European Journal of applied physiology
October 2019, Volume 119, Issue 10, pp 2375–2389| Cite as
Unexplained exertional intolerance associated with impaired systemic oxygen extraction
Purpose
The clinical investigation of exertional intolerance generally focuses on cardiopulmonary diseases, while peripheral factors are often overlooked. We hypothesize that a subset of patients exists whose predominant exercise limitation is due to abnormal systemic oxygen extraction (SOE).
Methods
We reviewed invasive cardiopulmonary exercise test (iCPET) results of 313 consecutive patients presenting with unexplained exertional intolerance. An exercise limit due to poor SOE was defined as peak exercise (Ca-vO2)/[Hb] ≤ 0.8 and VO2max < 80% predicted in the absence of a cardiac or pulmonary mechanical limit. Those with peak (Ca-vO2)/[Hb] > 0.8, VO2max ≥ 80%, and no cardiac or pulmonary limit were considered otherwise normal. The otherwise normal group was divided into hyperventilators (HV) and normals (NL). Hyperventilation was defined as peak PaCO2 < [1.5 × HCO3 + 6].
Results
Prevalence of impaired SOE as the sole cause of exertional intolerance was 12.5% (32/257). At peak exercise, poor SOE and HV had less acidemic arterial blood compared to NL (pHa = 7.39 ± 0.05 vs. 7.38 ± 0.05 vs. 7.32 ± 0.02, p < 0.001), which was explained by relative hypocapnia (PaCO2 = 29.9 ± 5.4 mmHg vs. 31.6 ± 5.4 vs. 37.5 ± 3.4, p < 0.001). For a subset of poor SOE, this relative alkalemia, also seen in mixed venous blood, was associated with a normal PvO2 nadir (28 ± 2 mmHg vs. 26 ± 4, p = 0.627) but increased SvO2 at peak exercise (44.1 ± 5.2% vs. 31.4 ± 7.0, p < 0.001).
Conclusions
We identified a cohort of patients whose exercise limitation is due only to systemic oxygen extraction, due to either an intrinsic abnormality of skeletal muscle mitochondrion, limb muscle microcirculatory dysregulation, or hyperventilation and left shift the oxyhemoglobin dissociation curve.
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European Journal of applied physiology
October 2019, Volume 119, Issue 10, pp 2375–2389| Cite as
Unexplained exertional intolerance associated with impaired systemic oxygen extraction
Purpose
The clinical investigation of exertional intolerance generally focuses on cardiopulmonary diseases, while peripheral factors are often overlooked. We hypothesize that a subset of patients exists whose predominant exercise limitation is due to abnormal systemic oxygen extraction (SOE).
Methods
We reviewed invasive cardiopulmonary exercise test (iCPET) results of 313 consecutive patients presenting with unexplained exertional intolerance. An exercise limit due to poor SOE was defined as peak exercise (Ca-vO2)/[Hb] ≤ 0.8 and VO2max < 80% predicted in the absence of a cardiac or pulmonary mechanical limit. Those with peak (Ca-vO2)/[Hb] > 0.8, VO2max ≥ 80%, and no cardiac or pulmonary limit were considered otherwise normal. The otherwise normal group was divided into hyperventilators (HV) and normals (NL). Hyperventilation was defined as peak PaCO2 < [1.5 × HCO3 + 6].
Results
Prevalence of impaired SOE as the sole cause of exertional intolerance was 12.5% (32/257). At peak exercise, poor SOE and HV had less acidemic arterial blood compared to NL (pHa = 7.39 ± 0.05 vs. 7.38 ± 0.05 vs. 7.32 ± 0.02, p < 0.001), which was explained by relative hypocapnia (PaCO2 = 29.9 ± 5.4 mmHg vs. 31.6 ± 5.4 vs. 37.5 ± 3.4, p < 0.001). For a subset of poor SOE, this relative alkalemia, also seen in mixed venous blood, was associated with a normal PvO2 nadir (28 ± 2 mmHg vs. 26 ± 4, p = 0.627) but increased SvO2 at peak exercise (44.1 ± 5.2% vs. 31.4 ± 7.0, p < 0.001).
Conclusions
We identified a cohort of patients whose exercise limitation is due only to systemic oxygen extraction, due to either an intrinsic abnormality of skeletal muscle mitochondrion, limb muscle microcirculatory dysregulation, or hyperventilation and left shift the oxyhemoglobin dissociation curve.
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Journal of Clinical Investigation
Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations
Alexandra H. Mandarano, Jessica Maya, Ludovic Giloteaux, Daniel L. Peterson, Marco Maynard, C. Gunnar Gottschalk, and Maureen R. Hanson
First published December 12, 2019
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease with no known cause or mechanism. There is an increasing appreciation for the role of immune and metabolic dysfunction in the disease. ME/CFS has historically presented in outbreaks, often has a flu-like onset, and results in inflammatory symptoms. Patients suffer from severe fatigue and post-exertional malaise. There is little known about the metabolism of specific immune cells in ME/CFS patients. To investigate immune metabolism in ME/CFS, we isolated CD4+ and CD8+ T cells from 53 ME/CFS patients and 45 healthy controls. We analyzed glycolysis and mitochondrial respiration in resting and activated T cells, along with markers related to cellular metabolism, and plasma cytokines. We found that ME/CFS CD8+ T cells have reduced mitochondrial membrane potential compared to healthy controls. Both CD4+ and CD8+ T cells from ME/CFS patients had reduced glycolysis at rest, while CD8+ T cells also had reduced glycolysis following activation. ME/CFS patients had significant correlations between measures of T cell metabolism and plasma cytokine abundance that differed from healthy control subjects. Our data indicate that patients have impaired T cell metabolism consistent with ongoing immune alterations in ME/CFS that may illuminate the mechanism behind this disease.
