Category: Pathophysiology

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back!

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) is a chronic multisystem illness of unconfirmed etiology. There are currently no biomarkers and/or signatures available to assist in the diagnosis of the syndrome and while numerous mechanisms have been hypothesized to explain the pathology of ME/CFS, the triggers and/or drivers remain unknown.

Initial studies suggested a potential role of the human herpesviruses especially Epstein-Barr virus (EBV) in the disease process but inconsistent and conflicting data led to the erroneous suggestion that these viruses had no role in the syndrome. New studies using more advanced approaches have now demonstrated that specific proteins encoded by EBV could contribute to the immune and neurological abnormalities exhibited by a subgroup of patients with ME/CFS. Elucidating the role of these herpesvirus proteins in ME/CFS may lead to the identification of specific biomarkers and the development of novel therapeutics.

Source: Ariza ME. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back! Biomolecules. 2021 Jan 29;11(2):185. doi: 10.3390/biom11020185. PMID: 33572802; PMCID: PMC7912523. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912523/ (Full text)

Genetic and epigenetic regulation of Catechol-O-methyltransferase in relation to inflammation in chronic fatigue syndrome and Fibromyalgia

Abstract:

Background: Catechol-O-methyltransferase (COMT) has been shown to influence clinical pain, descending modulation, and exercise-induced symptom worsening. COMT regulates nociceptive processing and inflammation, key pathophysiological features of Chronic Fatigue Syndrome and Fibromyalgia (CFS/FM). We aimed to determine the interactions between genetic and epigenetic mechanisms regulating COMT and its influence on inflammatory markers and symptoms in patients with CFS/FM.

Methods: A case-control study with repeated-measures design was used to reduce the chance of false positive and increase the power of our findings. Fifty-four participants (28 patients with CFS/FM and 26 controls) were assessed twice within 4 days. The assessment included clinical questionnaires, neurophysiological assessment (pain thresholds, temporal summation, and conditioned pain modulation), and blood withdrawal in order to assess rs4818, rs4633, and rs4680 COMT polymorphisms and perform haplotype estimation, DNA methylation in the COMT gene (both MB-COMT and S-COMT promoters), and cytokine expression (TNF-α, IFN-γ, IL-6, and TGF-β).

Results: COMT haplotypes were associated with DNA methylation in the S-COMT promoter, TGF-β expression, and symptoms. However, this was not specific for one condition. Significant between-group differences were found for increased DNA methylation in the MB-COMT promoter and decreased IFN-γ expression in patients.

Discussion: Our results are consistent with basic and clinical research, providing interesting insights into genetic-epigenetic regulatory mechanisms. MB-COMT DNA methylation might be an independent factor contributing to the pathophysiology of CFS/FM. Further research on DNA methylation in complex conditions such as CFS/FM is warranted. We recommend future research to employ a repeated-measure design to control for biomarkers variability and within-subject changes.

Source: Polli A, Hendrix J, Ickmans K, Bakusic J, Ghosh M, Monteyne D, Velkeniers B, Bekaert B, Nijs J, Godderis L. Genetic and epigenetic regulation of Catechol-O-methyltransferase in relation to inflammation in chronic fatigue syndrome and Fibromyalgia. J Transl Med. 2022 Oct 25;20(1):487. doi: 10.1186/s12967-022-03662-7. PMID: 36284330; PMCID: PMC9598022. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9598022/ (Full text)

Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease considered to be triggered by viral infections in a majority of cases. Symptoms overlap largely with those of post-acute sequelae of COVID-19/long-COVID implying common pathogenetic mechanisms. SARS-CoV-2 infection is risk factor for sustained latent virus reactivation that may account for the symptoms of post-viral fatigue syndromes. The aim of this study was first to investigate whether patients with ME/CFS and healthy donors (HDs) differed in their antibody response to mild/asymptomatic SARS-CoV-2 infection. Secondly, to analyze whether COVID-19 imposes latent virus reactivation in the cohorts.

Methods: Anti-SARS-CoV-2 antibodies were analyzed in plasma and saliva from non-vaccinated ME/CFS (n=95) and HDs (n=110) using soluble multiplex immunoassay. Reactivation of human herpesviruses 1-6 (HSV1, HSV2, VZV, EBV, CMV, HHV6), and human endogenous retrovirus K (HERV-K) was detected by anti-viral antibody fingerprints in saliva.

Results: At 3-6 months after mild/asymptomatic SARS-CoV-2 infection, virus-specific antibodies in saliva were substantially induced signifying a strong reactivation of latent viruses (EBV, HHV6 and HERV-K) in both cohorts. In patients with ME/CFS, antibody responses were significantly stronger, in particular EBV-encoded nuclear antigen-1 (EBNA1) IgG were elevated in patients with ME/CFS, but not in HDs. EBV-VCA IgG was also elevated at baseline prior to SARS-infection in patients compared to HDs.

