ME Association May Summary of ME/CFS Published Research | 19 June 2019


Charlotte Stephens, Research Correspondent, ME Association

ME Association Index of Published ME/CFS Research

The Index of Published ME/CFS Research has now been updated to take account of the research that has been published during the month of May 2019. It’s a little later than normal due to ME-related absence.

The Index is a useful way to locate and then read all relevant research on ME/CFS. It’s free to download and comes with an interactive contents table.

This is an A-Z list of all the most important ME/CFS research studies (and selected key documents and articles), listed by subject matter and author, with links to PubMed or the relevant Journal.

You can also find the index in the Research section of the website together with all the summary reviews that have been published.

ME/CFS research abstracts from studies published in May 2019

1. Ahmed SA et al. (2019)
Assessment of the scientific rigour of randomized controlled trials on the effectiveness of cognitive behavioural therapy and graded exercise therapy for patients with myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review.
Journal of Health Psychology [Epub ahead of print]

Abstract
Cognitive behavioural therapy and graded exercise therapy have been promoted as effective treatments for patients with myalgic encephalomyelitis/chronic fatigue syndrome. However, criticism on the scientific rigour of these studies has been raised. This review assessed the methodological quality of studies on the effectiveness of cognitive behavioural therapy and graded exercise therapy.

The methodological quality of the 18 included studies was found to be relatively low, as bias was prominently found, affecting the main outcome measures of the studies (fatigue, physical functioning and functional impairment/status). Future research should focus on including more objective outcome measures in a well-defined patient population.

2. Almenar-Perez E et al. (2019)
Epigenetic Components of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Uncover Potential Transposable Element Activation.
Clinical Therapeutics 41 (4): 675-698.

Abstract
Purpose: Studies to determine epigenetic changes associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remain scarce; however, current evidence clearly shows that methylation patterns of genomic DNA and noncoding RNA profiles of immune cells differ between patients and healthy subjects, suggesting an active role of these epigenetic mechanisms in the disease. The present study compares and contrasts the available ME/CFS epigenetic data in an effort to evidence overlapping pathways capable of explaining at least some of the dysfunctional immune parameters linked to this disease.

Methods: A systematic search of the literature evaluating the ME/CFS epigenome landscape was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. Differential DNA methylation and noncoding RNA differential expression patterns associated with ME/CFS were used to screen for the presence of transposable elements using the Dfam browser, a search program nurtured with the Repbase repetitive sequence database and the RepeatMasker annotation tool.

Findings: Unexpectedly, particular associations of transposable elements and ME/CFS epigenetic hallmarks were uncovered. A model for the disease emerged involving transcriptional induction of endogenous dormant transposons and structured cellular RNA interactions, triggering the activation of the innate immune system without a concomitant active infection.

Implications: Repetitive sequence filters (ie, RepeatMasker) should be avoided when analyzing transcriptomic data to assess the potential participation of repetitive sequences (“junk repetitive DNA”), representing >45% of the human genome, in the onset and evolution of ME/CFS. In addition, transposable element screenings aimed at designing cost-effective, focused empirical assays that can confirm or disprove the suspected involvement of transposon transcriptional activation in this disease, following the pilot strategy presented here, will require databases gathering large ME/CFS epigenetic datasets.

3. Bae J and Lin JS (2019)
Healthcare Utilization in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Analysis of US Ambulatory Healthcare Data, 2000-2009.
Frontiers in Pediatrics 7: 185.

Abstract
Background: ME/CFS is a complex and disabling illness with substantial economic burden and functional impairment comparable to heart disease and multiple sclerosis. Many patients with ME/CFS do not receive appropriate healthcare, partially due to lack of diagnostic tests, and knowledge/attitudes/beliefs about ME/CFS. This study was to assess the utility of US ambulatory healthcare data in profiling demographics, co-morbidities, and healthcare in ME/CFS. 

Methods: Data came from the National Ambulatory Medical Care Survey (NAMCS) and the National Hospital Ambulatory Medical Care Survey (NHAMCS) in the U.S. Weighted analysis was performed. We examined 9.06 billion adult visits from 2000 to 2009 NAMCS/NHAMCS data. ME/CFS-related visits were identified by ICD-9-CM code, 780.71, up to tertiary diagnosis. 

Results: We estimated 2.9 million (95% CI: 1.8-3.9 million) ME/CFS-related visits during 2000-2009, with no statistical evidence (p-trend = 0.31) for a decline or increase in ME/CFS-related visits. Internists, general and family practitioners combined provided 52.12% of these visits. Patients with ME/CFS-related visits were mostly in their 40 and 50 s (47.76%), female (66.07%), white (86.95%), metropolitan/urban residents (92.05%), and insured (87.26%). About 71% of ME/CFS patients had co-morbidities, including depression (35.79%), hypertension (31.14%), diabetes (20.30%), and arthritis (14.11%). As one quality indicator, physicians spent more time on ME/CFS-related visits than non-ME/CFSvisits (23.62 vs. 19.38 min, p = 0.065). As additional quality indicators, the top three preventive counseling services provided to patients with ME/CFS-related visits were diet/nutrition (8.33%), exercise (8.21%), and smoking cessation (7.24%). Compared to non-ME/CFS visits, fewer ME/CFS-related visits included counseling for stress management (0.75 vs. 3.14%, p = 0.010), weight reduction (0.88 vs. 4.02%, p = 0.002), injury prevention (0.04 vs. 1.64%, p < 0.001), and family planning/contraception (0.17 vs. 1.45%, p = 0.037). 

