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).
RESEARCH INDEX
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
ME/CFS Research Published 23 – 30 January 2023
It’s been an exceptionally busy week for research, with nine new ME/CFS studies and twelve new Long Covid studies.
We have highlighted one of the ME/CFS studies in detail below:
Paper eight (8) looks into post-exertional malaise (PEM), specifically the transcriptomic changes while undergoing exercise. The study of transcriptomics looks at the complete set of the RNA molecules and how their expression changes i.e. gene expression for molecules which help to make proteins.
For this study 20 female ME/CFS participants were recruited alongside 20 matched healthy controls. The participants underwent an exercise challenge and blood samples were analysed at three time points: before the exercise challenge (T0), maximal exertion (T1) and four hours after the exercise challenge (T2). The exercise challenge used was a standard maximal graded exercise test which consisted of pedalling for 2 min at 60 W (watts, unit of power), followed by an increase of 30 W every 2 min until they reached their maximal exertion.
This study yielded significant findings in a number of areas:
- At maximal exertion (T1) no significant changes in gene expression were found in ME/CFS patients, but there were changes in healthy controls, 102 genes showed significant changes. In healthy controls these changes related to signalling and integral functions of their immune cells, such as those effecting natural killer cells.
- At maximal exertion (T1) no significant changes in cell type abundance, such as immune cell types were found in ME/CFS patients. Although in healthy controls CD4+ T cells were decreased and natural killer cells (NK) were increased.
- In the recovery period (T2) ME/CFS patients had 1277 genes that were expressed differently, compared to the 831 in healthy controls. There were several pathways that were significantly affected in ME/CFS, these were related to dysregulated immune signalling pathways and dysfunctional cellular responses to stress, especially those functions relating to cytokines. In healthy controls, leukocyte activation and immune response-regulating signalling were more significantly affected.
- In the recovery period (T2) a number of differences were seen in the cell type abundance, where the types of cells looked at were all significantly different in healthy controls at T1 to T2.
Results from this study are fascinating and show that ME/CFS participants have a different response to exercise than healthy controls, where ME/CFS participants are unable to facilitate the transcriptomic changes that are needed in their immune system to allow recovery.
Furthermore, these results show that following exercise and in recovery, ME/CFS immune cells have dysfunctional cytokine signalling networks (involved in the immune system functioning) and are vulnerable to cell death due to poor defence systems and dysregulated epigenetic regulation of apoptotic pathways (programmed cell death). However, healthy controls regulate their lymphocytes (a type of immune cell) and inactivate the inflammatory response.
This is the second study we have seen of late showing different responses to exercise in ME/CFS and healthy controls, with the previous study delving into the metabolic effects (Germain et al., 2022, previous roundup comment and IACFS conference converage).
A few things to note about this study:
- All ME/CFS subjects met the 1996 CDC/Fukuda and 2003 Canadian Case definitions for ME/CFS, which means the diagnosis criteria was tighter than other studies we see.
- Additional effects were minimised in this study, as all participants had a uniform breakfast, and a range of additional diseases were ruled out. Although, receiving a different breakfast from usual could induce changes if vastly different from participants usual breakfast, for example if on a keto diet.
- A female only sample was used, which has advantages and disadvantages due to the high prevalence in the female sex as well as reported differences at a molecular level in other studies, but this is also a draw back as we don’t know if results would vary in males. Furthermore, this study also reduced any potential menstrual effects with participants completing a gynaecologic questionnaire to ensure blood collection occurred during the first two weeks of their menstrual cycle.
- Matched controls were used in this study, but there is no mention that these were sedentary.
- There are no details of illness duration, so we don’t know how this effects gene expression or changes with PEM, this therefore would have been a useful comparison to make.
- It is a great shame that there were no measurements taken 24 hours (or longer) after the exercise challenge, to discover if this further influenced gene expression, especially given that PEM tends to be delayed by 24-72 hours.
- Furthermore, most comparisons in this study focus on the changes between timepoints within the two groups and not between groups , for example when looking at cell type abundance data this is presented as the change at T2 from T1 in ME/CFS (and healthy controls) but the data does not tell us how at these timepoints ME/CFS participants differ from controls. Therefore, the abundance of cells could be similar (or different), just they change over time.
