ME Association March Summary of ME/CFS Published Research | 04 April 2019

April 4, 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 March 2019.

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 March 2019

1. Almenar-Perez E et al. (2019)
Impact of Polypharmacy on Candidate Biomarker miRNomes for the Diagnosis of Fibromyalgia and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Striking Back on Treatments.
Pharmaceutics 11 (3).
Fibromyalgia (FM) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are diseases of unknown etiology presenting complex and often overlapping symptomatology. Despite promising advances on the study of miRNomes of these diseases, no validated molecular diagnostic biomarker yet exists. Since FM and ME/CFS patient treatments commonly include polypharmacy, it is of concern that biomarker miRNAs are masked by drug interactions.

Aiming at discriminating between drug-effects and true disease-associated differential miRNA expression, we evaluated the potential impact of commonly prescribed drugs on disease miRNomes, as reported by the literature. By using the web search tools SM2miR, Pharmaco-miR, and repoDB, we found a list of commonly prescribed drugs that impact FM and ME/CFS miRNomes and therefore could be interfering in the process of biomarker discovery.

On another end, disease-associated miRNomes may incline a patient's response to treatment and toxicity. Here, we explored treatments for diseases in general that could be affected by FM and ME/CFS miRNomes, finding a long list of them, including treatments for lymphoma, a type of cancer affecting ME/CFS patients at a higher rate than healthy population.

We conclude that FM and ME/CFS miRNomes could help refine pharmacogenomic/pharmacoepigenomic analysis to elevate future personalized medicine and precision medicine programs in the clinic.

2. Bouquet J et al. (2019)
Whole blood human transcriptome and virome analysis of ME/CFS patients experiencing post-exertional malaise following cardiopulmonary exercise testing.
PLoS One 14 (3).
Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a syndrome of unknown etiology characterized by profound fatigue exacerbated by physical activity, also known as post-exertional malaise (PEM). Previously, we did not detect evidence of immune dysregulation or virus reactivation outside of PEM periods. Here we sought to determine whether cardiopulmonary exercise stress testing of ME/CFS patients could trigger such changes.

ME/CFS patients (n = 14) and matched sedentary controls (n = 11) were subjected to cardiopulmonary exercise on 2 consecutive days and followed up to 7 days post-exercise, and longitudinal whole blood samples analyzed by RNA-seq.

Although ME/CFS patients showed significant worsening of symptoms following exercise versus controls, with 8 of 14 ME/CFS patients showing reduced oxygen consumption on day 2, transcriptome analysis yielded only 6 differentially expressed gene (DEG) candidates when comparing ME/CFS patients to controls across all time points.

None of the DEGs were related to immune signalling, and no DEGs were found in ME/CFS patients before and after exercise. Virome composition (P = 0.746 by chi-square test) and number of viral reads (P = 0.098 by paired t-test) were not significantly associated with PEM.

These observations do not support transcriptionally-mediated immune cell dysregulation or viral reactivation in ME/CFS patients during symptomatic PEM episodes.

3. Catchpole S and Garip G (2019)
Acceptance and identity change: An interpretative phenomenological analysis of carers’ experiences in myalgic encephalopathy/chronic fatigue syndrome.
Journal of Health Psychology.
Myalgic encephalopathy/chronic fatigue syndrome is a debilitating condition and many people rely heavily on family carers. This study explored the caring experiences of seven family carers.

Four themes were established: relations with others, role and identity changes, coping with change and uncertainty, and information and support seeking.

Caring disrupted multiple areas of carers’ lives, including their identities and relationships. Scepticism from others about myalgic encephalopathy/chronic fatigue syndrome was particularly distressing.

Acceptance was important for coping and helped some carers achieve positive growth within spousal relationships.

Improving support and advice for carers and acknowledging their caring burden could improve their well-being.

4. Clark JE et al. (2019)
Network structure underpinning (dys)homeostasis in chronic fatigue syndrome; Preliminary findings.
PLoS One 14 (3).
Introduction: A large body of evidence has established a pattern of altered functioning in the immune system, autonomic nervous system and hypothalamic pituitary adrenal axis in chronic fatigue syndrome. However, the relationship between components within and between these systems is unclear. In this paper we investigated the underlying network structure of the autonomic system in patients and controls, and a larger network comprising all three systems in patients alone.

Methods: In a sample of patients and controls we took several measures of autonomic nervous system output during 10 minutes of supine rest covering tests of blood pressure variability, heart rate variability and cardiac output.

Awakening salivary cortisol was measured on each of two days with participants receiving 0.5mg dexamethasone during the afternoon of the first day. Basal plasma cytokine levels and the in vitro cytokine response to dexamethasone were also measured.

