Journal of Translational Medicine
Betsy Keller, Candace N. Receno, Carl J. Franconi, Sebastian Harenberg, Jared Stevens, Xiangling Mao, Staci R. Stevens, Geoff Moore, Susan Levine, John Chia, Dikoma Shungu & Maureen R. Hanson
Journal of Translational Medicine volume 22, Article number: 627 (2024)
Abstract
Background
Post-exertional malaise (PEM), the hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), represents a constellation of abnormal responses to physical, cognitive, and/or emotional exertion including profound fatigue, cognitive dysfunction, and exertion intolerance, among numerous other maladies. Two sequential cardiopulmonary exercise tests (2-d CPET) provide objective evidence of abnormal responses to exertion in ME/CFS but validated only in studies with small sample sizes. Further, translation of results to impairment status and approaches to symptom reduction are lacking.
Methods Participants with ME/CFS (Canadian Criteria; n = 84) and sedentary controls (CTL; n = 71) completed two CPETs on a cycle ergometer separated by 24 h. Two-way repeated measures ANOVA compared CPET measures at rest, ventilatory/anaerobic threshold (VAT), and peak effort between phenotypes and CPETs. Intraclass correlations described stability of CPET measures across tests, and relevant objective CPET data indicated impairment status. A subset of case–control pairs (n = 55) matched for aerobic capacity, age, and sex, were also analyzed.
Results Unlike CTL, ME/CFS failed to reproduce CPET-1 measures during CPET-2 with significant declines at peak exertion in work, exercise time, V˙e, V˙O2, V˙CO2, V˙ T, HR, O2pulse, DBP, and RPP. Likewise, CPET-2 declines were observed at VAT for V˙e/V˙CO2, PetCO2, O2pulse, work, V˙O2 and SBP. Perception of effort (RPE) exceeded maximum effort criteria for ME/CFS and CTL on both CPETs. Results were similar in matched pairs. Intraclass correlations revealed greater stability in CPET variables across test days in CTL compared to ME/CFS owing to CPET-2 declines in ME/CFS. Lastly, CPET-2 data signaled more severe impairment status for ME/CFS compared to CPET-1.
Conclusions Presently, this is the largest 2-d CPET study of ME/CFS to substantiate impaired recovery in ME/CFS following an exertional stressor. Abnormal post-exertional CPET responses persisted compared to CTL matched for aerobic capacity, indicating that fitness level does not predispose to exertion intolerance in ME/CFS. Moreover, contributions to exertion intolerance in ME/CFS by disrupted cardiac, pulmonary, and metabolic factors implicates autonomic nervous system dysregulation of blood flow and oxygen delivery for energy metabolism. The observable declines in post-exertional energy metabolism translate notably to a worsening of impairment status. Treatment considerations to address tangible reductions in physiological function are proffered.
Trial registration number: ClinicalTrials.gov, retrospectively registered, ID# NCT04026425, date of registration: 2019-07-17.
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ARTICLES| VOLUME 74, 102719, AUGUST 2024
Pre-existing sleep disturbances and risk of COVID-19: a meta-analysis
Jiawei Zhou,,Xia LiTing Zhang,Ziyan Liu,Peng Li,Na Yu,et al.
Open AccessPublished:July 05, 2024DOI:https://doi.org/10.1016/j.eclinm.2024.102719
Summary
Background
Sleep disturbances are widespread but usually overlooked health risk factors for coronavirus disease 2019 (COVID-19). We aimed to investigate the influence of pre-existing sleep disturbances on the susceptibility, severity, and long-term effects of COVID-19.
Methods
We searched PubMed, Web of Science, and Embase for relevant articles from inception to October 27, 2023 and updated at May 8, 2024. Sleep disturbances included obstructive sleep apnea (OSA), insomnia, abnormal sleep duration, night-shift work, and any other sleep disturbances. Outcomes were COVID-19 susceptibility, hospitalization, mortality, and long COVID. The effect sizes were pooled odds ratios (ORs) and 95% confidence intervals (95% CIs). This study is registered with PROSPERO (CRD42024503518).
Findings
A total of 48 observational studies (n = 8,664,026) were included. Pre-existing sleep disturbances increased the risk of COVID-19 susceptibility (OR = 1.12, 95% CI 1.07–1.18), hospitalization (OR = 1.25, 95% CI 1.15–1.36), mortality (OR = 1.45, 95% CI 1.19–1.78), and long COVID (OR = 1.36 95% CI 1.17–1.57). Subgroup analysis showed that younger individuals with sleep disturbances were associated with higher susceptibility and hospitalization and a lower risk of mortality than older individuals. Males with sleep disturbances were associated with higher mortality. For specific sleep disturbances, the susceptibility and hospitalization of COVID-19 were associated with OSA, abnormal sleep duration, and night-shift work; mortality of COVID-19 was linked to OSA; risk of long COVID was related to OSA, abnormal sleep duration and insomnia.
Interpretation
Pre-existing sleep disturbances, especially OSA, increased the risk of COVID-19 susceptibility, hospitalization, mortality, and long COVID. Age and sex played important roles in the effect of sleep disturbances on COVID-19.
Funding
The National Natural Science Foundation of China and the Key Laboratory of Respiratory Diseases of Liaoning Province.
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Post–Acute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) After Infection During Pregnancy
Metz, Torri D.; Reeder, Harrison T.; Clifton, Rebecca G.; More July 11, 2024
OBJECTIVE:
To estimate the prevalence of post–acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) after infection with SARS-CoV-2 during pregnancy and to characterize associated risk factors.
METHODS:
In a multicenter cohort study (NIH RECOVER [Researching COVID to Enhance Recovery]-Pregnancy Cohort), individuals who were pregnant during their first SARS-CoV-2 infection were enrolled across the United States from December 2021 to September 2023, either within 30 days of their infection or at differential time points thereafter. The primary outcome was PASC , defined as score of 12 or higher based on symptoms and severity as previously published by the NIH RECOVER-Adult Cohort, at the first study visit at least 6 months after the participant's first SARS-CoV-2 infection. Risk factors for PASC were evaluated, including sociodemographic characteristics, clinical characteristics before SARS-CoV-2 infection (baseline comorbidities, trimester of infection, vaccination status), and acute infection severity (classified by need for oxygen therapy). Multivariable logistic regression models were fitted to estimate associations between these characteristics and presence of PASC.
RESULTS:
Of the 1,502 participants, 61.1% had their first SARS-CoV-2 infection on or after December 1, 2021 (ie, during Omicron variant dominance); 51.4% were fully vaccinated before infection; and 182 (12.1%) were enrolled within 30 days of their acute infection. The prevalence of PASC was 9.3% (95% CI, 7.9–10.9%) measured at a median of 10.3 months (interquartile range 6.1–21.5) after first infection. The most common symptoms among individuals with PASC were postexertional malaise (77.7%), fatigue (76.3%), and gastrointestinal symptoms (61.2%). In a multivariable model, the proportion PASC positive with vs without history of obesity (14.9% vs 7.5%, adjusted odds ratio [aOR] 1.65, 95% CI, 1.12–2.43), depression or anxiety disorder (14.4% vs 6.1%, aOR 2.64, 95% CI, 1.79–3.88) before first infection, economic hardship (self-reported difficulty covering expenses) (12.5% vs 6.9%, aOR 1.57, 95% CI, 1.05–2.34), and treatment with oxygen during acute SARS-CoV-2 infection (18.1% vs 8.7%, aOR 1.86, 95% CI, 1.00–3.44) were associated with increased prevalence of PASC.
CONCLUSION:
The prevalence of PASC at a median time of 10.3 months after SARS-CoV-2 infection during pregnancy was 9.3% in the NIH RECOVER-Pregnancy Cohort. The predominant symptoms were postexertional malaise, fatigue, and gastrointestinal symptoms. Several socioeconomic and clinical characteristics were associated with PASC after infection during pregnancy.
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ARTICLES| VOLUME 59, 101946, MAY 2023
Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot study
Lucy E.M. Finnigan,Mark Philip Cassar,Margaret James Koziel,Joel Pradines,Hanan Lamlum,Karim Azer,et al.
Open AccessPublished:April 14, 2023DOI:https://doi.org/10.1016/j.eclinm.2023.101946
Summary: Background
‘Long COVID’ describes persistent symptoms, commonly fatigue, lasting beyond 12 weeks following SARS-CoV-2 infection. Potential causes include reduced mitochondrial function and cellular bioenergetics. AXA1125 has previously increased β-oxidation and improved bioenergetics in preclinical models along with certain clinical conditions, and therefore may reduce fatigue associated with Long COVID. We aimed to assess the efficacy, safety and tolerability of AXA1125 in Long COVID.
