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
There have been nine new ME/CFS studies and twenty-six new Long Covid studies this week.
We have highlighted one of the ME/CFS studies in more detail below:
Paper one (1) looks at developing a biomarker for ME/CFS through the use of oxygen consumption data combine with responses to the Short Form-36 (SF-36) questionnaire. This study used machine-based learning.
The Short Form-36 (SF-36) questionnaire reports on patient health status, assessing eight health concepts: physical functioning (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE), and mental health (MH).
This study used two datasets to investigate whether oxygen consumption and the responses to the SF-36 could provide a suitable biomarker. The first contained 2,347 records, where the second dataset was used to validate the findings with 239 patients with ME/CFS who had completed a cardiopulmonary exercise test (CPET). This is the first study to report data from these two datasets.
The study grouped patients according to their peak oxygen consumption, and this was based on predefined values in Weber’s Classification, which stratifies patients based on peak oxygen consumption (V̇O2), which is the gold-standard measure of exercise capacity.
The Weber’s classification allows patients to be separated into four groups: “Weber’s classification stratifies patients based on peak VO2 and anaerobic threshold to define functional exercise capacity: Mild to none (group A) when Peak VO2 value is > 20; Mild to moderate (group B) when Peak VO2 value range is 16-20; Moderate to severe (group C) when Peak VO2 value range is 10-16; and Severe (group D) when Peak VO2 value is < 10”.
The studied showed that:
- Grouping by the Weber classification is directly linked to the SF-36 scores.
- A lesser Weber's classification infers a worse outcome on the SF-36 questionnaire.
- For the female group, the highest number of patients were grouped in moderate to severe group for oxygen consumption (Group C), however, males were in the mild to none group (Group A).
- Machine learning proved a powerful tool in analysing data.
- The analysis then separated the patients into two groups, which corresponded to worse to better health status.
- The study concluded that oxygen consumption could be a possible biomarker for ME/CFS.
The data from this study is not too surprising, where a worse SF-36 score corresponds to a worse Weber’s classification. A few things to note about this study:
- The oxygen consumption data collected provides just a snapshot in time, so we don’t know how these findings would vary according to the different classifications over time.
- Data used is also only from one hospital centre, so we don’t know how representative this is for the whole ME/CFS population.
- Machine learning studies are very complex, but we don’t know which factors in the SF-36 affected the grouping of patients.
- As always there was an unequal balance of males and females.
- As the two datasets used in this study are approved trails, there is no information given on patient severity or diagnostic criteria, so we can’t comment on the sample used and its representativeness.
- There is no mention of control groups, which is fundamental to finding a biomarker to distinguish between healthy and those with ME/CFS.
Data from this study could provide a simple biomarker for ME/CFS, however, it does rely on completing a CPET which rules out those with severe ME and has been reported to take an average of two weeks to recover from (Moore et al., 2023). The authors suggest that analysing responses to the SF-36 questionnaire could help with early referral to ME/CFS specialists, if possible this is a positive takeaway from this study.
You may also be interested in reading this week, Paper three (3) is a systematic review of pregnancy and ME/CFS. I was part of the team collating the data for this review. You can read Dr Emma Slack’s comments on this paper on our website, furthermore, the ME Association is currently funding a new study examining pregnancy in ME/CFS.
ME/CFS Research References
Marcos Lacasa, Patricia Launois, Ferran Prados, José Alegre, Jordi Casas-Roma.
Clinical Therapeutics [Article in Press, Epub ahead of print]
Highlights
- ME/CFS is a disabling chronic disease with a lack of diagnostic tests.
- Oxygen consumption is a possible biomarker of CFS.
- O2 consumption allows classifying patients status according to the Weber's classification.
- A worse Weber's classification infers a worse outcome on the SF-36 questionnaire.
- Unsupervised machine learning is a powerful tool for analyzing data.
Abstract
Purpose: Myalgic encephalomyelitis, commonly referred to as chronic fatigue syndrome (ME/CFS), is a severe, disabling chronic disease and an objective assessment of prognosis is crucial to evaluate the efficacy of future drugs. Attempts are ongoing to find a biomarker to objectively assess the health status of (ME/CFS), patients.