Symptom outcome measures used were the fatigue impact scale and cognitive failures questionnaire. Mutual information criteria were used to construct networks describing the dependency amongst variables. Data from 42 patients and 9 controls were used in constructing autonomic networks, and 15 patients in constructing the combined network.

Results: The autonomic network in patients showed a more uneven distribution of information, with two distinct modules emerging dominated by systolic blood pressure during active stand and end diastolic volume and stroke volume respectively.

The combined network revealed strong links between elements of each of the three regulatory systems, characterised by three higher modules the centres of which were systolic blood pressure during active stand, stroke volume and ejection fraction respectively.

Conclusions: CFS is a complex condition affecting physiological systems. It is important that novel analytical techniques are used to understand the abnormalities that lead to CFS.

The underlying network structure of the autonomic system is significantly different to that of controls, with a small number of individual nodes being highly influential.

The combined network suggests links across regulatory systems which shows how alterations in single nodes might spread throughout the network to produce alterations in other, even distant, nodes. Replication in a larger cohort is warranted.

5. Cuesta A et al. (2019)
Fibromyalgia, Chronic Fatigue Syndrome, and Multiple Chemical Sensitivity: Illness Experiences.
Clinical Nursing Research [Epub ahead of print].
Fibromyalgia, chronic fatigue syndrome/myalgic encephalomyelitis, and multiple chemical sensitivity can be considered contested illnesses. The questioning of the status of these conditions as real diseases reduces feelings of legitimacy in those affected. The purpose of this study was to analyze subjectivity construction processes in people with these diseases.

A qualitative exploratory study was conducted from the perspective of hermeneutic phenomenology and ethnosociology. We used life stories for compiling data (13 informants were interviewed face-to-face), and sociological discourse analysis was developed.

Three main categories were identified: (a) self and grieving; (b) images and practices relating to fibromyalgia, chronic fatigue syndrome/myalgic encephalomyelitis, and multiple chemical sensitivity; and (c) relationships with health professionals.

This study shows that daily experiences of people living with these diseases are marked by stigmatization processes. The ultimate purpose of nursing care for people with these conditions should be to reduce their vulnerability and exclusion.

6. Davenport T et al. (2019)
Chronotropic Intolerance: An Overlooked Determinant of Symptoms and Activity Limitation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?
Frontiers in paediatrics 7: 82.
Post-exertional malaise (PEM) is the hallmark clinical feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). PEM involves a constellation of substantially disabling signs and symptoms that occur in response to physical, mental, emotional, and spiritual over-exertion.

Because PEM occurs in response to over-exertion, physiological measurements obtained during standardized exertional paradigms hold promise to contribute greatly to our understanding of the cardiovascular, pulmonary, and metabolic states underlying PEM.

In turn, information from standardized exertional paradigms can inform patho-etiologic studies and analeptic management strategies in people with ME/CFS. Several studies have been published that describe physiologic responses to exercise in people with ME/CFS, using maximal cardiopulmonary testing (CPET) as a standardized physiologic stressor.

In both non-disabled people and people with a wide range of health conditions, the relationship between exercise heart rate (HR) and exercise workload during maximal CPET are repeatable and demonstrate a positive linear relationship.

However, smaller or reduced increases in heart rate during CPET are consistently observed in ME/CFS. This blunted rise in heart rate is called chronotropic intolerance (CI). CI reflects an inability to appropriately increase cardiac output because of smaller than expected increases in heart rate.

The purposes of this review are to (1) define CI and discuss its applications to clinical populations; (2) summarize existing data regarding heart rate responses to exercise obtained during maximal CPET in people with ME/CFS that have been published in the peer-reviewed literature through systematic review and meta-analysis; and (3) discuss how trends related to CI in ME/CFS observed in the literature should influence future patho-etiological research designs and clinical practice.

7. Espinosa P and Urra JM (2019)
Decreased Expression of the CD57 Molecule in T Lymphocytes of Patients with Chronic Fatigue Syndrome.
Molecular Neurobiology [Epub ahead of print].
The chronic fatigue syndrome (CFS) is characterized by a prolonged incapacitating fatigue, headaches, sleep disturbances, and decreases in cognition, besides alterations in other physiological functions. At present, no specific biological markers have been described in this pathology.

In the present study, we analyzed in lymphocytes the CD57 expression for the diagnosis of CFS, evaluating both the percentage of blood lymphocytes expressing CD57 and the average amount of the molecule expressed per cell.

