Systematic review of Primary Outcome Measurements for CFS/ME in randomized controlled trials

Posted on 12/05/2020 by wames

Systematic review of primary Outcome Measurements for Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) in randomized controlled trials, by  Do-Young Kim, Jin-Seok Lee and Chang-Gue Son in J. Clin. Med. 2020, 9(11) 3463 [doi.org/10.3390/jcm9113463] (This article belongs to the Special Issue Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Diagnosis and Treatment)

 

Research abstract:

Background:

Due to its unknown etiology, the objective diagnosis and therapeutics of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) are still challenging.

Generally, the patient-reported outcome (PRO) is the major strategy driving treatment response because the patient is the most important judge of whether changes are meaningful.

Methods:

In order to determine the overall characteristics of the main outcome measurement applied in clinical trials for CFS/ME, we systematically surveyed the literature using two electronic databases, PubMed and the Cochrane Library, throughout June 2020. We analyzed randomized controlled trials (RCTs) for CFS/ME focusing especially on main measurements.

Results:

Fifty-two RCTs out of a total 540 searched were selected according to eligibility criteria. Thirty-one RCTs (59.6%) used single primary outcome and others adapted ≥2 kinds of measurements. In total, 15 PRO-derived tools were adapted (50 RCTs; 96.2%) along with two behavioral measurements for adolescents (4 RCTs; 7.7%). The 36-item Short Form Health Survey (SF-36; 16 RCTs), Checklist Individual Strength (CIS; 14 RCTs), and Chalder Fatigue Questionnaire (CFQ; 11 RCTs) were most frequently used as the main outcomes. Since the first RCT in 1996, Clinical Global Impression (CGI) and SF-36 have been dominantly used each in the first and following decade (26.1% and 28.6%, respectively), while both CIS and Multidimensional Fatigue Inventory (MFI) have been the preferred instruments (21.4% each) in recent years (2016 to 2020).

Conclusions:

This review comprehensively provides the choice pattern of the assessment tools for interventions in RCTs for CFS/ME. Our data would be helpful practically in the design of clinical studies for CFS/ME-related therapeutic development.

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Paradigm shift to disequilibrium in the genesis of orthostatic intolerance

Posted on 12/01/2020 by wames

Paradigme shift to disequilibrium in the genesis of orthostatic intolerance in patients with CFS, by K Miwa in European Heart Journal Vol 40, Supp 1, Oct 2019

 

Research abstract

Background
Chronic fatigue syndrome (CFS) characterized by severe disabling fatigue and prolonging post-exertional malaise. The dysfunction of the central nervous system associated with myalgic encephalomyelitis (ME) has been postulated as the main cause of CFS. Orthostatic intolerance (OI) causes a marked reduction in the activities of daily living and impairs the quality of life in patients with ME/CFS. OI has been surmised to be a cardiovascular symptom with cerebral hypo-perfusion and exaggerated sympathetic nervous activation.

Purpose
Postural instability or disequilibrium may be involved in the etiology of OI because postural stability is an essential element for static balance.

Methods
The study comprised 72 patients with ME/CFS (18 men and 54 women; mean age, 37±10 years), who underwent neurological examinations and the active 10-min standing test.

Results
Disequilibrium defined as instability on standing with their feet together and eyes shut, was detected in 23 (32%) patients while postural orthostatic tachycardia in 16 (22%). Compared with 49 patients without disequilibrium, patients with disequilibrium more prevalently failed to complete the 10-min standing test (74% vs. 4%, p<0.01) and body sway was significantly more prevalently observed during the test (100% vs. 12%, p<0.01).

The performance status score was significantly higher in patients with disequilibrium than those without it (median: 7 vs. 5, p<0.01), suggesting more severely restricted activity of daily living in the former. The prevalence of postural orthostatic tachycardia during the standing test was comparable between the patients with disequilibrium (23%) and those without it (22%, p=1.00). The 19 (26%) patients who failed to complete the 10-min standing test had disequilibrium more prevalently than those who completed it (89% vs. 11%, p<0.01).

Performance status score was significantly higher in patients who failed to complete it than those who completed it (median: 6 vs. 5, p<0.01), suggesting more severe restriction of activity of daily living in the former. Significantly higher rates of disequilibrium (89% vs. 11%, p<0.01), unstable standing on one leg (84% vs. 17%, p<0.01) as well as abnormal tandem gait (79% vs. 11%, p<0.01) were noted in patients who failed to complete it than those who completed it. Body sway during the standing test was significantly more prevalently observed in the patients who failed to complete it than those who completed it (89% vs. 23%, p<0.01).

