The weekly research round-up includes recent publications about ME/CFS and Long Covid. We highlight the studies that have particularly caught our interest and follow these with the full list of publications together with their abstracts (summaries).
The ME Association maintains a comprehensive index of published research on ME/CFS and Long Covid that is free to use and updated weekly.
Audio commentary by Dr Katrina Pears
There have been six 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Paper three (3) is a preprint (meaning it has not been peer-reviewed and the science verified) looking into the dysregulation of extracellular vesicles signalling following maximal exercise. Extracellular vesicles (EVs) are nanosized, membrane-bound particles which are naturally released from almost all types of cells. They can transport other molecules, such as DNA, RNA and proteins between cells as part of intracellular communication, particularly in immune system response.
This study recruited 18 females with ME/CFS and 17 age and BMI matched sedentary female controls. Plasma was taken before, 15 minutes and 24 hours following a maximal cardiopulmonary exercise test (CPET). A variety of advanced methods were used to characterise the EVs as well as their protein cargo (any protein which is carried within the vesicles).
A number of complex analyses and comparisons were made in this study, a summary of the findings include:
- Exercise effects the proteins within the EVs differently in ME/CFS than healthy controls.
- Changes in EV proteins following exercise in ME/CFS were found to correlate strongly to symptom severity.
- Many differences were seen in the EV concentration following exercise; at baseline and 15 minutes post-exercise, the ME/CFS subjects had a higher concentration of circulating EVs compared to the control group.
- The EV concentration in the controls increased significantly at 15-minutes to 24-hours after exercise, whereas the ME/CFS EV concentration was not significantly affected by exercise.
- 63 EV proteins increased due to exercise in ME/CFS patients whereas 178 EV proteins increased in controls, only 45 proteins were found to overlap.
- 15-minutes following exercise 13 EV proteins had lower abundances and three had higher abundances in the ME/CFS group. Following 24-hours after exercise only one protein was significantly increased in the ME/CFS group. The study refers to this as a fewer differentially abundant proteins (DAPs).
- A delayed increase in abundance of several EV proteins in response to exercise in ME/CFS patients compared to controls was also found.
- A range of activated and inhibited biological pathways were found in ME/CFS, and these pathways were also found to differ in ME/CFS patients verus controls at baseline.
- The differentially abundant proteins (DAPs) were involved in many pathways and systems, including platelet functions, muscle contraction (both smooth and skeletal muscle), cytoskeletal protein functions, the immune system, and brain signalling.
- Specific findings relating to proteins found in ME/CFS, included: dysregulated coagulation processes and immune signalling following exercise, impaired EV signalling in relation to muscle contraction, and changes in cytoskeletal proteins correlating to symptoms.
- Overall, the study demonstrated a highly disrupted EV signalling process (relating to proteins) post-exercise in ME/CFS and the failure to respond to exercise at the molecular level.
This is an interesting study adding some new findings to the field, it is a shame however, that as always the sample size is extremely limited. A few other things to note about this study:
- The study was restricted to females only 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 gender related differences) as well as the previously reported differences at a molecular level, but this is also a draw back as we don’t know if results would vary in males.
- ME/CFS patients met the Canadian Consensus Criteria for diagnosis.
- This study used sedentary controls, which is good, but their activity levels are still likely to be far higher than those with ME/CFS.
- This research was performed by a well-known group of researchers in the States who are led by Maureen Hanson. We have already seen exercise studies combined with metabolomics from some of these researchers, for example Germain et al., 2022 (roundup comment here) and Glass et al., 2023 (roundup comment here).
- This is yet another study which shows that ME/CFS sufferers have a different response following exercise at the biological level. Like many of the other previous studies looking at the effect of exercise, this has required intensive CPET to induce the changes. It has previously been found that the average recovery time for patients with ME/CFS following CPET is two-weeks, which questions the ethics of this method especially for its use in determining a biomaker. Furthermore, this also limits research to those who are physically able to complete the exercise challenge.
- There is a good description of the previous work on EVs in ME/CFS within this paper. We have also previously covered some of this promising research in our roundups, for example Bonilla et al., 2022 (research comment here)and González-Cebrián et al. 2022 (research comment here).
In conclusion, this is a very interesting, but complex piece of research which further adds to the evidence showing that people with ME/CFS have a different response to exercise than healthy controls at the biological level. These findings may also play a role in the post exertional malaise (PEM) experienced.
Furthermore, this week you may also be interested in reading paper five (5) which is a Master’s Thesis also looking at using EVs to establish a biomarker for ME/CFS.
ME/CFS Research References
1. Investigating the factors associated with meaningful improvement on the SF-36-PFS and exploring the appropriateness of this measure for young people with ME/CFS accessing an NHS specialist service: a prospective cohort study
Gaunt D, Brigden A, Metcalfe C, Loades M, Crawley E.
