Tag: 2022

Revisiting IgG antibody reactivity to Epstein-Barr virus in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and its potential application to disease diagnosis

Abstract:

Infections by the Epstein-Barr virus (EBV) are often at the disease onset of patients suffering from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, serological analyses of these infections remain inconclusive when comparing patients with healthy controls. In particular, it is unclear if certain EBV-derived antigens eliciting antibody responses have a biomarker potential for disease diagnosis. With this purpose, we re-analysed a previously published microarray data on the IgG antibody responses against 3,054 EBV-related antigens in 92 patients with ME/CFS and 50 HCs.

This re-analysis consisted of constructing different regression models for binary outcomes with the ability to classify patients and HCs. In these models, we tested for a possible interaction of different antibodies with age and gender. When analyzing the whole data set, there were no antibody responses that could be used to distinguish patients from healthy controls. A similar finding was obtained when comparing patients with noninfectious or unknown disease trigger to healthy controls.

However, when data analysis was restricted to the comparison between HCs and patients with a putative infection at disease onset, we could identify stronger antibody responses against two candidate antigens (EBNA4_0529 and EBNA6_0070). Using antibody responses to these two antigens together with age and gender, the final classification model had an estimated sensitivity and specificity of 0.833 and 0.720, respectively.

This reliable case-control discrimination suggested the use of the antibody levels related to these candidate viral epitopes as biomarkers for disease diagnosis in this subgroup of patients. When a bioinformatic analysis was performed on these epitopes, it revealed a potential molecular mimicry with several human proteins. To confirm these promising findings, a follow-up study will be conducted in a separate cohort of patients.

Source: Nuno Sepúlveda, João Malato, Franziska Sotzny, Anna D Grabowska, André Fonseca, Clara Cordeiro, Luís Graça, Przemyslaw Biecek, Uta Behrends, Josef Mautner, Francisco Westermeier, Eliana M Lacerda, Carmen Scheibenbogen. Revisiting IgG antibody reactivity to Epstein-Barr virus in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and its potential application to disease diagnosis, medRxiv 2022.04.20.22273990; doi: https://doi.org/10.1101/2022.04.20.22273990 https://www.medrxiv.org/content/10.1101/2022.04.20.22273990v1.full-text (Full text)

Alteration of Cortical Volume and Thickness in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS) patients suffer from neurocognitive impairment. In this study, we investigated cortical volumetric and thickness changes in ME/CFS patients and healthy controls (HC). We estimated mean surface-based cortical volume and thickness from 18 ME/CFS patients who met International Consensus Criteria (ICC) and 26 HC using FreeSurfer. Vertex-wise analysis showed significant reductions in the caudal middle frontal gyrus (p = 0.0016) and precuneus (p = 0.013) thickness in ME/CFS patients compared with HC.

Region based analysis of sub-cortical volumes found that amygdala volume (p = 0.002) was significantly higher in ME/CFS patients compared with HC. We also performed interaction-with-group regressions with clinical measures to test for cortical volume and thickness correlations in ME/CFS with opposite slopes to HC (abnormal). ME/CFS cortical volume and thickness regressions with fatigue, heart-rate variability, heart rate, sleep disturbance score, respiratory rate, and cognitive performance were abnormal. Our study demonstrated different cortical volume and thickness in ME/CFS patients and showed abnormal cortical volume and thickness regressions with key symptoms of ME/CFS patients.

Source: Thapaliya Kiran, Marshall-Gradisnik Sonya, Staines Donald, Su Jiasheng, Barnden Leighton. Alteration of Cortical Volume and Thickness in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Frontiers in Neuroscience, Vol 16, 2022. DOI=10.3389/fnins.2022.848730 https://www.frontiersin.org/articles/10.3389/fnins.2022.848730/full   (Full text)

Impact of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) on the quality of life of people with ME/CFS and their partners and family members: an online cross-sectional survey

Abstract:

Objectives: The aim of this study was to assess the impact of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) on the quality of life (QoL) of people with ME/CFS and their relative or partner (family member).

