Rethinking ME/CFS Diagnostic Reference Intervals via Machine Learning, and the Utility of Activin B for Defining Symptom Severity
Brett A. Lidbury 1,*,Badia Kita 2,Alice M. Richardson 1,Donald P. Lewis 3,Edwina Privitera 3,Susan Hayward 4,David de Kretser 2,5 andMark Hedger 4
*
Diagnostics 2019, 9(3), 79; https://doi.org/10.3390/diagnostics9030079
Received: 28 May 2019 / Revised: 9 July 2019 / Accepted: 15 July 2019 / Published: 19 July 2019
(This article belongs to the Special Issue Biomedical Insights that Inform the Diagnosis of ME/CFS)
Abstract
Biomarker discovery applied to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disabling disease of inconclusive aetiology, has identified several cytokines to potentially fulfil a role as a quantitative blood/serum marker for laboratory diagnosis, with activin B a recent addition. We explored further the potential of serum activin B as a ME/CFS biomarker, alone and in combination with a range of routine test results obtained from pathology laboratories. Previous pilot study results showed that activin B was significantly elevated for the ME/CFS participants compared to healthy (control) participants. All the participants were recruited via CFS Discovery and assessed via the Canadian/International Consensus Criteria. A significant difference for serum activin B was also detected for ME/CFS and control cohorts recruited for this study, but median levels were significantly lower for the ME/CFS cohort. Random Forest (RF) modelling identified five routine pathology blood test markers that collectively predicted ME/CFS at ≥62% when compared via weighted standing time (WST) severity classes. A closer analysis revealed that the inclusion of activin B to the panel of pathology markers improved the prediction of mild to moderate ME/CFS cases. Applying correct WST class prediction from RFA modelling, new reference intervals were calculated for activin B and associated pathology markers, where 24-h urinary creatinine clearance, serum urea and serum activin B showed the best potential as diagnostic markers. While the serum activin B results remained statistically significant for the new participant cohorts, activin B was found to also have utility in enhancing the prediction of symptom severity, as represented by WST class.
Keywords: myalgic encephalomyelitis; chronic fatigue syndrome; activin; pathology; biomarker; cytokine; machine learning; reference intervals
Pathological Mechanisms Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Daniel Missailidis,Sarah J. Annesley andPaul R. Fisher *
Department of Physiology Anatomy and Microbiology, La Trobe University, VIC 3086, Australia
*
Diagnostics 2019, 9(3), 80; https://doi.org/10.3390/diagnostics9030080
Received: 18 June 2019 / Revised: 15 July 2019 / Accepted: 19 July 2019 / Published: 20 July 2019
Biomedical Insights that Inform the Diagnosis of ME/CFS)
Abstract
The underlying molecular basis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is not well understood. Characterized by chronic, unexplained fatigue, a disabling payback following exertion (“post-exertional malaise”), and variably presenting multi-system symptoms, ME/CFS is a complex disease, which demands a concerted biomedical investigation from disparate fields of expertise. ME/CFS research and patient treatment have been challenged by the lack of diagnostic biomarkers and finding these is a prominent direction of current work. Despite these challenges, modern research demonstrates a tangible biomedical basis for the disorder across many body systems. This evidence is mostly comprised of disturbances to immunological and inflammatory pathways, autonomic and neurological dysfunction, abnormalities in muscle and mitochondrial function, shifts in metabolism, and gut physiology or gut microbiota disturbances. It is possible that these threads are together entangled as parts of an underlying molecular pathology reflecting a far-reaching homeostatic shift. Due to the variability of non-overlapping symptom presentation or precipitating events, such as infection or other bodily stresses, the initiation of body-wide pathological cascades with similar outcomes stemming from different causes may be implicated in the condition. Patient stratification to account for this heterogeneity is therefore one important consideration during exploration of potential diagnostic developments.View Full-Text
Keywords: myalgic encephalomyelitis; chronic fatigue syndrome; ME/CFS; diagnosis; metabolism; mitochondria; inflammation; immune system; signaling; gut microbiota
Diagnostics 2019, 9(3), 82; https://doi.org/10.3390/diagnostics9030082
Article
The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS
Alex A. Kashi 1,Ronald W. Davis 1,2 andRobert D. Phair 3,*
Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USA
Departments of Biochemistry and Genetics, Stanford University, Stanford, CA 94305, USA
Integrative Bioinformatics Inc., Mountain View, CA 94041, USA
Received: 24 May 2019 / Accepted: 24 July 2019 / Published: 26 July 2019
Abstract
:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating noncommunicable disease brandishing an enormous worldwide disease burden with some evidence of inherited genetic risk. Absence of measurable changes in patients’ standard blood work has necessitated ad hoc symptom-driven therapies and a dearth of mechanistic hypotheses regarding its etiology and possible cure. A new hypothesis, the indolamine-2,3-dioxygenase (IDO) metabolic trap, was developed and formulated as a mathematical model. The historical occurrence of ME/CFS outbreaks is a singular feature of the disease and implies that any predisposing genetic mutation must be common. A database search for common damaging mutations in human enzymes produces 208 hits, including IDO2 with four such mutations. Non-functional IDO2, combined with well-established substrate inhibition of IDO1 and kinetic asymmetry of the large neutral amino acid transporter, LAT1, yielded a mathematical model of tryptophan metabolism that displays both physiological and pathological steady-states. Escape from the pathological one requires an exogenous perturbation. This model also identifies a critical point in cytosolic tryptophan abundance beyond which descent into the pathological steady-state is inevitable. If, however, means can be discovered to return cytosolic tryptophan below the critical point, return to the normal physiological steady-state is assured. Testing this hypothesis for any cell type requires only labelled tryptophan, a means to measure cytosolic tryptophan and kynurenine, and the standard tools of tracer kinetics.
Keywords:
tryptophan metabolism; indoleamine-2,3-dioxygenase; bistability; kynurenine pathway; substrate inhibition; myalgic encephalomyelitis; chronic fatigue syndrome; mathematical model; critical point
Diagnostics 2019, 9(3), 70; https://doi.org/10.3390/diagnostics9030070
Article
Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases
Neil R. McGregor 1,*,Christopher W. Armstrong 2,Donald P. Lewis 3 andPaul R. Gooley 2
Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville VIC
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biochemistry Institute, 30 Flemington Road, Parkville VIC 3010, Australia
CFS Discovery, Donvale Medical Centre, Donvale VIC 3111, Australia
Received: 17 June 2019 / Accepted: 2 July 2019 / Published: 4 July 2019
Abstract
Post-exertional malaise (PEM) is a cardinal predictive symptom in the definition of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). If the cases overexert themselves they have what is termed “payback” resulting in a worsening of symptoms or relapse which can last for days, weeks or even months. The aim was to assess the changes in biochemistry associated with the cases self-reported PEM scores over a 7-day period and the frequency of reporting over a 12-month period. Forty-seven ME/CFS cases and age/sex-matched controls had a clinical examination, completed questionnaires; were subjected to standard serum biochemistry; had their serum and urine metabolomes analyzed in an observational study. Thirty-five of the 46 ME/CFS cases reported PEM in the last 7-days and these were allocated to the PEM group. The principal biochemical change related to the 7-day severity of PEM was the fall in the purine metabolite, hypoxanthine. This decrease correlated with alterations in the glucose:lactate ratio highly suggestive of a glycolytic anomaly. Increased excretion of urine metabolites within the 7-day response period indicated a hypermetabolic event was occurring. Increases in urine excretion of methylhistidine (muscle protein degradation), mannitol (intestinal barrier deregulation) and acetate were noted with the hypermetabolic event. These data indicate hypoacetylation was occurring, which may also be related to deregulation of multiple cytoplasmic enzymes and DNA histone regulation. These findings suggest the primary events associated with PEM were due to hypoacetylation and metabolite loss during the acute PEM response.
Human Microbiome Journal Volume 13, August 2019, 100061
A retrospective outcome study of 42 patients with Chronic Fatigue Syndrome, 30 of whom had Irritable Bowel Syndrome. Half were treated with oral approaches, and half were treated with Faecal Microbiome Transplantation
J.N.Kenyona ShellyCoeb HooshangIzadib
Abstract
The gut microbiome comprises the community of microorganisms in the intestinal tract. Research suggests that an altered microbiome may play a role in a wide range of disorders including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Methods
42 participants with ME/CFS with Irritable Bowel Syndrome (IBS) were allocated into one of two groups, 21 were treated with standard oral approaches, which centred around various nutritional remedies, probiotics, prebiotics, dietary advice and lifestyle advice. The second group who had mostly failed using oral approaches, were treated with Faecal Microbiome Transplantation (FMT). Each patient received 10 Implants, each from a different screened donor, and the Implants were processed under anaerobic conditions. The transplant is delivered via a paediatric rectal catheter, which is inserted through the anus to reach the lower part of the sigmoid colon.
