Insights into Metabolite Diagnostic Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a persistent and unexplained pathological state characterized by exertional and severely debilitating fatigue, with/without infectious or neuropsychiatric symptoms, and with a minimum duration of 6 consecutive months. Its pathogenesis is not fully understood. There are no firmly established diagnostic biomarkers or treatment, due to incomplete understanding of the etiology of ME/CFS and diagnostic uncertainty. Establishing a biomarker for the objective diagnosis is urgently needed to treat a lot of patients. Recently, research on ME/CFS using metabolome analysis methods has been increasing. Here, we overview recent findings concerning the metabolic features in patients with ME/CFS and the animal models which contribute to the development of diagnostic biomarkers for ME/CFS and its treatment. In addition, we discuss future perspectives of studies on ME/CFS.

Source: Yamano E, Watanabe Y, Kataoka Y. Insights into Metabolite Diagnostic Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci. 2021 Mar 26;22(7):3423. doi: 10.3390/ijms22073423. PMID: 33810365. https://pubmed.ncbi.nlm.nih.gov/33810365/

Comparative Survey of People with ME/CFS in Italy, Latvia, and the UK: A Report on Behalf of the Socioeconomics Working Group of the European ME/CFS Research Network (EUROMENE)

Abstract:

Background and Objectives: A comparative survey of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients was carried out in three countries, with the aim of identifying appropriate policy measures designed to alleviate the burden of disease both on patients and their families, and also on public institutions. The survey addressed demographic features, the economic impact of the disease on household incomes, patterns of medical and social care, specific therapies, social relationships, and the impact of the illness on quality of life.

Materials and Methods: Parallel surveys were undertaken in Italy, Latvia, and the UK. There were 88 completed responses from Italy, 75 from Latvia, and 448 from the UK. To facilitate comparisons, 95% confidence intervals were calculated in respect of responses to questions from all three countries. To explore to what extent general practitioners (GPs) manage ME/CFS disease, a separate questionnaire for GPs, with questions about the criteria for granting a diagnosis, laboratory examinations, the involvement of specialists, and methods of treatment, was undertaken in Latvia, and there were 91 completed responses from GPs.

Results: The results are presented in respect of sociodemographic information, household income, disease progression and management, perceived effectiveness of treatment, responsibility for medical care, personal care, difficulty explaining the illness, and quality of life. Demographic details were similar in all three countries, and the impact of illness on net household incomes and quality of life. There were significant differences between the three countries in illness progression and management, which may reflect differences in patterns of health care and in societal attitudes. Graded exercise therapy, practiced in the UK, was found to be universally ineffective.

Conclusions: There were similarities between respondents in all three countries in terms of demographic features, the impact of the illness on household incomes and on quality of life, and on difficulties experienced by respondents in discussing their illness with doctors, but also differences in patterns of medical care, availability of social care, and societal attitudes to ME/CFS.

Source: Brenna E, Araja D, Pheby DFH. Comparative Survey of People with ME/CFS in Italy, Latvia, and the UK: A Report on Behalf of the Socioeconomics Working Group of the European ME/CFS Research Network (EUROMENE). Medicina (Kaunas). 2021 Mar 23;57(3):300. doi: 10.3390/medicina57030300. PMID: 33806902. https://pubmed.ncbi.nlm.nih.gov/33806902/

Exogenous Transforming Growth Factor-β in Brain-Induced Symptoms of Central Fatigue and Suppressed Dopamine Production in Mice

Abstract:

Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is one of the most refractory diseases in humans and is characterized by severe central fatigue accompanied with various symptoms that affect daily life, such as impaired memory, depression, and somatic pain. However, the etiology and pathophysiological mechanisms of CFS remain unknown. To investigate the pathophysiological role of transforming growth factor (TGF)-β1, we injected a cytokine into the lateral ventricle of a C57BL/6 mouse. The intracranial injection of TGF-β1 increased the immobility duration in a forced swimming test (FST) and time spent at the closed arm in elevated plus maze (EPM) analysis.

