Tag: 2023

Sex differences in vascular endothelial function related to acute and long COVID-19

Abstract:

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has been at the forefront of health sciences research since its emergence in China in 2019 that quickly led to a global pandemic. As a result of this research, and the large numbers of infected patients globally, there were rapid enhancements made in our understanding of Coronavirus disease 2019 (COVID-19) pathology, including its role in the development of uncontrolled immune responses and its link to the development of endotheliitis and endothelial dysfunction.

There were also some noted differences in the rate and severity of infection between males and females with acute COVID. Some individuals infected with SARS-CoV-2 also experience long-COVID, an important hallmark symptom of this being Myalgic Encephalomyelitis-Chronic Fatigue Syndrome (ME-CFS), also experienced differently between males and females.

The purpose of this review is to discuss the impact of sex on the vasculature during acute and long COVID-19, present any link between ME-CFS and endothelial dysfunction, and provide evidence for the relationship between ME-CFS and the immune system. We also will delineate biological sex differences observed in other post viral infections and, assess if sex differences exist in how the immune system responds to viral infection causing ME-CFS.

Source: Kayla KA, Bédard-Matteau J, Rousseau S, Tabrizchi R, Noriko D. Sex differences in vascular endothelial function related to acute and long COVID-19. Vascul Pharmacol. 2023 Dec 1:107250. doi: 10.1016/j.vph.2023.107250. Epub ahead of print. PMID: 38043758. https://www.sciencedirect.com/science/article/abs/pii/S1537189123001106 (Full text)

Mitochondrial Dysfunction and Coenzyme Q10 Supplementation in Post-Viral Fatigue Syndrome: An Overview

Abstract:

Post-viral fatigue syndrome (PVFS) encompasses a wide range of complex neuroimmune disorders of unknown cause characterized by disabling post-exertional fatigue, myalgia and joint pain, cognitive impairments, unrefreshing sleep, autonomic dysfunction, and neuropsychiatric symptoms. It includes myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), and more recently post-COVID-19 condition (Long COVID).

To date, there are no definitive clinical case criteria and no FDA-approved pharmacological therapies for PVFS. Given the current lack of effective treatments, there is a need to develop novel therapeutic strategies for these disorders.

Mitochondria, the cellular organelles responsible for tissue energy production, have recently garnered attention in research into PVFS due to their crucial role in cellular bioenergetic metabolism in these conditions. Accumulating literature has identified a link between mitochondrial dysfunction and low-grade systemic inflammation in ME/CFS, FM, and Long COVID.

To address this issue, this article aimed to critically review the evidence relating to mitochondrial dysfunction in the pathogenesis of these disorders; in particular, to evaluate the effectiveness of coenzyme Q10 supplementation on chronic fatigue and pain symptoms as a novel therapeutic strategy for the treatment of PVFS.

Source: Mantle, D.; Hargreaves, I.P.; Domingo, J.C.; Castro-Marrero, J. Mitochondrial Dysfunction and Coenzyme Q10 Supplementation in Post-Viral Fatigue Syndrome: An Overview. Preprints 2023, 2023111554. https://doi.org/10.20944/preprints202311.1554.v1 https://www.preprints.org/manuscript/202311.1554/v1 (Full text available as PDF file)

Post-exertional malaise in daily life and experimental exercise models in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Post-exertional malaise (PEM) is commonly recognized as a hallmark of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and is often used as one of several criteria for diagnosing ME/CFS.

In this perspective paper we want to reflect on how PEM is understood, assessed, and evaluated in scientific literature, and to identify topics to be addressed in future research.

Studies show that patients use a wide variety of words and concepts to label their experience of PEM in everyday life, and they report physical or mental exertions as triggers of PEM. They also report that PEM may have an immediate or delayed onset and may last from a few days to several months.

When standardized exercise tests are used to trigger PEM experimentally, the exacerbation of symptoms has a more immediate onset but still shows a wide variability in duration.

There are indications of altered muscular metabolism and autonomic nervous responses if exercise is repeated on successive days in patients with ME/CFS. The decreased muscular capacity appears to be maintained over several days following such controlled exercise bouts. These responses may correspond to patients’ experiences of increased exertion.

Based on this background we argue that there is a need to look more closely into the processes occurring in the restitution period following exercise, as PEM reaches the peak in this phase.

Source: Nina K. Vøllestad, Anne Marit Mengshoel. Post-exertional malaise in daily life and experimental exercise models in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Frontiers in Physiology, Volume 14- 2023. https://www.frontiersin.org/articles/10.3389/fphys.2023.1257557/abstract

Effects of traditional Chinese mind-body exercises for patients with chronic fatigue syndrome: A systematic review and meta-analysis

Abstract:

Background: Chronic fatigue syndrome (CFS) is a global public health concern. We performed this systematic review of randomised controlled trials (RCTs) to evaluate the effects and safety of traditional Chinese mind-body exercises (TCME) for patients with CFS.

