ME Association November Summary of ME/CFS Published Research | 04 December 2018

December 4, 2018


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 November 2018.

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 to the Journal it was published in.

You can also find the index in the Research section of our website.

ME/CFS research abstracts from studies published in November 2018

1. Abonie US, et al. (2018)
Effects of activity pacing in patients with chronic conditions associated with fatigue complaints: a meta-analysis
Disability and Rehabilitation.

A meta-analysis was conducted to (1) determine the effect of activity pacing interventions on fatigue, physical functioning and physical activity among patients with chronic conditions associated with fatigue complaints, and to (2) examine potential moderator effects of trial characteristics (components of intervention and amount of patient-provider contact).

Six studies were included in the meta-analysis. Relevant content of the studies was extracted and rated on methodological quality. Random-effects modeling was used to pool data across studies. Medium (standardized mean difference =0.50) and marginal (standardized mean difference =0.34) effects were found for fatigue at post-treatment and follow-up respectively. Inconsequential effects were found for physical functioning and activity (standardized mean difference =0.08–0.30) at both assessment points.

Subgroup analyses revealed components of intervention and amount of patient-provider contact were not the source of variance. Minimal patient-provider contact had an effect on fatigue comparable in magnitude to more intensive contact.

This meta-analysis of activity pacing in patients with fatigue complaints suggests that activity pacing might have sustained beneficial effects on fatigue management, in particular on fatigue reduction. The divergence in effects for all outcomes suggests that alternative ways such as tailoring advice to individual’s behavior toward physical activity may be more successful.

In a relatively small sample this meta-analysis shows fatigue severity improved after activity pacing interventions and provides a basis to integrate activity pacing in activity stimulation programs for persons with chronic conditions. Activity pacing can feasibly be implemented within standard health care to manage fatigue and physical activity behaviors in persons with chronic conditions.

2. Bjørklund, et al. (2018)
Chronic fatigue syndrome (CFS): Suggestions for a nutritional treatment in the therapeutic approach
Biomedicine & Pharmacotherapy 109: 1000-1007.

Chronic fatigue syndrome (CFS) is known as a multi-systemic and complex illness, which induces fatigue and long-term disability in educational, occupational, social, or personal activities. The diagnosis of this disease is difficult, due to lacking a proper and suited diagnostic laboratory test, besides to its multifaceted symptoms.

Numerous factors, including environmental and immunological issues, and a large spectrum of CFS symptoms, have recently been reported. In this review, we focus on the nutritional intervention in CFS, discussing the many immunological, environmental, and nutritional aspects currently investigated about this disease.

Changes in immunoglobulin levels, cytokine profiles and B- and T- cell phenotype and declined cytotoxicityof natural killer cells, are commonly reported features of immune dysregulation in CFS. Also, some nutrient deficiencies (vitamin C, vitamin B complex, sodium, magnesium, zinc, folic acid, l-carnitine, l-tryptophan, essential fatty acids, and coenzyme Q10) appear to be important in the severity and exacerbation of CFS symptoms. This review highlights a far-driven analysis of mineral and vitamin deficiencies among CFS patients.

3. Blitshetyn S, et al. (2018)
Autonomic dysfunction and HPV immunization: an overview
Immunological Research [Epub ahead of print].

This article reviews the case series reported from several countries describing patients with suspected severe side effects to the HPV vaccines.

The described symptom clusters are remarkably similar and include disabling fatigue, headache, widespread pain, fainting, gastrointestinal dysmotility, limb weakness, memory impairment episodes of altered awareness, and abnormal movements.

This constellation of symptoms and signs has been labelled with different diagnoses such as complex regional pain syndrome (CRPS), postural orthostatic tachycardia syndrome (POTS), small fiber neuropathy (SFN), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), or fibromyalgia.

It is known that autoimmunity and autoantibodies are present in a subset of patients with CRPS, POTS, SFN, ME/CFS, and fibromyalgia. This article proposes that vaccine-triggered, immune-mediated autonomic dysfunction could lead to the development of de novo post-HPV vaccination syndrome possibly in genetically susceptible individuals.

Being cognizant that a temporal relationship between vaccination and symptom onset does not necessarily equate to causality, mounting evidence of case series calls for well-designed case-control studies to determine the prevalence and possible causation between these symptom clusters and HPV vaccines.

Since personalized medicine is gaining momentum, the use of adversomics and pharmacogenetics may eventually help identify individuals who are predisposed to HPV vaccine adverse events.