Design: A patient-partner, multinational, subject-initiated, cross-sectional online survey.

Setting: International survey using ME/CFS charities, support groups and social media.

Participants: Participants were self-selected with recruitment via social media. Inclusion criteria were aged 18 years or over and reported diagnosis of ME/CFS by health professional. 1418 people with ME/CFS and their 1418 family members from 30 countries participated in the survey. Participants with ME/CFS had a mean age of 45.8 years (range 18-81) and were predominantly women (1214 (85.6%) of 1418). Family members had a mean age of 51.9 years (range 18-87) and were predominantly men (women: 504 (35.5%) of 1418). 991 (70%) family members were partners of the people with ME/CFS.

Interventions: EuroQoL-5 Dimension (EQ-5D-3L), completed by people with ME/CFS, and Family Reported Outcome Measure (FROM-16) questionnaire, completed by family members.

Results: The mean overall health status on a Visual Analogue Scale for people with ME/CFS was 33.8 (0=worst, 100=best). People with ME/CFS were most affected by ability to perform usual activities, pain, mobility, self-care and least impacted by anxiety. For family members, the overall mean FROM-16 score was 17.9 (0=no impact, 32=worst impact), demonstrating a major impact on QoL. Impact on QoL was significantly correlated between the person with ME/CFS and their family member (p<0.0001). Family members were most impacted emotionally by worry, frustration and sadness and personally by family activities, holidays, sex life and finances.

Conclusions: To the best of our knowledge, this is the largest study on the impact of the QoL of persons with ME/CFS and their family members. While open participation surveys are limited by selection bias, this research has revealed a significant worldwide burden of ME/CFS on the QoL of people with ME/CFS and their family members.

Source: Vyas J, Muirhead N, Singh R, Ephgrave R, Finlay AY. Impact of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) on the quality of life of people with ME/CFS and their partners and family members: an online cross-sectional survey. BMJ Open. 2022 May 2;12(5):e058128. doi: 10.1136/bmjopen-2021-058128. PMID: 35501074. https://bmjopen.bmj.com/content/12/5/e058128  (Full text)

SARS-CoV-2 is associated with changes in brain structure in UK Biobank

Abstract:

There is strong evidence for brain-related abnormalities in COVID-19 1-13 . It remains unknown however whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. Here, we investigated brain changes in 785 UK Biobank participants (aged 51-81) imaged twice, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans, with 141 days on average separating their diagnosis and second scan, and 384 controls. The availability of pre-infection imaging data reduces the likelihood of pre-existing risk factors being misinterpreted as disease effects.

We identified significant longitudinal effects when comparing the two groups, including: (i) greater reduction in grey matter thickness and tissue-contrast in the orbitofrontal cortex and parahippocampal gyrus, (ii) greater changes in markers of tissue damage in regions functionally-connected to the primary olfactory cortex, and (iii) greater reduction in global brain size. The infected participants also showed on average larger cognitive decline between the two timepoints. Importantly, these imaging and cognitive longitudinal effects were still seen after excluding the 15 cases who had been hospitalised. These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease via olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious impact can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow up.

Source: Douaud G, Lee S, Alfaro-Almagro F, Arthofer C, Wang C, McCarthy P, Lange F, Andersson JLR, Griffanti L, Duff E, Jbabdi S, Taschler B, Keating P, Winkler AM, Collins R, Matthews PM, Allen N, Miller KL, Nichols TE, Smith SM. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. medRxiv [Preprint]. 2022 Mar 2:2021.06.11.21258690. doi: 10.1101/2021.06.11.21258690. Update in: Nature. 2022 Mar 7;: PMID: 34189535; PMCID: PMC8240690. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9046077/ (Full text)

Elevated ATG13 in serum of patients with ME/CFS stimulates oxidative stress response in microglial cells via activation of receptor for advanced glycation end products (RAGE)

Abstract:

Myalgic Encephalomyelitis, also known as Chronic Fatigue Syndrome (ME/CFS), is a multisystem illness characterized by extreme muscle fatigue associated with pain, neurocognitive impairment, and chronic inflammation. Despite intense investigation, the molecular mechanism of this disease is still unknown. Here we demonstrate that autophagy-related protein ATG13 is strongly upregulated in the serum of ME/CFS patients, indicative of impairment in the metabolic events of autophagy.

