Tag: 2024

Persistent Fatigue, Weakness, and Aberrant Muscle Mitochondria in Survivors of Critical COVID-19

Abstract:

Objectives: Persistent skeletal muscle dysfunction in survivors of critical illness due to acute respiratory failure is common, but biological data elucidating underlying mechanisms are limited. The objective of this study was to elucidate the prevalence of skeletal muscle weakness and fatigue in survivors of critical illness due to COVID-19 and determine if cellular changes associate with persistent skeletal muscle dysfunction.

Design: A prospective observational study in two phases: 1) survivors of critical COVID-19 participating in physical outcome measures while attending an ICU Recovery Clinic at short-term follow-up and 2) a nested cohort of patients performed comprehensive muscle and physical function assessments with a muscle biopsy; data were compared with non-COVID controls.

Setting: ICU Recovery Clinic and clinical laboratory.

Patients/subjects: Survivors of critical COVID-19 and non-COVID controls.

Interventions: None.

Measurements and main results: One hundred twenty patients with a median of 56 years old (interquartile range [IQR], 42-65 yr old), 43% female, and 33% individuals of underrepresented race attended follow-up 44 ± 17 days after discharge. Patients had a median Acute Physiology and Chronic Health Evaluation-II score of 24.0 (IQR, 16-29) and 98 patients (82%) required mechanical ventilation with a median duration of 14 days (IQR, 9-21 d). At short-term follow-up significant physical dysfunction was observed with 93% of patients reporting generalized fatigue and performing mean 218 ± 151 meters on 6-minute walk test (45% ± 30% of predicted). Eleven patients from this group agreed to participate in long-term assessment and muscle biopsy occurring a mean 267 ± 98 days after discharge. Muscle tissue from COVID exhibited a greater abundance of M2-like macrophages and satellite cells and lower activity of mitochondrial complex II and complex IV compared with controls.

Conclusions: Our findings suggest that aberrant repair and altered mitochondrial activity in skeletal muscle associates with long-term impairments in patients surviving an ICU admission for COVID-19.

Source: Mayer KP, Ismaeel A, Kalema AG, Montgomery-Yates AA, Soper MK, Kern PA, Starck JD, Slone SA, Morris PE, Dupont-Versteegden EE, Kosmac K. Persistent Fatigue, Weakness, and Aberrant Muscle Mitochondria in Survivors of Critical COVID-19. Crit Care Explor. 2024 Oct 16;6(10):e1164. doi: 10.1097/CCE.0000000000001164. PMID: 39412208; PMCID: PMC11487221. https://pmc.ncbi.nlm.nih.gov/articles/PMC11487221/ (Full text)

Epigenetic changes in patients with post-acute COVID-19 symptoms (PACS) and long-COVID: A systematic review

Abstract:

Background: Up to 30% of people infected with SARS-CoV-2 report disabling symptoms 2 years after the infection. Over 100 persistent symptoms have been associated with Post-Acute COVID-19 Symptoms (PACS) and/or long-COVID, showing a significant clinical heterogeneity. To develop effective, patient-targeted treatment, a better understanding of underlying mechanisms is needed. Epigenetics has helped elucidating the pathophysiology of several health conditions and it might help unravelling inter-individual differences in patients with PACS and long-COVID. As accumulating research is exploring epigenetic mechanisms in PACS and long-COVID, we systematically summarized the available literature on the topic.

Methods: We interrogated five databases (Medline, Embase, Web of Science, Scopus and medXriv/bioXriv) and followed PRISMA and SWiM guidelines to report our results.

Results: Eight studies were included in our review. Six studies explored DNA methylation in PACS and/or long-COVID, while two studies explored miRNA expression in long-COVID associated with lung complications. Sample sizes were mostly small and study quality was low or fair. The main limitation of the included studies was a poor characterization of the patient population that made a homogeneous synthesis of the literature challenging. However, studies on DNA methylation showed that mechanisms related to the immune and the autonomic nervous system, and cell metabolism might be implicated in the pathophysiology of PACS and long-COVID.

Conclusion: Epigenetic changes might help elucidating PACS and long-COVID underlying mechanisms, aid subgrouping, and point towards tailored treatments. Preliminary evidence is promising but scarce. Biological and epigenetic research on long-COVID will benefit millions of people suffering from long-COVID and has the potential to be transferable and benefit other conditions as well, such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We urge future research to employ longitudinal designs and provide a better characterization of included patients.

