Data and specimen-sharing tools offer new discovery opportunities for ME/CFS researchers

Summary: Within the field of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) research, two online tools: mapMECFS (Mathur and Carnes, 2021) and searchMECFS play a crucial role in advancing the understanding of ME/CFS by encouraging researchers to share and use data and biospecimens that are stored in centralized and easily accessible data portals

Overview: mapMECFS and searchMECFS are hosted by RTI International and funded by the National Institutes of Health (NIH). mapMECFS is the largest interactive portal and repository for ME/CFS data. It offers researchers from diverse disciplines a platform to share and integrate data from their ME/CFS research studies. searchMECFS is an interactive search tool that allows researchers to identify and request available biospecimens to conduct novel experiments.

Purpose and significance: mapMECFS aims to overcome the challenge of fragmented data sources in ME/CFS research by providing access to research results across many scientific disciplines and body systems. mapMECFS offers new opportunities for researchers by providing a centralized repository and tools to connect databases and enable exploration of complex study results. mapMECFS also serves as the repository for all experimental data generated from the use of biospecimens accessed through searchMECFS.

searchMECFS addresses the logistical challenge of biospecimen selection and access by assisting with the selection of biospecimens based on demographic and clinical attributes. Currently, searchMECFS houses demographic and clinical data from the Chronic Fatigue Initiative study and information about associated biospecimens stored in a central biorepository. Future plans include adding biospecimens from the Center for Disease Control and Prevention’s Multi-Site Clinical Assessment of ME/CFS study.

User registration and access: mapMECFS user registration is open to any researcher planning to use the data for research purposes. The secure registration process involves agreeing to the Data Use Agreement (DUA) and submitting a registration form that is reviewed by Program staff at NIH. Approved new users will either be added to an existing mapMECFS Organization or to a user-specific Organization created for them. Researchers approved to upload data will also be asked to complete a User Agreement.

To ensure secure data access, mapMECFS incorporates a two-tiered dataset structure. Private datasets, characterized by restricted visibility, are only accessible to users within the same Organization. Private datasets allow researchers to upload and prepare their data while they await the publication of the supporting manuscript. In contrast, public datasets are accessible to all approved users, fostering a collaborative and inclusive environment for research exploration.

Once a dataset’s supporting manuscript has been published, users are highly encouraged to make their results publicly available to registered users.

The registration process for searchMECFS mirrors that of mapMECFS, requiring similar information. Following approval, users can query the available biospecimens and associated demographic and clinical data. Once users identify their desired samples, they follow the link to the Biospecimen Resource Access Committee Application webpage where they find instructions and links to request the biospecimens of interest.

Data types and formats: mapMECFS supports a wide array of data types including proteomics, metabolomics, methylation, gene expression, microbiome, demographic, and health and survey data. The platform also accommodates supporting phenotype (clinical and demographic data) and data dictionaries. Data must be deidentified, so that all participant information is protected.

While formatting requirements vary for each data type, detailed documentation on the website guides researchers through the submission process, ensuring data consistency and integrity. The mapMECFS support team is also available to assist researchers with their data submissions.

Search and discovery: mapMECFS offers several features designed to assist researchers in accessing relevant data. These include (1) a user-friendly data explorer tool that enables researchers to effortlessly search for datasets containing specific analytes of interest and (2) a data integration tool which allows researchers to seamlessly merge clinical data files from specific cohorts.

searchMECFS provides an interactive query tool that can be used to build and execute data queries to find available biospecimens that meet the user’s specified search criteria. Users can add multiple search criteria to further enhance their search and refine their results.

Privacy and data standards: Participant privacy, a main priority, is covered within the DUAs and User Agreements. All data uploaded on mapMECFS must be free of Personally Identifiable Information (PII). Agreements also cover responsible data use including refraining from attempting to identify participants, safeguards against unintentional disclosure, prompt reporting of any unauthorized use, and restrictions on using the data for clinical or medical purposes. It is the uploader’s responsibility to ensure that PII is not present, participant privacy is fully protected, and sharing is compliant with all other governing policies (e.g., IRB-approved protocols, embargos).