Conclusions: Visits coded with ME/CFS did not increase from 2000 to 2009. Almost three quarters of ME/CFS-related visits were made by ME/CFS patients with other co-morbid conditions, further adding to complexity in ME/CFS healthcare. While physicians spent more time with ME/CFS patients, a lower proportion of ME/CFS patients received preventive counseling for weight reduction, stress management, and injury prevention than other patients despite the complexity of ME/CFS. NAMCS/NHAMCS data are useful in evaluating co-morbidities, healthcare utilization, and quality indicators for healthcare in ME/CFS.

4. Boneva RS et al. (2019)
Endometriosis as a Comorbid Condition in Chronic Fatigue Syndrome (CFS): Secondary Analysis of Data From a CFS Case-Control Study.
Frontiers in Pediatrics 7: 195

Abstract
Background: Endometriosis (EM) is a recognized co-morbid condition in women with chronic fatigue syndrome (CFS). This analysis evaluates the impact of EM on the health of women with CFS by comparing selected health characteristics and laboratory parameters in women with CFS with and without EM (CFS+EM and CFS-only).

Methods: This secondary analysis included all 36 women with CFS from a cross-sectional study of CFS in Wichita, KS, conducted between 2002 and 2003. The health characteristics and laboratory parameters of interest included functioning, fatigue, CFS-related symptoms, gynecologic history, routine laboratory parameters, inflammatory markers, cortisol levels, allostatic load, and sleep parameters (overnight polysomnography). We used parametric or non-parametric tests to compare group differences in the selected health characteristics and laboratory parameters. For examining the association between EM and variables of interest, logistic regression models were performed and odds ratios (OR) with 95% confidence intervals (CI) were reported for the magnitude of associations. Statistical significance was set at 0.05 (two-sided).

Results: The mean age of this study sample was 50.9 years. Of women with CFS, 36.1% reported having EM. Age and body mass index (BMI) did not differ between CFS+EM and CFS-only groups. When examining the impact of EM, compared to women with CFS-only, women with both CFS and EM were more likely to report chronic pelvic pain [OR = 9.00 (95% CI, 1.47–55.25)] and hysterectomy [OR = 10.3 (1.82–58.39)], had more CFS symptoms (6.8 ± 0.3 vs. 5.5 ± 0.3, p = 0.02), younger mean age at menopause onset (36.4 ± 3.0 vs. 47.0 ± 2.7 years, p = 0.03), higher mean number of obstructive apnea episodes per hour (20.3 vs. 4.4, p = 0.05) and reported more negative life events (15.8 vs. 4.4, p = 0.05). Other parameters did not differ significantly between the two groups.

Conclusions: We found more than a third of women with CFS reported endometriosis as a comorbid condition. The endometriosis comorbidity was associated with chronic pelvic pain, earlier menopause, hysterectomy, and more CFS-related symptoms. However, endometriosis in women with CFS did not appear to further impact functioning, fatigue, inflammatory markers, or other laboratory parameters. Further investigations including younger women are warranted.

5. Esfandyarpour R et al. (2019)
A nanoelectronics-blood-based diagnostic biomarker for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Proceedings of the National Academy of Science USA 116 (21): 10250-10257.

Abstract
There is not currently a well-established, if any, biological test to diagnose myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS). The molecular aberrations observed in numerous studies of ME/CFS blood cells offer the opportunity to develop a diagnostic assay from blood samples.

Here we developed a nanoelectronics assay designed as an ultrasensitive assay capable of directly measuring biomolecular interactions in real time, at low cost, and in a multiplex format. To pursue the goal of developing a reliable biomarker for ME/CFS and to demonstrate the utility of our platform for point-of-care diagnostics, we validated the array by testing patients with moderate to severe ME/CFS patients and healthy controls.

The ME/CFS samples’ response to the hyperosmotic stressor observed as a unique characteristic of the impedance pattern and dramatically different from the response observed among the control samples. We believe the observed robust impedance modulation difference of the samples in response to hyperosmotic stress can potentially provide us with a unique indicator of ME/CFS. Moreover, using supervised machine learning algorithms, we developed a classifier for ME/CFS patients capable of identifying new patients, required for a robust diagnostic tool.

