Muscle abnormalities worsen after post-exertional malaise in long COVID
Brent Appelman, Braeden T. Charlton, Richie P. Goulding, Tom J. Berkhoff, Ellen A. Breedveld, Wendy Noort, Carla Offringa, Frank W. Bloemers, Michel van Weeghel, Bauke V. Schomakers, Pedro Coelho, Jelle J. Posthuma, Eleonora Aronica, W. Joost Wiersinga, Michèle van Vugt & Rob C. I. Wüst
Nature Communications volume 15, Article number: 17 (2024) Cite this article
Abstract
A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear. With this longitudinal case-control study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of post-exertional malaise. This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases.
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Brain Behav Immun Health. 2024 Mar; 36: 100733.
Published online 2024 Feb 1. doi: 10.1016/j.bbih.2024.100733
PMCID: PMC10862402 PMID: 38352659
Low-dose naltrexone and NAD+ for the treatment of patients with persistent fatigue symptoms after COVID-19
Anar Isman,a Andy Nyquist,a,∗ Bailey Strecker,a Girish Harinath,a Virginia Lee,a Xingyu Zhang,b and Sajad Zalzalaa
Abstract
A subset of patients experiences persistent fatigue symptoms after COVID-19, and patients may develop long COVID, which is characterized by lasting systemic symptoms. No treatments for this condition have been validated and are urgently warranted. In this pilot study, we assessed whether treatment with low-dose naltrexone (LDN, 4.5 mg/day) and supplementation with NAD + through iontophoresis patches could improve fatigue symptoms and quality of life in 36 patients with persistent moderate/severe fatigue after COVID-19. We detected a significant increase from baseline in SF-36 survey scores after 12 weeks of treatment (mean total SF-36 score 36.5 [SD: 15.6] vs. 52.1 [24.8]; p < 0.0001), suggestive of improvement of quality of life. Furthermore, participants scored significantly lower on the Chalder fatigue scale after 12 weeks of treatment (baseline: 25.9 [4.6], 12 weeks: 17.4 [9.7]; p < 0.0001). We found a subset of 52 % of patients to be responders after 12 weeks of treatment. Treatment was generally safe, with mild adverse events previously reported for LDN, which could be managed with dose adjustments. The iontophoresis patches were associated with mild, short-lived skin irritation in 25 % of patients. Our data suggest treatment with LDN and NAD+ is safe and may be beneficial in a subset of patients with persistent fatigue after COVID-19. Larger randomized controlled trials will have to confirm our data and determine which patient subpopulations might benefit most from this strategy.
Keywords: COVID-19, Long COVID, Fatigue, Quality of life, Low dose naltrexone, NAD+, SF-36
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ARTICLE| VOLUME 5, ISSUE 1, 101373, JANUARY 16, 2024
Single-cell transcriptomics of the immune system in ME/CFS at baseline and following symptom provocation
Luyen Tien Vu ,Faraz Ahmed 7,Hongya Zhu 7,Maureen R. Hanson,Jennifer K. Grenier,Andrew Grimson 8,et al DOI:https://doi.org/10.1016/j.xcrm.2023.101373
Highlights
The ME/CFS immune system is profiled by scRNA-seq at baseline and after provocation.
Monocyte dysregulation is prominent and dysregulation correlates with disease severity
Platelets are also dysregulated, but this dysregulation resolves after provocation
Summary
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious and poorly understood disease. To understand immune dysregulation in ME/CFS, we use single-cell RNA sequencing (scRNA-seq) to examine immune cells in patient and control cohorts. Postexertional malaise (PEM), an exacerbation of symptoms following strenuous exercise, is a characteristic symptom of ME/CFS. To detect changes coincident with PEM, we applied scRNA-seq on the same cohorts following exercise. At baseline, ME/CFS patients display classical monocyte dysregulation suggestive of inappropriate differentiation and migration to tissue. We identify both diseased and more normal monocytes within patients, and the fraction of diseased cells correlates with disease severity. Comparing the transcriptome at baseline and postexercise challenge, we discover patterns indicative of improper platelet activation in patients, with minimal changes elsewhere in the immune system. Taken together, these data identify immunological defects present at baseline in patients and an additional layer of dysregulation in platelets.
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A phenomenological study on the lived experience of men with Chronic Fatigue Syndrome
Gracie Elizabeth Snellhttps://orcid.org/0000-0002-1472-8196[email protected], Catherine Heidi Seage https://orcid.org/0000-0002-8590-867X, and Jenny Mercer https://orcid.org/0000-0001-5917-0491View all authors and affiliations
Journal of Health Psychology Volume 29, Issue 3
https://doi.org/10.1177/13591053231186385
Abstract
Whilst chronic fatigue syndrome (CFS) has been widely researched amongst women, studies investigating how men experience a CFS diagnosis is limited. This study utilised an interpretative phenomenological approach to interview five men who have a medical diagnosis of CFS. Six themes emerged to demonstrate the participants’ experiences prior to, during and after obtaining their CFS diagnosis. Findings revealed that participants were initially reluctant to accept their condition, confounded by their perception that symptoms compromised their sense of masculinity. They also felt that healthcare professionals had limited recognition of CFS leading them to seek social support and legitimisation from other sources. The struggle to come to terms with a different lifestyle and sense of masculinity prevailed. Such knowledge could be effectively utilised by researchers, practitioners and employers to facilitate an increased understanding of male accounts of the condition and more bespoke interventions where required.
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Unravelling shared mechanisms: insights from recent ME/CFS research to illuminate long COVID pathologies
Sarah J. Annesley Daniel Missailidis Benjamin Heng Elisha K. Josev , Christopher W. Armstrong 7
Published:March 04, 2024DOI:https://doi.org/10.1016/j.molmed.2024.0
Highlights
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic illness often triggered by an initiating acute event, mainly viral infections. The transition from acute to chronic disease remains unknown, but interest in this phenomenon has escalated since the COVID-19 pandemic and the post-COVID-19 illness, termed ‘long COVID’ (LC). Both ME/CFS and LC share many clinical similarities. Here, we present recent findings in ME/CFS research focussing on proposed disease pathologies shared with LC. Understanding these disease pathologies and how they influence each other is key to developing effective therapeutics and diagnostic tests. Given that ME/CFS typically has a longer disease duration compared with LC, with symptoms and pathologies evolving over time, ME/CFS may provide insights into the future progression of LC.