The prevalence of postural orthostatic tachycardia during the standing test was comparable between the patients who failed to complete it and those who completed it (21% vs. 23%, p=1.00). Among the patients who failed to complete it 8 had the previous study records which revealed that 6 of them had completed it 6–24 months before when all the 6 patients had had no disequilibrium.

Conclusion
Disequilibrium should be recognized as an important cause of OI in patients with ME/CFS.

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Bias caused by reliance on patient-reported outcome measures in non-blinded randomized trials

Posted on 11/28/2020 by wames

Bias caused by reliance on patient-reported outcome measures in non-blinded randomized trials: an in-depth look at exercise therapy for chronic fatigue syndrome
by Michiel Tack, David M Tuller & Caroline Struthers in Fatigue: Biomedicine, Health & Behavior Vol 8, 2020 Issue 4, 25 Nov 2020 [doi.org/10.1080/21641846.2020.1848262]

 

Research abstract: 

Background
Several randomized trials have reported that graded exercise therapy (GET) is an effective treatment for chronic fatigue syndrome (CFS). These trials were not blinded and relied on patient-reported outcome measures (PROMs). We investigate whether bias introduced by this study design influenced the results.

Methods
We extracted standardized mean differences from the most recent meta-analysis on exercise therapy for CFS to analyze their size, consistency over time, and congruence with objective measurements. A narrative review methodology was used to examine mediation analyses, plausible mechanisms of improvement, and risk of response bias.

Results
Patient-reported improvements in exercise trials for CFS tend to be small, transient, and poorly supported by objective measurements. The risk of expectancy effects and response bias was high as patients were actively encouraged to adopt a positive attitude towards exercise therapy. Mediation analyses suggest that self-reported improvements in fatigue and physical function are not mediated by objective measures of fitness.

Conclusions
Treatment effects seen in exercise trials for CFS could be the result of bias associated with the use of PROMs in non-blinded trials. This might explain the discrepancy between positive results reported in randomized trials and views on exercise therapy expressed by patient organizations. We hope that this case study furthers critical assessment of patient-reported improvements in areas of medicine where blinding of therapists and trial participants faces practical limitations.

Read full paper

A summary of our paper on exercise therapy and bias caused by lack of blinding

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Podcast – Long COVID & ME/CFS

Posted on 11/27/2020 by wames

Long-term COVID & ME/CFS – a podcast

 

A TWiV podcast hosted by Prof Vincent Racaniello with Prof Mady Hornig, Fiona Lowenstein, Prof David Tuller and 2 patients to discuss long-term COVID & the similarities & differences with ME/CFS”. [1h 52min]

 

 

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Changes in DNA methylation profiles of ME/CFS patients reflect systemic dysfunctions

Posted on 11/27/2020 by wames

Changes in DNA methylation profiles of myalgic encephalomyelitis/chronic fatigue syndrome patients reflect systemic dysfunctions, by AM Helliwell, EC Sweetman,
PA Stockwell, CD Edgar, A Chatterjee & WP Tate in Clinical Epigenetics vol 12, no: 167 (2020)

 

Research abstract:

Background:
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a lifelong debilitating disease with a complex pathology not yet clearly defined. Susceptibility to ME/CFS involves genetic predisposition and exposure to environmental factors, suggesting an epigenetic association. Epigenetic studies with other ME/CFS cohorts have used array- based technology to identify differentially methylated individual sites. Changes in RNA quantities and protein abundance have been documented in our previous investigations with the same ME/CFS cohort used for this study.

Results:
DNA from a well-characterised New Zealand cohort of 10 ME/CFS patients and 10 age-/sex-matched healthy controls was isolated from peripheral blood mononuclear (PBMC) cells, and used to generate reduced genome-scale DNA methylation maps using reduced representation bisulphite sequencing (RRBS). The sequencing data were analysed utilising the DMAP analysis pipeline to identify differentially methylated fragments, and the MethylKit pipeline was used to quantify methylation differences at individual CpG sites.

DMAP identified 76 differentially methylated fragments and Methylkit identified 394 differentially methylated cytosines that included both hyper- and hypo-methylation. Four clusters were identified where differentially methylated DNA fragments overlapped with or were within close proximity to multiple differentially methylated individual cytosines. These clusters identified regulatory regions for 17 protein encoding genes related to metabolic and immune activity.

Analysis of differentially methylated gene bodies (exons/introns) identified 122 unique genes. Comparison with other studies on PBMCs from ME/CFS patients and controls with array technology showed 59% of the genes identified in this study were also found in one or more of these studies. Functional pathway enrichment analysis identified 30 associated pathways. These included immune, metabolic and neurological-related functions differentially regulated in ME/CFS patients compared to the matched healthy controls.