6. Filho AJ et al. (2019)
Shared microglial mechanisms underpinning depression and chronic fatigue syndrome and their comorbidities.
Behaviour and Brain Research [Epub ahead of print]

Abstract
In 2011, it was reviewed that a) there is a strong co-occurrence between major depression and chronic fatigue syndrome (CFS), with fatigue and physio-somatic symptoms being key symptoms of depression, and depressive symptoms appearing during the course of CFS; and b) the comorbidity between both disorders may in part be explained by activated immune-inflammatory pathways, including increased translocation of Gram-negative bacteria and increased levels of pro-inflammatory cytokines, such as interleukin (IL)-1. Nevertheless, the possible involvement of activated microglia in this comorbidity has remained unclear.

This paper aims to review microglial disturbances in major depression, CFS and their comorbidity. A comprehensive literature search was conducted using the PubMed / MEDLINE database to identify studies, which are relevant to this current review. Depressed patients present neuroinflammatory alterations, probably related to microglial activation, while animal models show that a microglial response to immune challenges including lipopolysaccharides is accompanied by depressive-like behaviors. Recent evidence from preclinical studies indicates that activated microglia have a key role in the onset of fatigue. In chronic inflammatory conditions, such as infections and senescence, microglia orchestrate an inflammatory microenvironment thereby causing fatigue.

In conclusion, based on our review we may posit that shared immune-inflammatory pathways and especially activated microglia underpin comorbid depression and CFS. As such, microglial activation and neuro-inflammation may be promising targets to treat the overlapping manifestations of both depression and CFS.

7. Gherardi RK et al. (2019)
Myalgia and chronic fatigue syndrome following immunization: macrophagic myofasciitis and animal studies support linkage to aluminum adjuvant persistency and diffusion in the immune system.
Autoimmune Reviews [Epub ahead of print]

Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multifactorial and poorly understood disabling disease. We present epidemiological, clinical and experimental evidence that ME/CFS constitutes a major type of adverse effect of vaccines, especially those containing poorly degradable particulate aluminum adjuvants. Evidence has emerged very slowly due to the multiplicity, lack of specificity, delayed onset, and frequent medical underestimation of ME/CFS symptoms.

It was supported by an epidemiological study comparing vaccinated vs unvaccinated militaries that remained undeployed during Gulf War II. Affected patients suffer from cognitive dysfunction affecting attention, memory and inter-hemispheric connexions, well correlated to brain perfusion defects and associated with a stereotyped and distinctive pattern of cerebral glucose hypometabolism. Deltoid muscle biopsy performed to investigate myalgia typically yields macrophagic myofasciitis (MMF), a histological biomarker assessing longstanding persistency of aluminum agglomerates within innate immune cells at site of previous immunization. MMF is seemingly linked to altered mineral particle detoxification by the xeno/autophagy machinery.

Comparing toxicology of different forms of aluminum and different types of exposure is misleading and inadequate and small animal experiments have turned old dogma upside down. Instead of being rapidly solubilized in the extracellular space, injected aluminum particles are quickly captured by immune cells and transported to distant organs and the brain where they elicit an inflammatory response and exert selective low dose long-term neurotoxicity. Clinical observations and experiments in sheep, a large animal like humans, confirmed both systemic diffusion and neurotoxic effects of aluminum adjuvants. Post-immunization ME/CFS represents the core manifestation of “autoimmune/inflammatory syndrome induced by adjuvants” (ASIA).

8. Giannoccaro MP et al. (2019)
Searching for Serum Antibodies to Neuronal Proteins in Patients With Myalgic Encephalopathy/Chronic Fatigue Syndrome.
Clinical Therapeutics 41 (5): 836-847.

Abstract
Purpose: A role for the immune system in causing myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is long suspected, but few studies have looked for specific autoantibodies that might contribute to the symptoms. Our aim was to look for evidence of antibodies to neuronal proteins in patients with ME/CSF.

Methods: Sera samples from 50 patients and 50 healthy individuals were sent coded to the Neuroimmunology Laboratory in Oxford. Screening for antibody binding to neuronal tissue was performed on brain tissue and neuronal cultures. Specific serum antibodies were assessed by antigen-specific cell-based assays and radioimmunoassays. After antibody testing, the associations between seropositive status and clinical data were investigated.

Findings: Overall, 8 patients and 11 participants were found to have some serum immunoreactivity toward neuronal or neuromuscular junction proteins, but only 1 patient and 2 participants had specific serum antibodies. Nevertheless, seropositive status in patients with ME was associated with shorter duration since onset and a more severe disease.

Implications: The results indicate no overall increased frequency of antibodies to neuronal proteins in ME/CSF and no evidence of a specific antibody that might be causative or contribute to clinical features in patients. However, the association of seropositive status with shorter duration of disease and more severe symptoms suggests a possible role of antibodies at onset in some patients and should be the focus of future studies.

9. Gregorowski A et al. (2019)
Child and adolescent chronic fatigue syndrome/myalgic encephalomyelitis: where are we now?
Curent Opinion in Pediatrics [Epub ahead of print].