4. Campen CM and Visser FC (2018)
The Abnormal Cardiac Index and Stroke Volume Index Changes During a Normal Tilt Table Test in ME/CFS Patients Compared to Healthy Volunteers, are Not Related to Deconditioning
Journal of Thrombosis and Circulation 107.
See also: ME Association Summary Review (23.11.18)


Background: A small study in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) patients undergoing tilt testing, showed that, despite a normal tilt test, stroke volumes and cardiac output were lower than in healthy volunteers. Moreover, it was suggested that this difference was related to deconditioning of patients. Aim of the study. We performed table testing in 150 ME/CFS patients. Stroke volumes and cardiac output were related to the severity of the disease.

Methods: In the patients the severity of the disease was clinically evaluated according to the ME criteria and scored as mild, moderate or severe disease. In a subgroup of 109 patients this clinical diagnosis was confirmed by the physical functioning score of the Rand-36 questionnaire. Significantly lower physical functioning scores (indicating worse functioning) were observed in the more severely affected patients. Stroke Volume Index (SVI) and Cardiac Index (CI) were measured by suprasternal aortic Doppler imaging in the supine position, prior to the tilt, and twice during the tilt. Thirty-seven healthy volunteers underwent the same tilt protocol.

Methods: In all patients and all healthy volunteers, a normal heart rate and blood pressure response was observed during the tilt. The decreases in SVI and CI during the tilt was significantly larger in patients compared to the SVI and CI decrease in HV. The decrease in SVI and CI were similar and not significantly different between the mild, moderate, and severe ME groups.

Conclusions: During a normal tilt table test decreases in SVI and CI decrease are significantly greater in ME/CFS patients than in HV, consistent with previous work. The absence of differences between patients with mild, moderate, and severe ME/CFS suggests that the decreases in stroke volumes and cardiac output are not related to deconditioning. Other factors like decreased blood volumes and autonomic dysfunction may cause this difference in the hemodynamic response between ME/CFS patients and HV.

5. Campen CM, et al. (2018a)
Blood Volume Status in ME/CFS Correlates With the Presence or Absence of Orthostatic Symptoms: Preliminary Results

Frontiers in Pediatrics 6: 352.

Introduction: Conflicting data have been published on the reduction of circulating blood volume in adults with Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The aim of the present study was to compare blood volumes based on the presence or absence of orthostatic symptoms.

Methods and Results: Twenty consecutive adults with ME/CFS participated in the study. All underwent dual isotope blood volume measurement and were evaluated for a clinical suspicion of orthostatic intolerance (OI).

The mean age was 34 (10) years, and median duration of disease was 7.5 (6–10) years. The mean (SD) absolute blood volume was 59 (8) ml/kg, a value −11 (7) ml/kg below the reference blood volume.

Of the 12 patients, 4 had no OI and 8 had a clinical suspicion of OI. In 8 patients with OI, absolute blood volumes were significantly lower than for the 4 without OI (56 [2] vs. 66 [5]; p < 0.05) as were the differences between the measured and the reference blood volume (−14 [2]; vs. −4 [3]; p < 0.02).

Conclusions: Adults with ME/CFS had a significantly lower blood volume if they had a clinical suspicion of OI compared to those without a clinical suspicion of OI, as well as a significantly lower blood volume compared to the expected value. The data suggest that accounting for symptoms of OI could enhance the detection of the subset with reduced blood volume.

6. Campen CM, et al. (2018b)
Low Sensitivity of Abbreviated Tilt Table Testing for Diagnosing Postural Tachycardia Syndrome in Adults With ME/CFS
Frontiers in Paediatrics 6: 349.

Introduction: Orthostatic intolerance is common among individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In some ME/CFS case definitions, orthostatic intolerance is considered a core feature of the disorder.

Some studies have employed tilt table tests lasting 2–5 min to diagnose one common form of orthostatic intolerance, postural tachycardia syndrome (POTS). We examined the diagnostic yield of abbreviated durations of tilt testing in adults meeting criteria for ME/CFS, and identified the proportion with POTS misdiagnosed using testing of <10 min.

Methods: Eligible participants were consecutive individuals satisfying study criteria for ME/CFS and POTS evaluated at the Stichting CardioZorg (SCZ, Hoofddorp, NL) between November 2012 and August 2018.

Individuals being treated with medications commonly used to manage orthostatic intolerance were excluded. Head-up tilt table testing involved 15 min of supine posture then 20 min at 70 degrees upright. Only the data from the first 10-min upright were used.

POTS was defined as an increase in HR during a maximum of 10 min of upright tilt of at least 30 beats per minute (bpm), in the absence of either classical or delayed orthostatic hypotension.

We measured the time until HR criteria for POTS were reached using survival curves, and compared survival curves between subgroups divided by age, sex, disease duration, and degree of hypocapnia during the test.

