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 by Katrina Pears
ME/CFS Research Published 13 – 19 June 2023
It’s been another incredibly busy week for research, with ten new ME/CFS studies and eleven new Long Covid studies.
We have also listed the ME/CFS references from the previous week below (6 – 12 June), where there were only three new published studies.
There have been several interesting studies this week, however, we have highlighted one of the ME/CFS studies in more detail below:
Paper one (1) is on the circular RNAs (circRNAs) present in the blood, which have been shown to have a unique pattern in ME/CFS.
Circular RNAs (CircRNAs) are single-stranded RNA molecules, which unlike a standard RNA molecule form a covalently (type of bond between two atoms) closed continuous loop. CircRNA are non-coding, and play a regulating role in gene expression, and an essential role in the process of biological development, including a critical role in the diagnosis of diseases, which may enable them to potentially act as diagnostic biomarkers and therapeutic targets. CircRNA research is still in its early stages and there is still more to be discovered about their biological function. (A review on CircRNA can be found by Zhou et al., 2020).
This study compared the expression profiles of CircRNAs in ME/CFS and sedentary controls before and after two sessions of cardiopulmonary exercise testing (CPET) in a seven-day period. This is the first study of its kind to delve into circRNA. This study used data collected by Bouquet et al., 2019, which used 14 ME/CFS patients and 11 sedentary controls which formerly looked into transcriptome and virome analysis (using RNA sequencing).
This study found a distinct circRNA expression profile in ME/CFS, in more detail they found:
- The number of detected circRNAs was higher in ME/CFS compared to healthy controls, indicating potential differences in circRNA expression associated with the disease.
- Human peripheral blood circRNA profile changes in response to exercise.
- Healthy controls showed an increase in the number of circRNAs following exercise testing, while no similar pattern was evident in ME/CFS patients, further highlighting physiological differences between the two groups.
- In ME/CFS, 14 circRNAs were highly expressed but absent in controls.
- Of these 14 circRNAS identified, significant enrichment of protein and gene regulative pathways were detected in five of them based on their predicted miRNA target genes. (The trends of specific circRNAs are discussed in the study.)
- The circRNA expression patterns were shown to remain altered five days after the CPET.
A few points about this study:
- It is very small therefore larger samples sizes are needed for verification. The results may also not represent a larger and more diverse sample.
- The sample was all females, this is acceptable due to the high prevalence in the female sex, (and also necessary due to the small sample size which would not be able to address sex related differences) as well as reported differences at a molecular level in other studies, but this is also a drawback as we don’t know if results would vary in males. (Also see Paper eight (8) and comments below.)
- The study re-analysed previous data and relies on a correct diagnosis of ME/CFS and robust protocols being performed by the previous researchers. Although, in the case of this study, the authors knowledge of ME/CFS can be questioned and they may be new to the field, with a few questionable references and interpretation.
- Sedentary controls were used, which is good but this is still a huge step away from the activity levels of those with ME/CFS, so it would be useful to compare to other illnesses.
- This study is not open access (i.e. not free to read), however, patients and caregivers can make a request to access from Elsevier journals (patientaccess@elsevier.com).
In conclusion, this is yet another study adding to the building evidence which has shown the unique changes in ME/CFS after exercise and during PEM. Results from this research lead us closer towards specific molecules (circRNA in this case) which could be targeted to develop a diagnostic test. However, ideally future diagnostic tests would need to be less invasive without the potential irreversible effects of PEM from the use of CPET.
Furthermore, leading on from this study this week Paper eight (8) shows that there are sex-dependent transcriptional changes in response to exercise in ME/CFS. We have reported on previous research by this group in our weekly roundups, which focussed on just a female cohort (see here). This study used an exercise challenge to provoke PEM and used RNA-sequencing (i.e. investigating the gene expression for molecules which help to make proteins).