The mice injected with TGF-β1 into their brain showed increased sensitivity to pain in a von Frey test, and had a decreased retention time on rotarod and latency time in a bright box in a passive avoidance test. In addition, the serum levels of muscle fatigue biomarkers, lactate dehydrogenase (LDH) and creatine kinase (CK), were significantly increased after administration of TGF-β1. Intracranial injection of TGF-β1 significantly reduced the production of tyrosine hydroxylase (TH) in the ventral tegmental area, accompanied by a decreased level of dopamine in the striatum. The suppression of TH expression by TGF-β1 was confirmed in the human neuroblastoma cell line, SH-SY5Y. These results, which show that TGF-β1 induced fatigue-like behaviors by suppressing dopamine production, suggest that TGF-β1 plays a critical role in the development of central fatigue and is, therefore, a potential therapeutic target of the disease.

Source: Lee WK, Kim Y, Jang H, Sim JH, Choi HJ, Shin Y, Choi JJ. Exogenous Transforming Growth Factor-β in Brain-Induced Symptoms of Central Fatigue and Suppressed Dopamine Production in Mice. Int J Mol Sci. 2021 Mar 4;22(5):2580. doi: 10.3390/ijms22052580. PMID: 33806649. https://pubmed.ncbi.nlm.nih.gov/33806649/

Angina Simultaneously Diagnosed with the Recurrence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) mainly affects young adults and can have a potential impact on social functioning. As this syndrome is associated with endothelial dysfunction, the heart can be damaged via ischemia due to endothelial damage. This might potentially lead to heart failure, which accounts for approximately 20% of deaths among patients with ME/CFS. While cardiac ischemia is thought be a pathophysiologically important manifestation of this syndrome, this is not yet reported. Herein, we present a case of a young female with newly diagnosed vasospastic or microvascular angina and concurrent exacerbation of ME/CFS severity. Her anginal symptoms, including exertional chest pain and transient chest discomfort, mimicked those of ME/CFS but were relieved after the administration of a calcium channel blocker. We emphasize the possibility of concurrent angina and exacerbation of ME/CFS and the importance of detecting cardiac ischemia to avoid unfavorable outcomes.

Source: Li K, Otsuka Y, Nakano Y, Omura D, Hasegawa K, Obika M, Ueda K, Kataoka H, Otsuka F. Angina Simultaneously Diagnosed with the Recurrence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Diagnostics (Basel). 2021 Mar 6;11(3):460. doi: 10.3390/diagnostics11030460. PMID: 33800953. https://pubmed.ncbi.nlm.nih.gov/33800953/

Ginger-separated moxibustion for chronic fatigue syndrome and its effect on intestinal flora

Abstract:

Objective: To observe the effect of ginger-separated moxibustion on fatigue state and intestinal flora in patients with chronic fatigue syndrome (CFS).

Methods: A total of 62 patients with CFS were randomly divided into an observation group (31 cases, 3 cases dropped off) and a control group (31 cases, 2 cases dropped off). The patients in the control group were treated with normal diet and moderate exercise; on the basis of the control group, the patients in the observation group were treated with ginger-separated moxibustion at Zhongwan (CV 12), Shenque (CV 8) and Guanyuan (CV 4), 30 min each time, once every other day, three times a week. Both groups were intervened for 4 weeks. Before and after treatment, the fatigue scale-14 (FS-14) was used to observe the improvement of fatigue state, and 16S rRNA detection technology was used to detect the distribution of intestinal flora.

Results: Compared before treatment, the FS-14 score was reduced after treatment in the observation group (P<0.01), and the reduction in the observation group was larger than that in the control group (P<0.01). The relative abundance of intestinal flora was similar between the observation group and control group at the phylum and genus level before treatment. After treatment, there was no significant change of intestinal flora in the control group. However, the enterobacteriaceae, corynebacterium, erysipelothrix, actinomycetes were increased in the observation group (P<0.05), and actinomycetes, ruminococcus, lactarius had obvious flora advantages compared with the control group (P<0.05).

Conclusion: The ginger-separated moxibustion could significantly improve the fatigue state in CFS patients, which may be related to the regulation of intestinal flora structure and the repair of intestinal barrier.

Source: Lin YF, Jin XQ, Zhu JF, Chen YD, Sheng JL, He JJ, Jin YY. [Ginger-separated moxibustion for chronic fatigue syndrome and its effect on intestinal flora]. Zhongguo Zhen Jiu. 2021 Mar 12;41(3):269-74. Chinese. doi: 10.13703/j.0255-2930.20200210-k0001. PMID: 33798308. https://pubmed.ncbi.nlm.nih.gov/33798308/

The neurological symptoms of COVID-19: a systematic overview of systematic reviews, comparison with other neurological conditions and implications for healthcare services

Abstract:

Aims: In response to the rapid spread of COVID-19, this paper provides health professionals with better accessibility to available evidence, summarising findings from a systematic overview of systematic reviews of the neurological symptoms seen in patients with COVID-19. Implications of so-called ‘Long Covid’ on neurological services and primary care and similarities with other neurological disorders are discussed.

