Network structure underpinning (dys)homeostasis in CFS

Posted on 04/01/2019 by wames

Network structure underpinning (dys)homeostasis in chronic fatigue syndrome; preliminary findings, by James E Clark, Wan-Fai Ng, Stephen Rushton, Stuart
Watson, Julia L Newton in PLoS One Vol 14, #3, Vol 14, #3, p e0213724 [Published: March 25, 2019]

Research abstract:

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.

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A validated scale for assessing the severity of acute infectious mononucleosis [glandular fever]

Posted on 03/29/2019 by wames

A validated scale for assessing the severity of acute infectious mononucleosis, by Ben Z Katz, Caroline Reuter, Yair Lupovitch, Kristen Gleason, Damani McClellan, Joseph Cotler, Leonard A Jason in The Journal of Pediatrics 2019

Research abstract:

Objectives:
To develop a scale for the severity of mononucleosis.

Study design:
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.

Results
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.

Conclusions:
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.

Read full paper

Assessment Tool Predicts Chronic Fatigue Syndrome Six Months after Mono

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Diagnostic sensitivity of 2-day cardiopulmonary exercise testing in ME/CFS

Posted on 03/28/2019 by wames

Diagnostic sensitivity of 2-day cardiopulmonary exercise testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, by Maximillian J Nelson,  Jonathan D Buckley, Rebecca L Thomson, Daniel Clark, Richard Kwiatek and Kade Davison in Journal of Translational Medicine 2019 17:80 [Published: 14 March 2019]

Research abstract:

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.

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Sharpe, Goldsmith & Chalder fail to restore confidence in the PACE trial findings

Posted on 03/27/2019 by wames

Response: Sharpe, Goldsmith and Chalder fail to restore confidence in the PACE trial findings, by Carolyn E Wilshire, Tom Kindlon in BMC Psychology 2019 7:19 [Published: 26 March 2019]

Abstract:

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.

Some extracts:

To summarise, Sharpe et al. “prefer” their modified definition because it generates similar rates of recovery to previous studies, and is also more consistent with “our clinical experience” ([5], p.. 6).Clearly, it is not appropriate to loosen the definition of recovery simply because things did not go as expected based on previous studies. Researchers need to be open to the possibility that their results may not align with previous findings, nor with their own preconceptions. That is the whole point of a trial. Otherwise, the enterprise ceases to be genuinely informative, and becomes an exercise in belief confirmation…

Putting aside the erroneous criticism regarding the APT arm, Sharpe and colleagues raised three further criticisms of our reanalysis. The first was that we did not adhere to “an a priori analysis plan” ([5], p. 1). This claim is puzzling, because of course we followed the Investigators’ own analysis plan as set out in their trial protocol – or to be precise, we followed it as closely as was possible, given the data we had available.

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Whole blood human transcriptome and virome analysis of ME/CFS patients experiencing post-exertional malaise following cardiopulmonary exercise testing

Posted on 03/27/2019 by wames

Whole blood human transcriptome and virome analysis of ME/CFS patients experiencing post-exertional malaise following cardiopulmonary exercise testing, by Jerome Bouquet, Tony Li, Jennifer L Gardy, Xiaoying Kang, Staci Stevens, Jared Stevens, Mark VanNess, Christopher Snell, James Potts, Ruth R Miller, Muhammad Morshed, Mark McCabe, Shoshana Parker, Miguel Uyaguari,  Patrick Tang, Theodore Steiner, Wee-Shian Chan, Astrid-Marie De Souza, Andre Mattman, David M Patrick , Charles Y Chiu in PLOS One March 21, 2019

Research abstract:
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 signaling, 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.

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Acceptance and identity change… carers’ experiences in ME/CFS

Posted on 03/26/2019 by wames

Acceptance and identity change: An interpretative phenomenological analysis of carers’ experiences in myalgic encephalopathy/chronic fatigue syndrome, by Sarah Catchpole, Gulcan Garip, in Journal of Health Psychology, March 21, 2019

 

Research abstract:

Care cloud tag image by John Hain from Pixabay 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.

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Chronotropic Intolerance: an overlooked determinant of symptoms & activity limitation in ME/CFS?

