The weekly research round-up includes recent publications about ME/CFS and Long Covid. We highlight the studies that have particularly caught our interest and follow these with the full list of publications together with their abstracts (summaries).
The ME Association maintains a comprehensive index of published research on ME/CFS and Long Covid that is free to use and updated weekly.
Audio commentary by Dr Katrina Pears
There have been seven new ME/CFS studies and twenty-four new Long Covid studies this week.
We have highlighted one of the ME/CFS studies in more detail below:
Paper two (2) this week is a preprint (meaning the science has not been peer-reviewed and verified) which looks into the antibody response to Epstein-Barr Virus (EBV) to establish whether this can be used for a diagnostic biomarker.
This work used a large public dataset available on IgG antibodies to 3,054 EBV peptides (previous study conducted by Loebel et al., 2017). IgG or immunoglobulin G is a type of antibody, which is created and released by plasma B cells. These antibodies protect you against infection by “remembering” which germs you've been exposed to before. If those germs come back, your immune system knows to attack them.
The study classified ME/CFS patients into two groups (n=92), with either an acute infection disease trigger (n=54) or an unknown disease trigger (including non-infection related triggers) (n=38), with 50 healthy controls. This study used machine learning to predict disease status, i.e. ME/CFS or healthy control.
In brief, the findings of this study included:
- When comparing all data, no one antibody could identify between ME/CFS and healthy controls.
- However, 26 antibodies grouped together could distinguish between ME/CFS patients with an infectious disease trigger and healthy controls, and this could be done with extremely high accuracy (90-100%).
- Performing further analysis into the 26 identified antibodies (bioinformatic analysis), which explored if these antibodies could explain the pathology via the mechanism of molecular mimicry (the structural similarity between foreign (such as microbes) and self-molecules of the host (i.e. us). However, they found no correlation between the importance of each antibody and the similarity of the structure of the antibody between human proteins and each EBV peptide recognised.
- The data did not support the hypothesis that antibodies recognising important EBV peptides as disease predictive had a high potential for cross-reactivity with human proteins.
- It is suggested that the role of EBV in ME/CFS related autoimmunity should be reconsidered under alternative theories, such as the self-nonself discrimination problem.
- The authors conclude that their study demonstrates the difficulty of finding anti-EBV antibodies that could be used as general markers of ME/CFS. In the best-case scenario for those with an infectious disease trigger, a set of 26 EBV antibodies can be used to identify between ME/CFS and healthy controls.
The main limitation of this research is its reliance on previous data, with no description being given on patient characteristics such as diagnostic criteria. However, the research was conducted by a well-known research group, led by Carmen Scheibenbogen, so we can be reassured that the study was thoroughly thought out.
In conclusion, this study has provided a list of possible EBV peptides whose associated IgG antibody responses could be used to diagnose ME/CFS where infection is reported as a trigger. This research also makes some interesting points for future research, showing the difficulty of finding a biomarker, the fact that a biomarker is likely to involve a range of different compounds (such as more than one antibody) and the heterogenous nature of ME/CFS. This means that one size does not fit all, with it likely that a generic disease will be incredibly difficult (if not impossible) to find.
Further reading on this topic can be found in our conference report from the Charité Fatigue Center ME/CFS Research Conference 2023, where we covered work from this group, see here (refer to talk 17, page 6). Additionally, we have previously covered human herpervirsuses (which included EBV) and their role in ME/CFS and Long Covid in a research review.
There have also been a number of other biomedical studies published this week, you may also be interested in reading:
- Paper five (5) which looks into catalytic antibodies, which cause the breakdown of the myelin basic protein (MBP), which is the second most abundant protein in the nervous system.
- Paper six (6) which looks into brain-regional characteristics and neuroinflammation.
- Paper seven (7) which looks into the dysregulation of the kynurenine pathway and how disruption in this pathway may contribute to symptomology.