The fundamental finding of this study showed that the pathways related to immune-cell signalling (including IL-12) and natural killer cell cytotoxicity were activated as a result of exertion in the male ME/CFS cohort, while females did not show significant changes in gene expression to meet the criteria for the differential expression. During the recovery period male ME/CFS patients had distinct changes in the regulation of specific cytokine signals (including IL-1β) but females had significant alterations in gene networks related to cell stress, response to herpes viruses, and NF-κβ signalling. Paper eight (8) therefore provides an insight into the different sex-specific pathophysiology in ME/CFS, showing the importance of investigating sex related differences.
ME/CFS Research References and Abstracts (13 – 19 June)
Yuning Cheng, Si-Mei Xu, Konii Takenaka, Grace Lindner, Ashton Curry-Hyde, Michael Janitz.
Gene, Volume 877, 2023, 147568.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with obscure aetiology. The underdiagnosis rate of ME/CFS is high due to the lack of diagnostic criteria based on objective markers.
In recent years, circRNAs have emerged as potential genetic biomarkers for neurological diseases, including Parkinson’s disease and Alzheimer’s disease, making them likely to have the same prospect of being biomarkers in ME/CFS. However, despite the extensive amount of research that has been performed on the transcriptomes of ME/CFS patients, all of them are solely focused on linear RNAs, and the profiling of circRNAs in ME/CFS has been completely omitted.
In this study, we investigated the expression profiles of circRNAs, comparing ME/CFS patients and controls before and after two sessions of cardiopulmonary exercise longitudinally.
In patients with ME/CFS, the number of detected circRNAs was higher compared to healthy controls, indicating potential differences in circRNA expression associated with the disease.
Additionally, healthy controls showed an increase in the number of circRNAs following exercise testing, while no similar pattern was evident in ME/CFS patients, further highlighting physiological differences between the two groups.
A lack of correlation was observed between differentially expressed circRNAs and their corresponding coding genes in terms of expression and function, suggesting the potential of circRNAs as independent biomarkers in ME/CFS.
Specifically, 14 circRNAs were highly expressed in ME/CFS patients but absent in controls throughout the exercise study, indicating a unique molecular signature specific to ME/CFS patients and providing potential diagnostic biomarkers for the disease. Significant enrichment of protein and gene regulative pathways were detected in relation to five of these 14 circRNAs based on their predicted miRNA target genes.
Overall, this is the first study to describe the circRNA expression profile in peripheral blood of ME/CFS patients, providing valuable insights into the molecular mechanisms underlying the disease.
2. Long COVID and myalgic encephalomyelitis: opportunities for understanding and research
W David Strain, Shane Davies, Sonya Chowdhury.
British Journal of Healthcare Management Vol. 29, No. 6
Abstract
Colleagues from the UK charity Action For M.E. discuss the overlap between long COVID and myalgic encephalomyelitis, and the implications of this for research into, and management of, these conditions.
3. Establishment and Evaluation of Animal Models of Chronic Fatigue Syndrome
Yue Li; Xiuzhen Han; Qiulu Xu; Hongtao Shang.
Chinese Journal of Experimental Traditional Medical Formulae ; (24): 234-242, 2023.
Abstract
Chronic fatigue syndrome （CFS） is a heterogeneous disease with dysfunction in multiple systems and multiple organs. Its etiology and pathogenesis have not been fully clarified, and its treatment also lacks specificity.
The key to studying CFS is developing animal models that reflect the underlying mechanisms and etiology of CFS. The existing CFS modeling methods are complicated and not unified. By sorting out relevant literature，the present study evaluated the modeling methods，modeling standards，mechanisms， and clinical coincidence of the immune model，the stress model， and the disease-syndrome combination model in traditional Chinese medicine （TCM）.
The immune model is mainly constructed from the perspective of pathophysiology， with easy operation and wide investigation, which can simulate the pathological characteristics of CFS to ensure pathogenesis research, but the experimental repeatability is general.