This study therefore aims to demonstrate that oxygen consumption is a biomarker of ME/CFS provides a method to classify patients diagnosed with ME/CFS based on their responses to the Short Form-36 (SF-36) questionnaire, which can predict oxygen consumption using cardiopulmonary exercise testing (CPET).
Methods: Two datasets were used in the study. The first contained SF-36 responses from 2,347 validated records of ME/CFS diagnosed participants, and an unsupervised machine learning model was developed to cluster the data. The second dataset was used as a validation set and included the cardiopulmonary exercise test (CPET) results of 239 participants diagnosed with ME/CFS. Participants from this dataset were grouped by peak oxygen consumption according to Weber's classification. The SF-36 questionnaire was correctly completed by only 92 patients, who were clustered using the machine learning model.
Two categorical variables were then entered into a contingency table: the cluster with values {0,1} and Weber classification {A, B, C, D} were assigned. Finally, the Chi-square test of independence was used to assess the statistical significance of the relationship between the two parameters.
Findings: The results indicate that the Weber classification is directly linked to the score on the SF-36 questionnaire. Furthermore, the 36-response matrix in the machine learning model was shown to give more reliable results than the subscale matrix (p − value < 0.05) for classifying patients with ME/CFS.
Implications: Low oxygen consumption on CPET can be considered a biomarker in patients with ME/CFS. Our analysis showed a close relationship between the cluster based on their SF-36 questionnaire score and the Weber classification, which was based on peak oxygen consumption during CPET. The dataset for the training model comprised raw responses from the SF-36 questionnaire, which is proven to better preserve the original information, thus improving the quality of the model.
Lerario, Fusunyan, Stave, Roldán, Keuroghlian, Turban, Perez, Maschi, Rosendale.
Journal of Psychosomatic Research: 111491. [Article in Press, Epub ahead of print]
Abstract
Objective: To describe the current literature on functional neurological disorder and functional somatic syndromes among sexual and gender minority people (SGM).
Methods: A search string with descriptors of SGM identity and functional disorders was entered into PubMed, Embase, Web of Science, PsycInfo, and CINAHL for articles published before May 24, 2022, yielding 3121 items entered into Covidence, where 835 duplicates were removed.
A neurologist and neuropsychiatrist screened titles and abstracts based on predefined criteria, followed by full-text review. A third neurologist adjudicated discrepancies. Eligible publications underwent systematic data extraction and statistical description.
Results: Our search identified 26 articles on functional disorders among SGM people. Most articles were case (13/26, 46%) or cross-sectional (4/26, 15%) studies. Gender minority people were represented in 50% of studies. Reported diagnoses included fibromyalgia (n = 8), functional neurological disorder (n = 8), somatic symptom disorder (n = 5), chronic fatigue syndrome (n = 3), irritable bowel syndrome (n = 2), and other functional conditions (n = 3).
Three cohort studies of fibromyalgia or somatic symptom disorder reported an overrepresentation of gender minority people compared to cisgender cohorts or general population measures.
Approximately half of case studies reported pediatric or adolescent onset (7/13, 54%), functional neurological disorder diagnosis (7/13, 54%), and symptom improvement coinciding with identity-affirming therapeutic interventions (7/13, 58%).
Conclusion: Despite a methodologically rigorous literature search, there are limited data on functional neurological disorder and functional somatic syndromes among SGM people. Several studies reported increased prevalence of select conditions among transgender people. More observational studies are needed regarding the epidemiology and clinical course of functional disorders among SGM people.
Slack E, Pears KA, Rankin J, Newton JL, Pearce M.
BMJ Open. 2023 Oct 5;13(10): e070366.
Abstract
Objectives: To identify, synthesise and appraise evidence relating to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and pregnancy.
Design: Mixed-methods systematic review, using convergent segregated design.
Data sources: MEDLINE, EMBASE, Scopus, PsycINFO, CINAHL, MedRxiv, PROSPERO and grey literature sources through 6 August 2023.
