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
Research has picked up again this week. There have been ten new ME/CFS studies and twenty-one new Long Covid studies this week.
We have highlighted one of the ME/CFS studies in more detail below:
Paper five (5) is a preprint study (meaning it has not been peer-reviewed and the science verified) which trials the use of faecal microbiota transplantation (FMT) on reducing ME/CFS symptoms. Studies on the gut microbiome in ME/CFS have previously shown an imbalance in the bacteria present, (such as Guo et al., 2023; Steinsvik et al., 2023; Xiong et al., 2023). Faecal microbiota transplantation can be used to restore gut bacteria back to its normal composition and diversity and so improve gut function. The process involves implanting normal or beneficial intestinal bacteria and yeasts from a healthy donor into the colon of a person where there has been evidence of harmful changes to the gut microbiota. In this study, a colonoscopy was used to transplant the faecal microbiota.
This study looked at the effect of FMT on fatigue severity and health-related quality of life (HRQOL) in 11 ME/CFS patients (10 females and 1 male). Four different questionnaires were used to evaluate if there was a change in fatigue and health. All patients were evaluated at baseline, then one and six months following FMT.
Disappointingly, the results were insignificant overtime, showing no significant improvements in fatigue or health. The study did find a slight, but statistically non-significant improvement in fatigue at 1-month using the modified fatigue impact scale (MFIS), but this was not further supported by the other questionnaires used (e.g. the Visual Analogue Scale (VAS)). The study however did find FMT to be safe and tolerated with no adverse effects.
Some things to note about this study:
- It was a randomized, double-blinded, placebo-controlled pilot study, meaning that patients or researchers did not know who was receiving what treatment. Here, 5 patients received FMT from a universal donor and 6 patients received the placebo, which was autologous FMT, i.e. receiving their own faecal transplantation.
- The study was a pilot study, hence the very small size. However, a small study size limits the extent to which significant findings can be found.
- There was a huge imbalance of males: females, in this case it might have been advantageous to have used use one sex.
- There was no control group, so if a benefit was found it would be hard to fully evaluate the findings.
- The average duration of illness was 6.3 years (±2.5 years) which is probably not very representative of the overall ME/CFS population which is likely to have much longer illness durations.
- There are several ways of administering FMT, but colonoscopy was chosen in this study as it has been shown to be a superior and more successful method of treating IBS. However, this also reduced the sample size in this study as a large proportion of patients withdrew from the study as they thought the procedure would be too burdensome for them.
- Probably the most disappointing factor of this study was that all outcomes measured were self-reported through questionnaires, and no biological specimens were analysed. It is especially disappointing that any change in gut microbia wasn’t analysed or for example IBS symptoms.
You can read more about faecal microbiota transplantation on our website, including a recent radio interview on the Today Programme and in our medical matters section.
In conclusion, results are disappointing as the study was well thought through as it was randomized, double-blinded and placebo, however, it lacks in its control group, size and was restricted by the outcomes measured. I feel with a few tweaks this study could have told us more about FMT in ME/CFS.
You may also be interested this week in Paper two (2) in the Long Covid reference section. This study looks at treating Long Covid with apheresis, which is an invasive procedure that involves removing blood from a vein, passing it through a machine that separates out any harmful constituents (in the case of Long Covid this tends to focus on the removal of the small blood clots) and then returns the remaining cleansed blood to the body.
In this study the researchers also analysed blood samples, and those who reported significant improvements after two rounds of apheresis showed a significant reduction in neurotransmitter autoantibodies, lipids, and inflammatory markers. It is worth looking at some of the graphs in this paper, as some staggering decreases in the biomarkers are reported, such as decrease in the inflammatory cytokine interleukin- 6 (IL-6) which is commonly reported in Long Covid research.
There are a few problems in this research, as here the study reports on 27 patients with Long Covid, there was no control group or placebo group. Furthermore, the study includes these 27 patients as they have reported clinical improvements, but we do not know from this how many were originally included or how many didn’t improve so were not included in the analysis.