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Epidemiology and Community Health: Research report
Influence of sleep problems and co-occurring musculoskeletal pain on long-term prognosis of chronic low back pain: the HUNT Study
Eivind Schjelderup Skarpsno, Paul Jarle Mork, Tom Ivar Lund Nilsen,
Anne Lovise Nordstoga
Abstract
Background We investigated the influence of sleeplessness and number of insomnia symptoms on the probability of recovery from chronic low back pain (LBP), and the possible interplay between sleeplessness and co-occurring musculoskeletal pain on this association.
Methods The study comprised data on 3712 women and 2488 men in the Norwegian HUNT study who reported chronic LBP at baseline in 1995–1997. A modified Poisson regression model was used to calculate adjusted risk ratios (RRs) for the probability of recovery from chronic LBP at follow-up in 2006–2008, associated with sleep problems and co-occurring musculoskeletal pain at baseline.
Results Compared with persons without sleeplessness, persons who often/always experienced sleeplessness had a lower probability of recovery from chronic LBP (RR 0.65, 95% CI 0.57 to 0.74 in women and RR 0.81, 95% CI 0.69 to 0.95 in men). Although there was no clear evidence of statistical interaction between sleeplessness and co-occurring musculoskeletal pain, women and men who often/always experienced sleeplessness and had ≥5 additional chronic pain sites had RRs of recovery of 0.40 (95% CI 0.33 to 0.48) and 0.59 (95% CI 0.45 to 0.78), respectively, compared with persons without sleeplessness and 1–2 chronic pain sites.
Conclusion These findings suggest that preventing or reducing sleep problems among people with chronic LBP may have the potential of improving the long-term prognosis of this condition, also among those with several additional pain sites.
View Full Text
http://dx.doi.org/10.1136/jech-2019-212734
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Journal: Fatigue: Biomedicine, Health & Behavior
Low-dose naltrexone in the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Olli Polo,Pia Pesonen &Essi Tuominen
Received 13 Sep 2019, Accepted 11 Nov 2019, Published online: 19 Nov 2019
ABSTRACT
Background: Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a common medical condition that limits physical and cognitive functions, with no known effective medical treatment.
Methods: We report on the safety and effectiveness data accumulated in clinical practice when treating ME/CFS with low-dose naltrexone (LDN, 3.0 – 4.5 mg/day). The medical records from 218 patients who received ar diagnosis of ME/CFS and LDN treatment during 2010–2014 were retrospectively analyzed.
Results: Outcome data were available in 92.2% of patients with an average follow-up time of 1.7 years. A positive treatment response to LDN was reported by 73.9% of the patients. Most patients experienced improved vigilance/alertness and improved physical and cognitive performance. Some patients reported less pain and fever, while 18.3% of patients did not report any treatment response to LDN. Mild adverse effects (insomnia, nausea) were common at the beginning of the treatment. Neither severe adverse effects nor long-term adverse symptoms were reported.
Conclusions: The high frequency of treatment response and good safety profile observed in this retrospective open label study could prompt prospective controlled studies to confirm the feasibility of LDN in alleviating ME/CFS symptoms.
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Brain Behav Immun. 2019 Nov 20. pii: S0889-1591(19)30762-7. doi: 10.1016/j.bbi.2019.11.015.
Identification of actin network proteins, talin-1 and filamin-A, in circulating extracellular vesicles as blood biomarkers for human myalgic encephalomyelitis/chronic fatigue syndrome.
Eguchi A1, Fukuda S2, Kuratsune H2, Nojima J3, Nakatomi Y4, Watanabe Y5, Feldstein AE
1 Department of Gastroenterology and Hepatology, School of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; JST, PRETO, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan; Department of Pediatrics, University of California San Diego (UCSD), La Jolla, CA 92093, USA. Electronic address: [email protected].
2 Department of Health Welfare Sciences, Kansai University of Welfare Sciences, Kashiwara 582-0026, Japan; Department of Endocrinology, Metabolism and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8586, Japan; RIKEN, Center for Biosystems Dynamics Research, Kobe 650-0047, Japan.
3 Department of Laboratory Science, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
4 Nakatomi Fatigue Care Clinic, Osaka 541-0043, Japan.
5 Department of Endocrinology, Metabolism and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8586, Japan; RIKEN, Center for Biosystems Dynamics Research, Kobe 650-0047, Japan; RIKEN Compass to Healthy Life Research Complex Program, Kobe 650-0047, Japan.