BMJ Open. 2023 Aug 24;13(8):e069110.
Objectives: Paediatric myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is relatively common and disabling, but little is known about the factors associated with outcome. We aimed to describe the number and characteristics of young people reaching the 10-point minimal clinically important difference (MCID) of SF-36-Physical Function Subscale (SF-36-PFS) and to investigate factors associated with reaching the MCID.
Design: Prospective observational cohort study.
Setting: A specialist UK National Health Service ME/CFS service, Southwest England; recruitment between March 2014 and August 2015.
Participants: 193 eligible patients with ME/CFS aged 8-17 years reported baseline data. 124 (65%) and 121 (63%) with outcome data at 6 and 12 months, respectively.
Outcome measures: SF-36-PFS (primary outcome). Chalder Fatigue Questionnaire, school attendance, visual analogue pain scale, Hospital Anxiety and Depression Scale, Spence Young People Anxiety Scale, Clinical Global Impression scale and EQ-5D-Y (secondary).
Results: At 6 months 48/120 (40%) had reached the MCID for SF-36-PFS. This had increased to 63/117 (54%) at 12 months. On the Clinical Global Impressions, 77% and 79% reported feeling either a little better, much better or very much better. Those with worse SF-36-PFS at baseline assessment were more likely to achieve the MCID for SF-36-PFS at 6 months (odds ratio 0.97, 95% confidence interval 0.96 to 0.99, p value 0.003), but there was weaker evidence of effect at 12 months (OR 0.98, 95% CI 0.97 to 1.00, p value 0.038). No other factors at baseline were associated with the odds of reaching the MCID at 6 months. However, at 12 months, there was strong evidence of an effect of pain on MCID (OR 0.97, 95% CI 0.95 to 0.99, p value 0.001) and SF-36-PFS on MCID (OR 0.96, 95% CI 0.94 to 0.98, p value 0.001).
Conclusions: 40% and 54% of young people reached the MCID at 6 and 12 months, respectively. No factors at assessment (other than SF-36-PFS at 6 months, and pain and SF-36-PFS at 12 months) are associated with MCID of SF-36-PFS at either 6 or 12 months. Further work is needed to explore the most appropriate outcome measure for capturing clinical meaningful improvement for young people with ME/CFS.
Franz Martin, Manuel Blanco Suárez, Paola Zambrano, Óscar Cáceres Calle, Miriam Almirall, Jose Alegre-Martín, Beatriz Lobo, Ana María Gonzalez-Castro, Javier Santos, Joan Carles Domingo, Joanna Jurek, Jesús Castro-Marrero.
Frontiers in Immunology: Volume 14 – 2023
Background: There is growing evidence of the significance of gastrointestinal complaints in the impairment of the intestinal mucosal barrier function and inflammation in fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome. However, data on intestinal permeability and gut barrier dysfunction in FM and ME/CFS are still limited with conflicting results.
This study aimed to assess circulating biomarkers potentially related to intestinal barrier dysfunction and bacterial translocation and their association with self-reported symptoms in these conditions.
Methods: A pilot multicentre, cross-sectional cohort study with consecutive enrolment of 22 patients with FM, 30 with ME/CFS, and 26 matched healthy controls. Plasma levels of anti-beta-lactoglobulin antibodies (IgG anti-beta-LGB), zonulin-1 (ZO-1), LPS, sCD14, and IL-1β) were assayed using ELISA. Demographic and clinical characteristics of the participants were recorded using validated self-reported outcome measures. The diagnostic accuracy of each biomarker was assessed using the ROC curve analysis.
Results: FM patients had significantly higher levels of anti-β-LGB, ZO-1, LPS, and sCD14 than healthy controls (all P < 0.0001). In ME/CFS patients, levels of anti-β-LGB, ZO-1, LPS, and sCD14 were significantly higher than controls, but lower than in FM (all P < 0.01), while there was no significant difference in IL-1β level. In the FM and ME/CFS cohorts, both anti-β-LGB and ZO-1 correlated significantly with LPS and sCD14 (P < 0.001 for both).
In the FM group, both anti-beta-LGB and ZO-1 were correlated significantly with physical and mental health components on the SF-36 scale (P < 0.05); whereas IL-1beta negatively correlated with the COMPASS-31 score (P < 0.05). In the ME/CFS cohort, ZO-1 was positively correlated with the COMPASS-31 score (P < 0.05).
The ROC curve analysis indicated a strong ability of anti-β-LGB, ZO-1, LPS, and sCD14 to predictively distinguish between FM and ME/CFS from healthy controls (P < 0.0001).
