 2025;8(1):e2455430. doi:10.1001/jamanetworkopen.2024.55430
Key Points
Question Does the risk of long COVID, or post-COVID condition, differ by sex?
Findings In this cohort study of 12 276 individuals, fe
Findings In this cohort study of 12 276 individuals, females had a significantly higher risk of long COVID compared with males after adjusting for sociodemographic and clinical risk factors. The sex-based difference in long COVID risk was age, pregnancy, and menopause dependent, with the highest risk among females aged 40 to 55 years.
Meaning These findings highlight the importance of evaluating differences in risk of long COVID after SARS-CoV-2 infection in males and females and of comparing biological mechanisms that may underlie sexually dimorphic long COVID trajectories.
Abstract
Importance A substantial number of individuals worldwide experience long COVID, or post-COVID condition. Other postviral and autoimmune conditions have a female predominance, but whether the same is true for long COVID, especially within different subgroups, is uncertain.
Objective To evaluate sex differences in the risk of developing long COVID among adults with SARS-CoV-2 infection.
Design, Setting, and Participants This cohort study used data from the National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER)–Adult cohort, which consists of individuals enrolled in and prospectively followed up at 83 sites in 33 US states plus Washington, DC, and Puerto Rico. Data were examined from all participants enrolled between October 29, 2021, and July 5, 2024, who had a qualifying study visit 6 months or more after their initial SARS-CoV-2 infection.
Exposure Self-reported sex (male, female) assigned at birth.
Main Outcomes and Measures Development of long COVID, measured using a self-reported symptom-based questionnaire and scoring guideline at the first study visit that occurred at least 6 months after infection. Propensity score matching was used to estimate risk ratios (RRs) and risk differences (95% CIs). The full model included demographic and clinical characteristics and social determinants of health, and the reduced model included only age, race, and ethnicity.
Results Among 12 276 participants who had experienced SARS-CoV-2 infection (8969 [73%] female; mean [SD] age at infection, 46 [15] years), female sex was associated with higher risk of long COVID in the primary full (RR, 1.31; 95% CI, 1.06-1.62) and reduced (RR, 1.44; 95% CI, 1.17-1.77) models. This finding was observed across all age groups except 18 to 39 years (RR, 1.04; 95% CI, 0.72-1.49). Female sex was associated with significantly higher overall long COVID risk when the analysis was restricted to nonpregnant participants (RR, 1.50; 95%: CI, 1.27-1.77). Among participants aged 40 to 54 years, the risk ratio was 1.42 (95% CI, 0.99-2.03) in menopausal female participants and 1.45 (95% CI, 1.15-1.83) in nonmenopausal female participants compared with male participants.
Conclusions and Relevance In this prospective cohort study of the NIH RECOVER-Adult cohort, female sex was associated with an increased risk of long COVID compared with male sex, and this association was age, pregnancy, and menopausal status dependent. These findings highlight the need to identify biological mechanisms contributing to sex specificity to facilitate risk stratification, targeted drug development, and improved management of long COVID.
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Chronic fatigue syndrome: Outcry over Cochrane decision to abandon review of exercise therapy
BMJ 2025; 388 doi: https://doi.org/10.1136/bmj.r169 (Published 27 January 2025)Cite this as: BMJ 2025;388:r169
Jacqui Wise
A decision to cancel a planned update of a Cochrane systematic review of exercise therapy for chronic fatigue syndrome has met with anger from a group advising the review and the patient community.
The decision has reignited calls for the review,1 which includes studies only up to May 2014, to be withdrawn for being outdated and misleading.
The review recommends exercise therapy to treat myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), concluding that this “probably has a positive effect on fatigue in adults compared to usual care or passive therapies.”
However, this treatment approach is controversial and has been criticised by patient groups who say that it can make symptoms worse. Guidelines from the National Institute for Health and Care Excellence, published in 2021, specifically advise against graded exercise therapy.2 Guidelines from the US Centers for Disease Control and Prevention also state that exercise therapy is not a cure for ME/CFS and that standard exercise recommendations for healthy people can be harmful for people with ME/CFS.3
The Cochrane systematic review was modified slightly by its authors in 2019 to place more emphasis on the limited applicability of the evidence to definitions of ME/CFS used in the included studies, the long term effects of exercise on symptoms of fatigue, and the limitations of evidence on harms that may occur.
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Hippocampal subfield volume alterations and associations with severity measures in long COVID and ME/CFS: A 7T MRI study
Kiran Thapaliya ,Sonya Marshall-Gradisnik,Natalie Eaton-Fitch,Markus Barth,Maira Inderyas,Leighton Barnden
Published: January 13, 2025 Plos one https://doi.org/10.1371/journal.pone.0316625
Abstract
Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients share similar symptoms including post-exertional malaise, neurocognitive impairment, and memory loss. The neurocognitive impairment in both conditions might be linked to alterations in the hippocampal subfields. Therefore, this study compared alterations in hippocampal subfields of 17 long COVID, 29 ME/CFS patients, and 15 healthy controls (HC). Structural MRI data was acquired with sub-millimeter isotropic resolution on a 7 Telsa MRI scanner and hippocampal subfield volumes were then estimated for each participant using FreeSurfer software. Our study found significantly larger volumes in the left hippocampal subfields of both long COVID and ME/CFS patients compared to HC. These included the left subiculum head (long COVID; p = 0.01, ME/CFS; p = 0.002,), presubiculum head (long COVID; p = 0.004, ME/CFS; p = 0.005), molecular layer hippocampus head (long COVID; p = 0.014, ME/CFS; p = 0.011), and whole hippocampal head (long COVID; p = 0.01, ME/CFS; p = 0.01). Notably, hippocampal subfield volumes were similar between long COVID and ME/CFS patients. Additionally, we found significant associations between hippocampal subfield volumes and severity measures of ‘Pain’, ‘Duration of illness’, ‘Severity of fatigue’, ‘Impaired concentration’, ‘Unrefreshing sleep’, and ‘Physical function’ in both conditions. These findings suggest that hippocampal alterations may contribute to the neurocognitive impairment experienced by long COVID and ME/CFS patients. Furthermore, our study highlights similarities between these two conditions.