6 Department of Pediatrics, University of California San Diego (UCSD), La Jolla, CA 92093, USA.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, debilitating disorder with a wide spectrum of symptoms, including pain, depression, and neurocognitive deterioration. Over 17 million people around the world have ME/CFS, predominantly women with peak onset at 30-50 years. Given the wide spectrum of symptoms and unclear etiology, specific biomarkers for diagnosis and stratification of ME/CFS are lacking. Here we show that actin network proteins in circulating extracellular vesicles (EVs) offer specific non-invasive biomarkers for ME/CFS. We found that circulating EVs were significantly increased in ME/CFS patients correlating to C-reactive protein, as well as biological antioxidant potential. Area under the receiver operating characteristic curve for circulating EVs was 0.80, allowing correct diagnosis in 90-94% of ME/CFS cases. From two independent proteomic analyses using circulating EVs from ME/CFS, healthy controls, idiopathic chronic fatigue, and depression, proteins identified from ME/CFS patients are involved in focal adhesion, actin skeletal regulation, PI3K-Akt signaling pathway, and Epstein-Barr virus infection. In particular, talin-1, filamin-A, and 14-3-3 family proteins were the most abundant proteins, representing highly specific ME/CFS biomarkers. Our results identified circulating EV number and EV-specific proteins as novel biomarkers for diagnosing ME/CFS, providing important information on the pathogenic mechanisms of ME/CFS.
Copyright © 2019 Elsevier Inc. All rights reserved.PMID:31759091 DOI:10.1016/j.bbi.2019.11.015
Research: REVIEW
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Understanding neuromuscular disorders in chronic fatigue syndrome
Yves Jammes, Frédérique Retornaz2
Abstract
Muscle failure has been demonstrated in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Neurophysiological tools demonstrate the existence of both central and peripheral fatigue in these patients. Central fatigue is deduced from the reduced amplitude of myopotentials evoked by transcranial magnetic stimulation of the motor cortex as well as by the muscle response to interpolated twitches during sustained fatiguing efforts. An impaired muscle membrane conduction velocity assessed by the reduced amplitude and lengthened duration of myopotentials evoked by direct muscle stimulation is the defining feature of peripheral fatigue. Some patients with ME/CFS show an increased oxidative stress response to exercise. The formation of lipid hydroperoxides in the sarcolemma, which alters ionic fluxes, could explain the reduction of muscle membrane excitability and potassium outflow often measured in these patients. In patients with ME/CFS, the formation of heat shock proteins (HSPs) is also reduced. Because HSPs protect muscle cells against the deleterious effects of reactive oxygen species, the lack of their production could explain the augmented oxidative stress and the consecutive alterations of myopotentials which could open a way for future treatment of ME/CFS.
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Brief Cognitive Behavioral Therapy For Chronic Pain
Results From a Clinical Demonstration Project in Primary Care Behavioral Health
Beehler, Gregory P. MA, PhD*,†; Murphy, Jennifer L. PhD‡,§; King, Paul R. PhD*,∥; Dollar, Katherine M. PhD¶; Kearney, Lisa K. PhD, ABPP¶,#; Haslam, Aaron PhD**; Wade, Michael MS¶; Goldstein, Wade R. MA*
The Clinical Journal of Pain: October 2019 - Volume 35 - Issue 10 - p 809–817
doi: 10.1097/AJP.0000000000000747
Abstract
Objectives:
Although cognitive behavioral therapy is an effective intervention for chronic pain, it is a lengthy treatment typically applied only in specialty care settings. The aim of this project was to collect preliminary effectiveness data for Brief Cognitive Behavioral Therapy for Chronic Pain (Brief CBT-CP), an abbreviated, modular form of treatment designed for use in primary care.
Methods:
A clinical demonstration project was conducted in which Brief CBT-CP was delivered to primary care patients by 22 integrated care providers practicing in the Primary Care Behavioral Health model of Veterans Health Administration primary care clinics. Brief measures were used at each appointment to collect patient-reported clinical outcomes.
Results:
One hundred eighteen patients provided sufficient data for analysis (male, 75%; mean age, 51.4 y). Multilevel modeling suggested that a composite measure of pain intensity and functional limitations showed statistically significant improvements by the third appointment (Cohen’s d=0.65). Pain-related self-efficacy outcomes showed a similar pattern of results but of smaller effect size (Cohen’s d=0.22). The exploratory analysis identified that Brief CBT-CP modules addressing psychoeducation and goal setting, pacing, and relaxation training were associated with the most significant gains in treatment outcomes.
Discussion:
These findings provide early support for the effectiveness of Brief CBT-CP when delivered by providers in every day Primary Care Behavioral Health settings. Results are discussed in relation to the need for additional research regarding the potential value of employing safe, population-based, nonpharmacological approaches to pain management in primary care.
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
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Bragee Clinics report
Signs of Intracranial Hypertension, Hypermobility and
Craniocervical Obstructions in patients with
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Björn Bragée , Anastasios Michos, Brandon Drum, Mikael Fahlgren, Robert
Szulkin, Bo C Bertilson
Division of Family Medicine and Primary Care,
Department of Neurobiology, Care Sciences
and Society, Karolinska Institutet, Stockholm, Sweden
Division of Family Medicine and Primary Care,Stockholm Health Care Services, Region
Stockholm, Huddinge, Sweden
ME center, Bragée Clinics, Stockholm, Sweden
Objective: To test the hypothesis that hypermobility and craniocervical obstructions is overrepresented in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and that a large portion of these patients may have a degree of intracranial hypertension explaining many of the symptoms of the ME/CFS syndrome.