Eligibility criteria: We included original research studies, expert opinion and grey literature reporting on ME/CFS and pregnancy/post partum (up to 2 years), risk of pregnancy outcomes with ME/CFS or experiences during pregnancy for mother, partner or health and social care professionals following ME/CFS during pregnancy, all where the evidence was relevant to a confirmed ME/CFS diagnosis prior to pregnancy.
Data extraction and synthesis: Three independent reviewers completed all screening, data extraction and quality assessment. Risk of bias was assessed using the mixed-methods appraisal tool V.2018. Qualitative and quantitative literature was analysed separately using thematic and descriptive syntheses. Findings were integrated through configuration.
Results: Searches identified 3675 articles, 16 met the inclusion criteria: 4 quantitative (1 grey), 11 qualitative (9 grey) and 1 grey mixed-methods study. Of the four quantitative studies that reported on ME/CFS severity during pregnancy, two suggested pregnancy negatively impacted on ME/CFS, one found most women had no change in ME/CFS symptoms and one found ME/CFS improved; this difference in symptom severity across studies was supported by the qualitative evidence.
The qualitative literature also highlighted the importance of individualised care throughout pregnancy and birth, and the need for additional support during family planning, pregnancy and with childcare. Only one quantitative study reported on pregnancy outcomes, finding decreased vaginal births and higher rates of spontaneous abortions and developmental and learning delays associated with pregnancies in those with ME/CFS.
Conclusions: Current evidence on ME/CFS in pregnancy is limited and findings inconclusive. More high-quality research is urgently needed to support the development of evidence-based guidelines on ME/CFS and pregnancy.
Karen Gimenez-Orenga, Eva Martin-Martinez, Lubov Nathanson, Elisa Oltra.
bioRxiv [preprint]
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and fibromyalgia (FM) are chronic diseases with poorly understood pathophysiology and diagnosis based on clinical assessment of unspecific symptoms.
The recent post-COVID-19 condition, which shares similarities with ME/CFS and FM, has raised concerns about viral-induced transcriptome changes in post-viral syndromes.
Viral infections, and other types of stress, are known to unleash human endogenous retroviruses (HERV) repression that if maintained could lead to symptom chronicity.
This study evaluated this possibility for ME/CFS and FM on a selected cohort of female patients complying with diagnosis criteria for ME/CFS, FM, or both, and matched healthy controls (n=43).
The results show specific HERV fingerprints for each disease, confirming biological differences between ME/CFS and FM. Unexpectedly, HERV profiles segregated patients that met both ME/CFS and FM clinical criteria from patients complying only with ME or FM criteria, while clearly differentiating patients from healthy subjects, supporting that the highly prevalent comorbidity condition must constitute a different nosological entity.
Moreover, HERV profiles exposed significant quantitative differences within the ME/CFS group that correlated with differences in immune gene expression and patient symptomatology, supporting ME/CFS patient subtyping and confirming immunological disturbances in this disease.
Pending issues include validation of HERV profiles as disease biomarkers of post-viral syndromes and understanding the role of HERV during infection and beyond.
Yukichika Yamamoto, Yuki Otsuka, Kazuki Tokumasu, Naruhiko Sunada, Yasuhiro Nakano, Hiroyuki Honda, Yasue Sakurada, Toru Hasegawa, Hideharu Hagiya, Fumio Otsuka.
Journal of the Endocrine Society, Volume 7, Issue Supplement_1, October-November 2023, bvad114.1370.
Abstract
Almost three years have passed since coronavirus disease 2019 (COVID-19) pandemic broke out, and along with the number of acute COVID-19 patients, the number of patients suffering from chronic prolonged symptoms after COVID-19, long COVID, or post COVID-19 condition, has also increased. We establised an outpatient clinic specialized for COVID-19 after care (CAC) in Okayama University Hospital in Japan in February 2021.
Our recent study has revealed that the most common symptom is “fatigue”, a part of which potentially may develop into myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, the pathogenesis and specific prognosticator have yet to be elucidated.
The aim of this study was to elucidate the clinical characteristics of patients who developed ME/CFS after COVID-19. This retrospective observational study investigated the patients who visited our CAC outpatient clinic between February 2021 and March 2022.