Citation: Thapaliya K, Marshall-Gradisnik S, Eaton-Fitch N, Barth M, Inderyas M, Barnden L (2025) Hippocampal subfield volume alterations and associations with severity measures in long COVID and ME/CFS: A 7T MRI study. PLoS ONE 20(1): e0316625. https://doi.org/10.1371/journal.pone.0316625
Editor: Daichi Sone, Jikei University School of Medicine, JAPAN
Received: August 21, 2024; Accepted: December 11, 2024; Published: January 13, 2025
Copyright: © 2025 Thapaliya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are present within the manuscript. The datasets from this study are not publicly available due to confidentiality agreements but could be available on reasonable request. Any request should be submitted to Chair, Griffith University Human Research Ethics Committee, by the e-mail [email protected] or phone (+61) 07 3735 2069.
Funding: This research was funded by ME Research UK (SCIO Charity Number SC036942) with the financial support of The Fred and Joan Davies Bequest. Other funding bodies include The Stafford Fox Medical Research Foundation (489798), the National Health and Medical Research Council (1199502), Talei Stewart, Buxton Foundation (4676), Henty Community (4879), Henty Lions Club (4880), Blake Beckett Trust Foundation (4579), Alison Hunter Memorial Foundation (4570), and the Change for ME Charity (4575).
Competing interests: The authors have declared that no competing interests exist.
Post-Exertional Malaise in Fatiguing Diseases: What to Know to Avoid Harmful Exercise Miriam E. Tucker December 20, 2024
Identifying the phenomenon of post-exertional malaise (PEM) in patients with fatiguing conditions is critical because it necessitates a far more cautious approach to exercise, experts said.
PEM is a defining feature of the condition myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and it is present in many people with long COVID. It is characterized by a worsening of fatigue and of other symptoms after previously tolerated physical or mental exertion, typically emerging 24-72 hours after the exertion and lasting days or weeks thereafter. The experience is often called a “crash.”
In a study presented at American College of Rheumatology (ACR) 2024 Annual Meeting, PEM was also identified in people with various rheumatologic conditions, ranging from 4% in those with osteoarthritis to 20% in those with fibromyalgia. The presence of PEM was also associated with worse pain, sleep, cognition, and other symptoms that are also characteristic of ME/CFS and many cases of long COVID.
“PEM assessment is becoming more important in those with long COVID, as we are assisting more of those with long durations of this condition…This is the first study we know of presenting PEM rates in a rheumatologic disease population,” Kaleb Michaud, PhD, director of FORWARD—The National Databank for Rheumatic Diseases and professor of rheumatology and immunology, University of Nebraska Medical Center, Omaha, Nebraska, said in his presentation of the data at the ACR meeting.
During the discussion period, study investigator Leonard H. Calabrese, DO, head of the Section of Clinical Immunology, Cleveland Clinic, Cleveland, commented, “PEM is seen with numerous post-acute infectious sequelae. It segregates with that population of patients who meet the diagnostic criteria for ME/CFS, of which 50%-70% of people will also meet criteria for fibromyalgia…This is a first step, but it has big ramifications regarding exercise.”
In an interview with Medscape Medical News, Calabrese said, “We recommend exercise to virtually everyone with fibromyalgia who doesn’t have ME/CFS,” but that the assessment tool used in the study, the 5-item DePaul Symptoms Questionnaire, isn’t adequate for assessing true PEM that would preclude exercise, despite being validated. “That instrument is inexact and lacks specificity…It just shows where the field is. We need better biomarkers.”
In Those With PEM, Exercise May Harm
Asked to comment, Brayden P. Yellman, MD, a rheumatologist at the Bateman Horne Center, Salt Lake City, Utah, told Medscape Medical News, “if there is an infection-associated chronic condition that meets criteria for what we would call ME/CFS or long COVID, and if there’s true post-exertional malaise, any graded exercise that ultimately leads to post-exertional malaise is harmful…There is a subset of people who have milder disease, who can sometimes do very mild exercise that does not trigger PEM, and they do see benefits over time very slowly with really carefully curated, carefully monitored exercise. But we have to be really careful.”
For the majority, however, the approach is to teach patients to pace their activities in order to avoid PEM, also referred to as staying within their “energy envelope.” Clinician resources are available on the Bateman Horne Center’s website.
This isn’t typically included in rheumatology training, Yellman noted. “Having completed an entire rheumatology fellowship and working in rheumatology, I was not taught at all about [then-termed] chronic fatigue syndrome. It was lumped under fibromyalgia. And of course, they teach about fibromyalgia because it’s a great mimic of a lot of inflammatory, rheumatological conditions, but the idea of [PEM], that pathognomonic feature that we see in infection-associated chronic conditions, was not once mentioned when I trained, in 2014 to 2016.”
