Special Issue "Biomedical Insights that Inform the Diagnosis of ME/CFS"

A special issue of Diagnostics (ISSN 2075-4418). This special issue belongs to the section "Pathology and Molecular Diagnostics".

Deadline for manuscript submissions: closed (31 May 2019).

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A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Brett Lidbury
Website
Guest Editor
Associate Professor, The National Centre for Epidemiology and Population Health, Research School of Population Health, College of Health and Medicine, The Australian National University, Canberra, Australia
Interests: infectious disease; pathology; machine learning; statistics; biomarkers; pattern recognition
Prof. Paul Fisher
Website
Guest Editor
Discipline of Microbiology, Department of Physiology Anatomy and Microbiology, School of Life Sciences, College of Science Health and Engineering, La Trobe University, Melbourne, Australia
Interests: mitochondrial biology and disease; neurodegenerative disease; AMPK; TOR complex I; cellular stress signalling
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Special Issue Information

Dear Colleagues,

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe, chronic health condition that is often misunderstood or ignored by the health establishment. The lack of definitive diagnostic markers that are used to separate ME/CFS patients from the healthy population, as well as from other chronic disorders, is problematic for both health professionals and researchers.

A consortium of Australian researchers have come together to understand ME/CFS systematically, ranging from a deep analysis of clinical and pathology data, to metabolomic profiles and the investigation of mitochondrial function. From this broad collaboration, a number of compelling insights have arisen that may form the basis of specific serum, blood, and/or urinary biomarkers of ME/CFS.

This Special Edition reports on a conference centred on these biomedical discoveries, and on the translation of these results into tangible, quantitative, and predictive markers, which could diagnose ME/CFS. The conference invites contributions from a range of international collaborators and colleagues, with the aim of sharing the latest results to allow for, as quickly as possible, the identification of disease marker patterns in order to elucidate the underlying biological mechanisms of ME/CFS. It is hoped that by supporting health professionals with developments in diagnostics for this condition, the patients and their families will benefit from an improved recognition of the biomedical underpinnings of the condition, and will be better able to access the care that is urgently required.

The Special Edition contains all of the speaker submissions and other accepted manuscripts contributing to our objective for Biomedical Insights that Inform the Diagnosis of ME/CFS.

ME/CFS. The biological basis, diagnosis, treatment, and management.

International Research Symposium

12–15 March 2019, Australia.

Proudly hosted by Emerge Australia

www.emerge.org.au/symposium

Dr. Brett Lidbury
Professor Paul Fisher
Guest editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Diagnostics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1400 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (11 papers)

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Editorial

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Open AccessEditorial
Biomedical Insights That Inform the Diagnosis of ME/CFS
Diagnostics 2020, 10(2), 92; https://doi.org/10.3390/diagnostics10020092 - 08 Feb 2020
Abstract
It is well known that myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS), whether considered as separate diseases or as the one chronic syndrome, continue to generate debate [...] Full article

Research

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Open AccessArticle
The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS
Diagnostics 2019, 9(3), 82; https://doi.org/10.3390/diagnostics9030082 - 26 Jul 2019
Cited by 1
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 [...] Read more.
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. Full article
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Open AccessArticle
Rethinking ME/CFS Diagnostic Reference Intervals via Machine Learning, and the Utility of Activin B for Defining Symptom Severity
Diagnostics 2019, 9(3), 79; https://doi.org/10.3390/diagnostics9030079 - 19 Jul 2019
Cited by 3
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 [...] Read more.
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. Full article
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Open AccessArticle
Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases
Diagnostics 2019, 9(3), 70; https://doi.org/10.3390/diagnostics9030070 - 04 Jul 2019
Cited by 2
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 [...] Read more.
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. Full article
Open AccessArticle
Evidence of Clinical Pathology Abnormalities in People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) from an Analytic Cross-Sectional Study
Diagnostics 2019, 9(2), 41; https://doi.org/10.3390/diagnostics9020041 - 10 Apr 2019
Cited by 7
Abstract
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 [...] Read more.
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. Full article
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Open AccessArticle
Assessment of Post-Exertional Malaise (PEM) in Patients with Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS): A Patient-Driven Survey
Diagnostics 2019, 9(1), 26; https://doi.org/10.3390/diagnostics9010026 - 02 Mar 2019
Cited by 3
Abstract
Considerable controversy has existed with efforts to assess post-exertional malaise (PEM), which is one of the defining features of myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). While a number of self-report questionnaires have been developed to assess this symptom, none have been [...] Read more.
Considerable controversy has existed with efforts to assess post-exertional malaise (PEM), which is one of the defining features of myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). While a number of self-report questionnaires have been developed to assess this symptom, none have been comprehensive, and a recent federal government report has recommended the development of a new PEM measure. The current study involved a community-based participatory research process in an effort to develop a comprehensive PEM instrument, with critical patient input shaping the item selection and overall design of the tool. A survey was ultimately developed and was subsequently completed by 1534 members of the patient community. The findings of this survey suggest that there are key domains of this symptom, including triggers, symptom onset, and duration, which have often not been comprehensively assessed in a previous PEM instrument. This study indicates that there are unique benefits that can be derived from patients collaborating with researchers in the measurement of key symptoms defining ME and CFS. Full article

