Tag: 2021

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)

RIP Dr. Jay A. Goldstein

I was deeply saddened to learn that Dr. Jay Goldstein had passed away on March 4, 2021. Dr. Goldstein was a pioneer among ME/CFS researchers and clinicians. He rose to prominence in the 1990s through his clinical practice, and through the publication of several seminal works, chief among them: Betrayal by the Brain : The Neurologic Basis of Chronic Fatigue Syndrome, Fibromyalgia Syndrome, and Related Neural Network Disorders, Tuning the Brain : Principles and Practice of Neurosomatic Medicine, and Chronic Fatigue Syndromes : The Limbic Hypothesis. In addition to his books, Dr. Goldstein was also one of the editors, along with Dr. Byron Hyde, of The Clinical and Scientific Basis of Myalgic Encephalomyelitis–Chronic Fatigue Syndrome, a collection of papers on clinical practice and research that remains unsurpassed in both depth and scope.

Dr. Goldstein believed that ME/CFS was the result of an insult to the limbic system, located deep within the brain. The limbic system is involved with memory, emotion, and regulation of the autonomic nervous system. This last function is of critical importance to maintaining homeostasis in the body, as the autonomic nervous system regulates appetite, body temperature, blood pressure, blood sugar, sleep, wakefulness, heart rate, digestion – in short, nearly every physiological function necessary for maintaining life.

Dr. Goldstein’s theory, as laid out in his book, Betrayal by the Brain, was that ME/CFS is essentially a communication problem between the limbic system and the rest of the nervous system. His “limbic hypothesis” essentially states that no matter what the underlying cause of ME/CFS, the result is an injury to the limbic system, which subsequently causes widespread neuroimmune dysfunction. He identified ME/CFS as a “neurosomatic” illness, that is, a disorder of central nervous system processing. Dr. Goldstein based his theory on what he knew of the brain, which was substantial, as well as what he had observed of his patients’ reactions to various psychotropic medications. Recent studies have shown that in his approach Dr. Goldstein was  far ahead of his time.

Dr. Goldstein will be sorely missed, not just for his tremendous insights but for his compassion and commitment to his patients. There will never be another like him. RIP Dr. Jay A. Goldstein.

Dissecting the nature of post-exertional malaise

Abstract:

Background: Post-exertional malaise (PEM) is a defining characteristic of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) but there is insufficient research dissecting the nature of PEM from the patients’ perspective.

Methods: A PEM questionnaire administered to 150 ME/CFS patients. It included open-ended questions about triggers, experiences, recovery, and prevention. Responses were re-coded into concise, representative topics. Chi-Square tests of independence were then used to test for differences and relationships between duration of ME/CFS illness (<4 years and >10 years), PEM onset and duration, and gender with PEM trigger, experience, recovery, and prevention.

Results: Physical exertion was the most common trigger of PEM. The onset of PEM occurred within minutes after physical exertion compared to within hours after cognitive exertion (<0.05). ME/CFS patients sick for <4 years reported stress as a trigger significantly more often than those sick for >10 years (<0.001). ME/CFS patients sick for <4 years experienced more orthostatic symptoms during PEM than those sick for >10 years. ME/CFS patients sick for >10 years reported using medications to recover from PEM significantly more that those sick for <4 years (<0.01). Pacing and avoiding specific triggers were common approaches to prevent PEM.

Conclusions: There are differences in PEM triggers, experiences and recovery based on duration of illness. Asking about PEM is important for diagnosis and to understand how to manage PEM. Given that PEM occurs more quickly after physical versus cognitive exertion, these results should instigate research on the relationship of upright posture, hypoperfusion and PEM.

Source: Megan Hartle, Lucinda Bateman & Suzanne D. Vernon (2021) Dissecting the nature of post-exertional malaise, Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2021.1905415 https://www.tandfonline.com/doi/full/10.1080/21641846.2021.1905415 (Full text)

Medical School Education on Myalgic Encephalomyelitis

Abstract:

Background and objectives: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome ME/CFS is a common complex multi-system disease with a significant impact on the quality of life of patients and their families, yet the majority of ME/CFS patients go unrecognised or undiagnosed. For two decades the medical education establishment in the UK has been challenged to remedy these failings, but little has changed. This study was designed to ascertain the current UK medical school education on ME/CFS and to identify challenges and opportunities to inform the future of medical education.

Materials and methods: A questionnaire, developed under the guidance of the Medical Schools Council, was sent to all 34 UK Medical Schools to collect data for the academic year 2018-2019.

Results: Responses were provided by 22 out of a total of 34 medical schools (65%). 59% of respondents taught ME/CFS, led by specialists drawn from 6 medical disciplines. Teaching delivery was usually by lecture; however, discussion case studies and e-learning were used. 7 schools included questions on ME/CFS in their examinations and 3 schools reported likely clinical exposure to ME/CFS patients. 64% of respondents were interested in receiving further teaching aids in ME/CFS. None of the schools shared details of their teaching syllabus so it was not possible to ascertain what students were being taught.

