Increased expression of activation antigens on CD8+ T lymphocytes in Myalgic Encephalomyelitis/chronic fatigue syndrome: inverse associations with lowered CD19+ expression and CD4+/CD8+ ratio, but no associations with (auto)immune, leaky gut, oxidative and nitrosative stress biomarkers

Abstract:

BACKGROUND: There is now evidence that specific subgroups of patients with Myalgic Encephalomyelitis / chronic fatigue syndrome (ME/CFS) suffer from a neuro-psychiatric-immune disorder. This study was carried out to delineate the expression of the activation markers CD38 and human leukocyte antigen (HLA) DR on CD4+ and CD8+ peripheral blood lymphocytes in ME/CFS.

METHODS: Proportions and absolute numbers of peripheral lymphocytes expressing CD3+, CD19+, CD4+, CD8+, CD38+ and HLA-DR+ were measured in ME/CFS (n=139), chronic fatigue (CF, n=65) and normal controls (n=40).

RESULTS: The proportions of CD3+, CD8+, CD8+CD38+ and CD8+HLA-DR+ were significantly higher in ME/CFS patients than controls, while CD38+, CD8+CD38+, CD8+HLA-DR+ and CD38+HLA-DR+ were significantly higher in ME/CFS than CF. The percentage of CD19+ cells and the CD4+/CD8+ ratio were significantly lower in ME/CFS and CF than in controls. There were highly significant inverse correlations between the increased expression of CD38+, especially that of CD8+CD38+, and the lowered CD4+/CD8+ ratio and CD19+ expression. There were no significant associations between the flow cytometric results and severity or duration of illness and peripheral blood biomarkers of oxidative and nitrosative stress (O&NS, i.e. IgM responses to O&N modified epitopes), leaky gut (IgM or IgA responses to LPS of gut commensal bacteria), cytokines (interleukin-1, tumor necrosis factor-α), neopterin, lysozyme and autoimmune responses to serotonin.

CONCLUSIONS: The results support that a) increased CD38 and HLA-DR expression on CD8+ T cells are biomarkers of ME/CFS; b) increased CD38 antigen expression may contribute to suppression of the CD4+/CD8+ ratio and CD19+ expression; c) there are different immune subgroups of ME/CFS patients, e.g. increased CD8+ activation marker expression versus inflammation or O&NS processes; and d) viral infections or reactivation may play a role in a some ME/CFS patients.

 

Source: Maes M, Bosmans E, Kubera M. Increased expression of activation antigens on CD8+ T lymphocytes in Myalgic Encephalomyelitis/chronic fatigue syndrome: inverse associations with lowered CD19+ expression and CD4+/CD8+ ratio, but no associations with (auto)immune, leaky gut, oxidative and nitrosative stress biomarkers. Neuro Endocrinol Lett. 2015;36(5):439-46. https://www.ncbi.nlm.nih.gov/pubmed/26707044

 

Significant other behavioural responses and patient chronic fatigue syndrome symptom fluctuations in the context of daily life: An experience sampling study

Abstract:

OBJECTIVE: Significant other responses to patients’ symptoms are important for patient illness outcomes in chronic fatigue syndrome (CFS/ME); negative responses have been associated with increased patient depression, whilst increased disability and fatigue have been associated with solicitous significant other responses. The current study aimed to examine the relationship between significant other responses and patient outcomes within the context of daily life.

DESIGN: Experience Sampling Methodology (ESM).

METHOD: Twenty-three patients with CFS/ME and their significant others were recruited from specialist CFS/ME services. Sixty momentary assessments, delivered using individual San Francisco Android Smartphones, were conducted over a period of 6 days. All participants reported on affect, dyadic contact, and significant other responses to the patient. Patients reported on symptom severity, disability, and activity management strategies.

RESULTS: Negative significant other responses were associated with increased patient symptom severity and distress reported at the same momentary assessment; there was evidence of a potentially mediating role of concurrent distress on symptom severity. Patient-perceived solicitous responses were associated with reduced patient activity and disability reported at the same momentary assessment. Lagged analyses indicate that momentary associations between significant other responses and patient outcomes are largely transitory; significant other responses were not associated with any of the patient outcomes at the subsequent assessment.

