Herpesviruses Serology Distinguishes Different Subgroups of Patients From the United Kingdom Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Biobank

The evidence of an association between Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and chronic herpesviruses infections remains inconclusive. Two reasons for the lack of consistent evidence are the large heterogeneity of the patients' population with different disease triggers and the use of arbitrary cutoffs for defining seropositivity. In this work we re-analyzed previously published serological data related to 7 herpesvirus antigens. Patients with ME/CFS were subdivided into four subgroups related to the disease triggers: S0-42 patients who did not know their disease trigger; S1-43 patients who reported a non-infection trigger; S2-93 patients who reported an infection trigger, but that infection was not confirmed by a lab test; and S3-48 patients who reported an infection trigger and that infection was confirmed by a lab test. In accordance with a sensitivity analysis, the data were compared to those from 99 healthy controls allowing the seropositivity cutoffs to vary within a wide range of possible values. We found a negative association between S1 and seropositivity to Epstein-Barr virus (VCA and EBNA1 antigens) and Varicella-Zoster virus using specific seropositivity cutoff. However, this association was not significant when controlling for multiple testing. We also found that S3 had a lower seroprevalence to the human cytomegalovirus when compared to healthy controls for all cutoffs used for seropositivity and after adjusting for multiple testing using the Benjamini-Hochberg procedure. However, this association did not reach statistical significance when using Benjamini-Yekutieli procedure. In summary, herpesviruses serology could distinguish subgroups of ME/CFS patients according to their disease trigger, but this finding could be eventually affected by the problem of multiple testing.

Download Full-text

Comparison of the finger plethysmography derived stroke volumes by Nexfin CO Trek and suprasternal aortic Doppler derived stroke volume measurements in adults with myalgic encephalomyelitis/chronic fatigue syndrome and in healthy controls

Technology and Health Care ◽

10.3233/thc-202669 ◽

2021 ◽

pp. 1-14

Author(s):

C. (Linda) M.C. van Campen ◽

Freek W.A. Verheugt ◽

Peter C. Rowe ◽

Frans C. Visser

Keyword(s):

Chronic Fatigue Syndrome ◽

Stroke Volume ◽

Chronic Fatigue ◽

Calibration Procedure ◽

Myalgic Encephalomyelitis ◽

Tilt Test ◽

Healthy Controls ◽

Tilt Testing ◽

Fatigue Syndrome ◽

Finger Plethysmography

BACKGROUND: Finger plethysmography derived stroke volumes are frequently measured during tilt table testing. There are two algorithms to determine stroke volumes: Modelflow and NexfinCO Trek. Most tilt studies used Modelflow, while there are differences between the two algorithms. OBJECTIVE: To compare stroke volume indices by Nexfin CO Trek (SVINexfinCOTrek) with suprasternal Doppler derived SVI (SVIDoppler) in healthy controls (HC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients during tilt testing. These patients may have a large SVI decrease during the tilt enabling a large range of SVI to be studied. METHODS: One hundred and fifty-four patients and 39 HC with a normal tilt test were included. Supine and end-tilt SVIDoppler and SVINexfinCOTrek were compared using the Bland-Altman analysis. Also, the effect of calibrating supine SVINexfinCOTrek to SVIDoppler was studied RESULTS: Supine and end-tilt SVINexfinCOTrek were significantly higher than SVIDoppler: both P< 0.005. Bias, limits of agreement, and percent error (PE) were high with PE’s between 37 and 43%. The calibration procedure resulted in an acceptable variance with a PE of 29%. CONCLUSIONS: SVINexfinCOTrek overestimates stroke volumes compared to SVIDoppler, leading to high PE’s. Calibration reduced variance to an acceptable level, allowing SVINexfinCOTrek to be used for assessment of SVI changes during tilt testing

Download Full-text

Reduced heart rate variability predicts fatigue severity in individuals with chronic fatigue syndrome/myalgic encephalomyelitis

Journal of Translational Medicine ◽

10.1186/s12967-019-02184-z ◽

2020 ◽

Vol 18 (1) ◽

Cited By ~ 2

Author(s):

Rosa María Escorihuela ◽

Lluís Capdevila ◽

Juan Ramos Castro ◽

María Cleofé Zaragozà ◽

Sara Maurel ◽

...