The study demonstrated a marked and significant decrease in the expression of CD57 in lymphocytes of CFS patients regarding healthy controls. In T lymphocytes, the decrease was significant both in the percentage of cells expressing CD57 (7.5 ± 1.2 vs 13.3 ± 1.6, p = 0.024) and in a more relevant way in the amount of CD57 molecule expressed per cell (331 ± 59 vs 1003 ± 104, p ≤ 0.0001). In non-T lymphocytes, the decrease was significant only in the amount of CD57 expressed per cell (379 ± 114 vs 691 ± 95, p = 0.007).

The study of CD57 antigen in blood lymphocytes is a useful marker that could cooperate in the diagnosis of CFS patients. Its decrease in T lymphocytes provides most valuable results than the results in other lymphocyte subpopulations.

8. Holtzman CS et al. (2019)
Assessment of Post-Exertional Malaise (PEM) in Patients with Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS): A Patient-Driven Survey.
Diagnostics 9 (1).
An ME Association Research Summary is available that covers this latest research exploring PEM.
Considerable controversy has existed with efforts to assess post-exertional malaise (PEM), which is one of the defining features of myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). While a number of self-report questionnaires have been developed to assess this symptom, none have been comprehensive, and a recent federal government report has recommended the development of a new PEM measure.

The current study involved a community-based participatory research process in an effort to develop a comprehensive PEM instrument, with critical patient input shaping the item selection and overall design of the tool. A survey was ultimately developed and was subsequently completed by 1534 members of the patient community.

The findings of this survey suggest that there are key domains of this symptom, including triggers, symptom onset, and duration, which have often not been comprehensively assessed in a previous PEM instrument. This study indicates that there are unique benefits that can be derived from patients collaborating with researchers in the measurement of key symptoms defining ME and CFS.

9. Janse A et al. (2019)
Implementation of stepped care for patients with chronic fatigue syndrome in community-based mental health care: outcomes at post-treatment and long-term follow-up.
Behavioural Cognition and Psychotherapy [Epub ahead of print].
Background: Cognitive behavioural therapy (CBT) is an evidence-based treatment for chronic fatigue syndrome (CFS). Stepped care for CFS, consisting of a minimal intervention followed by face-to-face CBT, was found efficacious when tested in a CFS specialist centre. Stepped care implemented in a community-based mental health centre (MHC) has not yet been evaluated.

Aims: (1) To test the effectiveness of stepped care for CFS implemented in a MHC at post-treatment and at long-term follow-up; and (2) compare post-treatment outcomes of implemented stepped care with treatment outcomes of a CFS specialist centre.

Method: An uncontrolled study was used to test effectiveness of stepped care implemented in a MHC (n = 123). The outcomes of implemented care were compared with the outcomes of specialist care reported in previous studies (n = 583). Data on outcomes from implemented stepped care were gathered at post-treatment and at long-term follow-up. Mixed models were used as method of analysis.

Results: Fatigue decreased, and physical functioning increased significantly following implemented stepped care (both p < .001). The follow-up was completed by 94 patients (78%) within 1-6 years after treatment. Treatment effects were sustained to follow-up. Patients in the MHC showed less improvement directly following stepped care compared with patients in a CFS specialist centre (p < .01).

Conclusion: Implemented stepped care for CFS is effective with sustained treatment gains at long-term follow-up. There is room for improvement when compared with outcomes of a CFS specialist centre. Some suggestions are made on how to improve stepped care.

10. Jeffrey M et al. (2019)
Treatment Avenues in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Split-gender Pharmacogenomic Study of Gene-expression Modules.
Clinical Therapeutics [Epub ahead of print].
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisymptom illness impacting up to 1 million people in the United States. As the pathogenesis and etiology of this complex condition are unclear, prospective treatments are limited. Identifying US Food and Drug Administration–approved drugs that may be repositioned as treatments for ME/CFS may offer a rapid and cost-effective solution.

Here we used gene-expression data from 33 patients with Fukuda-defined ME/CFS (23 females, 10 males) and 21 healthy demographically comparable controls (15 females, 6 males) to identify differential expression of predefined gene-module sets based on nonparametric statistics.

Differentially expressed gene modules were then annotated via over-representation analysis using the Consensus Pathway database. Differentially expressed modules were then regressed onto measures of fatigue and cross-referenced with drug atlas and pharmacogenomics databases to identify putative treatment agents.

The top 1% of modules identified in males indicated small effect sizes in modules associated with immune regulation and mitochondrial dysfunction. In females, modules identified included those related to immune factors and cardiac/blood factors, returning effect sizes ranging from very small to intermediate (0.147 < Cohen δ < 0.532).

Regression analysis indicated that B-cell receptors, T-cell receptors, tumor necrosis factor α, transforming growth factor β, and metabolic and cardiac modules were strongly correlated with multiple composite measures of fatigue. Cross-referencing identified genes with pharmacogenomics data indicated immunosuppressants as potential treatments of ME/CFS symptoms.

