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/

Frailty assessment for COVID-19 follow-up: a prospective cohort study

Abstract:

Background: The Clinical Frailty Scale (CFS) is increasingly used for clinical decision making in acute care but little is known about frailty after COVID-19.

Objectives: To investigate frailty and the CFS for post-COVID-19 follow-up.

Methods: This prospective multicentre cohort study included COVID-19 survivors aged ≥50 years presenting for a follow-up visit ≥3 months after the acute illness. Nine centres retrospectively collected pre-COVID-19 CFS and prospectively CFS at follow-up. Three centres completed the Frailty Index (FI), the short physical performance battery (SPPB), 30 s sit-to-stand test and handgrip strength measurements. Mixed effect logistic regression models accounting for repeated measurements and potential confounders were used to investigate factors associated with post-COVID-19 CFS. Criterion and construct validity were determined by correlating the CFS to other concurrently assessed frailty measurements and measures of respiratory impairment, respectively.

Results: Of the 288 participants 65% were men, mean (SD) age was 65.1 (9) years. Median (IQR) CFS at follow-up was 3 (2-3), 21% were vulnerable or frail (CFS ≥4). The CFS was responsive to change, correlated with the FI (r=0.69, p<0.001), the SPPB score (r=-0.48, p<0.001) (criterion validity) and with the St George’s Respiratory Questionnaire score (r=0.59, p<0.001), forced vital capacity %-predicted (r=-0.25, p<0.001), 6 min walk distance (r=-0.39, p<0.001) and modified Medical Research Council (mMRC) (r=0.59, p<0.001). Dyspnoea was significantly associated with a higher odds for vulnerability/frailty (per one mMRC adjusted OR 2.01 (95% CI 1.13 to 3.58), p=0.02).

Conclusions: The CFS significantly increases with COVID-19, and dyspnoea is an important risk factor for post-COVID-19 frailty and should be addressed thoroughly.

Source: Müller I, Mancinetti M, Renner A, Bridevaux PO, Brutsche MH, Clarenbach C, Garzoni C, Lenoir A, Naccini B, Ott S, Piquilloud L, Prella M, Que YA, Soccal PM, von Garnier C, Geiser TK, Funke-Chambour M, Guler S. Frailty assessment for COVID-19 follow-up: a prospective cohort study. BMJ Open Respir Res. 2022 Apr;9(1):e001227. doi: 10.1136/bmjresp-2022-001227. PMID: 35459694. https://bmjopenrespres.bmj.com/content/9/1/e001227.long (Full text)

Global Prevalence of Post COVID-19 Condition or Long COVID: A Meta-Analysis and Systematic Review

Abstract:

Introduction: This study aims to examine the worldwide prevalence of post COVID-19 condition, through a systematic review and meta-analysis.

Methods: PubMed, Embase, and iSearch were searched on July 5, 2021 with verification extending to March 13, 2022. Using a random effects framework with DerSimonian-Laird estimator, we meta-analyzed post COVID-19 condition prevalence at 28+ days from infection.

Results: 50 studies were included, and 41 were meta-analyzed. Global estimated pooled prevalence of post COVID-19 condition was 0.43 (95% CI: 0.39,0.46). Hospitalized and non-hospitalized patients have estimates of 0.54 (95% CI: 0.44,0.63) and 0.34 (95% CI: 0.25,0.46), respectively. Regional prevalence estimates were Asia- 0.51 (95% CI: 0.37,0.65), Europe- 0.44 (95% CI: 0.32,0.56), and North America- 0.31 (95% CI: 0.21,0.43). Global prevalence for 30, 60, 90, and 120 days after infection were estimated to be 0.37 (95% CI: 0.26,0.49), 0.25 (95% CI: 0.15,0.38), 0.32 (95% CI: 0.14,0.57) and 0.49 (95% CI: 0.40,0.59), respectively. Fatigue was the most common symptom reported with a prevalence of 0.23 (95% CI: 0.17,0.30), followed by memory problems (0.14 [95% CI: 0.10,0.19]).

Discussion: This study finds post COVID-19 condition prevalence is substantial; the health effects of COVID-19 appear to be prolonged and can exert stress on the healthcare system.

Source: Chen C, Haupert SR, Zimmermann L, Shi X, Fritsche LG, Mukherjee B. Global Prevalence of Post COVID-19 Condition or Long COVID: A Meta-Analysis and Systematic Review. J Infect Dis. 2022 Apr 16:jiac136. doi: 10.1093/infdis/jiac136. Epub ahead of print. PMID: 35429399. https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiac136/6569364?login=false (Full text available as PDF file)

Health-related quality of life in Young People with Chronic fatigue syndrome/ Myalgic encephalomyelitis

Abstract

Background: Chronic fatigue syndrome/Myalgic encephalomyelitis (CFS/ME) is a disease that affects people of all ages. CFS/ME significantly limits the activity level of those affected, including in relation to physical activity, schooling, occupational life and social life.