CONCLUSION: The results indicate that significant other responses are important influences on the day-to-day experience of CFS/ME. Further research examining patient outcomes in association with specific significant other behavioural responses is warranted and future interventions that target such significant other behaviours may be beneficial. Statement of contribution What is already known on this subject? The existing literature has identified that significant other responses are important with respect to patient outcomes in CFS/ME. In particular, when examined cross-sectionally and longitudinally, negative and solicitous significant other responses are associated with poorer illness outcomes. This study is the first to examine the momentary associations between negative and solicitous responses, as reported by the patient and significant other, and patient-reported outcomes. An ESM paradigm was used to assess these temporal relationships within the context of participants’ daily life. What does this study add? Negative responses were associated with increased momentary patient distress and symptoms. Perceived solicitousness was associated with activity limitation but less perceived disability. The impact of significant other responses on patient outcomes was found to be transitory.

© 2015 The Authors. British Journal of Health Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.

 

Source: Band R, Barrowclough C, Emsley R, Machin M, Wearden AJ. Significant other behavioural responses and patient chronic fatigue syndrome symptom fluctuations in the context of daily life: An experience sampling study. Br J Health Psychol. 2016 Sep;21(3):499-514. doi: 10.1111/bjhp.12179. Epub 2015 Dec 24. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991278/ (Full article)

 

Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by intense and debilitating fatigue not due to physical activity that has persisted for at least 6 months, post-exertional malaise, unrefreshing sleep, and accompanied by a number of secondary symptoms, including sore throat, memory and concentration impairment, headache, and muscle/joint pain.

In patients with post-exertional malaise, significant worsening of symptoms occurs following physical exertion and exercise challenge serves as a useful method for identifying biomarkers for exertion intolerance. Evidence suggests that intestinal dysbiosis and systemic responses to gut microorganisms may play a role in the symptomology of ME/CFS. As such, we hypothesized that post-exertion worsening of ME/CFS symptoms could be due to increased bacterial translocation from the intestine into the systemic circulation.

To test this hypothesis, we collected symptom reports and blood and stool samples from ten clinically characterized ME/CFS patients and ten matched healthy controls before and 15 minutes, 48 hours, and 72 hours after a maximal exercise challenge. Microbiomes of blood and stool samples were examined.

Stool sample microbiomes differed between ME/CFS patients and healthy controls in the abundance of several major bacterial phyla. Following maximal exercise challenge, there was an increase in relative abundance of 6 of the 9 major bacterial phyla/genera in ME/CFS patients from baseline to 72 hours post-exercise compared to only 2 of the 9 phyla/genera in controls (p = 0.005). There was also a significant difference in clearance of specific bacterial phyla from blood following exercise with high levels of bacterial sequences maintained at 72 hours post-exercise in ME/CFS patients versus clearance in the controls.

These results provide evidence for a systemic effect of an altered gut microbiome in ME/CFS patients compared to controls. Upon exercise challenge, there were significant changes in the abundance of major bacterial phyla in the gut in ME/CFS patients not observed in healthy controls. In addition, compared to controls clearance of bacteria from the blood was delayed in ME/CFS patients following exercise. These findings suggest a role for an altered gut microbiome and increased bacterial translocation following exercise in ME/CFS patients that may account for the profound post-exertional malaise experienced by ME/CFS patients.

 

Source: Shukla SK, Cook D, Meyer J, Vernon SD, Le T, Clevidence D, Robertson CE, Schrodi SJ, Yale S, Frank DN. Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). PLoS One. 2015 Dec 18;10(12):e0145453. doi: 10.1371/journal.pone.0145453. ECollection 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684203/ (Full article)

 

Effectiveness of a group-based self-management program for people with chronic fatigue syndrome: a randomized controlled trial

Abstract:

OBJECTIVE: To evaluate the effectiveness of a group-based self-management program for people with chronic fatigue syndrome.

DESIGN: A randomized controlled trial.

SETTING: Four mid-sized towns in southern Norway and two suburbs of Oslo.

SUBJECTS: A total of 137 adults with chronic fatigue syndrome.

INTERVENTION: A self-management program including eight biweekly meetings of 2.5 hours duration. The control group received usual care.

MAIN MEASURES: Primary outcome measure: Medical Outcomes Study-Short Form-36 physical functioning subscale.

SECONDARY OUTCOME MEASURES: Fatigue severity scale, self-efficacy scale, physical and mental component summary of the Short Form-36, and the illness cognition questionnaire (acceptance subscale). Assessments were performed at baseline, and at six-month and one-year follow-ups.

RESULTS: At the six-month follow-up, a significant difference between the two groups was found concerning fatigue severity ( p = 0.039) in favor of the control group, and concerning self-efficacy in favor of the intervention group ( p = 0.039). These significant differences were not sustained at the one-year follow-up. No significant differences were found between the groups concerning physical functioning, acceptance, and health status at any of the measure points. The drop-out rate was 13.9% and the median number of sessions attended was seven (out of eight).