A Thioflavin T-based protein aggregation assay, array screening for autophagy-related factors, densitometric analyses, and confirmation with ELISA revealed that the level of ATG13 was strongly elevated in serum samples of ME/CFS patients compared to age-matched controls. Moreover, our microglia-based oxidative stress response experiments indicated that serum samples of ME/CFS patients evoke the production of reactive oxygen species (ROS) and nitric oxide in human HMC3 microglial cells, whereas neutralization of ATG13 strongly diminishes the production of ROS and NO, suggesting that ATG13 plays a role in the observed stress response in microglial cells. Finally, an in vitro ligand binding assay provided evidence that ATG13 employs the Receptor for Advanced Glycation End-products (RAGE) to stimulate ROS in microglial cells.

Collectively, our results suggest that an impairment of autophagy following the release of ATG13 into serum could be a pathological signal in ME/CFS.

Source: Gottschalk G, Peterson D, Knox K, Maynard M, Whelan RJ, Roy A. Elevated ATG13 in serum of patients with ME/CFS stimulates oxidative stress response in microglial cells via activation of receptor for advanced glycation end products (RAGE). Mol Cell Neurosci. 2022 Apr 26:103731. doi: 10.1016/j.mcn.2022.103731. Epub ahead of print. PMID: 35487443. https://www.sciencedirect.com/science/article/abs/pii/S1044743122000379?via%3Dihub (Full text)

Separating patients with SEID from those with CFS in the French ME/CFS Association, with some thoughts on nomenclature

Abstract:

In 2015, the American Institute of Medicine, now called the National Academy of Medicine, (IOM/NAM) proposed new diagnostic criteria for both Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and a new label: Systemic Exertion Intolerance Disease (SEID). This study aimed to evaluate the SEID criteria among members of the French Association of ME/CFS (ASFC) and their opinion about this new name. We sent an anonymous questionnaire to 494 ASFC members, using French-translated questions derived from the IOM/NAM tool kit. Among the 178/231 responding subjects who reported ME/CFS diagnosis, 150 (84%) met the criteria of SEID. For each set of questions, we identified some of them that significantly distinguished SEID from non-SEID patients concerning unrefreshing sleep, cognitive disorders, and orthostatic intolerance items.
Forty-six percent of the respondents considered the “SEID” terminology as more appropriate than “CFS”, 39% considered it inappropriate, and 15% had no opinion. Some questions better identified the SEID criteria. The IOM/NAM SEID criteria captured a large part of ASFC members suffering from ME/CFS. However, this new SEID label was not well accepted by the subjects, nor were the other denominations, suggesting that a better term should be found. Pending development of specific markers, further work with patient communities is needed to find a more suitable label.
Source: Campagne J, Fornasieri I, Andreani B, Eginard M, de Korwin J-D. Separating Patients with SEID from Those with CFS in the French ME/CFS Association, with Some Thoughts on Nomenclature. Diagnostics. 2022; 12(5):1095. https://doi.org/10.3390/diagnostics12051095. https://www.mdpi.com/2075-4418/12/5/1095 (Full text available as PDF file)

EBV/HHV-6A dUTPases contribute to Myalgic Encephalomyelitis/Chronic-Fatigue-Syndrome pathophysiology by enhancing TFH cell differentiation and extrafollicular activities

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, debilitating multisystem illness of unknown etiology for which there is no cure and no diagnostic tests available. Despite increasing evidence implicating EBV and human herpesvirus-6A (HHV-6A) as potential causative infectious agents in a subset of ME/CFS patients, there are few mechanistic studies to address a causal relationship.