Conclusions: Biomarkers of intestinal barrier function and inflammation were associated with autonomic dysfunction assessed by COMPASS-31 scores in FM and ME/CFS respectively. Anti-β-LGB antibodies, ZO-1, LPS, and sCD14 may be putative predictors of intestinal barrier dysfunction in these cohorts. Further studies are needed to assess whether these findings are causal and can therefore be applied in clinical practice.
Ludovic Giloteaux, Katherine Anne Glass, Arnaud Germain, Sheng Zhang, Maureen R Hanson.
In healthy individuals, physical exercise improves cardiovascular health and muscle strength, alleviates fatigue, and reduces risk of chronic diseases. Although exercise is suggested as a lifestyle intervention to manage various chronic illnesses, it negatively affects people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), who suffer from exercise intolerance.
We hypothesized that altered extracellular vesicle (EV) signaling in ME/CFS patients after an exercise challenge may contribute to their prolonged and exacerbated negative response to exertion (post-exertional malaise).
EVs were isolated by size exclusion chromatography from the plasma of 18 female ME/CFS patients and 17 age- and BMI-matched female sedentary controls at three time points: before, 15 minutes, and 24 hours after a maximal cardiopulmonary exercise test.
EVs were characterized using nanoparticle tracking analysis and their protein cargo was quantified using Tandem Mass Tag-based (TMT) proteomics. The results show that exercise affects the EV proteome in ME/CFS patients differently than in healthy individuals and that changes in EV proteins after exercise are strongly correlated with symptom severity in ME/CFS.
Differentially abundant proteins in ME/CFS patients vs. controls were involved in many pathways and systems, including coagulation processes, muscle contraction (both smooth and skeletal muscle), cytoskeletal proteins, the immune system, and brain signaling.
Laura.C Peo, Katharina Wiehler, Johannes Paulick, Katrin Gerrer, Ariane Leone, Anja Viereck, Matthias Haegele, Silvia Stojanov, Cordula Warlitz, Silvia Augustin, Martin Alberer, DanielB.R. Hattesohl, Laura Froehlich, Carmen Scheibenbogen, Lorenz Mihatsch, Rafael Pricoco, Uta Behrends.
Purpose: A subset of patients with post-COVID-19 condition (PCC) fulfill the clinical criteria of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). To establish the diagnosis of ME/CFS for clinical and research purposes, comprehensive scores have to be evaluated.
Methods: We developed the Munich Berlin Symptom Questionnaires (MBSQs) and supplementary scoring sheets (SSSs) to allow for a rapid evaluation of common ME/CFS case definitions. The MBSQs were applied to young patients with chronic fatigue and post-exertional malaise (PEM) who presented to the MRI Chronic Fatigue Center for Young People (MCFC). Trials were retrospectively registered (NCT05778006, NCT05638724).
Results: Using the MBSQs and SSSs, we report on ten patients aged 11 to 25 years diagnosed with ME/CFS after asymptomatic SARS-CoV-2 infection or mild to moderate COVID-19. Results from their MBSQs and from well-established patient-reported outcome measures indicated severe impairments of daily activities and health-related quality of life.
Conclusions: ME/CFS can follow SARS-CoV-2 infection in patients younger than 18 years, rendering structured diagnostic approaches most relevant for pediatric PCC clinics. The MBSQs and SSSs represent novel diagnostic tools that can facilitate the diagnosis of ME/CFS in children, adolescents, and adults with PCC and other post-viral syndromes.
What is known: ME/CFS is a frequent debilitating illness. For diagnosis, an extensive differential diagnostic workup is required and the evaluation of clinical ME/CFS criteria. ME/CFS following COVID-19 has been reported in adults but not in pediatric patients younger than 19 years of age.
What is new: We present novel questionnaires (MBSQs), as tools to assess common ME/CFS case definitions in pediatric and adult patients with post-COVID-19 condition and beyond. We report on ten patients aged 11 to 25 years diagnosed with ME/CFS following asymptomatic SARS-CoV-2 infection or mild to moderate COVID-19.
Elena Støvring Yran
Master Thesis [University of Oslo]
ME/CFS is a debilitating disease thought to affect millions of individuals. Still, the etiology of ME/CFS is unknown, and there are no standard treatments or established biomarkers. The current symptom-based diagnosis is extensive, and the use of different diagnostic criteria contributes to heterogeneity among patients and may problematize the comparison of findings. Thus, the discovery of a biomarker for ME/CFS is urgent and would benefit both patients and the ME/CFS research field.
Extracellular vesicles (EVs) are membrane limited vesicles secreted by all cells to the extracellular environment and can be collected through biofluids. EVs serve many functions, including transferring functional proteins, lipids, and nucleic acids between cells, thus mediating cell-to-cell communication. EV secretion and cargo may reflect disease state and EVs thus pose great potential as source of minimally invasive biomarkers.
The primary aim of this project was to study EVs in plasma from ME/CFS patients and assess the potential of EVs as source of biomarkers for the disease.