Methods
Patients with fatigue-dominant Long COVID were recruited in this single-centre, double-blind, randomised controlled phase 2a pilot study completed in the UK. Patients were randomly assigned (1:1) using an Interactive Response Technology to receive either AXA1125 or matching placebo in a clinical-based setting. Each dose (33.9 g) of AXA1125 or placebo was administered orally in a liquid suspension twice daily for four weeks with a two-week follow-up period. The primary endpoint was the mean change from baseline to day 28 in the phosphocreatine (PCr) recovery rate following moderate exercise, assessed by 31P-magnetic resonance spectroscopy (MRS). All patients were included in the intention to treat analysis. This trial was registered at ClinicalTrials.gov, NCT05152849.
Findings
Between December 15th 2021, and May 23th 2022, 60 participants were screened, and 41 participants were randomised and included in the final analysis. Changes in skeletal muscle phosphocreatine recovery time constant (τPCr) and 6-min walk test (6MWT) did not significantly differ between treatment (n = 21) and placebo group (n = 20). However, treatment with AXA1125 was associated with significantly reduced day 28 Chalder Fatigue Questionnaire [CFQ-11] fatigue score when compared with placebo (least squares mean difference [LSMD] −4.30, 95% confidence interval (95% CI) −7.14, −1.47; P = 0.0039). Eleven (52.4%, AXA1125) and four (20.0%, placebo) patients reported treatment-emergent adverse events; none were serious or led to treatment discontinuation.
Interpretation
Although treatment with AXA1125 did not improve the primary endpoint (τPCr-measure of mitochondrial respiration), when compared to placebo, there were significant improvements in fatigue-based symptoms among patients living with Long COVID following a four-week treatment period. Further multicentre studies are needed to validate our findings in a larger cohort of patients with fatigue-dominant Long COVID.
Funding
Axcella Therapeutics.
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Original Investigation Public Health July 24, 2024
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome After SARS-CoV-2 Infection
Elizabeth R. Unger, MD, PhD1; Jin-Mann S. Lin, PhD1; Lauren E. Wisk, PhD2; et alHuihui Yu, PhD3; Michelle L’Hommedieu, PhD2; Helen Lavretsky, MD, MS4; Juan Carlos C. Montoy, MD, PhD5; Michael A. Gottlieb, MD6; Kristin L. Rising, MD, MSHP7,8; Nicole L. Gentile, MD, PhD9,10,11; Michelle Santangelo, MS12; Arjun K. Venkatesh, MD, MBA, MHS3,13; Robert M. Rodriguez, MD5; Mandy J. Hill, DrPH, MPH14; Rachel E. Geyer, MPH10; Efrat R. Kean, MD7; Sharon Saydah, PhD15; Samuel A. McDonald, MD, MS16,17; Ryan Huebinger, MD14; Ahamed H. Idris, MD16; Jocelyn Dorney, MPH3; Bala Hota, MD, MPH18; Erica S. Spatz, MD, MHS3,19; Kari A. Stephens, PhD10,20; Robert A. Weinstein, MD12,21; Joann G. Elmore, MD, MPH2; for the Innovative Support for Patients with SARS-CoV-2 Infections Registry (INSPIRE) Group
JAMA Netw Open. 2024;7(7):e2423555. doi:10.1001/jamanetworkopen.2024.23555
Key Points
Question Does prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)–like illness differ between individuals with an acute infection–like index illness who are COVID-19 positive or negative?
Findings In this cohort study of 4378 participants, the weighted prevalence of ME/CFS-like illness was 4.5% or less at 3 to 12 months after the index illness in the COVID-19–positive and COVID-19–negative groups, with no significant differences in odds of ME/CFS-like illness.
Meaning The findings suggest that ME/CFS-like illness following an acute infection–like index illness does not vary by COVID-19 test result.
Abstract
Importance Chronic symptoms reported following an infection with SARS-CoV-2, such as cognitive problems, overlap with symptoms included in the definition of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Objective To evaluate the prevalence of ME/CFS-like illness subsequent to acute SARS-CoV-2 infection, changes in ME/CFS symptoms through 12 months of follow-up, and the association of ME/CFS symptoms with SARS-CoV-2 test results at the acute infection–like index illness.
Design, Setting, and Participants This prospective, multisite, longitudinal cohort study (Innovative Support for Patients with SARS-CoV-2 Infections Registry [INSPIRE]) enrolled participants from December 11, 2020, to August 29, 2022. Participants were adults aged 18 to 64 years with acute symptoms suggestive of SARS-CoV-2 infection who received a US Food and Drug Administration–approved SARS-CoV-2 test at the time of illness and did not die or withdraw from the study by 3 months. Follow-up surveys were collected through February 28, 2023.
Exposure COVID-19 status (positive vs negative) at enrollment.
Main Outcome and Measures The main outcome was the weighted proportion of participants with ME/CFS-like illness based on the 2015 Institute of Medicine clinical case definition using self-reported symptoms.
Results A total of 4378 participants were included in the study. Most were female (3226 [68.1%]). Mean (SD) age was 37.8 (11.8) years. The survey completion rates ranged from 38.7% (3613 of 4738 participants) to 76.3% (1835 of 4738) and decreased over time. The weighted proportion of participants identified with ME/CFS-like illness did not change significantly at 3 through 12 months of follow-up and was similar in the COVID-19–positive (range, 2.8%-3.7%) and COVID-19–negative (range, 3.1%-4.5%) groups. Adjusted analyses revealed no significant difference in the odds of ME/CFS-like illness at any time point between COVID-19–positive and COVID-19–negative individuals (marginal odds ratio range, 0.84 [95% CI, 0.42-1.67] to 1.18 [95% CI, 0.55-2.51]).
Conclusions and Relevance In this prospective cohort study, there was no evidence that the proportion of participants with ME/CFS-like illness differed between those infected with SARS-CoV-2 vs those without SARS-CoV-2 infection up to 12 months after infection. A 3% to 4% prevalence of ME/CFS-like illness after an acute infection–like index illness would impose a high societal burden given the millions of persons infected with SARS-CoV-2.
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WebMD Health News
Long COVID Risk Has Dropped Since Start of Pandemic
Ralph Ellis July 19, 2024
Your chances of developing long COVID have significantly decreased since the pandemic began, offering a glimmer of hope and a sign of progress in the ongoing battle against the virus.
That's according to a new study published in The New England Journal of Medicine. Researchers at Washington University in St. Louis, who conducted the study, said that the drop was caused by vaccinations and changes in the virus itself.
"You can see a clear and significant difference in risk during the delta and omicron eras between the vaccinated and unvaccinated," Ziyad Al-Aly, MD, director of the Clinical Epidemiology Center at the VA St. Louis Health Care System and head of the research and development service, said in a statement. "So, if people think COVID is no big deal and decide to forgo vaccinations, they're essentially doubling their risk of developing long COVID."
Researchers analyzed the health records collected from March 1, 2020, through January 31, 2022, for 441,583 veterans who were infected with COVID-19 and 4.7 million veterans who were not infected.
Among unvaccinated people, long COVID was developed by 10.4% infected with the original strain of COVID, 9.5% infected with the Delta strain, and 7.7% infected with Omicron.
Among vaccinated people, long COVID occurred in 5.3% of those infected with the Delta strain and 3.5% of those infected with Omicron.
Al-Aly noted that among people infected with the Omicron strain, the chances of heart, brain, kidney, and lung problems declined while the risk of problems with metabolic function and the GI system increased.
"Each variant has its own fingerprint," Al-Aly said. "The original virus hit the respiratory system hard. Omicron targeted metabolic and GI issues. It's important because while the risk of long COVID is quantitatively lower, a person can be at a higher risk of developing an illness based on the part of the body that the COVID variant targets."
With long COVID, symptoms persist months or years after infection. Common symptoms include extreme fatigue, shortness of breath, loss of the sense of smell, and muscle aches.
According to the CDC's Household Pulse Survey, 18.4% of American adults say they've experienced long COVID at some point.
