The Reification of the Clinical Diagnosis of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) as an Immune and Oxidative Stress Disorder: Construction of a Data-driven Nomothethic Network and Exposure of ME/CFS Subgroups.

The approach towards myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains in a permanent state of crisis with fierce competition between the psychosocial school, which attributes ME/CFS to the perception of effort, and the medical approach (Maes and Twisk, BMC Med, 2010, 8, 35). The aim of this paper is to review how to construct a nomothetic model of ME/CFS using Partial Least Squares (PLS) path analysis and ensembling causome (bacterial translocation as assessed with IgM/IgA responses to LPS), protectome (lowered coenzyme Q10), adverse outcome pathways (AOP) including increased lysozyme, CD38+ T cell activation, cell-mediated immune activation (CMI), and IgM responses to oxidative specific epitopes and NO-adducts (IgM OSENO).Using PLS, we trained, tested and validated this knowledge- and data-driven causal ME/CFS model, which showed adequate convergence, construct and replicability validity.This bottom- up explicit data model of ME/CFS objectivates the descriptive narratives of the ME/CFS phenome, using causome-protectome-AOP data, whereby the abstract concept ME/CFS is translated into pathways, thereby securing the reification of the ME/CFS phenome. We found that 31.6% of the variance in the physiosomatic symptom dimension of ME/CFS was explained by the cumulative effects of CMI and CD38+ activation, IgM OSENO, IgA LPS, lysozyme (all positive) and coenzyme Q10 (inversely). Cluster analysis performed on the PLS-generated latent vector scores of all feature sets exposed three distinct immune groups of ME/CFS, namely one with increased lysozyme, one with increased CMI + CD38 activation + depressive symptoms, and another with increased bacterial translocation + autoimmune responses to OSENO.

¿Qué evidencia científica tienen los métodos propuestos para valorar la discapacidad laboral de los pacientes con síndrome de sensibilización central? / What scientific evidence do the current classifications have in order to assess occupational disability in patients with central sensitisation syndrome?

El síndrome de sensibilización central engloba enfermedades como la fibromialgia, el síndrome de fatiga crónica, la sensibilidad química múltiple y el síndrome de sensibilidad electromagnética. Estas afecciones han ido adquiriendo relevancia tanto médica como social por el aumento de la prevalencia, la ausencia de un tratamiento curativo, las limitaciones que provocan y los altos costes sanitarios que suponen. Además, todas ellas comparten una etiología desconocida y la ausencia de parámetros objetivos para establecer su diagnóstico y su gravedad. Se han propuesto múltiples métodos y clasificaciones para graduar la discapacidad de estos pacientes, pero en la actualidad ninguno de ellos ha conseguido una evidencia científica suficiente

Central sensitisation syndrome includes disorders such as fibromyalgia, chronic fatigue syndrome, multiple chemical sensitivity, and electromagnetic sensitivity syndrome. These disorders have been acquiring both medical and social relevance due to the increase in prevalence, the absence of a curative treatment, the limitations they cause, and the high healthcare costs they involve. Furthermore, all of them share an unknown aetiology and the absence of objective parameters to establish their diagnosis and severity. Multiple methods and classifications have been proposed to graduate the disability of these patients, but currently none of them have obtained sufficient evidence

Graded exercise therapy does not restore the ability to work in ME/CFS - Rethinking of a Cochrane review.

BACKGROUND: Cochrane recently amended its exercise review for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in response to an official complaint. OBJECTIVE: To determine if the amended review has addressed the concerns raised about the previous review and if exercise is an effective treatment that restores the ability to work in ME/CFS. METHOD: The authors reviewed the amended Cochrane exercise review and the eight trials in it by paying particular interest to the objective outcomes. We also summarised the recently published review of work rehabilitation and medical retirement for ME/CFS. RESULTS: The Cochrane review concluded that graded exercise therapy (GET) improves fatigue at the end of treatment compared to no-treatment. However, the review did not consider the unreliability of subjective outcomes in non-blinded trials, the objective outcomes which showed that GET is not effective, or the serious flaws of the studies included in the review. These flaws included badly matched control groups, relying on an unreliable fatigue instrument as primary outcome, outcome switching, p-hacking, ignoring evidence of harms, etc. The review did also not take into account that GET does not restore the ability to work. CONCLUSION: GET not only fails to objectively improve function significantly or to restore the ability to work, but it is also detrimental to the health of≥50% of patients, according to a multitude of patient surveys. Consequently, it should not be recommended.