CONCLUSIONS: The evaluated self-management program did not have any sustained effect, as compared with receiving usual care.

 

Source: Pinxsterhuis I, Sandvik L, Strand EB, Bautz-Holter E, Sveen U. Effectiveness of a group-based self-management program for people with chronic fatigue syndrome: a randomized controlled trial. Clin Rehabil. 2017 Jan;31(1):93-103. doi: 10.1177/0269215515621362. Epub 2016 Jul 11. https://www.ncbi.nlm.nih.gov/pubmed/26672998

 

The Many Neuroprogressive Actions of Tryptophan Catabolites (TRYCATs) that may be Associated with the Pathophysiology of Neuro-Immune Disorders

Abstract:

Many, if not all, chronic medical, neurodegenerative and neuroprogressive illnesses are characterised by chronic immune activation, oxidative and nitrosative stress (O&NS) and systemic inflammation. These factors, notably elevated pro-inflammatory cytokines, activate indoleamine 2,3-dioxygenase (IDO) leading to an upregulated tryptophan catabolite (TRYCAT) pathway of tryptophan degradation in the periphery and in the brain. In such conditions the TRYCAT pathway becomes the predominant system for tryptophan degradation in all body compartments.

In this paper we review the pathways whereby TRYCATs may play a role in neuro-inflammatory and neuroprogressive disease. Thus chronic activation of the TRYCAT pathway leads to the production of a range of neuroactive, neuroprotective and neurotoxic TRYCATs. Some TRYCATs such as quinolinic acid act as potent neurotoxins which inhibit ATP production by mitochondria, provoke increases in O&NS, disrupt neuron glial communication and blood brain barrier integrity, induce apoptosis of glial cells, directly damage neurons and function as a N-methyl D-aspartate (NMDA) receptor agonist.

Other TRYCATs such as kynurenic acid function as antagonists of NMDA, α- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptors and act to regulate levels of glutamate and dopamine.

The neuroprotective functions of this TRYCAT are likely exercised via engagement with alpha7 nicotinic acetylcholine and aryl hydrocarbon receptors but the neuroprotective effects stemming from elevated kynurenic acid levels come at the price of severely compromised neurocognitive function and emotional processing. Other TRYCATS also possess neurotoxic or neuroprotective properties via pro-oxidant and antioxidant effects.

Here we discuss the involvement of the above mentioned TRYCAT pathways in schizophrenia, Alzheimer’s disease and chronic fatigue syndrome.

Source: Morris G, Carvalho AF, Anderson G, Galecki P, Maes M. The Many Neuroprogressive Actions of Tryptophan Catabolites (TRYCATs) that may be Associated with the Pathophysiology of Neuro-Immune Disorders. Curr Pharm Des. 2016;22(8):963-77. https://www.ncbi.nlm.nih.gov/pubmed/26667000

 

Therapist Effects and the Impact of Early Therapeutic Alliance on Symptomatic Outcome in Chronic Fatigue Syndrome

Erratum in

Abstract:

Few studies have examined therapist effects and therapeutic alliance (TA) in treatments for chronic fatigue syndrome (CFS). Therapist effects are the differences in outcomes achieved by different therapists. TA is the quality of the bond and level of agreement regarding the goals and tasks of therapy. Prior research suffers the methodological problem that the allocation of therapist was not randomized, meaning therapist effects may be confounded with selection effects.

We used data from a randomized controlled treatment trial of 296 people with CFS. The trial compared pragmatic rehabilitation (PR), a nurse led, home based self-help treatment, a counselling-based treatment called supportive listening (SL), with general practitioner treatment as usual. Therapist allocation was randomized. Primary outcome measures, fatigue and physical functioning were assessed blind to treatment allocation. TA was measured in the PR and SL arms. Regression models allowing for interactions were used to examine relationships between (i) therapist and therapeutic alliance, and (ii) therapist and average treatment effect (the difference in mean outcomes between different treatment conditions).

We found no therapist effects. We found no relationship between TA and the average treatment effect of a therapist. One therapist formed stronger alliances when delivering PR compared to when delivering SL (effect size 0.76, SE 0.33, 95% CI 0.11 to 1.41). In these therapies for CFS, TA does not influence symptomatic outcome. The lack of significant therapist effects on outcome may result from the trial’s rigorous quality control, or random therapist allocation, eliminating selection effects. Further research is needed.