Stress modeling is a common method for a variety of neuropsychiatric disease, including CFS. Many different stressors can be employed to investigate the etiology of CFS, but their effects are unpredictable.
Compared with the two western medicine models mentioned above，the TCM disease-syndrome combination model integrates modern medicine with TCM theory，with high clinical coincidence and great practical value.
However, the TCM disease-syndrome combination model of CFS is still in the exploratory stage with a few types of models，which needs to be further improved， aiming to establish scientific，reasonable，simple， and efficient animal models to provide support for exploring the etiology，pathogenesis, and new treatment ideas of CFS.
Josev EK, Chen J, Seal M, Scheinberg A, Cole RC, Rowe K, Lubitz L, Knight SJ.
J Neurosci Res. 2023 Jun 18. [Epub ahead of print.]
Abstract
Recent studies in adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suggest that changes in brain white matter microstructural organization may correlate with core ME/CFS symptoms, and represent a potential biomarker of disease. However, this has yet to be investigated in the pediatric ME/CFS population.
We examined group differences in macrostructural and microstructural white matter properties, and their relationship with clinical measures, between adolescents recently diagnosed with ME/CFS and healthy controls.
Forty-eight adolescents (25 ME/CFS, 23 controls, mean age 16 years) underwent brain diffusion MRI, and a robust multi-analytic approach was used to evaluate white and gray matter volume, regional brain volume, cortical thickness, fractional anisotropy, mean/axial/radial diffusivity, neurite dispersion and density, fiber density, and fiber cross section.
From a clinical perspective, adolescents with ME/CFS showed greater fatigue and pain, poorer sleep quality, and poorer performance on cognitive measures of processing speed and sustained attention compared with controls. However, no significant group differences in white matter properties were observed, with the exception of greater white matter fiber cross section of the left inferior longitudinal fasciculus in the ME/CFS group compared with controls, which did not survive correction for intracranial volume.
Overall, our findings suggest that white matter abnormalities may not be predominant in pediatric ME/CFS in the early stages following diagnosis. The discrepancy between our null findings and white matter abnormalities identified in the adult ME/CFS literature could suggest that older age and/or longer illness duration influence changes in brain structure and brain-behavior relationships that are not yet established in adolescence.
Al-Hakeim HK, Khairi Abed A, Rouf Moustafa S, Almulla AF, Maes M.
Front Mol Neuroscience 16:1194769.
Abstract
Critical COVID-19 disease is accompanied by depletion of plasma tryptophan (TRY) and increases in indoleamine-dioxygenase (IDO)-stimulated production of neuroactive tryptophan catabolites (TRYCATs), including kynurenine (KYN). The TRYCAT pathway has not been studied extensively in association with the physiosomatic and affective symptoms of Long COVID.
In the present study, we measured serum TRY, TRYCATs, insulin resistance (using the Homeostatic Model Assessment Index 2-insulin resistance, HOMA2-IR), C-reactive protein (CRP), physiosomatic, depression, and anxiety symptoms in 90 Long COVID patients, 3-10 months after remission of acute infection.
We were able to construct an endophenotypic class of severe Long COVID (22% of the patients) with very low TRY and oxygen saturation (SpO2, during acute infection), increased kynurenine, KYN/TRY ratio, CRP, and very high ratings on all symptom domains.
One factor could be extracted from physiosomatic symptoms (including chronic fatigue-fibromyalgia), depression, and anxiety symptoms, indicating that all domains are manifestations of the common physio-affective phenome. Three Long COVID biomarkers (CRP, KYN/TRY, and IR) explained around 40% of the variance in the physio-affective phenome. The latter and the KYN/TRY ratio were significantly predicted by peak body temperature (PBT) and lowered SpO2 during acute infection.
One validated latent vector could be extracted from the three symptom domains and a composite based on CRP, KYN/TRY, and IR (Long COVID), and PBT and SpO2 (acute COVID-19).