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RESEARCH ARTICLE NEUROIMMUNOLOGY
Infection and chronic disease activate a systemic brain-muscle signaling axis
SHUO YANG HTTPS://ORCID.ORG/0000-0002-7929-0244 , MEIJIE TIAN HTTPS://ORCID.ORG/0000-0003-0547-9447, YULONG DAI, RONG WANG, [...], AND AARON JOHNSON HTTPS://ORCID.ORG/0000-0002-2783-5636 +12 authors
SCIENCE IMMUNOLOGY 12 Jul 2024 Vol 9, Issue 97 DOI: 10.1126/sciimmunol.adm7908
Editor’s summary
Neuroinflammation can cause symptoms outside of the central nervous system (CNS), including muscle pain and fatigue, yet how inflammatory signals in the brain are communicated to muscle remains to be determined. Using multiple models of CNS stress in fruit flies, Yang et al. identified that reactive oxygen species accumulation in the brain promoted expression of Upd3, a Drosophila ortholog of interleukin-6 (IL-6). IL-6 activated JAK-STAT signaling in skeletal muscle, resulting in mitochondrial dysfunction–impaired motor function. This axis was also activated in mice after CNS stress and evident in humans with neuroinflammation. This work identifies a conserved brain-to-muscle signaling axis that regulates muscle performance, which may be a promising therapeutic target. —Hannah Isles
Abstract
Infections and neurodegenerative diseases induce neuroinflammation, but affected individuals often show nonneural symptoms including muscle pain and muscle fatigue. The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood. We developed multiple models to investigate the impact of CNS stressors on motor function and found that Escherichia coli infections and SARS-CoV-2 protein expression caused reactive oxygen species (ROS) to accumulate in the brain. ROS induced expression of the cytokine Unpaired 3 (Upd3) in Drosophila and its ortholog, IL-6, in mice. CNS-derived Upd3/IL-6 activated the JAK-STAT pathway in skeletal muscle, which caused muscle mitochondrial dysfunction and impaired motor function. We observed similar phenotypes after expressing toxic amyloid-β (Aβ42) in the CNS. Infection and chronic disease therefore activate a systemic brain-muscle signaling axis in which CNS-derived cytokines bypass the connectome and directly regulate muscle physiology, highlighting IL-6 as a therapeutic target to treat disease-associated muscle dysfunction.
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Viruses:. 2024 Apr 8;16(4):572. doi: 10.3390/v16040572.
Herpesvirus Infection of Endothelial Cells as a Systemic Pathological Axis in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Jean M Nunes , Douglas B Kell , Etheresia Pretorius Affiliations Expand PMID: 38675914 PMCID: PMC11053605
Abstract
Understanding the pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is critical for advancing treatment options. This review explores the novel hypothesis that a herpesvirus infection of endothelial cells (ECs) may underlie ME/CFS symptomatology. We review evidence linking herpesviruses to persistent EC infection and the implications for endothelial dysfunction, encompassing blood flow regulation, coagulation, and cognitive impairment-symptoms consistent with ME/CFS and Long COVID. This paper provides a synthesis of current research on herpesvirus latency and reactivation, detailing the impact on ECs and subsequent systemic complications, including latent modulation and long-term maladaptation. We suggest that the chronicity of ME/CFS symptoms and the multisystemic nature of the disease may be partly attributable to herpesvirus-induced endothelial maladaptation. Our conclusions underscore the necessity for further investigation into the prevalence and load of herpesvirus infection within the ECs of ME/CFS patients. This review offers conceptual advances by proposing an endothelial infection model as a systemic mechanism contributing to ME/CFS, steering future research toward potentially unexplored avenues in understanding and treating this complex syndrome.
Keywords: endothelial cells; herpesvirus; myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
PubMed Disclaimer
Conflict of interest statement
The authors declare no conflicts of interest.
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J Transl Med. 2024; 22: 630. Published online 2024 Jul 5. doi: 10.1186/s12967-024-05412-3
PMCID: PMC11227206 PMID: 38970055
Potential pathophysiological role of the ion channel TRPM3 in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the therapeutic effect of low-dose naltrexone
Matthias Löhn1 and Klaus Josef Wirth1,2
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease with a broad overlap of symptomatology with Post-COVID Syndrome (PCS). Despite the severity of symptoms and various neurological, cardiovascular, microvascular, and skeletal muscular findings, no biomarkers have been identified. The Transient receptor potential melastatin 3 (TRPM3) channel, involved in pain transduction, thermosensation, transmitter and neuropeptide release, mechanoregulation, vasorelaxation, and immune defense, shows altered function in ME/CFS. Dysfunction of TRPM3 in natural killer (NK) cells, characterized by reduced calcium flux, has been observed in ME/CFS and PCS patients, suggesting a role in ineffective pathogen clearance and potential virus persistence and autoimmunity development. TRPM3 dysfunction in NK cells can be improved by naltrexone in vitro and ex vivo, which may explain the moderate clinical efficacy of low-dose naltrexone (LDN) treatment. We propose that TRPM3 dysfunction may have a broader involvement in ME/CFS pathophysiology, affecting other organs. This paper discusses TRPM3’s expression in various organs and its potential impact on ME/CFS symptoms, with a focus on small nerve fibers and the brain, where TRPM3 is involved in presynaptic GABA release.
Keywords: TRPM3 channel, Myalgic Encephalomyelitis/Chronic fatigue syndrome, ME/CFS, Post-COVID syndrome, Long-COVID, Exercise intolerance, GABA, Small fiber neuropathy, Naltrexone
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J Transl Med . 2024 Jul 5;22(1):630. doi: 10.1186/s12967-024-05412-3.
Potential pathophysiological role of the ion channel TRPM3 in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the therapeutic effect of low-dose naltrexone
Matthias Löhn 1, Klaus Josef Wirth 2 3
PMID: 38970055 PMCID: PMC11227206 DOI: 10.1186/s12967-024-05412-3
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease with a broad overlap of symptomatology with Post-COVID Syndrome (PCS). Despite the severity of symptoms and various neurological, cardiovascular, microvascular, and skeletal muscular findings, no biomarkers have been identified. The Transient receptor potential melastatin 3 (TRPM3) channel, involved in pain transduction, thermosensation, transmitter and neuropeptide release, mechanoregulation, vasorelaxation, and immune defense, shows altered function in ME/CFS. Dysfunction of TRPM3 in natural killer (NK) cells, characterized by reduced calcium flux, has been observed in ME/CFS and PCS patients, suggesting a role in ineffective pathogen clearance and potential virus persistence and autoimmunity development. TRPM3 dysfunction in NK cells can be improved by naltrexone in vitro and ex vivo, which may explain the moderate clinical efficacy of low-dose naltrexone (LDN) treatment. We propose that TRPM3 dysfunction may have a broader involvement in ME/CFS pathophysiology, affecting other organs. This paper discusses TRPM3's expression in various organs and its potential impact on ME/CFS symptoms, with a focus on small nerve fibers and the brain, where TRPM3 is involved in presynaptic GABA release.
Keywords: Exercise intolerance; GABA; Long-COVID; ME/CFS; Myalgic Encephalomyelitis/Chronic fatigue syndrome; Naltrexone; Post-COVID syndrome; Small fiber neuropathy; TRPM3 channel.
© 2024. The Author(s).
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J Cereb Blood Flow Metab . 2024 Aug 7:271678X241270528.
doi: 10.1177/0271678X241270528. Online ahead of print.
Absence of BOLD adaptation in chronic fatigue syndrome revealed by task functional MRI
Laura Schönberg 1 2, Abdalla Z Mohamed 1, Qiang Yu 1, Richard A Kwiatek 1, Peter Del Fante 1, Vince D Calhoun 3, Zack Y Shan 1
PMID: 39113421 DOI: 10.1177/0271678X241270528
Abstract
Neurological symptoms are central to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), yet its underlying neurophysiological mechanisms remain elusive. We examined a neglected aspect of task-based functional MRI, focusing on how blood oxygenation level-dependent (BOLD) signals alter during cognitive tasks in ME/CFS. This prospective observational study utilised MRI scans on ME/CFS participants and healthy controls (HCs) with sedentary lifestyles (ACTRN12622001095752). Participants completed two blocks of a Symbol Digit Modalities Test, with 30 trials per block split into two sets. The fMRI signal changes between blocks and sets were compared within and between groups. Thirty-four ME/CFS participants (38 years ± 10; 27 women) and 34 HCs (38 ± 10; 27 women), were evaluated. In the second task block, ME/CFS participants exhibited increased activation in the right postcentral gyrus, contrasting with decreased activation in multiple regions in HCs. These results were further confirmed by significantly higher bilateral dynamic changes (2nd vs 1st set) in the motor, sensory and cognitive cortex in ME/CFS compared to HCs and significant correlations between those changes in the left primary motor cortex with fatigue severities. BOLD adaptation, potentially improving energy economy, was absent in ME/CFS, which may provide an underlying neurophysiological process in ME/CFS.
Keywords: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); Symbol Digit Modalities Test (SDMT); fatigue severity; neurophysiological adaptation; task functional MRI (tfMRI).
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ACS Chemical NeuroscienceExpand
Research ArticleSeptember 20, 2024
Untargeted Metabolomics and Quantitative Analysis of Tryptophan Metabolites in Myalgic Encephalomyelitis Patients and Healthy Volunteers: A Comparative Study Using High-Resolution Mass Spectrometry
Sandy Abujrais,Theodosia Vallianatou,Jonas Bergquist*
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex illness characterized by severe and often disabling physical and mental fatigue. So far, scientists have not been able to fully pinpoint the biological cause of the illness and yet it affects millions of people worldwide. To gain a better understanding of ME/CFS, we compared the metabolic networks in the plasma of 38 ME/CFS patients to those of 24 healthy control participants. This involved an untargeted metabolomics approach in addition to the measurement of targeted substances including tryptophan and its metabolites, as well as tyrosine, phenylalanine, B vitamins, and hypoxanthine using liquid chromatography coupled to mass spectrometry. We observed significant alterations in several metabolic pathways, including the vitamin B3, arginine-proline, and aspartate-asparagine pathways, in the untargeted analysis. The targeted analysis revealed changes in the levels of 3-hydroxyanthranilic acid, 3-hydroxykynurenine, hypoxanthine, and phenylalanine in ME/CFS patients compared to the control group. These findings suggest potential alterations in immune system response and oxidative stress in ME/CFS patients.