Using size exclusion chromatography, EVs were enriched from plasma from ME/CFS patients (n = 20) and healthy controls (n=20). Success of EV isolation was determined in representative patient- and control EV pools (n=5) using western blotting and transmission electron microscopy. Western blot experiments for detection of EV markers CD9, CD63 and TSG101, and albumin, were optimized and confirmed enrichment of EVs and presence of non-EV eluates in the isolated samples.
EV enrichment was further validated through observation of intact EVs on transmission electron micrographs, however few CD63-positive EVs were observed. Through analysis of nanoparticle tracking analysis data, the isolated EV population primarily consisted of small EVs (< 200 nm). Within this EV population, meanand mode EV size was similar between cohorts, but the EV concentration was significantly elevated in samples from patients compared to controls (p = 0.006). However, statistical tests may have been influenced by high variation within the ME/CFS cohort.
Early-stage analysis of tandem mass spectrometry data identified 663 EV associated proteins. The majority of detected proteins overlapped with registered EV proteins, but only few differences could be observed between patient- and control derived samples. However, differential expression was not analyzed.
A biomarker for ME/CFS could not be suggested at this stage of the study, however increased EV concentration suggests abnormality in EV secretion in patients which strengthens their potential as source of biomarkers and further motivates EV research in ME/CFS and related diseases.
Tugce Pasin, Bilinc Dogruoz Karatekin, Ozge Pasin.
North Clin Istanb. Ahead of Print: NCI-53533
Objective: In this study, the frequency of chronic fatigue syndrome (CFS), sleep disturbances, and quality of life levels in mothers of children with cerebral palsy were compared in relation to the functional status of the child.
Methods: The caregivers were evaluated with the sociodemographic data form, Chalder Fatigue Scale, Fatigue Severity Scale, Pitsburg Sleep Quality Index and Short Form-12, respectively. In addition, the functional status of the child with cerebral palsy were evaluated with Gross Motor Function Classification System (GMFCS), Manual Ability Classification System (MACS), Communication Function Classification System (CFCS) and Eating and Drinking Ability Classification System (EDACS).
Results: According to CDC-1994 criteria 80.4% of the participating mothers have CFS (n=45). While the mean ChFS and FSS scores of housewives were found to be significantly higher than those of full-time workers (p=0.002; p=0.003, respectively), the mean SF-12 MCS was found to be significantly lower (p=0.007). The rate of housewives was found to be significantly higher in those diagnosed with CFS (p<0.001). Relationship between independent variables and dependent variables data sets as a result of canonical correlation analysis was obtained as 0.815. While the variable with the highest effect among the independent variables is the MACS variable, the variable with the highest percentage of explanation for the dependent variables is ChFS.
Conclusion: The frequency of chronic fatigue syndrome is very high in mothers of children with cerebral palsy, and the most important factors on the presence and severity of chronic fatigue syndrome are the mother's occupational status and the child's manual skills.
Long-COVID Research References
- Pattern of Post COVID Fatigue in Elderly Patients
- Persistent symptoms after COVID-19 are not associated with differential SARS-CoV-2 antibody or T cell immunity
- The novel application of the lightning process to treat long covid in primary care – case report
- The Persistence of SARS-CoV-2 and Its Role in Long Covid
- Prevalence of Post-Acute COVID-19 Sequalae and Average Time to Diagnosis Among Persons Living With HIV
- Incidence of long COVID and associated psychosocial characteristics in a large U.S. city
- Long Covid & Antidepressants
- Mast cell activation may contribute to adverse health transitions in COVID-19 patients with frailty
- Treatment of Brain Fog of Long COVID Syndrome: A Hypothesis
- True prevalence of long COVID in children: a narrative review
- The effects of COVID-19 on cognitive performance in a community-based cohort: a COVID symptom study biobank prospective cohort study
- Exercise Training in Non-Hospitalized Patients with Post-COVID-19 Syndrome-A Narrative Review
- SARS-CoV-2 Reinfections and Long COVID in the Post-Omicron Phase of the Pandemic
- Decreased physical performance despite objective and subjective maximal exhaustion in post-COVID-19 individuals with fatigue
- Long COVID and Significant Activity Limitation Among Adults, by Age — United States
- Prevalence of Symptoms ≤12 Months After Acute Illness, by COVID-19 Testing Status Among Adults — United States
- Myocarditis and Myocardial Injury in Long COVID Syndrome: A Comprehensive Review of the Literature
- SARS-CoV-2–Specific Immune Responses in Patients With Postviral Syndrome After Suspected COVID-19
- Long and Short-term Metformin Consumption as a Potential Therapy to Prevent Complications of COVID-19
- Cardiovascular risk factors predict who should have echocardiographic evaluation in long COVID
Dr Katrina Pears
The ME Association.