Conclusions:
Major differences were identified in the DNA methylation patterns of ME/CFS patients that clearly distinguished them from the healthy controls. Over half found in gene bodies with RRBS in this study had been identified in other ME/CFS studies using the same cells but with array technology. Within the enriched functional immune, metabolic and neurological pathways, a number of enriched neurotransmitter and neuropeptide reactome pathways highlighted a disturbed neurological pathophysiology within the patient group.

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A hierarchical logistic regression predicting rapid respiratory rates from post-exertional malaise

Posted on 11/26/2020 by wames

A hierarchical logistic regression predicting rapid respiratory rates from post-exertional malaise, by Joseph Cotler, Ben Z Katz, Corine Reurts-Post, Ruud Vermeulen & Leonard A Jason in Scientific Reports vol 10, no. 19933 (2020) Published online: 16 Nov 2020 [doi.org/10.1080/21641846.2020.1845287]

 

Research abstract: 

Background:
Past research has found high rates of hyperventilation in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), but hyperventilation can be influenced by psychological factors. Clinical respiratory rates have been less frequently assessed.

Aim
This study aimed to identify the predictors of rapid respiratory rates in patients referred an outpatient clinic specializing in ME/CFS.

Methods
Adults (n = 216) referred to an outpatient clinic specializing in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) participated in a two-day cardiopulmonary exercise test. As part of that evaluation, subjects had resting respiratory rates measured on two consecutive days. The current study used questionnaires to assess the relationship between tachypnea (rapid respiratory rates) and a variety of domains including post-exertional malaise (PEM), a common complaint in patients with ME/CFS, and psychiatric/somatic symptoms, using hierarchical logistic regression analysis.

Results
PEM was a significant predictor of tachypnea, while psychological/somatic assessments and sedentary behaviors were not significantly predictive of tachypnea.

Conclusions
These findings suggest that respiratory rate may be useful as an objective clinical metric of PEM, and potentially ME/CFS.

Read full article

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The profile of circulating microRNAs in ME & their relation to symptom severity, & disease pathophysiology

Posted on 11/25/2020 by wames

Profile of circulating microRNAs in myalgic encephalomyelitis and their relation to symptom severity, and disease pathophysiology, by Evguenia Nepotchatykh, Wesam Elremaly, Iurie Caraus, Christian Godbout, Corinne Leveau, Lynda Chalder, Catherine Beaudin, Emi Kanamaru, Renata Kosovskaia, Shawn Lauzon, Yanick Maillet, Anita Franco, Viorica Lascau-Coman, Saadallah Bouhanik, Yaned Patricia Gaitan, Dawei Li & Alain Moreau in Scientific Reports volume 10, no. 19620 (2020) 12 Nov 2020

 

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic disease, rooted in multi-system dysfunctions characterized by unexplained debilitating fatigue. Post-exertional malaise (PEM), defined as the exacerbation of the patient’s symptoms following minimal physical or mental stress, is a hallmark of ME/CFS. While multiple case definitions exist, there is currently no well-established biomarkers or laboratory tests to diagnose ME/CFS.

Our study aimed to investigate circulating microRNA expression in severely ill ME/CFS patients before and after an innovative stress challenge that stimulates PEM.

Our findings highlight the differential expression of eleven microRNAs associated with a physiological response to PEM. The present study uncovers specific microRNA expression signatures associated with ME/CFS in response to PEM induction and reports microRNA expression patterns associated to specific symptom severities.

The identification of distinctive microRNA expression signatures for ME/CFS through a provocation challenge is essential for the elucidation of the ME/CFS pathophysiology, and lead to accurate diagnoses, prevention measures, and effective treatment options.

 

CTV News: Montreal researchers develop new test to diagnose chronic fatigue syndrome

“We based our test on the cardinal symptom of the disease, which is discomfort after exertion,” said Moreau. “This is really what is most specific to myalgic encephalomyelitis.”

The test could also allow patients to be grouped into subgroups, in order not only to better understand the molecular mechanisms involved in certain symptoms but also to better select patients who could benefit from certain treatments.

“It becomes more interesting for both trying to work with more homogeneous subgroups to understand the disease and see what explains the severity or all of the symptoms,” said Moreau. “It may speed up research to better understand the disease.”

Finally, the test could allow early detection of patients in whom ME is developing, so that they can start treating them as quickly as possible.