Future directions and user engagement: The development of mapMECFS is guided by user input, prioritizing site enhancements according to the feedback received from researchers actively engaging with the platform. All site users are encouraged to contact the mapMECFS support team with suggestions to improve the site. RTI plans to expand the clinical and biological data within the site’s integration tool and improve data standards and automated quality assurance pipelines. RTI is also working with the ME/CFS research community to expand the number of datasets publicly available in mapMECFS and to increase the number of biospecimens available through searchMECFS.

Funders: US National Institutes of Health (NIH): National Institute of Neurological Disorders and Stroke (NINDS); National Institute of Allergy and Infectious Diseases (NIAID); National Heart, Lung, and Blood Institute (NHLBI); National Center for Complementary and Integrative Health (NCCIH); and National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Acknowledgement: This work was supported by the National Institutes of Health (NIH) under award number U24NS105535. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or RTI International.

Source: RTI International, USA

Heterogeneity in Measures of Illness among Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Is Not Explained by Clinical Practice: A Study in Seven U.S. Specialty Clinics

Abstract:

Background: One of the goals of the Multi-site Clinical Assessment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (MCAM) study was to evaluate whether clinicians experienced in diagnosing and caring for patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) recognized the same clinical entity.
Methods: We enrolled participants from seven specialty clinics in the United States. We used baseline data (n = 465) on standardized questions measuring general clinical characteristics, functional impairment, post-exertional malaise, fatigue, sleep, neurocognitive/autonomic symptoms, pain, and other symptoms to evaluate whether patient characteristics differed by clinic.
Results: We found few statistically significant and no clinically significant differences between clinics in their patients’ standardized measures of ME/CFS symptoms and function. Strikingly, patients in each clinic sample and overall showed a wide distribution in all scores and measures.
Conclusions: Illness heterogeneity may be an inherent feature of ME/CFS. Presenting research data in scatter plots or histograms will help clarify the challenge. Relying on case–control study designs without subgrouping or stratification of ME/CFS illness characteristics may limit the reproducibility of research findings and could obscure underlying mechanisms.
Source: Unger ER, Lin J-MS, Chen Y, Cornelius ME, Helton B, Issa AN, Bertolli J, Klimas NG, Balbin EG, Bateman L, et al. Heterogeneity in Measures of Illness among Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Is Not Explained by Clinical Practice: A Study in Seven U.S. Specialty Clinics. Journal of Clinical Medicine. 2024; 13(5):1369. https://doi.org/10.3390/jcm13051369 https://www.mdpi.com/2077-0383/13/5/1369 (Full text)

Spontaneous, persistent, T cell-dependent IFN-γ release in patients who progress to Long Covid

Abstract:

After acute infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a proportion of patients experience persistent symptoms beyond 12 weeks, termed Long Covid. Understanding the mechanisms that cause this debilitating disease and identifying biomarkers for diagnostic, therapeutic, and monitoring purposes are urgently required.

We detected persistently high levels of interferon-γ (IFN-γ) from peripheral blood mononuclear cells of patients with Long Covid using highly sensitive FluoroSpot assays. This IFN-γ release was seen in the absence of ex vivo peptide stimulation and remains persistently elevated in patients with Long Covid, unlike the resolution seen in patients recovering from acute SARS-CoV-2 infection. The IFN-γ release was CD8+ T cell-mediated and dependent on antigen presentation by CD14+ cells.

Longitudinal follow-up of our study cohort showed that symptom improvement and resolution correlated with a decrease in IFN-γ production to baseline levels. Our study highlights a potential mechanism underlying Long Covid, enabling the search for biomarkers and therapeutics in patients with Long Covid.

Source: Krishna BA, Lim EY, Metaxaki M, Jackson S, Mactavous L; NIHR BioResource; Lyons PA, Doffinger R, Bradley JR, Smith KGC, Sinclair J, Matheson NJ, Lehner PJ, Sithole N, Wills MR. Spontaneous, persistent, T cell-dependent IFN-γ release in patients who progress to Long Covid. Sci Adv. 2024 Feb 23;10(8):eadi9379. doi: 10.1126/sciadv.adi9379. Epub 2024 Feb 21. PMID: 38381822; PMCID: PMC10881041. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10881041/ (Full text)

Cognitive domains affected post-COVID-19; a systematic review and meta-analysis

Abstract:

Background and purpose: This review aims to characterize the pattern of post-COVID-19 cognitive impairment, allowing better prediction of impact on daily function to inform clinical management and rehabilitation.