Posted on 03/25/2019 by wames

Chronotropic intolerance: an overlooked determinant of symptoms and activity limitation in myalgic encephalomyelitis/chronic fatigue syndrome?, by Todd E. Davenport,  Mary Lehnen,  Staci R Stevens,  J. Mark VanNess,  Jared Stevens and  Christopher R Snell in Front. Pediatr. 22 March 2019

Review abstract:

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.

Meta-Analysis shows blunted heart rate contributes to activity intolerance in people with ME, by #MEAction

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Associations between autonomic & orthostatic self-report and physician ratings of Orthostatic Intolerance in youth

Posted on 03/22/2019 by wames

Associations between autonomic and orthostatic self-report and physician ratings of Orthostatic Intolerance in youth, by Katlin R Schultz, Ben Z Katz, Neil R Bockian, Leonard A Jason in Clinical Therapeutics 2019

Research abstract:

Purpose:
There is no known biological marker or physical assessment to diagnose chronic fatigue syndrome (CFS), leaving physicians to heavily rely on self-report measures regarding the symptoms associated with CFS.  Common symptoms of CFS include difficulty sleeping, joint pain, headaches, sore throat, cognitive dysfunction, physical exhaustion, dizziness, and nausea.

Because of the overlap among CFS symptoms and autonomic functioning, we examined the association between 2 self-report measures of orthostatic and autonomic symptoms and a physician’s report of autonomic functioning (measures of changes in blood pressure and pulse) to further understand the association among autonomic functioning within individuals with symptoms of CFS.

Methods:
With data from an ongoing study, we used independent t tests and Pearson correlation tests to assess the association among the orthostatic domain from the DePaul Symptom Questionnaire, Autonomic Symptom Checklist composite scores, and the physician’s assessment of orthostatic intolerance obtained from a sample of 191 participants, 42 who were healthy controls.

Findings:
No significant demographic differences were found between the CFS-like group and the healthy controls. Results indicate a significant correlation between orthostatic and autonomic functioning (r = 0.58) and a correlation with a low effect size among autonomic functioning and physician measures of orthostatic functioning (r = −0.01 to 0.29).

However, fewer correlations were found between self-reported symptoms of orthostatic functioning and the physician’s measures of orthostatic functioning.

Implications:
These results suggest that although orthostatic dysfunction is reported in children and adolescents with CFS-like symptoms, the physical measures of autonomic functioning in this study were unable to detect these symptoms.

Read the full text

 

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Posted on 03/21/2019 by wames

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Pharmaceutical interventions in CFS: a literature-based commentary

Posted on 03/21/2019 by wames

Pharmaceutical Interventions in Chronic Fatigue Syndrome: A Literature-based Commentary, by  Spencer Richman, Matthew C Morris, Gordon Broderick, Travis JA Craddock, Nancy G Klimas, Mary Ann Fletcher in Clinical Therapeutics [Available online 11 March 2019]

Research abstract:

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.

Read full article

Excerpt from Discussion:

The current literature on the treatment of ME/CFS leans strongly toward a single conclusion that there is no single solution. The assumption that a single drug can successfully treat ME/CFS is likely incorrect.

The multifaceted, complex nature of ME/CFS may instead be more effectively treated with combination therapies, tailored to the specific causes and symptoms present in each individual patient. These potential therapies will be supported by advancements in 2 fields.

First, advancements in systems biology and systems-level analysis of the biological drivers behind ME/CFS will more clearly inform researchers as to which illness mechanisms are viable targets for treatment.  Systems biology approaches have already been undertaken to analyze gene coexpression networks, perform pathway analysis, and explore metabolic pathway perturbations in ME/CFS.  Generating robust tools for system-wide analysis of ME/CFS, at all of the conventional “-omics” levels, may prove invaluable for the discovery of a treatment or cure.

While systems biology approaches are needed to conduct basic research into the underlying causes of ME/CFS, personalized medicine and translational medicine are the necessary complements to such research. Personalized or precision medicine is a field that seeks to tailor treatments to individuals or narrow groups of individuals based on genetic or epigenetic makeup as well as a variety of other nongeneralizable patient characteristics. It has been promoted by some as the future of medicine, and it may prove invaluable in treating patients with ME/CFS.

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