Conclusion: Our results denote an altered and chronically aroused anti-viral profile against latent viruses in ME/CFS. SARS-CoV-2 infection even in its mild/asymptomatic form is a potent trigger for reactivation of latent herpesviruses (EBV, HHV6) and endogenous retroviruses (HERV-K), as detected by antibody fingerprints locally in the oral mucosa (saliva samples). This has not been shown before because the antibody elevation is not detected systemically in the circulation/plasma.

Source: Apostolou Eirini, Rizwan Muhammad, Moustardas Petros, Sjögren Per, Bertilson Bo Christer, Bragée Björn, Polo Olli, Rosén Anders. Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome. Frontiers in Immunology, Vol 13, 2022. https://www.frontiersin.org/articles/10.3389/fimmu.2022.949787/full (Full text)

Systemic antibody responses against human microbiota flagellins are overrepresented in chronic fatigue syndrome patients

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with an unclear etiology and pathogenesis. Both an involvement of the immune system and gut microbiota dysbiosis have been implicated in its pathophysiology. However, potential interactions between adaptive immune responses and the microbiota in ME/CFS have been incompletely characterized. Here, we profiled antibody responses of patients with severe ME/CFS and healthy controls against microbiota and viral antigens represented as a phage-displayed 244,000 variant library.

Patients with severe ME/CFS exhibited distinct serum antibody epitope repertoires against flagellins of Lachnospiraceae bacteria. Training machine learning algorithms on this antibody-binding data demonstrated that immune responses against gut microbiota represent a unique layer of information beyond standard blood tests, providing improved molecular diagnostics for ME/CFS.

Together, our results point toward an involvement of the microbiota-immune axis in ME/CFS and lay the foundation for comparative studies with inflammatory bowel diseases and illnesses characterized by long-term fatigue symptoms, including post-COVID-19 syndrome.

Source: Vogl T, Kalka IN, Klompus S, Leviatan S, Weinberger A, Segal E. Systemic antibody responses against human microbiota flagellins are overrepresented in chronic fatigue syndrome patients. Sci Adv. 2022 Sep 23;8(38):eabq2422. doi: 10.1126/sciadv.abq2422. Epub 2022 Sep 23. PMID: 36149952. https://www.science.org/doi/10.1126/sciadv.abq2422 (Full text)

The potential role of ischaemia-reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implications

Abstract:

Ischaemia-reperfusion (I-R) injury, initiated via bursts of reactive oxygen species produced during the reoxygenation phase following hypoxia, is well known in a variety of acute circumstances. We argue here that I-R injury also underpins elements of the pathology of a variety of chronic, inflammatory diseases, including rheumatoid arthritis, ME/CFS and, our chief focus and most proximally, Long COVID.

Ischaemia may be initiated via fibrin amyloid microclot blockage of capillaries, for instance as exercise is started; reperfusion is a necessary corollary when it finishes. We rehearse the mechanistic evidence for these occurrences here, in terms of their manifestation as oxidative stress, hyperinflammation, mast cell activation, the production of marker metabolites and related activities.

Such microclot-based phenomena can explain both the breathlessness/fatigue and the post-exertional malaise that may be observed in these conditions, as well as many other observables. The recognition of these processes implies, mechanistically, that therapeutic benefit is potentially to be had from antioxidants, from anti-inflammatories, from iron chelators, and via suitable, safe fibrinolytics, and/or anti-clotting agents. We review the considerable existing evidence that is consistent with this, and with the biochemical mechanisms involved.

Source: Kell DB, Pretorius E. The potential role of ischaemia-reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implications. Biochem J. 2022 Aug 31;479(16):1653-1708. doi: 10.1042/BCJ20220154. PMID: 36043493. https://portlandpress.com/biochemj/article/479/16/1653/231696/The-potential-role-of-ischaemia-reperfusion-injury (Full text)

Genetic risk factors for ME/CFS identified using combinatorial analysis

Abstract:

Background:Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease that lacks known pathogenesis, distinctive diagnostic criteria, and effective treatment options. Understanding the genetic (and other) risk factors associated with the disease would begin to help to alleviate some of these issues for patients.

Methods: We applied both GWAS and the PrecisionLife combinatorial analytics platform to analyze ME/CFS cohorts from UK Biobank, including the Pain Questionnaire cohort, in a case-control design with 1,000 cycles of fully random permutation. Results from this study were supported by a series of replication and cohort comparison experiments, including use of disjoint Verbal Interview CFS, post-viral fatigue syndrome and fibromyalgia cohorts also derived from UK Biobank, and results compared for overlap and reproducibility.