Results: Of 627 individuals with ME/CFS evaluated during the study period, 155 met criteria for POTS. The median time to reaching HR criteria for POTS was 3 min. A two-minute tilt table test would miss 55% (95% CI, 48–63%) of those meeting POTS criteria over the course of 10 min upright. The median time to reaching HR criteria for POTS did not differ by sex, age, duration of ME/CFS, or hypocapnia during tilt.

Conclusions: Abbreviated tilt table testing misses a substantial proportion of those ultimately diagnosed with POTS during a 10-min tilt table test, and should be abandoned for the clinical diagnosis and in epidemiologic studies designed to estimate the prevalence of POTS among those with ME/CFS.

7. Carroll S, et al. (2018)
Adolescent and parent factors related to fatigue in paediatric multiple sclerosis and chronic fatigue syndrome: A comparative study
European Journal of Paediatric Neurology [Epub ahead of print].

Background: Fatigue is a disabling, poorly understood symptom in children and adolescents with multiple sclerosis (caMS), for which effective treatments are lacking. In paediatric Chronic Fatigue Syndrome (CFS), effective psychological interventions have been developed based on psychosocial factors associated with fatigue.

This study aimed to identify potentially modifiable factors of fatigue in caMS by comparing caMS, adolescents with CFS, healthy adolescents and their parents on measures of fatigue, psychosocial factors, and neurocognitive functioning.

Methods: 175 participants including 30 caMS (15 fatigued, 15 non-fatigued), 30 adolescents with CFS, 30 healthy controls, and their parents were compared on measures of self- and parent-reported fatigue, adolescent and parent cognitive behavioural responses to symptoms, sleep, psychological difficulties, parental distress and objectively measured neurocognitive functioning.

Results: Fatigue severity, functional impairment and cognitive behavioural responses to symptoms were equivalent in fatigued caMS and adolescents with CFS and were significantly higher than in healthy controls and non-fatigued caMS.

Neurocognitive functioning was impaired in both caMS groups but was normal in adolescents with CFS and healthy controls. No between-group differences were identified in adolescent sleep behaviour or psychological difficulties.

Parents of all illness groups had more unhelpful cognitions than parents of healthy controls. Psychological distress was elevated in parents of both fatigued groups.

Conclusions: Fifty percent of caMS reported clinically significant fatigue. Similarities between adolescent and parent cognitive behavioural factors in fatigued caMS and adolescents with CFS suggest important potential targets for intervention. Both fatigued and non-fatigued caMS had cognitive difficulties, suggesting that fatigue may need targeted intervention.

8. Castro-Marrero J, et al. (2018)
Low omega-3 index and polyunsaturated fatty acid status in patients with chronic fatigue syndrome/myalgic encephalomyelitis
Prostaglandins Leukotrienes and Essential Fatty Acids 139, 20-24.

Background: Several studies have suggested that low levels of omega-3 fatty acids (n-3 PUFAs) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are associated with cardiovascular risk, major depression, sleep problems, inflammation and other health-related issues.

So far, however, erythrocyte PUFA status in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) has not been established. This study aimed to determine whether n-3 PUFA content and omega-3 index are associated with measures in CFS/ME patients.

Methods: PUFA levels and omega-3 index were measured in 31 Spanish CFS/ME patients using the HS-Omega-3 Index method. Demographic and clinical characteristics and self-reported outcome measures were also recorded.

Results: A low mean omega-3 index (5.75%) was observed in 92.6% of the sample. Omega-3 index was inversely correlated with the AA/EPA ratio (p = 0.00002) and the BMI (p = 0.0106). In contrast, the AA/EPA ratio was positively associated with the BMI (p = 0.0038). No association for FIS-40 and PSQI measures was found (p > 0.05).

Conclusion: The low omega-3 index found in our CFS/ME patients may indicate increased risks for cardiovascular health, which should be further investigated. A low omega-3 index also suggests a pro-inflammatory state in these patients. Attempts should be made to increase the omega-3 index in CFS/ME patients, based on intervention trials assessing a potential therapeutic value.

9. Comhaire F (2018)
Why do some ME/CFS patients benefit from treatment with sodium dichloroacetate, but others do not? Medical Hypotheses 120: 65-67.

Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is an enigmatic disease the pathogenesis of which remains elusive.

Pragmatic proof-of-principle of the hypothetical mechanisms causing the clinical symptoms has been delivered, but it is hard to explain why some patients do respond favourably to treatment with sodium dichloroacetate (DCA), which enhances the activity of the mitochondrial enzyme pyruvate dehydrogenase, but other patients experience no benefit from this substance.

In a prospective trial including 35 ME/CFS patients, logistic regression analysis with stepwise elimination has identified 6 pre-treatment characteristics allowing for the differentiation between responders (n = 13) and non-responders (n = 22) with high accuracy (P < 0.0001; area under the ROC-curve = 0.92).