The results were assessed on a percentage basis before and after treatment, 0% being no improvement, 100% being maximum improvement. An exact non-parametric Mann-Whitney (one-tailed) test was used to compare medians from those on FMT compared with those receiving oral approaches only. On clinical experience over many years, the only way to judge improvement in Chronic Fatigue Syndrome as there is no test for Chronic Fatigue Syndrome, is my clinical assessment.
Results
The median for the FMT group was found to be significantly higher compared to the oral treatment group (Mann-Whitney U = 111.5, p = .003). Therefore, the FMT group improved to a greater extent (z = −2.761).
Conclusion
This study shows that FMT is a safe and a promising treatment for CFS associated with IBS. Adequately powered randomised controlled trials should be carried out to assess the effectiveness of FMT in patients with CFS and IBS.
Mitochondrial alterations in NK lymphocytes from ME/CFS patients
Isabel Barao Silvestre, Raul Y Dagda, Ruben K Dagda and Victor Darley-Usmar
J Immunol May 1, 2019, 202 (1 Supplement) 126.39;
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by profound fatigue, flu-like symptoms, trouble concentrating, and autonomic problems, all of which worsen after exertion. ME/CFS patients have impaired natural killer (NK) cell activity. NK lymphocytes are a critical first defense against viruses and cancer. ME/CFS patients have difficulties controlling viral infections and many develop non-Hodgkin’s lymphoma. Mitochondrial metabolism is crucial for immune cell function. Mitochondria dysfunction has been previously reported in ME/CFS, but it is not known whether the NK cells of these patients have altered mitochondrial metabolism that affect their activity and contribute to ME/CFS pathogenesis. More importantly, there is currently no efficient method to diagnose ME/CFS or assess efficacy of therapeutic interventions. The Bioenergetic Health Index (BHI) has been developed as promising and reliable surrogate readout of human health by measuring the bioenergetic status of immune cells. Variations in bioenergetic function in patient’s immune cells can reflect both metabolic stress and the mutable role of these cells in ME/CFS immunity and pathogenesis. In our study, we observed that the two main energy-generating mitochondrial pathways, oxidative phosphorylation and glycolysis (bioenergetics parameters), are deregulated in ME/CFS NK cells and in PBMCs. Moreover, we observed alterations in the morphology and membrane potential of the mitochondria of NK cells. These mitochondrial features can affect NK cell function and contribute to the severity of disease. To date, this is the first metabolism assessment of NK cells in ME/CFS and as potential new diagnostic tool for the disease.
• J-STAGE home Biological and Pharmaceutical ...Volume 42 (2019) Issue 7
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Induced by Repeated Forced Swimming in Mice
Takuya Ohba, Shinichi Domoto, Miyu Tanaka, Shinsuke Nakamura, Masamitsu Shimazawa, Hideaki Hara
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by disabling fatigue of at least 6 months, in addition to symptoms such as muscle pain and muscle weakness. There is no treatment provides long-term benefits to most patients. Recently, clinical research suggested the involvement of pyruvate dehydrogenase (PDH) in ME/CFS. PDH is a crucial enzyme in the mitochondria matrix that links glycolysis to the tricarboxylic acid cycle and oxidative phosphorylation. However, it is little known whether PDH could be a therapeutic target. The purpose of this study was to establish ME/CFS in mice and to investigate the involvement of PDH in ME/CFS. To induce the chronic fatigue in mice, a repeated forced swimming test was conducted. To evaluate fatigue, we measured immobility time in forced swimming test and starting time of grooming. An open field test was conducted on day 8. After 25 d of the forced swimming test, the mitochondrial fraction in gastrocnemius muscle was isolated and PDH activity was measured. Moreover, we evaluated the effect of PDH activation by administering sodium dichloroacetate (DCA). In ME/CFS mice group, the immobility time and starting time of grooming increased time-dependently. In addition, the moved distance was decreased in ME/CFS mice. PDH activity was decreased in the mitochondrial fraction of the gastrocnemius muscle of the forced swimming group. DCA treatment may be beneficial in preventing fatigue-like behavior in ME/CFS. These findings indicate that ME/CFS model was established in mice and that a decrease in mitochondrial PDH activity is involved with the symptom of ME/CFS.
Assessing cellular energy dysfunction in CFS/ME using a commercially available laboratory test
Scientific Reportsvolume 9, Article number: 11464 (2019) |
Abstract The mitochondrial energy score (MES) protocol, developed by the Myhill group, is marketed as a diagnostic test for chronic fatigue syndrome/Myalgic Encephalomyelitis (CFS/ME). This study assessed the reliability and reproducibility of the test, currently provided by private clinics, to assess its potential to be developed as an NHS accredited laboratory test. We replicated the MES protocol using neutrophils and peripheral blood mononuclear cells (PBMCs) from CFS/ME patients (10) and healthy controls (13). The protocol was then repeated in PBMCs and neutrophils from healthy controls to investigate the effect of delayed sample processing time used by the Myhill group. Experiments using the established protocol showed no differences between CFS/ME patients and healthy controls in any of the components of the MES (p ≥ 0.059). Delaying blood sample processing by 24 hours (well within the 72 hour time frame quoted by the Myhill group) significantly altered many of the parameters used to calculate the MES in both neutrophils and PBMCs. The MES test does not have the reliability and reproducibility required of a diagnostic test and therefore should not currently be offered as a diagnostic test for CFS/ME. The differences observed by the Myhill group may be down to differences in sample processing time between cohorts.
Diagnostics 2019, 9(3), 91; https://doi.org/10.3390/diagnostics9030091
Review
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Comprehensive Review
by Mateo Cortes Rivera 1,*,Claudio Mastronardi 2,Claudia T. Silva-Aldana 3,Mauricio Arcos-Burgos 4 andBrett A. Lidbury
Facultad de Medicina, Grupo de Investigación Neuros, Universidad del Rosario, Bogotá 110211, Colombia INPAC Research Group, Fundación Universitaria Sanitas, Bogotá 110211, Colombia Center for Research in Genetics and Genomics-CIGGUR, GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 110211, Colombia Group de Investigación en Psiquiatría (GIPSI), Instituto de Investigaciones Médicas, Facultad de Medicina, Universidad de Antioquia, Medellín 050002, Colombia The National Centre for Epidemiology and Population Health, RSPH, College of Health and Medicine, The Australian National University, Canberra ACT 2601, Australia
Received: 22 May 2019 / Accepted: 15 July 2019 / Published: 7 August 2019
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown aetiology that is recognized by the World Health Organization (WHO) and the United States Center for Disease Control and Prevention (US CDC) as a disorder of the brain. The disease predominantly affects adults, with a peak age of onset of between 20 and 45 years with a female to male ratio of 3:1. Although the clinical features of the disease have been well established within diagnostic criteria, the diagnosis of ME/CFS is still of exclusion, meaning that other medical conditions must be ruled out. The pathophysiological mechanisms are unclear but the neuro-immuno-endocrinological pattern of CFS patients gleaned from various studies indicates that these three pillars may be the key point to understand the complexity of the disease. At the moment, there are no specific pharmacological therapies to treat the disease, but several studies’ aims and therapeutic approaches have been described in order to benefit patients’ prognosis, symptomatology relief, and the recovery of pre-existing function. This review presents a pathophysiological approach to understanding the essential concepts of ME/CFS, with an emphasis on the population, clinical, and genetic concepts associated with ME/CFS.
Front. Immunol., 14 August 2019 | https://doi.org/10.3389/fimmu.2019.01946
Antibodies to Human Herpesviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients
Jonas Blomberg1†, Muhammad Rizwan1, Agnes Böhlin-Wiener1‡, Amal Elfaitouri2, Per Julin3,4, Olof Zachrisson5, Anders Rosén6* and Carl-Gerhard Gottfries5
Ehlers-Danlos syndromes
BMJ 2019; 366 doi: https://doi.org/10.1136/bmj.l4966 (Published 18 September 2019)Cite this as: BMJ 2019;366:l4966
What you need to know
This article is intended to support non-specialist clinicians to consider the diagnosis of this group of conditions in appropriate patients. It discusses the features of the different types of EDS and explains how clinicians can expect their patients to be managed in secondary care.