Source: Shekhar Patil M, Richter E, Fanning L, Hendrix J, Wyns A, Barrero Santiago L, Nijs J, Godderis L, Polli A. Epigenetic changes in patients with post-acute COVID-19 symptoms (PACS) and long-COVID: A systematic review. Expert Rev Mol Med. 2024 Oct 22;26:e29. doi: 10.1017/erm.2024.32. PMID: 39435694. https://www.cambridge.org/core/journals/expert-reviews-in-molecular-medicine/article/epigenetic-changes-in-patients-with-postacute-covid19-symptoms-pacs-and-longcovid-a-systematic-review/BCF992CF0E491FC0AD0FEDC3A8AFFD4B (Full text)

Assessment of the therapeutic potential of salubrinal for ME/CFS and long-COVID

Highlights:

  • Long-COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are enigmatic diseases sharing many characteristics.
  • The most debilitating aspects of these diseases are cognitive dysfunction, ‘brain fog’, and exercise intolerance, ‘post-exertional malaise’.
  • There is no cure for these diseases; treatment is palliative only.
  • Mitochondrial dysfunction with endoplasmic reticulum (ER) stress occurs in both diseases.
  • Salubrinal inhibits the phosphatase that dephosphorylates phospho-eukaryotic initiation factor-2α (peIF2α), a protective protein for cells undergoing ER stress when phosphorylated.
  • Salubrinal reduces the formation of Wiskott–Aldrich syndrome protein family member 3 (WASF3), a protein that causes mitochondrial dysfunction that is overexpressed in a cohort of ME/CFS patients.
  • Salubrinal reduces WASF3 expression, restoring mitochondrial function in fibroblasts of a patient with ME/CFS.

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic debilitating condition with no cure that shares commonality with long-COVID.

This review examines current understanding of long-COVID symptoms, characteristics of the affected population, the connection with ME/CFS, and the potential for salubrinal, an agent known for its influence on cellular stress pathways, to mitigate these disorders.

It also describes the historical development and mechanism of action of salubrinal, to mitigate endoplasmic reticulum (ER)/cellular stress responses, that could potentially contribute to symptom improvement in both ME/CFS and long-COVID patients.

Further research and clinical trials are warranted to advance our understanding of the potential role of salubrinal in improving the quality of life for individuals with long-COVID-related ME/CFS symptoms as well as ME/CFS patients.

Source: Aseel Warrayat, Ayah Ali, Joulin Waked, Darcy Tocci, Robert C. Speth. Assessment of the therapeutic potential of salubrinal for ME/CFS and long-COVID. Trends in Molecular Medicine, 2024. ISSN 1471-4914, https://doi.org/10.1016/j.molmed.2024.10.001. https://www.sciencedirect.com/science/article/abs/pii/S1471491424002685

Immune exhaustion in ME/CFS and long COVID

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are debilitating multisystemic conditions sharing similarities in immune dysregulation and cellular signaling pathways contributing to the pathophysiology. In this study, immune exhaustion gene expression was investigated in participants with ME/CFS or long COVID concurrently.

RNA was extracted from peripheral blood mononuclear cells isolated from participants with ME/CFS (n = 14), participants with long COVID (n = 15), and healthy controls (n = 18). Participants with ME/CFS were included according to Canadian Consensus Criteria. Participants with long COVID were eligible according to the case definition for “Post COVID-19 Condition” published by the World Health Organization. RNA was analyzed using the NanoString nCounter Immune Exhaustion gene expression panel.

Differential gene expression analysis in ME/CFS revealed downregulated IFN signaling and immunoglobulin genes, and this suggested a state of immune suppression. Pathway analysis implicated dysregulated macrophage activation, cytokine production, and immunodeficiency signaling.

Long COVID samples exhibited dysregulated expression of genes regarding antigen presentation, cytokine signaling, and immune activation. Differentially expressed genes were associated with antigen presentation, B cell development, macrophage activation, and cytokine signaling.

This investigation elucidates the intricate role of both adaptive and innate immune dysregulation underlying ME/CFS and long COVID, emphasizing the potential importance of immune exhaustion in disease progression.

Source: Natalie Eaton-Fitch, Penny Rudd, Teagan Er, Livia Hool, Lara Herrero, and Sonya Marshall-Gradisnik. Immune exhaustion in ME/CFS and long COVID. JCI Insight. 2024;9(20):e183810. https://doi.org/10.1172/jci.insight.183810. https://insight.jci.org/articles/view/183810 (Full text)

Hypothalamus Connectivity in Adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling illness of unknown etiology. Increasing evidence suggests hypothalamic involvement in ME/CFS pathophysiology, which has rarely been explored using magnetic resonance imaging (MRI) in the condition. This work aimed to use MRI to examine hypothalamus connectivity in adolescents with ME/CFS and explore how this relates to fatigue severity and illness duration.