A formula was derived generating the probability of belonging to the group of responders. This finding may assist in selecting ME/CFS patients suitable for treatment with DCA but requires further studies as to the predictive capacity of the derived formula.

10. De Meirleir KL, et al. (2018)
Evaluation of four clinical laboratory parameters for the diagnosis of myalgic encephalomyelitis
Journal of Translational Medicine 16 (1): 322.

Background: Myalgic encephalomyelitis (ME) is a complex and debilitating disease that often initially presents with flu-like symptoms, accompanied by incapacitating fatigue.

Currently, there are no objective biomarkers or laboratory tests that can be used to unequivocally diagnosis ME; therefore, a diagnosis is made when a patient meets series of a costly and subjective inclusion and exclusion criteria. The purpose of the present study was to evaluate the utility of four clinical parameters in diagnosing ME.

Methods: In the present study, we utilized logistic regression and classification and regression tree analysis to conduct a retrospective investigation of four clinical laboratory in 140 ME cases and 140 healthy controls.

Results: Correlations between the covariates ranged between [- 0.26, 0.61]. The best model included the serum levels of the soluble form of CD14 (sCD14), serum levels of prostaglandin E2 (PGE2), and serum levels of interleukin 8, with coefficients 0.002, 0.249, and 0.005, respectively, and p-values of 3 × 10-7, 1 × 10-5, and 3 × 10-3, respectively.

Conclusions: Our findings show that these parameters may help physicians in their diagnosis of ME and may additionally shed light on the pathophysiology of this disease.

11. Jason LA and Sunnquist M (2018)
The Development of the DePaul Symptom Questionnaire: Original, Expanded, Brief, and Pediatric Versions

Frontiers in Pediatrics 6: 330.

One of the key requirements of a reliable case definition is the use of standardized procedures for assessing symptoms. This article chronicles the development of the DePaul Symptom Questionnaire (DSQ) to assess symptoms of the major chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME) case definitions.

The original questionnaire has been modified and expanded over time to more fully capture symptoms from various adult case definitions, and a brief as well as pediatric version have also been developed. The DSQ has demonstrated very good psychometric properties in terms of test-retest reliability and sensitivity/specificity, as well as construct, predictive, and discriminant validity.

The DSQ allows for a clear characterization of a patient's illness and allows scientists and clinicians to improve diagnostic reliability and validity when employing case definitions of ME and CFS.

12. Kimura Y, et al. (2018)
Brain abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome: Evaluation by diffusional kurtosis imaging and neurite orientation dispersion and density imaging

Journal of Magnetic Resonance Imaging [Epub ahead of print].

Background: Diffusional kurtosis imaging (DKI) and neurite orientation dispersion and density imaging (NODDI) metrics provide more specific information regarding pathological changes than diffusion tensor imaging (DTI).

Purpose: To detect microstructural abnormalities in myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS) patients by using DKI and NODDI metrics.

Methods: Twenty ME/CFS patients and 23 healthy controls were recruited. Mean kurtosis (MK), neurite density index (NDI), orientation dispersion index (ODI), fractional anisotropy (FA), and mean diffusivity (MD) were calculated. The two-sample t-test analysis in SPM12 software was used to compare the differences between ME/CFS and control groups.

Results: In the ME/CFS patients, we observed significant FA decreases in the genu of the corpus callosum and the anterior limb of the right internal capsule (P < 0.05), but no significant difference in MD (P = 0.164); there were also significant MK decreases in the right frontal area, anterior cingulate gyrus, superior longitudinal fasciculus (SLF), and left parietal area (P < 0.05).

Significant NDI decreases were observed in the right posterior cingulate gyrus, SLF, and left frontal area of the ME/CFS patients (P < 0.05). Significant ODI decreases were seen in the bilateral occipital areas, right superior temporal gyrus, the anterior limb of internal capsule, and the posterior cingulate gyrus (P < 0.05), and significant ODI increases were revealed in the bilateral occipital and right temporal areas (P < 0.05).

Conclusion: Right SLF abnormalities may be a diagnostic marker for ME/CFS.

13. Lacerda EM, et al. (2018)
The UK ME/CFS Biobank: a disease-specific biobank for advancing clinical research into myalgic encephalomyelitis/chronic fatigue syndrome
Frontiers in Neurology [Epub ahead of print].


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling disease characterized by unexplained incapacitating fatigue, accompanied by variable multi-systemic symptoms. ME/CFS causes a significant personal and public health burden, and urgently requires the coordination of research efforts to investigate its etiology and pathophysiology and to develop and validate sensitive and specific biomarkers to confirm diagnosis.