How this article was created
The authors are members of the International Consortium on Ehlers-Danlos Syndromes and Related Disorders and participated in literature searches used for the basis of the articles written on the new classification of EDS published in 2017. The authors have more than 10 years’ experience of EDS patient consultations and data collection in the highly specialised EDS service.
Chronic exposure to insufficient sleep alters processes of pain habituation and sensitization
Simpson, Norah S.a; Scott-Sutherland, Jenniferb; Gautam, Shivac; Sethna, Navild; Haack, Monikab,*
PAIN: January 2018 - Volume 159 - Issue 1 - p 33–40
doi: 10.1097/j.pain.0000000000001053
Abstract
Chronic pain conditions are highly comorbid with insufficient sleep. While the mechanistic relationships between the 2 are not understood, chronic insufficient sleep may be 1 pathway through which central pain-modulatory circuits deteriorate, thereby contributing to chronic pain vulnerability over time. To test this hypothesis, an in-laboratory model of 3 weeks of restricted sleep with limited recovery (5 nights of 4-hour sleep per night followed by 2 nights of 8-hour sleep per night) was compared with 3 weeks of 8-hour sleep per night (control protocol). Seventeen healthy adults participated, with 14 completing both 3-week protocols. Measures of spontaneous pain, heat-pain thresholds, cold-pain tolerance (measuring habituation to cold over several weeks), and temporal summation of pain (examining the slope of pain ratings during cold water immersion) were assessed at multiple points during each protocol. Compared with the control protocol, participants in the sleep-restriction protocol experienced mild increases in spontaneous pain (P < 0.05). Heat-pain thresholds decreased after the first week of sleep restriction (P < 0.05) but normalized with longer exposure to sleep restriction. By contrast, chronic exposure to restricted sleep was associated with decreased habituation to, and increased temporal summation in response to cold pain (both P < 0.05), although only in the past 2 weeks of the sleep-restriction protocol. These changes may reflect abnormalities in central pain-modulatory processes. Limited recovery sleep did not completely resolve these alterations in pain-modulatory processes, indicating that more extensive recovery sleep is required. Results suggest that exposure to chronic insufficient sleep may increase vulnerability to chronic pain by altering processes of pain habituation and sensitization.
Pain-modulatory processes deteriorate with more chronic forms of sleep insufficiency and a couple of nights with limited recovery sleep do not resolve alterations.
Corresponding author. Address: 330 Brookline Ave, Dana 779, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Tel.: 617-667-5234. E-mail address: [email protected] (M. Haack).
© 2018 International Association for the Study of Pain
BMJ Open Sport Exerc Med. 2019 Jun 20;5(1):e000542. doi: 10.1136/bmjsem-2019-000542. eCollection 2019.
Novel insights of overtraining syndrome discovered from the EROS study.
Cadegiani FA1, Kater CE1.
Author information
Endocrinology, Universidade Federal de Sao Paulo, Sao Paulo, Brazil.
Abstract
BACKGROUND:
Excessive training and inadequate recovery could cause 'overtraining syndrome' (OTS), which is characterised by underperformance and fatigue. The pathophysiology of OTS is unclear. We aimed to describe novel mechanisms and risk factors associated with OTS, and thereby facilitate its early identification and prevention, from a comprehensive joint qualitative analysis of the findings from all the four arms of the Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study.
METHODS:
We compared the types and proportions of behavioural patterns of 67 evaluated parameters of OTS from 51 participants-athletes with OTS (OTS, n=14), healthy athletes (n=25) and healthy non-physically active controls (n=12). We performed overall and pairwise comparisons for statistically significant differences between the three groups (p<0.05).
RESULTS:
A total of 44 (65.7%) markers exhibited significant differences between the three groups: 32 (72.7%) showed a loss of the conditioning effect of exercise ('deconditioning'), 7 (15.9%) showed changes exclusive to OTS, 3 (6.8%) maintained the exercise-induced conditioning effects and 2 (4.5%) revealed an exacerbation of the adaptive changes to exercises.
CONCLUSION:
Our findings suggest that OTS is likely triggered by multiple factors, not restricted to excessive training, resulted from a chronic energy deprivation, leading to multiple losses in the conditioning processes typically observed in healthy athletes, as a combination of 'paradoxical deconditioning' processes, which explains the gradual and marked loss of physical conditioning found in OTS. We, therefore, suggest that the term 'paradoxical deconditioning syndrome' better represents the features of this syndrome.
KEYWORDS:
fatigue; hormones; overtraining syndrome; paradoxical deconditioning syndrome; sports endocrinology; sports performance
Hope, disappointment and perseverance: Reflections of people with Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Multiple Sclerosis participating in biomedical research.
Eliana Lacerda PhD, Clare McDermott PhD, Caroline C. Kingdon MSc, Jack Butterworth BA, Jacqueline M. Cliff PhD, Luis Nacul PhD
The Clinical Understanding and Research Excellence in ME/CFS group (CureME) at the London School of Hygiene & Tropical Medicine has supported and undertaken studies in immunology, genetics, virology, clinical medicine, epidemiology and disability. It established the UK ME/CFS Biobank (UKMEB), which stores data and samples from three groups: participants with ME/CFS, Multiple Sclerosis (MS) and healthy controls. Patient and public involvement have played a central role from its inception.
Aim To explore the views of participants with ME/CFS and MS on CureME research findings, dissemination and future biomedical research priorities. Method Five ME/CFS and MS focus groups were conducted at two UK sites. Discussions were transcribed and analysed thematically.
Results A total of 28 UKMEB participants took part: 16 with ME/CFS and 12 with MS. Five themes emerged: (a) Seeking coherence: participants’ reactions to initial research findings; (b) Seeking acceptance: participants explore issues of stigma and validation; (c) Seeking a diagnosis: participants explore issues around diagnosis in their lives; (d) Seeking a better future: participants’ ideas on future research; and (e) Seeking to share understanding: participants’ views on dissemination. Focus groups perceived progress in ME/CFS and MS research in terms of “putting together a jigsaw” of evidence through perseverance and collaboration. Conclusion This study provides insight into the emotional, social and practical importance of research to people with MS and ME/CFS, suggesting a range of research topics for the future. Findings should inform biomedical research directions in ME/CFS and MS, adding patients’ voices to a call for a more collaborative research culture. Source: https://onlinelibrary.wiley.com/doi/full/10.1111/hex.12857
Latent Class Analysis of a Heterogeneous International Sample of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Kayla A. Huber, Madison Sunnquist, Leonard A. Jason
Abstract Background: Individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) routinely display differences in symptomatology, as well as illness course, onset, duration, and functional disability. Given such diversity, previous work has attempted to identify symptom-based ME/CFS subtypes. However, results have been inconsistent.
Purpose: This study sought to elucidate potential subtypes of ME/CFS as well as explore the impact of subtype membership on health functioning. Methods: Twelve non-core (i.e., less frequently endorsed) symptoms were included in a latent class analysis of 1,210 adults with ME/CFS. Demographic and illness-related predictors of class membership were evaluated with a multinomial logistic regression. ANOVAs were then performed to determine if there were significant differences across class on the eight subscales of the ShortForm Health Survey (SF-36). Results: A six-class solution was selected, which consisted of one class that was likely to endorse all non-core symptoms, one class that was unlikely to endorse any noncore symptoms, and four classes that were likely to endorse either one or two non-core symptom domains (i.e., circulatory/neuroendocrine impairment, orthostatic intolerance, and gastro-intestinal distress). Significant functioning differences by class were present for all SF-36 subscales.