ME/CFS Research References
Kong L, Ren J, Fang S, Li Y, Wu Z, Zhou X, Hao Q, Fang M, Zhang YQ.
J Glob Health. 2023 Nov 24;13:04157.
Background: Chronic fatigue syndrome (CFS) is a global public health concern. We performed this systematic review of randomised controlled trials (RCTs) to evaluate the effects and safety of traditional Chinese mind-body exercises (TCME) for patients with CFS.
Methods: We comprehensively searched MEDLINE, Embase, Web of Science, PsycINFO, Cochrane Library, CNKI, VIP databases, and Wanfang Data from inception to October 2022 for eligible RCTs of TCME for CFS management. We used Cochran’s Q statistic and I2 to assess heterogeneity and conducted subgroup analyses based on different types of TCME, background therapy, and types of fatigue. We also assessed the quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach.
Results: We included 13 studies (n = 1187) with a maximal follow-up of 12 weeks. TCME included Qigong and Tai Chi. At the end of the treatment, compared with passive control, TCME probably reduces the severity of fatigue (standardised mean differences (SMD) = 0.85; 95% confidence interval (CI) = 0.64, 1.07, moderate certainty), depression (SMD = 0.53; 95% CI = 0.34, 0.72, moderate certainty), anxiety (SMD = 0.29; 95% CI = 0.11, 0.48, moderate certainty), sleep quality (SMD = 0.34; 95% CI = 0.10, 0.57, low certainty) and mental functioning (SMD = 0.90; 95% CI = 0.50, 1.29, low certainty).
Compared with other active control therapies, TCME results in little to no difference in the severity of fatigue (SMD = 0.08; 95% CI = -0.18, 0.34, low certainty). For long-term outcomes, TCME may improve anxiety (SMD = 1.74; 95% CI = 0.44, 3.03, low certainty) compared to passive control. We did not identify TCME-related serious adverse events.
Conclusions: In patients with CFS, TCME probably reduces post-intervention fatigue, depression, and anxiety and may improve sleep quality and mental function compared with passive control, but has limited long-term effects. These findings will help health professionals and patients with better clinical decision-making.
Fonseca, A.; Szysz, M.; Ly, H.T.; Cordeiro, C.; Sepúlveda, N.
Preprints 2023, 2023111523.
The diagnosis and the pathology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) remain under debate. However, there is a growing body of evidence for an autoimmune component in ME/CFS caused by the Epstein-Barr virus (EBV) and other viral infections.
In this work, we took advantage of a large public dataset on the IgG antibodies to 3,054 EBV peptides to understand whether these immune responses could be used as putative biomarkers for disease diagnosis and triggers of pathological autoimmunity in ME/CFS patients using healthy controls (HCs) as a comparator cohort. We then aimed at predicting disease status of study participants using a Super Learner algorithm targeting an accuracy of 85% when splitting data into train and test datasets.
When we compared data of all ME/CFS patients or data of a subgroup of these patients with non-infectious or unknown disease trigger to the dataset of HC, we could not find an antibody-based classifier that would meet the desired accuracy in the test dataset. In contrast, we could identify a 26-antibody classifier that could distinguish ME/CFS patients with an infectious disease trigger from HCs with 100% and 90% accuracies on the train and test sets, respectively.
We finally performed a bioinformatic analysis of the EBV peptides associated with these 26 antibodies. We found no correlation between the importance metric of the selected antibodies in the classifier and the maximal sequence homology between human proteins and each EBV peptide recognized by these antibodies.
In conclusion, these 26 antibodies against EBV have an effective potential for disease diagnosis of a subset of patients, but they are less likely to trigger pathological autoimmune responses that could explain the pathogenesis of ME/CFS.
Nina K. Vøllestad, Anne Marit Mengshoel.
Frontiers in Physiology, Volume 14- 2023.
Post-exertional malaise (PEM) is commonly recognized as a hallmark of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and is often used as one of several criteria for diagnosing ME/CFS.