This publication is licensed under CC-BY 4.0 .
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Original Investigation Public Health October 7, 2024
Post–COVID-19 Condition Fatigue Outcomes Among Danish Residents
Elisabeth O’Regan, MMedSc1; Lampros Spiliopoulos, MSc1; Ingrid Bech Svalgaard, MSc1; et alNete Munk Nielsen, MD, PhD1,2; Anna Irene Vedel Sørensen, PhD3; Peter Bager, PhD1; Poul Videbech, MD, PhD4,5; Steen Ethelberg, PhD3,6; Anders Koch, MD, MPH, PhD3,7; Anders Hviid, MSc, DMSC1,8
Author Affiliations Article Information
JAMA Netw Open. 2024;7(10):e2434863. doi:10.1001/jamanetworkopen.2024.34863
Key Points
Question Is SARS-CoV-2 infection associated with self-reported fatigue and postexertional malaise over time?
Findings In this population-based cohort study of 50 115 Danish participants, where most of the study population was vaccinated before testing for SARS-CoV-2, a 3% increase in self-reported fatigue and 2-fold increase in symptoms of postexertional malaise were found 2 to 18 months after infection, compared with noninfected controls. In the same period, persons hospitalized with acute SARS-CoV-2 infection experienced a 23% increase in fatigue.
Meaning The burden of post–COVID-19 condition fatigue was highest among patients with more severe cases of infection and was long-lasting, suggesting that patients with severe acute infection may benefit from clinical follow-up for fatigue.
Abstract
Importance Fatigue remains one of the most common and debilitating symptoms of post–COVID-19 condition; however, existing studies are limited to select populations and often lack noninfected controls. It also remains unclear to what extent severity of infection and psychiatric conditions, which are often linked to chronic fatigue, modify the risk of post–COVID-19 condition fatigue symptoms.
Objective To evaluate the impact of SARS-CoV-2 infection on self-reported fatigue and postexertional malaise over time and to explore possible risk factors, such as the impact of acute SARS-CoV-2 hospitalization and preexisting psychiatric conditions on postacute fatigue.
Design, Setting, and Participants In this cohort study, Danish residents aged 15 years and older were invited to participate in the EFTER-COVID survey, which used repeated, self-reported online questionnaires that collected information on fatigue (Fatigue Assessment Scale) and postexertional malaise scores (DePaul Symptom Questionnaire) after individuals’ index SARS-CoV-2 polymerase chain reaction test. Participants were included if they completed a baseline and at least 1 follow-up questionnaire 2 to 18 months after testing for SARS-CoV-2.
Exposure Testing for SARS-CoV-2 infection.
Main Outcomes and Measures The primary outcomes were fatigue and postexertional malaise 2 to 18 months after testing. Mixed-effects models were used to compare scores between SARS-CoV-2 test-positive and test-negative individuals (testing period April 2021 to February 2023).
Results Of a total of 50 115 participants (median [IQR] age at test date, 57 [46-67] years; 29 774 female [59.4%]), 25 249 were test positive and 24 866 were test negative. Most participants were vaccinated with at least 2 doses (21 164 test-negative participants [85.1%] and 22 120 test-positive participants [87.6%]) before their SARS-CoV-2 index test and fatigue reporting. In the period 2 to 18 months after testing, SARS-CoV-2 infection was associated with a small but significant 3% increase in self-reported fatigue scores (score ratio [SR], 1.03; 95% CI, 1.03-1.04) and higher odds of self-reported postexertional malaise (odds ratio, 2.04; 95% CI, 1.81-2.30), compared with test-negative participants. In the same period, hospitalization with SARS-CoV-2 increased fatigue scores by 23% (SR, 1.23; 95% CI, 1.20-1.26) compared with test-negative participants. Preexisting psychiatric conditions did not significantly modify postacute fatigue scores.
Conclusions and Relevance In this cohort study, SARS-CoV-2 infection was associated with a subtle increase in self-reported fatigue and postexertional malaise symptoms 2 to 18 months after mild infection. In contrast, individuals hospitalized with acute SARS-CoV-2 experienced a more substantial increase in postacute symptoms. Preexisting psychiatric conditions did not significantly modify the risk of postacute fatigue symptoms. The findings largely captured symptoms following first-time infections in a population where most had been vaccinated. Persons who experienced severe acute infection may benefit from clinical follow-up for fatigue.
Care for people with severe ME is “nonexistent,” says coroner in call to action
BMJ 2024; 387 doi: https://doi.org/10.1136/bmj.q2202 (Published 08 October 2024)
The complete lack of specialist care in England for patients with severe myalgic encephalomyelitis (ME or chronic fatigue syndrome) could cause deaths in future unless urgent action is taken, a coroner has warned.
The hard hitting prevention of future deaths (PFD) report by assistant coroner Deborah Archer on the death of Maeve Boothby O’Neill, 27, also highlighted the lack of research funding, training, and guidelines on treating the condition.
The report, thought to be the first such report on the death of a patient with ME, has been sent to the health and social care secretary, Wes Streeting, and health minister Andrew Gwynne; NHS England; the National Institute for Health and Care Excellence (NICE); the Medical Research Council; the National Institute for Health and Care Research; and the Medical Schools Council.
O’Neill, who was bedbound, died at home in October 2021 after three admissions to the Royal Devon and Exeter Hospital.
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University of Cambridge: Ultra-powered MRI scans show damage to brain’s ‘control centre’ is behind long-lasting Covid-19 symptoms
October 9, 2024
Using ultra-high-resolution scanners that can see the living brain in fine detail, researchers from the Universities of Cambridge and Oxford were able to observe the damaging effects Covid-19 can have on the brain.
University of Cambridge
Extracts
The study team scanned the brains of 30 people who had been admitted to hospital with severe Covid-19 early in the pandemic, before vaccines were available. The researchers found that Covid-19 infection damages the region of the brainstem associated with breathlessness, fatigue and anxiety.
The powerful MRI scanners used for the study, known as 7-Tesla or 7T scanners, can measure inflammation in the brain. Their results, published in the journal Brain, will help scientists and clinicians understand the long-term effects of Covid-19 on the brain and the rest of the body. Although the study was started before the long-term effects of Covid were recognised, it will help to better understand this condition.
The brainstem, which connects the brain to the spinal cord, is the control centre for many basic life functions and reflexes. Clusters of nerve cells in the brainstem, known as nuclei, regulate and process essential bodily functions such as breathing, heart rate, pain and blood pressure.
The researchers say the results could aid in the understanding of other conditions associated with inflammation of the brainstem, like MS and dementia. The 7T scanners could also be used to monitor the effectiveness of different treatments for brain diseases.
What Long COVID investigators can learn from four decades of ME/ CFS research
☆ Leonard A. Jason a , * Suzanne D. Vernon , Benjamin H. Natelson e b , Hector Bonilla , Monica Verduzco Gutierrez f c , Zaki A. Sherif , Lisa O’Brien g d , , Emily Taylor h ,
On behalf of the RECOVER consortium, by members of the Diagnostic Testing and Test Algorithms Subcommittee of the Commonalities with Other Post Viral Syndromes Task Force. We appreciate the edits and suggestions from Ben Z. Katz. a b c d e f g h DePaul University, USA Icahn School of Medicine at Mount Sina, USA Stanford University, USA Howard University, USA Bateman Horne Center, USA UT Health San Antonio, USA Utah Long Haulers, USA Solve/ME, USA ARTICLE INFO
ABSTRACT Keywords: Long COVID ME/CFS Similarities Case Definition Four decades of research in the field of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) have yielded lessons that may be instructive for those devising criteria to better comprehend Post-Acute Sequelae of SARS CoV-2 Infection (PASC) and Long COVID. For instance, substantial effort has been devoted to defining classification systems, operationalizing methods, and developing instruments with adequate reliability and validity in the ME/CFS field. The current article provides guidelines for developing a case definition for Long COVID and discusses the significance of psychometric issues and criterion variance, including how to specify symptoms, and develop thresholds, subtypes, and exclusionary conditions. ME/CFS research could enhance our knowledge of Long COVID pathophysiology, early diagnosis, prognosis, and the identification of effective treatments. Four decades of ME/CFS research: what Long COVID researchers
- Published: 05 July 2024
Betsy Keller, Candace N. Receno, Carl J. Franconi, Sebastian Harenberg, Jared Stevens, Xiangling Mao, Staci R. Stevens, Geoff Moore, Susan Levine, John Chia, Dikoma Shungu & Maureen R. Hanson
Journal of Translational Medicine volume 22, Article number: 627 (2024)
Abstract
Background
Post-exertional malaise (PEM), the hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), represents a constellation of abnormal responses to physical, cognitive, and/or emotional exertion including profound fatigue, cognitive dysfunction, and exertion intolerance, among numerous other maladies. Two sequential cardiopulmonary exercise tests (2-d CPET) provide objective evidence of abnormal responses to exertion in ME/CFS but validated only in studies with small sample sizes. Further, translation of results to impairment status and approaches to symptom reduction are lacking.