This narrative paper describes how people with ME/CFS, together with a multidisciplinary team of researchers, have established the UK ME/CFS Biobank (UKMEB), a unique research infrastructure specifically designed to expedite biomedical research into ME/CFS. We describe the journey that led to its conceptualization and operation, and how the resource has served as a model disease-specific biobank, aggregating human biospecimens alongside comprehensive health information on participants.

The UKMEB currently has data and samples from 600 donors including people with ME/CFS and a comparison group with multiple sclerosis and healthy controls. A longitudinal sub-cohort has been established of participants having follow-up assessments at multiple time-points. As an open resource for quality and ethical research into ME/CFS, biological samples and data have not only been analysed within our research team but have also been shared with researchers across Europe, America and the Middle East.

We continue to encourage researchers from academic and commercial sectors to access the UKMEB. Major steps have been taken and challenges remain; these include sustainability and expansion, and harmonization of processes to facilitate integration with other bioresources and databanks internationally.

14. McManimen SL, et al. (2018)
Effects of unsupportive social interactions, stigma, and symptoms on patients with myalgic encephalomyelitis and chronic fatigue syndrome
Journal of Community Psychology 46 (8): 959-971.


Prior research has found a heightened risk of suicide in patients with myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). It is possible that a number of factors including stigma, unsupportive social interactions, and severe symptoms could lead to the development of depression, suicidal ideation, and heightened risk of suicide in this patient population.

Prior studies have indicated that patients often report the legitimacy of their illness being questioned by family, friends, and even their physicians. This study aimed to determine whether stigma experienced, social support, symptomology, and functioning may be associated with depression and endorsement of suicidal ideation (SI) in patients with a self-reported diagnosis of ME or CFS.

Findings indicated that participants that endorsed both SI and depression, in contrast to those that did not, experienced more frequent unsupportive social interactions in the form of blame for their illness, minimization of its severity, and social distancing from others. In addition, 7.1% of patients with ME and CFS endorsed SI but do not meet the criteria for clinical depression

These findings highlight the importance of stigma and unsupportive social interactions as risk factors for suicidal thoughts or actions among patients with ME and CFS. Community psychologists have an important role to play in helping educate health care professionals and the public to these types of risk factors for patients marginalized by ME and CFS.

15. Nacul LC, et al. (2018)
Hand grip strength as a clinical biomarker for ME/CFS and disease severity
Frontiers in Neurology 9.

Background: The diagnosis of myalgic encephalomyelitis (ME/CFS) in research and clinical practice has largely relied on clinical history, which can be subjective in nature. Clinical signs are often subtle, overlap with other conditions, and are not formally included as part of diagnostic workup. The characterization of clinical signs and biomarkers is needed for better diagnosis and classification of patients and to monitor treatment response. Hand grip strength (HGS) has been used as an objective measure of muscle strength and fatigue, which is a primary symptom of ME/CFS. We assessed the potential usefulness of HGS as a diagnostic marker in ME/CFS.

Methods: We compared HGS measurements from participants in the UK ME/CFS Biobank, with groups consisting of people with ME/CFS of differing severity (n = 272), healthy (n = 136), multiple sclerosis (n = 76) controls, and others with chronic fatigue not meeting the diagnosis of ME/CFS (n = 37). We correlated the maximum and minimum of, and differences between, 3 repeated HGS measurements with parameters of disease severity, including fatigue and pain analog scales, and physical and mental component summaries from the SF-36v2TM questionnaire across recruitment groups.

Results: HGS indicators were associated with having ME/CFS, with magnitudes of association stronger in severely affected than in mild/moderately affected patients. Compared with healthy controls, being severely affected was associated with a reduction in minimum HGS of 15.3 kg (95%CI 19.3–11.3; p < 0.001), while being mild/moderately affected was associated with a 10.5 kg (95%CI 13.2–7.8; p < 0.001) reduction. The association persisted after adjusting for age, sex and body mass index. ME/CFS cases also showed lower values of maximum HGS and significant drops in values from the first to second and third trials, compared to other study groups. There were significant correlations between HGS indicators and clinical parameters of disease severity, including fatigue analog scale (Spearman's Rho = −0.40, p < 0.001), pain analog scale (Rho = −0.38, p < 0.001), and physical component summary (Rho = 0.42, p < 0.001).

Discussion: HGS is markedly reduced in ME/CFS, particularly in patients with more severe disease, and may indicate muscle and fatigue related symptoms. HGS is a potential diagnostic tool in ME/CFS, and could also be used to enhance patient phenotyping and as an outcome measure following interventions

16. Nguyen CB, et al. (2018)
Associations between clinical symptoms, plasma norepinephrine and deregulated immune gene networks in subgroups of adolescent with Chronic Fatigue Syndrome
Brain Behaviour and Immunity 889-1591 (18): 30796-30797.