Nonetheless, he added, “rheumatologists are definitely seeing this in their fibromyalgia patients and some of their other patients at a high rate, and I’m sure that they’re missing it, along with other comorbidities like orthostatic hypotension.”
Another expert asked to weigh in, Todd Davenport, PT, DPT, PhD, professor and chair of the Department of Physical Therapy at the University of the Pacific, Stockton, California, told Medscape Medical News, “Our experience is that the body’s responses to short bouts of exercise are abnormal, and graded exercise is unsuccessful and makes people worse…Clinicians should be particularly on the lookout for PEM in patients who are already reporting fatigue, such as with fibromyalgia and rheumatologic conditions that can have some diagnostic overlaps with ME/CFS, because you can get fooled into thinking that your well-meaning exercise program intended to help give them a little more juice during their daily activities actually might be harmful.”
There are several lines of evidence for abnormal responses to exercise in people with PEM, Davenport said. These include muscle worsening, cardiac preload failure and impaired systemic oxygen extraction, metabolic dysregulation, and abnormal immunologic and neurologic changes.
Several studies show impaired recovery after 2-day cardiopulmonary exercise testing, with the largest to date published in July 2024. Patients with PEM have also reported harm from prescribed exercise.
Yellman commented, “We think of PEM like an injury, where you need to recover. If you keep stacking injuries on top of it, that injury is never going to heal the same way again…We are still trying to understand the pathophysiology of ME/CFS in general, and of PEM. But if you think of it as a neuroinflammatory injury, and there’s some evidence suggesting neuroinflammation, you can kind of understand the approach of needing to heal and to recover.”
How Prevalent Is PEM in Rheumatologic Conditions?
For the study presented at the ACR meeting, data of people with confirmed rheumatic diseases were taken from the ongoing longitudinal US-based research database FORWARD. Participants completed biannual self-reported questionnaires during January-June 2024 that included the 5-item PEM subscale from the validated DePaul Symptoms Questionnaire.
Questions relate to frequency and severity of each of the five items: “Dead, heavy feeling after starting to exercise,” “next-day soreness or fatigue after nonstrenuous, everyday activities,” “mentally tired after the slightest effort,” “minimum exercise makes you physically tired,” and “physically drained or sick after mild activity.” Participants are asked to rate each item on a scale from 0 if not present to 1 (mild/a little of the time) up to 4 (very severe/all of the time).
A positive PEM result was defined as a frequency of at least two and simultaneous severity of at least two on any survey item. Additional questions asked about recent and previous SARS-CoV-2 infections, long COVID diagnoses, and comorbidities.
Of 1158 individuals who completed the PEM questionnaire, 7.5% overall met PEM criteria. By individual condition, the proportions were 4.4% with osteoarthritis, 7.4% with rheumatoid arthritis, 12.2% with systemic lupus erythematosus, 13.8% with fibromyalgia diagnosed by rheumatologists, and 20.3% with fibromyalgia based on the 2016 revised ACR criteria.
The overall PEM prevalence was 8.3% among those reporting ever having COVID-19 and 9.5% among those who had COVID-19 during July-December 2023. The PEM prevalence increased more dramatically with more severe COVID-19 — 17.2% among those who had been hospitalized for COVID-19, 22.0% of those ever diagnosed with long COVID, and 28.1% with a long COVID diagnosis in January 2024.
By diagnosis, 50% of individuals who met the ACR’s 2016 fibromyalgia criteria and currently had long COVID scored positively for PEM.
Measures of pain, fatigue, sleep, patient global assessment, activity score, polysymptomatic distress, disability, depression, anxiety, and other functional scores were all significantly worse among those scoring positive for PEM (P < .001), Michaud reported.
Better Tools Are Available
The developer of the DePaul questionnaire, Leonard Jason, PhD, director of the Center for Community Research and professor of psychology at DePaul College of Science and Health, Chicago, told Medscape Medical News that an updated 10-item screening tool specifically designed to screen for PEM adds some important elements missing from the 5-item version.
Here, patients are initially asked two questions: “Do you experience a worsening of your fatigue/energy related illness after engaging in minimal physical effort?” and “Do you experience a worsening of your fatigue/energy related illness after engaging in mental effort?” If they answer “yes” to either, the next question is “If you feel worse after activities, how long does this last?” Answers are coded from 0 to 6 (24 hours or more).
The fourth additional question then asks how quickly patients recover, while a fifth question asks whether the person is avoiding activity because it makes them feel worse (thereby potentially creating a false negative).
For those scoring positive on the 10-item screen, a more comprehensive measure could be used, such as this online screening tool, Jason said.
Yellman said that the Bateman Horne Center uses a “good day, bad day” questionnaire to tease out some of the same information. In addition, he noted that it’s important to capture the timeframe between the exertion and the onset of symptoms because PEM doesn’t start during or immediately after activity. “If somebody is mowing the lawn and they start feeling symptoms immediately, they’re probably, at least in ME/CFS, experiencing orthostatic intolerance. Post-exertional malaise occurs 12-72 hours later, when their function is severely reduced as compared to baseline.”
And of course, Davenport noted, listening to patients is key. “Patients will tell you wildly unusual responses to activity before you even do the work of trying to figure out what the activity was. They’ll tell you things like they can’t think as well, that they have to be in bed for 3 days to a week to 2 weeks, depending on the level of exertion.”