In this study we examined a large ME/CFS cohort (n=351) and 77 controls and demonstrate a significant increase in activin A and IL-21serum levels, which correlated with seropositivity for antibodies to the EBV and HHV-6 protein deoxyuridine-triphosphate nucleotidohydrolase (dUTPase), but not CXCL13. These cytokines are critical for T follicular helper (TFH) cell differentiation, generation of high-affinity antibodies and long-lived plasma cells. Notably, ME/CFS serum was sufficient to drive TFH cell differentiation via an activin A-dependent mechanism.

The lack of simultaneous CXCL13 increase with IL-21 indicates impaired TFH-function in ME/CFS. In vitro studies revealed that virus-dUTPases strongly induced activin A secretion while in vivo, EBV-dUTPase induced the formation of splenic marginal zone B and invariant NKTFH cells. Altogether, our data indicate abnormal germinal center (GC) activity in ME/CFS subjects and highlight a mechanism by which EBV and HHV6-dUTPases may alter GC and extrafollicular Ab responses.

Source: Cox BS, Alharshawi K, Mena-Palomo I, Lafuse WP, Ariza ME. EBV/HHV-6A dUTPases contribute to Myalgic Encephalomyelitis/Chronic-Fatigue-Syndrome pathophysiology by enhancing TFH cell differentiation and extrafollicular activities. JCI Insight. 2022 Apr 28:e158193. doi: 10.1172/jci.insight.158193. Epub ahead of print. PMID: 35482424. https://pubmed.ncbi.nlm.nih.gov/35482424/

Long COVID Citizen Scientists: Developing a Needs-Based Research Agenda by Persons Affected by Long COVID

Abstract:

Background: Long-term health consequences following acute SARS-CoV-2 infection, referred to as post-COVID-19 condition or Long COVID, are increasing, with population-based prevalence estimates for adults at around 20%. Persons affected by Long COVID report various health problems, yet evidence to guide clinical decision making remains scarce.

Objective: The present study aimed to identify Long COVID research priorities using a citizen science approach and solely considering the needs of those affected.

Methods: This citizen science study followed an iterative process of patient needs identification, evaluation and prioritisation. A Long COVID Citizen Science Board (21 persons with Long COVID, and seven with myalgic encephalomyelitis/chronic fatigue syndrome) and a Long COVID Working Group (25 persons with Long COVID, four patients with myalgic encephalomyelitis/chronic fatigue syndrome and one relative) were formed. The study included four activities: three remote meetings and one online survey. First, Board members identified the needs and research questions. Second, Working Group members and persons affected by Long COVID (241 respondents, 85.5% with Long COVID, 14.5% with myalgic encephalomyelitis/chronic fatigue syndrome and 7.1% relatives) evaluated the research questions on a 1-5 Likert scale using an online survey. Then the Board gave feedback on this evaluation. Finally, Board members set the priorities for research through voting and discussion.

Results: Sixty-eight research questions were generated by the Board and categorised into four research domains (medicine, healthcare services, socioeconomics and burden of disease) and 14 subcategories. Their average importance ratings were moderate to high and varied from 3.41 (standard deviation = 1.16) for sex-specific diagnostics to 4.86 (standard deviation = 0.41) for medical questions on treatment. Five topics were prioritised: “treatment, rehabilitation and chronic care management”, “availability of interfaces for treatment continuity”, “availability of healthcare structures”, “awareness and knowledge among professionals” and “prevalence of Long COVID in children and adolescents”.

Conclusions: To our knowledge, this is the first study developing a citizen-driven, explicitly patient-centred research agenda with persons affected by Long COVID, setting it apart from existing multi-stakeholder efforts. The identified priorities could guide future research and funding allocation. Our methodology establishes a framework for citizen-driven research agendas, suitable for transfer to other diseases.

Source: Ziegler S, Raineri A, Nittas V, Rangelov N, Vollrath F, Britt C, Puhan MA. Long COVID Citizen Scientists: Developing a Needs-Based Research Agenda by Persons Affected by Long COVID. Patient. 2022 Apr 28. doi: 10.1007/s40271-022-00579-7. Epub ahead of print. PMID: 35478078. https://link.springer.com/article/10.1007/s40271-022-00579-7 (Full text)

The incidence and characteristics of chronic pain and fatigue after 12 months later admitting with COVID-19; The Post- COVID 19 syndrome

Abstract:

Introduction: This study aimed to evaluate chronic pain and fatigue in patients 12 months after hospitalization for Covid-19.