25 adolescents with ME/CFS and 23 healthy controls completed a neuroimaging protocol consisting of structural and multishell diffusion-weighted imaging sequences, in addition to the PedsQL Multidimensional Fatigue Scale to assess fatigue severity. Information about illness duration was acquired at diagnosis. Preprocessing and streamlines tractography was performed using QSIPrep combined with a custom parcellation scheme to create structural networks. The number (degree) and weight (strength) of connections between lateralized hypothalamus regions and cortical and subcortical nodes were extracted, and relationships between connectivity measures, fatigue severity, and illness duration were performed using Bayesian regression models.

We observed weak-to-moderate evidence of increased degree, but not strength, of connections from the bilateral anterior-inferior (left: pd [%] = 99.18, median [95% CI] = -22.68[-40.96 to 4.45]; right: pd [%] = 99.86, median [95% CI] = -23.35[-38.47 to 8.20]), left anterior-superior (pd [%] = 99.33, median [95% CI] = -18.83[-33.45 to 4.07]) and total left hypothalamus (pd [%] = 99.44, median [95% CI] = -47.18[-83.74 to 11.03]) in the ME/CFS group compared with controls. Conversely, bilateral posterior hypothalamus degree decreased with increasing ME/CFS illness duration (left: pd [%] = 98.13, median [95% CI]: -0.47[-0.89 to 0.03]; right: pd [%] = 98.50, median [95% CI]:-0.43[-0.82 to 0.05]).

Finally, a weak relationship between right intermediate hypothalamus connectivity strength and fatigue severity was identified in the ME/CFS group (pd [%] = 99.35, median [95% CI] = -0.28[-0.51 to 0.06]), which was absent in controls. These findings suggest changes in hypothalamus connectivity may occur in adolescents with ME/CFS, warranting further investigation.

Source: Byrne H, Knight SJ, Josev EK, Scheinberg A, Beare R, Yang JYM, Oldham S, Rowe K, Seal ML. Hypothalamus Connectivity in Adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J Neurosci Res. 2024 Oct;102(10):e25392. doi: 10.1002/jnr.25392. PMID: 39431934. https://onlinelibrary.wiley.com/doi/10.1002/jnr.25392 (Full text(

Chronic Overlapping Pain Conditions in people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a sample from the Multi-site Clinical Assessment of ME/CFS (MCAM) study

Abstract:

Background: Chronic overlapping pain conditions (COPCs), pain-related conditions that frequently occur together, may occur in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and could impact illness severity. This study aimed to identify comorbid COPCs in patients with ME/CFS and evaluate their impact on illness severity.

Methods: We used data from 923 participants in the Multi-Site Clinical Assessment of ME/CFS study, conducted in seven U.S. specialty clinics between 2012 and 2020, who completed the baseline assessment (595 ME/CFS and 328 healthy controls (HC)). COPCs included chronic low back pain (cLBP), chronic migraine/headache (cMHA), fibromyalgia (FM), interstitial cystitis/irritable bladder (IC/IB), irritable bowel syndrome (IBS), temporomandibular disorder (TMD). Illness severity was assessed through questionnaires measuring symptoms and functioning. Multivariate analysis of variance and analysis of covariance models were used for analyses. Log-binomial regression analyses were used to compute prevalence of COPCs and prevalence ratios (PR) between groups with 95% confidence intervals. Both unadjusted and adjusted results with age and sex are presented.

Results: 76% of participants with ME/CFS had at least one COPCs compared to 17.4% of HC. Among ME/CFS participants, cMHA was most prevalent (48.1%), followed by FM (45.0%), cLBP (33.1%), and IBS (31.6%). All individual COPCs, except TMD, were significantly more frequent in females than males. The unadjusted PR (ME/CFS compared to HC) was highest for FM [147.74 (95% confidence interval (CI) = 20.83-1047.75], followed by cLBP [39.45 (12.73-122.27)], and IC/IB [13.78 (1.88-101.24)]. The significance and order did not change after age and sex adjustment. The COPC comorbidities of cLBP and FM each had a significant impact on most health measures, particularly in pain attributes (Cohen’s d effect size 0.8 or larger). While the impact of COPC comorbidities on non-pain attributes and quality of life measures was less pronounced than that on pain, statistically significant differences between ME/CFS participants with and without COPCs were still evident.