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Experts call for more research into long COVID, as study reveals high prevalence in WA
By Emily JB Smith, Rebecca Trigger, and Phoebe Pin (U Tube)
Posted Wed 3 Apr 2024 at 10:15amWednesday 3 Apr 2024 at 10:15am, updated Thu 4 Apr 2024 at 12:06am
The Australian National University (ANU) study surveyed 11,000 people who tested positive to COVID during a significant outbreak of the Omicron variant in WA in 2022.
The study published in March found almost 20 per cent of those patients were still suffering symptoms of fatigue, memory loss and concentration difficulties three months after they first became sick.
Lead researcher Mulu Woldegiorgis said there was little pre-existing data available on the topic, but that the new research suggested there was a high rate of long-term COVID-19 symptoms in WA.
In their report, Dr Woldegiorgis and her colleagues acknowledged one of the limitations of the ANU survey was that it relied on subjective symptom descriptions from patients, and the reported impact of their symptoms on work or study was not independently verified.
Dr Woldegiorgis said it was important for patients' symptoms to be taken seriously.
"I think it's real and it needs more investigation," she said.
"When we see its impact on work or study, more than one in six of those who used to work before their infection were not able to fully return to work or study due to their ongoing symptoms."
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A body–brain circuit that regulates body inflammatory responses
Hao Jin, Mengtong Li, Eric Jeong, Felipe Castro-Martinez & Charles S. Zuker
Nature (2024)Cite this article
We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.
Abstract
The body-brain axis is emerging as a principal conductor of organismal physiology. It senses and controls organ function1,2, metabolism3 and nutritional state4-6. Here, we show that a peripheral immune insult powerfully activates the body-brain axis to regulate immune responses. We demonstrate that pro- and anti-inflammatory cytokines communicate with distinct populations of vagal neurons to inform the brain of an emerging inflammatory response. In turn, the brain tightly modulates the course of the peripheral immune response. Genetic silencing of this body-to-brain circuit produced unregulated and out-of-control inflammatory responses. By contrast, activating, rather than silencing, this circuit affords exceptional neural control of immune responses. We used single-cell RNA sequencing, combined with functional imaging, to identify the circuit components of this neuro-immune axis, and showed that its selective manipulation can effectively suppress the pro-inflammatory response while enhancing an anti-inflammatory state. The brain-evoked transformation of the course of an immune response offers new possibilities in the modulation of a wide range of immune disorders, from autoimmune diseases to cytokine storm and shock.
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Front. Immunol., 18 January 2024 Sec. Viral Immunology
Volume 15 - 2024 | https://doi.org/10.3389/fimmu.2024.1341843
Metabolomic and immune alterations in long COVID patients with chronic fatigue syndrome
Suguru Saito1Shima Shahbaz1Xian Luo2Mohammed Osman3Desiree Redmond3Jan Willem Cohen Tervaert3Liang Li2,4Shokrollah Elahi1,5*†
Methods: We identified and studied metabolites and soluble biomarkers in plasma from LC individuals mainly exhibiting ME/CFS compared to age-sex-matched recovered individuals (R) without LC, acute COVID-19 patients (A), and to SARS-CoV-2 unexposed healthy individuals (HC).
Results: Through these analyses, we identified alterations in several metabolomic pathways in LC vs other groups. Plasma metabolomics analysis showed that LC differed from the R and HC groups. Of note, the R group also exhibited a different metabolomic profile than HC. Moreover, we observed a significant elevation in the plasma pro-inflammatory biomarkers (e.g. IL-1α, IL-6, TNF-α, Flt-1, and sCD14) but the reduction in ATP in LC patients. Our results demonstrate that LC patients exhibit persistent metabolomic abnormalities 12 months after the acute COVID-19 disease. Of note, such metabolomic alterations can be observed in the R group 12 months after the acute disease. Hence, the metabolomic recovery period for infected individuals with SARS-CoV-2 might be long-lasting. In particular, we found a significant reduction in sarcosine and serine concentrations in LC patients, which was inversely correlated with depression, anxiety, and cognitive dysfunction scores.
Conclusion: Our study findings provide a comprehensive metabolomic knowledge base and other soluble biomarkers for a better understanding of the pathophysiology of LC and suggests sarcosine and serine supplementations might have potential therapeutic implications in LC patients. Finally, our study reveals that LC disproportionally affects females more than males, as evidenced by nearly 70% of our LC patients being female.
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Published: 03 January 2024
Features of acute COVID-19 associated with post-acute sequelae of SARS-CoV-2 phenotypes: results from the IMPACC study
Al Ozonoff, Naresh Doni Jayavelu, Shanshan Liu, Esther Melamed, Carly E. Milliren, Jingjing Qi, Linda N. Geng, Grace A. McComsey, Charles B. Cairns, Lindsey R. Baden, Joanna Schaenman, Albert C. Shaw, Hady amaha, Vicki Seyfert-Margolis, Florian Krammer, Lindsey B. Rosen, Hanno Steen, Caitlin Syphurs, Ravi Dandekar, Casey P. Shannon, Rafick P. Sekaly, Lauren I. R. Ehrlich, David B. Corry, Farrah Kheradmand, IMPACC Network, Nadine Rouphael
Nature Communications volume 15, Article number: 216 (2024)
Abstract
Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multidomain), supporting heterogenous clinical presentations in PASC, with sub-phenotypes associated with female sex and distinctive comorbidities. During the acute phase of disease, a higher respiratory SARS-CoV-2 viral burden and lower Receptor Binding Domain and Spike antibody titers were associated with both the physical predominant and the multidomain deficit clusters. A lower frequency of circulating B lymphocytes by mass cytometry (CyTOF) was observed in the multidomain deficit cluster. Circulating fibroblast growth factor 21 (FGF21) was significantly elevated in the mental/cognitive predominant and the multidomain clusters. Future efforts to link PASC to acute anti-viral host responses may help to better target treatment and prevention of PASC.