Background: Chronic Fatigue Syndrome (CFS) is one of the most important causes of disability among adolescents while limited knowledge exists on genetic determinants underlying disease pathophysiology.

Methods: We analyzed deregulated immune-gene modules using Pathifier software on whole blood gene expression data (29 CFS patients, 18 controls). Deconvolution of immune cell subtypes based on gene expression profile was performed using CIBERSORT.

Supervised consensus clustering on pathway deregulation score (PDS) was used to define CFS subgroups. Associations between PDS and immune, neuroendocrine/autonomic and clinical markers were examined. The impact of plasma norepinephrine level on clinical markers over time was assessed in a larger cohort (91 patients).

Results: A group of 29 immune-gene sets was shown to differ patients from controls and detect subgroups within CFS.

Group 1P (high PDS, low norepinephrine, low naïve CD4+ composition) had strong association with levels of serum C-reactive protein and Transforming Growth Factor-beta. Group 2P (low PDS, high norepinephrine, high naïve CD4+ composition) had strong associations with neuroendocrine/autonomic markers. The corresponding plasma norepinephrine level delineated 91 patients into two subgroups with significant differences in fatigue score.

Conclusion: We identified 29 immune-gene sets linked to plasma norepinephrine level that could delineate CFS subgroups. Plasma norepinephrine stratification revealed that lower levels of norepinephrine were associated with higher fatigue. Our data suggests potential involvement of neuro-immune dysregulation and genetic stratification in CFS.

17. Nipate SS and Tiwari AH (2018)
Antioxidant and immunomodulatory properties of Spilanthes oleracea with potential effect in chronic fatigue syndrome infirmity
Journal of Ayurveda and Integrative Medicine [Epub ahead of print].

Background: Chronic fatigue syndrome (CFS) holds a mystery for researchers due to its multifactorial nature; hence, its diagnosis is still based on symptoms and aetiology remains obscured.

Number of scientific evidences regarding the role of oxidative stress, immune dysfunction in CFS and alleviation of symptoms with the help of nutritional supplements guided us to study effect of ethanolic extract of Spilanthes oleracea (SPE) in CFS.

Objectives: Present study was designed to evaluate antioxidant, immunomodulatory properties of S. oleracea flower to ameliorate CFS infirmity in mice.

Materials and Methods: In order to induce fatigue, experimental animals were stressed by chronic water – immersion stress model. Meanwhile, parameters like immobility period and tail withdrawal latency were assessed. On the 21st day, mice blood was collected and they were immediately sacrificed for biochemical estimations.

Results: Biochemical analysis results revealed that CFS elevates lipid peroxidation, nitrite level and diminishes the endogenous antioxidant enzyme like catalase level in stressed animal's brain homogenate.

Stressful condition developed muscle fatigue leading in alteration of lactate dehydrogenase level (LDH), Blood urea nitrogen (BUN) and Triglycerides (TG) levels.

Concurrent and chronic treatment of SPE for 21 days restored all these behavioural despairs and associated biochemical adaptation in mice in dose-dependent manner.

Conclusions: The outcome of this study indicates ability of SPE in amelioration of CFS by mitigating the oxidative stress and thus provide a powerful combat against CFS which may be due to its antioxidant and immunomodulatory properties.

18. Noda M, et al. (2018)
Glial Activation and Expression of the Serotonin Transporter in Chronic Fatigue Syndrome
Frontiers in Psychiatry 9.

Fatigue is commonly reported in a variety of illnesses and has major impact on quality of life. Chronic fatigue syndrome (CFS) is a debilitating syndrome of unknown etiology. The clinical symptoms include problems in neuroendocrine, autonomic, and immune systems.

It is becoming clear that the brain is the central regulator of CFS. For example, neuroinflammation, especially induced by activation of microglia and astrocytes, may play a prominent role in the development of CFS, though little is known about molecular mechanisms. Many possible causes of CFS have been proposed. However, in this mini-review, we summarize evidence for a role for microglia and astrocytes in the onset and the maintenance of immunologically induced CFS.

In a model using virus mimicking synthetic double-stranded RNA, infection causes sequential signalling such as increased blood brain barrier (BBB) permeability, microglia/macrophage activation through Toll-like receptor 3 (TLR3) signalling, secretion of IL-1β, upregulation of the serotonin transporter (5-HTT) in astrocytes, reducing extracellular serotonin (5-HT) levels and hence reduced activation of 5-HT1A receptor subtype. Hopefully, drug discovery targeting these pathways may be effective for CFS therapy.

19. Proal AD and Marshall T (2018)
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in the era of the human microbiome: persistent pathogens drive chronic symptoms by interfering with host metabolism, gene expression and immunity
Frontiers in Pediatrics [Epub ahead of print].