Additionally, patients receiving apheresis also received a Heparin treatment, which is used to prevent blood clots from forming in people who have certain medical conditions and is also used to reduce the chance of blood clots forming in certain medical procedures. Therefore, we do not know which treatment caused the positive effect.
We have covered apheresis in several of our website blogs, in medical matters and in a research summary covering treatments for Long Covid. However, at the moment there have been no properly conducted clinical trials (with placebos) to show that apheresis is safe and effective, furthermore, we need more haematologists to get involved with this area of research
ME/CFS Research References and Abstracts
Uhde, M., Indart, A.C., Green, P.H.R., Yolken, R.H., Cook, D.B., Shukla, S.K., Vernon, S.D., Alaedini, A.
Brain, Behavior, & Immunity – Health (2023).
Highlights
- Elevation of FABP2, a marker of intestinal cell damage in ME/CFS.
- Absence of optimal acute-phase LBP and sCD14 anti-microbial responses in ME/CFS.
- Compensatory but inadequate B cell response to microbial translocation in ME/CFS.
- Enhanced IL-10 regulatory response may drive the observed immunosuppression.
- Glucose and citrate metabolic dysfunction in ME/CFS may link the IL-10 activation and suppressed anti-microbial responses.
Abstract
The etiology and mechanism of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are poorly understood and no biomarkers have been established. Specifically, the relationship between the immunologic, metabolic, and gastrointestinal abnormalities associated with ME/CFS and their relevance to established symptoms of the condition remain unclear.
Relying on data from two independent cohorts of ME/CFS and control study participants, one at rest and one undergoing an exercise challenge, we identify a state of suppressed acute-phase innate immune response to microbial translocation in conjunction with a compromised gut epithelium.
This immunosuppression, along with observed enhancement of compensatory antibody responses to counter the microbial translocation, was associated with and may be mediated by alterations in glucose and citrate metabolism and an IL-10 immunoregulatory response.
Our findings provide novel insights into mechanistic pathways, biomarkers, and potential therapeutic targets in ME/CFS, including in the context of exertion, with relevance to both intestinal and extra-intestinal symptoms.
Carrasco-Querol, Noèlia; González Serra, Gemma; Bueno Hernández, Nerea; Gonçalves, Alessandra Queiroga; Pastor Cazalla, Marta; Bestratén del Pino, Pau; Montesó Curto, Pilar; Caballol Angelats, Rosa; Fusté Anguera, Immaculada; Sancho Sol, Mª Cinta; Castro Blanco, Elisabet; Vila-Martí, Anna; Medina-Perucha, Laura; Fernández-Sáez, José; Dalmau Llorca, M. Rosa; Aguilar Martín, Carina.
Medicine 102(17):p e33637.
Abstract
Introduction: Chronic pain, fatigue and insomnia are classic symptoms of fibromyalgia (FM) and chronic fatigue syndrome (CFS) and seriously affect quality of life. Nutrition and chronobiology are often overlooked in multicomponent approach despite their potential. This study aims to evaluate the effectiveness of a multidisciplinary group intervention based on nutrition, chronobiology, and physical exercise in the improvement of lifestyle and quality of life in FM and CFS.
Methods: Mixed-methods study based on a randomized clinical trial and qualitative analysis with a descriptive phenomenological approach. The study will be conducted in primary care in Catalonia. The control group will follow the usual clinical practice and the intervention group the usual practice plus the studied intervention (12 hours over 4 days).
The intervention based on nutrition, chronobiology and physical exercise will be designed considering participants’ opinions as collected in 4 focus groups. To evaluate effectiveness, EuroQol-5D, multidimensional fatigue inventory, VAS pain, Pittsburgh Sleep Quality Index, erMEDAS-17, biological rhythms interview of assessment in neuropsychiatry, REGICOR-Short, FIQR and Hospital Anxiety and Depression Scale questionnaires will be collected at baseline, and at 1, 3, 6, and 12 months post-intervention.
Food intake, body composition, resistance and, strength will also be evaluated. The effect size will be calculated using Cohen d and logistic regression models will be used to quantify the impact of the intervention by adjusting for different variables.
