Endocrine immune regulation in… women with CFS

Posted on 04/24/2019 by wames

Leveraging prior knowledge of endocrine immune regulation in the therapeutically relevant phenotyping of women with Chronic Fatigue Syndrome, by Matthew C Morris, Katherine Cooney, Hooman Sedghamiz, Maria Abreu, Fanny Collado, Elizabeth G Balbin, Travis JA Craddock, Nancy G Klimas, Gordon Broderick, Mary Ann Fletcher in Clinical Therapeutics, vol 41, issue 4, April 2019, pp 656-674.e4 [https://doi.org/10.1016/j.clinthera.2019.03.002]

 

Research abstract:

Purpose:
The complex and varied presentation of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has made it difficult to diagnose, study, and treat. Its symptoms and likely etiology involve multiple components of endocrine and immune regulation, including the hypothalamic-pituitary-adrenal axis, the hypothalamic-pituitary-gonadal axis, and their interactive oversight of immune function.

We propose that the persistence of ME/CFS may involve changes in the regulatory interactions across these physiological axes. We also propose that the robustness of this new pathogenic equilibrium may at least in part explain the limited success of conventional single-target therapies.

Methods:
A comprehensive model was constructed of female endocrine–immune signaling consisting of 28 markers linked by 214 documented regulatory interactions. This detailed model was then constrained to adhere to experimental measurements in a subset of 17 candidate immune markers measured in peripheral blood of patients with ME/CFS and healthy control subjects before, during, and after a maximal exercise challenge. A set of 26 competing numerical models satisfied these data to within 5% error.

Findings:
Mechanistically informed predictions of endocrine and immune markers that were either unmeasured or exhibited high subject-to-subject variability pointed to possible context-specific overexpression in ME/CFS at rest of corticotropin-releasing hormone, chemokine (C-X-C motif) ligand 8, estrogen, follicle-stimulating hormone (FSH), gonadotropin-releasing hormone 1, interleukin (IL)-23, and luteinizing hormone, and underexpression of adrenocorticotropic hormone, cortisol, interferon-γ, IL-10, IL-17, and IL-1α.

Simulations of rintatolimod and rituximab treatment predicted a shift in the repertoire of available endocrine–immune regulatory regimens. Rintatolimod was predicted to make available substantial remission in a significant subset of subjects, in particular those with low levels of IL-1α, IL-17, and cortisol; intermediate levels of progesterone and FSH; and high estrogen levels. Rituximab treatment was predicted to support partial remission in a smaller subset of patients with ME/CFS, specifically those with low norepinephrine, IL-1α, chemokine (C-X-C motif) ligand 8, and cortisol levels; intermediate FSH and gonadotropin-releasing hormone 1 levels; and elevated expression of tumor necrosis factor-α, luteinizing hormone, IL-12, and B-cell activation.

Implications:
Applying a rigorous filter of known signaling mechanisms to experimentally measured immune marker expression in ME/CFS has highlighted potential new context-specific markers of illness. These novel endocrine and immune markers may offer useful candidates in delineating new subtypes of ME/CFS and may inform on refinements to the inclusion criteria and instrumentation of new and ongoing trials involving rintatolimod and rituximab treatment protocols.

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Cellular immune function in ME/CFS: increased MAIT cell frequency

Posted on 04/17/2019 by wames

Cellular immune function in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), by Jacqueline M Cliff, Elizabeth C King, Ji-Sook Lee, Nuno Sepulveda, Asia-Sofia Wolf, Caroline Kingdon, Erinna Bowman, Hazel M. Dockrell, Luis C. Nacul, Eliana Lacerda, Eleanor Riley in Front. Immunol., 16 April 2019, https://doi.org/10.3389/fimmu.2019.00796

Research abstract:

Lead author Dr Jackie Cliff

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition with unknown aetiology, unclear pathophysiology and with no diagnostic test or biomarker available. Many patients report their ME/CFS began after an acute infection, and subsequent increased
frequency of infections, such as colds or influenza, is common. These factors imply an altered immunological status exists in ME/CFS, in at least a proportion of patients, yet previous studies of peripheral
immunity have been discrepant and inconclusive.