TRIAL REGISTRATION: ISRCTN74156610.

 

Source: Goldsmith LP, Dunn G, Bentall RP, Lewis SW, Wearden AJ. Therapist Effects and the Impact of Early Therapeutic Alliance on Symptomatic Outcome in Chronic Fatigue Syndrome. PLoS One. 2015 Dec 14;10(12):e0144623. doi: 10.1371/journal.pone.0144623. ECollection 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4685991/ (Full article)

 

Extended B cell phenotype in patients with myalgic encephalomyelitis/chronic fatigue syndrome: a cross-sectional study

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous condition of unknown aetiology characterized by multiple symptoms including fatigue, post-exertional malaise and cognitive impairment, lasting for at least 6 months.

Recently, two clinical trials of B cell depletion therapy with rituximab (anti-CD20) reported convincing improvement in symptoms. A possible but undefined role for B cells has therefore been proposed. Studies of the relative percentages of B cell subsets in patients with ME/CFS have not revealed any reproducible differences from healthy controls (HC). In order to explore whether more subtle alterations in B cell subsets related to B cell differentiation exist in ME/CFS patients we used flow cytometry to immunophenotype CD19⁺ B cells. The panel utilized immunoglobulin (Ig)D, CD27 and CD38 (classical B cell subsets) together with additional markers.

A total of 38 patients fulfilling Canadian, Centre for Disease Control and Fukuda ME/CFS criteria and 32 age- and sex-matched HC were included. We found no difference in percentages of classical subsets between ME/CFS patients and HC. However, we observed an increase in frequency (P < 0·01) and expression (MFI; P = 0·03) of CD24 on total B cells, confined to IgD⁺ subsets. Within memory subsets, a higher frequency of CD21⁺ CD38⁻ B cells (> 20%) was associated with the presence of ME/CFS [odds ratio: 3·47 (1·15-10·46); P = 0·03] compared with HC, and there was a negative correlation with disease duration.

In conclusion, we identified possible changes in B cell phenotype in patients with ME/CFS. These may reflect altered B cell function and, if confirmed in other patient cohorts, could provide a platform for studies based on clinical course or responsiveness to rituximab therapy.

© 2016 British Society for Immunology.

 

Source: Mensah F, Bansal A, Berkovitz S, Sharma A, Reddy V, Leandro MJ, Cambridge G. Extended B cell phenotype in patients with myalgic encephalomyelitis/chronic fatigue syndrome: a cross-sectional study. Clin Exp Immunol. 2016 May;184(2):237-47. doi: 10.1111/cei.12749. Epub 2016 Feb 22. https://www.ncbi.nlm.nih.gov/pubmed/26646713

 

Borderline Intracranial Hypertension Manifesting as Chronic Fatigue Syndrome Treated by Venous Sinus Stenting

Abstract:

Chronic fatigue syndrome and cases of idiopathic intracranial hypertension without signs of raised intracranial pressure can be impossible to distinguish without direct measurement of intracranial pressure. Moreover, lumbar puncture, the usual method of measuring intracranial pressure, can produce a similar respite from symptoms in patients with chronic fatigue as it does in idiopathic intracranial hypertension. This suggests a connection between them, with chronic fatigue syndrome representing a forme fruste variant of idiopathic intracranial hypertension. If this were the case, then treatments available for idiopathic intracranial hypertension might be appropriate for chronic fatigue.

We describe a 49-year-old woman with a long and debilitating history of chronic fatigue syndrome who was targeted for investigation of intracranial pressure because of headache, then diagnosed with borderline idiopathic intracranial hypertension after lumbar puncture and cerebrospinal fluid drainage. Further investigation showed narrowings at the anterior ends of the transverse sinuses, typical of those seen in idiopathic intracranial hypertension and associated with pressure gradients.

Stenting of both transverse sinuses brought about a life-changing remission of symptoms with no regression in 2 years of follow-up. This result invites study of an alternative approach to the investigation and management of chronic fatigue.