Discussion: It expected that the intervention will improve the patients’ quality of life, fatigue, pain and insomnia, as well as food and physical exercise habits, providing effectiveness evidence of a new therapy in addressing these syndromes in Primary Heath Care. Improvements in the quality of life will have a positive socioeconomic impact by reducing health expenditure on recurrent medical consultation, medication, complementary medical tests, etc and favor the maintenance of an active working life and productivity.
Breanna Weigel, Natalie Eaton-Fitch, Kiran Thapaliya, Sonya Marshall-Gradisnik.
Popul. Med. 2023;5(Supplement):A372
Abstract
Background and Οbjective: Considerable overlap exists in the clinical presentation of Post COVID-19 Condition and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The current study aimed to compare symptoms and patient-reported Quality of Life (QoL) among people with Post COVID-19 Condition and ME/CFS in Australia.
Methods: QoL data was collected from n=61 ME/CFS patients, n=31 Post COVID-19 Condition patients, and n=54 Healthy Controls (HCs) via validated instruments. The ME/CFS and Post COVID-19 Condition participants also provided self-reported severity and frequency of symptoms derived from the Canadian and International Consensus Criteria for ME/CFS and the World Health Organization case definition for Post COVID-19 Condition.
Study variables were compared with Chi-square, Fisher’s exact, Fisher-Freeman-Halton, Mann-Whitney U, and Kruskal-Wallis H tests using Statistical Package for the Social Sciences version 29. Symptom clusters among the two illness cohorts were identified with hierarchical cluster analysis.
Results: ME/CFS was associated with a higher prevalence of short-term memory loss (p=0.039), muscle weakness (p<0.001), lymphadenopathy (p=0.013), and nausea (p=0.003). People with ME/CFS also reported more severe light-headedness (p=0.011) and more frequent unrefreshed sleep (p=0.011), but less frequent heart palpitations (p=0.040). Symptom prevalence, severity, and frequency were otherwise comparable. Few differences existed in the QoL of the two illness cohorts, both of which returned significantly impaired QoL scores when compared with HCs (p<0.001). Cluster analysis of symptom prevalence revealed four clusters: 1) Low gastrointestinal, low neurosensory; 2) Moderate gastrointestinal, low orthostatic and memory loss; 3) Moderate gastrointestinal, high orthostatic and memory loss; and 4) High gastrointestinal, high pain, which did not differ in sociodemographic information, illness status, or diagnostic criteria met.
Conclusions: Post COVID-19 Condition and ME/CFS are remarkably similar in presentation and, like ME/CFS, Post COVID-19 Condition has a profound and negative impact on patient QoL. Gastrointestinal symptoms may have a role in determining ME/CFS and Post COVID-19 Condition subtypes.
Kielland A, Liu J, Jason LA.
J Health Psychol. 2023 Apr 28:13591053231169191.
Abstract
Public health and welfare systems request documentation on approaches to diagnose, treat, and manage myalgic encephalomyelitis and assess disability-benefit conditions.
Our objective is to document ME patients' experiences with services/interventions and assess differences between those meeting different diagnostic criteria, importantly the impact of post-exertional malaise.
We surveyed 660 fatigue patients in Norway using respondent-driven sampling and applied validated DePaul University algorithms to estimate Canadian and Fukuda criteria proxies.
Patients on average perceived most interventions as having low-to-negative health effects. Responses differed significantly between sub-groups for some key interventions. The PEM score was strongly associated with the experience of most interventions.
Better designed and targeted interventions are needed to prevent harm to the patient group. The PEM score appears to be a strong determinant and adequate tool for assessing patient tolerance for certain interventions. There is no known treatment for ME, and “do-no-harm” should be a guiding principle in all practice.
Salonen TE, Jokinen E, Satokari R, Lahtinen P.
ResearchSquare [Preprint]
Abstract
Background: Chronic fatigue syndrome (CFS) is a disabling illness of unknown aetiology. Disruption of gut microbiota may play a role in several neurological disorders. In this study, the effect of faecal microbiota transplantation (FMT) on fatigue severity and health-related quality of life (HRQOL) in patients with CFS was evaluated.