Methods: This is a retrospective cross-sectional study, performed at a specialist clinic for referred patients with severe ME/CFS fulfilling the Canada Consensus Criteria. The first 272 consecutive patients with ME/CFS were invited, and 229 of these whom had signed the informed consent within six weeks were included. Hypermobility was assessed using the Beighton score. The position of cerebellar tonsils, the optic nerve sheath diameter and eyeball transverse diameter were measured in magnetic resonance imaging scans of the brain as measures correlated to intracranial hypertension. Findings of obstructions in the craniocervical junction and the cervical spine were assessed through MRI scans of the cervical spine. Radiological assessments were made by an experienced radiologist.
Results: 190 women with a mean age of 45 years and 39 males with a mean age of 44 years were included. Hypermobility was found in 111 (49%) of the patients. Of the 205 patients with brain MRI scanning, increased diameter of the optic nerve sheath was found in 112 patients (55%), signs of possible intracranial hypertension expressed as the quote of the diameter of optic nerve/eyeball transverse diameter in left or right side were present in 171 patients (83%), and values seen with more severe states of intracranial hypertension were found in 65 of the patients (32%). Obstruction in the foramen magnum by cerebellar tonsils under the McRae line was found in 115 patients (56%). Findings of obstruction of the cervical spinal canal were found in 100 of the 125 patients (80%) with cervical scans. There was a significant overrepresentation of signs of hypermobility, intracranial hypertension and obstructions in the cranio-cervical region compared with general population.
Conclusion: These findings, which confirms our hypothesis, may explain the widespread symptoms these patients express. If confirmed in further studies, new diagnostic and therapeutic approaches to this widespread neurological syndrome should be considered.
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From Cold Spring Harbor Laboratory
Perturbation of effector and regulatory T cell subsets in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Ece Karhan, Courtney Gunter, Vida Ravanmehr, Meghan Horne, Lina Kozhaya, Stephanie Renzullo, Lindsey Placek, Joshy George, View ORCID ProfilePeter N. Robinson, Suzannne D Vernon, Lucinda Bateman, Derya Unutmaz
doi: https://doi.org/10.1101/2019.12.23.887505
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder of unknown etiology, and diagnosis of the disease is largely based on clinical symptoms. We hypothesized that immunological disruption is the major driver of this disease and analyzed a large cohort of ME/CFS patient or control blood samples for differences in T cell subset frequencies and functions. We found that the ratio of CD4+ to CD8+ T cells and the proportion of CD8+ effector memory T cells were increased, whereas NK cells were reduced in ME/CFS patients younger than 50 years old compared to a healthy control group. Remarkably, major differences were observed in Th1, Th2, Th17 and mucosal-associated invariant T (MAIT) T cell subset functions across all ages of patients compared to healthy subjects. While CCR6+ Th17 cells in ME/CFS secreted less IL-17 compared to controls, their overall frequency was higher. Similarly, MAIT cells from patients secreted lower IFNgamma;, GranzymeA and IL-17 upon activation. Together, these findings suggest chronic stimulation of these T cell populations in ME/CFS patients. In contrast, the frequency of regulatory T cells (Tregs), which control excessive immune activation, was higher in ME/CFS patients. Finally, using a machine learning algorithm called random forest, we determined that the set of T cell parameters analyzed could identify more than 90% of the subjects in the ME/CFS cohort as patients (93% true positive rate or sensitivity). In conclusion, these multiple and major perturbations or dysfunctions in T cell subsets in ME/CFS patients suggest potential chronic infections or microbiome dysbiosis. These findings also have implications for development of ME/CFS specific immune biomarkers and reveal potential targets for novel therapeutic interventions.
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Scientific Reports MC6906377 2019; 9: 18817.
Published online 2019 Dec 11. doi: 10.1038/s41598-019-55473-4 PMCID: PMC6906377
PMID: 31827223
Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with Myalgic encephalomyelitis/Chronic fatigue syndrome
Alaa Ghali,1 Carole Lacout,1 Maria Ghali,2 Aline Gury,1 Anne-Berengere Beucher,1 Pierre Lozac’h,1 Christian Lavigne,1 and Geoffrey Urbanski (France)
Abstract
Elevated blood lactate after moderate exercise was reported in some of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We hypothesised that blood lactate could be also elevated in resting conditions. We aimed investigating the frequency of elevated lactate at rest in ME/CFS patients, and comparing characteristics of ME/CFS patients with and without elevated lactate. Patients fulfilling international consensus criteria for ME/CFS who attended the internal medicine department of University hospital Angers-France between October 2011 and December 2017 were included retrospectively. All patients were systematically hospitalised for an aetiological workup and overall assessment. We reviewed their medical records for data related to the assessment: clinical characteristics, comorbidities, fatigue features, post-exertional malaise (PEM) severity, and results of 8 lactate measurements at rest. Patients having ≥1 lactate measurement ≥2 mmol/L defined elevated lactate group. The study included 123 patients. Elevated (n = 55; 44.7%) and normal (n = 68; 55.3%) lactate groups were comparable except for PEM, which was more severe in the elevated lactate group after adjusting for age at disease onset, sex, and comorbidities (OR 2.47, 95% CI: 1.10–5.55). ME/CFS patients with elevated blood lactate at rest may be at higher risk for more severe PEM. This finding may be of interest in ME/CFS management.