Methods: We comprehensively searched MEDLINE, Embase, Web of Science, PsycINFO, Cochrane Library, CNKI, VIP databases, and Wanfang Data from inception to October 2022 for eligible RCTs of TCME for CFS management. We used Cochran’s Q statistic and I2 to assess heterogeneity and conducted subgroup analyses based on different types of TCME, background therapy, and types of fatigue. We also assessed the quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach.

Results: We included 13 studies (n = 1187) with a maximal follow-up of 12 weeks. TCME included Qigong and Tai Chi. At the end of the treatment, compared with passive control, TCME probably reduces the severity of fatigue (standardised mean differences (SMD) = 0.85; 95% confidence interval (CI) = 0.64, 1.07, moderate certainty), depression (SMD = 0.53; 95% CI = 0.34, 0.72, moderate certainty), anxiety (SMD = 0.29; 95% CI = 0.11, 0.48, moderate certainty), sleep quality (SMD = 0.34; 95% CI = 0.10, 0.57, low certainty) and mental functioning (SMD = 0.90; 95% CI = 0.50, 1.29, low certainty).

Compared with other active control therapies, TCME results in little to no difference in the severity of fatigue (SMD = 0.08; 95% CI = -0.18, 0.34, low certainty). For long-term outcomes, TCME may improve anxiety (SMD = 1.74; 95% CI = 0.44, 3.03, low certainty) compared to passive control. We did not identify TCME-related serious adverse events.

Conclusions: In patients with CFS, TCME probably reduces post-intervention fatigue, depression, and anxiety and may improve sleep quality and mental function compared with passive control, but has limited long-term effects. These findings will help health professionals and patients with better clinical decision-making.

Source: Kong L, Ren J, Fang S, Li Y, Wu Z, Zhou X, Hao Q, Fang M, Zhang YQ. Effects of traditional Chinese mind-body exercises for patients with chronic fatigue syndrome: A systematic review and meta-analysis. J Glob Health. 2023 Nov 24;13:04157. doi: 10.7189/jogh.13.04157. PMID: 37994837; PMCID: PMC10666566. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10666566/ (Full text)

DNA Methylation Changes in Blood Cells of Fibromyalgia and Chronic Fatigue Syndrome Patients

Abstract:

Purpose: Fibromyalgia (FM) and Chronic Fatigue Syndrome (CFS) affect 0.4% and 1% of society, respectively, and the prevalence of these pain syndromes is increasing. To date, no strong association between these syndromes and the genetic background of affected individuals has been shown. Therefore, it is plausible that epigenetic changes might play a role in the development of these syndromes.

Patients and Methods: Three previous studies have attempted to elaborate the involvement of genome-wide methylation changes in blood cells in the development of fibromyalgia and chronic fatigue syndrome. These studies included 22 patients with fibromyalgia and 127 patients with CFS, and the results of the studies were largely discrepant. Contradicting results of those studies may be attributed to differences in the omics data analysis approaches used in each study. We reanalyzed the data collected in these studies using an updated and coherent data-analysis framework.

Results: Overall, the methylation changes that we observed overlapped with previous results only to some extent. However, the gene set enrichment analyses based on genes annotated to methylation changes identified in each of the analyzed datasets were surprisingly coherent and uniformly associated with the physiological processes that, when affected, may result in symptoms characteristic of fibromyalgia and chronic fatigue syndrome

Conclusion: Methylomes of the blood cells of patients with FM and CFS in three independent studies have shown methylation changes that appear to be implicated in the pathogenesis of these syndromes.

Source: Przybylowicz PK, Sokolowska KE, Rola H, Wojdacz TK. DNA Methylation Changes in Blood Cells of Fibromyalgia and Chronic Fatigue Syndrome Patients. J Pain Res. 2023;16:4025-4036 https://doi.org/10.2147/JPR.S439412 https://www.dovepress.com/dna-methylation-changes-in-blood-cells-of-fibromyalgia-and-chronic-fat-peer-reviewed-fulltext-article-JPR (Full text)

Brain-regional characteristics and neuroinflammation in ME/CFS patients from neuroimaging: A systematic review and meta-analysis

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition characterized by an elusive etiology and pathophysiology. This study aims to evaluate the pathological role of neuroinflammation in ME/CFS by conducting an exhaustive analysis of 65 observational studies.

Four neuroimaging techniques, including magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), electroencephalography (EEG), and positron emission tomography (PET), were employed to comparatively assess brain regional structure, metabolite profiles, electrical activity, and glial activity in 1529 ME/CFS patients (277 males, 1252 females) and 1715 controls (469 males, 1246 females). Clinical characteristics, including sex, age, and fatigue severity, were consistent with established epidemiological patterns.