OMF: Montréal ME/CFS Research Center Paper Published in Scientific Reports

MicroRNAs can represent potential indicators for diseases such as ME/CFS, and changes in microRNA expression could indicate cellular dysfunction and degeneration. Using a test to induce mild-but-reproducible Post Exertional Malaise (PEM), our team has so far uncovered and validated 11 different microRNAs associated with ME/CFS that are capable of differentiating ME/CFS patients from healthy patients — with 90 percent accuracy! 

This post-exertional stress challenge provoking PEM in ME/CFS patients has helped us gain unprecedented insight into the pathophysiology of ME/CFS. Based on the 11 different microRNA signatures discovered in ME/CFS, machine learning algorithms have also led to the classification of ME/CFS patients into four clusters associated with symptom severity.

These exciting results could lead to the development of a new, non-invasive diagnostic test for ME/CFS, a prognostic tool used to predict future cases, and identification of effective treatment options.

The Scientist: Blood MicroRNA Patterns Linked to Chronic Fatigue Syndrome

To Williams, the major value of the study lies in an analysis Moreau’s team conducted with the microRNA data that untangles the molecular pathways the 11 sequences are involved in.

This revealed that 7 out of the 11 microRNAs were involved in regulating immune functions, which “certainly fits with one arm of the research that suggests that immune activation is very important in leading to chronic fatigue,” she says.

An additional network analysis flagged the key genes each microRNA is associated with and other diseases they’ve been linked to, which included viral infection, sleep disorders, and cognitive impairments. “Using a network approach, you can start to shed light on which cellular processes are important. And then if that ties in with what we know already about the cellular processes in ME/CFS, then that all begins to paint a bit of a picture.”

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Video: Activity & energy management – Pacing

Posted on 11/25/2020 by wames

Dialogues for a neglected illness: Activity and energy management – Pacing

 

The Dialogues for ME/CFS project (also known as Dialogues for a neglected illness) has produced a new video explaining pacing for health professionals.

“Pacing is an individualized approach to managing physical, cognitive, and emotional energy within a patient’s specific limits by carefully planning where and how to spend their available energy. It is a critical tool to prevent and/or reduce PEM”  [Diagnosing and treating ME/CFS – ME/CFS Clinician Coalition USA July 2020]

“Striking the right balance between activity and rest is one of the most difficult aspects of coming to terms with M.E. On one hand is the need to take an appropriate amount of rest and relaxation, especially during the very early stages, as well as during periods of relapse or an exacerbation of symptoms. On the other is a natural desire to want to increase physical and mental activity when you’re starting to feel that some improvement is, at last, being made.

Achieving the right balance also has to take into account the fact that exceeding your limitations by sometimes only a very small amount can easily cause an exacerbation of symptoms…”        [ME Association website]


Watch video (15 mins) & read transcript 

The video features:

  • Dr Charles Shepherd (GP)
  • Dr Luis Nacul (biobank & researcher)
  • Dr Chris Snell (expert in exercise physiology)
  • Prof Mark VanNess (expert in exercise physiology)
  • Prof Todd Davenport (expert in exercise physiology)
  • 2 patients

From the Dialogues website:

Pacing has sometimes veered towards encouraging incremental increases in activity based on the idea that deconditioning contributes to ME/CFS. However, studies using cardiopulmonary exercise testing (CPET) have demonstrated an impairment in aerobic metabolism in ME/CFS that is not seen in people who are deconditioned.  The use of incremental increases in activity aiming to reduce deconditioning and increase tolerance, is therefore NOT recommended by the exercise scientists in this video. Their repeated CPET shows that when people with ME/CFS ‘push’ themselves or unknowingly keep trying to do too much, their symptoms increase and functional capacity decreases.

For decades, patients have been stigmatised and subjected to pressure to ‘do more’, or ‘try harder’, by society and the medical profession. Media headlines disseminated poor quality research, medical education for ME/CFS has been inaccurate or virtually non-existent and the old (2007) NICE Guideline advised graded exercise therapy (GET) as treatment. These circumstances have been harmful for patients and led to deteriorations in health, prolonged severe disability and social isolation.

In a very welcome turnaround in attitude, the new NICE guideline draft (2020) recognises that GET and treatments that exacerbate symptoms are harmful.

 

Other films from the project:

  • Introduction to ME/CFS
  • Post-Exertional Malaise
  • Severe & Very Severe ME / CFS
  • Graded Exercise Therapy
  • Patients’ Accounts – Symptoms
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Deep phenotyping of ME/CFS in Japanese population

Posted on 11/23/2020 by wames

Deep phenotyping of myalgic encephalomyelitis/chronic fatigue syndrome in Japanese population, by Toshimori Kitami, Sanae Fukuda, Tamotsu Kato, Kouzi Yamaguti, Yasuhito Nakatomi, Emi Yamano, Yosky Kataoka, Kei Mizuno, Yuuri Tsuboi, Yasushi Kogo, Harukazu Suzuki, Masayoshi Itoh, Masaki Suimye Morioka, Hideya Kawaji, Haruhiko Koseki, Jun Kikuchi, Yoshihide Hayashizaki, Hiroshi Ohno, Hirohiko Kuratsune & Yasuyoshi Watanabe in Scientific Reports vol 10, no: 19933 (2020) 16 Nov 2020

 

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and debilitating disease with no molecular diagnostics and no treatment options.