Yellman, Davenport, and several other colleagues are currently working on a paper that will explain the differences between pacing and graded exercise, define PEM, and provide guidelines. They aim to submit it in time for publication early next year. In the meantime, the Bateman Horne Center’s website provides numerous resources for healthcare professionals and patients.
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Machine learning and multi-omics in precision medicine for ME/CFS - Huang, Lidbury, Thomas, Gooley & Armstrong
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex and multifaceted disorder that defies simplistic characterisation.
Traditional approaches to diagnosing and treating ME/CFS have often fallen short due to the condition's heterogeneity and the lack of validated biomarkers.
The growing field of precision medicine offers a promising approach which focuses on the genetic and molecular underpinnings of individual patients.
In this review, we explore how machine learning and multi-omics (genomics, transcriptomics, proteomics, and metabolomics) can transform precision medicine in ME/CFS research and healthcare.
We provide an overview on machine learning concepts for analysing large-scale biological data, highlight key advancements in multi-omics biomarker discovery, data quality and integration strategies, while reflecting on ME/CFS case study examples.
We also highlight several priorities, including the critical need for applying robust computational tools and collaborative data-sharing initiatives in the endeavour to unravel the biological intricacies of ME/CFS.
source: Journal of Translational Medicine, Open Access
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Journal of General Internal Medicine
Incidence and Prevalence of Post-COVID-19 Myalgic Encephalomyelitis: A Report from the Observational RECOVER-Adult Study
Original Research Open access Published: 13 January 2025
Suzanne D. Vernon PhD, Tianyu Zheng MS, Hyungrok Do PhD, Vincent C. Marconi MD, Leonard A. Jason PhD,
Benjamin H. Natelson MD, Zaki A. Sherif PhD, Hector Fabio Bonilla MD, Emily Taylor MA, Janet M. Mullington PhD, Hassan Ashktorab PhD, Adeyinka O. Laiyemo MD, Hassan Brim PhD, Thomas F. Patterson MD, Teresa T. Akintonwa BA, Anisha Sekar BA, Michael J. Peluso MD, Nikita Maniar MD, Lucinda Bateman MD, Leora I. Horwitz MD & Rachel Hess MD on behalf of the NIH Researching COVID to Enhance Recovery (RECOVER) Consortium
Abstract
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may occur after infection. How often people develop ME/CFS after SARS-CoV-2 infection is unknown.
Objective
To determine the incidence and prevalence of post-COVID-19 ME/CFS among adults enrolled in the Researching COVID to Enhance Recovery (RECOVER-Adult) study.
Design, Setting, and Participants
RECOVER-Adult is a longitudinal observational cohort study conducted across the U.S. We included participants who had a study visit at least 6 months after infection and had no pre-existing ME/CFS, grouped as (1) acute infected, enrolled within 30 days of infection or enrolled as uninfected who became infected (n=4515); (2) post-acute infected, enrolled greater than 30 days after infection (n=7270); and (3) uninfected (1439).
Measurements
Incidence rate and prevalence of post-COVID-19 ME/CFS based on the 2015 Institute of Medicine ME/CFS clinical diagnostic criteria.
Results
The incidence rate of ME/CFS in participants followed from time of SARS-CoV-2 infection was 2.66 (95% CI 2.63–2.70) per 100 person-years while the rate in matched uninfected participants was 0.93 (95% CI 0.91–10.95) per 100 person-years: a hazard ratio of 4.93 (95% CI 3.62–6.71). The proportion of all RECOVER-Adult participants that met criteria for ME/CFS following SARS-CoV-2 infection was 4.5% (531 of 11,785) compared to 0.6% (9 of 1439) in uninfected participants. Post-exertional malaise was the most common ME/CFS symptom in infected participants (24.0%, 2830 of 11,785). Most participants with post-COVID-19 ME/CFS also met RECOVER criteria for long COVID (88.7%, 471 of 531).
Limitations
The ME/CFS clinical diagnostic criteria uses self-reported symptoms. Symptoms can wax and wane.
Conclusion
ME/CFS is a diagnosable sequela that develops at an increased rate following SARS-CoV-2 infection. RECOVER provides an unprecedented opportunity to study post-COVID-19 ME/CFS.
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Articles The Lancet
Volume 49101161February 2025
Efficacy of repeated immunoadsorption in patients with post-COVID myalgic encephalomyelitis/chronic fatigue syndrome and elevated β2-adrenergic receptor autoantibodies: a prospective cohort study
Elisa Steina ∙ Cornelia Heindricha ∙ Kirsten Wittkea ∙ Claudia Kedora ∙ Rebekka Rusta,c ∙ Helma Freitaga∙ et al.
Summary
Background
Since the pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the leading trigger for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Evidence indicates that autoimmunity plays an important pathophysiological role. We aimed to evaluate the effectiveness of IA treatment in post-COVID ME/CFS patients.
Methods
This pre-post study included 20 post-coronavirus disease 2019 (COVID) ME/CFS patients found to have elevated β2 adrenergic autoantibodies (β2 AR-AB) between October 2022 and October 2023. Patients, with a median disease duration of 22 months (IQR: 15–31), were treated with five immunoadsorption sessions at Charité - Universitätsmedizin Berlin, Germany. Seven were male and 13 female, with a median age of 40 years (IQR: 36–51). The primary end point was the change in the Short Form (36) Health Survey physical functioning domain (SF36 PF) from baseline to four weeks post immunoadsorption. Key symptoms were assessed via questionnaires over six months. Handgrip strength and EndoPAT® measurements were used to evaluate muscle fatigue and vascular dysfunction. Seven patients who worsened after an initial response received a second cycle.
