Exploring the Joint Potential of Inflammation, Immunity, and Receptor-Based Biomarkers for Evaluating ME/CFS Progression

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic condition with no identified diagnostic biomarkers to date. Its prevalence is as high as 0.89% according to metastudies, with a quarter of patients bed-or home-bound, which presents a serious public health challenge. Investigations into the inflammation-immunity axis is encouraged by links to outbreaks and disease waves. Recently, research of our group revealed that antibodies to beta2adrenergic (anti-β2AdR) and muscarinic acetylcholine (anti-M4) receptors demonstrate sensitivity to the progression of ME/CFS.

The purpose of this study is to investigate the joint potential of inflammatome -characterized by interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, IL-21, Il-23, IL-6, IL-17A, Activin-B, immunome (IgG1, IgG2, IgG3, IgG4, IgM, IgA) and receptor-based biomarkers (anti-M3, anti-M4, anti-β2AdR) determined for evaluating ME/CFS progression, and to identify an optimal selection for future validation in prospective clinical studies.

Methods: A dataset was used originating from 188 persons, including 54 healthy controls, 30 patients classified as “mild” by severity, 73 as “moderate,” and 31 as “severe,” clinically assessed by Fukuda/CDC 1994 and International consensus criteria. Markers characterizing inflammatome, immunome, and receptor-based biomarkers were determined in blood plasma via ELISA and multiplex methods.

Statistical analysis was done via correlation analysis, principal component, and linear discriminant analysis, and random forest classification; inter-group differences tested via nonparametric Kruskal-Wallis H test followed by the two-stage linear step-up procedure of Benjamini, Krieger, and Yekutieli, and via Mann-Whitney U test.

The association between inflammatome and immunome markers is broader and stronger (coupling) in severe group. Principal component factoring separate components affiliated with inflammatome, immunome, and receptor biomarkers. Random forest modeling demonstrates an out-of-box accuracy for splitting healthy/with condition groups of over 90%, and of 45% for healthy/severity groups. Classifiers with the highest potential are anti-β2AdR, anti-M4, IgG4, IL-2, and IL-6.

Discussion: Association between inflammatome and immunome markers is a candidate for controlled clinical study of ME/CFS progression markers that could be used for treatment individualization. Thus, coupling effects between inflammation and immunity have a potential for the identification of prognostic factors in the context of ME/CFS progression mechanism studies.

Source: Uldis Berkis, Simons Svirskis, Angelika Krumina, Sabine Gravelsina, Anda Vilmane, Diana Araja, Zaiga Nora-Krukle, Modra Murovska. Exploring the Joint Potential of Inflammation, Immunity, and Receptor-Based Biomarkers for Evaluating ME/CFS Progression. Frontiers in Immunology. Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders. Volume 14- 2023.  https://www.frontiersin.org/articles/10.3389/fimmu.2023.1294758/abstract

An international survey of experiences and attitudes towards transcutaneous auricular vagus nerve stimulation for people with Myalgic Encephalomyelitis/chronic fatigue syndrome

Abstract:

Background and objectives: Myalgic encephalomyelitis (ME) is a complex, multi-system neurological condition. Dysfunction of the autonomic nervous system is a primary feature in diagnostic criteria, and management may include attempts to stimulate the parasympathetic nervous system. Transcutaneous auricular vagus nerve stimulation is an intervention that has been researched in neurological disorders, e.g. epilepsy, depression. While little evidence exists for its use in ME, this survey aims to explore the experiences and attitudes of people with ME to this intervention.

Methods: A 31-question online survey was devised and released on ME websites, Twitter and Facebook pages. People with ME read the information sheet and followed an online link to the survey. The survey was open for four weeks and all answers were anonymous.

Results: 116 responses were received. 56% of respondents reported favourable effects. Benefits of transcutaneous auricular vagus nerve stimulation were identified in relation to post exertional malaise, pain, gut problems, urinary problems, mental health, and the ability to leave the house. 67.2% of respondents would recommend the intervention to other people with ME. However, 4.3% would not recommend it and 6% reported it made them worse. 8.6% received support in setting up the device from healthcare workers.

Conclusion: The survey highlights that many people with ME experience significant benefits from using transcutaneous auricular vagus nerve stimulation; however due to potential negative effects there is the need for formal intervention studies to clearly identify safe parameters.