A perspective on causation of the chronic fatigue syndrome by considering its nosology.

The causes of chronic fatigue syndrome (CFS) remain unknown, with many failures to replicate new findings. This may be because the condition is hard to diagnose, difficult to classify, or because of its heterogeneous nature. Authors have problems in differentiating CFS from myalgic encephalomyelitis (ME), which leads many to label it as a hybrid CFS/ME or ME/CFS. Attempts to validate the many published criterion-based definitions have ended in failure. The International Classification of Diseases provide several different descriptions to choose from, although the latest 11th edition has narrowed this down. This paper describes conventional attempts to define and classify the illness, suggesting that this may be what leads to a failure to replicate putative causes. The approach to CFS/ME may require a shift in the assumption that the illness is homogeneous. An alternative approach is provided by studies suggesting that the condition is heterogeneous. CONCLUSION: The way forward may be to be over-inclusive regarding the diagnosis as a first step, while subdividing the condition into likely subgroups as a means of finding valid and reliable associations with potential causes. Studies of aetiology must involve prospective designs since cross-sectional studies cannot inform either aetiology or pathophysiology.

[From neurasthenia to post-exertion disease: Evolution of the diagnostic criteria of chronic fatigue syndrome/myalgic encephalomyelitis]. / De la neurastenia a la enfermedad postesfuerzo: evolución de los criterios diagnósticos del síndrome de fatiga crónica/encefalomielitis miálgica.

Changes in the terminology and diagnostic criteria for chronic fatigue syndrome/myalgic encephalomyelitis are explained in this paper. This syndrome is a complex and controversial entity of unknown origins. It appears in the medical literature in 1988, although clinical pictures of chronic idiopathic fatigue have been identified since the nineteenth century with different names, from neurasthenia, epidemic neuromyasthenia, and benign myalgic encephalomyelitis up to the current proposal of disease of intolerance to effort (post-effort). All of them allude to a chronic state of generalised fatigue of unknown origin, with limitations to physical and mental effort, accompanied by a set of symptoms that compromise diverse organic systems. The International Classification of Diseases (ICD-10) places this syndrome in the section on neurological disorders (G93.3), although histopathological findings have not yet been found to clarify it. Multiple organic alterations have been documented, but a common biology that clarifies the mechanisms underlying this disease has not been established. It is defined as a neuro-immune-endocrine dysfunction, with an exclusively clinical diagnosis and by exclusion. Several authors have proposed to include CFS/ME within central sensitivity syndromes, alluding to central sensitisation as the common pathophysiological substrate for this, and other syndromes. The role of the family doctor is a key figure in the disease, from the detection of those patients who present a fatigue of unknown nature that is continuous or intermittent for more than 6 months, in order to make an early diagnosis and establish a plan of action against a chronic disease with high levels of morbidity in the physical and mental sphere. OBJECTIVE: To carry out a bibliographic review of the terminology and diagnostic criteria of the chronic fatigue syndrome/myalgic encephalomyelitis, in order to clarify the pathology conceptually, as a usefulness in the diagnosis of Primary Care physicians.

Varied Presentation of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and the Needs for Classification and Clinician Education: A Case Series.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, heterogeneous and serious disease. In this article, we analyze the cases of 3 patients with ME/CFS. Due to the disbeliefs, misconceptions, and stigmas that are attached to ME/CFS, patient diagnosis is made after years of disease progression. Over this period, physicians tried to determine the etiology of the disease, taking into account its onset and symptoms. The suspected conditions correlated with possible subgroups that researchers speculate may exist in ME/CFS. Therefore, a registry of well-selected data on clinical history could help to cluster patients into more homogenous groups, and could be beneficial for research.

