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 24 – 31 October 2022
There have been seven new ME/CFS studies and thirteen studies on Long Covid.
Included in the listings for this weeks research are two theses, one a PhD thesis looking at enteroviruses (EVs) as the cause of ME/CFS (Paper six (6)) and the other a Masters Thesis looking at the support in New Zealand schools for ME/CFS and epilepsy (Paper seven (7)).
We have highlighted two studies below:
Paper one (1) is yet another paper looking at the overlapping conditions ME/CFS and Fibromyalgia (FM). This study looked at the role of the enzyme Catechol-O-methyltransferase (COMT) in these two conditions. COMT is involved in the degradation of neurotransmitters (such as dopamine) as well as various other compounds and drugs. COMT has been shown to affect pain, decrease modulation and worsen exercise induce symptoms. There are two types of COMT, the soluble short form (S-COMT) and the member bound long form (MB-COMT).
This study used 28 women participants with ME/CFS and FM and 26 healthy controls, where questionnaires, neurophysical assessment and blood samples were taken. This allowed for assessment should different interactions be carried out, e.g. the link between COMT compounds, DNA methylation, inflammation, and symptoms.
The researchers found significant association between the different COMT enzymes and DNA methylation, where COMT enzymes associated with higher activity showed lower DNA methylation, however, this finding was found in all participants (i.e. including controls).
What was specific to the CFS/ME and FM population, however, was the increased DNA methylation in MB-COMT enzyme, as well as significant lower expression of the inflammatory cytokine interferon gamma (IFN-γ). From this the authors suggest that MB-COMT DNA methylation might have an important role in the pathophysiology of ME/CFS and FM.
MB-COMT DNA methylation may have a role as higher methylation levels result in lower enzymatic activity and worsening of symptoms. However, I feel there is currently a lack of evidence to support this finding as there are currently no studies which have investigated MB-COMT methylation relevance in conditions which are characterised by persistent pain or fatigue, therefore, there is very little other evidence to support these findings. This is yet another avenue which needs further investigation.
One of the strengths (but also a weakness) of this study is the inclusion of only women, due to the higher prevalence in women as well as the sex differences which exist in pain and immune function. It would however be interesting to know how these findings differ in the male population. Similar to the study we reported last week on FM, it is hard to know whether these findings are related to both or one of the conditions as there was no group with only ME/CFS and a separate FM group. Therefore, it is difficult to know the importance of these findings in the pathology of either condition. Furthermore, the authors say that the results were “not specific for one condition” but I am not sure how they were intending to confirm this with their study design.
Paper four (4) is a novel preprint study (meaning it has not been peer-viewed and the science verified), here the researchers investigated the single cell RNA sequencing of immune cells (single-cell RNA-seq (scRNA-seq)) in ME/CFS patients and sedentary controls before and after exercise. They aimed to find immune cell types with dysregulated transcriptomes in ME/CFS (the whole set of RNA molecules, from coding to non-coding RNA).
This study found some unique new findings, in ME/CFS patients they found:
- dysregulation of certain immune cells, particularly the monocytes (a type of white blood cell) showed the strongest signal, suggesting inappropriate differentiation and migration to tissue,
- the fraction of abnormal monocytes correlated with the degree of disease severity,
- altered platelet transcriptomes (whole set of RNA molecules), which significantly changed further following exercise, suggesting platelet activity is associated with or contributes to PEM,
- however, most gene dysregulation found was consistent before and after exercise.
This study provides promising results, further supporting the evidence for problems in the immune system in ME/CFS. Although this further adds to the debate on the role of platelet activity/microclots in ME/CFS (and Long Covid) and linking this to PEM. However, it leads to avenues which need further investigation: monocytes and platelets.
Apart from providing some interesting new findings, it is also nice to see that the authors seem to have a good grasp on ME/CFS as they acknowledge that post-exertional malaise (PEM) is a defining symptom.
As a side, some of my concerns over this study currently are due to how it is presented, and it is currently rather lengthy. As this is a preprint, the study has not been formatted for submission into a scientific journal, so some details are hard to find, for example, the authors describe this as a large cohort but there are no details in the abstract or the methods. The only details are in the results section, which describes 30 ME/CFS patients and 28 controls, which in my opinion is not large, but average. Furthermore, the abstract/summary does not include the significance of these results or quote any figures which is unusual and is something I would like to see at a quick glance.
You may also be interested in reading paper five (5) which is a preprint study on the new NICE guideline and Dr Charles Shepherd is one of the authors. As this is a pre-print, all comments are welcome and can be added to the pre-print website.
ME/CFS Research References and Abstracts
Polli, A., Hendrix, J., Ickmans, K. et al.
J Transl Med 20, 487 (2022).