Of the 234 patients, 139 (59.4%) had fatigue symptoms, of whom 50 (21.4%) met the criteria for ME/CFS (ME/CFS group), while other 89 did not (non-ME/CFS group); 95 patients had no fatigue complaints (no-fatigue group). Although the patients’ backgrounds were not significantly different among the three groups, the ME/CFS group presented the highest scores on the self-rating symptom scales, including the Fatigue Assessment Scale (FAS), EuroQol, and Self-Rating Depression Scale (SDS).
Of note, serum ferritin levels, which were correlated to FAS and SDS scores, were significantly higher in the ME/CFS group (193.0 μg/mL; interquartile range (IQR), 58.8-353.8) than those of non-ME/CFS (98.2 μg/mL; 40.4-251.5) and no-fatigue (86.7 μg/mL; 37.5-209.0) groups, and this trend was prominent in the female patients.
Endocrine workup further showed that the ME/CFS group had higher thyrotropin levels but lower growth hormone levels in the serum, and that insulin-like growth factor (IGF)-I levels were inversely correlated with ferritin levels (R = -0.328, p < 0.05).
Collectively, we revealed that serum ferritin levels could be a possible predictor for developing ME/CFS related to long COVID, especially in female patients.
Earlier studies have suggested that hyperferritinemia is a clinical feature in the patients of long COVID, in which hepcidin-like effects could also be involved. Our present study also uncovered a relationship between hyperferrinemia and endocrine disorders among patients developing ME/CFS after COVID-19, although further investigations are necessary to understand the characteristics of ferritin metabolism.
6. Dysautonomia and small fiber neuropathy in postCOVID condition and Chronic Fatigue Syndrome
Naiara Azcue, Rocio Del Pino, Marian Acera, Tamara Fernandez Valle, et al.
ResearchSquare [Preprint]
Abstract
Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and post-COVID condition can present similarities such as fatigue, brain fog, autonomic and neuropathic symptoms.
Methods: The study included 87 patients with post-COVID condition, 50 patients with ME/CFS, and 50 HC. The hemodynamic autonomic function was evaluated using the deep breathing technique, Valsalva maneuver, and Tilt test. The presence of autonomic and sensory small fiber neuropathy (SFN) was assessed with the Sudoscan and with heat and cold evoked potentials, respectively.
Finally, a complete neuropsychological evaluation was performed. The objective of this study was to analyze and compare the autonomic and neuropathic symptoms in post-COVID condition with ME/CFS, and healthy controls (HC), as well as, analyze the relationship of these symptoms with cognition and fatigue.
Results: Statistically significant differences were found between groups in heart rate, with ME/CFS group presenting the highest (H = 18.3; p ≤ .001). The Postural Orthostatic Tachycardia Syndrome (POTS), and pathological values in palms on the Sudoscan were found in 31% and 34% of ME/CFS, and 13.8% and 19.5% of post-COVID patients, respectively. Concerning evoked potentials, statistically significant differences were found in response latency to heat stimuli between groups (H = 23.6; p ≤ .01). Latency was highest in ME/CFS, and lowest in HC.
Regarding cognition, lower parasympathetic activation was associated with worse cognitive performance.
Conclusions: Both syndromes were characterized by inappropriate tachycardia at rest, with a high percentage of patients with POTS. The prolonged latencies for heat stimuli suggested damage to unmyelinated fibers. The higher proportion of patients with pathological results for upper extremities on the Sudoscan suggested a non-length-dependent SFN.
Banovic I, Scrima F, Fornasieri I, Beaugerie L, Coquart J, Fourgon C, Iodice P, Nion-Larmurier I, Savoye G, Sorin AL, Tourny C, Augustinova M.
BMC Psychol. 2023 Oct 10;11(1):324.
Abstract
Background: Psychometric validation of the Multidimensional Chronic Asthenia Scale (MCAS) was conducted in order to provide an effective tool for assessing the health-related quality of life of French-speaking patients with chronic asthenia (CA).