Source: Karen Leslie, Nicola Clague-Baker, Mohammad Abdelfattah Atallah Madi, Dawn Wiley, Andrea Parker, Michelle Bull & Natalie Hilliard. (2023) An international survey of experiences and attitudes towards transcutaneous auricular vagus nerve stimulation for people with Myalgic Encephalomyelitis/chronic fatigue syndrome, Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2023.2286029 https://www.tandfonline.com/doi/abs/10.1080/21641846.2023.2286029

Severe mental illness, race/ethnicity, multimorbidity and mortality following COVID-19 infection: nationally representative cohort study

Abstract:

Background: The association of COVID-19 with death in people with severe mental illness (SMI), and associations with multimorbidity and ethnicity, are unclear.

Aims: To determine all-cause mortality in people with SMI following COVID-19 infection, and assess whether excess mortality is affected by multimorbidity or ethnicity.

Method: This was a retrospective cohort study using primary care data from the Clinical Practice Research Database, from February 2020 to April 2021. Cox proportional hazards regression was used to estimate the effect of SMI on all-cause mortality during the first two waves of the COVID-19 pandemic.

Results: Among 7146 people with SMI (56% female), there was a higher prevalence of multimorbidity compared with the non-SMI control group (n = 653 024, 55% female). Following COVID-19 infection, the SMI group experienced a greater risk of death compared with controls (adjusted hazard ratio (aHR) 1.53, 95% CI 1.39-1.68). Black Caribbean/Black African people were more likely to die from COVID-19 compared with White people (aHR = 1.22, 95% CI 1.12-1.34), with similar associations in the SMI group and non-SMI group (P for interaction = 0.73). Following infection with COVID-19, for every additional multimorbidity condition, the aHR for death was 1.06 (95% CI 1.01-1.10) in the SMI stratum and 1.16 (95% CI 1.15-1.17) in the non-SMI stratum (P for interaction = 0.001).

Conclusions: Following COVID-19 infection, patients with SMI were at an elevated risk of death, further magnified by multimorbidity. Black Caribbean/Black African people had a higher risk of death from COVID-19 than White people, and this inequity was similar for the SMI group and the control group.

Source: Das-Munshi J, Bakolis I, Bécares L, Dyer J, Hotopf M, Ocloo J, Stewart R, Stuart R, Dregan A. Severe mental illness, race/ethnicity, multimorbidity and mortality following COVID-19 infection: nationally representative cohort study. Br J Psychiatry. 2023 Nov;223(5):518-525. doi: 10.1192/bjp.2023.112. PMID: 37876350; PMCID: PMC7615273. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7615273/ (Full text)

Immunological Patient Stratification in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease characterized by profound fatigue, post-exertional malaise (PEM), and neurocognitive dysfunction. Immune dysregulation and gastrointestinal symptoms are commonly observed in ME/CFS patients. Despite affecting approximately 0.89% of the general population, the underlying pathophysiological mechanisms remain poorly understood. This study aimed to elucidate the relationship between immunological characteristics and intestinal barrier function in ME/CFS patients.

ME/CFS patients were stratified into two groups based on their immune competence. After documentation of detailed medical records, serum and plasma samples were collected for assessment of inflammatory immune mediators and biomarkers for intestinal barrier integrity by ELISA. We found reduced complement protein C4a levels in immunodeficient ME/CFS patients suggesting a sub-group specific innate immune dysregulation. ME/CFS patients without immunodeficiencies exhibit a mucosal barrier leakage, as indicated by elevated levels of Lipopolysaccharide-binding protein (LBP).

Stratifying ME/CFS patients based on immune competence enabled the distinction of two subgroups with different pathophysiological patterns. The study highlights the importance of emphasizing precise patient stratification in ME/CFS, particularly in the context of defining suitable treatment strategies. Given the substantial health and socioeconomic burden associated with ME/CFS, urgent attention and research efforts are needed to define causative treatment approaches.

Source: Rohrhofer, J.; Hauser, L.; Lettenmaier, L.; Lutz, L.; Koidl, L.; Gentile, S.A.; Ret, D.; Stingl, M.; Untersmayr, E. Immunological Patient Stratification in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Preprints 2023, 2023112007. https://doi.org/10.20944/preprints202311.2007.v1 https://www.preprints.org/manuscript/202311.2007/v1 (Full text available as PDF file)

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)