Ethical classification of ME/CFS in the United Kingdom.

Few conditions have sparked as much controversy as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Professional consensus has long suggested that the condition should be classified as psychiatric, while patients and advocacy groups have insisted it is a serious biological disease that requires medical care and research to develop it. This longstanding debate shifted in 2015, when U.S. governmental health authorities fully embraced medical classification and management. Given that some globally respected health authorities now insist that ME/CFS is a serious biological disease, this paper asks whether it can be ethical for the U.K. practice guideline now in development to characterize the condition as a mental health disorder. Following a brief history of ME/CFS controversy, I offer three arguments to show that it would be unethical for the U.K. to now characterize ME/CFS as a mental health condition, considering the relevance of that conclusion for ME/CFS guidelines elsewhere and for other contested conditions.

How have selection bias and disease misclassification undermined the validity of myalgic encephalomyelitis/chronic fatigue syndrome studies?

Myalgic encephalomyelitis/chronic fatigue syndrome has been a controversial diagnosis, resulting in tensions between patients and professionals providing them with care. A major constraint limiting progress has been the lack of a 'gold standard' for diagnosis; with a number of imperfect clinical and research criteria used, each defining different, though overlapping, groups of people with myalgic encephalomyelitis or chronic fatigue syndrome. We review basic epidemiological concepts to illustrate how the use of more specific and restrictive case definitions could improve research validity and drive progress in the field by reducing selection bias caused by diagnostic misclassification.

Chronic Widespread Pain in a tertiary pain clinic: classification overlap and use of a patient generated quality of life instrument.

Background and aims This study has two main aims: (1) To explore the overlap between classification criteria in patients with Chronic Widespread Pain (CWP) and (2) To explore the use of the Patient Generated Index (PGI) as a quality of life (QoL) measure in this patient group. Methods Patients with Widespread Pain (ICD-11: pain in four or more out of five bodily regions, i.e. the four quadrants and axially) in a tertiary pain outpatient clinic were assessed according to classification criteria for Fibromyalgia [FM, American College of Rheumatology (ACR) criteria of 1990, 2010, 2011 and 2016], Chronic Fatigue Syndrome [CFS, Fukuda, Canada and International Consensus Criteria (ICC)] and Bodily Distress Syndrome (BDS). Furthermore, patients completed the PGI to assess QoL, and electronic questionnaires including demographic variables and standardised patient-reported outcome measures (PROMs). Results All patients (n=33) fulfilled the criteria for musculoskeletal type single-organ BDS, 81.8% met the 2016 modified criteria for FM, 30.3% met the Canada criteria for CFS and 24.2% met the criteria for multi-organ type BDS. There was substantial agreement between the 2016 and the 2011 and 2010 criteria sets for FM compared to the 1990 criteria (κ=0.766 and 0.673 compared to 0.279). Patients generally scored low on the PGI, indicating poor QoL (mean PGI 28.9, SD 19.8, range 0-100). Conclusions Our findings support the use of the term musculoskeletal type single-organ BDS to describe patients with CWP and the 2016 revision of the FM criteria. The PGI provides useful clinical information which is not captured by standardised PROMs. Implications The terminology of CWP has become less ambiguous as the new ICD-11 is closely related to the generalised pain criterion of the modified 2016 FM definition. Studies based on the 1990 classification criteria for FM should not be directly compared to studies based on later criteria set. The PGI may be a supplement to other measurements to portray patients' individual concerns in patients with complex symptom disorders.

A new approach to find biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) by single-cell Raman micro-spectroscopy.