Keyword(s):

Heart Rate ◽

Heart Rate Variability ◽

Chronic Fatigue Syndrome ◽

Frequency Domain ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Healthy Controls ◽

Fatigue Syndrome ◽

Potential Biomarker ◽

Fatigue Severity

Abstract Background Heart rate variability (HRV) is an objective, non-invasive tool to assessing autonomic dysfunction in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). People with CFS/ME tend to have lower HRV; however, in the literature there are only a few previous studies (most of them inconclusive) on their association with illness-related complaints. To address this issue, we assessed the value of different diurnal HRV parameters as potential biomarker in CFS/ME and also investigated the relationship between these HRV indices and self-reported symptoms in individuals with CFS/ME. Methods In this case–control study, 45 female patients who met the 1994 CDC/Fukuda definition for CFS/ME and 25 age- and gender-matched healthy controls underwent HRV recording-resting state tests. The intervals between consecutive heartbeats (RR) were continuously recorded over three 5-min periods. Time- and frequency-domain analyses were applied to estimate HRV variables. Demographic and clinical features, and self-reported symptom measures were also recorded. Results CFS/ME patients showed significantly higher scores in all symptom questionnaires (p < 0.001), decreased RR intervals (p < 0.01), and decreased HRV time- and frequency-domain parameters (p < 0.005), except for the LF/HF ratio than in the healthy controls. Overall, the correlation analysis reached significant associations between the questionnaires scores and HRV time- and frequency-domain measurements (p < 0.05). Furthermore, separate linear regression analyses showed significant relationships between self-reported fatigue symptoms and mean RR (p = 0.005), RMSSD (p = 0.0268) and HFnu indices (p = 0.0067) in CFS/ME patients, but not in healthy controls. Conclusions Our findings suggest that ANS dysfunction presenting as increased sympathetic hyperactivity may contribute to fatigue severity in individuals with ME/CFS. Further studies comparing short- and long-term HRV recording and self-reported outcome measures with previous studies in larger CFS/ME cohorts are urgently warranted.

Download Full-text

Evidence of Clinical Pathology Abnormalities in People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) from an Analytic Cross-Sectional Study

Diagnostics ◽

10.3390/diagnostics9020041 ◽

2019 ◽

Vol 9 (2) ◽

pp. 41 ◽

Cited By ~ 6

Author(s):

Nacul ◽

de Barros ◽

Kingdon ◽

Cliff ◽

Clark ◽

...

Keyword(s):

Chronic Fatigue Syndrome ◽

Chronic Fatigue ◽

Cross Sectional Study ◽

Myalgic Encephalomyelitis ◽

Activity Levels ◽

Healthy Controls ◽

Sectional Study ◽

Cross Sectional ◽

Fatigue Syndrome ◽

Laboratory Test Results

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease presenting with extreme fatigue, post-exertional malaise, and other symptoms. In the absence of a diagnostic biomarker, ME/CFS is diagnosed clinically, although laboratory tests are routinely used to exclude alternative diagnoses. In this analytical cross-sectional study, we aimed to explore potential haematological and biochemical markers for ME/CFS, and disease severity. We reviewed laboratory test results from 272 people with ME/CFS and 136 healthy controls participating in the UK ME/CFS Biobank (UKMEB). After corrections for multiple comparisons, most results were within the normal range, but people with severe ME/CFS presented with lower median values (p < 0.001) of serum creatine kinase (CK; median = 54 U/L), compared to healthy controls (HCs; median = 101.5 U/L) and non-severe ME/CFS (median = 84 U/L). The differences in CK concentrations persisted after adjusting for sex, age, body mass index, muscle mass, disease duration, and activity levels (odds ratio (OR) for being a severe case = 0.05 (95% confidence interval (CI) = 0.02–0.15) compared to controls, and OR = 0.16 (95% CI = 0.07–0.40), compared to mild cases). This is the first report that serum CK concentrations are markedly reduced in severe ME/CFS, and these results suggest that serum CK merits further investigation as a biomarker for severe ME/CFS.

