Tag: Nacul

The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: a meta-analysis of public DNA methylation and gene expression data

Abstract:

People with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report a high frequency of viral infections and flu-like symptoms during their disease course. Since this reporting is in line with different immunological abnormalities and altered gene expression profiles observed in the disease, we aimed to explore whether the expression of the human angiotensin-converting enzyme-2 (ACE2), the major cell entry receptor for SARS-CoV-2, is also altered in this neglected clinical population. In particular, a low expression of ACE2 is usually indicative of a high risk of developing COVID-19.

We then performed a meta-analysis of public data on CpG DNA methylation and gene expression of this enzyme and its homologous ACE protein in peripheral blood mononuclear cells and related subsets. We found that patients with ME/CFS have decreased methylation levels of four CpG probes in the ACE locus (cg09920557, cg19802564, cg21094739, and cg10468385) and of another probe in the promoter region of the ACE2 gene (cg08559914). We also found a decreased expression of ACE2 but not of ACE in patients with ME/CFS when compared to healthy controls.

Accordingly, in newly collected data, we found evidence for a higher proportion of samples with an ACE2 expression below the limit of detection in patients with ME/CFS than in healthy controls. Altogether, patients with ME/CFS could be at a higher COVID-19 risk when infected by SARS-CoV-2. To further support this conclusion, similar research should be conducted for other human cell entry receptors and other cell types, namely, those mainly targeted by the virus.

Source: Malato J, Sotzny F, Bauer S, Freitag H, Fonseca A, Grabowska AD, Graça L, Cordeiro C, Nacul L, Lacerda EM, Castro-Marrero J, Scheibenbogen C, Westermeier F, Sepúlveda N. The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: a meta-analysis of public DNA methylation and gene expression data. Heliyon. 2021 Jul 29;7(8):e07665. doi: 10.1016/j.heliyon.2021.e07665. Epub ahead of print. PMID: 34341773; PMCID: PMC8320404. https://pubmed.ncbi.nlm.nih.gov/34341773/

Herpesviruses Serology Distinguishes Different Subgroups of Patients From the United Kingdom Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Biobank

Abstract:

The evidence of an association between Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and chronic herpesviruses infections remains inconclusive. Two reasons for the lack of consistent evidence are the large heterogeneity of the patients’ population with different disease triggers and the use of arbitrary cutoffs for defining seropositivity. In this work we re-analyzed previously published serological data related to 7 herpesvirus antigens. Patients with ME/CFS were subdivided into four subgroups related to the disease triggers: S0-42 patients who did not know their disease trigger; S1-43 patients who reported a non-infection trigger; S2-93 patients who reported an infection trigger, but that infection was not confirmed by a lab test; and S3-48 patients who reported an infection trigger and that infection was confirmed by a lab test.

In accordance with a sensitivity analysis, the data were compared to those from 99 healthy controls allowing the seropositivity cutoffs to vary within a wide range of possible values. We found a negative association between S1 and seropositivity to Epstein-Barr virus (VCA and EBNA1 antigens) and Varicella-Zoster virus using specific seropositivity cutoff. However, this association was not significant when controlling for multiple testing. We also found that S3 had a lower seroprevalence to the human cytomegalovirus when compared to healthy controls for all cutoffs used for seropositivity and after adjusting for multiple testing using the Benjamini-Hochberg procedure. However, this association did not reach statistical significance when using Benjamini-Yekutieli procedure. In summary, herpesviruses serology could distinguish subgroups of ME/CFS patients according to their disease trigger, but this finding could be eventually affected by the problem of multiple testing.

Source: Domingues TD, Grabowska AD, Lee JS, Ameijeiras-Alonso J, Westermeier F, Scheibenbogen C, Cliff JM, Nacul L, Lacerda EM, Mouriño H, Sepúlveda N. Herpesviruses Serology Distinguishes Different Subgroups of Patients From the United Kingdom Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Biobank. Front Med (Lausanne). 2021 Jul 5;8:686736. doi: 10.3389/fmed.2021.686736. PMID: 34291062; PMCID: PMC8287507. https://pubmed.ncbi.nlm.nih.gov/34291062/

European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE): Expert Consensus on the Diagnosis, Service Provision, and Care of People with ME/CFS in Europe

Abstract:

Designed by a group of ME/CFS researchers and health professionals, the European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) has received funding from the European Cooperation in Science and Technology (COST)-COST action 15111-from 2016 to 2020. The main goal of the Cost Action was to assess the existing knowledge and experience on health care delivery for people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in European countries, and to enhance coordinated research and health care provision in this field. We report our findings and make recommendations for clinical diagnosis, health services and care for people with ME/CFS in Europe, as prepared by the group of clinicians and researchers from 22 countries and 55 European health professionals and researchers, who have been informed by people with ME/CFS.