Chronic fatigue syndrome (CFS), also called myalgic encephalomyelitis (ME), is a debilitating disorder characterized by physical and mental exhaustion. Mitochondrial and energetic dysfunction has been investigated in CFS patients due to a hallmark relationship with fatigue; however, no consistent conclusion has yet been achieved. Single-cell Raman spectra (SCRS) are label-free biochemical profiles, indicating phenotypic fingerprints of single cells. In this study, we applied a new approach using single-cell Raman microspectroscopy (SCRM) to examine ρ0 cells that lack mitochondrial DNA (mtDNA), and peripheral blood mononuclear cells (PBMCs) from CFS patients and healthy controls. The experimental results show that Raman bands associated with phenylalanine in ρ0 cells and CFS patient PBMCs were significantly higher than those of the wild-type model and healthy controls. As similar changes were observed in the ρ0 cell model with a known deficiency in the mitochondrial respiratory chain as well as in CFS patients, our results suggest that the increase in cellular phenylalanine may be related to mitochondrial/energetic dysfunction in both systems. Interestingly, phenylalanine can be used as a potential biomarker for the diagnosis of CFS by SCRM. A machine learning classification model achieved an accuracy rate of 98% correctly assigning Raman spectra to either the CFS group or the control group. SCRM combined with a machine learning algorithm therefore has the potential to become a diagnostic tool for CFS.

Chronic Fatigue Syndrome: From Chronic Fatigue to More Specific Syndromes.

In the last decade, a group of chronic disorders associated with fatigue (CDAF) emerged as the leading cause of chronic fatigue, chronic pain, and functional impairment, all of which have been often labeled in clinical practice as chronic fatigue syndrome (CFS) or fibromyalgia. While these chronic disorders arise from various pathophysiologic mechanisms, a shared autoimmune or immune-mediated etiology could shift the focus from symptomatic treatment of fatigue and pain to targeted immunomodulatory and biological therapy. A clinical paradigm shift is necessary to reevaluate CFS and fibromyalgia diagnoses and its relationship to the CDAF entities, which would ultimately lead to a change in diagnostic and therapeutic algorithm for patients with chronic fatigue and chronic pain. Rather than uniformly apply the diagnoses of CFS or fibromyalgia to any patient presenting with unexplained chronic fatigue or chronic pain, it may be more beneficial and therapeutically effective to stratify these patients into more specific diagnoses in the CDAF group.

Structural brain changes versus self-report: machine-learning classification of chronic fatigue syndrome patients.

Chronic fatigue syndrome (CFS) is a disorder associated with fatigue, pain, and structural/functional abnormalities seen during magnetic resonance brain imaging (MRI). Therefore, we evaluated the performance of structural MRI (sMRI) abnormalities in the classification of CFS patients versus healthy controls and compared it to machine learning (ML) classification based upon self-report (SR). Participants included 18 CFS patients and 15 healthy controls (HC). All subjects underwent T1-weighted sMRI and provided visual analogue-scale ratings of fatigue, pain intensity, anxiety, depression, anger, and sleep quality. sMRI data were segmented using FreeSurfer and 61 regions based on functional and structural abnormalities previously reported in patients with CFS. Classification was performed in RapidMiner using a linear support vector machine and bootstrap optimism correction. We compared ML classifiers based on (1) 61 a priori sMRI regional estimates and (2) SR ratings. The sMRI model achieved 79.58% classification accuracy. The SR (accuracy = 95.95%) outperformed both sMRI models. Estimates from multiple brain areas related to cognition, emotion, and memory contributed strongly to group classification. This is the first ML-based group classification of CFS. Our findings suggest that sMRI abnormalities are useful for discriminating CFS patients from HC, but SR ratings remain most effective in classification tasks.

Integration of DNA methylation & health scores identifies subtypes in myalgic encephalomyelitis/chronic fatigue syndrome.