Conclusions: These results are suggestive of subtypes of ME/CFS and, if replicated, may assist physicians in providing tailored treatment to patients and allow researchers to form more homogeneous samples. Source: HHS Public Access https://bit.ly/2kiHA1A
The IDO Metabolic Trap Hypothesis For The Etiology of ME/CFS
Alex A. Kashi , Ronald W. Davis and Robert D. Phair
Abstract Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating noncommunicable disease brandishing an enormous worldwide disease burden with some evidence of inherited genetic risk. Absence of measurable changes in patients’ standard blood work has necessitated ad hoc symptom-driven therapies and a dearth of mechanistic hypotheses regarding its etiology and possible cure. A new hypothesis, the indolamine-2,3-dioxygenase (IDO) metabolic trap, was developed and formulated as a mathematical model. The historical occurrence of ME/CFS outbreaks is a singular feature of the disease and implies that any predisposing genetic mutation must be common. A database search for common damaging mutations in human enzymes produces 208 hits, including IDO2 with four such mutations. Non-functional IDO2, combined with well-established substrate inhibition of IDO1 and kinetic asymmetry of the large neutral amino acid transporter, LAT1, yielded a mathematical model of tryptophan metabolism that displays both physiological and pathological steady-states. Escape from the pathological one requires an exogenous perturbation. This model also identifies a critical point in cytosolic tryptophan abundance beyond which descent into the pathological steady-state is inevitable. If, however, means can be discovered to return cytosolic tryptophan below the critical point, return to the normal physiological steady-state is assured. Testing this hypothesis for any cell type requires only labelled tryptophan, a means to measure cytosolic tryptophan and kynurenine, and the standard tools of tracer kinetics. Source: Diagnostics, https://www.mdpi.com/2075-4418/9/3/82 Open access. Full text: https://www.mdpi.com/2075-4418/9/3/82/htm
Diagnostic Sensitivity of 2-Day Cardiopulmonary Exercise Testing in ME/CFS Diagnostic sensitivity of 2-day cardiopulmonary exercise testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Maximillian J. Nelson, Jonathan D. Buckley, Rebecca L. Thomson, Daniel Clark, Richard Kwiatek & Kade Davison
Abstract Background There are no known objective biomarkers to assist with the diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A small number of studies have shown that ME/CFS patients exhibit an earlier onset of ventilatory threshold (VT) on the second of two cardiopulmonary exercise tests (CPET) performed on consecutive days. However, cut-off values which could be used to differentiate between ME/CFS patients have not been established.
Methods 16 ME/CFS patients and 10 healthy controls underwent CPET on a cycle-ergometer on 2-consecutive days. Heart rate (HR), ventilation, ratings of perceived exertion (RPE) and work rate (WR) were assessed on both days.
Results WR at VT decreased from day 1 to day 2 and by a greater magnitude in ME/CFS patients (p < 0.01 group × time interaction). No interaction effects were found for any other parameters. ROC curve analysis of the percentage change in WR at VT revealed decreases of − 6.3% to − 9.8% provided optimal sensitivity and specificity respectively for distinguishing between patients with ME/CFS and controls.
Conclusion The decrease in WR at VT of 6.3–9.8% on the 2nd day of consecutive-day CPET may represent an objective biomarker that can be used to assist with the diagnosis of ME/CFS. Source: BMC https://bit.ly/2YrHEya (open access)
From Pathophysiological Insights to Novel Therapeutic Opportunities Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: From Pathophysiological Insights to Novel Therapeutic Opportunities
Gerwyn Morris, Basant K. Puri, Adam J. Walker. Michael Maes, Andre F.Carvalho, Ken Walder, Catherine Mazza. Michael Berk
Abstract Myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) is a common and disabling condition with a paucity of effective and evidence-based therapies reflecting a major unmet need. Cognitive behavioural therapy and graded exercise are of modest benefit for only some ME/CFS patients, and many sufferers report aggravation of symptoms of fatigue with exercise. The presence of a multiplicity of pathophysiological abnormalities, in at least the subgroup of people with ME/CFS diagnosed with the current international consensus “Fukuda” criteria, points to numerous potential therapeutic targets. Such abnormalities include extensive data showing that at least a subgroup has a pro-inflammatory state, increased oxidative and nitrosative stress, disruption of gut mucosal barriers and mitochondrial dysfunction together with dysregulated bioenergetics. In this paper, these pathways are summarised, and data regarding promising therapeutic options that target these pathways are highlighted; they include coenzyme Q10, melatonin, curcumin, molecular hydrogen and N-acetylcysteine. These data are promising yet preliminary, suggesting hopeful avenues to address this major unmet burden of illness.
Source: Elsevier https://bit.ly/2lY9VuG, Paywall
The Development of the DePaul Symptom Questionnaire: Original, Expanded, Brief, and Pediatric Versions
Leonard A. Jason* and Madison Sunnquist - Center for Community Research, DePaul University, Chicago, IL, United States
One of the key requirements of a reliable case definition is the use of standardized procedures for assessing symptoms. This article chronicles the development of the DePaul Symptom Questionnaire (DSQ) to assess symptoms of the major chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME) case definitions.
The original questionnaire has been modified and expanded over time to more fully capture symptoms from various adult case definitions, and a brief as well as pediatric version have also been developed. The DSQ has demonstrated very good psychometric properties in terms of testretest reliability and sensitivity/specificity, as well as construct, predictive, and discriminant validity. The DSQ allows for a clear characterization of a patient’s illness and allows scientists and clinicians to improve diagnostic reliability and validity when employing case definitions of ME and CFS. Since 1994, many researchers have used the Fukuda et al. chronic fatigue syndrome (CFS) case definition to select cases, but problems emerged in part due to this case definition not requiring core symptoms of CFS .
In contrast, myalgic encephalomyelitis (ME) and CFS specialists have developed several adult case definitions that require essential symptoms of ME and CFS: the Canadian Consensus Criteria ME (CCC), the ME-International Consensus Criteria (ICC), and Systemic Exertion Intolerance Disease (SEID). These case definitions are a set of rules that allows investigators and clinicians to determine who has and who does not have an illness. In other words, the goals involve sensitivity (selecting those with the illness) and specificity (not selecting those without the illness).
Criterion variance represents the largest source of diagnostic unreliability for case definitions, and it involves specifying symptoms to classify patients’ symptoms into diagnostic categories . Criterion variance can occur when there are multiple case definitions without a consensus on which symptoms need to be manifested to arrive at a diagnosis. In addition, case definition unreliability occurs when there is no consensus on scoring rules that specify how to determine whether a particular symptom is severe enough to qualify as satisfying criteria for the case definition, or when symptoms are not assessed by standardized instruments.
These issues can result in investigators selecting samples of patients who are different on fundamental aspects of this illness. The consequences of these types of unreliability include difficulties replicating findings at different laboratories, estimating prevalence rates, identifying biomarkers, and determining effective treatments. ME and CFS case definitions have some overlapping and some different diagnostic criteria.
In spite of the fact that there are currently alternative case definitions, it is still important to develop standardized ways to measure the symptoms just as this has occurred with other illnesses. The National Institutes of Health/Centers for Disease Control and Prevention (NIH/CDC) Common Data Elements (CDE) working group has recently recommended a set of instruments to be used by researchers, and for baseline symptoms the working group recommended using either the DePaul Symptom Questionnaire (DSQ) or a combined instrument using both the CDC’s Symptom Inventory (SI) as well as items from the DSQ (even though the SI and DSQ differ on a number of dimensions, including the time period in which symptoms are measured and anchor points for the assessment of symptoms). Because of the recommendation for the use of the DSQ, this article reviews the genesis and psychometric properties of the different versions of the DSQ.
Source: https://bit.ly/2m0Yi6c Open access
Work Rehabilitation And Medical Retirement For Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients A Review and Appraisal of Diagnostic Strategies
by Mark Vink and Friso Vink-Niese Received: 7 June 2019 / Revised: 11 September 2019 / Accepted: 13 September 2019 / Published: 20 September 2019 (This article belongs to the Special Issue Biomedical Insights that Inform the Diagnosis of ME/CFS) https://bit.ly/2svVX3i
Abstract Myalgic Encephalomyelitis/Chronic Fatigue Syndrome leads to severe functional impairment and work disability in a considerable number of patients. The majority of patients who manage to continue or return to work, work parttime instead of full time in a physically less demanding job. The prognosis in terms of returning to work is poor if patients have been on longterm sick leave for more than two to three years. Being older and more ill when falling ill are associated with a worse employment outcome. Cognitive behavioral therapy and graded exercise therapy do not restore the ability to work. Consequently, many patients will eventually be medically retired depending on the requirements of the retirement policy, the progress that has been made since they have fallen ill in combination with the severity of their impairments compared to the sort of work they do or are offered to do. However, there is one thing that occupational health physicians and other doctors can do to try and prevent chronic and severe incapacity in the absence of effective treatments. Patients who are given a period of enforced rest from the onset, have the best prognosis. Moreover, those who work or go back to work should not be forced to do more than they can to try and prevent relapses, long-term sick leave and medical retirement.