The UK ME/CFS Biobank, which has collected blood samples from nearly 300 clinically-confirmed ME/CFS patients, enables large-scale studies of immunological function in phenotypically well-characterised participants. In this study, herpes virus serological status and T cell, B cell, NK cell and monocyte populations were investigated in 251 ME/CFS patients, including 54 who were severely affected, and compared with those from 107 healthy participants and with 46 patients with Multiple Sclerosis. There were no differences in seroprevalence for six human herpes viruses between ME/CFS and healthy controls, although seroprevalence for the Epstein-Barr virus was higher in multiple sclerosis patients.

Contrary to previous reports, no significant differences were observed in NK cell numbers, subtype proportions or in vitro responsiveness between ME/CFS patients and healthy control participants. In contrast, the T cell compartment was altered in ME/CFS, with reduced proportions of effector memory CD8+ T cells and of intermediately differentiated CD8+ T cells in ME/CFS. Conversely, there as a significantly increased proportion of mucosal associated invariant cells (MAIT) cells, especially in severely affected ME/CFS patients.

These abnormalities demonstrate that an altered immunological state does exist in ME/CFS, particularly in severely affected people. This may simply reflect ongoing or recent infection, or may indicate future increased susceptibility to infection. Longitudinal studies of ME/CFS patients are needed to help to determine cause and effect and thus any
potential benefits of immuno-modulatory treatments for ME/CFS.

Lay summary: Increased MAIT cell frequency in ME/CFS

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Evidence of clinical pathology abnormalities in people with ME/CFS…

Posted on 04/15/2019 by wames

Evidence of clinical pathology abnormalities in people with Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) from an analytic cross-sectional study, by Luis Nacul, Barbara de Barros, Caroline C Kingdon, Jacqueline M Cliff, Taane G Clark, Kathleen Mudie, Hazel M Dockrell, Eliana M Lacerda in Diagnostics Vol 9, #2, p 41 [April 10, 2019]

 

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease presenting with extreme fatigue, post-exertional malaise, and other symptoms. In the absence of a diagnostic biomarker, ME/CFS is diagnosed clinically, although laboratory tests are routinely used to exclude alternative diagnoses.

In this analytical cross-sectional study, we aimed to explore potential haematological and biochemical markers for ME/CFS, and disease severity. We reviewed laboratory test results from 272 people with ME/CFS and 136 healthy controls participating in the UK ME/CFS Biobank (UKMEB).

After corrections for multiple comparisons, most results were within the normal range, but people with severe ME/CFS presented with lower median values (p < 0.001) of serum creatine kinase (CK; median=54 U/L), compared to healthy controls (HCs; median=101.5 U/L) and non-severe ME/CFS (median=84 U/L). The differences in CK concentrations persisted after adjusting for sex, age, body mass index, muscle mass, disease duration, and activity levels (odds ratio (OR) for being a severe case=0.05 (95% confidence interval (CI)=0.02-0.15) compared to controls, and OR=0.16 (95% CI=0.07-0.40), compared to mild cases).

This is the first report that serum CK concentrations are markedly reduced in severe ME/CFS, and these results suggest that serum CK merits further investigation as a biomarker for severe ME/CFS.

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Dr Nina Muirhead asks doctors to believe in ME

Posted on 04/12/2019 by wames

Royal College of Physicians blog, 10 April 2019: Do you really believe in ME?

With many in the medical profession misunderstanding ME, Dr Nina Muirhead recounts her own experience with the illness and how it reshaped her understanding of it. Dr Nina Muirhead is a dermatologist in Buckinghamshire Healthcare NHS Trust and a research supervisor at Cardiff medical school.

Introduction:

Many doctors can find themselves in the position of the patient, and being informed of one’s own diagnosis can be a frightening and emotional experience. Eighteen months ago, after seeing thirteen different doctors and undergoing multiple tests and investigations, not only was I given a diagnosis of a condition that I didn’t know about or understand, it was an illness I didn’t believe in.

Ten months after developing acute Epstein Barr Virus Glandular Fever I was diagnosed with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) by my outstanding and well-informed GP. Prior to becoming ill, I had a vague notion that ME/CFS was an illness related to deconditioning. How wrong I was. The NICE guidelines had perpetuated my misunderstanding of ME/CFS by recommending Cognitive Behavioural Therapy (CBT) and Graded Exercise (GET).