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STATE-OF-THE-ART REVIEW| FEBRUARY 07 2024
Postacute Sequelae of SARS-CoV-2 in Children
Suchitra Rao, MBBS, MSCS;Rachel S. Gross, MD, MS;Sindhu Mohandas, MD;Cheryl R. Stein, PhD;Abigail Case, MD;Benard Dreyer, MD;Nathan M. Pajor, MD;H. Timothy Bunnell, PhD;David Warburton, MD;E lizabeth Berg, MD;Jonathan B. Overdevest, MD;Mark Gorelik, MD;Joshua Milner, MD;Sejal Saxena, BA;Ravi Jhaveri, MD;John C. Wood, MD, PhD;Kyung E. Rhee, MD, MSc, MA;Rebecca Letts, BA;Christine Maughan, BS; Nick Guthe, BA;Leah Castro-Baucom, MA;Melissa S. Stockwell, MD, MPH
Pediatrics (2024) 153 (3): e2023062570.
https://doi.org/10.1542/peds.2023-062570
The coronavirus disease 2019 (COVID-19) pandemic has caused significant medical, social, and economic impacts globally, both in the short and long term. Although most individuals recover within a few days or weeks from an acute infection, some experience longer lasting effects. Data regarding the postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC) in children, or long COVID, are only just emerging in the literature. These symptoms and conditions may reflect persistent symptoms from acute infection (eg, cough, headaches, fatigue, and loss of taste and smell), new symptoms like dizziness, or exacerbation of underlying conditions. Children may develop conditions de novo, including postural orthostatic tachycardia syndrome, myalgic encephalomyelitis/chronic fatigue syndrome, autoimmune conditions and multisystem inflammatory syndrome in children. This state-of-the-art narrative review provides a summary of our current knowledge about PASC in children, including prevalence, epidemiology, risk factors, clinical characteristics, underlying mechanisms, and functional outcomes, as well as a conceptual framework for PASC based on the current National Institutes of Health definition. We highlight the pediatric components of the National Institutes of Health-funded Researching COVID to Enhance Recovery Initiative, which seeks to characterize the natural history, mechanisms, and long-term health effects of PASC in children and young adults to inform future treatment and prevention efforts. These initiatives include electronic health record cohorts, which offer rapid assessments at scale with geographical and demographic diversity, as well as longitudinal prospective observational cohorts, to estimate disease burden, illness trajectory, pathobiology, and clinical manifestations and outcomes.
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ORIGINAL RESEARCH article
Front. Pediatr., 18 January 2024
Sec. Children and Health
Volume 11 - 2023 | https://doi.org/10.3389/fped.2023.1266738
One-year follow-up of young people with ME/CFS following infectious mononucleosis by Epstein-Barr virus
Rafael Pricoco1 Paulina Meidel1 Tim Hofberger1 Hannah Zietemann1 Yvonne Mueller1 Katharina Wiehler1 Kaja Michel1 Johannes Paulick1 Ariane Leone1 Matthias Haegele1 Sandra Mayer-Huber1 Katrin Gerrer1 Kirstin Mittelstrass1 Carmen Scheibenbogen2 Herbert Renz-Polster3 Lorenz Mihatsch1*† Uta Behrends1,4,†
Methods: 12 adolescents and 13 young adults were diagnosed with IM-triggered ME/CFS at our specialized tertiary outpatient service by clinical criteria requiring post-exertional malaise (PEM) and a history of confirmed EBV primary infection as triggering event. Demographic information, laboratory findings, frequency and severity of symptoms, physical functioning, and health-related quality of life (HRQoL) were assessed and re-evaluated 6 and 12 months later.
Results: Young adults displayed more severe symptoms as well as worsening of fatigue, physical and mental functioning, and HRQoL throughout the study, compared to adolescents. After one year, 6/12 (54%) adolescents no longer met the diagnostic criteria for ME/CFS while all young adults continued to fulfill the Canadian consensus criteria. Improvement in adolescents was evident in physical functioning, symptom frequency and severity, and HRQoL, while young adults showed little improvement. EBV serology and EBV DNA load did not correlate with distinct clinical features of ME/CFS, and clinical chemistry showed no evidence of inflammation. Remarkably, the median time from symptom onset to ME/CFS diagnosis was 13.8 (IQR: 9.1–34.9) months.
Conclusions: ME/CFS following EBV-IM is a severely debilitating disease often diagnosed late and with limited responses to conventional medical care, especially in adults. Although adolescents may have a better prognosis, their condition can fluctuate and significantly impact their HRQoL. Our data emphasize that biomarkers and effective therapeutic options are also urgently needed to improve medical care and pave the way to recovery.
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2024 Jan;13(1):e12403. doi: 10.1002/jev2.12403.
Dysregulation of extracellular vesicle protein cargo in female myalgic encephalomyelitis/chronic fatigue syndrome cases and sedentary controls in response to maximal exercise
Ludovic Giloteaux 1, Katherine A Glass 1, Arnaud Germain 1, Carl J Franconi 1, Sheng Zhang 2, Maureen R Hanson 1
PMID: 38173127 PMCID: PMC10764978 DOI: 10.1002/jev2.12403
Abstract
In healthy individuals, physical exercise improves cardiovascular health and muscle strength, alleviates fatigue and reduces the risk of chronic diseases. Although exercise is suggested as a lifestyle intervention to manage various chronic illnesses, it negatively affects people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), who suffer from exercise intolerance. We hypothesized that altered extracellular vesicle (EV) signalling in ME/CFS patients after an exercise challenge may contribute to their prolonged and exacerbated negative response to exertion (post-exertional malaise). EVs were isolated by size exclusion chromatography from the plasma of 18 female ME/CFS patients and 17 age- and BMI-matched female sedentary controls at three time points: before, 15 min, and 24 h after a maximal cardiopulmonary exercise test. EVs were characterized using nanoparticle tracking analysis and their protein cargo was quantified using Tandem Mass Tag-based (TMT) proteomics. The results show that exercise affects the EV proteome in ME/CFS patients differently than in healthy individuals and that changes in EV proteins after exercise are strongly correlated with symptom severity in ME/CFS. Differentially abundant proteins in ME/CFS patients versus controls were involved in many pathways and systems, including coagulation processes, muscle contraction (both smooth and skeletal muscle), cytoskeletal proteins, the immune system and brain signalling.
Keywords: ME/CFS; chronic fatigue syndrome; exercise; extracellular vesicle cargo; myalgic encephalomyelitis; proteomics.
© 2024 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.
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Exp Physiol . 2024 Jun 14. doi: 10.1113/EP091986. Online ahead of print.