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December 27, 2019
Comparison of Lemborexant With Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults With Insomnia DisorderA Phase 3 Randomized Clinical Trial
Russell Rosenberg, PhD1; Patricia Murphy, PhD2,3; Gary Zammit, PhD4; et alDavid Mayleben, PhD5; Dinesh Kumar, PhD3; Shobha Dhadda, PhD3; Gleb Filippov, MD, PhD3; Antonia LoPresti, MD3; Margaret Moline, PhD3
JAMA Netw Open. 2019;2(12):e1918254. doi:10.1001/jamanetworkopen.2019.18254
Key Points
Question Does lemborexant therapy effectively treat insomnia disorder in patients 55 years and older compared with placebo and zolpidem tartrate extended release therapy?
Findings In this randomized double-blind clinical trial of 1006 participants 55 years and older with insomnia disorder, lemborexant therapy significantly improved both latency to persistent sleep and sleep maintenance (wake-after-sleep onset and sleep efficiency) compared objectively via polysomnography with both placebo and zolpidem tartrate extended release therapy. Efficacy was also demonstrated on patient-reported end points of sleep onset, sleep efficiency, and wake-after-sleep onset for both doses of lemborexant compared with placebo.
Meaning Lemborexant therapy may provide an additional option for sleep onset and sleep maintenance difficulties in older patients with insomnia disorder.
Abstract
Importance Insomnia disorder is prevalent and associated with health risks in older adults; however, efficacy and safety issues with existing treatments create significant unmet needs in this patient population.
Objective To compare treatment with the orexin receptor antagonist lemborexant with placebo and zolpidem tartrate extended release in participants with insomnia disorder.
Design, Setting, and Participants The Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older With Insomnia Disorder (SUNRISE 1) clinical trial was a global randomized double-blind parallel-group placebo-controlled active-comparator phase 3 study conducted at 67 sites in North America and Europe from May 31, 2016, to January 30, 2018. Data analyses were conducted from January 31, 2018, to September 10, 2018. Participants were 55 years and older with insomnia disorder characterized by reported sleep maintenance difficulties and confirmed by sleep history, sleep diary, and polysomnography. Participants could have also had sleep onset difficulties.
Interventions Participants received placebo, zolpidem tartrate extended release (6.25 mg), or lemborexant (5 mg or 10 mg) for 1 month at bedtime.
Main Outcomes and Measures Paired polysomnograms were collected at baseline, the first 2 nights, and the last 2 nights of treatment. The primary end point was the change from baseline in latency to persistent sleep for lemborexant therapy vs placebo. Key secondary end points were changes from baseline in sleep efficiency and wake-after-sleep onset compared with placebo, and wake-after-sleep onset in the second half of the night compared with zolpidem therapy.
Results Among 1006 participants randomized (placebo, n = 208; zolpidem, n = 263; lemborexant 5 mg, n = 266; and lemborexant 10 mg, n = 269), 869 (86.4%) were women and the median age was 63 years (range, 55-88 years). Both doses of lemborexant therapy demonstrated statistically significant greater changes from baseline on objective sleep onset as assessed by latency to persistent sleep (log transformed) that was measured using polysomnography at the end of 1 month of treatment (nights 29 and 30) compared with placebo (primary end point for least squares geometric means treatment ratio vs placebo: for lemborexant 5 mg, 0.77; 95% CI, 0.67-0.89; P < .001; for lemborexant 10 mg, 0.72; 95% CI, 0.63-0.83; P < .001). For nights 29 and 30, as measured using polysomnography, the mean change from baseline in sleep efficiency (LSM treatment difference vs placebo for lemborexant 5 mg, 7.1%; 95% CI, 5.6%-8.5%; P < .001 and for lemborexant 10 mg, 8.0%; 95% CI, 6.6%-9.5%; P < .001) and wake-after-sleep onset (least squares mean treatment ratio vs placebo for lemborexant 5 mg, −24.0 min; 95% CI, −30.0 to −18.0 min; P < .001 and for lemborexant 10 mg, −25.4 min; 95% CI, −31.4 to −19.3 min; P < .001) were significantly greater for both doses of lemborexant therapy compared with placebo. Also, for nights 29 and 30, wake-after-sleep onset in the second half of the night (least squares mean treatment difference vs zolpidem for lemborexant 5 mg, −6.7 min; 95% CI, −11.2 to −2.2 min; P = .004 and for lemborexant 10 mg, −8.0 min; 95% CI, −12.5 to −3.5 min; P < .001) was significantly greater for both doses of lemborexant therapy compared with zolpidem therapy measured using polysomnography. Six participants (4 in the zolpidem group and 2 in the lemborexant 5 mg group) reported serious adverse events; none were treatment-related. Other adverse events were mostly mild or moderate in severity.
Conclusions and Relevance In this randomized clinical trial, lemborexant therapy significantly improved both sleep onset and sleep maintenance, including in the second half of the night, compared with both placebo and zolpidem measured objectively using polysomnography. Lemborexant therapy was well tolerated.