Methods: Randomized, placebo-controlled pilot trial. Patients and researchers were blinded to treatment assignment. 11 patients with CFS (10 female and 1 male, mean age 42.2 years and mean duration of CFS 6.3 years) were randomly assigned to receive either FMT from a universal donor (n = 5) or autologous FMT (n = 6) via colonoscopy.
Patients’ HRQOL was assessed by using visual analog scale (VAS) and self-reporting questionnaires Modified Fatigue Impact Scale (MFIS), 15D and EQ-5D-3L. Patients’ HRQOL was evaluated at baseline, and 1 and 6 months after the FMT.
Results: The baseline VAS scores in the FMT and placebo groups were 62.4 and 76.0 (p = 0.29). 1-month scores were 60.0 and 73.7 and 6-months scores 72.8 and 69.5, respectively. Total MFIS scores in the FMT and placebo groups were 59.6 and 61.0 at the baseline (p = 0.80), 53.5 and 62.0 at 1 month and 58.6 and 56.2 at 6 months.
Compared to the baseline scores, differences at 1 and 6 months were statistically insignificant both in VAS and in MFIS. The 15D and EQ-5D-3L profiles did not change after the FMT or placebo. FMT-related adverse events were not reported.
Conclusion: FMT was safe but did not relieve symptoms or improve the HRQOL of patients with CFS. Small number of study subjects limits the generalizability of these results.
Grande T, Grande B, Gerner P, Hammer S, Stingl M, Vink M, Hughes BM.
Medicina. 2023; 59(4):719.
Abstract
Myalgic encephalomyelitis/chronic fatigue (ME/CFS) is a post-infectious, chronic disease that can lead to severe impairment and, even, total disability. Although the disease has been known for a long time, and has been coded in the ICD since 1969 (G93.3), medical research has not yet been able to reach a consensus regarding its physiological basis and how best to treat it.
Against the background of these shortcomings, psychosomatic disease models have been developed and psychotherapeutic treatments have been derived from them, but their empirical testing has led to sobering results. According to the current state of research, psychotherapy and psychosomatic rehabilitation have no curative effect in the treatment of ME/CFS.
Nevertheless, we see numerous patients in practices and outpatient clinics who suffer severely as a result of their illness and whose mental well-being and coping strategies would benefit from psychotherapeutic help.
In this article, we outline a psychotherapeutic approach that serves this need, taking into account two basic characteristics of ME/CFS: firstly, the fact that ME/CFS is a physical illness and that curative treatment must therefore be physical; and secondly, the fact that post exertional malaise (PEM) is a cardinal symptom of ME/CFS and thus warrants tailored psychotherapeutic attention.
Lei C, Chen J, Huang Z, Men Y, Qian Y, Yu M, Xu X, Li L, Zhao X, Jiang Y, Liu Y.
Front Pharmacol. 2023 Apr 10;14:1163638.
Abstract
Background: Chronic fatigue syndrome (CFS) is characterized by significant and persistent fatigue. Ginseng is a traditional anti-fatigue Chinese medicine with a long history in Asia, as demonstrated by clinical and experimental studies. Ginsenoside Rg1 is mainly derived from ginseng, and its anti-fatigue metabolic mechanism has not been thoroughly explored.
Methods: We performed non-targeted metabolomics of rat serum using LC-MS and multivariate data analysis to identify potential biomarkers and metabolic pathways. In addition, we implemented network pharmacological analysis to reveal the potential target of ginsenoside Rg1 in CFS rats. The expression levels of target proteins were measured by PCR and Western blotting.
Results: Metabolomics analysis confirmed metabolic disorders in the serum of CFS rats. Ginsenoside Rg1 can regulate metabolic pathways to reverse metabolic biases in CFS rats. We found a total of 34 biomarkers, including key markers Taurine and Mannose 6-phosphate. AKT1, VEGFA and EGFR were identified as anti-fatigue targets of ginsenoside Rg1 using network pharmacological analysis. Finally, biological analysis showed that ginsenoside Rg1 was able to down-regulate the expression of EGFR.