The NICE guidelines had perpetuated my misunderstanding of ME/CFS by recommending Cognitive Behavioural Therapy and Graded Exercise

From my experience of ME/CFS there was no psychological component whatsoever, besides which exercise, if anything, was making me worse not better. I was not deconditioned or frightened to exercise. The symptoms were more consistent with a brain tumour or multiple sclerosis. The reality is ME/CFS is a serious, heritable, neurological condition and I was shocked to discover subsequently that my grandmother had died from it aged 42.

Read the full blog

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Meeting the educational needs of young ME/CFS patients: role of the treating physician

Posted on 04/10/2019 by wames

Meeting the educational needs of young, ME/CFS patients: role of the treating physician, by Faith R. Newton in Front. Pediatr., 02 April 2019 https://doi.org/10.3389/fped.2019.00104

 

Article introduction:
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling, chronic disease characterized by the body’s inability to produce sufficient energy for normal everyday activities.

Children with ME/CFS experience debilitating fatigue referred to as post-exertional malaise (PEM) after minimal mental or physical exertion which is not relieved by sleep. It can significantly reduce the ability of the child to take part in personal, educational, or social activities and can compromise executive function, and can result in a moderate to severe disability.

As many as 1% of school-age children suffer from this disease in varying degrees of severity, and ME/CFS has been shown to negatively impact school attendance, participation, connectedness, and academic performance (1). Some studies suggest that ME/CFS may be the major cause of extended school absences (2).

Whereas, the literature supplying practice-based guidance for other chronic conditions affecting children in school, such as Autism and Attention Deficit Hyperactivity Disorder (ADHD) will be found in educational journals, very little guidance for students with ME/CFS appears in the clinical medicine literature. Although school nurses are beginning to play a larger role in supporting these children, physicians or healthcare providers retain primary responsibility of informing the school system of the needed adjustments for the young ME/CFS patient to succeed in the school environment.

This article argues that the physician has a much broader responsibility to provide diagnostic, symptomatic, and treatment information about ME/CFS than they would with other conditions such as Autism or ADHD that qualify students for special services. For students with ME/CFS, the physician’s letter required in the school’s evaluation process is a critical resource to advise and guide education professionals regarding appropriate student placement, classroom support, and instructional accommodations or modifications. The specifics of what should be included in a model physician’s letter are included.

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FM, CFS & MCS: illness experiences

Posted on 04/09/2019 by wames

Fibromyalgia, Chronic Fatigue Syndrome, and Multiple Chemical Sensitivity: Illness Experiences, by Almudena Alameda Cuesta, Álvaro Pazos Garciandía, Cristina Oter Quintana in Clinical Nursing Research [First Published March 27, 2019] https://doi.org/10.1177/1054773819838679

Research abstract:

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.

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ME & CFS case definitions: effects of requiring a substantial reduction in functioning

Posted on 04/07/2019 by wames

Myalgic encephalomyelitis and chronic fatigue syndrome case definitions: effects of requiring a substantial reduction in functioning, by Samantha Scartozzi, Madison Sunnquist & Leonard A Jason in Fatigue: Biomedicine, Health & Behavior [Published online: 01 Apr 2019] https://doi.org/10.1080/21641846.2019.1600825

Research abstract:

Background: Current case definitions for myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) require an individual to report a ‘substantial reduction’ in activity levels, when compared to premorbid functioning. However, little guidance is provided on how to measure these reductions, as well as what level of reduction should be deemed ‘substantial,’ leading to inconsistencies in how this criterion is applied across research settings.

Purpose: The current study examined the influence of substantial reduction criterion on case definitions.

Method: The current study analyzed an international convenience sample of 1002 individuals with ME or CFS, 53 healthy controls, and 260 controls with other chronic illnesses.

Results: Findings indicated that the utility of the substantial reduction criterion varied by case definition, with more stringent case definitions not needing this criterion to identify cases.

Conclusion: These results suggest that the requirement of a substantial reduction in functioning may be redundant when case definitions specify that individuals must endorse a set of core symptoms at specified frequency and severity levels.

Funding was provided by NIAID (grant number AI105781).

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Decreased expression of the CD57 molecule in T Lymphocytes of patients with CFS

Posted on 04/05/2019 by wames

Decreased Expression of the CD57 Molecule in T Lymphocytes of Patients with Chronic Fatigue Syndrome, by P Espinosa, J M Urra in  Mol Neurobiol (2019) [Online: 21 March 2019]

Research abstract:
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.