- Lastly, it is disappointing that there is no comparison between baseline data (T0) for ME/CFS participants and healthy controls showing how gene expression differs (or is similar) for this study group.
Overall, I think this study is very neat and well performed, as always its main limitation is sample size. The paper itself is easy to read and not too lengthy. This research is a good example of international collaboration, furthermore the MEA Ramsay Research Fund supports Professor Elsa Oltra in Spain.
A few of the other studies which are worth mentioning this week are:
- Paper five (5) which is a very impressive PhD thesis investigating the genetic and immunological causes of ME/CFS. This work had a novel finding when looking at the genetic association with the gene PDE10A, which is also implicated in Parkinson’s and Huntington’s disease. Furthermore, other avenues were ruled out when studying immune T-cells as T-cell clonal expansion was not found to be greater in those with ME/CFS. Additionally to this thesis, previous published work by this author looked at the genetic risk factors in ME/CFS.
- Paper six (6) which looks at the use of Panax ginseng with the results suggesting that this helps to accelerate recovery from fatigue in rats. This study is similar to a previous study we have commented on using red ginseng.
ME/CFS Research References and Abstracts
Mieke Hulens,1 Wim Dankaerts,1 Ricky Rasschaert,2 Frans Bruyninckx,3 Peter De Mulder,4 Chris Bervoets.
Journal of Pain Research 16: 205—219
Abstract
The etiopathogenesis of fibromyalgia (FM) and chronic fatigue syndrome (CFS) is not yet elucidated. Hypothalamo-pituitary-adrenal (HPA) axis dysfunction is reflected in the hormonal disturbances found in FM and CFS.
Some study groups have introduced a novel hypothesis that moderate or intermittent intracranial hypertension may be involved in the etiopathogenesis of FM and CFS.
In these conditions, hormonal disturbances may be caused by the mechanical effect of increased cerebrospinal fluid pressure, which hampers blood flow in the pituitary gland. Severe intracranial pressure may compress the pituitary gland, resulting in primary empty sella (ES), potentially leading to pituitary hormone deficiencies.
The aim of this narrative review was to explore whether similar hormonal changes and symptoms exist between primary ES and FM or CFS and to link them to cerebrospinal fluid pressure dysregulation.
A thorough search of the PubMed and Web of Science databases and the reference lists of the included studies revealed that several clinical characteristics were more prevalent in primary ES, FM or CFS patients than in controls, including increased cerebrospinal fluid pressure, obesity, female sex, headaches and migraine, fatigue, visual disturbances (visual acuity and eye motility abnormalities), vestibulocochlear disturbances (vertigo and neurosensorial hearing loss), and bodily pain (radicular pain and small-fiber neuropathy).
Furthermore, challenge tests of the pituitary gland showed similar abnormalities in all three conditions: blunted adrenocorticotropic hormone, cortisol, growth hormone, luteinizing hormone, and thyroid stimulating hormone responses and an increased prolactin response.
The findings of this narrative review provide further support for the hypothesis that moderately or intermittently increased cerebrospinal fluid pressure is involved in the pathogenesis of FM and CFS and should stimulate further research into the etiopathogenesis of these conditions.
2. Myalgic encephalomyelitis/chronic fatigue syndrome: an overview of current evidence
Ludwig B, Olbert E, Trimmel K, Seidel S, Rommer PS, Müller C, Struhal W, Berger T.
Nervenarzt. 2023 Jan 25. German. [Epub ahead of print.]
Abstract
Over the past 5 years both media and scientific interest has surged regarding the disorder myalgic encephalomyelitis and chronic fatigue syndrome (ME/CFS), not least because of the clinically similar manifestation in long COVID or post-COVID.
In this review we discuss the process of clinical diagnosis and randomized controlled therapeutic studies on ME/CFS, and the similarities or differences to long COVID and post-COVID.
So far, neither clear pathophysiologically causal nor therapeutic evidence-based results on ME/CFS have been identified in the many years of scientific research.
Given the evident psychiatric comorbidity rates in patients with a diagnosis of ME/CFS, a psychosomatic etiology of this syndrome should be considered. Furthermore, a precise and reliable diagnostic classification based on stricter criteria would benefit both pathophysiological and therapeutic research.