Cell-free DNA kinetics in response to muscle-damaging exercise: A drop jump study
Ema Juškevičiūtė 1 2, Elmo Neuberger 2, Nerijus Eimantas 1, Kirsten Heinkel 2, Perikles Simon 2, Marius Brazaitis 1
PMID: 38875105 DOI: 10.1113/EP091986
Abstract
A significant increase in circulating cell-free DNA (cfDNA) occurs with physical exercise, which depends on the type of exertion and the duration. The aims of this study were as follows: (1) to investigate the time course of cfDNA and conventional markers of muscle damage from immediately after to 96 h after muscle-damaging exercise; and (2) to investigate the relationship between cfDNA and indicators of primary (low-frequency fatigue and maximal voluntary isometric contraction) and secondary (creatine kinase and delayed-onset muscle soreness) muscle damage in young healthy males. Fourteen participants (age, 22 ± 2 years; weight, 84.4 ± 11.2 kg; height, 184.0 ± 7.4 cm) performed 50 intermittent drop jumps at 20 s intervals. We measured cfDNA and creatine kinase concentrations, maximal voluntary isometric contraction torque, low-frequency fatigue and delayed-onset muscle soreness before and at several time points up to 96 h after exercise. Plasma cfDNA levels increased from immediately postexercise until 72 h postexercise (P < 0.01). Elevation of postexercise cfDNA was correlated with both more pronounced low-frequency fatigue (r = -0.52, P = 3.4 × 10-11) and delayed-onset muscle soreness (r = 0.32, P = 0.00019). Levels of cfDNA change in response to severe primary and secondary muscle damage after exercise. Levels of cfDNA exhibit a stronger correlation with variables related to primary muscle damage than to secondary muscle damage, suggesting that cfDNA is a more sensitive marker of acute loss of muscle function than of secondary inflammation or damaged muscle fibres.
Keywords: blood markers; cell‐free DNA; eccentric exercise; muscle damage.
© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.
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Published: 04 January 2024
Muscle abnormalities worsen after post-exertional malaise in long COVID
Brent Appelman, Braeden T. Charlton, Richie P. Goulding, Tom J. Kerkhoff, Ellen A. Breedveld, Wendy Noort, Carla Offringa, Frank W. Bloemers, Michel van Weeghel, Bauke V. Schomakers, Pedro Coelho, Jelle J. Posthuma, Eleonora Aronica, W. Joost Wiersinga, Michèle van Vugt & Rob C. I. Wüst
Nature Communications volume 15, Article number: 17 (2024)
Abstract
A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear. With this longitudinal case-control study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of post-exertional malaise. This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases.
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Successful Subcutaneous Immunoglobulin Therapy in a Case Series of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
GEPUBLICEERD OP 24 juni 2024 Sjogren, Bragée, Britton
Abstract
Purpose
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains an enigma with no curable treatment options at hand. Although patients with ME/CFS are a heterogeneous group, a large proportion of patients present with an infection-driven symptomatology, making them potential responders to immunologic treatments, such as immunoglobulin (IG).
Previous studies on IG treatment in patients with ME/CFS have not been consistent but have described beneficial effects in subgroups of patients.
Methods
Here we present data on a series of cases (n = 17) with infection-related ME/CFS (as defined by disease history and ongoing recurrent infections) treated with subcutaneous low-dose IG (0.06 g/kg/mo) over 5 weeks with continuous monitoring of symptoms.
Findings
Patients were predominantly female (65%) with mild-to-moderate disease severity (82%) and with poor self-reported quality of life (median, 25 on a 0-100 scale) and working ability (median, 5 on a 0-100 scale) before treatment. After 5 weeks of treatment with low-dose IG, significant improvements in symptoms, quality of life, and working ability were noted (all P < 0.05). Among the 7 patients who reported the highest benefit of the treatment, quality of life increased by 35 units (on a 0-100 scale), with 1 patient reporting complete elimination of ME/CFS symptoms. No serious side effects were detected with the treatment.
Implications
In this limited-sized case series, we found pronounced beneficial effects of low-dose IG in a large proportion of patients with infection-related ME/CFS. Further well-controlled studies are needed to verify the potential benefits of IG treatment in patients with ME/CFS with infection-driven symptomatology.
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Source: Clinical Therapeutics, open access
Ageing Res Rev. 2024 Jun 28:102400. doi: 10.1016/j.arr.2024.102400. Online ahead of print.
Long COVID as a Disease of Accelerated Biological Aging: An Opportunity to Translate Geroscience Interventions
Areez Shafqat 1, Mary Clare Masters 2, Utkarsh Tripathi 3, Tamara Tchkonia 4, James L Kirkland 5, Shahrukh K Hashmi 6
PMID: 38945306 DOI: 10.1016/j.arr.2024.102400
Abstract
It has been four years since long COVID-the protracted consequences that survivors of COVID-19 face-was first described. Yet, this entity continues to devastate the quality of life of an increasing number of COVID-19 survivors without any approved therapy. Furthermore, there remains a paucity of clinical trials addressing the biological root causes of this disease. Notably, the symptoms of long COVID-including but not limited to exercise intolerance, cognitive impairment, orthostasis, and functional decline-are typically seen with advancing age. Leveraging this similarity, we posit that Geroscience-which aims to target the biological drivers of aging to prevent age-associated conditions as a group-could offer promising therapeutic avenues for long COVID. Bearing this in mind, this review presents a framework for studying long COVID as a state of effectively accelerated biological aging. Thus, we comprehensively review here the role of biological hallmarks of aging in long COVID, identifying research gaps and proposing directions for future preclinical and clinical studies.
Keywords: Cellular Senescence; Dysbiosis; Geroscience; Inflammation; Long COVID; Mitochondrial Dysfunction.
Copyright © 2024 Elsevier B.V. All rights reserved.
Brent Appelman, Braeden T. Charlton, Richie P. Goulding, Tom J. Berkhoff, Ellen A. Breedveld, Wendy Noort, Carla Offringa, Frank W. Bloemers, Michel van Weeghel, Bauke V. Schomakers, Pedro Coelho, Jelle J. Posthuma, Eleonora Aronica, W. Joost Wiersinga, Michèle van Vugt & Rob C. I. Wüst
Nature Communications volume 15, Article number: 17 (2024) Cite this article
Abstract
A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear. With this longitudinal case-control study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of post-exertional malaise. This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases.
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Brain Behav Immun Health. 2024 Mar; 36: 100733.