Read the whole paper (open access) here: https://bit.ly/2mtq4sj
Brett A. Lidbury 1,*,Badia Kita 2,Alice M. Richardson 1,Donald P. Lewis 3,Edwina Privitera 3,Susan Hayward 4,David de Kretser 2,5 andMark Hedger 4
*
Diagnostics 2019, 9(3), 79; https://doi.org/10.3390/diagnostics9030079
Received: 28 May 2019 / Revised: 9 July 2019 / Accepted: 15 July 2019 / Published: 19 July 2019
(This article belongs to the Special Issue Biomedical Insights that Inform the Diagnosis of ME/CFS)
Abstract
Biomarker discovery applied to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disabling disease of inconclusive aetiology, has identified several cytokines to potentially fulfil a role as a quantitative blood/serum marker for laboratory diagnosis, with activin B a recent addition. We explored further the potential of serum activin B as a ME/CFS biomarker, alone and in combination with a range of routine test results obtained from pathology laboratories. Previous pilot study results showed that activin B was significantly elevated for the ME/CFS participants compared to healthy (control) participants. All the participants were recruited via CFS Discovery and assessed via the Canadian/International Consensus Criteria. A significant difference for serum activin B was also detected for ME/CFS and control cohorts recruited for this study, but median levels were significantly lower for the ME/CFS cohort. Random Forest (RF) modelling identified five routine pathology blood test markers that collectively predicted ME/CFS at ≥62% when compared via weighted standing time (WST) severity classes. A closer analysis revealed that the inclusion of activin B to the panel of pathology markers improved the prediction of mild to moderate ME/CFS cases. Applying correct WST class prediction from RFA modelling, new reference intervals were calculated for activin B and associated pathology markers, where 24-h urinary creatinine clearance, serum urea and serum activin B showed the best potential as diagnostic markers. While the serum activin B results remained statistically significant for the new participant cohorts, activin B was found to also have utility in enhancing the prediction of symptom severity, as represented by WST class.
Keywords: myalgic encephalomyelitis; chronic fatigue syndrome; activin; pathology; biomarker; cytokine; machine learning; reference intervals
Pathological Mechanisms Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Daniel Missailidis,Sarah J. Annesley andPaul R. Fisher *
Department of Physiology Anatomy and Microbiology, La Trobe University, VIC 3086, Australia
*
Diagnostics 2019, 9(3), 80; https://doi.org/10.3390/diagnostics9030080
Received: 18 June 2019 / Revised: 15 July 2019 / Accepted: 19 July 2019 / Published: 20 July 2019
Biomedical Insights that Inform the Diagnosis of ME/CFS)
Abstract
The underlying molecular basis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is not well understood. Characterized by chronic, unexplained fatigue, a disabling payback following exertion (“post-exertional malaise”), and variably presenting multi-system symptoms, ME/CFS is a complex disease, which demands a concerted biomedical investigation from disparate fields of expertise. ME/CFS research and patient treatment have been challenged by the lack of diagnostic biomarkers and finding these is a prominent direction of current work. Despite these challenges, modern research demonstrates a tangible biomedical basis for the disorder across many body systems. This evidence is mostly comprised of disturbances to immunological and inflammatory pathways, autonomic and neurological dysfunction, abnormalities in muscle and mitochondrial function, shifts in metabolism, and gut physiology or gut microbiota disturbances. It is possible that these threads are together entangled as parts of an underlying molecular pathology reflecting a far-reaching homeostatic shift. Due to the variability of non-overlapping symptom presentation or precipitating events, such as infection or other bodily stresses, the initiation of body-wide pathological cascades with similar outcomes stemming from different causes may be implicated in the condition. Patient stratification to account for this heterogeneity is therefore one important consideration during exploration of potential diagnostic developments.View Full-Text
Keywords: myalgic encephalomyelitis; chronic fatigue syndrome; ME/CFS; diagnosis; metabolism; mitochondria; inflammation; immune system; signaling; gut microbiota
Diagnostics 2019, 9(3), 82; https://doi.org/10.3390/diagnostics9030082
Article
The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS
Alex A. Kashi 1,Ronald W. Davis 1,2 andRobert D. Phair 3,*
Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USA
Departments of Biochemistry and Genetics, Stanford University, Stanford, CA 94305, USA
Integrative Bioinformatics Inc., Mountain View, CA 94041, USA
Received: 24 May 2019 / Accepted: 24 July 2019 / Published: 26 July 2019
Abstract
:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating noncommunicable disease brandishing an enormous worldwide disease burden with some evidence of inherited genetic risk. Absence of measurable changes in patients’ standard blood work has necessitated ad hoc symptom-driven therapies and a dearth of mechanistic hypotheses regarding its etiology and possible cure. A new hypothesis, the indolamine-2,3-dioxygenase (IDO) metabolic trap, was developed and formulated as a mathematical model. The historical occurrence of ME/CFS outbreaks is a singular feature of the disease and implies that any predisposing genetic mutation must be common. A database search for common damaging mutations in human enzymes produces 208 hits, including IDO2 with four such mutations. Non-functional IDO2, combined with well-established substrate inhibition of IDO1 and kinetic asymmetry of the large neutral amino acid transporter, LAT1, yielded a mathematical model of tryptophan metabolism that displays both physiological and pathological steady-states. Escape from the pathological one requires an exogenous perturbation. This model also identifies a critical point in cytosolic tryptophan abundance beyond which descent into the pathological steady-state is inevitable. If, however, means can be discovered to return cytosolic tryptophan below the critical point, return to the normal physiological steady-state is assured. Testing this hypothesis for any cell type requires only labelled tryptophan, a means to measure cytosolic tryptophan and kynurenine, and the standard tools of tracer kinetics.
Keywords:
tryptophan metabolism; indoleamine-2,3-dioxygenase; bistability; kynurenine pathway; substrate inhibition; myalgic encephalomyelitis; chronic fatigue syndrome; mathematical model; critical point
Diagnostics 2019, 9(3), 70; https://doi.org/10.3390/diagnostics9030070
Article
Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases
Neil R. McGregor 1,*,Christopher W. Armstrong 2,Donald P. Lewis 3 andPaul R. Gooley 2
Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville VIC
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biochemistry Institute, 30 Flemington Road, Parkville VIC 3010, Australia
CFS Discovery, Donvale Medical Centre, Donvale VIC 3111, Australia
Received: 17 June 2019 / Accepted: 2 July 2019 / Published: 4 July 2019
Abstract
Post-exertional malaise (PEM) is a cardinal predictive symptom in the definition of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). If the cases overexert themselves they have what is termed “payback” resulting in a worsening of symptoms or relapse which can last for days, weeks or even months. The aim was to assess the changes in biochemistry associated with the cases self-reported PEM scores over a 7-day period and the frequency of reporting over a 12-month period. Forty-seven ME/CFS cases and age/sex-matched controls had a clinical examination, completed questionnaires; were subjected to standard serum biochemistry; had their serum and urine metabolomes analyzed in an observational study. Thirty-five of the 46 ME/CFS cases reported PEM in the last 7-days and these were allocated to the PEM group. The principal biochemical change related to the 7-day severity of PEM was the fall in the purine metabolite, hypoxanthine. This decrease correlated with alterations in the glucose:lactate ratio highly suggestive of a glycolytic anomaly. Increased excretion of urine metabolites within the 7-day response period indicated a hypermetabolic event was occurring. Increases in urine excretion of methylhistidine (muscle protein degradation), mannitol (intestinal barrier deregulation) and acetate were noted with the hypermetabolic event. These data indicate hypoacetylation was occurring, which may also be related to deregulation of multiple cytoplasmic enzymes and DNA histone regulation. These findings suggest the primary events associated with PEM were due to hypoacetylation and metabolite loss during the acute PEM response.
Human Microbiome Journal Volume 13, August 2019, 100061
A retrospective outcome study of 42 patients with Chronic Fatigue Syndrome, 30 of whom had Irritable Bowel Syndrome. Half were treated with oral approaches, and half were treated with Faecal Microbiome Transplantation
J.N.Kenyona ShellyCoeb HooshangIzadib
Abstract
The gut microbiome comprises the community of microorganisms in the intestinal tract. Research suggests that an altered microbiome may play a role in a wide range of disorders including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Methods
42 participants with ME/CFS with Irritable Bowel Syndrome (IBS) were allocated into one of two groups, 21 were treated with standard oral approaches, which centred around various nutritional remedies, probiotics, prebiotics, dietary advice and lifestyle advice. The second group who had mostly failed using oral approaches, were treated with Faecal Microbiome Transplantation (FMT). Each patient received 10 Implants, each from a different screened donor, and the Implants were processed under anaerobic conditions. The transplant is delivered via a paediatric rectal catheter, which is inserted through the anus to reach the lower part of the sigmoid colon.
The results were assessed on a percentage basis before and after treatment, 0% being no improvement, 100% being maximum improvement. An exact non-parametric Mann-Whitney (one-tailed) test was used to compare medians from those on FMT compared with those receiving oral approaches only. On clinical experience over many years, the only way to judge improvement in Chronic Fatigue Syndrome as there is no test for Chronic Fatigue Syndrome, is my clinical assessment.