AIM: To identify subtypes in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) based on DNA methylation profiles and health scores. METHODS: DNA methylome profiles in immune cells were integrated with symptomatology from 70 women with ME/CFS using similarity network fusion to identify subtypes. RESULTS: We discovered four ME/CFS subtypes associated with DNA methylation modifications in 1939 CpG sites, three RAND-36 categories and five DePaul Symptom Questionnaire measures. Methylation patterns of immune response genes and differences in physical functioning and postexertional malaise differentiated the subtypes. CONCLUSION: ME/CFS subtypes are associated with specific DNA methylation differences and health symptomatology and provide additional evidence of the potential relevance of metabolic and immune differences in ME/CFS with respect to specific symptoms.

Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue, commonly accompanied by cognitive dysfunction, sleeping disturbances, orthostatic intolerance, fever, lymphadenopathy, and irritable bowel syndrome (IBS). The extent to which the gastrointestinal microbiome and peripheral inflammation are associated with ME/CFS remains unclear. We pursued rigorous clinical characterization, fecal bacterial metagenomics, and plasma immune molecule analyses in 50 ME/CFS patients and 50 healthy controls frequency-matched for age, sex, race/ethnicity, geographic site, and season of sampling. RESULTS: Topological analysis revealed associations between IBS co-morbidity, body mass index, fecal bacterial composition, and bacterial metabolic pathways but not plasma immune molecules. IBS co-morbidity was the strongest driving factor in the separation of topological networks based on bacterial profiles and metabolic pathways. Predictive selection models based on bacterial profiles supported findings from topological analyses indicating that ME/CFS subgroups, defined by IBS status, could be distinguished from control subjects with high predictive accuracy. Bacterial taxa predictive of ME/CFS patients with IBS were distinct from taxa associated with ME/CFS patients without IBS. Increased abundance of unclassified Alistipes and decreased Faecalibacterium emerged as the top biomarkers of ME/CFS with IBS; while increased unclassified Bacteroides abundance and decreased Bacteroides vulgatus were the top biomarkers of ME/CFS without IBS. Despite findings of differences in bacterial taxa and metabolic pathways defining ME/CFS subgroups, decreased metabolic pathways associated with unsaturated fatty acid biosynthesis and increased atrazine degradation pathways were independent of IBS co-morbidity. Increased vitamin B6 biosynthesis/salvage and pyrimidine ribonucleoside degradation were the top metabolic pathways in ME/CFS without IBS as well as in the total ME/CFS cohort. In ME/CFS subgroups, symptom severity measures including pain, fatigue, and reduced motivation were correlated with the abundance of distinct bacterial taxa and metabolic pathways. CONCLUSIONS: Independent of IBS, ME/CFS is associated with dysbiosis and distinct bacterial metabolic disturbances that may influence disease severity. However, our findings indicate that dysbiotic features that are uniquely ME/CFS-associated may be masked by disturbances arising from the high prevalence of IBS co-morbidity in ME/CFS. These insights may enable more accurate diagnosis and lead to insights that inform the development of specific therapeutic strategies in ME/CFS subgroups.

[Chronic Fatigue Syndrome: A Critical Review]. / Das chronische Müdigkeitssyndrom ­ ein kritischer Diskurs.

Chronic fatigue syndrome (CFS), also called myalgic encephalomyelitis (ME), is a challenge to physicians. CFS prevalence is below 1 % in a general population. There are no convincing models that might explain etiology and pathogenesis of CFS as an independent, unique disease. No consistent diagnostic criteria are available. In the differential diagnosis of chronic fatigue, a variety of somatic (e. g. chronic infectious diseases, multiple sclerosis, endocrinological disorders) and psychiatric/psychosomatic diseases should be considered. After exclusion of somatic causes, there is a significant overlap with major depression and somatoform disorders. Exercise therapy, antidepressants and psychotherapy are useful treatment options. Unless there is enough evidence for neuroinflammation, aggressive immunotherapies like rituximab should not be considered. In sum, there is not enough evidence to assume that CFS is an independent, unique disease.

Heterogeneity in chronic fatigue syndrome - empirically defined subgroups from the PACE trial.