Llinos Haf Spencer, Annie Hendry, Abraham Makanjuola, Bethany F Anthony, Jacob Davies, http://orcid.org/0000-0003-1435-163XKalpa Pisavadia, Dyfrig Hughes, Deb Fitzsimmons, Clare Wilkinson, Rhiannon Tudor Edwards, Ruth Lewis, Alison Cooper, Adrian G Edwards.
medRxiv [Preprint]
Abstract
Previous research has categorised symptoms of COVID-19 / Long COVID into 12 thematic areas including: fever, myalgia, fatigue, impaired cognitive function, and that COVID-19 survivors had reduced levels of physical function, activities of daily living, and health-related quality of life.
Our aim was to review the evidence for interventions or best practice to support people with Long COVID, or similar post-viral conditions characterised by fatigue, to return to normal activities.
Evidence was included from guidelines, systematic reviews (SR), and primary studies. The primary studies focussed on Long COVID (LC) indicated that there should be a needs-based focus to care for those with LC.
Consideration should be given to individuals living with LC in the same way as people with disabilities are accommodated in terms of workplace adjustment.
Two SRs indicated that non-pharmaceutical interventions (NPIs) for patients with LC or chronic fatigue syndrome could help improve function for activities of daily life. However, the third, most recent SR, concluded that there is a lack of robust evidence for NPIs.
LC fatigue management methods may be beneficial under certain conditions. One SR reported work capability as an outcome however they did not find any studies which evaluated the impact of interventions on return to work/ normal life.
One primary study, on individuals with CFS, described a written self-management programme. Following this intervention there was an 18% increase in the number of patients in employment.
Policy and practice implications: Long COVID is still being established as a post-viral condition with many symptoms. Patient-centred treatment options such as occupational therapy, self-management therapy and talking therapy may be considered in the same way as for other debilitating conditions. Return-to-work accommodations are needed for all workers unable to return to full-time employment.
Due to the nature of the studies included, there was little reported evidence of effectiveness of getting individuals back into their normal activities.
Kunihisa Miwa
Circulation Reports, Article ID CR-22-0114.
Abstract
Background: Orthostatic intolerance markedly affects the day-to-day activities of patients with myalgic encephalomyelitis (ME) or chronic fatigue syndrome. Chronotropic incompetence (CI), defined as an impaired chronotropic response or reduced increases in heart rate during exercise and resulting in lower exercise capacity, may also be observed during orthostasis in patients with ME.
Methods and Results: In this study, the recordings of 101 adult patients with ME (36 men, 65 women; mean [±SD] age 37±12 years) who underwent conventional active 10-min standing tests at least 3 times to determine the presence of CI were analyzed.
Recordings were selected for 13 patients who experienced tests both with and without exhibiting postural orthostatic tachycardia syndrome (POTS; an increase in heart rate of ≥30beats/min or an actual heart rate of ≥120beats/min) while also both successfully completing and failing to complete 10-min standing on different occasions.
Subjects in whom failure without POTS was observed in any test(s) while success was associated with POTS on other occasions were considered positive for CI during orthostasis. Of the 13 patients, 12 (92%) were CI positive, 5 (38%) of whom exclusively failed the tests without experiencing POTS.
Conclusions: Some patients with ME were CI positive during standing tests, suggesting impaired sympathetic activation. The presence of POTS appears to be essential for maintaining orthostasis in these patients.
Joshua James Dibble
PhD Thesis [University of Edinburgh]
Abstract
This thesis describes two investigations into the disease Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), specifically its genetic aetiology and immune system alterations.
The first study investigated the genetic basis of ME/CFS using Genome-wide Association Studies (GWAS) by attempting to replicate and extend results previously found using UK Biobank cohort data. GWAS attempt to identify associations between DNA variants and phenotypes. T
his GWAS was novel, conducted on new phenotypes constructed by combining those in the most up-to-date UK Biobank data release. A new, previously unseen, genome-wide significant association was found on chromosome 6 for males with ME/CFS within the gene PDE10A. Further results were not genome-wide significant, but many were suggestive and hence independent replication may justify further research.
A previous analysis on the UK Biobank cohort had identified an indicative association in females between variants around the SLC25A15 gene at genome-wide significance. I adopted a hypothesis that the dietary protein intake of people with the CFS risk variants would be lower than those with the alternative alleles, due to potentially reduced production of mitochondrial ornithine transporter 1 (ORNT1). However, this association with dietary protein intake was not supported by UK Biobank data.