Review

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Open AccessReview
Work Rehabilitation and Medical Retirement for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. A Review and Appraisal of Diagnostic Strategies
Diagnostics 2019, 9(4), 124; https://doi.org/10.3390/diagnostics9040124 - 20 Sep 2019
Cited by 1
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 part-time instead of full time in a physically less demanding job. The [...] Read more.
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 part-time 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 long-term 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 behavioural 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. Full article
Open AccessReview
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Comprehensive Review
Diagnostics 2019, 9(3), 91; https://doi.org/10.3390/diagnostics9030091 - 07 Aug 2019
Cited by 5
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 [...] Read more.
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. Full article
Open AccessReview
Pathological Mechanisms Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Diagnostics 2019, 9(3), 80; https://doi.org/10.3390/diagnostics9030080 - 20 Jul 2019
Cited by 5
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 [...] Read more.
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. Full article

Other

Open AccessCommentary
Current Research Provides Insight into the Biological Basis and Diagnostic Potential for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Diagnostics 2019, 9(3), 73; https://doi.org/10.3390/diagnostics9030073 - 10 Jul 2019
Cited by 3
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe fatigue illness that occurs most commonly following a viral infection, but other physiological triggers are also implicated. It has a profound long-term impact on the life of the affected person. ME/CFS is diagnosed primarily by [...] Read more.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe fatigue illness that occurs most commonly following a viral infection, but other physiological triggers are also implicated. It has a profound long-term impact on the life of the affected person. ME/CFS is diagnosed primarily by the exclusion of other fatigue illnesses, but the availability of multiple case definitions for ME/CFS has complicated diagnosis for clinicians. There has been ongoing controversy over the nature of ME/CFS, but a recent detailed report from the Institute of Medicine (Academy of Sciences, USA) concluded that ME/CFS is a medical, not psychiatric illness. Importantly, aspects of the biological basis of the ongoing disease have been revealed over the last 2–3 years that promise new leads towards an effective clinical diagnostic test that may have a general application. Our detailed molecular studies with a preclinical study of ME/CFS patients, along with the complementary research of others, have reported an elevation of inflammatory and immune processes, ongoing neuro-inflammation, and decreases in general metabolism and mitochondrial function for energy production in ME/CFS, which contribute to the ongoing remitting/relapsing etiology of the illness. These biological changes have generated potential molecular biomarkers for use in diagnostic ME/CFS testing. Full article
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Open AccessPerspective
Myalgic Encephalomyelitis or What? The International Consensus Criteria
Diagnostics 2019, 9(1), 1; https://doi.org/10.3390/diagnostics9010001 - 20 Dec 2018
Cited by 2
Abstract
Myalgic encephalomyelitis (ME) is a neuromuscular disease with two distinctive types of symptoms (muscle fatigability or prolonged muscle weakness after minor exertion and symptoms related to neurological disturbance, especially of sensory, cognitive, and autonomic functions) and variable involvement of other bodily systems. Chronic [...] Read more.
Myalgic encephalomyelitis (ME) is a neuromuscular disease with two distinctive types of symptoms (muscle fatigability or prolonged muscle weakness after minor exertion and symptoms related to neurological disturbance, especially of sensory, cognitive, and autonomic functions) and variable involvement of other bodily systems. Chronic fatigue syndrome (CFS), introduced in 1988 and re-specified in 1994, is defined as (unexplained) chronic fatigue accompanied by at least four out of eight listed (ill-defined) symptoms. Although ME and CFS are two distinct clinical entities (with partial overlap), CFS overshadowed ME for decades. In 2011, a panel of experts recommended abandoning the label CFS and its definition and proposed a new definition of ME: the International Consensus Criteria for ME (ME-ICC). In addition to post-exertional neuroimmune exhaustion (PENE), a mandatory feature, a patient must experience at least three symptoms related to neurological impairments; at least three symptoms related to immune, gastro-intestinal, and genitourinary impairments; and at least one symptom related to energy production or transportation impairments to meet the diagnosis of ME-ICC. A comparison between the original definition of ME and the ME-ICC shows that there are some crucial differences between ME and ME-ICC. Muscle fatigability, or long-lasting post-exertional muscle weakness, is the hallmark feature of ME, while this symptom is facultative for the diagnosis under the ME-ICC. PENE, an abstract notion that is very different from post-exertional muscle weakness, is the hallmark feature of the ME-ICC but is not required for the diagnosis of ME. The diagnosis of ME requires only two type of symptoms (post-exertional muscle weakness and neurological dysfunction), but a patient has to experience at least eight symptoms to meet the diagnosis according to the ME-ICC. Autonomic, sensory, and cognitive dysfunction, mandatory for the diagnosis of ME, are not compulsory to meet the ME-ICC subcriteria for ‘neurological impairments’. In conclusion, the diagnostic criteria for ME and of the ME-ICC define two different patient groups. Thus, the definitions of ME and ME-ICC are not interchangeable. Full article
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