Conclusions: UK medical school teaching in ME/CFS is shown to be inadequate. Several medical disciplines, with known differences about the disease, need to set these aside to give greater clarity in teaching undergraduates so they can more easily recognise and diagnose ME/CFS. Improvements are proposed in ME/CFS medical education consistent with the international paradigm shift in biomedical understanding of this disease. Many medical schools (64% of respondents) acknowledge this need by expressing a strong appetite for the development of further teaching aids and materials. The GMC and MSC are called upon to use their considerable influence to bring about the appropriate changes to medical school curricula so future doctors can recognise, diagnose and treat ME/CFS. The GMC should also consider creating a registered speciality encompassing ME/CFS, post viral fatigue and Long Covid.

Source: Muirhead, N.; Muirhead, J.; Lavery, G.; Marsh, B. Medical School Education on Myalgic Encephalomyelitis. Preprints 2021, 2021030420 https://www.preprints.org/manuscript/202103.0420/v1

We Already Know Enough to Avoid Making the Same Mistakes Again With Long COVID

Based on experience with past coronaviruses, the emerging challenge of prolonged symptoms after infection with the novel coronavirus 2019 (SARS-CoV-2) is unsurprising. Data from a large international web-based patient survey indicate substantial symptom overlap between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) at 6 months following the onset of first symptoms, including three quarters of participants suffering from fatigue and postexertional malaise, and over half with cognitive dysfunction.4 Apparent similarities between the presentations of long COVID and ME/CFS suggest that we may apply what we have learned from ME/CFS to long COVID.

Source: Todd E. Davenport, Staci R. Stevens, Jared Stevens, Christopher R. Snell, J. Mark Van Ness. We Already Know Enough to Avoid Making the Same Mistakes Again With Long COVID. Journal of Orthopedic & Sports Physical Therapy. Published online on March 10, 2021
https://doi.org/10.2519/jospt.blog.20210310

Understanding the economic impact of myalgic encephalomyelitis/chronic fatigue syndrome in Ireland: a qualitative study

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling and complex chronic disease of unknown origin, whose symptoms, severity, and progression are extremely variable. Despite being relatively common, the condition is poorly understood and routine diagnostic tests and biomarkers are unavailable. There is no evidence on the economic impact of ME/CFS in Ireland.

Methods: Adopting a patient and public involvement approach, we undertook three semi-structured focus groups, which together included 15 ME/CFS patients and 6 informal carers, to consider costs related to ME/CFS in Ireland, including how and why they arise. Focus groups were audio-recorded and transcribed verbatim, and we employed thematic analysis following the approach set out in Braun and Clarke (2006).

Results: Themes from the data were: (1) Healthcare barriers and costs; (2) Socioeconomic costs; (3) Costs of disability; and, (4) Carer-related costs. Patient participants described a range of barriers to effective healthcare that led to extra costs, including delays getting a diagnosis, poor awareness/understanding of the condition by healthcare professionals, and a lack of effective treatments. These were linked to poor prognosis of the illness by participants who, as a result, faced a range of indirect costs, including poorer labour market and education outcomes, and lower economic well-being. Direct extra costs of disability were also described, often due to difficulties accessing appropriate services and supports. Informal carer participants described a range of impacts, including time costs, burnout, and impacts on work and study.

Conclusions: The data suggests that ME/CFS patients face a wide range of costs, while there are also wider societal costs in the form of costs to the health service, lost productivity, and impacts on informal carers. These results will inform ongoing research that aims to quantify the economic burden of ME/CFS in Ireland and raise awareness of the illness amongst healthcare providers and policymakers.

Source: Cullinan J, Ní Chomhraí O, Kindlon T, Black L, Casey B. Understanding the economic impact of myalgic encephalomyelitis/chronic fatigue syndrome in Ireland: a qualitative study. HRB Open Res. 2020 Dec 4;3:88. doi: 10.12688/hrbopenres.13181.1. PMID: 33659857; PMCID: PMC7898356. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898356/ (Full text)

COVID-19: A methyl-group assault?

Abstract:

The socio-economic implications of COVID-19 are devastating. Considerable morbidity is attributed to ‘long-COVID’ – an increasingly recognized complication of infection. Its diverse symptoms are reminiscent of vitamin B12 deficiency, a condition in which methylation status is compromised. We suggest why SARS-CoV-2 infection likely leads to increased methyl-group requirements and other disturbances of one-carbon metabolism. We propose these might explain the varied symptoms of long-COVID. Our suggested mechanism might also apply to similar conditions such as myalgic encephalomyelitis/chronic fatigue syndrome. The hypothesis is evaluable by detailed determination of vitamin B12 and folate status, including serum formate as well as homocysteine and methylmalonic acid, and correlation with viral and host RNA methylation and symptomatology. If confirmed, methyl-group support should prove beneficial in such individuals.

Source: McCaddon A, Regland B. COVID-19: A methyl-group assault? Med Hypotheses. 2021 Feb 18;149:110543. doi: 10.1016/j.mehy.2021.110543. Epub ahead of print. PMID: 33657459; PMCID: PMC7890339. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890339/ (Full text)