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Challenging claims that fearful avoidance beliefs about activity in ME & CFS can be targeted with CBT/GET.

Posted on 04/04/2019 by wames

Cognitive-behavorial and graded exercise therapies for chronic fatigue (syndrome) are associated with lower levels of work/school attendance, by Frank N M Twisk in J Behav Med [Published online 28 March 2019]

Psychological and demographic factors associated with fatigue and social adjustment in young people with severe chronic fatigue syndrome/myalgic encephalomyelitis: a preliminary mixed-methods study, Sheila Ali, Lucy Adamczyk, Mary Burgess, Trudie Chalder in Journal of Behavioral Medicine pp 1–13 [First Online: 25 January 2019]

Twisk comments on the recent study by Ali and colleagues which reported that stronger fear avoidance beliefs at baseline were associated with higher fatigue approximately 5 months later (T2) and worse social adjustment at T1 and T2, and female gender and treatment were associated with lower work/school attendance at T1 and T2.

Ali et al. conclude: ‘‘Fearful beliefs about activity could be targeted using cognitive-behavioural interventions’’.

Twisk makes 3 challenges to the study results:

  1. the patients investigated cannot be qualified as CFS patients, let alone ME patients – the discredited Oxford criteria was used for selection
  2. The results do not support the claim that CBT & GET are effective rehabilitative treatments as in most cases (25/41) treatment was associated with lower work/school attendance at baseline and after 5 months.
  3. In spite of claiming their study ‘‘did not allow for causal inferences to be made’ they conclude that fearful beliefs could have ‘‘developed as a result of being so severely ill’’

Twisk believes the study actually shows that there is a need for accurate diagnosis (ME, CFS or CF) and that CBT and GET are neither effective nor safe.

Read the full article

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CBT & GET are ‘unsuitable treatments or management approaches for ME/CFS’

Posted on 04/04/2019 by wames

The results of the Forward ME and Oxford Brookes University patient survey on CBT and GET in ME/CFS have been published.

2,274 people with ME/CFS of all ages responded to the online survey with their experiences of cognitive behavioural therapy and/or graded exercise therapy. 80.4% were female and 98.5% said they experience post-exertional malaise.

Conclusions from Forward ME Executive Summary:

The results show clearly that cognitive behavioural therapy and graded exercise therapy are unsuitable treatments or management approaches for ME/CFS. The changes in severity and the worsening of symptoms are clear indications that the therapies being offered are having adverse effects on the health of individuals.

CBT, while may be effective for a minority in helping with mental health challenges such as depression or anxiety, is shown to be ineffective in a considerable proportion of people and even led to almost half of respondents reporting worse symptoms.

GET is shown to cause considerable deterioration in physical and mental health. It has led to people becoming more severe and the open questions have given us insight into the worsening symptoms that have developed when patients have increased their activity beyond their capabilities.

The results show that although NICE might not recommend GET for the severely affected, they are clearly being given GET at the clinical level. This could be because clinics are not tailoring their management advice to the individual (as NICE recommends) or are simply not aware of the unsuitability of aerobic/exercise for people with ME/CFS.

Alongside this the analysis of the survey provided by Oxford Brookes University show that people with ME/CFS have experienced negative effects with regard to welfare and benefits when choosing whether or not participate in these treatments. Results also show that the adverse effects of the treatment has had a considerable impact on the employment and education capabilities of individuals.

We acknowledge that there may be some bias in the results of the survey due to the promotion of the survey being organised by ME charities rather than NHS organisations. There are also limitations in self-reported data. However, we feel the scale of the response demonstrates the strength of feeling and harm on this issue.

As there is a commitment that this new guideline be ‘patient led’ we believe that the responses should carry considerable weight in the consideration of effective treatment or management approaches. There is also an ethical question[1] whether the current management recommendations relating to CBT and GET can continue while the development is underway when their suitability is evident.

Our collective recommendation is that GET and CBT be removed from the NICE guideline for ME/CFS.

Read more about the survey results on the ME Association website: Forward ME and Oxford Brookes University announce results of patient survey on CBT and GET in ME/CFS

#MEAction: GET and CBT are not safe for ME – summary of survey results

Full report     Survey appendices

ME Research UK: Forward-ME survey on patients’ experiences of CBT and GET

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