Methods: A systematic review and meta-analysis of neurocognitive sequelae following COVID-19 was conducted, following PRISMA-S guidelines. Studies were included if they reported domain-specific cognitive assessment in patients with COVID-19 at >4 weeks post-infection. Studies were deemed high-quality if they had >40 participants, utilized healthy controls, had low attrition rates and mitigated for confounders.

Results: Five of the seven primary Diagnostic and Statistical Manual of Mental Disorders (DSM-5) cognitive domains were assessed by enough high-quality studies to facilitate meta-analysis. Medium effect sizes indicating impairment in patients post-COVID-19 versus controls were seen across executive function (standardised mean difference (SMD) -0.45), learning and memory (SMD -0.55), complex attention (SMD -0.54) and language (SMD -0.54), with perceptual motor function appearing to be impacted to a greater degree (SMD -0.70). A narrative synthesis of the 56 low-quality studies also suggested no obvious pattern of impairment.

Conclusions: This review found moderate impairments across multiple domains of cognition in patients post-COVID-19, with no specific pattern. The reported literature was significantly heterogeneous, with a wide variety of cognitive tasks, small sample sizes and disparate initial disease severities limiting interpretability. The finding of consistent impairment across a range of cognitive tasks suggests broad, as opposed to domain-specific, brain dysfunction. Future studies should utilize a harmonized test battery to facilitate inter-study comparisons, whilst also accounting for the interactions between COVID-19, neurological sequelae and mental health, the interplay between which might explain cognitive impairment.

Source: Fanshawe JB, Sargent BF, Badenoch JB, Saini A, Watson CJ, Pokrovskaya A, Aniwattanapong D, Conti I, Nye C, Burchill E, Hussain ZU, Said K, Kuhoga E, Tharmaratnam K, Pendered S, Mbwele B, Taquet M, Wood GK, Rogers JP, Hampshire A, Carson A, David AS, Michael BD, Nicholson TR, Paddick SM, Leek CE. Cognitive domains affected post-COVID-19; a systematic review and meta-analysis. Eur J Neurol. 2024 Feb 20:e16181. doi: 10.1111/ene.16181. Epub ahead of print. PMID: 38375608. https://onlinelibrary.wiley.com/doi/10.1111/ene.16181 (Full text)

A Case Report of Chronic Epipharyngitis With Chronic Fatigue Treated With Epipharyngeal Abrasive Therapy (EAT)

Abstract:

A case of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with chronic epipharyngitis was treated with epipharyngeal abrasive therapy (EAT). The symptoms of ME/CFS improved along with the improvement of chronic epipharyngitis. The patient was followed up with endocrine and autonomic function tests.

Endocrine function tests included salivary cortisol and salivary α-amylase activity. Salivary α-amylase activity was stimulated by EAT. EAT improved the diurnal variability of salivary cortisol secretion. Autonomic function tests included heart rate variability analysis by orthostatic stress test. EAT normalized parasympathetic and sympathetic reflexes over time and regulated autonomic balance.

Based on the improvement of symptoms and test results, EAT was considered effective for ME/CFS. A literature review was conducted on the mechanism of the therapeutic effect of EAT on ME/CFS.

Source: Hirobumi I. A Case Report of Chronic Epipharyngitis With Chronic Fatigue Treated With Epipharyngeal Abrasive Therapy (EAT). Cureus. 2024 Feb 23;16(2):e54742. doi: 10.7759/cureus.54742. PMID: 38405656; PMCID: PMC10884883. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10884883/ (Full text)

Impact of sleep disruption on cognitive function in patients with postacute sequelae of SARS-CoV-2 infection: initial findings from a Neuro-COVID-19 clinic

Abstract:

Introduction: Fatigue, brain fog, and sleep disturbance are among the most common symptoms of postacute sequelae of SARS-CoV-2 infection (PASC). We sought to determine the impact of sleep disruption on cognition and quality of life in patients with neurologic manifestations of PASC (Neuro-PASC).
Methods: Thirty-nine patients were recruited from Neuro-COVID-19 clinic. Mean age was 48.1 years, 71.8% were female, and 82% were never hospitalized for COVID-19. Patients were evaluated via clinical assessment, quality-of-life measures in domains of cognitive function, fatigue, sleep disturbance, anxiety, and depression, NIH Toolbox cognitive tests, and 7 days of wrist actigraphy.
Results: The median number of neurologic symptoms attributed to PASC was 6, with brain fog being the most common in 89.7%. Regarding non-neurologic symptoms, 94.9% complained of fatigue and 74.4% of insomnia. Patients reported significant impairment in all quality-of-life domains and performed worse in a task of attention compared to a normative US population. Actigraphy showed Neuro-PASC patients had lower sleep efficiency, longer sleep latency (both p < 0.001), and later sleep midpoint (p = 0.039) compared to 71 age-matched healthy controls with no PASC history. Self-reported cognitive symptoms correlated with the severity of fatigue (p < 0.001), anxiety (p = 0.05), and depression (p < 0.01). Objective evidence of sleep disruption measured by wakefulness after sleep onset, sleep efficiency, and latency were associated with decreased performance in attention and processing speed.
Conclusion: Prospective studies including larger populations of patients are needed to fully determine the interplay of sleep disruption on the cognitive function and quality of life of patients with PASC.

Source: Kathryn J Reid, Louis T Ingram, Millenia Jimenez, Zachary S Orban, Sabra M Abbott, Daniela Grimaldi, Kristen L Knutson, Phyllis C Zee, Igor J Koralnik, Mathew B Maas, Impact of sleep disruption on cognitive function in patients with postacute sequelae of SARS-CoV-2 infection: initial findings from a Neuro-COVID-19 clinic, SLEEP Advances, Volume 5, Issue 1, 2024, zpae002, https://doi.org/10.1093/sleepadvances/zpae002 https://academic.oup.com/sleepadvances/article/5/1/zpae002/7517273 (Full text)

People with Long Covid and ME/CFS Exhibit Similarly Impaired Dexterity and Bimanual Coordination: A Case-Case-Control Study

Abstract:

Purpose: Dexterity and bimanual coordination had not previously been compared between people with long COVID and people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Therefore, this study determined dexterity and bimanual coordination in people with long COVID (∼16 month illness duration; n=21) and ME/CFS (∼16 year illness duration; n=20), versus age-matched healthy controls (n=20).

Methods: Dexterity, and bimanual coordination was determined using the Purdue pegboard test.

Results: The main findings of the present investigation were that people with ME/CFS and people with long COVID were generally comparable for Purdue pegboard tests (p>0.556 and d<0.36 for pairwise comparisons). It is worth noting however, that both these patient groups performed poorer in the Perdue pegboard test than healthy controls (p<0.169 and d>0.40 for pairwise comparisons).

Conclusions: These data suggest that both people with long COVID and people with ME/CFS have similarly impaired dexterity, and bimanual coordination. Therefore, there is an urgent need for interventions to target dexterity and bimanual coordination in people with ME/CFS, and given the current pandemic, people with long COVID.

Source: Sanal-Hayes NEM, Hayes LD, Mclaughlin M, Berry ECJ, Sculthorpe NF. People with Long Covid and ME/CFS Exhibit Similarly Impaired Dexterity and Bimanual Coordination: A Case-Case-Control Study. Am J Med. 2024 Feb 23:S0002-9343(24)00091-3. doi: 10.1016/j.amjmed.2024.02.003. Epub ahead of print. PMID: 38403179. https://www.amjmed.com/article/S0002-9343(24)00091-3/fulltext (Full text)

Association between fatigue, peripheral serotonin, and L-carnitine in hypothyroidism and in chronic fatigue syndrome

Abstract:

Background: Fatigue of unknown origin is a hallmark symptom in chronic fatigue syndrome (CFS) and is also found in 20% of hypothyroidism patients despite appropriate levothyroxine treatment. Here, we suggest that in these disorders, peripheral serotonin levels are low, and elevating them to normal range with L-carnitine is accompanied with reduced fatigue.

Methods: We conducted a retrospective analysis of follow-up clinical data (CFS N=12; hypothyroidism with fatigue N=40) where serum serotonin and fatigue levels were compared before vs. after 7 weeks of oral L-carnitine supplementation.

Results: After L-carnitine, serotonin increased (8-fold in CFS, Sig. = 0.002, 6-fold in hypothyroidism, Sig. < 0.001) whereas fatigue decreased (2-fold in both CFS and hypothyroidism, Sig. = 0.002 for CFS, Sig. < 0.001 for hypothyroidism). There was a negative correlation between serotonin level and fatigue (for CFS, rho = -0.49 before and -0.67 after L-carnitine; for hypothyroidism, rho = -0.24 before and -0.83 after L-carnitine).