 

Source: Higgins N, Pickard J, Lever A. Borderline Intracranial Hypertension Manifesting as Chronic Fatigue Syndrome Treated by Venous Sinus Stenting. J Neurol Surg Rep. 2015 Nov;76(2):e244-7. doi: 10.1055/s-0035-1564060. Epub 2015 Sep 14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648738/ (Full article)

 

Fatigue in adults with post-infectious fatigue syndrome: a qualitative content analysis

Abstract:

BACKGROUND: Fatigue is a major problem among individuals with post-infectious fatigue syndrome (PIFS), also known as chronic fatigue syndrome or myalgic encephalomyelitis. It is a complex phenomenon that varies across illnesses. From a nursing perspective, knowledge and understanding of fatigue in this illness is limited. Nurses lack confidence in caring for these patients and devalue their professional role. The aim of this study was to explore in-depth the experiences of fatigue among individuals with PIFS. A detailed description of the phenomenon of fatigue is presented. Increased knowledge would likely contribute to more confident nurses and improved nursing care.

METHODS: A qualitative study with open interviews was employed. In-depth interviews with patients were fully transcribed and underwent a qualitative content analysis. A maximum variation sample of 26 affected adults between 26-59 years old was recruited from a population diagnosed at a fatigue outpatient clinic.

RESULTS: The fatigue was a post-exertional, multidimensional, fluctuating phenomenon with varying degrees of severity and several distinct characteristics and was accompanied by concomitant symptoms. Fatigue was perceived to be an all-pervasive complex experience that substantially reduced the ability to function personally or professionally. A range of trigger mechanisms evoked or worsened the fatigue, but the affected were not always aware of what triggered it. There was an excessive increase in fatigue in response to even minor activities. An increase in fatigue resulted in the exacerbation of other concomitant symptoms. The term fatigue does not capture the participants’ experiences, which are accompanied by a considerable symptom burden that contributes to the illness experience and the severe disability.

CONCLUSIONS: Although some aspects of the fatigue experience have been reported previously, more were added in our study, such as the dimension of awakening fatigue and the characteristic beyond time, when time passes unnoticed. We also identified trigger mechanisms such as emotional, neurological, social, financial, and pressure on oneself or from others. This in-depth exploration of fatigue in PIFS provides an overview of the dimensions, characteristics, and trigger mechanisms of fatigue, thus making better clinical observations, early recognition, improved communication with patients and more appropriate nursing interventions possible.

 

Source: Stormorken E, Jason LA, Kirkevold M. Fatigue in adults with post-infectious fatigue syndrome: a qualitative content analysis. BMC Nurs. 2015 Nov 28;14:64. doi: 10.1186/s12912-015-0115-5. ECollection 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662830/ (Full article)

 

Reductions in circulating levels of IL-16, IL-7 and VEGF-A in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Recently, differences in the levels of various chemokines and cytokines were reported in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as compared with controls. Moreover, the analyte profile differed between chronic ME/CFS patients of long duration versus patients with disease of less than 3 years. In the current study, we measured the plasma levels of 34 cytokines, chemokines and growth factors in 100 chronic ME/CFS patients of long duration and in 79 gender and age-matched controls.

We observed highly significant reductions in the concentration of circulating interleukin (IL)-16, IL-7, and Vascular Endothelial Growth Factor A (VEGF-A) in ME/CFS patients. All three biomarkers were significantly correlated in a multivariate cluster analysis. In addition, we identified significant reductions in the concentrations of fractalkine (CX3CL1) and monokine-induced-by-IFN-γ (MIG; CXCL9) along with increases in the concentrations of eotaxin 2 (CCL24) in ME/CFS patients.

Our data recapitulates previous data from another USA ME/CFS cohort in which circulating levels of IL-7 were reduced. Also, a reduced level of VEGF-A was reported previously in sera of patients with Gulf War Illness as well as in cerebral spinal fluid samples from a different cohort of USA ME/CFS patients.

To our knowledge, we are the first to test for levels of IL-16 in ME/CFS patients. In combination with previous data, our work suggests that the clustered reduction of IL-7, IL-16 and VEGF-A may have physiological relevance to ME/CFS disease. This profile is ME/CFS-specific since measurement of the same analytes present in chronic infectious and autoimmune liver diseases, where persistent fatigue is also a major symptom, failed to demonstrate the same changes. Further studies of other ME/CFS and overlapping disease cohorts are warranted in future.

Copyright © 2015 Elsevier Ltd. All rights reserved.

 

Source: Landi A, Broadhurst D, Vernon SD, Tyrrell DL, Houghton M. Reductions in circulating levels of IL-16, IL-7 and VEGF-A in myalgic encephalomyelitis/chronic fatigue syndrome. Cytokine. 2016 Feb;78:27-36. doi: 10.1016/j.cyto.2015.11.018. Epub 2015 Nov 28. https://www.ncbi.nlm.nih.gov/pubmed/26615570