Abstract
The current review aims to determine the recent evidence regarding cause, impact, effective treatment and prognosis of children and young people (CYP) affected by chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) at a time when the National Institute for Clinical Excellence guidelines in the United Kingdom are being reviewed and more research is called for worldwide.

CFS/ME is a debilitating illness with no clear cause. This review describes the heterogeneous clinical picture and the effects on the young person and family. Comorbidities such as mood disorders and pain are discussed including evidence for treatment. The various aetiological hypotheses are discussed and the precipitating factors identified. The evidence base is limited regarding effective treatment for CYP with CFS/ME, particularly the severely affected group. A large trial of online cognitive behavioural therapy with teenagers is being explored in the United Kingdom. The Lightning Process has been shown to be effective when added to medical care.

Current evidence is hampered by different diagnostic criteria, the heterogeneous nature of the condition, and limited number of small studies. There is a clear need for more research and larger studies exploring the cause of and most effective treatment for CYP with CFS/ME.

10. Josev EK et al. (2019)
Resting-state functional connectivity, cognition, and fatigue in response to cognitive exertion: a novel study in adolescents with chronic fatigue syndrome.
Brian Imaging and Behaviour [Epub ahead of print].

Abstract
Emerging evidence suggests that central nervous system dysfunction may underlie the core symptoms of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) in adults, such as cognitive disturbance, fatigue and post-exertional malaise. Research into brain dysfunction in the pediatric CFS/ME context, however, is severely lacking. It is unclear whether the adolescent CFS/ME brain functions differently compared with healthy peers, particularly in situations where significant mental effort is required.

This study used resting-state functional MRI in a novel repeated-measures design to evaluate intrinsic connectivity, cognitive function, and subjective fatigue, before and after a period of cognitive exertion in 48 adolescents (25 CFS/ME, 23 healthy controls).

Results revealed little evidence for a differential effect of cognitive exertion in CFS/ME compared with controls. Both groups demonstrated a similar rate of reduced intrinsic functional connectivity within the default mode network (DMN), reduced sustained attentional performance, slower processing speed, and increased subjective fatigue as a result of cognitive exertion. However, CFS/ME adolescents consistently displayed higher subjective fatigue, and controls outperformed the CFS/ME group overall on cognitive measures of processing speed, sustained attention and new learning. No brain-behavior relationships were observed between DMN connectivity, cognitive function, and fatigue over time.

These findings suggest that effortful cognitive tasks may elicit similar levels of energy expenditure across all individuals in the form of reduced brain functioning and associated fatigue. However, CFS/ME may confer a lower starting threshold from which to access energy reserves and cognitive resources when cognitive effort is required.

11. Kristiansen MS et al. (2019)
Clinical symptoms and markers of disease mechanisms in adolescent chronic fatigue following Epstein-Barr virus infection: An exploratory cross-sectional study.
Brain, Behaviour and Immunity [Epub ahead of print].

Abstract
Acute Epstein-Barr virus (EBV) infection is a trigger of chronic fatigue (CF) and Chronic Fatigue Syndrome (CFS). The aim of this cross-sectional study was to explore clinical symptoms as well as markers of disease mechanisms in fatigued and non-fatigued adolescents 6 months after EBV-infection, and in healthy controls.

A total of 200 adolescents (12–20 years old) with acute EBV infection were assessed 6 months after the initial infectious event and divided into fatigued (EBV CF+) and non-fatigued (EBV CF−) cases based on questionnaire score. The EBV CF+ cases were further sub-divided according to case definitions of CFS. In addition, a group of 70 healthy controls with similar distribution of sex and age was included.

Symptoms were mapped with a questionnaire. Laboratory assays included EBV PCR and serology; detailed blood leukocyte phenotyping and serum high-sensitive C-reactive protein; and plasma and urine cortisol and catecholamines. Assessment of autonomic activity was performed with continuous, non-invasive monitoring of cardiovascular variables during supine rest, controlled breathing and upright standing.

Differences between EBV CF+ and EBV CF− were assessed by simple and multiple linear regression adjusting for sex as well as symptoms of depression and anxiety. A p-value ≤ 0.05 was considered statistically significant. This study is part of the CEBA-project (Chronic fatigue following acute Epstein-Barr virus infection in adolescents).

The EBV CF+ group had significantly higher scores for all clinical symptoms. All markers of infection and most immune, neuroendocrine and autonomic markers were similar across the EBV CF+ and EBV CF− group. However, the EBV CF+ group had slightly higher serum C-reactive protein (0.48 vs 0.43 mg/L, p = 0.031, high-sensitive assay), total T cell (CD3+) count (median 1573 vs 1481 × 106 cells/L, p = 0.012), plasma norepinephrine (1420 vs 1113 pmol/L, p = 0.01) and plasma epinephrine (363 vs 237 nmol/L, p = 0.032); lower low-frequency:high frequency (LF/HF) ratio of heart rate variability at supine rest (0.63 vs 0.76, p = 0.008); and an attenuated decline in LF/HF ratio during controlled breathing (−0.11 vs −0.25, p = 0.002). Subgrouping according to different CFS diagnostic criteria did not significantly alter the results. Within the EBV CF+ group, there were no strong correlations between clinical symptoms and markers of disease mechanisms. In a multiple regression analysis, serum CRP levels were independently associated with serum cortisol (B = 4.5 × 10−4, p < 0.001), urine norepinephrine(B = 9.6 × 10−2, p = 0.044) and high-frequency power of heart rate variability (B = –3.7 × 10−2, p = 0.024).