Results: Combinatorial analysis revealed 199 SNPs mapping to 14 genes, that were significantly associated with 91% of the cases in the ME/CFS population. These SNPs were found to stratify by shared cases into 15 clusters (communities) made up of 84 high-order combinations of between 3-5 SNPs. p-values for these communities range from 2.3 × 10−10 to 1.6 × 10−72. Many of the genes identified are linked to the key cellular mechanisms hypothesized to underpin ME/CFS, including vulnerabilities to stress and/or infection, mitochondrial dysfunction, sleep disturbance and autoimmune development. We identified 3 of the critical SNPs replicated in the post-viral fatigue syndrome cohort and 2 SNPs replicated in the fibromyalgia cohort. We also noted similarities with genes associated with multiple sclerosis and long COVID, which share some symptoms and potentially a viral infection trigger with ME/CFS.

Conclusions: This study provides the first detailed genetic insights into the pathophysiological mechanisms underpinning ME/CFS and offers new approaches for better diagnosis and treatment of patients

Source: Sayoni Das, Krystyna Taylor, James Kozubek, Jason Sardell, Steve Gardner. Genetic Risk Factors for ME/CFS Identified using Combinatorial Analysis. medRxiv 2022.09.09.22279773; doi: https://doi.org/10.1101/2022.09.09.22279773  https://www.medrxiv.org/content/10.1101/2022.09.09.22279773v2.full-text (Full text)

Fatigue in ANCA-associated vasculitis (AAV) and systemic sclerosis (SSc): similarities with Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A critical review of the literature

Abstract:

Introduction: Persistent debilitating fatigue is a frequent complaint in patients with systemic autoimmune rheumatic diseases (SARDs). Fatigue is, however, frequently overlooked in the clinic, and patients who successfully achieve remission of their disease, often still have a lowered quality of life due to its persistence. How similar is this fatigue to Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), what is this fatigue associated with, and what tools/approaches (if any), have resulted in the improvement of fatigue in these patients is poorly defined.

Areas covered: Similarities between the pathophysiology of ME/CFS, systemic sclerosis (SSc) and primary systemic vasculitides (PSV) are discussed, followed by an in-depth review of the prevalence and correlates of fatigue in these diseases. The authors reviewed literature from MEDLINE, APA PsycInfo, Embase, and CINAHL.

Expert opinion: Persistent fatigue is a prominent feature in SARDs and may not be associated with components commonly associated with disease activity and/or progression. Immune and metabolic commonalities exist between ME/CFS, SSc, and PSVs – suggesting that common pathways inherent to the diseases and fatigue may be present. We suggest that patients with features of ME/CFS need to be identified by treating physicians, as they may require alternative approaches to therapy to improve their quality of life.

Source: van Eeden C, Osman MS, Cohen Tervaert JW. Fatigue in ANCA-associated vasculitis (AAV) and systemic sclerosis (SSc): similarities with Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A critical review of the literature. Expert Rev Clin Immunol. 2022 Aug 31:1-22. doi: 10.1080/1744666X.2022.2116002. Epub ahead of print. PMID: 36045606. https://pubmed.ncbi.nlm.nih.gov/36045606/

A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity

Abstract:

A subset of patients has long-lasting symptoms after mild to moderate Coronavirus disease 2019 (COVID-19). In a prospective observational cohort study, we analyze clinical and laboratory parameters in 42 post-COVID-19 syndrome patients (29 female/13 male, median age 36.5 years) with persistent moderate to severe fatigue and exertion intolerance six months following COVID-19. Further we evaluate an age- and sex-matched postinfectious non-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome cohort comparatively.

Most post-COVID-19 syndrome patients are moderately to severely impaired in daily live. 19 post-COVID-19 syndrome patients fulfill the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome. Disease severity and symptom burden is similar in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome and non-COVID-19/myalgic encephalomyelitis/chronic fatigue syndrome patients. Hand grip strength is diminished in most patients compared to normal values in healthy.

Association of hand grip strength with hemoglobin, interleukin 8 and C-reactive protein in post-COVID-19 syndrome/non-myalgic encephalomyelitis/chronic fatigue syndrome and with hemoglobin, N-terminal prohormone of brain natriuretic peptide, bilirubin, and ferritin in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome may indicate low level inflammation and hypoperfusion as potential pathomechanisms.