In this perspective paper we want to reflect on how PEM is understood, assessed, and evaluated in scientific literature, and to identify topics to be addressed in future research.
Studies show that patients use a wide variety of words and concepts to label their experience of PEM in everyday life, and they report physical or mental exertions as triggers of PEM. They also report that PEM may have an immediate or delayed onset and may last from a few days to several months.
When standardized exercise tests are used to trigger PEM experimentally, the exacerbation of symptoms has a more immediate onset but still shows a wide variability in duration.
There are indications of altered muscular metabolism and autonomic nervous responses if exercise is repeated on successive days in patients with ME/CFS. The decreased muscular capacity appears to be maintained over several days following such controlled exercise bouts. These responses may correspond to patients' experiences of increased exertion.
Based on this background we argue that there is a need to look more closely into the processes occurring in the restitution period following exercise, as PEM reaches the peak in this phase.
Mantle, D.; Hargreaves, I.P.; Domingo, J.C.; Castro-Marrero, J.
Preprints 2023, 2023111554.
Post-viral fatigue syndrome (PVFS) encompasses a wide range of complex neuroimmune disorders of unknown cause characterized by disabling post-exertional fatigue, myalgia and joint pain, cognitive impairments, unrefreshing sleep, autonomic dysfunction, and neuropsychiatric symptoms. It includes myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), and more recently post-COVID-19 condition (Long COVID).
To date, there are no definitive clinical case criteria and no FDA-approved pharmacological therapies for PVFS. Given the current lack of effective treatments, there is a need to develop novel therapeutic strategies for these disorders.
Mitochondria, the cellular organelles responsible for tissue energy production, have recently garnered attention in research into PVFS due to their crucial role in cellular bioenergetic metabolism in these conditions. Accumulating literature has identified a link between mitochondrial dysfunction and low-grade systemic inflammation in ME/CFS, FM, and Long COVID.
To address this issue, this article aimed to critically review the evidence relating to mitochondrial dysfunction in the pathogenesis of these disorders; in particular, to evaluate the effectiveness of coenzyme Q10 supplementation on chronic fatigue and pain symptoms as a novel therapeutic strategy for the treatment of PVFS.
Raisa Masood, Taryn E. LeRoy, Michael A. Moverman, Matthew W. Feldman, Ashley Rogerson, and Matthew J. Salzler.
Global Spine Journal. 2023;0(0).
Study Design: Systematic Review
Objective: To perform a systematic review assessing the relationship between functional somatic syndromes (FSSs) and clinical outcomes after spine surgery.
Methods: A systematic review of online databases (PubMed and Web of Science) through December 2021 was conducted via PRISMA guidelines to identify all studies investigating the impact of at least one FSS (fibromyalgia, irritable bowel syndrome (IBS), chronic headaches/migraines, interstitial cystitis, chronic fatigue syndrome, multiple chemical sensitivity) on outcomes after spine surgery. Outcomes of interest included patient reported outcome measures (PROMs), postoperative opioid use, cost of care, complications, and readmission rates.
Results: A total of 207 records were identified. Seven studies (n = 40,011 patients) met inclusion criteria with a mean MINORS score of 16.6 out of 24. Four studies (n = 21,086) reported postoperative opioid use; fibromyalgia was a strong risk factor for long-term opioid use after surgery whereas the association with chronic migraines remains unclear. Two studies (n = 233) reported postoperative patient reported outcome measures (PROMs) with mixed results suggesting a possible association between fibromyalgia and less favorable PROMs. One study (n = 18,692) reported higher postoperative complications in patients with fibromyalgia.
Conclusion: Patients with fibromyalgia and possibly migraines are at higher risk for prolonged postoperative opioid use and less favorable PROMs after spine surgery. There is limited research on the relationship between other Functional somatic syndromes (FSSs) and outcomes following spine surgery. Growing evidence suggests the variation in outcomes after spine procedures may be attributed to non-identifiable organic patient factors such as FSSs.