Source: Nacul L, Authier FJ, Scheibenbogen C, Lorusso L, Helland IB, Martin JA, Sirbu CA, Mengshoel AM, Polo O, Behrends U, Nielsen H, Grabowski P, Sekulic S, Sepulveda N, Estévez-López F, Zalewski P, Pheby DFH, Castro-Marrero J, Sakkas GK, Capelli E, Brundsdlund I, Cullinan J, Krumina A, Bergquist J, Murovska M, Vermuelen RCW, Lacerda EM. European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE): Expert Consensus on the Diagnosis, Service Provision, and Care of People with ME/CFS in Europe. Medicina (Kaunas). 2021 May 19;57(5):510. doi: 10.3390/medicina57050510. PMID: 34069603. https://pubmed.ncbi.nlm.nih.gov/34069603/

Salivary DNA loads for human herpes viruses 6 and 7 are correlated with disease phenotype in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a complex chronic condition affecting multiple body systems, with unknown cause, unclear pathogenesis mechanisms, and fluctuating symptoms which may lead to severe debilitation. It is frequently reported to have been triggered by an infection, particularly with herpes virus family members; however, there are no clear differences in exposure to, or seroprevalence of, any herpes virus in people with ME/CFS and healthy individuals. Herpes viruses exist in lytic and latent forms, and it is possible that ME/CFS is associated with viral reactivation, which has not been detectable previously due to insensitive testing methods.

Saliva samples were collected from 30 people living with ME/CFS at monthly intervals for six months and at times when they experienced symptom exacerbation, as well as from 14 healthy control individuals. The viral DNA load of the nine human herpes viruses was determined by digital droplet PCR. Symptoms were assessed by questionnaire at each time point.

Human herpes virus (HHV) 6B, HHV-7, herpes simplex virus 1 and Epstein Barr virus were detectable within the saliva samples, with higher HHV-6B and HHV-7 viral loads detected in people with ME/CFS than in healthy controls. Participants with ME/CFS could be broadly separated into two groups: one group displayed fluctuating patterns of herpes viruses detectable across the six months while the second group displayed more stable viral presentation. In the first group, there was positive correlation between HHV-6B and HHV-7 viral load and severity of symptom scores, including pain, neurocognition and autonomic dysfunction.

The results indicate that fluctuating viral load, related to herpesvirus reactivation state, may play a role in ME/CFS pathogenesis, or might be a consequence of dysregulated immune function. The sampling strategy and molecular tools developed permit large-scale epidemiological investigations.

Contribution to the Field The cause of ME/CFS and the mechanisms underlying disease pathogenesis are not known, although symptoms are often triggered by infection. Human herpes virus (HHV) family members have been implicated, although there is no difference in the seroprevalence of any HHV in people with ME/CFS and healthy controls, showing there is similar prior infection rate. HHVs exist in either latent or active, lytic, phases in the human host, and it is possible that ME/CFS symptoms and their severity is related to HHV reactivation from a latent state. We have used droplet digital PCR, a sensitive and specific method, to measure the prevalence and DNA concentration of HHVs in the saliva of people with ME/CFS and controls, and analysed the correlation with disease over a six-month timecourse. We found that two HHVs, HHV-7 and HHV-6B, were elevated in saliva from people with ME/CFS, and that in people who were severely affected by ME/CFS, the concentration HHV DNA correlated with symptom severity over time in a subgroup of patients with fluctuating salivary HHV repertoire. Our study demonstrates the feasibility of measuring HHV concentration in readily acquired samples, enabling future large-scale studies aimed at testing the causal role of HHV reactivation in ME/CFS disease.

Source: Ji-Sook Lee, Eliana M. Lacerda, Luis Nacul, Caroline C. Kingdon, Jasmin Norris, Shennae O’Boyle, Chrissy H. Roberts, Luigi Palla, Eleanor M. Riley, Jacqueline M. Cliff. Salivary DNA loads for human herpes viruses 6 and 7 are correlated with disease phenotype in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome.
medRxiv 2021.01.06.20248486; doi: https://doi.org/10.1101/2021.01.06.20248486 https://www.medrxiv.org/content/10.1101/2021.01.06.20248486v1.full-text  (Full text)

How Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Progresses: The Natural History of ME/CFS

Abstract:

We propose a framework for understanding and interpreting the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) that considers wider determinants of health and long-term temporal variation in pathophysiological features and disease phenotype throughout the natural history of the disease. As in other chronic diseases, ME/CFS evolves through different stages, from asymptomatic predisposition, progressing to a prodromal stage, and then to symptomatic disease. Disease incidence depends on genetic makeup and environment factors, the exposure to singular or repeated insults, and the nature of the host response. In people who develop ME/CFS, normal homeostatic processes in response to adverse insults may be replaced by aberrant responses leading to dysfunctional states.