Methods Participants with ME/CFS (Canadian Criteria; n = 84) and sedentary controls (CTL; n = 71) completed two CPETs on a cycle ergometer separated by 24 h. Two-way repeated measures ANOVA compared CPET measures at rest, ventilatory/anaerobic threshold (VAT), and peak effort between phenotypes and CPETs. Intraclass correlations described stability of CPET measures across tests, and relevant objective CPET data indicated impairment status. A subset of case–control pairs (n = 55) matched for aerobic capacity, age, and sex, were also analyzed.
Results Unlike CTL, ME/CFS failed to reproduce CPET-1 measures during CPET-2 with significant declines at peak exertion in work, exercise time, V˙e, V˙O2, V˙CO2, V˙ T, HR, O2pulse, DBP, and RPP. Likewise, CPET-2 declines were observed at VAT for V˙e/V˙CO2, PetCO2, O2pulse, work, V˙O2 and SBP. Perception of effort (RPE) exceeded maximum effort criteria for ME/CFS and CTL on both CPETs. Results were similar in matched pairs. Intraclass correlations revealed greater stability in CPET variables across test days in CTL compared to ME/CFS owing to CPET-2 declines in ME/CFS. Lastly, CPET-2 data signaled more severe impairment status for ME/CFS compared to CPET-1.
Conclusions Presently, this is the largest 2-d CPET study of ME/CFS to substantiate impaired recovery in ME/CFS following an exertional stressor. Abnormal post-exertional CPET responses persisted compared to CTL matched for aerobic capacity, indicating that fitness level does not predispose to exertion intolerance in ME/CFS. Moreover, contributions to exertion intolerance in ME/CFS by disrupted cardiac, pulmonary, and metabolic factors implicates autonomic nervous system dysregulation of blood flow and oxygen delivery for energy metabolism. The observable declines in post-exertional energy metabolism translate notably to a worsening of impairment status. Treatment considerations to address tangible reductions in physiological function are proffered.
Trial registration number: ClinicalTrials.gov, retrospectively registered, ID# NCT04026425, date of registration: 2019-07-17.
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ARTICLES| VOLUME 74, 102719, AUGUST 2024
Pre-existing sleep disturbances and risk of COVID-19: a meta-analysis
Jiawei Zhou,,Xia LiTing Zhang,Ziyan Liu,Peng Li,Na Yu,et al.
Open AccessPublished:July 05, 2024DOI:https://doi.org/10.1016/j.eclinm.2024.102719
Summary
Background
Sleep disturbances are widespread but usually overlooked health risk factors for coronavirus disease 2019 (COVID-19). We aimed to investigate the influence of pre-existing sleep disturbances on the susceptibility, severity, and long-term effects of COVID-19.
Methods
We searched PubMed, Web of Science, and Embase for relevant articles from inception to October 27, 2023 and updated at May 8, 2024. Sleep disturbances included obstructive sleep apnea (OSA), insomnia, abnormal sleep duration, night-shift work, and any other sleep disturbances. Outcomes were COVID-19 susceptibility, hospitalization, mortality, and long COVID. The effect sizes were pooled odds ratios (ORs) and 95% confidence intervals (95% CIs). This study is registered with PROSPERO (CRD42024503518).
Findings
A total of 48 observational studies (n = 8,664,026) were included. Pre-existing sleep disturbances increased the risk of COVID-19 susceptibility (OR = 1.12, 95% CI 1.07–1.18), hospitalization (OR = 1.25, 95% CI 1.15–1.36), mortality (OR = 1.45, 95% CI 1.19–1.78), and long COVID (OR = 1.36 95% CI 1.17–1.57). Subgroup analysis showed that younger individuals with sleep disturbances were associated with higher susceptibility and hospitalization and a lower risk of mortality than older individuals. Males with sleep disturbances were associated with higher mortality. For specific sleep disturbances, the susceptibility and hospitalization of COVID-19 were associated with OSA, abnormal sleep duration, and night-shift work; mortality of COVID-19 was linked to OSA; risk of long COVID was related to OSA, abnormal sleep duration and insomnia.
Interpretation
Pre-existing sleep disturbances, especially OSA, increased the risk of COVID-19 susceptibility, hospitalization, mortality, and long COVID. Age and sex played important roles in the effect of sleep disturbances on COVID-19.
Funding
The National Natural Science Foundation of China and the Key Laboratory of Respiratory Diseases of Liaoning Province.
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Post–Acute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) After Infection During Pregnancy
Metz, Torri D.; Reeder, Harrison T.; Clifton, Rebecca G.; More July 11, 2024
OBJECTIVE:
To estimate the prevalence of post–acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) after infection with SARS-CoV-2 during pregnancy and to characterize associated risk factors.
METHODS:
In a multicenter cohort study (NIH RECOVER [Researching COVID to Enhance Recovery]-Pregnancy Cohort), individuals who were pregnant during their first SARS-CoV-2 infection were enrolled across the United States from December 2021 to September 2023, either within 30 days of their infection or at differential time points thereafter. The primary outcome was PASC , defined as score of 12 or higher based on symptoms and severity as previously published by the NIH RECOVER-Adult Cohort, at the first study visit at least 6 months after the participant's first SARS-CoV-2 infection. Risk factors for PASC were evaluated, including sociodemographic characteristics, clinical characteristics before SARS-CoV-2 infection (baseline comorbidities, trimester of infection, vaccination status), and acute infection severity (classified by need for oxygen therapy). Multivariable logistic regression models were fitted to estimate associations between these characteristics and presence of PASC.
RESULTS:
Of the 1,502 participants, 61.1% had their first SARS-CoV-2 infection on or after December 1, 2021 (ie, during Omicron variant dominance); 51.4% were fully vaccinated before infection; and 182 (12.1%) were enrolled within 30 days of their acute infection. The prevalence of PASC was 9.3% (95% CI, 7.9–10.9%) measured at a median of 10.3 months (interquartile range 6.1–21.5) after first infection. The most common symptoms among individuals with PASC were postexertional malaise (77.7%), fatigue (76.3%), and gastrointestinal symptoms (61.2%). In a multivariable model, the proportion PASC positive with vs without history of obesity (14.9% vs 7.5%, adjusted odds ratio [aOR] 1.65, 95% CI, 1.12–2.43), depression or anxiety disorder (14.4% vs 6.1%, aOR 2.64, 95% CI, 1.79–3.88) before first infection, economic hardship (self-reported difficulty covering expenses) (12.5% vs 6.9%, aOR 1.57, 95% CI, 1.05–2.34), and treatment with oxygen during acute SARS-CoV-2 infection (18.1% vs 8.7%, aOR 1.86, 95% CI, 1.00–3.44) were associated with increased prevalence of PASC.
CONCLUSION:
The prevalence of PASC at a median time of 10.3 months after SARS-CoV-2 infection during pregnancy was 9.3% in the NIH RECOVER-Pregnancy Cohort. The predominant symptoms were postexertional malaise, fatigue, and gastrointestinal symptoms. Several socioeconomic and clinical characteristics were associated with PASC after infection during pregnancy.
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ARTICLES| VOLUME 59, 101946, MAY 2023
Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot study
Lucy E.M. Finnigan,Mark Philip Cassar,Margaret James Koziel,Joel Pradines,Hanan Lamlum,Karim Azer,et al.
Open AccessPublished:April 14, 2023DOI:https://doi.org/10.1016/j.eclinm.2023.101946
Summary: Background
‘Long COVID’ describes persistent symptoms, commonly fatigue, lasting beyond 12 weeks following SARS-CoV-2 infection. Potential causes include reduced mitochondrial function and cellular bioenergetics. AXA1125 has previously increased β-oxidation and improved bioenergetics in preclinical models along with certain clinical conditions, and therefore may reduce fatigue associated with Long COVID. We aimed to assess the efficacy, safety and tolerability of AXA1125 in Long COVID.