Results
The median for the FMT group was found to be significantly higher compared to the oral treatment group (Mann-Whitney U = 111.5, p = .003). Therefore, the FMT group improved to a greater extent (z = −2.761).
Conclusion
This study shows that FMT is a safe and a promising treatment for CFS associated with IBS. Adequately powered randomised controlled trials should be carried out to assess the effectiveness of FMT in patients with CFS and IBS.
Mitochondrial alterations in NK lymphocytes from ME/CFS patients
Isabel Barao Silvestre, Raul Y Dagda, Ruben K Dagda and Victor Darley-Usmar
J Immunol May 1, 2019, 202 (1 Supplement) 126.39;
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by profound fatigue, flu-like symptoms, trouble concentrating, and autonomic problems, all of which worsen after exertion. ME/CFS patients have impaired natural killer (NK) cell activity. NK lymphocytes are a critical first defense against viruses and cancer. ME/CFS patients have difficulties controlling viral infections and many develop non-Hodgkin’s lymphoma. Mitochondrial metabolism is crucial for immune cell function. Mitochondria dysfunction has been previously reported in ME/CFS, but it is not known whether the NK cells of these patients have altered mitochondrial metabolism that affect their activity and contribute to ME/CFS pathogenesis. More importantly, there is currently no efficient method to diagnose ME/CFS or assess efficacy of therapeutic interventions. The Bioenergetic Health Index (BHI) has been developed as promising and reliable surrogate readout of human health by measuring the bioenergetic status of immune cells. Variations in bioenergetic function in patient’s immune cells can reflect both metabolic stress and the mutable role of these cells in ME/CFS immunity and pathogenesis. In our study, we observed that the two main energy-generating mitochondrial pathways, oxidative phosphorylation and glycolysis (bioenergetics parameters), are deregulated in ME/CFS NK cells and in PBMCs. Moreover, we observed alterations in the morphology and membrane potential of the mitochondria of NK cells. These mitochondrial features can affect NK cell function and contribute to the severity of disease. To date, this is the first metabolism assessment of NK cells in ME/CFS and as potential new diagnostic tool for the disease.
• J-STAGE home Biological and Pharmaceutical ...Volume 42 (2019) Issue 7
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Induced by Repeated Forced Swimming in Mice
Takuya Ohba, Shinichi Domoto, Miyu Tanaka, Shinsuke Nakamura, Masamitsu Shimazawa, Hideaki Hara
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by disabling fatigue of at least 6 months, in addition to symptoms such as muscle pain and muscle weakness. There is no treatment provides long-term benefits to most patients. Recently, clinical research suggested the involvement of pyruvate dehydrogenase (PDH) in ME/CFS. PDH is a crucial enzyme in the mitochondria matrix that links glycolysis to the tricarboxylic acid cycle and oxidative phosphorylation. However, it is little known whether PDH could be a therapeutic target. The purpose of this study was to establish ME/CFS in mice and to investigate the involvement of PDH in ME/CFS. To induce the chronic fatigue in mice, a repeated forced swimming test was conducted. To evaluate fatigue, we measured immobility time in forced swimming test and starting time of grooming. An open field test was conducted on day 8. After 25 d of the forced swimming test, the mitochondrial fraction in gastrocnemius muscle was isolated and PDH activity was measured. Moreover, we evaluated the effect of PDH activation by administering sodium dichloroacetate (DCA). In ME/CFS mice group, the immobility time and starting time of grooming increased time-dependently. In addition, the moved distance was decreased in ME/CFS mice. PDH activity was decreased in the mitochondrial fraction of the gastrocnemius muscle of the forced swimming group. DCA treatment may be beneficial in preventing fatigue-like behavior in ME/CFS. These findings indicate that ME/CFS model was established in mice and that a decrease in mitochondrial PDH activity is involved with the symptom of ME/CFS.
Assessing cellular energy dysfunction in CFS/ME using a commercially available laboratory test
Scientific Reportsvolume 9, Article number: 11464 (2019) |
Abstract The mitochondrial energy score (MES) protocol, developed by the Myhill group, is marketed as a diagnostic test for chronic fatigue syndrome/Myalgic Encephalomyelitis (CFS/ME). This study assessed the reliability and reproducibility of the test, currently provided by private clinics, to assess its potential to be developed as an NHS accredited laboratory test. We replicated the MES protocol using neutrophils and peripheral blood mononuclear cells (PBMCs) from CFS/ME patients (10) and healthy controls (13). The protocol was then repeated in PBMCs and neutrophils from healthy controls to investigate the effect of delayed sample processing time used by the Myhill group. Experiments using the established protocol showed no differences between CFS/ME patients and healthy controls in any of the components of the MES (p ≥ 0.059). Delaying blood sample processing by 24 hours (well within the 72 hour time frame quoted by the Myhill group) significantly altered many of the parameters used to calculate the MES in both neutrophils and PBMCs. The MES test does not have the reliability and reproducibility required of a diagnostic test and therefore should not currently be offered as a diagnostic test for CFS/ME. The differences observed by the Myhill group may be down to differences in sample processing time between cohorts.
Diagnostics 2019, 9(3), 91; https://doi.org/10.3390/diagnostics9030091
Review
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Comprehensive Review
by Mateo Cortes Rivera 1,*,Claudio Mastronardi 2,Claudia T. Silva-Aldana 3,Mauricio Arcos-Burgos 4 andBrett A. Lidbury
Facultad de Medicina, Grupo de Investigación Neuros, Universidad del Rosario, Bogotá 110211, Colombia INPAC Research Group, Fundación Universitaria Sanitas, Bogotá 110211, Colombia Center for Research in Genetics and Genomics-CIGGUR, GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 110211, Colombia Group de Investigación en Psiquiatría (GIPSI), Instituto de Investigaciones Médicas, Facultad de Medicina, Universidad de Antioquia, Medellín 050002, Colombia The National Centre for Epidemiology and Population Health, RSPH, College of Health and Medicine, The Australian National University, Canberra ACT 2601, Australia
Received: 22 May 2019 / Accepted: 15 July 2019 / Published: 7 August 2019
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown aetiology that is recognized by the World Health Organization (WHO) and the United States Center for Disease Control and Prevention (US CDC) as a disorder of the brain. The disease predominantly affects adults, with a peak age of onset of between 20 and 45 years with a female to male ratio of 3:1. Although the clinical features of the disease have been well established within diagnostic criteria, the diagnosis of ME/CFS is still of exclusion, meaning that other medical conditions must be ruled out. The pathophysiological mechanisms are unclear but the neuro-immuno-endocrinological pattern of CFS patients gleaned from various studies indicates that these three pillars may be the key point to understand the complexity of the disease. At the moment, there are no specific pharmacological therapies to treat the disease, but several studies’ aims and therapeutic approaches have been described in order to benefit patients’ prognosis, symptomatology relief, and the recovery of pre-existing function. This review presents a pathophysiological approach to understanding the essential concepts of ME/CFS, with an emphasis on the population, clinical, and genetic concepts associated with ME/CFS.
Front. Immunol., 14 August 2019 | https://doi.org/10.3389/fimmu.2019.01946
Antibodies to Human Herpesviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients
Jonas Blomberg1†, Muhammad Rizwan1, Agnes Böhlin-Wiener1‡, Amal Elfaitouri2, Per Julin3,4, Olof Zachrisson5, Anders Rosén6* and Carl-Gerhard Gottfries5
- 1Section of Clinical Microbiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
- 2Department of Infectious Disease and Tropical Medicine, Faculty of Public Health, Benghazi University, Benghazi, Libya
- 3Neurological Rehabilitation Clinic, Stora Sköndal, Sköndal, Sweden
- 4Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
- 5Gottfries Clinic AB, Mölndal, Sweden
- 6Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
Ehlers-Danlos syndromes
BMJ 2019; 366 doi: https://doi.org/10.1136/bmj.l4966 (Published 18 September 2019)Cite this as: BMJ 2019;366:l4966
- Neeti Ghali, consultant clinical geneticist1,
- Glenda Sobey, consultant dermatologist and clinical lead2,
- Nigel Burrows, consultant dermatologist3
What you need to know
- Ehlers-Danlos syndromes (EDS) are inherited connective tissue disorders with variable severity; features include skin fragility, joint hypermobility, and rupture of blood vessels and internal organs
- Consider the diagnosis of an EDS subtype in patients with any combination of easy bruising, poor scar formation, hyperextensible skin, joint hypermobility, joint pains without evidence of arthritis, and unexplained arterial or bowel rupture
- Joint hypermobility alone is not enough to diagnose an EDS subtype, and not all types of EDS have pronounced hypermobility
- Thirteen different types of EDS are currently recognised, with the molecular basis known in all except for hypermobile EDS
- Genetic testing is recommended for EDS types with a known molecular cause to confirm the diagnosis.