Download Full-text

Cell-Based Blood Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

International Journal of Molecular Sciences ◽

10.3390/ijms21031142 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1142

Author(s):

Daniel Missailidis ◽

Oana Sanislav ◽

Claire Y. Allan ◽

Sarah J. Annesley ◽

Paul R. Fisher

Keyword(s):

Chronic Fatigue Syndrome ◽

Sensitivity And Specificity ◽

Respiratory Function ◽

Death Rate ◽

Frozen Storage ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Healthy Controls ◽

Fatigue Syndrome ◽

Mitochondrial Respiratory

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a devastating illness whose biomedical basis is now beginning to be elucidated. We reported previously that, after recovery from frozen storage, lymphocytes (peripheral blood mononuclear cells, PBMCs) from ME/CFS patients die faster in culture medium than those from healthy controls. We also found that lymphoblastoid cell lines (lymphoblasts) derived from these PBMCs exhibit multiple abnormalities in mitochondrial respiratory function and signalling activity by the cellular stress-sensing kinase Target Of Rapamycin Complex 1 (TORC1). These differences were correlated with disease severity, as measured by the Richardson and Lidbury weighted standing test. The clarity of the differences between these cells derived from ME/CFS patient blood and those from healthy controls suggested that they may provide useful biomarkers for ME/CFS. Here, we report a preliminary investigation into that possibility using a variety of analytical classification tools, including linear discriminant analysis, logistic regression and receiver operating characteristic (ROC) curve analysis. We found that results from three different tests—lymphocyte death rate, mitochondrial respiratory function and TORC1 activity—could each individually serve as a biomarker with better than 90% sensitivity but only modest specificity vís a vís healthy controls. However, in combination, they provided a cell-based biomarker with sensitivity and specificity approaching 100% in our sample. This level of sensitivity and specificity was almost equalled by a suggested protocol in which the frozen lymphocyte death rate was used as a highly sensitive test to triage positive samples to the more time consuming and expensive tests measuring lymphoblast respiratory function and TORC1 activity. This protocol provides a promising biomarker that could assist in more rapid and accurate diagnosis of ME/CFS.

Download Full-text

Accurate and Objective Determination of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Disease Severity with a Wearable Sensor

10.21203/rs.3.rs-48360/v1 ◽

2020 ◽

Author(s):

Turner Palombo ◽

Andrea Campos ◽

Suzanne D. Vernon ◽

Shad Roundy

Keyword(s):

Chronic Fatigue Syndrome ◽

Disease Severity ◽

Large Scale ◽

Objective Measure ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Measurement Unit ◽

Healthy Controls ◽

Fatigue Syndrome ◽

Significant Measure

Abstract Background Approximately 2.5 million people in the U.S. suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This disease negatively impacts patients’ ability to function, often resulting in difficulty maintaining employment, sustaining financial independence, engaging socially with others, and in particularly severe cases, consistently and adequately performing activities of daily living. The focus of this research was to develop a sensor-based method to measure upright activity defined as time with feet on the floor and referred to as UpTime, as an indicator of ME/CFS disease severity.Methods A commercially available inertial measurement unit (IMU), the Shimmer, was selected for this research. A Kalman filter was used to convert IMU data collected by the Shimmer to angle estimates. Angle estimate accuracy was confirmed by comparison to a motion capture system. Leg angle estimates were then converted to personalized daily UpTime scores using a critical angle of 39º from vertical to differentiate between upright (feet on the floor) and not upright. A six-day, case-control study with 15 subjects (five healthy controls, five moderate-level ME/CFS, and five severe-level ME/CFS) was conducted to determine the utility of UpTime for assessing disease severity.Results UpTime was found to be a significant measure of ME/CFS disease severity. Severely ill ME/CFS patients spend less than 20% of each day with feet on the floor. Moderately ill ME/CFS patients spend between 20–30% of each day with feet on the floor. Healthy controls have greater than 30% UpTime. IMU-measured UpTime was more precise than self-reported hours of upright activity which were over-estimated by patients.Conclusions UpTime is an accurate and objective measure of upright activity, a measure that can be used to assess disease severity in ME/CFS patients. Due to its ability to accurately monitor upright activity, UpTime can also be used as a reliable endpoint for evaluating ME/CFS treatment efficacy. Future studies with larger samples and extended data collection periods are required to fully confirm the use of UpTime as a measure of disease severity in ME/CFS. With the added perspective of large-scale studies, this sensor-based platform could provide a recovery path for individuals struggling with ME/CFS.

Download Full-text

Potential of Activin B as a Clinical Biomarker in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Biomolecules ◽

10.3390/biom11081189 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1189

Author(s):

Sabine Gravelsina ◽

Zaiga Nora-Krukle ◽

Anda Vilmane ◽

Simons Svirskis ◽

Katrine Vecvagare ◽

...