The findings from our analysis suggest that ME/CFS symptoms are perpetuated by immune dysregulation that may be approached via immune modulation–based treatment strategies.

11. Jonsjo MA et al. (2019)
Acceptance & Commitment Therapy for ME/CFS (Chronic Fatigue Syndrome) – A feasibility study.
Journal of Contextual Behaviour Science [Epub ahead of print].
Acceptance and Commitment Therapy has not been evaluated for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) to date. However, recent studies indicate the importance of psychological flexibility for well-being in this condition. The present study is a preliminary evaluation of the feasibility of an ACT-based behavior medicine treatment protocol for ME/CFS.

40 adult individuals, fulfilling the 1994 Centers for Disease Control and Prevention and the 2003 clinical case criteria for ME/CFS, consecutively started an individual 13-session ACT-treatment. Data were collected pre-treatment, mid-treatment, post-treatment, and at 3- and 6-month follow-ups. Linear mixed effects modeling was used to analyze treatment effects on ME/CFS-related disability, psychological flexibility, ME/CFS symptoms, anxiety, depression and health-related quality of life.

80% (32) of the participants completed the treatment. ME/CFS-related disability (d = 0.80, p < .001) and psychological flexibility (d=1.07, p < .001) improved between pre- and post-treatment and remained stable between follow-ups. Similar results were found for secondary outcomes.

Results indicate that the treatment was accepted by the participants, with a small drop-out rate and was safe with no harmful effects during or after treatment and also efficient with stable improvements in numerous outcomes.

12. Katz BZ et al. (2019)
A Validated Scale for Assessing the Severity of Acute Infectious Mononucleosis.
The Journal of Pediatrics [Epub ahead of print].
One to 5 percent of college students develop infectious mononucleosis annually, and about 10% meet criteria for chronic fatigue syndrome (CFS) 6 months following infectious mononucleosis. We developed a severity of mononucleosis scale based on a review of the literature.

College students were enrolled, generally when they were healthy. When the students developed infectious mononucleosis, an assessment was made as to the severity of their infectious mononucleosis independently by 2 physicians using the severity of mononucleosis scale. This scale was correlated with corticosteroid use and hospitalization. Six months following infectious mononucleosis, an assessment is made for recovery from infectious mononucleosis or meeting 1 or more case definitions of CFS.

In total, 126 severity of mononucleosis scales were analyzed. The concordance between the 2 physician reviewers was 95%. All 3 hospitalized subjects had severity of mononucleosis scores ≥2. Subjects with severity of mononucleosis scores of ≥1 were 1.83 times as likely to be given corticosteroids. Students with severity of mononucleosis scores of 0 or 1 were less likely to meet more than 1 case definition of CFS 6 months following infectious mononucleosis.

The severity of mononucleosis scale has interobserver, concurrent and predictive validity for hospitalization, corticosteroid use, and meeting criteria for CFS 6 months following infectious mononucleosis.

13. Lin W et al. (2019)
Jin's three-needle acupuncture technique for chronic fatigue syndrome: a study protocol for a multicentre, randomized, controlled trial.
Trials 20 (1): 155.
Background: With an unclear pathomechanism, no confirmed treatment regimen has been established for chronic fatigue syndrome (CFS). Acupuncture is applied as an alternative therapy for CFS. As a kind of acupuncture therapy, Jin's three-needle acupuncture (JTN) has been applied to treat CFS. However, few large-sample randomised controlled trials on JTN treatment for CFS have been reported. We designed this study to evaluate the efficacy and safety of JTN treatment for CFS.

Method/Design: This study is a multicentre, single-blind, randomised controlled trial. Patients who meet the inclusion criteria will be recruited and randomly assigned to either the JTN treatment group or the basic acupuncture group. Both interventions will be conducted for five consecutive days per week and last for 2 weeks.

The primary outcome is the effective rate based on the 14-item Fatigue Scale (FS-14) score. Other outcome measures include the Fatigue Assessment Scale (FAI), the Depression Status Inventory (DSI), and the Self-rating Anxiety Scale (SAS). Plasma adrenocorticotropic hormone (ACTH), plasma cortisol, and serum levels of IL-2 and IFN-γ will also be measured in this study. Adverse events will be observed and recorded for the safety evaluation.

Discussion: This study may help to identify the efficacy and safety of JTN acupuncture treatment for CFS.

14. Loades ME et al. (2019)
Perfectionism and beliefs about emotions in adolescents with chronic fatigue syndrome and their parents: a preliminary investigation in a case control study nested within a cohort.
Psychological Health [Epub ahead of print].