To identify potential markers of this illness, we profiled 48 patients and 52 controls for standard laboratory tests, plasma metabolomics, blood immuno-phenotyping and transcriptomics, and fecal microbiome analysis. Here, we identified a set of 26 potential molecular markers that distinguished ME/CFS patients from healthy controls. Monocyte number, microbiome abundance, and lipoprotein profiles appeared to be the most informative markers.

When we correlated these molecular changes to sleep and cognitive measurements of fatigue, we found that lipoprotein and microbiome profiles most closely correlated with sleep disruption while a different set of markers correlated with a cognitive parameter.

Sleep, lipoprotein, and microbiome changes occur early during the course of illness suggesting that these markers can be examined in a larger cohort for potential biomarker application. Our study points to a cluster of sleep-related molecular changes as a prominent feature of ME/CFS in our Japanese cohort.

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Accurate & objective determination of ME/CFS disease severity with a wearable sensor

Posted on 11/20/2020 by wames

Accurate and objective determination of myalgic encephalomyelitis/chronic fatigue syndrome disease severity with a wearable sensor, by Turner Palombo, Andrea Campos, Suzanne D Vernon, Shad Roundy in J Transl Med. 2020 Nov 10;18(1):423 [doi: 10.1186/s12967-020-02583-7]

 

Research abstract:

Background:

Approximately 2.5 million people in the U.S. suffer from myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS). This disease negatively impacts patients’ ability to function, often resulting in difficulty maintaining employment, sustaining financial independence, engaging socially with others, and in particularly severe cases, consistently and adequately performing activities of daily living. The focus of this research was to develop a sensor-based method to measure upright activity defined as time with feet on the floor and referred to as UpTime, as an indicator of ME/CFS disease severity.

Methods:

A commercially available inertial measurement unit (IMU), the Shimmer, was selected for this research. A Kalman filter was used to convert IMU data collected by the Shimmer to angle estimates. Angle estimate accuracy was confirmed by comparison to a motion capture system. Leg angle estimates were then converted to personalized daily UpTime scores using a critical angle of 39º from vertical to differentiate between upright (feet on the floor) and not upright. A 6-day, case-control study with 15 subjects (five healthy controls, five moderate-level ME/CFS, and five severe-level ME/CFS) was conducted to determine the utility of UpTime for assessing disease severity.

Results:

UpTime was found to be a significant measure of ME/CFS disease severity. Severely ill ME/CFS patients spend less than 20% of each day with feet on the floor. Moderately ill ME/CFS patients spend between 20-30% of each day with feet on the floor. Healthy controls have greater than 30% UpTime. IMU-measured UpTime was more precise than self-reported hours of upright activity which were over-estimated by patients.

The angle of each lower leg is compared to the critical angle (θc) to determine uprightness. Accelerometer measurements (ax, ay, and az) and gyroscope (i.e. angular rate) measurements (p, q, and r) are in the local coordinate frame—x, y, and z. Roll (ϕ) and pitch (θ) are measured using the fixed global coordinate frame—X, Y, and Z

Conclusions:

UpTime is an accurate and objective measure of upright activity, a measure that can be used to assess disease severity in ME/CFS patients. Due to its ability to accurately monitor upright activity, UpTime can also be used as a reliable endpoint for evaluating ME/CFS treatment efficacy. Future studies with larger samples and extended data collection periods are required to fully confirm the use of UpTime as a measure of disease severity in ME/CFS.

With the added perspective of large-scale studies, this sensor-based platform could provide a recovery path for individuals struggling with ME/CFS.

 

Bateman Horne Center: Turning a Self-Report Questionnaire into a Wearable Device, by Suzanne D Vernon

Solve ME/CFS: Defining the Postural Contributors to Post-Exertional Malaise (PEM) in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

If the proposed measure successfully detects changes in the amount of time in an upright posture, it will then be submitted to the FDA’s biomarker qualification program to qualify it for use in ME/CFS clinical trials. The existence of an FDA qualified biomarker and clinical outcome measure will be an important inducement to researchers and pharmaceutical companies to develop effective treatments.

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