Keyword(s):

Chronic Fatigue Syndrome ◽

Complex Disease ◽

Clinical Symptoms ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Healthy Controls ◽

Fatigue Syndrome ◽

Age Related ◽

Diagnostic Potential ◽

Clinical Biomarker

Reliable serum biomarkers are of immense need for diagnostic purposes of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)—a disabling and complex disease for which diagnosis is mainly based on clinical symptoms. The aim of this study was to evaluate a possible diagnostic potential of activin B by directly comparing 134 cases of ME/CFS with 54 healthy controls. Analyses of human activin B level in plasma samples were performed using a validated human activin B ELISA assay. The results of the study show that activin B levels did not differ statistically significantly between ME/CFS patients and healthy controls (p = 0.6511). No gender or age-related differences in activin B levels were observed in the ME/CFS group and healthy controls. The level of activin B tended to decrease with increasing visual analogue scale score (r = −0.2004; p = 0.5085) nevertheless the results obtained so far does not support the clinical utility of activin B as a biomarker for ME/CFS.

Download Full-text

Cell-Based Blood Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

10.20944/preprints202002.0029.v1 ◽

2020 ◽

Author(s):

Daniel Missailidis ◽

Oana Sanislav ◽

Claire Allan ◽

Sarah Annesley ◽

Paul Fisher

Keyword(s):

Chronic Fatigue Syndrome ◽

Sensitivity And Specificity ◽

Respiratory Function ◽

Death Rate ◽

Frozen Storage ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Healthy Controls ◽

Fatigue Syndrome ◽

Mitochondrial Respiratory

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a devastating illness whose biomedical basis is now beginning to be elucidated. We reported previously that, after recovery from frozen storage, lymphocytes (peripheral blood monocytic cells, PBMCs) from ME/CFS patients die faster in culture medium than those from healthy controls. We also found that lymphoblastoid cell lines (lymphoblasts) derived from these PBMCs exhibit multiple abnormalities in mitochondrial respiratory function and signalling activity by the cellular stress-sensing kinase TORC1. These differences were correlated with disease severity, as measured by the Richardson and Lidbury Weighted Standing Test. The clarity of the differences between these cells derived from ME/CFS patient blood and those from healthy controls suggested that they may provide useful biomarkers for ME/CFS. Here we report a preliminary investigation into that possibility using a variety of analytical classification tools, including linear discriminant analysis, logistic regression and Receiver Operating Characteristic (ROC) curve analysis. We found that results from three different tests, lymphocyte death rate, mitochondrial respiratory function and TORC1 activity could each individually serve as biomarker with better than 90% sensitivity but only modest specificity vís a vís healthy controls. However, in combination they provided a cell-based biomarker with sensitivity and specificity approaching 100% in our sample. This level of sensitivity and specificity was almost equalled by a suggested protocol in which the frozen lymphocyte death rate was used as a highly sensitive test to triage positive samples to the more time consuming and expensive tests measuring lymphoblast respiratory function and TORC1 activity. This protocol provides a promising biomarker that could assist in more rapid and accurate diagnosis of ME/CFS.

Download Full-text

Cytokines in the Cerebrospinal Fluids of Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Mediators of Inflammation ◽

10.1155/2015/929720 ◽

2015 ◽

Vol 2015 ◽

pp. 1-4 ◽

Cited By ~ 30

Author(s):

D. Peterson ◽

E. W. Brenu ◽

G. Gottschalk ◽

S. Ramos ◽

T. Nguyen ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Chronic Fatigue Syndrome ◽

Preliminary Investigation ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Healthy Controls ◽

Gm Csf ◽

Fatigue Syndrome ◽

Human Cytokine

Objectives. Previous research has provided evidence for dysregulation in peripheral cytokines in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). To date only one study has examined cytokines in cerebrospinal fluid (CSF) samples of CFS/ME patients. The purpose of this pilot study was to examine the role of cytokines in CSF of CFS/ME patients.Methods. CSF was collected from 18 CFS/ME patients and 5 healthy controls. The CSF samples were examined for the expression of 27 cytokines (interleukin- (IL-) 1β, IL-1ra, IL-2, IL-4, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17, basic FGF, eotaxin, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1 (MCAF), MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, and VEGF) using the Bio-Plex Human Cytokine 27-plex Assay.Results. Of the 27 cytokines examined, only IL-10 was significantly reduced in the CFS/ME patients in comparison to the controls.Conclusions. This preliminary investigation suggests that perturbations in inflammatory cytokines in the CSF of CFS/ME patients may contribute to the neurological discrepancies observed in CFS/ME.