The illness ME/CFS has been repeatedly tied to infectious agents such as Epstein Barr Virus. Expanding research on the human microbiome now allows ME/CFS-associated pathogens to be studied as interacting members of human microbiome communities. Humans harbor these vast ecosystems of bacteria, viruses and fungi in nearly all tissue and blood.

Most well-studied inflammatory conditions are tied to dysbiosis or imbalance of the human microbiome. While gut microbiome dysbiosis has been identified in ME/CFS, microbes and viruses outside the gut can also contribute to the illness. Pathobionts, and their associated proteins/metabolites, often control human metabolism and gene expression in a manner that pushes the body towards a state of illness.

Intracellular pathogens, including many associated with ME/CFS, drive microbiome dysbiosis by directly interfering with human transcription, translation, and DNA repair processes. Molecular mimicry between host and pathogen proteins/metabolites further complicates this interference. Other human pathogens disable mitochondria or dysregulate host nervous system signaling.

Antibodies and/or clonal T cells identified in patients with ME/CFS are likely activated in response to these persistent microbiome pathogens. Different human pathogens have evolved similar survival mechanisms to disable the host immune response and host metabolic pathways. The metabolic dysfunction driven by these organisms can result in similar clusters of inflammatory symptoms.

ME/CFS may be driven by this pathogen-induced dysfunction, with the nature of dysbiosis and symptom presentation varying based on a patient’s unique infectious and environmental history. Under such conditions, patients would benefit from treatments that support the human immune system in an effort to reverse the infectious disease process.

20. Saha AK, et al. (2018)
Erythrocyte Deformability as a Potential Biomarker for Chronic Fatigue Syndrome

Blood [Epub ahead of print]
See also: ME Association Summary Review (04 December 2018)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is arguably the last major disease we know almost nothing about. It is a multi-systemic illness of unknown etiology affecting millions of individuals worldwide, with the capacity to persist for several years.

ME/CFS is characterized by disabling fatigue of at least 6 months, accompanied serious fatigue and musculoskeletal pain, in addition to impaired short-term memory or concentration, and unrefreshing sleep or extended post-exertional. While the etiology of the disease is still debated, evidence suggest oxidative damage to immune and hematological systems as one of the pathophysiological mechanisms of the disease.

Erythrocytes are potent scavengers of oxidative stress, and their shape changes appreciably in response to oxidative stress and certain inflammatory conditions including obesity and diabetes.

The shape of erythrocyte’s change from biconcave discoid to an ellipsoid due to shear flow in microcapillaries that provides a larger specific surface area-to-volume ratio for optimal microvascular perfusion and tissue oxygenation establishing the importance not only of total hematocrit but also of the capacity for large deformations in physiology.

Clinically, ME/CFS patients show normal arterial oxygen saturation but nothing much is known about microvascular perfusion. In this work, we tested the hypothesis that the erythrocyte deformability in ME/CFS is adversely affected, using a combination of biophysical and biochemical techniques…

Taken together, our data demonstrates that the significant decrease in deformability of RBCs from ME/CFS patients may have origins in oxidative stress and suggests that altered microvascular perfusion can be a possible cause for ME/CFS symptoms. Our data also suggests that RBC deformability may serve as a potential biomarker for ME/CFS, albeit further studies are necessary for non-specific classification of the disease.

21. Simeonova D, et al. (2018)
Recognizing the leaky gut as a trans-diagnostic target for neuro-immune disorders using clinical chemistry and molecular immunology assays
Current Topics in Medicinal Chemistry [Epub ahead of print].

Background: Increased intestinal permeability with heightened translocation of Gram-negative bacteria, also known as “leaky gut”, is associated with the pathophysiology of neuroimmune disorders, such as major depressive disorder (MDD), chronic fatigue syndrome (CSF) and (deficit) schizophrenia, as well as with general medical disorders, including irritable bowel syndrome.

This review aims to summarize clinical biochemistry and molecular immunology tests that may aid in the recognition of leaky gut in clinical practice.

Methods: We searched online libraries, including PubMed/MEDLINE, Google Scholar and Scopus, with the key words: “diagnosis” or “biomarkers” and “leaky gut”, “bacterial translocation”, and “intestinal permeability” and focused on papers describing tests that may aid in the clinical recognition of leaky gut.

Results: To evaluate tight junction barrier integrity, serum IgG/IgA/IgM responses to occludin and zonulin and IgA responses to actomyosin should be evaluated.

The presence of cytotoxic bacterial products in serum can be evaluated using IgA/IgM responses to sonicated samples of common Gram-negative gut commensal bacteria and assays of serum lipopolysaccharides (LPSs) and other bacterial toxins, including cytolethal distenting toxin, subunit B.