Conclusion: Our results suggest ginsenoside Rg1 has an anti-fatigue effect, impacting the metabolism of Taurine and Mannose 6-phosphate through EGFR regulation. This demonstrates ginsenoside Rg1 is a promising alternative treatment for patients presenting with chronic fatigue syndrome.
Barbara Stussman, Brice Calco, Gina Norato, Angelique Gavin, Snigdha Chigurupati, Avindra Nath, Brian Walitt
medRxiv [Preprint]
Abstract
Background: A central feature of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is post exertional malaise (PEM), which is an acute worsening of symptoms after a physical, emotional and/or mental exertion. PEM is also a feature of Long COVID. Dynamic measures of PEM have historically included scaled questionnaires which have not been validated in ME/CFS. To enhance our understanding of PEM and how best to measure it, we conducted semi-structured qualitative interviews (QIs) at the same intervals as Visual Analog Scale (VAS) measures after a Cardiopulmonary Exercise Test (CPET).
Methods: Ten ME/CFS and nine healthy volunteers participated in a CPET. For each participant, PEM symptom VAS (7 symptoms) and semi-structured QIs were administered at six timepoints over 72 hours before and after a single CPET. QI data were used to plot the severity of PEM at each time point and identify the self-described most bothersome symptom for each patient. QI data were used to determine the symptom trajectory and peak of PEM. Performance of QI and VAS data were compared to each other using Spearman correlations.
Results: QIs documented that each ME/CFS volunteer had a unique PEM experience, with differences noted in the onset, severity, trajectory over time, and most bothersome symptom. No healthy volunteers experienced PEM. Scaled QI data were able to identify PEM peaks and trajectories, even when VAS scales were unable to do so due to known ceiling and floor effects. QI and VAS fatigue data corresponded well prior to exercise (baseline, r=0.7) but poorly at peak PEM (r=0.28) and with the change from baseline to peak (r=0.20). When the most bothersome symptom identified from QIs was used, these correlations improved (r=.0.77, 0.42. and 0.54 respectively) and reduced the observed VAS scale ceiling and floor effects.
Conclusion: QIs were able to capture changes in PEM severity and symptom quality over time in all the ME/CFS volunteers, even when VAS scales failed to do so. Information collected from QIs also improved the performance of VAS. Measurement of PEM can be improved by using a quantitative-qualitative mixed model approach.
Hultman A, Cohen AK and Soares L.
Front. Rehabil. Sci. 4:1122673.
Abstract
Long COVID disproportionately affects premenopausal women, but relatively few studies have examined Long COVID's impact on female reproductive health. We conduct a review of the literature documenting the female reproductive health impacts of Long COVID which may include disruptions to the menstrual cycle, gonadal function, ovarian sufficiency, menopause, and fertility, as well as symptom exacerbation around menstruation.
Given limited research, we also review the reproductive health impacts of overlapping and associated illnesses including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), postural orthostatic tachycardia syndrome (POTS), connective tissue disorders like Ehlers-Danlos syndrome (EDS), and endometriosis, as these illnesses may help to elucidate reproductive health conditions in Long COVID.
These associated illnesses, whose patients are 70%–80% women, have increased rates of dysmenorrhea, amenorrhea, oligomenorrhea, dyspareunia, endometriosis, infertility, vulvodynia, intermenstrual bleeding, ovarian cysts, uterine fibroids and bleeding, pelvic congestion syndrome, gynecological surgeries, and adverse pregnancy complications such as preeclampsia, maternal mortality, and premature birth. Additionally, in Long COVID and associated illnesses, symptoms can be impacted by the menstrual cycle, pregnancy, and menopause.
We propose priorities for future research and reproductive healthcare in Long COVID based on a review of the literature. These include screening Long COVID patients for comorbid and associated conditions; studying the impacts of the menstrual cycle, pregnancy, and menopause on symptoms and illness progression; uncovering the role of sex differences and sex hormones in Long COVID and associated illnesses; and addressing historical research and healthcare inequities that have contributed to detrimental knowledge gaps for this patient population.
Hampilos, N., Germain, A., Mao, X., Hanson, M., & Shungu, D.