Objectives: To investigate perfectionism and beliefs about emotions in adolescents with chronic fatigue syndrome (CFS) and their parents.

Design: Case-control comparing adolescents (age 11-18) with CFS (N = 121), asthma (N = 27) and healthy controls (N = 78) with a 3-month follow up for CFS participants.

Main outcome measures: Adolescents: Chalder Fatigue Questionnaire, physical functioning, Beliefs about Emotions scale (BES), Child and Adolescent Perfectionism Scale, Frost Multidimensional Perfectionism Scale (FMPS). Parents: BES, FMPS, Self-sacrificing scale, Affective styles questionnaire.

Results: Adolescents with CFS did not consistently report higher levels of perfectionism and unhelpful beliefs about emotions than adolescents with asthma or healthy adolescents. Mothers' and adolescents' beliefs about emotions and unhelpful perfectionism were significantly associated (p = .007). Linear regression found that neither adolescent perfectionism nor beliefs about emotions accounted for variance in subsequent fatigue or physical functioning.

Conclusion: Parental perfectionism and emotion regulation style may contribute to perfectionism in adolescents with CFS. Parental representations could contribute to fatigue maintenance.

15. Loades ME et al. (2019)
Cognitive and behavioural responses to symptoms in adolescents with chronic fatigue syndrome: A case-control study nested within a cohort.
Clinical Child Psychology and Psychiatry [Epub ahead of print].

Background: What adolescents think about symptoms and what they do in response could contribute to fatigue maintenance. We compared the cognitive and behavioural responses of adolescents and their parents with chronic fatigue syndrome (CFS; N = 121) and asthma (N = 27) and explored the predictive value of these variables on fatigue and functioning in CFS.

Method: Consecutively referred adolescents with CFS were recruited. Questionnaires, completed by adolescents and parents, assessed fatigue, functioning, mood and cognitive and behavioural responses to symptoms. Age-matched adolescents with asthma completed the same questionnaires. Adolescents with CFS completed questionnaires again approximately 3 months later.

Results: Adolescents with CFS scored higher on all unhelpful cognitive and behavioural subscales than adolescents with asthma. Parents’ cognitions about their child’s symptoms were associated with adolescent’s own cognitions. Unhelpful cognitive and behavioural responses, particularly, damage beliefs, predicted subsequent fatigue in CFS, and all-or-nothing behaviour, catastrophising and damage beliefs predicted subsequent physical functioning.

Conclusion: Unhelpful cognitive and behavioural responses to symptoms appear to be particularly prominent in adolescents with CFS. There is some consistency but not a perfect match between cognitive and behavioural responses to symptoms reported by adolescents and their parents. These responses could be contributing to fatigue maintenance and disability.

16. Nelson MJ et al. (2019)
Diagnostic sensitivity of 2-day cardiopulmonary exercise testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Journal of Translational Medicine 17 (1): 80.
Background: There are no known objective biomarkers to assist with the diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A small number of studies have shown that ME/CFS patients exhibit an earlier onset of ventilatory threshold (VT) on the second of two cardiopulmonary exercise tests (CPET) performed on consecutive days. However, cut-off values which could be used to differentiate between ME/CFS patients have not been established.

Methods: 16 ME/CFS patients and 10 healthy controls underwent CPET on a cycle-ergometer on 2-consecutive days. Heart rate (HR), ventilation, ratings of perceived exertion (RPE) and work rate (WR) were assessed on both days.

Results: WR at VT decreased from day 1 to day 2 and by a greater magnitude in ME/CFS patients (p < 0.01 group × time interaction). No interaction effects were found for any other parameters. ROC curve analysis of the percentage change in WR at VT revealed decreases of − 6.3% to − 9.8% provided optimal sensitivity and specificity respectively for distinguishing between patients with ME/CFS and controls.

Conclusion: The decrease in WR at VT of 6.3–9.8% on the 2nd day of consecutive-day CPET may represent an objective biomarker that can be used to assist with the diagnosis of ME/CFS.

17. Noble S et al. (2019)
Could disease labelling have positive effects? An experimental study exploring the effect of the chronic fatigue syndrome label on intended social support.
Patient Education and Counselling 102 (3): 486-493.
Objective: Chronic fatigue syndrome (CFS) patients report limited social support, which can affect symptom severity. Friends are a key source of social support for young adults with CFS, but there is limited research on friends' responses to the CFS label. We explored the potential benefits or harms of the CFS label for shaping the potential for social support from a friend's perspective.

Method: 207 university students responded to hypothetical scenarios about a close friend experiencing CFS. Participants were randomly allocated to either the CFS-label or no-label conditions. The potential for social support was operationalised as attitude (sympathetic or hostile), intended treatment support and intended behavioural support.