Trial Registrations ClinicalTrials.gov identifier: NCT02783729; EudraCT identifier: 2015-001463-39
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Transient receptor potential melastatin 2 channels are overexpressed in myalgic encephalomyelitis/chronic fatigue syndrome patients
Cassandra Balinas, Helene Cabanas, Donald Staines Sonya Marshall-Gradisnik
Journal of Translational Medicine volume 17, Article number: 401 (2019)
Abstract
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is hallmarked by a significant reduction in natural killer (NK) cell cytotoxicity, a mechanism tightly regulated by calcium (Ca2+). Interestingly, interleukin-2 (IL-2) increases NK cell cytotoxicity. Transient receptor potential melastatin 2 (TRPM2) ion channels are fundamental for Ca2+ signalling in NK cells. This pilot investigation aimed to characterise TRPM2 and CD38 surface expression in vitro on NK cells in ME/CFS patients. This investigation furthermore examined the pharmaceutical effect of 8-bromoadenosine phosphoribose (8-Br-ADPR) and N6-Benzoyladenosine-3′,5′-cyclic monophosphate (N6-Bnz-cAMP) on TRPM2 and CD38 surface expression and NK cell cytotoxicity between ME/CFS and healthy control (HC) participants.
Methods
Ten ME/CFS patients (43.45 ± 12.36) and 10 HCs (43 ± 12.27) were age and sex-matched. Isolated NK cells were labelled with fluorescent antibodies to determine baseline and drug-treated TRPM2 and CD38 surface expression on NK cell subsets. Following IL-2 stimulation, NK cell cytotoxicity was measured following 8-Br-ADPR and N6-Bnz-cAMP drug treatments by flow cytometry.
Results
Baseline TRPM2 and CD38 surface expression was significantly higher on NK cell subsets in ME/CFS patients compared with HCs. Post IL-2 stimulation, TRPM2 and CD38 surface expression solely decreased on the CD56DimCD16+ subset. 8-Br-ADPR treatment significantly reduced TRPM2 surface expression on the CD56BrightCD16Dim/− subset within the ME/CFS group. Baseline cell cytotoxicity was significantly reduced in ME/CFS patients, however no changes were observed post drug treatment in either group.
Conclusion
Overexpression of TRPM2 on NK cells may function as a compensatory mechanism to alert a dysregulation in Ca2+ homeostasis to enhance NK cell function in ME/CFS, such as NK cell cytotoxicity. As no improvement in NK cell cytotoxicity was observed within the ME/CFS group, an impairment in the TRPM2 ion channel may be present in ME/CFS patients, resulting in alterations in [Ca2+]i mobilisation and influx, which is fundamental in driving NK cell cytotoxicity. Differential expression of TRPM2 between NK cell subtypes may provide evidence for their role in the pathomechanism involving NK cell cytotoxicity activity in ME/CFS.
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Original Paper Published: 23 January 2020
The Prevalence of Pediatric Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in a Community-Based Sample
Child & Youth Care Forum (2020)Cite this article
Abstract
Background
Most pediatric prevalence studies of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have been based upon data from tertiary care centers, a process known for systematic biases such as excluding youth of lower socioeconomic status and those less likely to have access to health care. In addition, most pediatric ME/CFS epidemiologic studies have not included a thorough medical and psychiatric examination. The purpose of this study was to determine the prevalence of pediatric ME/CFS from an ethnically and sociodemographically diverse community-based random sample.
Method
A sample of 10,119 youth aged 5–17 from 5622 households in the Chicagoland area were screened. Following evaluations, a team of physicians made final diagnoses. Youth were given a diagnosis of ME/CFS if they met criteria for three selected case definitions. A probabilistic, multi-stage formula was used for final prevalence calculations.
Results
The prevalence of pediatric ME/CFS was 0.75%, with a higher percentage being African American and Latinx than Caucasian. Of the youth diagnosed with ME/CFS, less than 5% had been previously diagnosed with the illness.
Conclusions
Many youth with the illness have not been previously diagnosed with ME/CFS. These findings point to the need for better ways to identify and diagnose youth with this illness.
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Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids
by Arnaud Germain 1,Dinesh K. Barupal 2,Susan M. Levine 1 andMaureen R. Hanson 1,*
1
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
2
UC Davis Genome Center—Metabolomics, University of California, Davis, CA 95616, USA
*
Author to whom correspondence should be addressed.