Conclusions: More than 75% of ME/CFS participants had one or more COPCs. Multiple COPCs further exacerbated illness severity, especially among females with ME/CFS. Assessment and management of COPCs may help improve the health and quality of life for patients with ME/CFS.

Source: Fall EA, Chen Y, Lin JS, Issa A, Brimmer DJ, Bateman L, Lapp CW, Podell RN, Natelson BH, Kogelnik AM, Klimas NG, Peterson DL, Unger ER; MCAM Study Group. Chronic Overlapping Pain Conditions in people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a sample from the Multi-site Clinical Assessment of ME/CFS (MCAM) study. BMC Neurol. 2024 Oct 18;24(1):399. doi: 10.1186/s12883-024-03872-0. PMID: 39425035; PMCID: PMC11488184. https://pmc.ncbi.nlm.nih.gov/articles/PMC11488184/ (Full text)

Naturally acquired adaptive immunity to Streptococcus pneumoniae is impaired in rheumatoid arthritis patients

Abstract:

Objectives: Patients with rheumatoid arthritis (RA) have an increased susceptibility to infections, including those caused by Streptococcus pneumoniae. Why RA is associated with increased susceptibility to S. pneumoniae is poorly understood. This study aims to assess the effects of RA and B-cell depletion therapy on naturally acquired antibody responses to 289 S. pneumoniae protein antigens using a novel protein array.

Methods: IgG responses to S. pneumoniae were characterised in serum from RA patients and disease controls (myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)) using whole-cell ELISA, a flow cytometry opsonisation assay and an S. pneumoniae protein array. For the RA patients, results were compared before and after B-cell depletion therapy.

Results: Compared to a well-characterised disease control group of ME/CFS patients, RA patients had reduced antibody responses to multiple S. pneumoniae protein antigens, with significant IgG recognition of approximately half the number of antigens along with reduced median strengths of these responses. Reduction in multiple array antigen-specific responses also correlated with reduced IgG opsonisation of S. pneumoniae. Although B-cell depletion therapy with rituximab did not reduce overall IgG recognition of S. pneumoniae in the RA group, it was associated with marked disruption of pre-existing IgG repertoire to protein antigens in individual patients.

Conclusion: These data show RA is associated with major disruption of naturally acquired adaptive immunity to S. pneumoniae, which can be assessed rapidly using a protein antigen array and is likely to contribute towards the increased incidence of pneumonia in patients with RA.

Source: Ercoli G, Selway-Clarke H, Truijen D, Folkmanaite M, Oulton T, Norris-Grey C, Nakajima R, Felgner P, Wren BW, Tetteh K, Croucher NJ, Leandro M, Cambridge G, Brown JS. Naturally acquired adaptive immunity to Streptococcus pneumoniae is impaired in rheumatoid arthritis patients. Clin Transl Immunology. 2024 Oct 15;13(10):e70012. doi: 10.1002/cti2.70012. PMID: 39416767; PMCID: PMC11480415. https://pmc.ncbi.nlm.nih.gov/articles/PMC11480415/ (Full text)

This Is CFS Art Launches Online Exhibit Showcasing Artists Living with CFS/ME

[Swansea, NSW, Australia] – [3 October] – This Is CFS Art is excited to announce the launch of its new website, thisiscfs.art, a unique online space dedicated to showcasing the incredible work of artists who live with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). This online exhibit aims to highlight the resilience and creativity of these artists, offering a meaningful outlet for their voices and stories.

CFS/ME affects millions globally, yet they tend to feel invisible. The invisibility applies to both the range of symptoms that are usually not obvious for outsiders but can be very debilitating, and the fact that CFS/ME sufferers often ‘drop out’ of their life and become invisible to society. This Is CFS Art seeks to change that by providing a way to show what it means to live with CFS/ME in a variety artworks submitted by a range of artists.

“I am committed to amplifying the voices of artists who live with CFS/ME,” said Zoe Wright, Founder of This is CFS Art. “Through this platform, I hope to make visible both the disease itself and the people living with it. At the same time, this exhibit celebrates the resilience and creativity of these artists.”

Founder Zoe Wright lives with CFS/ME herself and has found art a helpful way to express the feelings and experiences of living with a chronic condition that is so little understood.

Visit thisiscfs.art today to explore the powerful artistic expressions of those living with CFS/ME. Artists living with the condition are invited to submit their own artwork through the website.

About CFS Art: CFS Art is dedicated to showcasing the work of contemporary artists who live with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. Through this platform, CFS Art seeks to raise awareness of the condition and celebrate the incredible talent and creativity of those affected.