Findings
The treatment was generally well tolerated, reducing total immunoglobulin G by 79% (CI: 73–84%) and β2 AR-AB by 77% (CI: 58–95%). Patients demonstrated a mean increase in the SF36 PF of 17.75 points (CI: 13.41–26.16), with the greatest improvement occurring between months two and three, and significant gains maintained through month six. 14/20 (70%) patients were categorized as responders with an increase in the SF36 PF of ≥ ten points. Further lasting improvements were reported in fatigue, post-exertional malaise, pain, cognitive, autonomic, and immunological symptoms. Female patients had increased repeat handgrip strength at month six.
Interpretation
Immunoadsorption may improve symptoms in post-COVID ME/CFS patients. The beneficial effects of IgG depletion suggest a significant role for autoantibodies and disturbed B-cell function in the condition's pathophysiology.
Funding
Funded by The Federal Ministry of Education and Research and the Weidenhammer Zöbele Research Foundation.
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Women’s Immune Systems May Explain Increased Long COVID Diagnoses
Samantha Anderer
JAMA. 2025;333(3):194-195. doi:10.1001/jama.2024.25505
Women are more likely than men to experience post–COVID-19 condition, also known as long COVID, and a new study from Science Translational Medicine identified a possible explanation.
In an analysis of blood samples from 45 participants taken during and after SARS-CoV-2 infection, the authors identified sex-specific immune pathways in acute infection that were associated with subsequent development of long COVID. Females with long COVID displayed a decreased expression of transforming growth factor β1, whereas males who developed long COVID expressed more of the protein. Additionally, compared with those who recovered, women with long COVID expressed more of the RNA gene XIST, which plays a role in autoimmunity. Despite the sex-specific markers, there were some consistencies across sexes, such as increased expression of proinflammatory monocytes.
The results could help inform tailored therapeutic interventions for long COVID, the authors stated.
Published Online: December 20, 2024. doi:10.1001/jama.2024.25505
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Original Investigation Infectious Diseases January 22, 2025
Sex Differences in Long COVID
Dimpy P. Shah, MD, PhD1; Tanayott Thaweethai, PhD2,3; Elizabeth W. Karlson, MD, MS4; et al for the RECOVER Consortium
JAMA Netw Open. 2025;8(1):e2455430. doi:10.1001/jamanetworkopen.2024.55430
Key Points
Question Does the risk of long COVID, or post-COVID condition, differ by sex?
Findings In this cohort study of 12 276 individuals, females had a significantly higher risk of long COVID compared with males after adjusting for sociodemographic and clinical risk factors. The sex-based difference in long COVID risk was age, pregnancy, and menopause dependent, with the highest risk among females aged 40 to 55 years.
Meaning These findings highlight the importance of evaluating differences in risk of long COVID after SARS-CoV-2 infection in males and females and of comparing biological mechanisms that may underlie sexually dimorphic long COVID trajectories.
Abstract
Importance A substantial number of individuals worldwide experience long COVID, or post-COVID condition. Other postviral and autoimmune conditions have a female predominance, but whether the same is true for long COVID, especially within different subgroups, is uncertain.
Objective To evaluate sex differences in the risk of developing long COVID among adults with SARS-CoV-2 infection.
Design, Setting, and Participants This cohort study used data from the National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER)–Adult cohort, which consists of individuals enrolled in and prospectively followed up at 83 sites in 33 US states plus Washington, DC, and Puerto Rico. Data were examined from all participants enrolled between October 29, 2021, and July 5, 2024, who had a qualifying study visit 6 months or more after their initial SARS-CoV-2 infection.
Exposure Self-reported sex (male, female) assigned at birth.
Main Outcomes and Measures Development of long COVID, measured using a self-reported symptom-based questionnaire and scoring guideline at the first study visit that occurred at least 6 months after infection. Propensity score matching was used to estimate risk ratios (RRs) and risk differences (95% CIs). The full model included demographic and clinical characteristics and social determinants of health, and the reduced model included only age, race, and ethnicity.
Results Among 12 276 participants who had experienced SARS-CoV-2 infection (8969 [73%] female; mean [SD] age at infection, 46 [15] years), female sex was associated with higher risk of long COVID in the primary full (RR, 1.31; 95% CI, 1.06-1.62) and reduced (RR, 1.44; 95% CI, 1.17-1.77) models. This finding was observed across all age groups except 18 to 39 years (RR, 1.04; 95% CI, 0.72-1.49). Female sex was associated with significantly higher overall long COVID risk when the analysis was restricted to nonpregnant participants (RR, 1.50; 95%: CI, 1.27-1.77). Among participants aged 40 to 54 years, the risk ratio was 1.42 (95% CI, 0.99-2.03) in menopausal female participants and 1.45 (95% CI, 1.15-1.83) in nonmenopausal female participants compared with male participants.
Conclusions and Relevance In this prospective cohort study of the NIH RECOVER-Adult cohort, female sex was associated with an increased risk of long COVID compared with male sex, and this association was age, pregnancy, and menopausal status dependent. These findings highlight the need to identify biological mechanisms contributing to sex specificity to facilitate risk stratification, targeted drug development, and improved management of long COVID.