Methods: Firstly, a systematic overview of current reviews of neurological symptoms of COVID-19 was conducted. Secondly, the implications of these findings are discussed in relation to the potential effect on neurological services and the similarities in the experience of patients with COVID-19 and those with other neurological disorders. A total of 45 systematic reviews were identified within seven databases, published between 11 April 2020 and 15 October 2020, following a search in June 2020, updated on 20 October 2020.

Results: The results indicated that COVID-19 exhibits two types of neurological symptoms; life-threatening symptoms such as Guillain-Barre Syndrome (GBS) and encephalitis, and less devastating symptoms such as fatigue and myalgia. Many of these so-called lesser symptoms appear to be emerging as longer-term for some sufferers and have been recently labelled Long Covid. When compared, these less devastating symptoms are very similar to other neurological conditions such as chronic fatigue syndrome (CFS) and functional neurological disorder (FND).

Conclusion: Implications for neurological healthcare services in the United Kingdom (UK) may include longer waiting times and a need for more resources (including more qualified health professionals). There is also a possible change-effect on health professionals’ perceptions of other neurological conditions such as CFS and FND. Future research is recommended to explore changes in health professionals’ perceptions of neurological symptoms because of COVID-19.

Source: Wildwing T, Holt N. The neurological symptoms of COVID-19: a systematic overview of systematic reviews, comparison with other neurological conditions and implications for healthcare services. Ther Adv Chronic Dis. 2021 Jan 28;12:2040622320976979. doi: 10.1177/2040622320976979. PMID: 33796241; PMCID: PMC7970685. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970685/  (Full text)

Skewing of the B cell receptor repertoire in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition characterized by fatigue and post-exertional malaise, accompanied by various signs of neurological and autonomic dysfunction. ME/CFS is often triggered by an infectious episode and associated with an aberrant immune system. Here we report that ME/CFS is a disorder characterized by skewed B cell receptor gene usage. By applying a next-generation sequencing to determine the clone-based IGHV/IGHD/IGHJ repertoires, we revealed a biased usage of several IGHV genes in peripheral blood B cells from ME/CFS patients. Results of receiver operating characteristic (ROC) analysis further indicated a possibility of distinguishing patients from healthy controls, based on the skewed B cell repertoire. Meanwhile, B cell clones using IGHV3-30 and IGHV3-30-3 genes were more frequent in patients with an obvious infection-related episode at onset, and correlated to expression levels of interferon response genes in plasmablasts. Collectively, these results imply that B cell responses in ME/CFS are directed against an infectious agents or priming antigens induced before disease onset.

Source: Sato W, Ono H, Matsutani T, Nakamura M, Shin I, Amano K, Suzuki R, Yamamura T. Skewing of the B cell receptor repertoire in myalgic encephalomyelitis/chronic fatigue syndrome. Brain Behav Immun. 2021 Mar 29:S0889-1591(21)00153-7. doi: 10.1016/j.bbi.2021.03.023. Epub ahead of print. PMID: 33794313. https://pubmed.ncbi.nlm.nih.gov/33794313/

The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: analysis of high-throughput genetic, epigenetic, and gene expression studies

Abstract:

Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) show specific epigenetic and gene expression signatures of the disease. However, it is unknown whether these signatures in ME/CFS include abnormal levels of the human angiotensin-converting enzyme ACE and ACE2, the latter being the main receptor described for host-cell invasion by SARS-CoV-2. To investigate that, we first reviewed published case-control genome-wide association studies based on single nucleotide polymorphism data, case-control epigenome-wide association studies based on DNA methylation data, and case-control gene expression studies based on microarray data.

From these published studies, we did not find any evidence for a difference between patients with ME/CFS and healthy controls in terms of genetic variation, DNA methylation, and gene expression levels of ACE and ACE2 . In line with this evidence, the analysis of a new data set on the ACE/ACE2 gene expression in peripheral blood mononuclear cells did not find any differences between a female cohort of 37 patients and 34 age-matched healthy controls. Future studies should be conducted to extend this investigation to other potential receptors used by SARS-CoV-2. These studies will help researchers and clinicians to better assess the health risk imposed by this virus when infecting patients with this debilitating disease.