Published online 2024 Feb 1. doi: 10.1016/j.bbih.2024.100733
PMCID: PMC10862402 PMID: 38352659
Low-dose naltrexone and NAD+ for the treatment of patients with persistent fatigue symptoms after COVID-19
Anar Isman,a Andy Nyquist,a,∗ Bailey Strecker,a Girish Harinath,a Virginia Lee,a Xingyu Zhang,b and Sajad Zalzalaa
Abstract
A subset of patients experiences persistent fatigue symptoms after COVID-19, and patients may develop long COVID, which is characterized by lasting systemic symptoms. No treatments for this condition have been validated and are urgently warranted. In this pilot study, we assessed whether treatment with low-dose naltrexone (LDN, 4.5 mg/day) and supplementation with NAD + through iontophoresis patches could improve fatigue symptoms and quality of life in 36 patients with persistent moderate/severe fatigue after COVID-19. We detected a significant increase from baseline in SF-36 survey scores after 12 weeks of treatment (mean total SF-36 score 36.5 [SD: 15.6] vs. 52.1 [24.8]; p < 0.0001), suggestive of improvement of quality of life. Furthermore, participants scored significantly lower on the Chalder fatigue scale after 12 weeks of treatment (baseline: 25.9 [4.6], 12 weeks: 17.4 [9.7]; p < 0.0001). We found a subset of 52 % of patients to be responders after 12 weeks of treatment. Treatment was generally safe, with mild adverse events previously reported for LDN, which could be managed with dose adjustments. The iontophoresis patches were associated with mild, short-lived skin irritation in 25 % of patients. Our data suggest treatment with LDN and NAD+ is safe and may be beneficial in a subset of patients with persistent fatigue after COVID-19. Larger randomized controlled trials will have to confirm our data and determine which patient subpopulations might benefit most from this strategy.
Keywords: COVID-19, Long COVID, Fatigue, Quality of life, Low dose naltrexone, NAD+, SF-36
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ARTICLE| VOLUME 5, ISSUE 1, 101373, JANUARY 16, 2024
Single-cell transcriptomics of the immune system in ME/CFS at baseline and following symptom provocation
Luyen Tien Vu ,Faraz Ahmed 7,Hongya Zhu 7,Maureen R. Hanson,Jennifer K. Grenier,Andrew Grimson 8,et al DOI:https://doi.org/10.1016/j.xcrm.2023.101373
Highlights
The ME/CFS immune system is profiled by scRNA-seq at baseline and after provocation.
Monocyte dysregulation is prominent and dysregulation correlates with disease severity
Platelets are also dysregulated, but this dysregulation resolves after provocation
Summary
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious and poorly understood disease. To understand immune dysregulation in ME/CFS, we use single-cell RNA sequencing (scRNA-seq) to examine immune cells in patient and control cohorts. Postexertional malaise (PEM), an exacerbation of symptoms following strenuous exercise, is a characteristic symptom of ME/CFS. To detect changes coincident with PEM, we applied scRNA-seq on the same cohorts following exercise. At baseline, ME/CFS patients display classical monocyte dysregulation suggestive of inappropriate differentiation and migration to tissue. We identify both diseased and more normal monocytes within patients, and the fraction of diseased cells correlates with disease severity. Comparing the transcriptome at baseline and postexercise challenge, we discover patterns indicative of improper platelet activation in patients, with minimal changes elsewhere in the immune system. Taken together, these data identify immunological defects present at baseline in patients and an additional layer of dysregulation in platelets.
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A phenomenological study on the lived experience of men with Chronic Fatigue Syndrome
Gracie Elizabeth Snellhttps://orcid.org/0000-0002-1472-8196[email protected], Catherine Heidi Seage https://orcid.org/0000-0002-8590-867X, and Jenny Mercer https://orcid.org/0000-0001-5917-0491View all authors and affiliations
Journal of Health Psychology Volume 29, Issue 3
https://doi.org/10.1177/13591053231186385
Abstract
Whilst chronic fatigue syndrome (CFS) has been widely researched amongst women, studies investigating how men experience a CFS diagnosis is limited. This study utilised an interpretative phenomenological approach to interview five men who have a medical diagnosis of CFS. Six themes emerged to demonstrate the participants’ experiences prior to, during and after obtaining their CFS diagnosis. Findings revealed that participants were initially reluctant to accept their condition, confounded by their perception that symptoms compromised their sense of masculinity. They also felt that healthcare professionals had limited recognition of CFS leading them to seek social support and legitimisation from other sources. The struggle to come to terms with a different lifestyle and sense of masculinity prevailed. Such knowledge could be effectively utilised by researchers, practitioners and employers to facilitate an increased understanding of male accounts of the condition and more bespoke interventions where required.
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Unravelling shared mechanisms: insights from recent ME/CFS research to illuminate long COVID pathologies
Sarah J. Annesley Daniel Missailidis Benjamin Heng Elisha K. Josev , Christopher W. Armstrong 7
Published:March 04, 2024DOI:https://doi.org/10.1016/j.molmed.2024.0
Highlights
- Approximately half of patients with long COVID (LC) fulfil the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The two conditions share clinical similarities and proposed disease pathologies, but it is still unclear whether they also share common molecular abnormalities.
- Most consistently altered pathologies in ME/CFS and LC include an increased reliance on alternatives to carbohydrates as substrates for energy production and altered gut microbiota, with a reduction in butyrate-synthesising bacteria.
- Therapeutic approaches targeted at the autoimmune response showed early promising results, but have not passed further clinical trials.
- ME/CFS and LC research has identified potential biomarkers, which need to be replicated and validated, with the most accurate and clinically practicable appearing to be measurements of RNAs for ME/CFS.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic illness often triggered by an initiating acute event, mainly viral infections. The transition from acute to chronic disease remains unknown, but interest in this phenomenon has escalated since the COVID-19 pandemic and the post-COVID-19 illness, termed ‘long COVID’ (LC). Both ME/CFS and LC share many clinical similarities. Here, we present recent findings in ME/CFS research focussing on proposed disease pathologies shared with LC. Understanding these disease pathologies and how they influence each other is key to developing effective therapeutics and diagnostic tests. Given that ME/CFS typically has a longer disease duration compared with LC, with symptoms and pathologies evolving over time, ME/CFS may provide insights into the future progression of LC.
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Experts call for more research into long COVID, as study reveals high prevalence in WA
By Emily JB Smith, Rebecca Trigger, and Phoebe Pin (U Tube)
Posted Wed 3 Apr 2024 at 10:15amWednesday 3 Apr 2024 at 10:15am, updated Thu 4 Apr 2024 at 12:06am
- In short: A study conducted in WA found nearly 20 per cent of COVID-19 patients experienced debilitating symptoms like fatigue and memory loss three months after infection.