This article is intended to support non-specialist clinicians to consider the diagnosis of this group of conditions in appropriate patients. It discusses the features of the different types of EDS and explains how clinicians can expect their patients to be managed in secondary care.
How this article was created
The authors are members of the International Consortium on Ehlers-Danlos Syndromes and Related Disorders and participated in literature searches used for the basis of the articles written on the new classification of EDS published in 2017. The authors have more than 10 years’ experience of EDS patient consultations and data collection in the highly specialised EDS service.
Chronic exposure to insufficient sleep alters processes of pain habituation and sensitization
Simpson, Norah S.a; Scott-Sutherland, Jenniferb; Gautam, Shivac; Sethna, Navild; Haack, Monikab,*
PAIN: January 2018 - Volume 159 - Issue 1 - p 33–40
doi: 10.1097/j.pain.0000000000001053
Abstract
Chronic pain conditions are highly comorbid with insufficient sleep. While the mechanistic relationships between the 2 are not understood, chronic insufficient sleep may be 1 pathway through which central pain-modulatory circuits deteriorate, thereby contributing to chronic pain vulnerability over time. To test this hypothesis, an in-laboratory model of 3 weeks of restricted sleep with limited recovery (5 nights of 4-hour sleep per night followed by 2 nights of 8-hour sleep per night) was compared with 3 weeks of 8-hour sleep per night (control protocol). Seventeen healthy adults participated, with 14 completing both 3-week protocols. Measures of spontaneous pain, heat-pain thresholds, cold-pain tolerance (measuring habituation to cold over several weeks), and temporal summation of pain (examining the slope of pain ratings during cold water immersion) were assessed at multiple points during each protocol. Compared with the control protocol, participants in the sleep-restriction protocol experienced mild increases in spontaneous pain (P < 0.05). Heat-pain thresholds decreased after the first week of sleep restriction (P < 0.05) but normalized with longer exposure to sleep restriction. By contrast, chronic exposure to restricted sleep was associated with decreased habituation to, and increased temporal summation in response to cold pain (both P < 0.05), although only in the past 2 weeks of the sleep-restriction protocol. These changes may reflect abnormalities in central pain-modulatory processes. Limited recovery sleep did not completely resolve these alterations in pain-modulatory processes, indicating that more extensive recovery sleep is required. Results suggest that exposure to chronic insufficient sleep may increase vulnerability to chronic pain by altering processes of pain habituation and sensitization.
Pain-modulatory processes deteriorate with more chronic forms of sleep insufficiency and a couple of nights with limited recovery sleep do not resolve alterations.
Corresponding author. Address: 330 Brookline Ave, Dana 779, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Tel.: 617-667-5234. E-mail address: [email protected] (M. Haack).
© 2018 International Association for the Study of Pain
BMJ Open Sport Exerc Med. 2019 Jun 20;5(1):e000542. doi: 10.1136/bmjsem-2019-000542. eCollection 2019.
Novel insights of overtraining syndrome discovered from the EROS study.
Cadegiani FA1, Kater CE1.
Author information
Endocrinology, Universidade Federal de Sao Paulo, Sao Paulo, Brazil.
Abstract
BACKGROUND:
Excessive training and inadequate recovery could cause 'overtraining syndrome' (OTS), which is characterised by underperformance and fatigue. The pathophysiology of OTS is unclear. We aimed to describe novel mechanisms and risk factors associated with OTS, and thereby facilitate its early identification and prevention, from a comprehensive joint qualitative analysis of the findings from all the four arms of the Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study.
METHODS:
We compared the types and proportions of behavioural patterns of 67 evaluated parameters of OTS from 51 participants-athletes with OTS (OTS, n=14), healthy athletes (n=25) and healthy non-physically active controls (n=12). We performed overall and pairwise comparisons for statistically significant differences between the three groups (p<0.05).
RESULTS:
A total of 44 (65.7%) markers exhibited significant differences between the three groups: 32 (72.7%) showed a loss of the conditioning effect of exercise ('deconditioning'), 7 (15.9%) showed changes exclusive to OTS, 3 (6.8%) maintained the exercise-induced conditioning effects and 2 (4.5%) revealed an exacerbation of the adaptive changes to exercises.
CONCLUSION:
Our findings suggest that OTS is likely triggered by multiple factors, not restricted to excessive training, resulted from a chronic energy deprivation, leading to multiple losses in the conditioning processes typically observed in healthy athletes, as a combination of 'paradoxical deconditioning' processes, which explains the gradual and marked loss of physical conditioning found in OTS. We, therefore, suggest that the term 'paradoxical deconditioning syndrome' better represents the features of this syndrome.
KEYWORDS:
fatigue; hormones; overtraining syndrome; paradoxical deconditioning syndrome; sports endocrinology; sports performance
Hope, disappointment and perseverance: Reflections of people with Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Multiple Sclerosis participating in biomedical research.
Eliana Lacerda PhD, Clare McDermott PhD, Caroline C. Kingdon MSc, Jack Butterworth BA, Jacqueline M. Cliff PhD, Luis Nacul PhD
The Clinical Understanding and Research Excellence in ME/CFS group (CureME) at the London School of Hygiene & Tropical Medicine has supported and undertaken studies in immunology, genetics, virology, clinical medicine, epidemiology and disability. It established the UK ME/CFS Biobank (UKMEB), which stores data and samples from three groups: participants with ME/CFS, Multiple Sclerosis (MS) and healthy controls. Patient and public involvement have played a central role from its inception.
Aim To explore the views of participants with ME/CFS and MS on CureME research findings, dissemination and future biomedical research priorities. Method Five ME/CFS and MS focus groups were conducted at two UK sites. Discussions were transcribed and analysed thematically.
Results A total of 28 UKMEB participants took part: 16 with ME/CFS and 12 with MS. Five themes emerged: (a) Seeking coherence: participants’ reactions to initial research findings; (b) Seeking acceptance: participants explore issues of stigma and validation; (c) Seeking a diagnosis: participants explore issues around diagnosis in their lives; (d) Seeking a better future: participants’ ideas on future research; and (e) Seeking to share understanding: participants’ views on dissemination. Focus groups perceived progress in ME/CFS and MS research in terms of “putting together a jigsaw” of evidence through perseverance and collaboration. Conclusion This study provides insight into the emotional, social and practical importance of research to people with MS and ME/CFS, suggesting a range of research topics for the future. Findings should inform biomedical research directions in ME/CFS and MS, adding patients’ voices to a call for a more collaborative research culture. Source: https://onlinelibrary.wiley.com/doi/full/10.1111/hex.12857
Latent Class Analysis of a Heterogeneous International Sample of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Kayla A. Huber, Madison Sunnquist, Leonard A. Jason
Abstract Background: Individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) routinely display differences in symptomatology, as well as illness course, onset, duration, and functional disability. Given such diversity, previous work has attempted to identify symptom-based ME/CFS subtypes. However, results have been inconsistent.
Purpose: This study sought to elucidate potential subtypes of ME/CFS as well as explore the impact of subtype membership on health functioning. Methods: Twelve non-core (i.e., less frequently endorsed) symptoms were included in a latent class analysis of 1,210 adults with ME/CFS. Demographic and illness-related predictors of class membership were evaluated with a multinomial logistic regression. ANOVAs were then performed to determine if there were significant differences across class on the eight subscales of the ShortForm Health Survey (SF-36). Results: A six-class solution was selected, which consisted of one class that was likely to endorse all non-core symptoms, one class that was unlikely to endorse any noncore symptoms, and four classes that were likely to endorse either one or two non-core symptom domains (i.e., circulatory/neuroendocrine impairment, orthostatic intolerance, and gastro-intestinal distress). Significant functioning differences by class were present for all SF-36 subscales.