Additionally, I investigated associations between the human leukocyte antigen (HLA) alleles and the ME/CFS phenotype using UK Biobank data. Associations between alleles within the HLA-C and -DQB1 genes had previously been found in a cohort of Norwegian people with ME/CFS, and my goal was to seek replication of these results in a larger dataset. None of the associations found in the UK Biobank proved to be genome-wide significant.
In my second study I investigated the use of T-cell clonal diversity as a potential biomarker for ME/CFS. This project used cells from CureME Biobank samples in collaboration with Systems Biology Laboratory (SBL). I developed a data analysis pipeline to analyse T-cell receptor (TCR) genomic DNA data based on the best practices currently used in the fields of immunology and mathematical biology. This approach used a mathematical notion of entropy as a measure for the diversity of TCR repertoires, in this way combining all of the most commonly used metrics in mathematical biology. When combined, these measures form a profile for each repertoire, a set of which can be sorted using a machine learning algorithm to partition the repertoires into subgroups.
My hypothesis was that the T-cell clonal expansion of people with ME/CFS would be greater than for healthy controls, and comparable to disease (multiple sclerosis) controls. Although this method was able to effectively classify TCR chains using simulated data, results from experimentally-derived data did not support the hypothesis, with the most effective classifications for both CD4+ and CD8+ cells failing to pass corrections for multiple hypothesis significance testing.
Lay summary
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease that affects millions of people around the world. Very little is understood about the cause or progression of the disease, and there is no known cure. At present, there is also no reliable clinical test to determine whether a person has ME/CFS.
This thesis explores the potential for a genetic or immunological basis for ME/CFS, with the goal to eventually find a biomarker that could be used in diagnosis.
The first part of this thesis investigates whether genetic variants are more (or less) common among those with ME/CFS than in the general population. In particular, the region of the genome that encodes immune system proteins was of interest, as previous studies have shown associations between this region and the disease.
Using strict statistical thresholds, none of the previously found associations were replicated. However, one new association was found, with the gene PDE10A, which is implicated in central nervous system diseases, such as Parkinsons and Huntingtons disease. This association has never been seen before, and would require replication in a new cohort before its role in ME/CFS could be confirmed. However, it represents a promising avenue for new research.
The second part of this thesis investigates T-cells. These are highly specialised immune cells in the blood, each of which targets an antigen (foreign substance) such as from a virus. When a T-cell recognises this antigen, it clones itself repeatedly. This clonal expansion is measurable, and can serve as evidence of immune system activation.
My hypothesis was that this immune signature could be used to distinguish people with ME/CFS from healthy controls and others diagnosed with another disease.
I used a mathematical measure of diversity and a machine learning method to sort their immune profiles into groups. However, the pattern of immune activation was not sufficiently clear to provide consistent classification. Hence, the role of the immune system in ME/CFS is still unclear, and the utility of this method as a diagnostic biomarker is not proved.
Zhang G, Lu B, Wang E, Wang W, Li Z, Jiao L, Li H, Wu W.
Pharm Biol. 2023 Dec;61(1):316-323.
Abstract
Context: Panax ginseng C. A. Meyer (Araliaceae) is a tonic herb used in ancient Asia.
Objective: This study investigated the antifatigue effect of P. ginseng on chronic fatigue rats.
Materials and methods: Sprague-Dawley rats were divided into control, model and EEP (ethanol extraction of P. ginseng roots) (50, 100 and 200 mg/kg) groups (n = 8). The rats were subcutaneously handled with loaded swimming once daily for 26 days, except for the control group. The animals were intragastrically treated with EEP from the 15th day. On day 30, serum, liver and muscles were collected, and the PI3K/Akt/mTOR signalling pathway was evaluated.
Results: The swimming times to exhaust of the rats with EEP were significantly longer than that without it. EEP spared the amount of muscle glycogen, hepatic glycogen and blood sugar under the chronic state. In addition, EEP significantly (p < 0.05) decreased serum triglycerides (1.24 ± 0.17, 1.29 ± 0.04 and 1.20 ± 0.21 vs. 1.58 ± 0.13 mmol/L) and total cholesterol (1.64 ± 0.36, 1.70 ± 0.15 and 1.41 ± 0.19 vs. 2.22 ± 0.19 mmol/L) compared to the model group. Regarding the regulation of energy, EEP had a positive impact on promoting ATPase activities and relative protein expression of the PI3K/Akt/mTOR pathway.