Thus, the predominantly neuro-immune manifestations, underlined by a hyper-metabolic state, that characterize early disease, may be followed by various processes leading to multi-systemic abnormalities and related symptoms. This abnormal state and the effects of a range of mediators such as products of oxidative and nitrosamine stress, may lead to progressive cell and metabolic dysfunction culminating in a hypometabolic state with low energy production.

These processes do not seem to happen uniformly; although a spiraling of progressive inter-related and self-sustaining abnormalities may ensue, reversion to states of milder abnormalities is possible if the host is able to restate responses to improve homeostatic equilibrium. With time variation in disease presentation, no single ME/CFS case description, set of diagnostic criteria, or molecular feature is currently representative of all patients at different disease stages. While acknowledging its limitations due to the incomplete research evidence, we suggest the proposed framework may support future research design and health care interventions for people with ME/CFS.

Source: Nacul L, O’Boyle S, Palla L, et al. How Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Progresses: The Natural History of ME/CFS. Front Neurol. 2020;11:826. Published 2020 Aug 11. doi:10.3389/fneur.2020.00826 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431524/ (Full text)

Health Care Responsibility and Compassion-Visiting the Housebound Patient Severely Affected by ME/CFS

Abstract:

Many people with severe Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) commonly receive no care from healthcare professionals, while some have become distanced from all statutory medical services. Paradoxically, it is often the most seriously ill and needy who are the most neglected by those responsible for their healthcare. Reasons for this include tensions around the complexity of making an accurate diagnosis in the absence of a biomarker, the bitter debate about the effectiveness of the few available treatments, and the very real stigma associated with the diagnosis.

Illness severity often precludes attendance at healthcare facilities, and if an individual is well enough to be able to attend an appointment, the presentation will not be typical; by definition, patients who are severely affected are home-bound and often confined to bed. We argue that a holistic model, such as ‘‘Compassion in Practice’’, can help with planning appointments and caring for people severely affected by ME/CFS. We show how this can be used to frame meaningful interactions between the healthcare practitioners (HCPs) and the homebound patient.

Source: Kingdon, C.; Giotas, D.; Nacul, L.; Lacerda, E. Health Care Responsibility and Compassion-Visiting the Housebound Patient Severely Affected by ME/CFS. Healthcare 2020, 8, 197. https://www.mdpi.com/2227-9032/8/3/197/htm (Full text)

Review of the Quality Control Checks Performed by Current Genome-Wide and Targeted-Genome Association Studies on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Introduction:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease characterized by persistent fatigue and post-exertion malaise, accompanied by other symptoms (1, 2). The direct cause of the disease remains elusive, but it may include genetic factors alongside environmental triggers, such as strong microbial infections and other stressors (3, 4).

With the aim to identify putative genetic factors that could explain the pathophysiological mechanisms of ME/CFS, four genome-wide association studies (GWAS) and two targeted-genome association studies (TGAS) were conducted in the past decade (5–10). In the four GWAS, thousands of genetic markers located across the whole genome were evaluated for their statistical association with ME/CFS (5–8). The two TGAS had the same statistical objective of the four GWAS, but alternatively investigated the association of the disease with numerous genetic markers located in candidate genes related to inflammation and immunity (9) and in genes encoding diverse adrenergic receptors (10).

The findings from all these different studies suggested conflicting evidence of genetic association with ME/CFS: from absence of association (7), through mild association (10) up to moderate associations of a relatively small number of genetic markers (5, 6, 9). The most optimistic GWAS suggested more than 5,500 candidate gene-disease associations (8). This inconsistency in the reported findings prompted us to review the respective data. With this purpose, the present opinion paper first revisits the recommended quality control (QC) checks for GWAS and TGAS, and then summarizes which ones were performed by those studies on ME/CFS.

Source: Grabowska AD, Lacerda EM, Nacul L, Sepúlveda N. Review of the Quality Control Checks Performed by Current Genome-Wide and Targeted-Genome Association Studies on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front Pediatr. 2020;8:293. Published 2020 Jun 12. doi:10.3389/fped.2020.00293 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304330/ (Full text)

HERV-K and HERV-W transcriptional activity in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/MS) is an incapacitating chronic disease that dramatically compromise the life quality. The CFS/ME pathogenesis is multifactorial, and it is believed that immunological, metabolic and environmental factors play a role. It is well documented an increased activity of Human endogenous retroviruses (HERVs) from different families in autoimmune and neurological diseases, making these elements good candidates for biomarkers or even triggers for such diseases.

METHODS: Here the expression of Endogenous retroviruses K and W (HERV-K and HERV-W) was determined in blood from moderately and severely affected ME/CFS patients through real time PCR.

RESULTS: HERV-K was overexpressed only in moderately affected individuals but HERV-W showed no difference.