In conclusion, the physio-affective phenome of Long COVID is a manifestation of inflammatory responses during acute and Long COVID, and lowered plasma tryptophan and increased kynurenine may contribute to these effects.
Natalie A. Bai, Christie S. Richardson.
Chronic Dis Transl Med. 2023;1–8.
Abstract
Lyme disease is the most common vector-borne illness in the United States and has been causing significant morbidity since its discovery in 1977. It is well-documented that about 10% of patients properly treated with antibiotics never fully recover, but instead go on to develop a chronic illness dubbed, posttreatment Lyme disease syndrome (PTLDS) characterized by severe fatigue, cognitive slowing, chronic pain, and sleep difficulties.
This review includes 18 studies that detail the symptoms of patients with PTLDS and uses qualitative analysis to compare them to myalgic encephalitis/chronic fatigue syndrome (ME/CFS), a strikingly similar syndrome.
In the majority of the PTLDS studies, at least four of the six major symptoms of ME/CFS were also noted, including substantial impairment in activity level and fatigue for more than 6 months, post-exertional malaise, and unrefreshing sleep. In one of the included PTLDS articles, 26 of the 29 ME/CFS symptoms were noted.
This study adds to the expanding literature on the post-active phase of infection syndromes, which suggests that chronic illnesses such as PTLDS and ME/CFS have similar pathogenesis despite different infectious origins.
Key points
- This systematic review uses qualitative analysis to compare posttreatment Lyme disease syndrome to myalgic encephalitis/chronic fatigue syndrome, both of which are post-active phases of infection syndromes.
- The result of this review suggests that chronic illnesses such as PTLDS and ME/CFS have similar pathogenesis despite different infectious origins.
Ulf Hannestad, Eirini Apostolou, Per Sjogren, Björn Bragée, Olli Polo, Bo C. Bertilson and Anders Rosén.
Front. Med. Sec. Infectious Diseases: Pathogenesis and Therapy, Volume 10 – 2023.
Abstract
The post-viral fatigue syndromes long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have multiple, potentially overlapping, pathological processes. These include persisting reservoirs of virus e.g. SARS-CoV-2 in long COVID patient's tissues, immune dysregulation with or without reactivation of underlying pathogens, such as Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV6), as we recently described in ME/CFS, and possibly yet unidentified viruses.
In the present study we tested saliva samples from two cohorts for IgG against human adenovirus (HAdV): patients with ME/CFS (n=84) and healthy controls (n=94), with either mild/asymptomatic SARS-CoV-2 infection or no infection.
A significantly elevated anti-HAdV IgG response after SARS-CoV-2 infection was detected exclusively in the patient cohort. Longitudinal/time analysis, before and after COVID-19, in the very same individuals confirmed HAdV IgG elevation after. In plasma there was no HAdV IgG elevation.
We conclude that COVID-19 triggered reactivation of dormant HAdV in the oral mucosa of chronic fatigue patients indicating an exhausted dysfunctional antiviral immune response in ME/CFS, allowing reactivation of adenovirus upon stress encounter such as COVID-19.
Gamer J, Van Booven DJ, Zarnowski O, Arango S, Elias M, Kurian A, Joseph A, Perez M, Collado F, Klimas N, et al.
International Journal of Molecular Sciences. 2023; 24(12):10255.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multi-symptom illness characterized by debilitating fatigue and post-exertional malaise (PEM). Numerous studies have reported sex differences at the epidemiological, cellular, and molecular levels between male and female ME/CFS patients.
To gain further insight into these sex-dependent changes, we evaluated differential gene expression by RNA-sequencing (RNA-Seq) in 33 ME/CFS patients (20 female, 13 male) and 34 matched healthy controls (20 female and 14 male) before, during, and after an exercise challenge intended to provoke PEM.