Metabolites 2020, 10(1), 34; https://doi.org/10.3390/metabo10010034 (registering DOI)
Received: 20 December 2019 / Revised: 9 January 2020 / Accepted: 12 January 2020 / Published: 14 January 2020
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Abstract
The latest worldwide prevalence rate projects that over 65 million patients suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), an illness with known effects on the functioning of the immune and nervous systems. We performed an extensive metabolomics analysis on the plasma of 52 female subjects, equally sampled between controls and ME/CFS patients, which delivered data for about 1750 blood compounds spanning 20 super-pathways, subdivided into 113 sub-pathways. Statistical analysis combined with pathway enrichment analysis points to a few disrupted metabolic pathways containing many unexplored compounds. The most intriguing finding concerns acyl cholines, belonging to the fatty acid metabolism sub-pathway of lipids, for which all compounds are consistently reduced in two distinct ME/CFS patient cohorts. We compiled the extremely limited knowledge about these compounds and regard them as promising in the quest to explain many of the ME/CFS symptoms. Another class of lipids with far-reaching activity on virtually all organ systems are steroids; androgenic, progestin, and corticosteroids are broadly reduced in our patient cohort. We also report on lower dipeptides and elevated sphingolipids abundance in patients compared to controls. Disturbances in the metabolism of many of these molecules can be linked to the profound organ system symptoms endured by ME/CFS patients. View Full-Text
Keywords: ME/CFS; metabolomics; acyl cholines; steroids; dipeptides; lipids
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“Altered T cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)”
Principal Investigators: Liisa Selin (PhD), Anna Gil (PhD)
University of Massachusetts Medical School
Our understanding of the immunological defects present in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is severely lacking compared to other disorders, leading to a major barrier to research, diagnosis, and treatment. ME/CFS is a complex disorder affecting numerous organ systems and biological processes with studies focusing on changes in cytokines, metabolism, and identifying a potential causative infectious agent. In this pilot study, we propose to examine the role of a novel subset of immune cells, CD4+CD8+ T cells in the pathology of ME/CFS.
We recently discovered not only an increased frequency of this otherwise rare T cell in a group of ME/CFS patients we were studying, but also that they were highly activated producing unusual cytokines. We observed a difference in the activation profile of these cells in mild and severe cases of ME/CFS. In my long career of studying human T cell responses during viral infections I have never previously observed an increase in this cell type. We will examine the role they may play in the highly dysregulated immune response of ME/CFS patients. Much of the published data seems to suggest that ME/CFS may be preceded by infection, and the chronic manifestation of illness may represent an altered host response to infection, or an inability to resolve inflammation.
Based on our preliminary data, we will examine in a larger cohort, whether this unique subset of CD4+CD8+ T cells is increased in all ME/CFS donors, or does it only occur in a subgroup. We will also assess its role in mediating the disease by examining its frequency and alterations in its function in ME/CFS patients, manifesting either a mild or severe form of the disease as compared to healthy donors. Also, T cells have unique receptors (TCR) that they use to recognize foreign pathogens and eliminate them. Sometimes these TCR also inadvertently recognize self-proteins and lead to autoimmune diseases.
In our preliminary studies examining the TCR repertoire of the CD4+CD8+ population there was strong evidence they were expanded by recognizing an antigen. At this time, we do not know if this is a self or a pathogen antigen. We will therefore explore the TCR repertoire of this unique population of CD4+CD8+ T cells in order to find characteristics that will help us identify the potential antigen that is driving their expansion and activation. This would be a major step in the field potentially leading to the identification a specific infectious or autoimmune response that could be the main driver of the immunological basis of ME/CFS. Studying these unique cells (CD4+CD8+ T cells) in a larger population of ME/CFS patients has the potential to give us a biomarker (much needed for this disease) while giving us clues to the mechanisms driving the pathology of ME/CFS and thus therapy.
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Tick-Borne Encephalitis Virus, United Kingdom
Maya Holding; Stuart D. Dowall; Jolyon M. Medlock; Daniel P. Carter; Steven T. Pullan; James Lewis; Richard Vipond; Mara S. Rocchi; Matthew Baylis; Roger Hewson
Emerging Infectious Diseases. 2020;26(1):90-96.
Abstract
During February 2018–January 2019, we conducted large-scale surveillance for the presence and prevalence of tick-borne encephalitis virus (TBEV) and louping ill virus (LIV) in sentinel animals and ticks in the United Kingdom. Serum was collected from 1,309 deer culled across England and Scotland. Overall, 4% of samples were ELISA-positive for the TBEV serocomplex. A focus in the Thetford Forest area had the highest proportion (47.7%) of seropositive samples. Ticks collected from culled deer within seropositive regions were tested for viral RNA; 5 of 2,041 ticks tested positive by LIV/TBEV real-time reverse transcription PCR, all from within the Thetford Forest area. From 1 tick, we identified a full-length genomic sequence of TBEV. Thus, using deer as sentinels revealed a potential TBEV focus in the United Kingdom. This detection of TBEV genomic sequence in UK ticks has important public health implications, especially for undiagnosed encephalitis.
Introduction
The only tickborne flavivirus in the United Kingdom documented to cause disease in vertebrates is louping ill virus (LIV), a vivirus transmitted by the deer/sheep tick, Ixodes ricinus.[1] This tick species is the most abundant and widely distributed tick species in the United Kingdom and a known vector of Lyme borreliosis. LIV is most commonly detected in sheep, cattle, and red grouse and has been reported in Scotland, Wales, and England (primarily Cumbria, Devon, and North Yorkshire).[1] Humans are incidental hosts for LIV, and infection has been reported infrequently; ≈45 clinical cases have been linked to encephalitis during the past 85 years.[1,2] However, the short window of acute infection leads to uncertainty about whether suspected cases resulted from LIV infection or some other cause, although serologic analysis to analyze recent exposure through induction of IgM-specific responses, in combination with clinical symptoms, could inform a presumptive diagnosis. Human cases are mostly linked to occupational exposure, particularly in abattoir or farm workers and occasionally in laboratory staff.[2] Although the UK Animal and Plant Health Agency holds a database of confirmed diagnoses of LIV in livestock,[3,4] the distribution and regional prevalence of LIV has not been fully defined. Records of distribution and regional prevalence are based on voluntary submissions by farmers and veterinarians from symptomatic livestock,[1] from which private submissions are not integrated. Serologic analysis has been complicated; some animals received vaccination before its withdrawal.