Journal of Clinical and Translational Science, 7(S1), 137-138
Abstract
Objectives/Goals: Strong evidence has implicated oxidative stress (OS) as a disease mechanism in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The study aim was to assess whether a C>T single nucleotide polymorphism (SNP) (rs1800668), which reduces the activity of glutathione peroxidase 1 (GPX1), is associated with brain OS in patients with ME/CFS.
Methods/Study Population: Study population: The study enrolled 20 patients with ME/CFS diagnosed according to Canadian Consensus Criteria, and 11 healthy control (HC) subjects.
Genotyping: DNA was extracted from whole blood samples, amplified by PCR, and purified. Sanger sequencing was used for genotyping. 1H
MRS: Proton magnetic resonance spectroscopy (1H MRS) was used to measure levels of glutathione (GSH)— a primary tissue antioxidant and OS marker— in a 3x3x2 cm3 occipital cortex (OCC) voxel. GSH spectra were recorded in 15 minutes with the standard J-editing technique. The resulting GSH peak area was normalized to tissue water level in the voxel.
Statistical Analysis: T-tests were used to compare OCC GSH levels between ME/CFS and HC groups, and between the study’s genotype groups (group 1: CC, group 2: combined TC and TT).
Results/Anticipated Results: Clinical characteristics: ME/CFS and HC groups were comparable on age and BMI but not on sex (p = 0.038). Genotype frequencies: Genotype frequencies in the ME/CFS group were 0.55 (CC), 0.25 (TC) and 0.2 (TT); and 0.636 (CC), 0.364 (TC), and 0 (TT) in the HC group. GSH levels: There was a trend-level lower mean OCC GSH in ME/CFS than in HC (0.0015 vs 0.0017; p = 0.076). GSH levels by genotype group interaction: Within the ME/CFS group but not in the combined ME/CFS and HC group or HC group alone, GSH levels were lower in the TC and TT genotypes than in CC genotypes (0.00143 vs 0.00164; p = 0.018).
Discussion/Significance: This study found that the presence of a C>T SNP in GPX1 is associated with lower mean GSH levels and, hence, brain oxidative stress, in ME/CFS patients. If validated in a larger cohort, this finding may support targeted antioxidant therapy based on their genotype as a potentially effective treatment for patients with ME/CFS.
Long-COVID Research References
- Damage to endothelial barriers and its contribution to long COVID
- Clinical improvement of Long-COVID is associated with reduction in autoantibodies, lipids, and inflammation following therapeutic apheresis
- Nutritional Support During Long COVID: A Systematic Scoping Review
- The impact of Long COVID Syndrome treatment and rehabilitation: systematic review and meta-analysis of patient-reported outcomes
- Review of Neurological Manifestations of SARS-CoV-2
- Recuperative herbal formula Jing Si maintains vasculature permeability balance, regulates inflammation and assuages concomitants of “Long-Covid”
- Physical activity levels respiratory and peripheral muscle strength and pulmonary function in young post-COVID-19 patients
- Lung perfusion assessment in children with long-COVID: A pilot study
- Year in Review: Long COVID and Pulmonary Rehabilitation
- Post-COVID—More than chronic fatigue?
- COVID-19: Post-recovery Manifestations
- Battling the unknown: Using composite vignettes to portray lived experiences of COVID-19 and long-COVID
- Recuperative herbal formula Jing Si maintains vasculature permeability balance, regulates inflammation and assuages concomitants of “Long-Covid”
- Long-COVID, is a New Syndrome?
- Increased insulin resistance is associated with depressive symptoms due to Long COVID
- Antihistamines as an early treatment for Covid-19
- Proteomic profiling demonstrates inflammatory and endotheliopathy signatures associated with impaired cardiopulmonary exercise hemodynamic profile in Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome
- Long Covid: conceptualizing the challenges for public health
- Ambient air pollution exposure linked to long COVID among young adults: a nested survey in a population-based cohort in Sweden
- Netosis -A double-edged sword in the Pathogenesis of LONG COVID
- Intrinsic factors behind long-COVID: I. Prevalence of the extracellular vesicles
Dr Katrina Pears,
Research Correspondent.
The ME Association.