In adolescents, CF and CFS 6 months after acute EBV infection are associated with high symptom burden, but no signs of increased viral load and only subtle alterations of immune, autonomic, and neuroendocrine markers of which no one is strongly correlated with symptom scores. A slight sympathetic over parasympathetic predominance is evident in CF and might explain slightly increased CRP levels.

12. Loades ME et al. (2019)
Psychometric properties of the Cognitive and Behavioural Responses Questionnaire (CBRQ) in adolescents with chronic fatigue syndrome.
Behavioural and Cognitive Psychotherapy [Epub ahead of print]. Link:

Abstract
Background: To better understand the maintenance of chronic fatigue syndrome (CFS), a valid and reliable measure of cognitive and behavioural responses to symptoms is required. Such a measure could also assess beliefs and coping behaviours in the context of fatigue in other somatic conditions.

Aims: We aimed to establish the psychometric properties of both the Cognitive and Behavioural Responses Questionnaire (CBRQ) and its shortened version (CBRQ-S) in adolescents with CFS.

Method: The full questionnaire was completed by a clinical cohort of adolescents (n = 121) presenting to specialist CFS units in the UK.

Results: Both the CBRQ and CBRQ-S had good internal consistency. The CBRQ scores were strongly associated with depression, anxiety, school and social functioning, but weakly associated with fatigue and physical functioning, providing evidence of validity.

Conclusion: Both the 40-item and the 18-item versions of the CBRQ were found to be reliable and valid in adolescents with CFS. To minimize unnecessary burden, the 18-item version is favoured. Using this assessment tool in future studies, including intervention studies, may help to better target interventions during clinical practice and improve outcomes.

13. Loades ME et al. (2019)
Obstacles to recruitment in paediatric studies focusing on mental health in a physical health context: the experiences of clinical gatekeepers in an observational cohort study.
BMC Medical Research Methodology 19: 89.

Abstract
Background: Studies in both paediatric and psychiatric settings often experience problems in recruitment. This can compromise the ability of the study to recruit to target, meaning studies are potentially underpowered. It can also result in a biased sample if a non-representative group are selectively recruited. Recruitment to studies in health contexts often depends on healthcare professionals, who act as gatekeepers by screening patients for eligibility and obtaining consent for the research team to contact them. The experience of health professionals as gatekeepers in paediatric studies is poorly understood and may affect whether recruitment is successful or not.

Methods: Six out of seven eligible healthcare professionals from a specialist paediatric chronic fatigue syndrome (CFS) team were interviewed. All participants were undertaking initial clinical assessments within which they were asked to identify eligible patients for an observational study of co-morbid mental health problems in adolescents with confirmed CFS/ME. This study had experienced particular recruitment problems, more so than other studies in the same service. Interview questions were designed to explore perceptions of research, and barriers and facilitators of recruitment. Interviews were audio recorded and transcribed verbatim. Thematic analysis was used.

Results: Participants espoused their commitment to the value of research. However, they perceived there to be a number of barriers to recruitment. Barriers within the clinical context included time pressures and the emotional nature of initial clinical assessments. Barriers posed by the wider research context included recruiting to multiple studies at the same time. Factors specific to the observational study of mental health in CFS/ME included aspects of the study design, such as the name and nature of the study, as well as the focus of the study itself. Participants made a number of recommendations about how recruitment barriers could be overcome.

Conclusions: The current study highlights the need to carefully consider, at design stage, how to overcome potential barriers to recruitment. Gatekeepers should be actively involved at this stage to ensure that the study is set up in such a way to best enable recruitment activities within the clinical setting.

14. Nojima N (2019)
Paradox of diagnosis: the positive effects and limitations of diagnosis in myalgic encephalomyelitis/chronic fatigue syndrome (me/cfs) and fibromyalgia (fm) sufferers.
Osaka Human Sciences 5: 55-70.

Abstract
Diagnosis is a topic of discussion in recent studies on contested illnesses. Without an accurate medical diagnosis, sufferers face the risk that people may think they are malingering or faking. Therefore, receiving a diagnosis can be a critical event for sufferers because it legitimizes their illness. This paper explores how diagnosis impacts the illness experience of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or fibromyalgia (FM) sufferers.

The findings can be divided into the positive effects and limitations of diagnosis. Positive effects of diagnosis include achieving relief because of the legitimation of suffering and liberation from guilt; however, diagnosis posits several shortcomings. Often, despite being diagnosed, others fail to recognize the sufferers’ condition as a serious disease or as a disease at all. This paradox of diagnosis highlights the significance of delegitimizing sufferers’ experiences and the vulnerability of legitimate diagnosis.