Conclusions: These results are suggestive of subtypes of ME/CFS and, if replicated, may assist physicians in providing tailored treatment to patients and allow researchers to form more homogeneous samples. Source: HHS Public Access https://bit.ly/2kiHA1A
The IDO Metabolic Trap Hypothesis For The Etiology of ME/CFS
Alex A. Kashi , Ronald W. Davis and Robert D. Phair
Abstract Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating noncommunicable disease brandishing an enormous worldwide disease burden with some evidence of inherited genetic risk. Absence of measurable changes in patients’ standard blood work has necessitated ad hoc symptom-driven therapies and a dearth of mechanistic hypotheses regarding its etiology and possible cure. A new hypothesis, the indolamine-2,3-dioxygenase (IDO) metabolic trap, was developed and formulated as a mathematical model. The historical occurrence of ME/CFS outbreaks is a singular feature of the disease and implies that any predisposing genetic mutation must be common. A database search for common damaging mutations in human enzymes produces 208 hits, including IDO2 with four such mutations. Non-functional IDO2, combined with well-established substrate inhibition of IDO1 and kinetic asymmetry of the large neutral amino acid transporter, LAT1, yielded a mathematical model of tryptophan metabolism that displays both physiological and pathological steady-states. Escape from the pathological one requires an exogenous perturbation. This model also identifies a critical point in cytosolic tryptophan abundance beyond which descent into the pathological steady-state is inevitable. If, however, means can be discovered to return cytosolic tryptophan below the critical point, return to the normal physiological steady-state is assured. Testing this hypothesis for any cell type requires only labelled tryptophan, a means to measure cytosolic tryptophan and kynurenine, and the standard tools of tracer kinetics. Source: Diagnostics, https://www.mdpi.com/2075-4418/9/3/82 Open access. Full text: https://www.mdpi.com/2075-4418/9/3/82/htm
Diagnostic Sensitivity of 2-Day Cardiopulmonary Exercise Testing in ME/CFS Diagnostic sensitivity of 2-day cardiopulmonary exercise testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Maximillian J. Nelson, Jonathan D. Buckley, Rebecca L. Thomson, Daniel Clark, Richard Kwiatek & Kade Davison
Abstract Background There are no known objective biomarkers to assist with the diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A small number of studies have shown that ME/CFS patients exhibit an earlier onset of ventilatory threshold (VT) on the second of two cardiopulmonary exercise tests (CPET) performed on consecutive days. However, cut-off values which could be used to differentiate between ME/CFS patients have not been established.
Methods 16 ME/CFS patients and 10 healthy controls underwent CPET on a cycle-ergometer on 2-consecutive days. Heart rate (HR), ventilation, ratings of perceived exertion (RPE) and work rate (WR) were assessed on both days.
Results WR at VT decreased from day 1 to day 2 and by a greater magnitude in ME/CFS patients (p < 0.01 group × time interaction). No interaction effects were found for any other parameters. ROC curve analysis of the percentage change in WR at VT revealed decreases of − 6.3% to − 9.8% provided optimal sensitivity and specificity respectively for distinguishing between patients with ME/CFS and controls.
Conclusion The decrease in WR at VT of 6.3–9.8% on the 2nd day of consecutive-day CPET may represent an objective biomarker that can be used to assist with the diagnosis of ME/CFS. Source: BMC https://bit.ly/2YrHEya (open access)
From Pathophysiological Insights to Novel Therapeutic Opportunities Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: From Pathophysiological Insights to Novel Therapeutic Opportunities
Gerwyn Morris, Basant K. Puri, Adam J. Walker. Michael Maes, Andre F.Carvalho, Ken Walder, Catherine Mazza. Michael Berk
Abstract Myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) is a common and disabling condition with a paucity of effective and evidence-based therapies reflecting a major unmet need. Cognitive behavioural therapy and graded exercise are of modest benefit for only some ME/CFS patients, and many sufferers report aggravation of symptoms of fatigue with exercise. The presence of a multiplicity of pathophysiological abnormalities, in at least the subgroup of people with ME/CFS diagnosed with the current international consensus “Fukuda” criteria, points to numerous potential therapeutic targets. Such abnormalities include extensive data showing that at least a subgroup has a pro-inflammatory state, increased oxidative and nitrosative stress, disruption of gut mucosal barriers and mitochondrial dysfunction together with dysregulated bioenergetics. In this paper, these pathways are summarised, and data regarding promising therapeutic options that target these pathways are highlighted; they include coenzyme Q10, melatonin, curcumin, molecular hydrogen and N-acetylcysteine. These data are promising yet preliminary, suggesting hopeful avenues to address this major unmet burden of illness.
Source: Elsevier https://bit.ly/2lY9VuG, Paywall
The Development of the DePaul Symptom Questionnaire: Original, Expanded, Brief, and Pediatric Versions
Leonard A. Jason* and Madison Sunnquist - Center for Community Research, DePaul University, Chicago, IL, United States
One of the key requirements of a reliable case definition is the use of standardized procedures for assessing symptoms. This article chronicles the development of the DePaul Symptom Questionnaire (DSQ) to assess symptoms of the major chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME) case definitions.
The original questionnaire has been modified and expanded over time to more fully capture symptoms from various adult case definitions, and a brief as well as pediatric version have also been developed. The DSQ has demonstrated very good psychometric properties in terms of testretest reliability and sensitivity/specificity, as well as construct, predictive, and discriminant validity. The DSQ allows for a clear characterization of a patient’s illness and allows scientists and clinicians to improve diagnostic reliability and validity when employing case definitions of ME and CFS. Since 1994, many researchers have used the Fukuda et al. chronic fatigue syndrome (CFS) case definition to select cases, but problems emerged in part due to this case definition not requiring core symptoms of CFS .
In contrast, myalgic encephalomyelitis (ME) and CFS specialists have developed several adult case definitions that require essential symptoms of ME and CFS: the Canadian Consensus Criteria ME (CCC), the ME-International Consensus Criteria (ICC), and Systemic Exertion Intolerance Disease (SEID). These case definitions are a set of rules that allows investigators and clinicians to determine who has and who does not have an illness. In other words, the goals involve sensitivity (selecting those with the illness) and specificity (not selecting those without the illness).
Criterion variance represents the largest source of diagnostic unreliability for case definitions, and it involves specifying symptoms to classify patients’ symptoms into diagnostic categories . Criterion variance can occur when there are multiple case definitions without a consensus on which symptoms need to be manifested to arrive at a diagnosis. In addition, case definition unreliability occurs when there is no consensus on scoring rules that specify how to determine whether a particular symptom is severe enough to qualify as satisfying criteria for the case definition, or when symptoms are not assessed by standardized instruments.
These issues can result in investigators selecting samples of patients who are different on fundamental aspects of this illness. The consequences of these types of unreliability include difficulties replicating findings at different laboratories, estimating prevalence rates, identifying biomarkers, and determining effective treatments. ME and CFS case definitions have some overlapping and some different diagnostic criteria.
In spite of the fact that there are currently alternative case definitions, it is still important to develop standardized ways to measure the symptoms just as this has occurred with other illnesses. The National Institutes of Health/Centers for Disease Control and Prevention (NIH/CDC) Common Data Elements (CDE) working group has recently recommended a set of instruments to be used by researchers, and for baseline symptoms the working group recommended using either the DePaul Symptom Questionnaire (DSQ) or a combined instrument using both the CDC’s Symptom Inventory (SI) as well as items from the DSQ (even though the SI and DSQ differ on a number of dimensions, including the time period in which symptoms are measured and anchor points for the assessment of symptoms). Because of the recommendation for the use of the DSQ, this article reviews the genesis and psychometric properties of the different versions of the DSQ.
Source: https://bit.ly/2m0Yi6c Open access
Work Rehabilitation And Medical Retirement For Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients A Review and Appraisal of Diagnostic Strategies
by Mark Vink and Friso Vink-Niese Received: 7 June 2019 / Revised: 11 September 2019 / Accepted: 13 September 2019 / Published: 20 September 2019 (This article belongs to the Special Issue Biomedical Insights that Inform the Diagnosis of ME/CFS) https://bit.ly/2svVX3i
Abstract Myalgic Encephalomyelitis/Chronic Fatigue Syndrome leads to severe functional impairment and work disability in a considerable number of patients. The majority of patients who manage to continue or return to work, work parttime instead of full time in a physically less demanding job. The prognosis in terms of returning to work is poor if patients have been on longterm sick leave for more than two to three years. Being older and more ill when falling ill are associated with a worse employment outcome. Cognitive behavioral therapy and graded exercise therapy do not restore the ability to work. Consequently, many patients will eventually be medically retired depending on the requirements of the retirement policy, the progress that has been made since they have fallen ill in combination with the severity of their impairments compared to the sort of work they do or are offered to do. However, there is one thing that occupational health physicians and other doctors can do to try and prevent chronic and severe incapacity in the absence of effective treatments. Patients who are given a period of enforced rest from the onset, have the best prognosis. Moreover, those who work or go back to work should not be forced to do more than they can to try and prevent relapses, long-term sick leave and medical retirement.
Read the whole paper (open access) here: https://bit.ly/2mtq4sj
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