Abstract
Background: Catechol-O-methyltransferase (COMT) has been shown to influence clinical pain, descending modulation, and exercise-induced symptom worsening. COMT regulates nociceptive processing and inflammation, key pathophysiological features of Chronic Fatigue Syndrome and Fibromyalgia (CFS/FM).
We aimed to determine the interactions between genetic and epigenetic mechanisms regulating COMT and its influence on inflammatory markers and symptoms in patients with CFS/FM.
Methods: A case-control study with repeated-measures design was used to reduce the chance of false positive and increase the power of our findings. Fifty-four participants (28 patients with CFS/FM and 26 controls) were assessed twice within 4 days.
The assessment included clinical questionnaires, neurophysiological assessment (pain thresholds, temporal summation, and conditioned pain modulation), and blood withdrawal in order to assess rs4818, rs4633, and rs4680 COMT polymorphisms and perform haplotype estimation, DNA methylation in the COMT gene (both MB-COMT and S-COMT promoters), and cytokine expression (TNF-α, IFN-γ, IL-6, and TGF-β).
Results: COMT haplotypes were associated with DNA methylation in the S-COMT promoter, TGF-β expression, and symptoms. However, this was not specific for one condition. Significant between-group differences were found for increased DNA methylation in the MB-COMT promoter and decreased IFN-γ expression in patients.
Discussion: Our results are consistent with basic and clinical research, providing interesting insights into genetic-epigenetic regulatory mechanisms. MB-COMT DNA methylation might be an independent factor contributing to the pathophysiology of CFS/FM.
Further research on DNA methylation in complex conditions such as CFS/FM is warranted. We recommend future research to employ a repeated-measure design to control for biomarkers variability and within-subject changes.
Xu XS, Ma W, Xiong LJ, Zhai CT, Li W, Tian YF.
Zhen Ci Yan Jiu. 2022 Oct 25;47(10):878-84. [Article in Chinese.]
Abstract
Objective: To observe the effect of herbal cake-separated moxibustion (HCSM) on serum lactic acid (BLA) level and AMPK/PGC-1α signaling pathway in the quadriceps femoris in chronic fatigue syndrome (CFS) rats, so as to explore its mechanisms underlying improvement of CFS.
Methods: According to the random number table, 50 SD rats were divided into blank control, model, HCSM, sham HCSM and medication (herbal medicine gavage) groups, with 10 rats in each group. The CFS model was established by using chronic restraint and exhaustive swimming, alternately, once daily for 21 days.
The herbal cake was made of Xiaoyao Powder (Mental Ease Powder, composed of [Danggui (Radix Angelicae Sinensis), Baishao (Radix Paeoniae Alba), Chaihu (Radix Bupleuri), Fuling (Poria), Baizhu (Rhizoma Atractylodis, Macrocephalae), etc.].
The HCSM was applied to “Shenque” (CV8), “Guanyuan “(CV4), bilateral “Zusanli” (ST36) and “Qimen” (LR14), 5 moxa-cones for each acupoint, once daily for 10 days. For sham HCSM, the excipient was instead of herbal cake, and the same 5 moxa-cones was given as the HCSM group.
Rats of the medication group received gavage of Xiaoyao Powder suspension (60 mg·kg-1), once daily for 10 days. The open field test and tail suspension test were conducted for determining the animals' locomotor activity.
The blood sample was taken from the abdominal aorta under anesthesia for assaying the levels of serum BLA, chemokine ligand CXCL9 and β-endorphin (EP) by ELISA. Bilateral quadriceps femoris were sampled for observing histopathological changes after staining with conventional H.E. technique, and for detecting the expression levels of phosphorylated AMP-activated protein kinase (p-AMPK) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) by using immunohistochemistry.
Results: Compared with the blank control group, the number of rearing and horizontal grid-crossing times, struggling times of tail suspension test were significantly decreased (P<0.05), and the immobility time was obviously prolonged (P<0.05) in the model group.
Compared with the model group, both HCSM and medication groups had a significant increase of rearing, horizontal grid-crossing times and struggling times (P<0.05), and the immobility time had a significant decrease (P<0.05). But there were no significant differences in the total movement distance among the 5 groups (P>0.05), and in the 5 indexes of behavioral measurements between the HCSM and medication groups (P>0.05). The sham HCSM could also evidently increase the struggling times and reduce the immobility time (P<0.05).
The contents of serum BLA, CXCL9 and β-EP were obviously higher in the model group than in the blank control group (P<0.05), as well as remarkably lower in the HCSM and medication groups than in the model group (P<0.05).
Whereas the expression levels of muscular p-AMPK and PGC-1α were considerably lower in the model group than in the blank control group (P<0.05), and significantly increased in both HCSM and medication groups relevant to the model group (P<0.05).