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: analysis of high-throughput genetic, epigenetic, and gene expression studies. medRxiv [Preprint]. 2021 Mar 24:2021.03.23.21254175. doi: 10.1101/2021.03.23.21254175. PMID: 33791744; PMCID: PMC8010776. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010776/ (Full text)

An exploratory study of discrepancies between objective and subjective measurement of the physical activity level in female patients with chronic fatigue syndrome

Abstract:

Objective: To explore the ability of a self-report activity diary to measure the physical activity level (PAL) in female patients with chronic fatigue syndrome (CFS) and whether illness-related complaints, health-related quality of life domains (HRQOL) or demographic factors are associated with discrepancies between self-reported and objectively measured PAL.

Methods: Sixty-six patients with CFS, recruited from the chronic fatigue clinic of a university hospital, and twenty matched healthy controls wore an accelerometer (Actical) for six consecutive days and registered their activities in an activity diary in the same period. Participants’ demographic data was collected and all subjects completed the CFS Symptom List (illness-related complaints) daily and Short-Form-36 (HRQOL domains) during the first and second appointment.

Results: A significant, but weak association between the activity diary and Actical was present in patients with CFS (rs = 0.376 and rs = 0.352; p < 0.001) and a moderately strong association in healthy controls (rs = 0.605; and rs = 0.644; p < 0.001) between week and weekend days, respectively. A linear mixed model identified a negative association between age and the discrepancy between the self-reported and objective measure of PA in both patients with CFS and healthy controls.

Conclusion: The activity diary showed limited ability to register the PAL in female patients with CFS. The discrepancy between measures was not explained by illness-related complaints, HRQOL domains or demographic factors. The activity diary cannot replace objective activity monitoring measured with an accelerometer, but may provide additional information about the perceived activity.

Source: Vergauwen K, Huijnen IPJ, Smeets RJEM, Kos D, van Eupen I, Nijs J, Meeus M. An exploratory study of discrepancies between objective and subjective measurement of the physical activity level in female patients with chronic fatigue syndrome. J Psychosom Res. 2021 Mar 10;144:110417. doi: 10.1016/j.jpsychores.2021.110417. Epub ahead of print. PMID: 33773330. https://pubmed.ncbi.nlm.nih.gov/33773330/

A report on comorbidity of chronic fatigue syndrome, postural tachycardia syndrome, and narcolepsy with 5,10-methylenetetrahydrofolate reductase (MTHFR) mutation in an adolescent

A 16-year-old male adolescent was hospitalized complaining of intermittent dizziness, drowsiness, and fatigue for approximately 2 years. The patient had an episode of fever and pharyngalgia lasting nearly 2 weeks and had undergone appendectomy because of acute appendicitis before the presentation of the above symptoms. He suffered from severe dizziness mostly after switching from a supine to an upright posture when he was getting up in the morning. The symptom of dizziness usually persisted for minutes to hours and could be partially alleviated by recumbency. In addition, he felt drowsy and fatigued all day despite a total sleep duration of 14 to 15 h per day. All the symptoms could be partially mitigated by complete bed rest for 1 or 2 weeks, but he relapsed after taking part in normal school life again. Additionally, the feeling of fatigue was obviously aggravated after exertion or infection. He was unable to focus on his studies and had to withdraw from school for a long time. As a result, there was a decline in academic performance after the onset of illness. He used to benefit from taking carnitine and folate; however, the improvement was limited in enabling him to take part in normal social and school life. He was physically and mentally healthy before the presentation and did not feel disgusted with learning in the past. No family history of cardiovascular or nervous system disease was evident. The study was approved by the Ethics Committee of Peking University First Hospital (No. 2020- 415).

Source: Liao, Ying; Qi, Jian-Guang; Yan, Hui; Zhang, Qing-You; Ji, Tao-Yun; Chang, Xing-Zhi; Yang, Hai-Po; Jin, Hong-Fang; Du, Jun-Bao A report on comorbidity of chronic fatigue syndrome, postural tachycardia syndrome, and narcolepsy with 5,10-methylenetetrahydrofolate reductase (MTHFR) mutation in an adolescent, Chinese Medical Journal: March 25, 2021 – Volume Publish Ahead of Print – Issue – doi: 10.1097/CM9.0000000000001387  https://journals.lww.com/cmj/Citation/9000/A_report_on_comorbidity_of_chronic_fatigue.98688.aspx (Full text)