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Nature: Published: 17 January 2025
Association between chronic fatigue syndrome/myalgic encephalomyelitis and cardiovascular disease
Mawulorm K. I. Denu, Ritika Revoori, Cherita Eghan, Fredrick Larbi Kwapong, Andrew Hillman, Cornelius A. Normeshie, Kofi Poku Berko, Emily L. Aidoo & Maame Araba E. Buadu
Scientific Reports volume 15, Article number: 2294 (2025) 101 Altmetric
Abstract
Chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is a medical condition characterized by severe and prolonged fatigue that is not relieved by rest or attributed to any underlying medical or psychological condition. Individuals with CFS/ME are considered to have an increased risk of a wide range of comorbid conditions, including cardiovascular disease (CVD). The association between CFS/ME and CVD is not fully understood. To determine the prevalence of CFS/ME in a sample population and examine its association with CVD. Weighted sample size data of 114,834 was analyzed from the 2021–2022 national health interview survey (NHIS). Information on sociodemographic factors, CVD risk factors, and history of CFS/ME and CVD were collected. Multivariable logistic regression model was used to determine the association between CFS/ME and CVD, adjusting for traditional CVD risk factors (age, sex, race, hypertension, diabetes, dyslipidemia, smoking, and body mass index (BMI). Median age of participants was 53 years, and majority of participants were female (53.9%). Prevalence of CFS/ME was 1.2%. A history of CFS/ME was significantly associated with CVD (aOR 3.26, 95%CI 2.85, 3.72, p-value: <0.001) after adjusting for traditional CVD risk factors. A history of CFS/ME was independently associated with CVD after adjusting for traditional CVD risk factors. Patients with CFS/ME need close evaluation for CVD. Further studies are needed to better understand the relationship between CFS/ME and CVD.
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Recovery from Exercise in Persons with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
March 2023 Medicina 59(3):571 DOI:10.3390/medicina59030571 License CC BY 4.0
Authors:
Geoffrey E. Moore Betsy A Keller Ithaca College Jared Stevens Xiangling Mao Weill Cornell Medicine
Abstract and Figures
Background and Objectives:
Post-exertional malaise (PEM) is the hallmark of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but there has been little effort to quantitate the duration of PEM symptoms following a known exertional stressor. Using a Symptom Severity Scale (SSS) that includes nine common symptoms of ME/CFS, we sought to characterize the duration and severity of PEM symptoms following two cardiopulmonary exercise tests separated by 24 h (2-day CPET).
Materials and Methods: Eighty persons with ME/CFS and 64 controls (CTL) underwent a 2-day CPET. ME/CFS subjects met the Canadian Clinical Criteria for diagnosis of ME/CFS; controls were healthy but not participating in regular physical activity. All subjects who met maximal effort criteria on both CPETs were included. SSS scores were obtained at baseline, immediately prior to both CPETs, the day after the second CPET, and every two days after the CPET-1 for 10 days. Results: There was a highly significant difference in judged recovery time (ME/CFS = 12.7 ± 1.2 d; CTL = 2.1 ± 0.2 d, mean ± s.e.m., Chi2 = 90.1, p < 0.0001). The range of ME/CFS patient recovery was 1–64 days, while the range in CTL was 1–10 days; one subject with ME/CFS had not recovered after one year and was not included in the analysis. Less than 10% of subjects with ME/CFS took more than three weeks to recover. There was no difference in recovery time based on the level of pre-test symptoms prior to CPET-1 (F = 1.12, p = 0.33). Mean SSS scores at baseline were significantly higher than at pre-CPET-1 (5.70 ± 0.16 vs. 4.02 ± 0.18, p < 0.0001). Pharmacokinetic models showed an extremely prolonged decay of the PEM response (Chi2 > 22, p < 0.0001) to the 2-day CPET.
Conclusions: ME/CFS subjects took an average of about two weeks to recover from a 2-day CPET, whereas sedentary controls needed only two days. These data quantitate the prolonged recovery time in ME/CFS and improve the ability to obtain well-informed consent prior to doing exercise testing in persons with ME/CFS. Quantitative monitoring of PEM symptoms may provide a method to help manage PEM.
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Nnature scientific reports Published: 28 January 2025
Novel brain SPECT imaging unravels abnormal cerebral perfusion in patients with postural orthostatic tachycardia syndrome and cognitive dysfunction
Marie-Claire Seeley, Howard O’Brien, Gemma Wilson, Clair Coat, Tess Smith, Kevin Hickson, Reynold Casse, Amanda J. Page, Celine Gallagher & Dennis H. Lau
Scientific Reports volume 15, Article number: 3487 (2025)
Abstract
Cognitive dysfunction is frequently reported in individuals with postural orthostatic tachycardia syndrome (POTS), possibly resulting from reduced cerebral blood flow (CBF). We used brain SPECT, an accessible imaging modality that has not been systematically evaluated in this patient group. Retrospective review of participants from our registry was undertaken to identify those who had a brain SPECT performed for investigation of cognitive dysfunction. Abnormal CBF was taken as z-score > 2 standard deviations of healthy control reference values. Patient reported outcome measures (PROMs) such as autonomic, gastric and quality of life symptom scores were analyzed. From a total of 56 participants (mean 34.8 ± 10.7 years, 88% females), PROMs indicate: moderate to severe autonomic dysfunction in 75%; at least mild to moderate gastroparesis in 23%; low global health rating and utility scores. Abnormal CBF was seen in 61% but did not differ by POTS triggers. The regions with the lowest mean z-scores were the lateral prefrontal and sensorimotor cortices. Hierarchal regression analyses found number of brain regions with abnormal CBF, autonomic and gastric symptoms to account for 51% of variances in health utility. Cerebral hypoperfusion is prevalent in those with POTS and cognitive dysfunction even whilst supine, contributing to reduced quality of life.