Methods
Patients with fatigue-dominant Long COVID were recruited in this single-centre, double-blind, randomised controlled phase 2a pilot study completed in the UK. Patients were randomly assigned (1:1) using an Interactive Response Technology to receive either AXA1125 or matching placebo in a clinical-based setting. Each dose (33.9 g) of AXA1125 or placebo was administered orally in a liquid suspension twice daily for four weeks with a two-week follow-up period. The primary endpoint was the mean change from baseline to day 28 in the phosphocreatine (PCr) recovery rate following moderate exercise, assessed by 31P-magnetic resonance spectroscopy (MRS). All patients were included in the intention to treat analysis. This trial was registered at ClinicalTrials.gov, NCT05152849.
Findings
Between December 15th 2021, and May 23th 2022, 60 participants were screened, and 41 participants were randomised and included in the final analysis. Changes in skeletal muscle phosphocreatine recovery time constant (τPCr) and 6-min walk test (6MWT) did not significantly differ between treatment (n = 21) and placebo group (n = 20). However, treatment with AXA1125 was associated with significantly reduced day 28 Chalder Fatigue Questionnaire [CFQ-11] fatigue score when compared with placebo (least squares mean difference [LSMD] −4.30, 95% confidence interval (95% CI) −7.14, −1.47; P = 0.0039). Eleven (52.4%, AXA1125) and four (20.0%, placebo) patients reported treatment-emergent adverse events; none were serious or led to treatment discontinuation.
Interpretation
Although treatment with AXA1125 did not improve the primary endpoint (τPCr-measure of mitochondrial respiration), when compared to placebo, there were significant improvements in fatigue-based symptoms among patients living with Long COVID following a four-week treatment period. Further multicentre studies are needed to validate our findings in a larger cohort of patients with fatigue-dominant Long COVID.
Funding
Axcella Therapeutics.
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Original Investigation Public Health July 24, 2024
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome After SARS-CoV-2 Infection
Elizabeth R. Unger, MD, PhD1; Jin-Mann S. Lin, PhD1; Lauren E. Wisk, PhD2; et alHuihui Yu, PhD3; Michelle L’Hommedieu, PhD2; Helen Lavretsky, MD, MS4; Juan Carlos C. Montoy, MD, PhD5; Michael A. Gottlieb, MD6; Kristin L. Rising, MD, MSHP7,8; Nicole L. Gentile, MD, PhD9,10,11; Michelle Santangelo, MS12; Arjun K. Venkatesh, MD, MBA, MHS3,13; Robert M. Rodriguez, MD5; Mandy J. Hill, DrPH, MPH14; Rachel E. Geyer, MPH10; Efrat R. Kean, MD7; Sharon Saydah, PhD15; Samuel A. McDonald, MD, MS16,17; Ryan Huebinger, MD14; Ahamed H. Idris, MD16; Jocelyn Dorney, MPH3; Bala Hota, MD, MPH18; Erica S. Spatz, MD, MHS3,19; Kari A. Stephens, PhD10,20; Robert A. Weinstein, MD12,21; Joann G. Elmore, MD, MPH2; for the Innovative Support for Patients with SARS-CoV-2 Infections Registry (INSPIRE) Group
JAMA Netw Open. 2024;7(7):e2423555. doi:10.1001/jamanetworkopen.2024.23555
Key Points
Question Does prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)–like illness differ between individuals with an acute infection–like index illness who are COVID-19 positive or negative?
Findings In this cohort study of 4378 participants, the weighted prevalence of ME/CFS-like illness was 4.5% or less at 3 to 12 months after the index illness in the COVID-19–positive and COVID-19–negative groups, with no significant differences in odds of ME/CFS-like illness.
Meaning The findings suggest that ME/CFS-like illness following an acute infection–like index illness does not vary by COVID-19 test result.
Abstract
Importance Chronic symptoms reported following an infection with SARS-CoV-2, such as cognitive problems, overlap with symptoms included in the definition of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Objective To evaluate the prevalence of ME/CFS-like illness subsequent to acute SARS-CoV-2 infection, changes in ME/CFS symptoms through 12 months of follow-up, and the association of ME/CFS symptoms with SARS-CoV-2 test results at the acute infection–like index illness.
Design, Setting, and Participants This prospective, multisite, longitudinal cohort study (Innovative Support for Patients with SARS-CoV-2 Infections Registry [INSPIRE]) enrolled participants from December 11, 2020, to August 29, 2022. Participants were adults aged 18 to 64 years with acute symptoms suggestive of SARS-CoV-2 infection who received a US Food and Drug Administration–approved SARS-CoV-2 test at the time of illness and did not die or withdraw from the study by 3 months. Follow-up surveys were collected through February 28, 2023.
Exposure COVID-19 status (positive vs negative) at enrollment.
Main Outcome and Measures The main outcome was the weighted proportion of participants with ME/CFS-like illness based on the 2015 Institute of Medicine clinical case definition using self-reported symptoms.
Results A total of 4378 participants were included in the study. Most were female (3226 [68.1%]). Mean (SD) age was 37.8 (11.8) years. The survey completion rates ranged from 38.7% (3613 of 4738 participants) to 76.3% (1835 of 4738) and decreased over time. The weighted proportion of participants identified with ME/CFS-like illness did not change significantly at 3 through 12 months of follow-up and was similar in the COVID-19–positive (range, 2.8%-3.7%) and COVID-19–negative (range, 3.1%-4.5%) groups. Adjusted analyses revealed no significant difference in the odds of ME/CFS-like illness at any time point between COVID-19–positive and COVID-19–negative individuals (marginal odds ratio range, 0.84 [95% CI, 0.42-1.67] to 1.18 [95% CI, 0.55-2.51]).
Conclusions and Relevance In this prospective cohort study, there was no evidence that the proportion of participants with ME/CFS-like illness differed between those infected with SARS-CoV-2 vs those without SARS-CoV-2 infection up to 12 months after infection. A 3% to 4% prevalence of ME/CFS-like illness after an acute infection–like index illness would impose a high societal burden given the millions of persons infected with SARS-CoV-2.
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WebMD Health News
Long COVID Risk Has Dropped Since Start of Pandemic
Ralph Ellis July 19, 2024
Your chances of developing long COVID have significantly decreased since the pandemic began, offering a glimmer of hope and a sign of progress in the ongoing battle against the virus.
That's according to a new study published in The New England Journal of Medicine. Researchers at Washington University in St. Louis, who conducted the study, said that the drop was caused by vaccinations and changes in the virus itself.
"You can see a clear and significant difference in risk during the delta and omicron eras between the vaccinated and unvaccinated," Ziyad Al-Aly, MD, director of the Clinical Epidemiology Center at the VA St. Louis Health Care System and head of the research and development service, said in a statement. "So, if people think COVID is no big deal and decide to forgo vaccinations, they're essentially doubling their risk of developing long COVID."
Researchers analyzed the health records collected from March 1, 2020, through January 31, 2022, for 441,583 veterans who were infected with COVID-19 and 4.7 million veterans who were not infected.
Among unvaccinated people, long COVID was developed by 10.4% infected with the original strain of COVID, 9.5% infected with the Delta strain, and 7.7% infected with Omicron.
Among vaccinated people, long COVID occurred in 5.3% of those infected with the Delta strain and 3.5% of those infected with Omicron.
Al-Aly noted that among people infected with the Omicron strain, the chances of heart, brain, kidney, and lung problems declined while the risk of problems with metabolic function and the GI system increased.
"Each variant has its own fingerprint," Al-Aly said. "The original virus hit the respiratory system hard. Omicron targeted metabolic and GI issues. It's important because while the risk of long COVID is quantitatively lower, a person can be at a higher risk of developing an illness based on the part of the body that the COVID variant targets."
With long COVID, symptoms persist months or years after infection. Common symptoms include extreme fatigue, shortness of breath, loss of the sense of smell, and muscle aches.
According to the CDC's Household Pulse Survey, 18.4% of American adults say they've experienced long COVID at some point.