Methods: Items resulting from the initial formulation of the self-reported MCAS (along with other materials) were completed by French-speaking volunteers with inactive or active inflammatory bowel disease (IBD-I vs. IBD-A) or chronic fatigue syndrome (CFS). Responses from 621 participants (180 patients with IBD-A, 172 with IBD-I, 269 with CFS) collected in a single online survey were divided into three subsamples to test the construct validity of the MCAS (Step 1, N = 240), to confirm its factorial structure (Step 2, N = 204) and to explore its convergent-discriminant validity with the Fatigue Symptoms Inventory (FSI) and revised Piper Fatigue Scale (r-PFS, Step 3, N = 177).
Results: Steps 1 and 2 showed that, as expected, MCAS has four dimensions: feeling of constraint (FoC), physical (PC), life (LC) and interpersonal consequences (IC), which are also related to the duration of CA (i.e., the longer it lasts, the more the dimensions are impacted). The results further showed that the MCAS is sensitive enough to capture between-group differences, with the CFS group being the most impaired, followed by IBD-A and IBD-I.
While convergent-discriminant validity between the 4 factors of MCAS and FSI and r-PFS, respectively, was satisfactory overall, Step 3 also pointed to some limitations that call for future research (e.g., shared variances between the PC and IC dimensions of MCAS and behavioral dimension of r-PFS).
Conclusion: Despite these limitations, the MCAS clearly constitutes a promising tool for measuring quantitative differences (i.e., severity/intensity) in CA associated with various diseases, but also, and importantly, the clinically important differences in domains of its expression (i.e., qualitative differences).
Keferstein, L.G.
Preprints 2023, 2023100637.
Abstract
Background: This study aimed to compile and analyze an assortment of research findings concerning potential therapeutic strategies for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The understanding of the multifaceted nature of ME/CFS and the need for varied and personalized therapeutic approaches were central to this investigation.
Methods: A comprehensive review and analysis of various studies conducted on ME/CFS was undertaken. These studies covered a wide array of interventions, including pharmacological treatments, nutritional supplements, dietary changes, physical therapies, and lifestyle modifications. The analysis pertained to the effectiveness of these interventions, potential physiological and biochemical markers, and the response of ME/CFS patients to different treatment strategies.
Results: The 22 selected papers investigated demonstrated varied responses to the multitude of interventions. While some interventions showed significant improvement in fatigue and biochemical parameters, others found no significant differences between the treated and control groups. Potential physiological and biochemical markers for ME/CFS, such as impaired T cell metabolism, reduced flow-mediated dilation, and decreased work rate at the ventilatory threshold, were highlighted.
Conclusion: The findings underscored the complexity of ME/CFS and the need for personalized treatment strategies. Despite mixed results and several limitations, these studies collectively contributed to understanding ME/CFS's complex pathophysiology and treatment, laying the groundwork for future research towards more effective therapeutic strategies for this debilitating disease.
Jentro Dest and Daan Grosemans.
Master Thesis [University of Hasselt]
Abstract
Our Master’s thesis falls within the research domain of Rehabilitation Sciences and Physiotherapy. In our study we investigated patients with chronic fatigue syndrome (CFS).
CFS is a complicated disorder of which the pathology is still poorly understood. Due to the significant prevalence, the socio-economic impact of the disorder is high. In addition to the physiological dysfunctions that are often reported in CFS literature, patients can also experience altered symptom perception. Patients for example show increased subjective responses to unpleasant somatic stimuli in comparison with healthy persons (Van den Houte et al., 2018). Therefore, this study project fits within the domain of pain, fatigue and somatically unexplained physical symptoms.
Despite a lot of articles reporting the role of altered symptom perception, they mainly focused on symptom perception in the lab. However, these laboratory measurements do not take day-to-day variability in symptoms into account.
We think that the lack of studies investigating the symptomatology in CFS patients via ecological momentary measurements is a gap in the literature. Therefore, in our study, we executed symptom assessments in the lab and in daily life.
In addition, we investigated the interactions between the reported symptoms and heart rate variability (HRV) in order to investigate, on a small scale, if psychological and physiological dysfunctions in patients do not work independently.
Extra information about the pathology of CFS is useful to all professionals in rehabilitation sciences and physical therapy who work with CFS patients. It will help professionals to understand the complex problem of CFS better and to tailor the care for these patients.