Regional alterations were most frequently identified in the cerebral cortex, with a notable focus on the frontal cortex. However, our meta-analysis data revealed a significant hypoactivity in the insular and thalamic regions, contrary to observed frequencies. These abnormalities, occurring in pivotal network hubs bridging reason and emotion, disrupt connections with the limbic system, contributing to the hallmark symptoms of ME/CFS.

Furthermore, we discuss the regions where neuroinflammatory features are frequently observed and address critical neuroimaging limitations, including issues related to inter-rater reliability. This systematic review serves as a valuable guide for defining regions of interest (ROI) in future neuroimaging investigations of ME/CFS

Source: Lee JS, Sato W, Son CG. Brain-regional characteristics and neuroinflammation in ME/CFS patients from neuroimaging: A systematic review and meta-analysis. Autoimmun Rev. 2023 Nov 26:103484. doi: 10.1016/j.autrev.2023.103484. Epub ahead of print. PMID: 38016575. https://www.sciencedirect.com/science/article/pii/S1568997223002185 (Full text)

Dysregulation of the Kynurenine Pathway, Cytokine Expression Pattern, and Proteomics Profile Link to Symptomology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Dysregulation of the kynurenine pathway (KP) is believed to play a significant role in neurodegenerative and cognitive disorders. While some evidence links the KP to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), further studies are needed to clarify the overall picture of how inflammation-driven KP disturbances may contribute to symptomology in ME/CFS.

Here, we report that plasma levels of most bioactive KP metabolites differed significantly between ME/CFS patients and healthy controls in a manner consistent with their known contribution to symptomology in other neurological disorders. Importantly, we found that enhanced production of the first KP metabolite, kynurenine (KYN), correlated with symptom severity, highlighting the relationship between inflammation, KP dysregulation, and ME/CFS symptomology.

Other significant changes in the KP included lower levels of the downstream KP metabolites 3-HK, 3-HAA, QUIN, and PIC that could negatively impact cellular energetics. We also rationalized KP dysregulation to changes in the expression of inflammatory cytokines and, for the first time, assessed levels of the iron (Fe)-regulating hormone hepcidin that is also inflammation-responsive. Levels of hepcidin in ME/CFS decreased nearly by half, which might reflect systemic low Fe levels or possibly ongoing hypoxia.

We next performed a proteomics screen to survey for other significant differences in protein expression in ME/CFS. Interestingly, out of the seven most significantly modulated proteins in ME/CFS patient plasma, 5 proteins have roles in maintaining gut health, which considering the new appreciation of how gut microbiome and health modulates systemic KP could highlight a new explanation of symptomology in ME/CFS patients and potential new prognostic biomarker/s and/or treatment avenues.

Source: Kavyani B, Ahn SB, Missailidis D, Annesley SJ, Fisher PR, Schloeffel R, Guillemin GJ, Lovejoy DB, Heng B. Dysregulation of the Kynurenine Pathway, Cytokine Expression Pattern, and Proteomics Profile Link to Symptomology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Mol Neurobiol. 2023 Nov 28. doi: 10.1007/s12035-023-03784-z. Epub ahead of print. PMID: 38015302. https://pubmed.ncbi.nlm.nih.gov/38015302/

Catalytic Antibodies May Contribute to Demyelination in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Here we report preliminary data demonstrating that some patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may have catalytic autoantibodies that cause the breakdown of myelin basic protein (MBP). We propose that these MBP-degradative antibodies are important to the pathophysiology of ME/CFS, particularly in the occurrence of white matter disease/demyelination. This is supported by magnetic resonance imagining studies that show these findings in patients with ME/CFS and could explain symptoms of nerve pain and muscle weakness.

In this work, we performed a series of experiments on patient plasma samples where we isolated and characterized substrate-specific antibodies that digest MBP. We also tested glatiramer acetate (copaxone), an FDA approved immunomodulator to treat multiple sclerosis, and found that it inhibits ME/CFS antibody digestion of MBP. Furthermore, we found that aprotinin, which is a specific serine protease inhibitor, specifically prevents breakdown of MBP while the other classes of protease inhibitors had no effect. This coincides with the published literature describing catalytic antibodies as having serine protease-like activity. Postpandemic research has also provided several reports of demyelination in COVID-19.

Because COVID-19 has been described as a trigger for ME/CFS, demyelination could play a bigger role in patient symptoms for those recently diagnosed with ME/CFS. Therefore, by studying proteolytic antibodies in ME/CFS, their target substrates, and inhibitors, a new mechanism of action could lead to better treatment and a possible cure for the disease.