Compared with the sham HCSM group, the contents of BLA, CXCL9 and β-EP in serum of the HCSM group and contents of CXCL9, β-EP in medication group were significantly decreased (P<0.05), and the protein expressions of p-AMPK and PGC-1α in quadriceps femoris in both HCSM and medication groups were significantly increased (P<0.05).
H.E. staining showed smaller intercellular space, uneven cytoplasmic staining in some muscle fibers, nucleus pyknosis and condensation, and inflammatory cell infiltration in the model group, which was milder in both HCSM and medication groups.
Conclusion: HCSM can mitigate the stress behavioral state in CFS rats, which may be related with its functions in lowering the levels of serum BLA, CXCL9 and β-EP, and activating AMPK/PGC-1α signaling pathway (balancing energy metabolism) in the quadriceps femoris.
Putra HA, Park K, Yamashita F.
J Clin Med. 2022 Oct 13;11(20):6037
Abstract
The relationship between fatigue perception and regional gray matter volume (rGMV) has seldom been studied in healthy adults. Therefore, this study aimed to analyze sex differences in the correlation between rGMV and fatigue perception using Chalder's fatigue questionnaire (CFQ).
The CFQ was used to analyze the sexual features of rGMV related to the degree of perceived fatigue in 2955 healthy adults (male = 1560, female = 1395) of various ages (20-89 years, median 56). A higher CFQ score denotes a higher perceived fatigue level by the participant.
According to the CFQ scores in males, the volumes of the right orbital part of the inferior frontal gyrus and left precuneus were negatively correlated (i.e., smaller rGMV had a higher CFQ score), whereas the left angular gyrus was positively correlated.
In females, the right inferior temporal gyrus was negative, whereas the left middle temporal gyrus and right putamen were positive (i.e., larger rGMV had a higher CFQ score).
The lack of identified regions in this large-scale study between males and females might be related to sex differences in clinical or pathological fatigue morbidities. Additionally, the sex differences in the negative or positive correlations between rGMV and fatigue perception may contribute to a better understanding of the neuronal mechanism in the early stages of fatigue development.
Faraz Ahmed, Luyen Tien Vu, Hongya Zhu, David Shing Huk Iu, Elizabeth A. Fogarty, Yeonui Kwak, Weizhong Chen, Carl J. Franconi, Paul R. Munn, Susan M. Levine, Jared Stevens, Xiangling Mao, Dikoma C. Shungu, Geoffrey E. Moore, Betsy A. Keller, Maureen R. Hanson, Jennifer K. Grenier, Andrew Grimson
bioRxiv [Preprint]
Abstract
ME/CFS is a serious and poorly understood disease. To understand immune dysregulation in ME/CFS, we used single-cell RNA-seq (scRNA-seq) to examine immune cells in cohorts of patients and controls.
Post-exertional malaise (PEM), an exacerbation of symptoms following strenuous exercise, is a characteristic symptom of ME/CFS. Thus, to detect changes coincident with PEM, we also performed scRNA-seq on the same cohorts following exercise.
At baseline, ME/CFS patients displayed dysregulation of classical monocytes suggestive of inappropriate differentiation and migration to tissue.
We were able to identify both diseased and more normal monocytes within patients, and the fraction of diseased cells correlated with metrics of disease severity. Comparing the transcriptome at baseline and post-exercise challenge, we discovered patterns indicative of improper platelet activation in patients, with minimal changes elsewhere in the immune system.
Taken together, these data identify immunological defects present at baseline in patients and an additional layer of dysregulation following exercise.
Highlights: ME/CFS is a debilitating disease with unknown causes. Here, we provide, for the first time, an extensive single cell resolution dataset detailing the gene expression programs of circulating immune cells of ME/CFS cases at baseline and after symptom provocation.
We were able to detect robust dysregulation in certain immune cells from patients, with dysregulation of classical monocytes manifesting the strongest signal.
Indeed, the fraction of aberrant monocytes in ME/CFS patients correlated with the degree of disease severity. Surprisingly, platelet transcriptomes were also altered in ME/CFS, and they were the only component of the immune system that showed large-scale changes following symptom provocation.
Kingdon, C.C.; Lowe, A.; Shepherd, C.; Nacul, L.
Preprints 2022, 2022110016.
Abstract
The new NICE guideline for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), published in October 2021, makes significant changes in treatment recommendations.
It acknowledges the complexity of this chronic medical condition, which always impacts quality of life and can be profoundly disabling, recognising the prejudice and stigma that people with ME/CFS often experience in the absence of any specific diagnostic test.