Results: The CFS label elicited a greater potential for social support, with significantly higher sympathetic responses, lower rejecting responses and greater support for active treatment. These effects were significantly greater in men compared to women. There was no effect on intended behavioural support.

Conclusion: This study suggests the CFS label may increase the potential for social support. Young adults, particularly men, held more supportive attitudes towards their friend when the CFS label was used.

Implications: The effects of labels on the potential for social support need to be considered when evaluating the usefulness of a disease label.

18. Richman S et al. (2019)
Pharmaceutical Interventions in Chronic Fatigue Syndrome: A Literature-based Commentary.
Clinical Therapeutics [Epub ahead of print].
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder characterized by prolonged periods of fatigue, chronic pain, depression, and a complex constellation of other symptoms.

Currently, ME/CFS has no known cause, nor are the mechanisms of illness well understood. Therefore, with few exceptions, attempts to treat ME/CFS have been directed mainly toward symptom management.

These treatments include antivirals, pain relievers, antidepressants, and oncologic agents as well as other single-intervention treatments. Results of these trials have been largely inconclusive and, in some cases, contradictory. Contributing factors include a lack of well-designed and -executed studies and the highly heterogeneous nature of ME/CFS, which has made a single etiology difficult to define.

Because the majority of single-intervention treatments have shown little efficacy, it may instead be beneficial to explore broader-acting combination therapies in which a more focused precision-medicine approach is supported by a systems-level analysis of endocrine and immune co-regulation.

19. Sharpe M et al. (2019)
The PACE trial of treatments for chronic fatigue syndrome: a response to WILSHIRE et al.
BMC Psychology 7 (1): 15.
This response has been addressed by Tom Kindlon and Carolyn Wilshire (26.03.19) see below.
Chronic Fatigue Syndrome (CFS) is chronic disabling illness characterized by severe disabling fatigue, typically made worse by exertion. Myalgic Encephalomyelitis (ME) is thought by some to be the same disorder (then referred to as CFS/ME) and by others to be different. There is an urgent need to find effective treatments for CFS.

The UK Medical Research Council PACE trial published in 2011 compared available treatments and concluded that when added to specialist medical care, cognitive behaviour therapy and graded exercise therapy were more effective in improving both fatigue and physical function in participants with CFS, than both adaptive pacing therapy and specialised medical care alone.

In this paper, we respond to the methodological criticisms of the trial and a reanalysis of the trial data reported by Wilshire at al. We conclude that neither the criticisms nor the reanalysis offer any convincing reason to change the conclusions of the PACE trial.

20. Slomko J et al. (2019)
Prevalence and characteristics of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) in Poland: a cross-sectional study.
BMJ Open 9 (3).
Objectives: The aim of this study was to estimate the prevalence of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and describe illness characteristics in a community population in Poland.

Participants: Of the cohort of 1400 who self-presented with fatigue only 69 subsequently were confirmed as having CFS/ME using the Fukuda criteria.

Main outcome measures: Participants completed the following screening symptom assessment tools: Chalder Fatigue Scale, Hospital Anxiety and Depression Scale (HADS), Epworth Sleepiness Scale (ESS), Composite Autonomic Symptom Score 31 (COMPASS 31), Quality of Life Scale (QOLS). Haemodynamic and autonomic parameters were automatically measured at rest with a Task Force Monitor.

Results: In 1308, from 1400 (93%) individuals who identified themselves as fatigued, recognised chronic conditions were identified, for example, neurological (n=280, 21.5%), neurodegenerative (n=200, 15%), psychiatric (n=654, 50%) and immunologic (n=174, 13.5%) disorders.

The remaining 69 participants (mean age 38.3±8.5) met the Fukuda definition for CFS/ME and had baseline objective assessment. The majority had experienced symptoms for over 2 years with 37% having symptoms for 2-5 years and 21.7% for more than 10 years.

The COMPASS 31 indicated that 50% have symptoms consistent with orthostatic intolerance. About 43/69 (62%) had Epworth sleepiness scores ≥10, i.e., consistent with excessive daytime sleepiness, 26/69 (38%) had significant anxiety and 22/69 (32%) depression measured by HADS A & D.

Quality of life is significantly impaired in those with Fukuda criteria CFS (QLS score 64±11) with significant negative relationships between quality of life and fatigue (p<0.0001), anxiety (p=0.0009), depression (p<0.0001) and autonomic symptoms (p=0.04).

Conclusion: This is the first study to summarise illness characteristics of Polish CFS/ME patients. Our study has confirmed that fatigue is a common and under-recognised symptom affecting the Polish population.