For more information, please visit thisiscfs.art

-Zoe Wright

Contact: Zoe Wright
Founder
www.thisiscfs.art

Six-Week Supplementation with Creatine in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Magnetic Resonance Spectroscopy Feasibility Study at 3 Tesla

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic medical condition with no specific pharmacological treatment. Creatine, a nutrient essential for maintaining energy homeostasis in the cells, is a candidate for interventions in ME/CFS.

Methods: Fourteen participants with ME/CFS received supplementation with 16 g creatine monohydrate for 6 weeks. Before starting creatine and on the last day of treatment, participants underwent brain magnetic resonance spectroscopy (MRS) scanning of the pregenual anterior cingulate cortex (pgACC) and dorsolateral prefrontal cortex (DLPFC), followed by symptom, cognition, and hand-grip strength assessments.

Results: Eleven participants completed the study. Creatine treatment increased creatine concentration in both the pgACC and DLPFC (p = 0.004 and 0.012, respectively), decreased fatigue and reaction time (RT) on congruent and incongruent trials of the Stroop test (p = 0.036 and 0.014, respectively), and increased hand-grip strength (p = 0.0004). There was a positive correlation between increases in pgACC creatine and changes in RT on Stroop congruent and incongruent trials (p = 0.048 and p = 0.022, respectively). Creatine was well tolerated, and none of the participants stopped treatment.

Conclusion: Creatine supplementation over six weeks in ME/CFS patients increased brain creatine and improved fatigue and some aspects of cognition. Despite its methodological limitations, this study encourages placebo-controlled investigations of creatine treatment in ME/CFS.

Source: Godlewska BR, Sylvester AL, Emir UE, Sharpley AL, Clarke WT, Martens MAG, Cowen PJ. Six-Week Supplementation with Creatine in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Magnetic Resonance Spectroscopy Feasibility Study at 3 Tesla. Nutrients. 2024 Sep 30;16(19):3308. doi: 10.3390/nu16193308. PMID: 39408275. https://www.mdpi.com/2072-6643/16/19/3308 (Full text)

Immunometabolic changes and potential biomarkers in CFS peripheral immune cells revealed by single-cell RNA sequencing

Abstract:

The pathogenesis of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains unclear, though increasing evidence suggests inflammatory processes play key roles. In this study, single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) was used to decipher the immunometabolic profile in 4 ME/CFS patients and 4 heathy controls.

We analyzed changes in the composition of major PBMC subpopulations and observed an increased frequency of total T cells and a significant reduction in NKs, monocytes, cDCs and pDCs. Further investigation revealed even more complex changes in the proportions of cell subpopulations within each subpopulation. Gene expression patterns revealed upregulated transcription factors related to immune regulation, as well as genes associated with viral infections and neurodegenerative diseases.

CD4+ and CD8+ T cells in ME/CFS patients show different differentiation states and altered trajectories, indicating a possible suppression of differentiation. Memory B cells in ME/CFS patients are found early in the pseudotime, indicating a unique subtype specific to ME/CFS, with increased differentiation to plasma cells suggesting B cell overactivity. NK cells in ME/CFS patients exhibit reduced cytotoxicity and impaired responses, with reduced expression of perforin and CD107a upon stimulation. Pseudotime analysis showed abnormal development of adaptive immune cells and an enhanced cell-cell communication network converging on monocytes in particular.

Our analysis also identified the estrogen-related receptor alpha (ESRRA)-APP-CD74 signaling pathway as a potential biomarker for ME/CFS in peripheral blood. In addition, data from the GSE214284 database confirmed higher ESRRA expression in the monocyte cell types of male ME/CFS patients. These results suggest a link between immune and neurological symptoms.

The results support a disease model of immune dysfunction ranging from autoimmunity to immunodeficiency and point to amyloidotic neurodegenerative signaling pathways in the pathogenesis of ME/CFS. While the study provides important insights, limitations include the modest sample size and the evaluation of peripheral blood only.

These findings highlight potential targets for diagnostic biomarkers and therapeutic interventions. Further research is needed to validate these biomarkers and explore their clinical applications in managing ME/CFS.

Source: Sun Y, Zhang Z, Qiao Q, Zou Y, Wang L, Wang T, Lou B, Li G, Xu M, Wang Y, Zhang Z, Hou X, Chen L, Zhao R. Immunometabolic changes and potential biomarkers in CFS peripheral immune cells revealed by single-cell RNA sequencing. J Transl Med. 2024 Oct 11;22(1):925. doi: 10.1186/s12967-024-05710-w. PMID: 39394558. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-05710-w (Full text)