15. Perez M et al. (2019)
Genetic Predisposition for Immune System, Hormone, and Metabolic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Study.
Frontiers in Pediatrics 7: 206.

Abstract
Introduction: Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a multifactorial illness of unknown etiology with considerable social and economic impact. To investigate a putative genetic predisposition to ME/CFS we conducted genome-wide single-nucleotide polymorphism (SNP) analysis to identify possible variants.

Methods: 383 ME/CFS participants underwent DNA testing using the commercial company 23andMe. The deidentified genetic data was then filtered to include only non-synonymous and nonsense SNPs from exons and microRNAs, and SNPs close to splice sites. The frequencies of each SNP were calculated within our cohort and compared to frequencies from the Kaviar reference database. Functional annotation of pathway sets containing SNP genes with high frequency in ME/CFS was performed using over-representation analysis via ConsensusPathDB. Furthermore, these SNPs were also scored using the Combined Annotation Dependent Depletion (CADD) algorithm to gauge their deleteriousness.

Results: 5693 SNPs were found to have at least 10% frequency in at least one cohort (ME/CFS or reference) and at least two-fold absolute difference for ME/CFS. Functional analysis identified the majority of SNPs as related to immune system, hormone, metabolic, and extracellular matrix organization. CADD scoring identified 517 SNPs in these pathways that are among the 10% most deleteriousness substitutions to the human genome.

16. Raijmakers RPH et al. (2019)
A possible role for mitochondrial-derived peptides humanin and MOTS-c in patients with Q fever fatigue syndrome and chronic fatigue syndrome.
Journal of Translational Medicine 17 (1): 157.

Abstract
Background: Q fever fatigue syndrome (QFS) is a well-documented state of prolonged fatigue following around 20% of acute Q fever infections. It has been hypothesized that low grade inflammation plays a role in its aetiology. In this study, we aimed to identify transcriptome profiles that could aid to better understand the pathophysiology of QFS.

Methods: RNA of monocytes was collected from QFS patients (n = 10), chronic fatigue syndrome patients (CFS, n = 10), Q fever seropositive controls (n = 10), and healthy controls (n = 10) who were age- (± 5 years) and sex-matched. Transcriptome analysis was performed using RNA sequencing.

Results: Mitochondrial-derived peptide (MDP)-coding genes MT-RNR2 (humanin) and MT-RNR1 (MOTS-c) were differentially expressed when comparing QFS (- 4.8 log2-fold-change P = 2.19 × 10-9 and – 4.9 log2-fold-change P = 4.69 × 10-8), CFS (- 5.2 log2-fold-change, P = 3.49 × 10-11 – 4.4 log2-fold-change, P = 2.71 × 10-9), and Q fever seropositive control (- 3.7 log2-fold-change P = 1.78 × 10-6 and – 3.2 log2-fold-change P = 1.12 × 10-5) groups with healthy controls, resulting in a decreased median production of humanin in QFS patients (371 pg/mL; Interquartile range, IQR, 325-384), CFS patients (364 pg/mL; IQR 316-387), and asymptomatic Q fever seropositive controls (354 pg/mL; 292-393).

Conclusions: Expression of MDP-coding genes MT-RNR1 (MOTS-c) and MT-RNR2 (humanin) is decreased in CFS, QFS, and, to a lesser extent, in Q fever seropositive controls, resulting in a decreased production of humanin. These novel peptides might indeed be important in the pathophysiology of both QFS and CFS.

17. Rekeland IG et al. (2019)
Rituximab Serum Concentrations and Anti-Rituximab Antibodies During B-Cell Depletion Therapy for Myalgic Encephalopathy/Chronic Fatigue Syndrome.
Clinical Therapeutics 41 (5): 806-814.

Abstract
Previous Phase II trials indicated clinical benefit from B-cell depletion using the monoclonal anti-CD20 antibody rituximab in patients with myalgic encephalopathy/chronic fatigue syndrome (ME/CFS). The association between rituximab serum concentrations and the effect and clinical relevance of antidrug antibodies (ADAs) against rituximab in ME/CFS is unknown. We retrospectively measured rituximab concentrations and ADAs in serum samples from patients included in an open-label Phase II trial with maintenance rituximab treatment (KTS-2-2010) to investigate possible associations with clinical improvement and clinical and biochemical data.

Patients with ME/CFS fulfilling the Canadian criteria received rituximab (500 mg/m2) infusions: 2 infusions 2 weeks apart (induction), followed by maintenance treatment at 3, 6, 10, and 15 months. The measured rituximab concentrations and ADAs in serum samples included 23 of 28 patients from the trial.