- It indicated a higher prevalence of long-term symptoms in WA compared to earlier studies in Australia, the UK, and Canada.
- What's next? Authorities are being urged to develop more practical policies to assist people with long COVID.
The Australian National University (ANU) study surveyed 11,000 people who tested positive to COVID during a significant outbreak of the Omicron variant in WA in 2022.
The study published in March found almost 20 per cent of those patients were still suffering symptoms of fatigue, memory loss and concentration difficulties three months after they first became sick.
Lead researcher Mulu Woldegiorgis said there was little pre-existing data available on the topic, but that the new research suggested there was a high rate of long-term COVID-19 symptoms in WA.
In their report, Dr Woldegiorgis and her colleagues acknowledged one of the limitations of the ANU survey was that it relied on subjective symptom descriptions from patients, and the reported impact of their symptoms on work or study was not independently verified.
Dr Woldegiorgis said it was important for patients' symptoms to be taken seriously.
"I think it's real and it needs more investigation," she said.
"When we see its impact on work or study, more than one in six of those who used to work before their infection were not able to fully return to work or study due to their ongoing symptoms."
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A body–brain circuit that regulates body inflammatory responses
Hao Jin, Mengtong Li, Eric Jeong, Felipe Castro-Martinez & Charles S. Zuker
Nature (2024)Cite this article
We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.
Abstract
The body-brain axis is emerging as a principal conductor of organismal physiology. It senses and controls organ function1,2, metabolism3 and nutritional state4-6. Here, we show that a peripheral immune insult powerfully activates the body-brain axis to regulate immune responses. We demonstrate that pro- and anti-inflammatory cytokines communicate with distinct populations of vagal neurons to inform the brain of an emerging inflammatory response. In turn, the brain tightly modulates the course of the peripheral immune response. Genetic silencing of this body-to-brain circuit produced unregulated and out-of-control inflammatory responses. By contrast, activating, rather than silencing, this circuit affords exceptional neural control of immune responses. We used single-cell RNA sequencing, combined with functional imaging, to identify the circuit components of this neuro-immune axis, and showed that its selective manipulation can effectively suppress the pro-inflammatory response while enhancing an anti-inflammatory state. The brain-evoked transformation of the course of an immune response offers new possibilities in the modulation of a wide range of immune disorders, from autoimmune diseases to cytokine storm and shock.
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Front. Immunol., 18 January 2024 Sec. Viral Immunology
Volume 15 - 2024 | https://doi.org/10.3389/fimmu.2024.1341843
Metabolomic and immune alterations in long COVID patients with chronic fatigue syndrome
Suguru Saito1Shima Shahbaz1Xian Luo2Mohammed Osman3Desiree Redmond3Jan Willem Cohen Tervaert3Liang Li2,4Shokrollah Elahi1,5*†
- 1School of Dentistry, Division of Foundational Sciences, Edmonton, AB, Canada
- 2The Metabolomics Innovation Centre, University of Alberta, Edmonton, AB, Canada
- 3Department of Medicine, Division of Rheumatology, Edmonton, AB, Canada
- 4Department of Chemistry, University of Alberta, Edmonton, AB, Canada
- 5Li Ka Shing Institute of Virology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
Methods: We identified and studied metabolites and soluble biomarkers in plasma from LC individuals mainly exhibiting ME/CFS compared to age-sex-matched recovered individuals (R) without LC, acute COVID-19 patients (A), and to SARS-CoV-2 unexposed healthy individuals (HC).
Results: Through these analyses, we identified alterations in several metabolomic pathways in LC vs other groups. Plasma metabolomics analysis showed that LC differed from the R and HC groups. Of note, the R group also exhibited a different metabolomic profile than HC. Moreover, we observed a significant elevation in the plasma pro-inflammatory biomarkers (e.g. IL-1α, IL-6, TNF-α, Flt-1, and sCD14) but the reduction in ATP in LC patients. Our results demonstrate that LC patients exhibit persistent metabolomic abnormalities 12 months after the acute COVID-19 disease. Of note, such metabolomic alterations can be observed in the R group 12 months after the acute disease. Hence, the metabolomic recovery period for infected individuals with SARS-CoV-2 might be long-lasting. In particular, we found a significant reduction in sarcosine and serine concentrations in LC patients, which was inversely correlated with depression, anxiety, and cognitive dysfunction scores.
Conclusion: Our study findings provide a comprehensive metabolomic knowledge base and other soluble biomarkers for a better understanding of the pathophysiology of LC and suggests sarcosine and serine supplementations might have potential therapeutic implications in LC patients. Finally, our study reveals that LC disproportionally affects females more than males, as evidenced by nearly 70% of our LC patients being female.
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Published: 03 January 2024
Features of acute COVID-19 associated with post-acute sequelae of SARS-CoV-2 phenotypes: results from the IMPACC study
Al Ozonoff, Naresh Doni Jayavelu, Shanshan Liu, Esther Melamed, Carly E. Milliren, Jingjing Qi, Linda N. Geng, Grace A. McComsey, Charles B. Cairns, Lindsey R. Baden, Joanna Schaenman, Albert C. Shaw, Hady amaha, Vicki Seyfert-Margolis, Florian Krammer, Lindsey B. Rosen, Hanno Steen, Caitlin Syphurs, Ravi Dandekar, Casey P. Shannon, Rafick P. Sekaly, Lauren I. R. Ehrlich, David B. Corry, Farrah Kheradmand, IMPACC Network, Nadine Rouphael
Nature Communications volume 15, Article number: 216 (2024)
Abstract
Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multidomain), supporting heterogenous clinical presentations in PASC, with sub-phenotypes associated with female sex and distinctive comorbidities. During the acute phase of disease, a higher respiratory SARS-CoV-2 viral burden and lower Receptor Binding Domain and Spike antibody titers were associated with both the physical predominant and the multidomain deficit clusters. A lower frequency of circulating B lymphocytes by mass cytometry (CyTOF) was observed in the multidomain deficit cluster. Circulating fibroblast growth factor 21 (FGF21) was significantly elevated in the mental/cognitive predominant and the multidomain clusters. Future efforts to link PASC to acute anti-viral host responses may help to better target treatment and prevention of PASC.