The guideline outlines steps for accurate diagnosis, recognising post-exertional malaise as a core symptom; importantly, ME/CFS can now be diagnosed after just 3 months in a bid to improve long-term health outcomes.
It recommends the need for individual, tailored management by a multi-disciplinary team, ensuring that the wellbeing of the individual is paramount.
The guideline makes clear that any programme based on fixed incremental increases in physical activity or exercise, for example graded exercise therapy (GET), should not be offered as a treatment for ME/CFS and emphasises that cognitive behavioural therapy (CBT) should only be offered as a supportive intervention. Because of the rigorous methodology required by NICE Committee review and the inclusion of the testimony of people with lived experience as committee members, this guideline will influence the future diagnosis and management of ME/CFS in the UK and beyond.
O'Neal, Adam James
PhD thesis [Cornell University]
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system disease whose etiological basis has not been established. Over the years, several pathogenic agents have been implicated with no one pathogen being conclusively identified as responsible for induction of a large number of cases.
Enteroviruses (EVs) as a cause of ME/CFS have sometimes been proposed, as they are known agents of acute respiratory and gastrointestinal infections that may persist in chronic infection sites, including the central nervous system, muscle, and heart, potentially resulting in chronic conditions that have symptom constellations like those of ME/CFS.
To gain insight into the association between EVs and ME/CFS, I conducted a comprehensive review of EV studies in ME/CFS and followed this with 1) a broad serological survey of ME/CFS antibody levels to 122 pathogenic antigens and 2) designed and conducted EV-specific targeted RNA sequencing.
A review of prior ME/CFS investigations in ME/CFS revealed a strong prevalence of chronic EV infections across ME/CFS cohorts. The broad survey of anti-pathogen antibody levels in ME/CFS cases did not implicate any one pathogen as a causative factor in ME/CFS, nor do they rule out common pathogens that frequently infect the US population. However, the results did reveal sex-based differences in steady-state humoral immunity, both within the ME/CFS cohort and when compared to trends seen in the healthy control cohort.
Furthermore, I find that our EV-specific probe set allows efficient viral detection when as few as 10 molecules are present in 1ml of blood. However, whether the technology is employed directly on patient samples or following attempts at in vitro biological amplification, EVs were undetected in both ME/CFS and healthy control samples despite all approaches that were pursued.
This work establishes a thorough understanding of the current EV-ME/CFS related literature while simultaneously providing an acutely sensitive and comprehensive approach that will be useful in the future for screening biopsy or cadaver samples from any individuals suspected of having a chronic EV infection.
Kirstin Louise Bierre
Master Thesis [Massey University, Manawatu Campus, New Zealand]
Abstract
Medical advancements have changed the prognosis of many paediatric conditions, leading to a rise in the number of children with chronic health conditions (CHCs) who require support to gain equitable education opportunities and outcomes. Two CHCs that impact on schooling are myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and epilepsy.
Previous research has detailed different supports offered by schools, but there is a gap in the literature regarding the support of children with ME/CFS and epilepsy in New Zealand schools.
The current research aimed to gather parents’ perceptions on the different supports available in New Zealand for their children/youth with ME/CFS or epilepsy to help with the impact their CHC has on schooling.
Participants included 20 parents of children with ME/CFS (11-20 years) and 23 parents of children with epilepsy (6-18 years). A mixed methods online survey asked for parents’ perceptions of the impact that ME/CFS and epilepsy had on schooling and the support available in ‘Mainstream’ and ‘Other’ schools.
Through mixed method analysis, including descriptive statistics and thematic analysis, six main themes and subthemes were identified; 1) Let-down by their own bodies, 1.1) Damaging self-concept; 2) Struggle for validation; 3) Luck of the draw: Both supportive and unsupportive experiences, 3.1) Teachers operating in a rigid system, and 3.2) Gratitude from parents; 4) Ill-suited support, 4.1) Other schools as transitional institutions; 5) Lack of understanding and discrimination; and 6) Impact of COVID-19.
These themes revealed perceptions of positive support experiences with understanding teachers who formed trusting/positive relationships with parents, as well as negative experiences centred around a lack of understanding from a restrictive system not well designed to support their children with ME/CFS or epilepsy. Condition specific subthemes revealed differences between ME/CFS and epilepsy – related to condition legitimacy, symptom visibility, and funding opportunities.
Findings were also interpreted using a socio-ecological framework, which highlighted the interrelated environments surrounding the child/youth, including teachers/classrooms, schools, health/education policies, and western health conceptualisations, which likely influenced support. These findings shed light on parents’ perceptions of the support of their child/youth with ME/CFS or epilepsy in New Zealand, with the hopes of informing future research or support initiatives.
Long-COVID Research References
Dr Katrina Pears,
Research Correspondent.
The ME Association.