There were no significant differences in mean serum rituximab concentrations between 14 patients experiencing clinical improvement versus 9 patients with no improvement. Female patients had higher mean serum rituximab concentrations than male patients at 3 months (P = 0.05). There was a significant negative correlation between B-cell numbers in peripheral blood at baseline and rituximab serum concentration at 3 months (r = -0.47; P = 0.03). None of the patients had ADAs at any time point.

Clinical improvement of patients with ME/CFS in the KTS-2-2010 trial was not related to rituximab serum concentrations or ADAs. This finding is also in line with a recent randomized trial questioning the efficacy of rituximab in ME/CFS. Rituximab concentrations and ADAs still offer supplemental information when interpreting the results of these trials.

18. Theoharides TC (2019)
In Search of Effective Treatments for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Clinical Therapeutics 41 (5): 796-797.

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized primarily by severe, unexplained fatigue accompanied by dysfunctional homeostasis with possible focal inflammation in the hypothalamus. Scientists have struggled to identify the pathogenesis of ME/CFS. In the April issue of Clinical Therapeutics, experts report their findings on the diagnosis and possible causes of ME/CFS. However, effective treatments remain elusive and the presence of comorbidities further complicates the search for a cure.

19. Thomas et al. (2019)
Measurements of Recovery and Predictors of Outcome in an Untreated Chronic Fatigue Syndrome Sample.
Journal of Health and Medical Sciences 2 (2): 167-178.

Abstract
The current study examined a large cohort of untreated Chronic Fatigue Syndrome patients at initial assessment and at specific time points over a three-year period. Methods used in previous studies to assess patient health, were validated and used to assess recovery and improvement. Possible predictors of outcome would then be identified by assessing improvements in health status at specific follow-up points. The illness was also assessed in terms of recovery and improvement by using health related and psychosocial measures together with the aetiology of the illness. These were further used to investigate possible mechanisms influencing or predicting recovery or improvement.

Two-hundred and twenty-six patients completed wide ranging questionnaires at initial assessment and again six and eighteen months and three years later. A current state of health score was used to measure recovery over time and analyses conducted to investigate the relationship between this and other health related measures. Regression analyses were conducted to assess predictors of improvement and recovery.

Spontaneous recovery rates in the untreated patient at three-year follow-up were low (6%). The data suggested, however, that illness length, symptom severity and health status have an important role in recovery. Although there was no evidence to suggest an association between illness onset type and subsequent recovery or psychopathology scores at initial assessment and recovery, regression analyses did indicate that levels of anxiety, cognitive difficulties and social support at initial assessment predict a positive outcome. The state of health measure was validated as a method of accurately assessed the health status of patients and was used as an indicator of improvement and recovery within this group.

Spontaneous recovery in the patient group was associated with several factors measured at initial assessment. However, further studies are necessary to more fully identify the factors which affect recovery or improvement and to investigate the exact nature of the mechanisms involved.

The present study shows that spontaneous recovery of CFS patients is rare. Treatment or management is essential, and the efficacy of different approaches must be assessed.

20. Tsai SY et al. (2019)
Increased risk of chronic fatigue syndrome following psoriasis: a nationwide population-based cohort study.
Journal of Translational Medicine 17 (1): 154.

Abstract
Background: The onset of chronic fatigue syndrome (CFS) has been shown to be associated with several immunological conditions such as infections or atopy. The aim of this study was to clarify the risk of chronic fatigue syndrome following the diagnosis of psoriasis, an immune-related dermatological disease, by analyzing the National Health Insurance Research Database of Taiwan.

Method: 2616 patients aged 20 years or older with newly diagnosed psoriasis during 2004-2008 and 10,464 participants without psoriasis were identified. Both groups were followed up until the diagnoses of CFS were made at the end of 2011.

Results: The relationship between psoriasis and the subsequent risk of CFS was estimated through Cox proportional hazards regression analysis, with the incidence density rates being 2.27 and 3.58 per 1000 person-years among the non-psoriasis and psoriasis populations, respectively (adjusted hazard ratio [HR] = 1.48, with 95% confidence interval [CI] 1.07-2.06). In the stratified analysis, the psoriasis group were consistently associated with a higher risk of CFS in male sex (HR = 2.05, 95% CI 1.31-3.20) and age group of ≥ 60 years old (HR = 2.32, 95% CI 1.33-4.06). In addition, we discovered that the significantly increased risk of CFS among psoriasis patients is attenuated after they receive phototherapy and/or immunomodulatory drugs.

Conclusions: The data from this population-based retrospective cohort study revealed that psoriasis is associated with an elevated risk of subsequent CFS, which is differentiated by sex and age.

21. Twisk FNM (2019)
Myalgic Encephalomyelitis, Chronic Fatigue Syndrome, and Chronic Fatigue: Three Distinct Entities Requiring Complete Different Approaches.
Letter to the Editor, Current Rheumatological Reports 21 (6): 27.

Abstract
A recent review implicates that myalgic encephalomyelitis (ME), chronic fatigue syndrome(CFS), and chronic fatigue are part of the “fatigue spectrum” and recommends “longitudinal studies integrating biopsychosocial approaches to inform early management and targeted rehabilitation strategies.”