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STATE-OF-THE-ART REVIEW| FEBRUARY 07 2024
Postacute Sequelae of SARS-CoV-2 in Children
Suchitra Rao, MBBS, MSCS;Rachel S. Gross, MD, MS;Sindhu Mohandas, MD;Cheryl R. Stein, PhD;Abigail Case, MD;Benard Dreyer, MD;Nathan M. Pajor, MD;H. Timothy Bunnell, PhD;David Warburton, MD;E lizabeth Berg, MD;Jonathan B. Overdevest, MD;Mark Gorelik, MD;Joshua Milner, MD;Sejal Saxena, BA;Ravi Jhaveri, MD;John C. Wood, MD, PhD;Kyung E. Rhee, MD, MSc, MA;Rebecca Letts, BA;Christine Maughan, BS; Nick Guthe, BA;Leah Castro-Baucom, MA;Melissa S. Stockwell, MD, MPH
Pediatrics (2024) 153 (3): e2023062570.
https://doi.org/10.1542/peds.2023-062570
The coronavirus disease 2019 (COVID-19) pandemic has caused significant medical, social, and economic impacts globally, both in the short and long term. Although most individuals recover within a few days or weeks from an acute infection, some experience longer lasting effects. Data regarding the postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC) in children, or long COVID, are only just emerging in the literature. These symptoms and conditions may reflect persistent symptoms from acute infection (eg, cough, headaches, fatigue, and loss of taste and smell), new symptoms like dizziness, or exacerbation of underlying conditions. Children may develop conditions de novo, including postural orthostatic tachycardia syndrome, myalgic encephalomyelitis/chronic fatigue syndrome, autoimmune conditions and multisystem inflammatory syndrome in children. This state-of-the-art narrative review provides a summary of our current knowledge about PASC in children, including prevalence, epidemiology, risk factors, clinical characteristics, underlying mechanisms, and functional outcomes, as well as a conceptual framework for PASC based on the current National Institutes of Health definition. We highlight the pediatric components of the National Institutes of Health-funded Researching COVID to Enhance Recovery Initiative, which seeks to characterize the natural history, mechanisms, and long-term health effects of PASC in children and young adults to inform future treatment and prevention efforts. These initiatives include electronic health record cohorts, which offer rapid assessments at scale with geographical and demographic diversity, as well as longitudinal prospective observational cohorts, to estimate disease burden, illness trajectory, pathobiology, and clinical manifestations and outcomes.
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ORIGINAL RESEARCH article
Front. Pediatr., 18 January 2024
Sec. Children and Health
Volume 11 - 2023 | https://doi.org/10.3389/fped.2023.1266738
One-year follow-up of young people with ME/CFS following infectious mononucleosis by Epstein-Barr virus
Rafael Pricoco1 Paulina Meidel1 Tim Hofberger1 Hannah Zietemann1 Yvonne Mueller1 Katharina Wiehler1 Kaja Michel1 Johannes Paulick1 Ariane Leone1 Matthias Haegele1 Sandra Mayer-Huber1 Katrin Gerrer1 Kirstin Mittelstrass1 Carmen Scheibenbogen2 Herbert Renz-Polster3 Lorenz Mihatsch1*† Uta Behrends1,4,†
- 1MRI Chronic Fatigue Center for Young People (MCFC), Children’s Hospital, TUM School of Medicine, Technical University of Munich and Munich Municipal Hospital Schwabing, Munich, Germany
- 2Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin and Berlin Institute of Health (BIH), Berlin, Germany
- 3Mannheim Institute of Public Health, Social and Preventive Medicine, University Medicine Mannheim, Heidelberg, Germany
- 4German Center for Infection Research (partner site Munich), Munich, Germany
Methods: 12 adolescents and 13 young adults were diagnosed with IM-triggered ME/CFS at our specialized tertiary outpatient service by clinical criteria requiring post-exertional malaise (PEM) and a history of confirmed EBV primary infection as triggering event. Demographic information, laboratory findings, frequency and severity of symptoms, physical functioning, and health-related quality of life (HRQoL) were assessed and re-evaluated 6 and 12 months later.
Results: Young adults displayed more severe symptoms as well as worsening of fatigue, physical and mental functioning, and HRQoL throughout the study, compared to adolescents. After one year, 6/12 (54%) adolescents no longer met the diagnostic criteria for ME/CFS while all young adults continued to fulfill the Canadian consensus criteria. Improvement in adolescents was evident in physical functioning, symptom frequency and severity, and HRQoL, while young adults showed little improvement. EBV serology and EBV DNA load did not correlate with distinct clinical features of ME/CFS, and clinical chemistry showed no evidence of inflammation. Remarkably, the median time from symptom onset to ME/CFS diagnosis was 13.8 (IQR: 9.1–34.9) months.
Conclusions: ME/CFS following EBV-IM is a severely debilitating disease often diagnosed late and with limited responses to conventional medical care, especially in adults. Although adolescents may have a better prognosis, their condition can fluctuate and significantly impact their HRQoL. Our data emphasize that biomarkers and effective therapeutic options are also urgently needed to improve medical care and pave the way to recovery.
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2024 Jan;13(1):e12403. doi: 10.1002/jev2.12403.
Dysregulation of extracellular vesicle protein cargo in female myalgic encephalomyelitis/chronic fatigue syndrome cases and sedentary controls in response to maximal exercise
Ludovic Giloteaux 1, Katherine A Glass 1, Arnaud Germain 1, Carl J Franconi 1, Sheng Zhang 2, Maureen R Hanson 1
PMID: 38173127 PMCID: PMC10764978 DOI: 10.1002/jev2.12403
Abstract
In healthy individuals, physical exercise improves cardiovascular health and muscle strength, alleviates fatigue and reduces the risk of chronic diseases. Although exercise is suggested as a lifestyle intervention to manage various chronic illnesses, it negatively affects people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), who suffer from exercise intolerance. We hypothesized that altered extracellular vesicle (EV) signalling in ME/CFS patients after an exercise challenge may contribute to their prolonged and exacerbated negative response to exertion (post-exertional malaise). EVs were isolated by size exclusion chromatography from the plasma of 18 female ME/CFS patients and 17 age- and BMI-matched female sedentary controls at three time points: before, 15 min, and 24 h after a maximal cardiopulmonary exercise test. EVs were characterized using nanoparticle tracking analysis and their protein cargo was quantified using Tandem Mass Tag-based (TMT) proteomics. The results show that exercise affects the EV proteome in ME/CFS patients differently than in healthy individuals and that changes in EV proteins after exercise are strongly correlated with symptom severity in ME/CFS. Differentially abundant proteins in ME/CFS patients versus controls were involved in many pathways and systems, including coagulation processes, muscle contraction (both smooth and skeletal muscle), cytoskeletal proteins, the immune system and brain signalling.