Download Full-text

Evaluating Routine Blood Tests According to Clinical Symptoms and Diagnostic Criteria in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Journal of Clinical Medicine ◽

10.3390/jcm10143105 ◽

2021 ◽

Vol 10 (14) ◽

pp. 3105

Author(s):

Ingrid H. Baklund ◽

Toril Dammen ◽

Torbjørn Åge Moum ◽

Wenche Kristiansen ◽

Daysi Sosa Duarte ◽

...

Keyword(s):

Chronic Fatigue Syndrome ◽

Clinical Symptoms ◽

Chronic Fatigue ◽

Mean Difference ◽

Myalgic Encephalomyelitis ◽

Psychiatric Evaluation ◽

Healthy Controls ◽

Blood Tests ◽

Fatigue Syndrome ◽

And Gender

There is a lack of research regarding blood tests within individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and between patients and healthy controls. We aimed to compare results of routine tests between patients and healthy controls. Data from 149 patients diagnosed with ME/CFS based on clinical and psychiatric evaluation as well as on the DePaul Symptom Questionnaire, and data from 264 healthy controls recruited from blood donors were compared. One-way ANCOVA was conducted to examine differences between ME/CFS patients and healthy controls, adjusting for age and gender. Patients had higher sedimentation rate (mean difference: 1.38, 95% CI: 0.045 to 2.714), leukocytes (mean difference: 0.59, 95% CI: 0.248 to 0.932), lymphocytes (mean difference: 0.27, 95% CI: 0.145 to 0.395), neutrophils (mean difference: 0.34, 95% CI: 0.0 89 to 0.591), monocytes (mean difference: 0.34, 95% CI: 0.309 to 0.371), ferritin (mean difference: 28.13 95% CI: −1.41 to 57.672), vitamin B12 (mean difference: 83.43, 95% CI: 62.89 to 124.211), calcium (mean difference: 0.02, 95% CI: −0.02 to 0.06), alanine transaminase (ALAT) (mean difference: 3.30, 95% CI: −1.37 to -7.971), low-density lipoproteins (mean difference: 0.45, 95% CI: 0.104 to 0.796), and total proteins (mean difference: 1.53, 95% CI: −0.945 to 4.005) than control subjects. The patients had lower potassium levels (mean difference: 0.11, 95% CI: 0.056 to 0.164), creatinine (mean difference: 2.60; 95% CI: 0.126 to 5.074) and creatine kinase (CK) (mean difference: 37.57 95% CI: −0.282 to 75.422) compared to the healthy controls. Lower CK and creatinine levels may suggest muscle damage and metabolic abnormalities in ME/CFS patients.

Download Full-text

Caring for the Patient with Severe or Very Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Healthcare ◽

10.3390/healthcare9101331 ◽

2021 ◽

Vol 9 (10) ◽

pp. 1331

Author(s):

Jose G. Montoya ◽

Theresa G. Dowell ◽

Amy E. Mooney ◽

Mary E. Dimmock ◽

Lily Chu

Keyword(s):

Chronic Fatigue Syndrome ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Accurate Information ◽

Patient Centered ◽

Clinical Guidance ◽

Fatigue Syndrome ◽

Wide Range ◽

Patient’S Experience ◽

Total Care

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) can cause a wide range of severity and functional impairment, leaving some patients able to work while others are homebound or bedbound. The most severely ill patients may need total care. Yet, patients with severe or very severe ME/CFS struggle to receive appropriate medical care because they cannot travel to doctors’ offices and their doctors lack accurate information about the nature of this disease and how to diagnose and manage it. Recently published clinical guidance provides updated information about ME/CFS but advice on caring for the severely ill is limited. This article is intended to fill that gap. Based on published clinical guidance and clinical experience, we describe the clinical presentation of severe ME/CFS and provide patient-centered recommendations on diagnosis, assessment and approaches to treatment and management. We also provide suggestions to support the busy provider in caring for these patients by leveraging partnerships with the patient, their caregivers, and other providers and by using technology such as telemedicine. Combined with compassion, humility, and respect for the patient’s experience, such approaches can enable the primary care provider and other healthcare professionals to provide the care these patients require and deserve.

Download Full-text