ME is a neuromuscular disease distinguished by muscle fatigability (prolonged muscle weakness after minor exertion) and specific signs of neurological dysfunction. ME is not equivalent to CFS, as proposed by the authors. CFS is defined as unexplained chronic fatigue accompanied by at least four out of a list of eight specific symptoms. CFS is a distinct clinical entity and not merely a severe variant of CF, as suggested. Proof that CF, CFS, and ME are part of a “fatigue continuum” and that CF can convert to CFS at a later stage is lacking.

Biopsychosocial approaches for early management and rehabilitation of CF, as promoted by the authors, are at odds with the current understandings of ME, CFS, and CF. The (bio)psychosocial explanatory models for ME and CFS have proven to be invalid, and the associated interventions, cognitive behavioral therapy and graded exercise therapy, have shown to be ineffective and even potentially harmful.

ME, CFS, and CF are three very distinct clinical entities. Interventions justified by (bio)psychosocial models appear to be unsuccessful and potentially noxious. To develop effective treatments, it is crucial to make a clear distinction between ME, CFS, and CF and to leave the (bio)psychosocial explanations and therapies behind us.

22. Vink M and Vink-Niese A (2019)
Cognitive behavioural therapy for myalgic encephalomyelitis/chronic fatigue syndrome is not effective. Re-analysis of a Cochrane review.
Health Psychology Open 6 (1).

Abstract
Analysis of the 2008 Cochrane review of cognitive behavioural therapy for chronic fatigue syndrome shows that seven patients with mild chronic fatigue syndrome need to be treated for one to report a small, short-lived subjective improvement of fatigue. This is not matched by an objective improvement of physical fitness or employment and illness benefit status. Most studies in the Cochrane review failed to report on safety or adverse reactions. Patient evidence suggests adverse outcomes in 20 per cent of cases. If a trial of a drug or surgical procedure uncovered a similar high rate, it would be unlikely to be accepted as safe. It is time to downgrade cognitive behavioural therapy to an adjunct support-level therapy, rather than a treatment for chronic fatigue syndrome.

23. Williams MV et al. (2019)
Epstein-Barr Virus dUTPase Induces Neuroinflammatory Mediators: Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Clinical Therapeutics 41 (5): 848;863.

Abstract
Purpose: neuroinflammation is a common feature in myalgic encephalomyelitis/chronic fatigue syndrome(me/cfs), affecting 85%-90% of all patients, yet the underlying mechanism or mechanisms responsible for the initiation and/or promotion of this process is largely unknown. multiple reports, however, have suggested a role for epstein-barr virus (ebv), in particular, in me/cfs, but its potential role, if any, in the neuroinflammatory process has not been addressed.

In support of this premise, studies by our group have found that the ebv protein deoxyuridine triphosphate nucleotidohydrolase (dutpase) induces anxiety and sickness behaviors in female mice. We also found that a small subset of patients with me/cfs exhibited prolonged and significantly elevated neutralizing antibodies against ebv dutpase protein in serum, which inversely correlated with me/cfs symptoms. a larger me/cfs case-control cohort study further confirmed that a significant percentage of patients with me/cfs (30.91%-52.7%) were simultaneously producing antibodies against multiple human herpesviruses-encoded dutpases and/or human dutpase. altogether, these findings suggest that ebv dutpase protein may be involved in the neuroinflammatory process observed in me/cfs. thus, the aim of the present study was to determine whether the ebv dutpase protein could contribute to neuroinflammation by altering the expression of genes involved with maintaining blood-brain barrier (bbb) integrity and/or modulating synaptic plasticity.

Methods: with the use of human immortalized astrocytes, microglia, and cerebral microvascular endothelial cells, we conducted time-course (0-24 h) experiments with ebv dutpase protein (10 μg/ml) to determine what effect(s) it may have on the expression of genes involved with bbb permeability, astrocytes and microglia cell function, tryptophan metabolism, and synaptic plasticity by quantitative reverse transcription polymerase chain reaction (qrt-pcr). In parallel, in vivo studies were conducted in female c57bl/6 mice. mice were injected by the intraperitoneal route with ebv dutpase protein (10 μg) or vehicle daily for 5 days, and the brains were collected and processed for further qrt-pcr analysis of the in vivo effect of the dutpase on the dopamine/serotonin and γ-aminobutyric acid/glutamate pathways, which are important for brain function, using rt2 profiler pcr arrays.

Findings: ebv dutpase protein altered the expression in vitro (12 of 15 genes and 32 of 1000 proteins examined) and in vivo (34 of 84 genes examined) of targets with central roles in bbb integrity/function, fatigue, pain synapse structure, and function, as well as tryptophan, dopamine, and serotonin metabolism.

Implications: The data suggest that in a subset of patients with me/cfs, the ebv dutpase could initiate a neuroinflammatory reaction, which contributes to the fatigue, excessive pain, and cognitive impairments observed in these patients.

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