Source: Kedor C, Freitag H, Meyer-Arndt L, Wittke K, Hanitsch LG, Zoller T, Steinbeis F, Haffke M, Rudolf G, Heidecker B, Bobbert T, Spranger J, Volk HD, Skurk C, Konietschke F, Paul F, Behrends U, Bellmann-Strobl J, Scheibenbogen C. A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity. Nat Commun. 2022 Aug 30;13(1):5104. doi: 10.1038/s41467-022-32507-6. PMID: 36042189. https://www.nature.com/articles/s41467-022-32507-6 (Full text)

Diminished Cardiopulmonary Capacity During Post-Exertional Malaise

Abstract:

Reduced functional capacity and post-exertional malaise following physical activity are hallmark symptoms of Chronic Fatigue Syndrome (CFS). That these symptoms are often delayed may explain the equivocal results for clinical cardiopulmonary exercise testing with CFS patients. The reproducibility of VO2 max in healthy subjects is well documented. This may not be the case with CFS due to delayed recovery symptoms.

Purpose: To compare results from repeated exercise tests as indicators of post-exertional malaise in CFS.

Methods: Peak oxygen consumption (VO2 peak), percentage of predicted peak heart rate (HR%), and VO2 at anaerobic threshold (AT), were compared between six CFS patients and six control subjects for two maximal exercise tests separated by 24 hours.

Results: Multivariate analysis showed no significant differences between control and CFS, respectively, for test 1: VO2 peak (28.4 ± 7.2 ml/ kg/min; 26.2 ± 4.9 ml/kg/min), AT (17.5 ± 4.8 ml/kg/min; 15.0 ± 4.9 ml/ kg/min) or HR% (87.0 ± 25.4%; 94.8 ± 8.8%). However, for test 2 the CFS patients achieved significantly lower values for both VO2 peak (28.9 ± 8.0 ml/kg/min; 20.5 ± 1.8 ml/kg/min, p = 0.031) and AT (18.0 ± 5.2 ml/kg/min; 11.0 ± 3.4 ml/kg/min, p = 0.021). HR% was not significantly different (97.6 ± 27.2%; 87.8 ± 9.3%, p = 0.07). A follow-up classification analysis differentiated between CFS patients and controls with an overall accuracy of 92%.

Conclusion: In the absence of a second exercise test, the lack of any significant differences for the first test would appear to suggest no functional impairment in CFS patients. However, the results from the second test indicate the presence of a CFS related post-exertional malaise. It might be concluded then that a single exercise test is insufficient to demonstrate functional impairment in CFS patients. A second test may be necessary to document the atypical recovery response and protracted malaise unique to CFS.

Source: J. Mark Vanness, Christopher R. Snell & Staci R. Stevens (2007) Diminished Cardiopulmonary Capacity During Post-Exertional Malaise, Journal of Chronic Fatigue Syndrome, 14:2, 77-85, DOI: 10.1300/J092v14n02_07

Reproducibility of Measurements Obtained During Cardiopulmonary Exercise Testing in Individuals With Fatiguing Health Conditions – A Case Series

Abstract:

Purpose: Measurements obtained during maximal cardiopulmonary exercise testing (CPET) demonstrate high test–retest reliability, which indicates low error variance. However, measurements obtained from people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may depart from typically observed high reproducibility, which could represent functionally relevant biological variability that is characteristic of the underlying pathophysiology. The purpose of this case series was to document individual experiences with test–retest variability in CPET measurements in individuals with ME/CFS compared with other fatiguing health conditions.

Methods: In this case series, 6 women matched for age and body mass index underwent 2 maximal CPETs spaced 24 hours apart. Clients comprised 1 sedentary individual without fatigue, 1 active individual without fatigue, 1 individual with multiple sclerosis (MS), 1 individual diagnosed with HIV, 1 individual with ME/CFS and low maximal volume of oxygen consumed (VO2max), and 1 high-functioning individual with ME/CFS and high VO2max. Percent change in CPET measurements between tests was calculated for each client.

Results: Nondisabled clients and clients with MS and HIV reproduced or improved in their volume of oxygen consumed (VO2), workload (WL), heart rate (HR), and minute ventilation (VE) at ventilatory anaerobic threshold (VAT) and at peak exercise (except peak WL and VE for the individual with HIV). Neither individual with ME/CFS reproduced VO2, WL, HR, or VE at VAT within literature estimates.

Conclusions: Measurements during CPET for individual patients may relate to potential condition-specific deficits in cardiac, pulmonary, and metabolic functioning.

Source: Larson, Benjamin PT, DPT1; Davenport, Todd E. PT, DPT, MPH, OCS2,3; Stevens, Staci R. MA3; Stevens, Jared BS3; Van Ness, J. Mark PhD3,4; Snell, Christopher R. PhD3. Reproducibility of Measurements Obtained During Cardiopulmonary Exercise Testing in Individuals With Fatiguing Health Conditions: A Case Series. Cardiopulmonary Physical Therapy Journal: October 2019 – Volume 30 – Issue 4 – p 145-152 doi: 10.1097/CPT.0000000000000100 https://journals.lww.com/cptj/Abstract/2019/10000/Reproducibility_of_Measurements_Obtained_D%20uring.4.aspx