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The search for a blood-based biomarker for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS): from biochemistry to electrophysiology
Krista S. P. Clarke, Caroline C. Kingdon, Michael Pycraft Hughes, Eliana Mattos Lacerda, Rebecca Lewis, Emily J. Kruchek, Robert A. Dorey & Fatima H. Labeed
Journal of Translational Medicine volume 23, Article number: 149 (2025) Cite this article
Abstract
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease of unknown aetiology characterised by symptoms of post-exertional malaise (PEM) and fatigue leading to substantial impairment in functioning. Other key symptoms include cognitive impairment and unrefreshing sleep, with many experiencing pain. To date there is no complete understanding of the triggering pathomechanisms of disease, and no quantitative biomarker available with sufficient sensitivity, specificity, and adoptability to provide conclusive diagnosis. Clinicians thus eliminate differential diagnoses, and rely on subjective, unspecific, and disputed clinical diagnostic criteria—a process that often takes years with patients being misdiagnosed and receiving inappropriate and sometimes detrimental care. Without a quantitative biomarker, trivialisation, scepticism, marginalisation, and misunderstanding of ME/CFS continues despite the significant disability for many. One in four individuals are bed-bound for long periods of time, others have difficulties maintaining a job/attending school, incurring individual income losses of thousands, while few participate in social activities.
Main body
Recent studies have reported promising quantifiable differences in the biochemical and electrophysiological properties of blood cells, which separate ME/CFS and non-ME/CFS participants with high sensitivities and specificities—demonstrating potential development of an accessible and relatively non-invasive diagnostic biomarker. This includes profiling immune cells using Raman spectroscopy, measuring the electrical impedance of blood samples during hyperosmotic challenge using a nano-electronic assay, use of metabolomic assays, and certain techniques which assess mitochondrial dysfunction. However, for clinical application, the specificity of these biomarkers to ME/CFS needs to be explored in more disease controls, and their practicality/logistics considered. Differences in cytokine profiles in ME/CFS are also well documented, but finding a consistent, stable, and replicable cytokine profile may not be possible. Increasing evidence demonstrates acetylcholine receptor and transient receptor potential ion channel dysfunction in ME/CFS, though how these findings could translate to a diagnostic biomarker are yet to be explored.
Conclusion
Different biochemical and electrophysiological properties which differentiate ME/CFS have been identified across studies, holding promise as potential blood-based quantitative diagnostic biomarkers for ME/CFS. However, further research is required to determine their specificity to ME/CFS and adoptability for clinical use.
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Original Investigation Infectious Diseases January 22, 2025
Sex Differences in Long COVID
Dimpy P. Shah, MD, PhD1; et al ; for the RECOVER Consortium
JAMA Netw Open. 2025;8(1):e2455430. doi:10.1001/jamanetworkopen.2024.55430
Key Points
Question Does the risk of long COVID, or post-COVID condition, differ by sex?
Findings In this cohort study of 12 276 individuals, fe
Findings In this cohort study of 12 276 individuals, females had a significantly higher risk of long COVID compared with males after adjusting for sociodemographic and clinical risk factors. The sex-based difference in long COVID risk was age, pregnancy, and menopause dependent, with the highest risk among females aged 40 to 55 years.
Meaning These findings highlight the importance of evaluating differences in risk of long COVID after SARS-CoV-2 infection in males and females and of comparing biological mechanisms that may underlie sexually dimorphic long COVID trajectories.
Abstract
Importance A substantial number of individuals worldwide experience long COVID, or post-COVID condition. Other postviral and autoimmune conditions have a female predominance, but whether the same is true for long COVID, especially within different subgroups, is uncertain.
Objective To evaluate sex differences in the risk of developing long COVID among adults with SARS-CoV-2 infection.
Design, Setting, and Participants This cohort study used data from the National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER)–Adult cohort, which consists of individuals enrolled in and prospectively followed up at 83 sites in 33 US states plus Washington, DC, and Puerto Rico. Data were examined from all participants enrolled between October 29, 2021, and July 5, 2024, who had a qualifying study visit 6 months or more after their initial SARS-CoV-2 infection.
Exposure Self-reported sex (male, female) assigned at birth.
Main Outcomes and Measures Development of long COVID, measured using a self-reported symptom-based questionnaire and scoring guideline at the first study visit that occurred at least 6 months after infection. Propensity score matching was used to estimate risk ratios (RRs) and risk differences (95% CIs). The full model included demographic and clinical characteristics and social determinants of health, and the reduced model included only age, race, and ethnicity.