Methods: We studied the COVID-19 patients discharged from Hospital, March 10 and April 20, 2020.

Results: A total of 157 patients were included in this study. Forty-three patients (27.4%) complained of chronic fatigue and muscle weakness in the last six months. The visual analog fatigue scale (VAFS) score of 3.84 ± 1.48 was obtained. Forty patients (25.5%) were suspected of Chronic Fatigue Syndrome (CFS).Twenty-four patients (15.3%) had severe chronic pain or exacerbation of previous chronic pain, most of which were reported in the lower back (70.8%) and lower extremities (66.7%). Pain intensity had a mean score of 2.33 ± 0.87 and was mainly described as “muscle cramps,” “persistent dull pain,” and “boring and numbing.” In women, chronic pain and fatigue, extended hospital stays, ICU admission, and depressed mood were common than in men.For these pain and fatigue, 37% used nonsteroidal anti-inflammatory drugs, and 16.3% used antidepressants. Only one person had applied for physiotherapy, and none of the patients had received psychotherapy.

Conclusion: Fatigue and chronic pain in patients recovering from COVID-19 are common complications, even after 12 months of illness.

Source: Janbazi L, Kazemian A, Mansouri K, Madani SP, Yousefi N, Vahedifard F, Raissi G. The incidence and characteristics of chronic pain and fatigue after 12 months later admitting with COVID-19; The Post- COVID 19 syndrome. Am J Phys Med Rehabil. 2022 Apr 13. doi: 10.1097/PHM.0000000000002030. Epub ahead of print. PMID: 35473921.  https://pubmed.ncbi.nlm.nih.gov/35473921/

Ginger-indirect moxibustion plus acupuncture versus acupuncture alone for chronic fatigue syndrome: a randomized controlled trial

Abstract:

Objective: To assess the efficacy and safety of ginger-indirect moxibustion for chronic fatigue syndrome (CFS).

Methods: In this central randomized, controlled trial, 290 CFS participants were recruited and randomly allocated to group A (ginger-indirect moxibustion plus acupuncture) or group B (acupuncture alone). The study consisted of a treatment period of 8 weeks with a total of 24 treatments (3 sessions per week, every other day), and a follow-up period of 12 weeks. The outcome was measured by Fatigue Severity Scale (FSS), Psychological Health Report (SPHERE), the Self-rating depression scale (SDS) and the Hamilton anxiety scale (HAMA) at baseline, 2, 4, 6, 8, 12 and 20 weeks.

Results: With the treatment undergoing, the changes of FSS, SPHERE, SDS and HAMA scores in both groups increased gradually, and the effect maintained at the 12th week. Between groups, significantly higher score changes were seen in group A in FSS after 4 weeks treatment (11.94 9.12, 95%: 0.94, 4.7) and in SPHERE after 2 weeks treatment (3.7 2.27, 95%: 0.56, 2.31). But for SDS and HAMA, the improvement did not differ significantly between groups. No severe adverse events were reported.

Conclusion: Ginger-indirect moxibustion is a safe and effective intervention to relieve fatigue and accompanying physical symptoms of CFS.

Source: Tingting MA, Jie WU, Lijie Y, Fen F, Huilin Y, Jinhua Z, Yanjin Z, Qing N, Lirong H, Youbing L, Jue Y, Guiquan C, Tianshu H, Li W, Yuanfang R, Jing T. Ginger-indirect moxibustion plus acupuncture versus acupuncture alone for chronic fatigue syndrome: a randomized controlled trial. J Tradit Chin Med. 2022 Apr;42(2):242-249. doi: 10.19852/j.cnki.jtcm.20211214.003. PMID: 35473345. https://pubmed.ncbi.nlm.nih.gov/35473345/