Major factors associated with increased gut permeability, including gut dysbiosis and yeast overgrowth, use of NSAIDs and alcohol, food hypersensitivities (IgE-mediated), food intolerances (IgG-mediated), small bacterial overgrowth (SIBO), systemic inflammation, psychosocial stressors, some infections (e.g., HIV) and dietary patterns, should be assessed.

Stool samples can be used to assay gut dysbiosis, gut inflammation and decreased mucosal defenses using assays of fecal growth of bacteria, yeast and fungi and stool assays of calprotectin, secretory IgA, β-defensin, α-antitrypsin, lysozyme and lactoferrin.

Blood and breath tests should be used to exclude common causes of increased gut permeability, namely, food hypersensitivities and intolerances, SIBO, lactose intolerance and fructose malabsorption.

Discussion: Here, we propose strategies to recognize “leaky gut” in a clinical setting using the most adequate clinical chemistry and molecular immunology assays.

22. Tuuminen T, et al. (2018)
Dampness and mold hypersensitivity syndrome and vaccination as risk factors for chronic fatigue syndrome
Autoimmune Reviews [Epub ahead of print]

Abstract not currently available.

23. VanElzakker MB, et al. (2018)
Neuroinflammation and cytokines in myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS): A critical review of research methods

Frontiers in Neurology [Epub ahead of print].

Myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) is the label given to a syndrome that can include long-term flu-like symptoms, profound fatigue, trouble concentrating, and autonomic problems, all of which worsen after exertion. It is unclear how many individuals with this diagnosis are suffering from the same condition or have the same underlying pathophysiology, and the discovery of biomarkers would be clarifying.

The name “myalgic encephalomyelitis” essentially means “muscle pain related to central nervous system inflammation” and many efforts to find diagnostic biomarkers have focused on one or more aspects of neuroinflammation, from periphery to brain. As the field uncovers the relationship between the symptoms of this condition and neuroinflammation, attention must be paid to the biological mechanisms of neuroinflammation and issues with its potential measurement.

The current review focuses on three methods used to study putative neuroinflammation in ME/CFS: 1) positron emission tomography (PET) neuroimaging using translocator protein (TSPO) binding radioligand 2) magnetic resonance spectroscopy (MRS) neuroimaging and 3) assays of cytokines circulating in blood and cerebrospinal fluid. PET scanning using TSPO-binding radioligand is a promising option for studies of neuroinflammation. However, methodological difficulties that exist both in this particular technique and across the ME/CFS neuroimaging literature must be addressed for any results to be interpretable.

We argue that the vast majority of ME/CFS neuroimaging has failed to use optimal techniques for studying brainstem, despite its probable centrality to any neuroinflammatory causes or autonomic effects. MRS is discussed as a less informative but more widely available, less invasive, and less expensive option for imaging neuroinflammation, and existing studies using MRS neuroimaging are reviewed. Studies seeking to find a peripheral circulating cytokine “profile” for ME/CFS are reviewed, with attention paid to the biological and methodological reasons for lack of replication among these studies.

We argue that both the biological mechanisms of cytokines and the innumerable sources of potential variance in their measurement make it unlikely that a consistent and replicable diagnostic cytokine profile will ever be discovered.

24. Wantanabe Y (2018)
Brain Science on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Brain and Nerves 70 (11): 1193-1201.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. A variety of studies have been performed to establish objective biomarkers of the disease, including positron emission tomography (PET) molecular imaging and neuro-functional imaging using magnetic resonance imaging (MRI) and magnetoencephalogram (MEG).

In this chapter, we summarize the results from PET, MRI, and MEG imaging. Regional cerebral blood flow and glucose utilization rates are decreased in patients with ME/CFS as compared with age- and sex-matched healthy subjects. Acetyl-L-carnitine uptake into the releasable pool of glutamate and serotonin transporters densities are decreased in a few specific brain regions, mostly in the anterior cingulate in the patients.

Although it is hypothesized that brain inflammation is involved in the pathophysiology of ME/CFS, there was no direct evidence of neuroinflammation in patients. Our recent PET study successfully demonstrated that neuroinflammation is present in widespread brain areas in ME/CFS patients, and is associated with the severity of neuropsychological symptoms. Evaluation of neuroinflammation in patients with ME/CFS may be essential for understanding the core pathophysiology, as well as for developing objective diagnostic criteria and effective medical treatments for ME/CFS.

By using specific neurological features of these patients such as prefrontal cortical atrophies and the over-guarding phenomenon were found using MRI and functional MRI, respectively. We here describe related pathophysiological findings and topics in order to aid in the development of future therapies for ME/CFS patients.

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