Conclusions: Our results suggested that EEP effectively relieved chronic fatigue, providing evidence that P. ginseng could be a potential dietary supplement to accelerate recovery from fatigue.
Luo L, Zhang Y, Huang T, Zhou F, Xiong C, Liu Y, Zhai P, Wang G, Tan J, Jiao C, Chen X, Yu J, Qiao Y, Ren S, Hu X, Zhan J and Cheng J.
Front. Psychiatry 13:1047014.
Abstract
Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a group of chronic conscious fatigue that is not easily relieved by rest and is accompanied by corresponding physiological dysfunction and psychological symptoms. However, due to the insufficient understanding of the pathogenesis of ME/CFS, there is currently a lack of effective treatment methods.
In addition, there are few surveys on the current status of ME/CFS in the central region of China, and the data on ME/CFS among university students in the central region are lacking. This group conducted a survey on university students in Wuhan, Hubei Province in 2022 to collect and analyze the current status of ME/CFS among university students in central China for the first time, aiming to understand the current development of ME/CFS among university students, investigate the influencing factors of its prevalence, fill the data gaps, and provide a reliable basis for developing interventions for chronic fatigue syndrome among university students.
Methods: A cross-sectional study was conducted among university students in a university in Hubei province. Data were collected via online questionnaire surveys. The contents included demographic characteristics, lifestyles, disease history, depression, anxiety, sleep, ME/CFS and other associated factors. SAS 9.4 statistical software was used to analyze and estimate the effect of associated factors on ME/CFS.
Results: A total of 1826 subjects were included in the final analysis. The results showed that the prevalence of ME/CFS in university students was 6.25%. Univariate analysis showed that exercise, alcohol consumption, study, overnights, diet, anxiety, depression, and sleep quality were associated with ME/CFS (P < 0.05). Multivariate analysis showed that overnights, overeating, anxiety, and sleep quality were independent risk factors, while learning was a protective factor.
Conclusion: College students should pay enough attention to ME/CFS, improve their understanding of ME/CFS, and improve people’s ability to understand ME/CFS.
Van Booven DJ, Gamer J, Joseph A, Perez M, Zarnowski O, Pandya M, Collado F, Klimas N, Oltra E, Nathanson L.
International Journal of Molecular Sciences. 2023; 24(3):2698.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex multi-organ illness characterized by unexplained debilitating fatigue and post-exertional malaise (PEM), which is defined as a worsening of symptoms following even minor physical or mental exertion.
Our study aimed to evaluate transcriptomic changes in ME/CFS female patients undergoing an exercise challenge intended to precipitate PEM.
Our time points (baseline before exercise challenge, the point of maximal exertion, and after an exercise challenge) allowed for the exploration of the transcriptomic response to exercise and recovery in female patients with ME/CFS, as compared to healthy controls (HCs).
Under maximal exertion, ME/CFS patients did not show significant changes in gene expression, while HCs demonstrated altered functional gene networks related to signaling and integral functions of their immune cells.
During the recovery period (commonly during onset of PEM), female ME/CFS patients showed dysregulated immune signaling pathways and dysfunctional cellular responses to stress. The unique functional pathways identified provide a foundation for future research efforts into the disease, as well as for potential targeted treatment options.
9. Treatment Harms to Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Marks DF.
Adv Bioeng Biomed Sci Res, 6(1), 01-04.
Abstract
Despite evidence of physiological and cellular abnormalities in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS), the dominant therapeutic approach has been cognitive behaviour therapy (CBT) and graded exercise therapy (GET). Patients report distress and dissatisfaction following healthcare encounters based on GET and CBT.
A significant body of research suggests that CBT and GET are harmful for many patients with ME/CFS. These findings raise ethical concerns and suggest that more collaborative working between scientists, therapists and patients would be helpful in making scientific progress in this difficult field.
Long-COVID Research References
Dr Katrina Pears,
Research Correspondent.
The ME Association.