Michael Anthony Jensen, Miranda Lee Dafoe, Julie Wilhelmy, Layla Cervantes, Anna N Okumu, Lucas Kipp, Mohsen Nemat-Gorgani, and Ronald Wayne Davis.
Biochemistry 2023, November 27, 2023.
Here we report preliminary data demonstrating that some patients with myalgic encephalomyelitis/chronic fatiguesyndrome (ME/CFS) may have catalytic autoantibodies that cause the breakdown of myelin basic protein (MBP).
We propose that these MBP-degradative antibodies are important to the pathophysiology of ME/CFS, particularly in the occurrence of white matter disease/demyelination. This is supported by magnetic resonance imagining studies that show these findings in patients with ME/CFS and could explain symptoms of nerve pain and muscle weakness.
In this work, we performed a series of experiments on patient plasma samples where we isolated and characterized substrate-specific antibodies that digest MBP. We also tested glatiramer acetate (copaxone), an FDA approved immunomodulator to treat multiple sclerosis, and found that it inhibits ME/CFS antibody digestion of MBP.
Furthermore, we found that aprotinin, which is a specific serine protease inhibitor, specifically prevents breakdown of MBP while the other classes of protease inhibitors had no effect. This coincides with the published literature describing catalytic antibodies as having serine protease-like activity.
Postpandemic research has also provided several reports of demyelination in COVID-19. Because COVID-19 has been described as a trigger for ME/CFS, demyelination could play a bigger role in patient symptoms for those recently diagnosed with ME/CFS. Therefore, by studying proteolytic antibodies in ME/CFS, their target substrates, and inhibitors, a new mechanism of action could lead to better treatment and a possible cure for the disease.
Jin-Seok Lee, Wakiro Sato, Chang-Gue Son.
Autoimmunity Reviews, Available online 26 November 2023, 103484. [In Press, Journal Pre-proof}
- Neuroinflammation is the most convincing hypothesis for ME/CFS pathophysiology, explaining its multifaceted symptoms and pathological features.
- Across various neuroimaging techniques, including MRI, MRS, PET, and EEG, the frontal cortex was the most frequently observed region.
- Our meta-analysis data showed that not only the insula and thalamus showed significant hypoactivity, but also the limbic system.
- Cortical-limbic disconnection leads to the abnormalities of metabolite and brain waves, which eventually contribute to main symptoms of ME/CFS.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition characterized by an elusive etiology and pathophysiology. This study aims to evaluate the pathological role of neuroinflammation in ME/CFS by conducting an exhaustive analysis of 65 observational studies.
Four neuroimaging techniques, including magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), electroencephalography (EEG), and positron emission tomography (PET), were employed to comparatively assess brain regional structure, metabolite profiles, electrical activity, and glial activity in 1529 ME/CFS patients (277 males, 1252 females) and 1715 controls (469 males, 1246 females).
Clinical characteristics, including sex, age, and fatigue severity, were consistent with established epidemiological patterns. Regional alterations were most frequently identified in the cerebral cortex, with a notable focus on the frontal cortex. However, our meta-analysis data revealed a significant hypoactivity in the insular and thalamic regions, contrary to observed frequencies. These abnormalities, occurring in pivotal network hubs bridging reason and emotion, disrupt connections with the limbic system, contributing to the hallmark symptoms of ME/CFS.
Furthermore, we discuss the regions where neuroinflammatory features are frequently observed and address critical neuroimaging limitations, including issues related to inter-rater reliability. This systematic review serves as a valuable guide for defining regions of interest (ROI) in future neuroimaging investigations of ME/CFS.
Bahar Kavyani, Seong Beom Ahn, Daniel Missailidis, Sarah J. Annesley, Paul R. Fisher, Richard Schloeffel, Gilles J. Guillemin, David B. Lovejoy & Benjamin Heng.