21. Tomas C et al. (2019)
Mitochondrial complex activity in permeabilised cells of chronic fatigue syndrome patients using two cell types.
PeerJ 7: e6500.
An ME Association Research Summary from Dr Cara Tomas has also been produced.
Abnormalities in mitochondrial function have previously been shown in chronic fatigue syndrome (CFS) patients, implying that mitochondrial dysfunction may contribute to the pathogenesis of disease. This study builds on previous work showing that mitochondrial respiratory parameters are impaired in whole cells from CFS patients by investigating the activity of individual mitochondrial respiratory chain complexes.

Two different cell types were used in these studies in order to assess individual complex activity locally in the skeletal muscle (myotubes) (n = 6) and systemically (peripheral blood mononuclear cells (PBMCs)) (control n = 6; CFS n = 13). Complex I, II and IV activity and respiratory activity supported by fatty acid oxidation and glutaminolysis were measured using extracellular flux analysis.

Cells were permeabilised and combinations of substrates and inhibitors were added throughout the assays to allow states of mitochondrial respiration to be calculated and the activity of specific aspects of respiratory activity to be measured.

Results showed there to be no significant differences in individual mitochondrial complex activity or respiratory activity supported by fatty acid oxidation or glutaminolysis between healthy control and CFS cohorts in either skeletal muscle (p ≥ 0.190) or PBMCs (p ≥ 0.065).

This is the first study to use extracellular flux analysisto investigate individual mitochondrial complex activity in permeabilised cells in the context of CFS.

The lack of difference in complex activity in CFS PBMCs suggests that the previously observed mitochondrial dysfunction in whole PBMCs is due to causes upstream of the mitochondrial respiratory chain.

22. Twisk FNM (2019)
Cognitive-behavioural and graded exercise therapies for chronic fatigue (syndrome) are associated with lower levels of work/school attendance.
Journal of Behavioural Medicine [Epub ahead of print].

23. Wilshire CE et al. (2019)
Response: Sharpe, Goldsmith and Chalder fail to restore confidence in the PACE trial findings
BMC Psychology.
In a recent paper, we argued that the conclusions of the PACE trial of chronic fatigue syndrome are problematic because the pre-registered protocol was not adhered to. We showed that when the originally specific outcomes and analyses are used, the evidence for the effectiveness of CBT and graded exercise therapy is weak.

In a companion paper to this article, Sharpe, Goldsmith and Chalder dismiss the concerns we raised and maintain that the original conclusions are robust. In this rejoinder, we clarify one misconception in their commentary, and address seven additional arguments they raise in defence of their conclusions.

We conclude that none of these arguments is sufficient to justify digressing from the pre-registered trial protocol. Specifically, the PACE authors view the trial protocol as a preliminary plan, subject to honing and improvement as time progresses, whereas we view it as a contract that should not be broken except in extremely unusual circumstances.

While the arguments presented by Sharpe and colleagues inspire some interesting reflections on the scientific process, they fail to restore confidence in the PACE trial’s conclusions.

24. Worm-Smeitink M et al. (2019)
Internet-Based Cognitive Behavioral Therapy in Stepped Care for Chronic Fatigue Syndrome: Randomized Noninferiority Trial.
Journal of Medical Internet Research 21 (3).
Background: Internet-based cognitive behavioral therapy (I-CBT) leads to a reduction of fatigue severity and disability in adults with chronic fatigue syndrome (CFS). However, not all patients profit, and it remains unclear how I-CBT is best embedded in the care of CFS patients.

Objective: This study aimed to compare the efficacy of stepped care, using therapist-assisted I-CBT, followed by face-to-face (f2f) cognitive behavioral therapy (CBT) when needed, with f2f CBT (treatment as usual [TAU]) on fatigue severity. The secondary aim was to investigate treatment efficiency.

Methods: A total of 363 CFS patients were randomized to 1 of the 3 treatment arms (n=121). There were 2 stepped care conditions that differed in the therapists' feedback during I-CBT: prescheduled or on-demand. When still severely fatigued or disabled after I-CBT, the patients were offered f2f CBT. Noninferiority of both stepped care conditions to TAU was tested using analysis of covariance.

The primary outcome was fatigue severity (Checklist Individual Strength). Disabilities (Sickness Impact Profile -8), physical functioning (Medical Outcomes Survey Short Form-36), psychological distress (Symptom Checklist-90), and proportion of patients with clinically significant improvement in fatigue were the secondary outcomes. The amount of invested therapist time was compared between stepped care and TAU. Exploratory comparisons were made between the stepped care conditions of invested therapist time and proportion of patients who continued with f2f CBT.