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RESEARCH ARTICLE NEUROIMMUNOLOGY
Infection and chronic disease activate a systemic brain-muscle signaling axis
SHUO YANG HTTPS://ORCID.ORG/0000-0002-7929-0244 , MEIJIE TIAN HTTPS://ORCID.ORG/0000-0003-0547-9447, YULONG DAI, RONG WANG, [...], AND AARON JOHNSON HTTPS://ORCID.ORG/0000-0002-2783-5636 +12 authors
SCIENCE IMMUNOLOGY 12 Jul 2024 Vol 9, Issue 97 DOI: 10.1126/sciimmunol.adm7908
Editor’s summary
Neuroinflammation can cause symptoms outside of the central nervous system (CNS), including muscle pain and fatigue, yet how inflammatory signals in the brain are communicated to muscle remains to be determined. Using multiple models of CNS stress in fruit flies, Yang et al. identified that reactive oxygen species accumulation in the brain promoted expression of Upd3, a Drosophila ortholog of interleukin-6 (IL-6). IL-6 activated JAK-STAT signaling in skeletal muscle, resulting in mitochondrial dysfunction–impaired motor function. This axis was also activated in mice after CNS stress and evident in humans with neuroinflammation. This work identifies a conserved brain-to-muscle signaling axis that regulates muscle performance, which may be a promising therapeutic target. —Hannah Isles
Abstract
Infections and neurodegenerative diseases induce neuroinflammation, but affected individuals often show nonneural symptoms including muscle pain and muscle fatigue. The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood. We developed multiple models to investigate the impact of CNS stressors on motor function and found that Escherichia coli infections and SARS-CoV-2 protein expression caused reactive oxygen species (ROS) to accumulate in the brain. ROS induced expression of the cytokine Unpaired 3 (Upd3) in Drosophila and its ortholog, IL-6, in mice. CNS-derived Upd3/IL-6 activated the JAK-STAT pathway in skeletal muscle, which caused muscle mitochondrial dysfunction and impaired motor function. We observed similar phenotypes after expressing toxic amyloid-β (Aβ42) in the CNS. Infection and chronic disease therefore activate a systemic brain-muscle signaling axis in which CNS-derived cytokines bypass the connectome and directly regulate muscle physiology, highlighting IL-6 as a therapeutic target to treat disease-associated muscle dysfunction.
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Viruses:. 2024 Apr 8;16(4):572. doi: 10.3390/v16040572.
Herpesvirus Infection of Endothelial Cells as a Systemic Pathological Axis in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Jean M Nunes , Douglas B Kell , Etheresia Pretorius Affiliations Expand PMID: 38675914 PMCID: PMC11053605
Abstract
Understanding the pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is critical for advancing treatment options. This review explores the novel hypothesis that a herpesvirus infection of endothelial cells (ECs) may underlie ME/CFS symptomatology. We review evidence linking herpesviruses to persistent EC infection and the implications for endothelial dysfunction, encompassing blood flow regulation, coagulation, and cognitive impairment-symptoms consistent with ME/CFS and Long COVID. This paper provides a synthesis of current research on herpesvirus latency and reactivation, detailing the impact on ECs and subsequent systemic complications, including latent modulation and long-term maladaptation. We suggest that the chronicity of ME/CFS symptoms and the multisystemic nature of the disease may be partly attributable to herpesvirus-induced endothelial maladaptation. Our conclusions underscore the necessity for further investigation into the prevalence and load of herpesvirus infection within the ECs of ME/CFS patients. This review offers conceptual advances by proposing an endothelial infection model as a systemic mechanism contributing to ME/CFS, steering future research toward potentially unexplored avenues in understanding and treating this complex syndrome.
Keywords: endothelial cells; herpesvirus; myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
PubMed Disclaimer
Conflict of interest statement
The authors declare no conflicts of interest.
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J Transl Med. 2024; 22: 630. Published online 2024 Jul 5. doi: 10.1186/s12967-024-05412-3
PMCID: PMC11227206 PMID: 38970055
Potential pathophysiological role of the ion channel TRPM3 in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the therapeutic effect of low-dose naltrexone
Matthias Löhn1 and Klaus Josef Wirth1,2
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease with a broad overlap of symptomatology with Post-COVID Syndrome (PCS). Despite the severity of symptoms and various neurological, cardiovascular, microvascular, and skeletal muscular findings, no biomarkers have been identified. The Transient receptor potential melastatin 3 (TRPM3) channel, involved in pain transduction, thermosensation, transmitter and neuropeptide release, mechanoregulation, vasorelaxation, and immune defense, shows altered function in ME/CFS. Dysfunction of TRPM3 in natural killer (NK) cells, characterized by reduced calcium flux, has been observed in ME/CFS and PCS patients, suggesting a role in ineffective pathogen clearance and potential virus persistence and autoimmunity development. TRPM3 dysfunction in NK cells can be improved by naltrexone in vitro and ex vivo, which may explain the moderate clinical efficacy of low-dose naltrexone (LDN) treatment. We propose that TRPM3 dysfunction may have a broader involvement in ME/CFS pathophysiology, affecting other organs. This paper discusses TRPM3’s expression in various organs and its potential impact on ME/CFS symptoms, with a focus on small nerve fibers and the brain, where TRPM3 is involved in presynaptic GABA release.
Keywords: TRPM3 channel, Myalgic Encephalomyelitis/Chronic fatigue syndrome, ME/CFS, Post-COVID syndrome, Long-COVID, Exercise intolerance, GABA, Small fiber neuropathy, Naltrexone
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J Transl Med . 2024 Jul 5;22(1):630. doi: 10.1186/s12967-024-05412-3.
Potential pathophysiological role of the ion channel TRPM3 in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the therapeutic effect of low-dose naltrexone
Matthias Löhn 1, Klaus Josef Wirth 2 3
PMID: 38970055 PMCID: PMC11227206 DOI: 10.1186/s12967-024-05412-3
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease with a broad overlap of symptomatology with Post-COVID Syndrome (PCS). Despite the severity of symptoms and various neurological, cardiovascular, microvascular, and skeletal muscular findings, no biomarkers have been identified. The Transient receptor potential melastatin 3 (TRPM3) channel, involved in pain transduction, thermosensation, transmitter and neuropeptide release, mechanoregulation, vasorelaxation, and immune defense, shows altered function in ME/CFS. Dysfunction of TRPM3 in natural killer (NK) cells, characterized by reduced calcium flux, has been observed in ME/CFS and PCS patients, suggesting a role in ineffective pathogen clearance and potential virus persistence and autoimmunity development. TRPM3 dysfunction in NK cells can be improved by naltrexone in vitro and ex vivo, which may explain the moderate clinical efficacy of low-dose naltrexone (LDN) treatment. We propose that TRPM3 dysfunction may have a broader involvement in ME/CFS pathophysiology, affecting other organs. This paper discusses TRPM3's expression in various organs and its potential impact on ME/CFS symptoms, with a focus on small nerve fibers and the brain, where TRPM3 is involved in presynaptic GABA release.
Keywords: Exercise intolerance; GABA; Long-COVID; ME/CFS; Myalgic Encephalomyelitis/Chronic fatigue syndrome; Naltrexone; Post-COVID syndrome; Small fiber neuropathy; TRPM3 channel.
© 2024. The Author(s).
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J Cereb Blood Flow Metab . 2024 Aug 7:271678X241270528.
doi: 10.1177/0271678X241270528. Online ahead of print.
Absence of BOLD adaptation in chronic fatigue syndrome revealed by task functional MRI
Laura Schönberg 1 2, Abdalla Z Mohamed 1, Qiang Yu 1, Richard A Kwiatek 1, Peter Del Fante 1, Vince D Calhoun 3, Zack Y Shan 1
PMID: 39113421 DOI: 10.1177/0271678X241270528
Abstract
Neurological symptoms are central to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), yet its underlying neurophysiological mechanisms remain elusive. We examined a neglected aspect of task-based functional MRI, focusing on how blood oxygenation level-dependent (BOLD) signals alter during cognitive tasks in ME/CFS. This prospective observational study utilised MRI scans on ME/CFS participants and healthy controls (HCs) with sedentary lifestyles (ACTRN12622001095752). Participants completed two blocks of a Symbol Digit Modalities Test, with 30 trials per block split into two sets. The fMRI signal changes between blocks and sets were compared within and between groups. Thirty-four ME/CFS participants (38 years ± 10; 27 women) and 34 HCs (38 ± 10; 27 women), were evaluated. In the second task block, ME/CFS participants exhibited increased activation in the right postcentral gyrus, contrasting with decreased activation in multiple regions in HCs. These results were further confirmed by significantly higher bilateral dynamic changes (2nd vs 1st set) in the motor, sensory and cognitive cortex in ME/CFS compared to HCs and significant correlations between those changes in the left primary motor cortex with fatigue severities. BOLD adaptation, potentially improving energy economy, was absent in ME/CFS, which may provide an underlying neurophysiological process in ME/CFS.
Keywords: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); Symbol Digit Modalities Test (SDMT); fatigue severity; neurophysiological adaptation; task functional MRI (tfMRI).
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ACS Chemical NeuroscienceExpand
Research ArticleSeptember 20, 2024
Untargeted Metabolomics and Quantitative Analysis of Tryptophan Metabolites in Myalgic Encephalomyelitis Patients and Healthy Volunteers: A Comparative Study Using High-Resolution Mass Spectrometry
Sandy Abujrais,Theodosia Vallianatou,Jonas Bergquist*
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex illness characterized by severe and often disabling physical and mental fatigue. So far, scientists have not been able to fully pinpoint the biological cause of the illness and yet it affects millions of people worldwide. To gain a better understanding of ME/CFS, we compared the metabolic networks in the plasma of 38 ME/CFS patients to those of 24 healthy control participants. This involved an untargeted metabolomics approach in addition to the measurement of targeted substances including tryptophan and its metabolites, as well as tyrosine, phenylalanine, B vitamins, and hypoxanthine using liquid chromatography coupled to mass spectrometry. We observed significant alterations in several metabolic pathways, including the vitamin B3, arginine-proline, and aspartate-asparagine pathways, in the untargeted analysis. The targeted analysis revealed changes in the levels of 3-hydroxyanthranilic acid, 3-hydroxykynurenine, hypoxanthine, and phenylalanine in ME/CFS patients compared to the control group. These findings suggest potential alterations in immune system response and oxidative stress in ME/CFS patients.