Mol Neurobiol (2023).
Dysregulation of the kynurenine pathway (KP) is believed to play a significant role in neurodegenerative and cognitive disorders. While some evidence links the KP to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), further studies are needed to clarify the overall picture of how inflammation-driven KP disturbances may contribute to symptomology in ME/CFS.
Here, we report that plasma levels of most bioactive KP metabolites differed significantly between ME/CFS patients and healthy controls in a manner consistent with their known contribution to symptomology in other neurological disorders.
Importantly, we found that enhanced production of the first KP metabolite, kynurenine (KYN), correlated with symptom severity, highlighting the relationship between inflammation, KP dysregulation, and ME/CFS symptomology. Other significant changes in the KP included lower levels of the downstream KP metabolites 3-HK, 3-HAA, QUIN, and PIC that could negatively impact cellular energetics.
We also rationalized KP dysregulation to changes in the expression of inflammatory cytokines and, for the first time, assessed levels of the iron (Fe)-regulating hormone hepcidin that is also inflammation-responsive. Levels of hepcidin in ME/CFS decreased nearly by half, which might reflect systemic low Fe levels or possibly ongoing hypoxia.
We next performed a proteomics screen to survey for other significant differences in protein expression in ME/CFS. Interestingly, out of the seven most significantly modulated proteins in ME/CFS patient plasma, 5 proteins have roles in maintaining gut health, which considering the new appreciation of how gut microbiome and health modulates systemic KP could highlight a new explanation of symptomology in ME/CFS patients and potential new prognostic biomarker/s and/or treatment avenues.
Long-COVID Research References
- Association between long COVID and vaccination: A 12-month follow-up study in a low- to middle-income country
- Fatigue in patients with long covid
- Post-COVID-19 irritable bowel syndrome: an integrative review
- “It’s a rollercoaster”: the recovery and return to work experiences of workers with long COVID
- A prospective study on endocrine function in patients with long-COVID symptoms
- Development and management of gastrointestinal symptoms in long-term COVID-19
- Antiphospholipid antibodies are enriched post-acute COVID-19 but do not modulate the thrombotic risk
- Is there a role for growth hormone replacement in adults to control acute and post-acute COVID-19?
- Asthma is a risk factor for general fatigue of long COVID in Japanese nation-wide cohort study
- Data Resource Profile: the Children and Young People with Long COVID (CLoCk) Study
- Persisting Shadows: Unraveling the Impact of Long COVID-19 on Cardiovascular, Nervous, and Respiratory Systems
- True prevalence of long-COVID in a nationwide, population cohort study
- What is useful to know post COVID-19?
- Cerebrospinal fluid findings in patients with neurological manifestations in post-COVID-19 syndrome
- Effect of Vitamin D in Long COVID Patients
- Post-Acute Sequelae of COVID-19 (PASC) in Pediatrics: Factors That Impact Symptom Severity and Referral to Treatment
- Trauma Shaping the Psychopathological Correlates of Patients with Long-COVID: A 6-Months Longitudinal Study with Repeated Measures Mixed Models
- Navigating the Post-COVID-19 Immunological Era: Understanding Long COVID-19 and Immune Response
- The lingering symptoms of post-COVID-19 condition (long-COVID): a prospective cohort study
- Trauma Shaping the Psychopathological Correlates of Patients with Long-COVID: A 6-Months Longitudinal Study with Repeated Measures Mixed Models
- Long-term neurological dysfunction associated with COVID-19: Lessons from influenza and inflammatory diseases?
- Clinical Spectrum of Pediatric Long COVID and Impact of COVID-19 Vaccines on the Clinical Course
- Long COVID Incidence by Sociodemographic Factors in a Large National Payor Database
- Persistence of Omicron-Related Long COVID: Examining Prevalence and Impact at 12 Months Post-Acute Infection
Dr Katrina Pears,
The ME Association.