High levels of school absence among young people with CFS/ME result in loss of important learning and social development among peers. As such, there is increasing uncertainty about their future, and personal and socio-economic consequences could put them at risk of becoming disabled at a young age. Measurements of health-related quality of life (HRQoL), including being able to function in school, have shown that young people with CFS/ME score lower than their counterparts without CFS/ME.

Aims: The overall aim of this project was to explore HRQoL among young people with CFS/ME, including the factors associated with HRQoL in relation to school and everyday life.

More specifically, the aim was to firstly (Study1) examine HRQoL, including factors that are positively or negatively associated with HRQoL, in a cohort of young people with CFS/ME.

Study 1, along with the previous literature, provided the basis for an in-depth study (Study 2) to investigate the positive and negative factors that young people with CFS/ME experience in school and everyday life.

Based on the findings from Study 1 and Study 2, a third study (Study 3) was planned to explore teachers’, counsellors’ and school nurses’ experiences with educational and social adaptation at school for young people with CFS/ME.

Method: To explore HRQoL and the factors associated with HRQoL among young people with CFS/ME (Studies 1 & 2), a cross-sectional survey- and interview-based study was conducted. The participants of the cross-sectional study were recruited to participate in the interview study.

To explore the experiences of teachers, counsellors and school nurses with education and social adaptions at school for young people with CFS/ME (Study 3), an interview study was conducted with participants recruited among school personnel and school nurses in secondary school (educating students aged 13-16), high school (educating students aged 16-19) and educational psychological services (EPS).

Results: A total of 63 participants were included in the cross-sectional study, 18 of whom participated in the interview study. A total of 12 participants were included in the interview study with the teachers, counsellors and school nurses. In the cross-sectional study (Study 1), young people with CFS/ME scored lower on HRQoL than their counterparts who were healthy or had other chronic diseases. Contact with school and teachers was associated with a higher HRQoL among young people with CFS/ME.

This association could be due to that more contact resulted from adaptations of education and social life at school, or that fewer health problems due to CFS/ME had abled the young people to maintain the contact with school and teachers.

In Study 2, it was found that an adapted plan for education and social life at school for young people with CFS/ME could increase the possibility of continuing schooling with peers. The lack of an adapted plan for education and social life at school could lead to increased school absence as well as loss of education, social contact and development among peers. Subsequently, this could lead to depressive thoughts and worry about the future.

The school personnel and school nurses in Study 3 experienced that young people with CFS/ME lost confidence in school. The challenges experienced by school personnel included (1) understanding students’ needs before they received a diagnosis and before school personnel received information from healthcare providers and (2) maintaining the teacher–student relationship and (3) the continuity of teaching.

In terms of measures for better management, early problematization of school absence, interdisciplinary collaboration on early measures, ensuring the maintenance of the teacher–student relationship and increasing CFS/ME-related competence in schools were proposed. These measures could contribute to prevent loss of function and school absence among young people with CFS/ME.

Conclusion: HRQoL among young people with CFS/ME was associated with contact with school and teachers, but a causal relationship could not be proven.

Interviews with young people with CFS/ME and school personnel suggested that interdisciplinary strategies for early adaptations to education and social life at school for young people with CFS/ME may benefit education and social development among peers for young people with CFS/ME. Lack of educational and social adaptations at school might lead to loss of education, social life and development among peers.

Source: Similä, Wenche Ann. Health-related quality of life in Young People with Chronic fatigue syndrome/ Myalgic encephalomyelitis. Doctoral thesis. https://ntnuopen.ntnu.no/ntnu-xmlui/handle/11250/2991015

Molecular Hydrogen as a Medical Gas for the Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Possible Efficacy Based on a Literature Review

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disorder that is characterized by fatigue that persists for more than 6 months, weakness, sleep disturbances, and cognitive dysfunction.

There are multiple possible etiologies for ME/CFS, among which mitochondrial dysfunction plays a major role in abnormal energy metabolism.

The potential of many substances for the treatment of ME/CFS has been examined; however, satisfactory outcomes have not yet been achieved. The development of new substances for curative, not symptomatic, treatments is desired.

Molecular hydrogen (H2) ameliorates mitochondrial dysfunction by scavenging hydroxyl radicals, the most potent oxidant among reactive oxygen species.

Animal experiments and clinical trials reported that H2 exerted ameliorative effects on acute and chronic fatigue. Therefore, we conducted a literature review on the mechanism by which H2 improves acute and chronic fatigue in animals and healthy people and showed that the attenuation of mitochondrial dysfunction by H2 may be involved in the ameliorative effects.

Although further clinical trials are needed to determine the efficacy and mechanism of H2 gas in ME/CFS, our literature review suggested that H2 gas may be an effective medical gas for the treatment of ME/CFS.

Source: Shin-ichi Hirano, Yusuke Ichikawa, Bunpei Sato, Yoshiyasu Takefuji and Fumitake Satoh. Molecular Hydrogen as a Medical Gas for the Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Possible Efficacy Based on a Literature Review. Front. Neurol., 11 April 2022  https://doi.org/10.3389/fneur.2022.841310 (Full text)