Our findings revealed that pathways related to immune-cell signaling (including IL-12) and natural killer cell cytotoxicity were activated as a result of exertion in the male ME/CFS cohort, while female ME/CFS patients did not show significant enough changes in gene expression to meet the criteria for the differential expression.
Functional analysis during recovery from an exercise challenge showed that male ME/CFS patients had distinct changes in the regulation of specific cytokine signals (including IL-1β). Meanwhile, female ME/CFS patients had significant alterations in gene networks related to cell stress, response to herpes viruses, and NF-κβ signaling.
The functional pathways and differentially expressed genes highlighted in this pilot project provide insight into the sex-specific pathophysiology of ME/CFS.
Jinushi R, Masuda S, Tanisaka Y, Nishiguchi S, Shionoya K, Sato R, Sugimoto K, Shin T, Shiomi R, Fujita A, Mizuide M, Ryozawa S.
J Transl Med. 2023 Jun 19;21(1):398.
Abstract
Background: Myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease (ME/CFS/SEID) is a condition diagnosed primarily based on clinical symptoms, including prolonged fatigue and post-exertional malaise; however, there is no specific test for the disease. Additionally, diagnosis can be challenging since healthcare professionals may lack sufficient knowledge about the disease. Prior studies have shown that patients with ME/CFS/SEID have low serum acylcarnitine levels, which may serve as a surrogate test for patients suspected of having this disease. This systematic review and meta-analysis aimed to investigate the differences in serum acylcarnitine levels between patients with ME/CFS/SEID and healthy controls.
Methods: This systematic review was conducted using PubMed and Ichushi-Web databases. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, we included all studies from the databases' inception until February 17, 2023, that evaluated blood tests in both patients with ME/CFS/SEID and healthy control groups. The primary endpoint was the difference in serum acylcarnitine levels between the two groups.
Results: The electronic search identified 276 studies. Among them, seven met the eligibility criteria. The serum acylcarnitine levels were analyzed in 403 patients with ME/CFS/SEID. The patient group had significantly lower serum acylcarnitine levels when compared with the control group, and the statistical heterogeneity was high.
Conclusion: The patient group had significantly lower serum acylcarnitine levels when compared with the control group. In the future, the measurement of serum acylcarnitine levels, in addition to clinical symptoms, may prove to be a valuable diagnostic tool for this condition.
Dolp R, Wardle DP, Khalid-Khan S.
Int J Adolesc Med Health. 2023 Jun 20. [Epub ahead of print.]
Abstract
Objectives: Paediatric Chronic Fatigue Syndrome (pCFS) is a common condition that significantly disrupts a healthy psychosocial development. Psychiatric symptoms associated with pCFS are conceptualized as either part of its complex etiology, its consequence, or as a comorbidity. However, patients with this condition are rarely seen by psychiatrists. This scoping review aims to explore the role of psychiatry in the diagnosis and treatment of pCFS.
Content: A scoping review of literature was conducted using MEDLINE, EMBASE, Cochrane and PsycINFO. Databases were searched for articles describing psychiatric involvement in the diagnosis or treatment of children and adolescents (age ≤ 18) with pCFS. A grey literature search was also conducted to identify additional guidelines and national recommendations to identify the role of psychiatry in the diagnosis and treatment of pCFS.
Summary: The search provided 436 articles of which 16 met inclusion criteria. Grey literature search identified 12 relevant guidelines. Most studies and guidelines did not include any psychiatric involvement in the care of patients with pCFS. If psychiatry was mentioned, it was used interchangeably with psychological interventions or in the context of treating distinct psychiatric comorbidities and suicidal ideation.
Outlook: The role of psychiatry in diagnosis and treatment of pCFS is poorly defined. Future research is required to understand how psychiatrists can contribute to the care of patients with pCFS.
ME/CFS Research References and Abstracts (6 – 12 June)
Long-COVID Research References
Dr Katrina Pears,
Research Correspondent.
The ME Association.