CONCLUSIONS: This is the first report about HERV-K differential expression in moderate ME/CFS. Although the relationship between HERVs and ME/CFS has yet to be proven, the observation of this phenomenon deserves further attention.

Source: Rodrigues LS, da Silva Nali LH, Leal COD, Sabino EC, Lacerda EM, Kingdon CC, Nacul L, Romano CM. HERV-K and HERV-W transcriptional activity in myalgic encephalomyelitis/chronic fatigue syndrome. Auto Immun Highlights. 2019 Nov 15;10(1):12. doi: 10.1186/s13317-019-0122-8. eCollection 2019 Dec. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065355/ (Full text)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome as a Hyper-Regulated Immune System Driven by an Interplay Between Regulatory T Cells and Chronic Human Herpesvirus Infections

Abstract:

Autoimmunity and chronic viral infections are recurrent clinical observations in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a complex disease with an unknown cause. Given these observations, the regulatory CD4+ T cells (Tregs) show promise to be good candidates for the underlying pathology due to their capacity to suppress the immune responses against both self and microbial antigens. Here, we discussed the overlooked role of these cells in the chronicity of Human Herpes Virus 6 (HHV6), Herpes Simplex 1 (HSV1), and Epstein-Barr virus (EBV), as often reported as triggers of ME/CFS.

Using simulations of the cross-regulation model for the dynamics of Tregs, we illustrated that mild infections might lead to a chronically activated immune responses under control of Tregs if the responding clone has a high autoimmune potential. Such infections promote persistent inflammation and possibly fatigue. We then hypothesized that ME/CFS is a condition characterized by a predominance of this type of infections under control of Tregs. In contrast, healthy individuals are hypothesized to trigger immune responses of a virus-specific clone with a low autoimmune potential.

According to this hypothesis, simple model simulations of the CD4+ T-cell repertoire could reproduce the increased density and percentages of Tregs observed in patients suffering from the disease, when compared to healthy controls. A deeper analysis of Tregs in the pathogenesis of ME/CFS will help to assess the validity of this hypothesis.

Copyright © 2019 Sepúlveda, Carneiro, Lacerda and Nacul.

Source: Sepúlveda N, Carneiro J, Lacerda E, Nacul L. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome as a Hyper-Regulated Immune System Driven by an Interplay Between Regulatory T Cells and Chronic Human Herpesvirus Infections. Front Immunol. 2019 Nov 21;10:2684. doi: 10.3389/fimmu.2019.02684. eCollection 2019. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883905/ (Full article)

Myalgic encephalomyelitis/chronic fatigue Syndrome (ME/CFS): Investigating care practices pointed out to disparities in diagnosis and treatment across European Union

Abstract:

ME/CFS is a chronic, complex, multisystem disease that often limits the health and functioning of the affected patients. Diagnosing patients with ME/CFS is a challenge, and many different case definitions exist and are used in clinical practice and research. Even after diagnosis, medical treatment is very challenging. Symptom relief and coping may affect how patients live with their disease and their quality of life. There is no consensus on which diagnostic criteria should be used and which treatment strategies can be recommended for patients.

The purpose of the current project was to map the landscape of the Euromene countries in respect of national guidelines and recommendations for case definition, diagnosis and clinical approaches for ME/CFS patients. A 23 items questionnaire was sent out by email to the members of Euromene. The form contained questions on existing guidelines for case definitions, treatment/management of the disease, tests and questionnaires applied, and the prioritization of information for data sampling in research. We obtained information from 17 countries. Five countries reported having national guidelines for diagnosis, and five countries reported having guidelines for clinical approaches.

For diagnostic purposes, the Fukuda criteria were most often recommended, and also the Canadian Consensus criteria, the International Consensus Criteria and the Oxford criteria were used. A mix of diagnostic criteria was applied within those countries having no guidelines. Many different questionnaires and tests were used for symptom registration and diagnostic investigation. For symptom relief, pain and anti-depressive medication were most often recommended. Cognitive Behavioral Therapy and Graded Exercise treatment were often recommended as disease management and rehabilitative/palliative strategies.

The lack of consistency in recommendations across European countries urges the development of regulations, guidance and standards. The results of this study will contribute to the harmonization of diagnostic criteria and treatment for ME/CFS in Europe.

Source: Strand EB, Nacul L, Mengshoel AM, Helland IB, Grabowski P, Krumina A, Alegre-Martin J, Efrim-Budisteanu M, Sekulic S, Pheby D, Sakkas GK, Sirbu CA, Authier FJ; European Network on ME/CFS (EUROMENE). Myalgic encephalomyelitis/chronic fatigue Syndrome (ME/CFS): Investigating care practices pointed out to disparities in diagnosis and treatment across European Union. PLoS One. 2019 Dec 5;14(12):e0225995. doi: 10.1371/journal.pone.0225995. eCollection 2019. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225995 (Full article)