This publication is licensed under CC-BY 4.0 .
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Original Investigation Public Health October 7, 2024
Post–COVID-19 Condition Fatigue Outcomes Among Danish Residents
Elisabeth O’Regan, MMedSc1; Lampros Spiliopoulos, MSc1; Ingrid Bech Svalgaard, MSc1; et alNete Munk Nielsen, MD, PhD1,2; Anna Irene Vedel Sørensen, PhD3; Peter Bager, PhD1; Poul Videbech, MD, PhD4,5; Steen Ethelberg, PhD3,6; Anders Koch, MD, MPH, PhD3,7; Anders Hviid, MSc, DMSC1,8
Author Affiliations Article Information
JAMA Netw Open. 2024;7(10):e2434863. doi:10.1001/jamanetworkopen.2024.34863
Key Points
Question Is SARS-CoV-2 infection associated with self-reported fatigue and postexertional malaise over time?
Findings In this population-based cohort study of 50 115 Danish participants, where most of the study population was vaccinated before testing for SARS-CoV-2, a 3% increase in self-reported fatigue and 2-fold increase in symptoms of postexertional malaise were found 2 to 18 months after infection, compared with noninfected controls. In the same period, persons hospitalized with acute SARS-CoV-2 infection experienced a 23% increase in fatigue.
Meaning The burden of post–COVID-19 condition fatigue was highest among patients with more severe cases of infection and was long-lasting, suggesting that patients with severe acute infection may benefit from clinical follow-up for fatigue.
Abstract
Importance Fatigue remains one of the most common and debilitating symptoms of post–COVID-19 condition; however, existing studies are limited to select populations and often lack noninfected controls. It also remains unclear to what extent severity of infection and psychiatric conditions, which are often linked to chronic fatigue, modify the risk of post–COVID-19 condition fatigue symptoms.
Objective To evaluate the impact of SARS-CoV-2 infection on self-reported fatigue and postexertional malaise over time and to explore possible risk factors, such as the impact of acute SARS-CoV-2 hospitalization and preexisting psychiatric conditions on postacute fatigue.
Design, Setting, and Participants In this cohort study, Danish residents aged 15 years and older were invited to participate in the EFTER-COVID survey, which used repeated, self-reported online questionnaires that collected information on fatigue (Fatigue Assessment Scale) and postexertional malaise scores (DePaul Symptom Questionnaire) after individuals’ index SARS-CoV-2 polymerase chain reaction test. Participants were included if they completed a baseline and at least 1 follow-up questionnaire 2 to 18 months after testing for SARS-CoV-2.
Exposure Testing for SARS-CoV-2 infection.
Main Outcomes and Measures The primary outcomes were fatigue and postexertional malaise 2 to 18 months after testing. Mixed-effects models were used to compare scores between SARS-CoV-2 test-positive and test-negative individuals (testing period April 2021 to February 2023).
Results Of a total of 50 115 participants (median [IQR] age at test date, 57 [46-67] years; 29 774 female [59.4%]), 25 249 were test positive and 24 866 were test negative. Most participants were vaccinated with at least 2 doses (21 164 test-negative participants [85.1%] and 22 120 test-positive participants [87.6%]) before their SARS-CoV-2 index test and fatigue reporting. In the period 2 to 18 months after testing, SARS-CoV-2 infection was associated with a small but significant 3% increase in self-reported fatigue scores (score ratio [SR], 1.03; 95% CI, 1.03-1.04) and higher odds of self-reported postexertional malaise (odds ratio, 2.04; 95% CI, 1.81-2.30), compared with test-negative participants. In the same period, hospitalization with SARS-CoV-2 increased fatigue scores by 23% (SR, 1.23; 95% CI, 1.20-1.26) compared with test-negative participants. Preexisting psychiatric conditions did not significantly modify postacute fatigue scores.
Conclusions and Relevance In this cohort study, SARS-CoV-2 infection was associated with a subtle increase in self-reported fatigue and postexertional malaise symptoms 2 to 18 months after mild infection. In contrast, individuals hospitalized with acute SARS-CoV-2 experienced a more substantial increase in postacute symptoms. Preexisting psychiatric conditions did not significantly modify the risk of postacute fatigue symptoms. The findings largely captured symptoms following first-time infections in a population where most had been vaccinated. Persons who experienced severe acute infection may benefit from clinical follow-up for fatigue.
Care for people with severe ME is “nonexistent,” says coroner in call to action
BMJ 2024; 387 doi: https://doi.org/10.1136/bmj.q2202 (Published 08 October 2024)
The complete lack of specialist care in England for patients with severe myalgic encephalomyelitis (ME or chronic fatigue syndrome) could cause deaths in future unless urgent action is taken, a coroner has warned.
The hard hitting prevention of future deaths (PFD) report by assistant coroner Deborah Archer on the death of Maeve Boothby O’Neill, 27, also highlighted the lack of research funding, training, and guidelines on treating the condition.
The report, thought to be the first such report on the death of a patient with ME, has been sent to the health and social care secretary, Wes Streeting, and health minister Andrew Gwynne; NHS England; the National Institute for Health and Care Excellence (NICE); the Medical Research Council; the National Institute for Health and Care Research; and the Medical Schools Council.
O’Neill, who was bedbound, died at home in October 2021 after three admissions to the Royal Devon and Exeter Hospital.
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University of Cambridge: Ultra-powered MRI scans show damage to brain’s ‘control centre’ is behind long-lasting Covid-19 symptoms
October 9, 2024
Using ultra-high-resolution scanners that can see the living brain in fine detail, researchers from the Universities of Cambridge and Oxford were able to observe the damaging effects Covid-19 can have on the brain.
University of Cambridge
Extracts
The study team scanned the brains of 30 people who had been admitted to hospital with severe Covid-19 early in the pandemic, before vaccines were available. The researchers found that Covid-19 infection damages the region of the brainstem associated with breathlessness, fatigue and anxiety.
The powerful MRI scanners used for the study, known as 7-Tesla or 7T scanners, can measure inflammation in the brain. Their results, published in the journal Brain, will help scientists and clinicians understand the long-term effects of Covid-19 on the brain and the rest of the body. Although the study was started before the long-term effects of Covid were recognised, it will help to better understand this condition.
The brainstem, which connects the brain to the spinal cord, is the control centre for many basic life functions and reflexes. Clusters of nerve cells in the brainstem, known as nuclei, regulate and process essential bodily functions such as breathing, heart rate, pain and blood pressure.
The researchers say the results could aid in the understanding of other conditions associated with inflammation of the brainstem, like MS and dementia. The 7T scanners could also be used to monitor the effectiveness of different treatments for brain diseases.
What Long COVID investigators can learn from four decades of ME/ CFS research
☆ Leonard A. Jason a , * Suzanne D. Vernon , Benjamin H. Natelson e b , Hector Bonilla , Monica Verduzco Gutierrez f c , Zaki A. Sherif , Lisa O’Brien g d , , Emily Taylor h ,
On behalf of the RECOVER consortium, by members of the Diagnostic Testing and Test Algorithms Subcommittee of the Commonalities with Other Post Viral Syndromes Task Force. We appreciate the edits and suggestions from Ben Z. Katz. a b c d e f g h DePaul University, USA Icahn School of Medicine at Mount Sina, USA Stanford University, USA Howard University, USA Bateman Horne Center, USA UT Health San Antonio, USA Utah Long Haulers, USA Solve/ME, USA ARTICLE INFO
ABSTRACT Keywords: Long COVID ME/CFS Similarities Case Definition Four decades of research in the field of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) have yielded lessons that may be instructive for those devising criteria to better comprehend Post-Acute Sequelae of SARS CoV-2 Infection (PASC) and Long COVID. For instance, substantial effort has been devoted to defining classification systems, operationalizing methods, and developing instruments with adequate reliability and validity in the ME/CFS field. The current article provides guidelines for developing a case definition for Long COVID and discusses the significance of psychometric issues and criterion variance, including how to specify symptoms, and develop thresholds, subtypes, and exclusionary conditions. ME/CFS research could enhance our knowledge of Long COVID pathophysiology, early diagnosis, prognosis, and the identification of effective treatments. Four decades of ME/CFS research: what Long COVID researchers
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