Conclusions: These findings suggest a new link between low peripheral serotonin, L-carnitine, and fatigue.

Source: Tommi Raij, Kari Raij. Association between fatigue, peripheral serotonin, and L-carnitine in hypothyroidism and in chronic fatigue syndrome. Front. Endocrinol. Sec. Neuroendocrine Science, Volume 15 – 2024 | doi: 10.3389/fendo.2024.1358404 https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1358404/abstract

Identifying the mental health burden in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients in Switzerland: A pilot study

Highlights:

  • First time study on mental health and well-being among ME/CFS patients in Switzerland.
  • High level (68.5%) of stigmatization reported due to ME/CFS.
  • Overall, ME/CFS led to a third of the patients and to half of the male patients to have suicidal thoughts.
  • ME/CFS led to secondary depression in 14.8% of the patients.
  • Lack of disease recognition and adequate patient support.

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating chronic disease of significant public health and clinical importance. It affects multiple systems in the body and has neuro-immunological characteristics. The disease is characterized by a prominent symptom called post-exertional malaise (PEM), as well as abnormalities in the immune-inflammatory pathways, mitochondrial dysfunctions and disturbances in neuroendocrine pathways. The purpose of this study was to evaluate the impact of ME/CFS on the mental health and secondary psychosocial manifestations of patients, as well as their coping mechanisms.

Method: In 2021, a descriptive cross-sectional study was conducted in Switzerland. A self-administered paper questionnaire survey was used to gather data from 169 individuals diagnosed with ME/CFS.

Results: The majority of the patients (90.5%) reported a lack of understanding of their disease, resulting in patients avoiding talking about the disease due to disbelief, trivialization and avoidance of negative reactions. They felt most supported by close family members (67.1%). Two thirds of the patients (68.5%) experienced stigmatization. ME/CFS had a negative impact on mental health in most patients (88.2%), leading to sadness (71%), hopelessness for relief (66.9%), suicidal thoughts (39.3%) and secondary depression (14.8%). Half of the male patients experienced at least one suicidal thought since clinical onset. Factors significantly associated with depression were the lack of cure, disabilities associated with ME/CFS, social isolation and the fact that life was not worth anymore with ME/CFS. The three main factors contributing to suicidal thoughts were (i) being told the disease was only psychosomatic (89.5%), (ii) being at the end of one’s strength (80.7%) and (iii) not feeling being understood by others (80.7%).

Conclusion: This study provided first time significant insights into the mental and psychological well-being of ME/CFS patients in Switzerland. The findings highlight the substantial experiences of stigmatization, secondary depression and suicidal thoughts compared to other chronic diseases, calling for an urgent need in Switzerland to improve ME/CFS patient’s medical, psychological and social support, in order to alleviate the severe mental health burden associated with this overlooked somatic disease.

Source: Rahel Susanne König, Daniel Henry Paris, Marc Sollberger, Rea Tschopp.  Identifying the mental health burden in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients in Switzerland: A pilot study, HELIYON (2024), doi: https:// doi.org/10.1016/j.heliyon.2024.e27031. https://www.sciencedirect.com/science/article/pii/S2405844024030627 (Full text)

The Head-Up Tilt Table Test as a Measure of Autonomic Functioning among Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) often experience autonomic symptoms. In the present study, we evaluated 193 adults seeking treatment for ME/CFS, who were recruited from an outpatient clinic. The participants completed a head-up tilt table test to assess two common types of orthostatic intolerance, namely, postural orthostatic tachycardia syndrome (POTS) and orthostatic hypotension (OH).
During the tilt test, 32.5% of the participants demonstrated POTS or OH. The participants with either of these two common types of orthostatic intolerance were found to have more problems with sleep and post-exertional malaise as assessed by the DePaul Symptom Questionnaire; these patients also reported more physical and health function limitations. The implications of the findings are discussed.
Source: Jason LA, McGarrigle WJ, Vermeulen RCW. The Head-Up Tilt Table Test as a Measure of Autonomic Functioning among Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Journal of Personalized Medicine. 2024; 14(3):238. https://doi.org/10.3390/jpm14030238 https://www.mdpi.com/2075-4426/14/3/238 (Full text)