Our study is situated in a larger study project with the title “Identifying (psycho)physiology-based subgroups in chronic fatigue syndrome and their relevance for rehabilitation” and with study number S66452. The project is reimbursed by Fonds Wetenschappelijk Onderzoek. The project runs in collaboration with the Multidisciplinary Diagnostic Center of UZ Leuven, the Multidisciplinary Expertise Center Tumi Therapeutics, the Vlaams Instituut voor Biotechnologie KU Leuven Raes Lab and IMEC. All laboratory tasks were conducted in the University Hospital of Leuven.
The study is written in line with the central format. The study topics and research questions were determined in collaboration with Msc. Y. Dooms and Dr. Maaike Van Den Houte. Due to the fact that the study was a component of an ongoing research project, we were not involved in decisions about research design or methodology.
We carried out the academic writing procedure concerning this Master’s thesis. During the writing procedure, we received input from Msc. Y. Dooms. The thesis was written in close cooperation amongst both of us. We both independently contributed to the thesis, reviewed it, and wrote multiple sections together. The data-analysis was done in collaboration with Dr. Maaike Van Den Houte.
Long-COVID Research References
- Low-dose naltrexone use for the management of post-acute sequelae of COVID-19
- SARS-CoV-2 spike antigen-specific B cell and antibody responses in pre-vaccination period COVID-19 convalescent males and females with or without post-covid condition
- Accelerating discovery: A novel flow cytometric method for detecting fibrin(ogen) amyloid microclots using long COVID as a model
- Intrinsic factors behind long-COVID: II. SARS-CoV-2, extracellular vesicles, and neurological disorders
- Unveiling the Mysteries of Long COVID Syndrome: Exploring the Distinct Tissue and Organ Pathologies Linked to Prolonged COVID-19 Symptoms
- Post-COVID Neuropsychiatric Complications in Children and Adolescents: a Study Design for Early Diagnosis and Treatment Using Innovative Technologies
- A descriptive exploration of younger and older adults' experiences of Integrative Medical Group Visits for Long COVID
- Adipose-derived, autologous mesenchymal stem cell therapy for patients with post-COVID-19 syndrome: an intermediate-size expanded access program
- Pathophysiology and potential treatment of long COVID: A report of signal index cases and call for targeted research
- Metabolic Fingerprinting for the Diagnosis of Clinically Similar Long COVID and Fibromyalgia Using a Portable FT-MIR Spectroscopic Combined with Chemometrics
- Habitual short sleepers with pre-existing medical conditions are at higher risk of Long COVID
- Longitudinal Evaluation of an Integrated Post–COVID-19/Long COVID Management Program Consisting of Digital Interventions and Personal Support: Randomized Controlled Trial
- Pathophysiology and potential treatment of long COVID: A report of signal index cases and call for targeted research
- How long is Long-COVID? Symptomatic improvement between 12 and 18 months in a prospective cohort study
- Unraveling Post-COVID-19 Immune Dysregulation Using Machine Learning-based Immunophenotyping
- Monocytes subpopulations pattern in the acute respiratory syndrome coronavirus 2 virus infection and after long COVID-19
- From ‘mental fog' to post-acute COVID-19 syndrome's executive function alteration: Implications for clinical approach
- Acupuncture as an Additional Method of Rehabilitation Post-COVID-19: a randomized controlled trial
- Improvements during long-term fasting in patients with long COVID a case series and literature review
- Role of Tau protein in long COVID and Potential Therapeutic Targets
- Effects of pulmonary rehabilitation in subterranean salt chambers on functional status, chest mobility, and endurance of patients with post-covid syndrome
- Role of Microglia, Decreased Neurogenesis and Oligodendrocyte Depletion in Long COVID-Mediated Brain Impairments
- Genomic communication via circulating extracellular vesicles and long-term health consequences of COVID-19
- Impact of Post-COVID-19 or Long COVID-19 on Cognition and Health
- The hidden pandemic: a qualitative study on how middle-aged women make sense of managing their long COVID symptoms
- Low growth hormone secretion associated with post-acute sequelae SARS-CoV-2 infection (PASC) neurologic symptoms: A case-control pilot study
Dr Katrina Pears,
Research Correspondent.
The ME Association.