Results Among 12 276 participants who had experienced SARS-CoV-2 infection (8969 [73%] female; mean [SD] age at infection, 46 [15] years), female sex was associated with higher risk of long COVID in the primary full (RR, 1.31; 95% CI, 1.06-1.62) and reduced (RR, 1.44; 95% CI, 1.17-1.77) models. This finding was observed across all age groups except 18 to 39 years (RR, 1.04; 95% CI, 0.72-1.49). Female sex was associated with significantly higher overall long COVID risk when the analysis was restricted to nonpregnant participants (RR, 1.50; 95%: CI, 1.27-1.77). Among participants aged 40 to 54 years, the risk ratio was 1.42 (95% CI, 0.99-2.03) in menopausal female participants and 1.45 (95% CI, 1.15-1.83) in nonmenopausal female participants compared with male participants.
Conclusions and Relevance In this prospective cohort study of the NIH RECOVER-Adult cohort, female sex was associated with an increased risk of long COVID compared with male sex, and this association was age, pregnancy, and menopausal status dependent. These findings highlight the need to identify biological mechanisms contributing to sex specificity to facilitate risk stratification, targeted drug development, and improved management of long COVID.
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Chronic fatigue syndrome: Outcry over Cochrane decision to abandon review of exercise therapy
BMJ 2025; 388 doi: https://doi.org/10.1136/bmj.r169 (Published 27 January 2025)Cite this as: BMJ 2025;388:r169
Jacqui Wise
A decision to cancel a planned update of a Cochrane systematic review of exercise therapy for chronic fatigue syndrome has met with anger from a group advising the review and the patient community.
The decision has reignited calls for the review,1 which includes studies only up to May 2014, to be withdrawn for being outdated and misleading.
The review recommends exercise therapy to treat myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), concluding that this “probably has a positive effect on fatigue in adults compared to usual care or passive therapies.”
However, this treatment approach is controversial and has been criticised by patient groups who say that it can make symptoms worse. Guidelines from the National Institute for Health and Care Excellence, published in 2021, specifically advise against graded exercise therapy.2 Guidelines from the US Centers for Disease Control and Prevention also state that exercise therapy is not a cure for ME/CFS and that standard exercise recommendations for healthy people can be harmful for people with ME/CFS.3
The Cochrane systematic review was modified slightly by its authors in 2019 to place more emphasis on the limited applicability of the evidence to definitions of ME/CFS used in the included studies, the long term effects of exercise on symptoms of fatigue, and the limitations of evidence on harms that may occur.
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Hippocampal subfield volume alterations and associations with severity measures in long COVID and ME/CFS: A 7T MRI study
Kiran Thapaliya ,Sonya Marshall-Gradisnik,Natalie Eaton-Fitch,Markus Barth,Maira Inderyas,Leighton Barnden
Published: January 13, 2025 Plos one https://doi.org/10.1371/journal.pone.0316625
Abstract
Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients share similar symptoms including post-exertional malaise, neurocognitive impairment, and memory loss. The neurocognitive impairment in both conditions might be linked to alterations in the hippocampal subfields. Therefore, this study compared alterations in hippocampal subfields of 17 long COVID, 29 ME/CFS patients, and 15 healthy controls (HC). Structural MRI data was acquired with sub-millimeter isotropic resolution on a 7 Telsa MRI scanner and hippocampal subfield volumes were then estimated for each participant using FreeSurfer software. Our study found significantly larger volumes in the left hippocampal subfields of both long COVID and ME/CFS patients compared to HC. These included the left subiculum head (long COVID; p = 0.01, ME/CFS; p = 0.002,), presubiculum head (long COVID; p = 0.004, ME/CFS; p = 0.005), molecular layer hippocampus head (long COVID; p = 0.014, ME/CFS; p = 0.011), and whole hippocampal head (long COVID; p = 0.01, ME/CFS; p = 0.01). Notably, hippocampal subfield volumes were similar between long COVID and ME/CFS patients. Additionally, we found significant associations between hippocampal subfield volumes and severity measures of ‘Pain’, ‘Duration of illness’, ‘Severity of fatigue’, ‘Impaired concentration’, ‘Unrefreshing sleep’, and ‘Physical function’ in both conditions. These findings suggest that hippocampal alterations may contribute to the neurocognitive impairment experienced by long COVID and ME/CFS patients. Furthermore, our study highlights similarities between these two conditions.
Citation: Thapaliya K, Marshall-Gradisnik S, Eaton-Fitch N, Barth M, Inderyas M, Barnden L (2025) Hippocampal subfield volume alterations and associations with severity measures in long COVID and ME/CFS: A 7T MRI study. PLoS ONE 20(1): e0316625. https://doi.org/10.1371/journal.pone.0316625
Editor: Daichi Sone, Jikei University School of Medicine, JAPAN
Received: August 21, 2024; Accepted: December 11, 2024; Published: January 13, 2025
Copyright: © 2025 Thapaliya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are present within the manuscript. The datasets from this study are not publicly available due to confidentiality agreements but could be available on reasonable request. Any request should be submitted to Chair, Griffith University Human Research Ethics Committee, by the e-mail [email protected] or phone (+61) 07 3735 2069.
Funding: This research was funded by ME Research UK (SCIO Charity Number SC036942) with the financial support of The Fred and Joan Davies Bequest. Other funding bodies include The Stafford Fox Medical Research Foundation (489798), the National Health and Medical Research Council (1199502), Talei Stewart, Buxton Foundation (4676), Henty Community (4879), Henty Lions Club (4880), Blake Beckett Trust Foundation (4579), Alison Hunter Memorial Foundation (4570), and the Change for ME Charity (4575).
Competing interests: The authors have declared that no competing interests exist.
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