Keywords: ME/CFS; chronic fatigue syndrome; exercise; extracellular vesicle cargo; myalgic encephalomyelitis; proteomics.
© 2024 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.
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Exp Physiol . 2024 Jun 14. doi: 10.1113/EP091986. Online ahead of print.
Cell-free DNA kinetics in response to muscle-damaging exercise: A drop jump study
Ema Juškevičiūtė 1 2, Elmo Neuberger 2, Nerijus Eimantas 1, Kirsten Heinkel 2, Perikles Simon 2, Marius Brazaitis 1
PMID: 38875105 DOI: 10.1113/EP091986
Abstract
A significant increase in circulating cell-free DNA (cfDNA) occurs with physical exercise, which depends on the type of exertion and the duration. The aims of this study were as follows: (1) to investigate the time course of cfDNA and conventional markers of muscle damage from immediately after to 96 h after muscle-damaging exercise; and (2) to investigate the relationship between cfDNA and indicators of primary (low-frequency fatigue and maximal voluntary isometric contraction) and secondary (creatine kinase and delayed-onset muscle soreness) muscle damage in young healthy males. Fourteen participants (age, 22 ± 2 years; weight, 84.4 ± 11.2 kg; height, 184.0 ± 7.4 cm) performed 50 intermittent drop jumps at 20 s intervals. We measured cfDNA and creatine kinase concentrations, maximal voluntary isometric contraction torque, low-frequency fatigue and delayed-onset muscle soreness before and at several time points up to 96 h after exercise. Plasma cfDNA levels increased from immediately postexercise until 72 h postexercise (P < 0.01). Elevation of postexercise cfDNA was correlated with both more pronounced low-frequency fatigue (r = -0.52, P = 3.4 × 10-11) and delayed-onset muscle soreness (r = 0.32, P = 0.00019). Levels of cfDNA change in response to severe primary and secondary muscle damage after exercise. Levels of cfDNA exhibit a stronger correlation with variables related to primary muscle damage than to secondary muscle damage, suggesting that cfDNA is a more sensitive marker of acute loss of muscle function than of secondary inflammation or damaged muscle fibres.
Keywords: blood markers; cell‐free DNA; eccentric exercise; muscle damage.
© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.
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Published: 04 January 2024
Muscle abnormalities worsen after post-exertional malaise in long COVID
Brent Appelman, Braeden T. Charlton, Richie P. Goulding, Tom J. Kerkhoff, Ellen A. Breedveld, Wendy Noort, Carla Offringa, Frank W. Bloemers, Michel van Weeghel, Bauke V. Schomakers, Pedro Coelho, Jelle J. Posthuma, Eleonora Aronica, W. Joost Wiersinga, Michèle van Vugt & Rob C. I. Wüst
Nature Communications volume 15, Article number: 17 (2024)
Abstract
A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear. With this longitudinal case-control study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of post-exertional malaise. This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases.
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Successful Subcutaneous Immunoglobulin Therapy in a Case Series of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
GEPUBLICEERD OP 24 juni 2024 Sjogren, Bragée, Britton
Abstract
Purpose
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains an enigma with no curable treatment options at hand. Although patients with ME/CFS are a heterogeneous group, a large proportion of patients present with an infection-driven symptomatology, making them potential responders to immunologic treatments, such as immunoglobulin (IG).
Previous studies on IG treatment in patients with ME/CFS have not been consistent but have described beneficial effects in subgroups of patients.
Methods
Here we present data on a series of cases (n = 17) with infection-related ME/CFS (as defined by disease history and ongoing recurrent infections) treated with subcutaneous low-dose IG (0.06 g/kg/mo) over 5 weeks with continuous monitoring of symptoms.
Findings
Patients were predominantly female (65%) with mild-to-moderate disease severity (82%) and with poor self-reported quality of life (median, 25 on a 0-100 scale) and working ability (median, 5 on a 0-100 scale) before treatment. After 5 weeks of treatment with low-dose IG, significant improvements in symptoms, quality of life, and working ability were noted (all P < 0.05). Among the 7 patients who reported the highest benefit of the treatment, quality of life increased by 35 units (on a 0-100 scale), with 1 patient reporting complete elimination of ME/CFS symptoms. No serious side effects were detected with the treatment.
Implications
In this limited-sized case series, we found pronounced beneficial effects of low-dose IG in a large proportion of patients with infection-related ME/CFS. Further well-controlled studies are needed to verify the potential benefits of IG treatment in patients with ME/CFS with infection-driven symptomatology.
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Source: Clinical Therapeutics, open access
Ageing Res Rev. 2024 Jun 28:102400. doi: 10.1016/j.arr.2024.102400. Online ahead of print.
Long COVID as a Disease of Accelerated Biological Aging: An Opportunity to Translate Geroscience Interventions
Areez Shafqat 1, Mary Clare Masters 2, Utkarsh Tripathi 3, Tamara Tchkonia 4, James L Kirkland 5, Shahrukh K Hashmi 6
PMID: 38945306 DOI: 10.1016/j.arr.2024.102400
Abstract
It has been four years since long COVID-the protracted consequences that survivors of COVID-19 face-was first described. Yet, this entity continues to devastate the quality of life of an increasing number of COVID-19 survivors without any approved therapy. Furthermore, there remains a paucity of clinical trials addressing the biological root causes of this disease. Notably, the symptoms of long COVID-including but not limited to exercise intolerance, cognitive impairment, orthostasis, and functional decline-are typically seen with advancing age. Leveraging this similarity, we posit that Geroscience-which aims to target the biological drivers of aging to prevent age-associated conditions as a group-could offer promising therapeutic avenues for long COVID. Bearing this in mind, this review presents a framework for studying long COVID as a state of effectively accelerated biological aging. Thus, we comprehensively review here the role of biological hallmarks of aging in long COVID, identifying research gaps and proposing directions for future preclinical and clinical studies.
Keywords: Cellular Senescence; Dysbiosis; Geroscience; Inflammation; Long COVID; Mitochondrial Dysfunction.
Copyright © 2024 Elsevier B.V. All rights reserved.
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