Results: Noninferiority was indicated, as the upper boundary of the one-sided 98.75% CI of the difference in the change in fatigue severity between both forms of stepped care and TAU were below the noninferiority margin of 5.2 (4.25 and 3.81, respectively). The between-group differences on the secondary outcomes were also not significant (P=.11 to P=.79). Both stepped care formats required less therapist time than TAU (median 8 hours, 9 minutes and 7 hours, 25 minutes in stepped care vs 12 hours in TAU; P<.001).

The difference in therapist time between both stepped care formats was not significant. Approximately half of the patients meeting step-up criteria for f2f CBT after I-CBT did not continue.

Conclusions: Stepped care, including I-CBT followed by f2f CBT when indicated, is noninferior to TAU of f2f CBT and requires less therapist time. I-CBT for CFS can be used as a first step in stepped care.

25. Yasui M et al. (2019)
Hyperactivation of proprioceptors induces microglia-mediated long-lasting pain in a rat model of chronic fatigue syndrome.
Journal of Neuroinflammation 16: 67.
Background: Patients diagnosed with chronic fatigue syndrome (CFS) or fibromyalgia experience chronic pain. Concomitantly, the rat model of CFS exhibits microglial activation in the lumbar spinal cord and pain behavior without peripheral tissue damage and/or inflammation. The present study addressed the mechanism underlying the association between pain and chronic stress using this rat model.

Methods: Chronic or continuous stress-loading (CS) model rats, housed in a cage with a thin level of water (1.5 cm in depth), were used. The von Frey test and pressure pain test were employed to measure pain behavior. The neuronal and microglial activations were immunohistochemically demonstrated with antibodies against ATF3 and Iba1. Electromyography was used to evaluate muscle activity.

Results: The expression of ATF3, a marker of neuronal hyperactivity or injury, was first observed in the lumbar dorsal root ganglion (DRG) neurons 2 days after CS initiation. More than 50% of ATF3-positive neurons simultaneously expressed the proprioceptor markers TrkC or VGluT1, whereas the co-expression rates for TrkA, TrkB, IB4, and CGRP were lower than 20%.

Retrograde labeling using fluorogold showed that ATF3-positive proprioceptive DRG neurons mainly projected to the soleus. Substantial microglial accumulation was observed in the medial part of the dorsal horn on the fifth CS day. Microglial accumulation was observed around a subset of motor neurons in the dorsal part of the ventral horn on the sixth CS day. The motor neurons surrounded by microglia were ATF3-positive and mainly projected to the soleus. Electromyographic activity in the soleus was two to three times higher in the CS group than in the control group.

These results suggest that chronic proprioceptor activation induces the sequential activation of neurons along the spinal reflex arc, and the neuronal activation further activates microglia along the arc. Proprioceptor suppression by ankle joint immobilization significantly suppressed the accumulation of microglia in the spinal cord, as well as the pain behavior.

Conclusion: Our results indicate that proprioceptor-induced microglial activation may be a key player in the initiation and maintenance of abnormal pain in patients with CFS.

26. Zhang F et al. (2019)
Artificial intelligence-based discovery of the association between depression and chronic fatigue syndrome.
Journal of Affective Disorders [Epub ahead of print].
Background: Both of the modern medicine and the traditional Chinese medicine classify depressive disorder (DD) and chronic fatigue syndrome (CFS) to one type of disease. Unveiling the association between depressive and the fatigue diseases provides a great opportunity to bridge the modern medicine with the traditional Chinese medicine.

Methods: In this work, 295 general participants were recruited to complete Zung Self-Rating Depression Scales and Chalder Fatigue Scales, and meanwhile, to donate plasma and urine samples for 1H NMR-metabolic profiling. Artificial intelligence methods was used to analysis the underlying association between DD and CFS. Principal components analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were used to analyze the metabolic profiles with respect to gender and age. Variable importance in projection and t-test were employed in conjunction with the PLS-DA models to identify the metabolite biomarkers. Considering the asymmetry and complexity of the data, convolutional neural networks (CNN) model, an artificial intelligence method, was built to analyze the data characteristics between each groups.

Results: The results showed the gender- and age-related differences for the candidate biomarkers of the DD and the CFS diseases and indicated the same and different biomarkers of the two diseases. PCA analysis for the data characteristics reflected that DD and CFS was separated completely in plasma metabolite. However, DD and CFS was merged into one group.

Limitation: Lack of transcriptomic analysis limits the understanding of the association of the DD and the CFS diseases on gene level.

Conclusion: The unmasked candidate biomarkers provide reliable evidence to explore the commonality and differences of the depressive and the fatigue diseases, and thereby, bridge over the traditional Chinese medicine with the modern medicine.

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