BACKGROUND: Chronic fatigue syndrome is likely to be a heterogeneous condition. Previous studies have empirically defined subgroups using combinations of clinical and biological variables. We aimed to explore the heterogeneity of chronic fatigue syndrome. METHOD: We used baseline data from the PACE trial, which included 640 participants with chronic fatigue syndrome. Variable reduction, using a combination of clinical knowledge and principal component analyses, produced a final dataset of 26 variables for 541 patients. Latent class analysis was then used to empirically define subgroups. RESULTS: The most statistically significant and clinically recognizable model comprised five subgroups. The largest, 'core' subgroup (33% of participants), had relatively low scores across all domains and good self-efficacy. A further three subgroups were defined by: the presence of mood disorders (21%); the presence of features of other functional somatic syndromes (such as fibromyalgia or irritable bowel syndrome) (21%); or by many symptoms - a group which combined features of both of the above (14%). The smallest 'avoidant-inactive' subgroup was characterized by physical inactivity, belief that symptoms were entirely physical in nature, and fear that they indicated harm (11%). Differences in the severity of fatigue and disability provided some discriminative validation of the subgroups. CONCLUSIONS: In addition to providing further evidence for the heterogeneity of chronic fatigue syndrome, the subgroups identified may aid future research into the important aetiological factors of specific subtypes of chronic fatigue syndrome and the development of more personalized treatment approaches.

Systemic exercise intolerance disease: What's in a name?

The syndrome characterized primarily by chronic, disabling fatigue without adequate explanation has been of interest to patients, clinicians and researchers. Chronic fatigue syndrome (CFS) is a widely used term for this condition in scientific and lay literature but is not acceptable to many patients because of perceived stigma due to implied psychological causation. CFS has recently been replaced by systemic exercise intolerance disease (SEID) by the Institute of medicine with the objectives of providing and disseminating evidence-based criteria and to provide a more acceptable name for this condition. Simultaneously, changes have taken place in DSM-5 with regards to this condition. Mental health professionals need to be aware of this change in the interests of patient care. The need to replace CFS with SEID and the nosological changes also indicate an inability to do away with the Descartian mind-body dualism despite efforts to the contrary and a need to debate the failure of the bio-psycho-social model to 'mainstream' and destigmatize psychiatry.

Illness progression in chronic fatigue syndrome: a shifting immune baseline.

BACKGROUND: Validation of biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) across data sets has proven disappointing. As immune signature may be affected by many factors, our objective was to explore the shift in discriminatory cytokines across ME/CFS subjects separated by duration of illness. METHODS: Cytokine expression collected at rest across multiple studies for female ME/CFS subjects (i) 18 years or younger, ill for 2 years or less (n = 18), (ii) 18-50 years of age, ill for 7 years (n = 22), and (iii) age 50 years or older (n = 28), ill for 11 years on average. Control subjects were matched for age and body mass index (BMI). Data describing the levels of 16 cytokines using a chemiluminescent assay was used to support the identification of separate linear classification models for each subgroup. In order to isolate the effects of duration of illness alone, cytokines that changed significantly with age in the healthy control subjects were excluded a priori. RESULTS: Optimal selection of cytokines in each group resulted in subsets of IL-1α, 6, 8, 15 and TNFα. Common to any 2 of 3 groups were IL-1α, 6 and 8. Setting these 3 markers as a triple screen and adjusting their contribution according to illness duration sub-groups produced ME/CFS classification accuracies of 75-88 %. The contribution of IL-1α, higher in recently ill adolescent ME/CFS subjects was progressively less important with duration. While high levels of IL-8 screened positive for ME/CFS in the recently afflicted, the opposite was true for subjects ill for more than 2 years. Similarly, while low levels of IL-6 suggested early ME/CFS, the reverse was true in subjects over 18 years of age ill for more than 2 years. CONCLUSIONS: These preliminary results suggest that IL-1α, 6 and 8 adjusted for illness duration may serve as robust biomarkers, independent of age, in screening for ME/CFS.