Source: Jensen MA, Dafoe ML, Wilhelmy J, Cervantes L, Okumu AN, Kipp L, Nemat-Gorgani M, Davis RW. Catalytic Antibodies May Contribute to Demyelination in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Biochemistry. 2023 Nov 27. doi: 10.1021/acs.biochem.3c00433. Epub ahead of print. PMID: 38011893. https://pubs.acs.org/doi/10.1021/acs.biochem.3c00433 (Full text)

Chronic Fatigue and Dysautonomia following COVID-19 Vaccination Is Distinguished from Normal Vaccination Response by Altered Blood Markers

Abstract:

SARS-CoV-2 mRNA vaccination can entail chronic fatigue/dysautonomia tentatively termed post-acute COVID-19 vaccination syndrome (PACVS). We explored receptor autoantibodies and interleukin-6 (IL-6) as somatic correlates of PACVS. Blood markers determined before and six months after first-time SARS-CoV-2 vaccination of healthy controls (N = 89; 71 females; mean/median age: 39/49 years) were compared with corresponding values of PACVS-affected persons (N = 191; 159 females; mean/median age: 40/39 years) exhibiting chronic fatigue/dysautonomia (≥three symptoms for ≥five months after the last SARS-CoV-2 mRNA vaccination) not due to SARS-CoV-2 infection and/or confounding diseases/medications.

Normal vaccination response encompassed decreases in 11 receptor antibodies (by 25-50%, p < 0.0001), increases in two receptor antibodies (by 15-25%, p < 0.0001) and normal IL-6. In PACVS, serological vaccination-response appeared significantly (p < 0.0001) altered, allowing discrimination from normal post-vaccination state (sensitivity = 90%, p < 0.0001) by increased Angiotensin II type 1 receptor antibodies (cut-off ≤ 10.7 U/mL, ROC-AUC = 0.824 ± 0.027), decreased alpha-2B adrenergic receptor antibodies (cut-off ≥ 25.2 U/mL, ROC-AUC = 0.828 ± 0.025) and increased IL-6 (cut-off ≤ 2.3 pg/mL, ROC-AUC = 0.850 ± 0.022). PACVS is thus indicated as a somatic syndrome delineated/detectable by diagnostic blood markers.

Source: Semmler A, Mundorf AK, Kuechler AS, Schulze-Bosse K, Heidecke H, Schulze-Forster K, Schott M, Uhrberg M, Weinhold S, Lackner KJ, Pawlitzki M, Meuth SG, Boege F, Ruhrländer J. Chronic Fatigue and Dysautonomia following COVID-19 Vaccination Is Distinguished from Normal Vaccination Response by Altered Blood Markers. Vaccines (Basel). 2023 Oct 26;11(11):1642. doi: 10.3390/vaccines11111642. PMID: 38005974. https://www.mdpi.com/2076-393X/11/11/1642 (Full text)

IgG Antibody Responses to Epstein-Barr Virus in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Their Effective Potential for Disease Diagnosis and Pathological Antigenic Mimicry

Abstract:

The diagnosis and the pathology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) remain under debate. However, there is a growing body of evidence for an autoimmune component in ME/CFS caused by the Epstein-Barr virus (EBV) and other viral infections.
In this work, we took advantage of a large public dataset on the IgG antibodies to 3,054 EBV peptides to understand whether these immune responses could be used as putative biomarkers for disease diagnosis and triggers of pathological autoimmunity in ME/CFS patients using healthy controls (HCs) as a comparator cohort. We then aimed at predicting disease status of study participants using a Super Learner algorithm targeting an accuracy of 85% when splitting data into train and test datasets.
When we compared data of all ME/CFS patients or data of a subgroup of these patients with non-infectious or unknown disease trigger to the dataset of HC, we could not find an antibody-based classifier that would meet the desired accuracy in the test dataset. In contrast, we could identify a 26-antibody classifier that could distinguish ME/CFS patients with an infectious disease trigger from HCs with 100% and 90% accuracies on the train and test sets, respectively.
We finally performed a bioinformatic analysis of the EBV peptides associated with these 26 antibodies. We found no correlation between the importance metric of the selected antibodies in the classifier and the maximal sequence homology between human proteins and each EBV peptide recognized by these antibodies.
In conclusion, these 26 antibodies against EBV have an effective potential for disease diagnosis of a subset of patients, but they are less likely to trigger pathological autoimmune responses that could explain the pathogenesis of ME/CFS.
Source: Fonseca, A.; Szysz, M.; Ly, H.T.; Cordeiro, C.; Sepúlveda, N. IgG Antibody Responses to Epstein-Barr Virus in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Their Effective Potential for Disease Diagnosis and Pathological Antigenic Mimicry. Preprints 2023, 2023111523. https://doi.org/10.20944/preprints202311.1523.v1 https://www.preprints.org/manuscript/202311.1523/v1 (Full text available as PDF file)