Tick-borne encephalitis virus (TBEV) is a closely related flavivirus that, although known to be less virulent than LIV for sheep,[5] causes a neurologic disease (tick-borne encephalitis [TBE]) after transmission to humans by infected ticks, producing clinical disease in an estimated one third of TBEV infections.[6] TBE typically has a biphasic course starting with a prodromal phase with influenza-like symptoms, followed by a symptom-free interval before neurologic disease occurs; neurologic disease ranges from mild meningitis to severe encephalitis with or without myelitis and spinal paralysis.[7] Three classic subtypes of TBEV are recognized: European (TBEV-Eu), Siberian, and Far Eastern. Two additional TBEV subtypes have recently been proposed: Baikalian subtype and the Himalayan subtype.[8] TBEV-Eu is the prevailing subtype in Western Europe where it is primarily transmitted by I. ricinus ticks and is maintained within forest and meadow biotypes in endemic foci. In the United Kingdom, TBE is considered an imported disease; opportunities for the virus to become established principally are limited because the UK climate was not thought to support the specific conditions required for enzoonotic cycles to be established for TBEV to become endemic.[9] However, changes in climate have affected the emergence, distribution, and abundance of I. ricinus in the United Kingdom;[10] thus, the risk for tickborne disease has increased.[11] A recent study provided evidence that co-infestation of tick larvae and nymphs occurs in small mammals in UK woodland.[12] The increasing range of TBEV in Western Europe was underscored recently when the Netherlands reported its first human case in 2016.[13] Moreover, retrospective serologic screening of deer serum samples and molecular analysis of questing ticks found evidence of TBEV circulation in the Netherlands as far back as 2010 and 2015.[13,14] Given the increasing possibility that TBEV could be circulating in the United Kingdom, Public Health England developed a surveillance program focusing on wild animals and ticks.
In TBEV-endemic areas in continental Europe, the prevalence of TBEV in questing ticks is low, rarely exceeding 1% even in regions where the incidence of human infections is high.[15] Therefore, instead of screening ticks directly, we used sentinel animals first to identify serologic evidence of TBEV to highlight sites for focused tick testing by specific TBEV detection using real-time reverse transcription PCR (rRT-PCR). Deer are proven as reliable sentinels for identifying areas where TBEV is present[13,15] because they have a limited home range, are available in large numbers, and are broadly dispersed within the surveillance areas. They also show long-lasting antibody responses after natural exposure to flaviviruses.[15,16]
For our study, collectors retrieved blood samples from deer culled in England and Scotland during February 2018–January 2019; when available, they also collected tick samples. We tested the blood samples for TBEV or LIV antibodies and the ticks for the presence of viral RNA by rRT-PCR.
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Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations
Alexandra H. Mandarano, Jessica Maya, Ludovic Giloteaux, Daniel L. Peterson, Marco Maynard, C. Gunnar Gottschalk, and Maureen R. Hanson
First published December 12, 2019 – Journal of clinical investigation
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease with no known cause or mechanism. There is an increasing appreciation for the role of immune and metabolic dysfunction in the disease. ME/CFS has historically presented in outbreaks, often has a flu-like onset, and results in inflammatory symptoms. Patients suffer from severe fatigue and post-exertional malaise. There is little known about the metabolism of specific immune cells in ME/CFS patients. To investigate immune metabolism in ME/CFS, we isolated CD4+ and CD8+ T cells from 53 ME/CFS patients and 45 healthy controls. We analyzed glycolysis and mitochondrial respiration in resting and activated T cells, along with markers related to cellular metabolism, and plasma cytokines. We found that ME/CFS CD8+ T cells have reduced mitochondrial membrane potential compared to healthy controls. Both CD4+ and CD8+ T cells from ME/CFS patients had reduced glycolysis at rest, while CD8+ T cells also had reduced glycolysis following activation. ME/CFS patients had significant correlations between measures of T cell metabolism and plasma cytokine abundance that differed from healthy control subjects. Our data indicate that patients have impaired T cell metabolism consistent with ongoing immune alterations in ME/CFS that may illuminate the mechanism behind this disease.
Graphical Abstract
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Medicine. 98(43):e17600, OCTOBER 2019
DOI: 10.1097/MD.0000000000017600
,
PMID: 31651868
Issn Print: 0025-7974
Publication Date: October 2019
Evidence of altered cardiac autonomic regulation in myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review and meta-analysis
Maximillian Nelson;Jasvir Bahl;Jonathan Buckley;Rebecca Thomson;Kade Davison;
Abstract Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition with no reliable diagnostic biomarkers. Studies have shown evidence of autonomic dysfunction in patients with ME/CFS, but results have been equivocal. Heart rate (HR) parameters can reflect changes in autonomic function in healthy individuals; however, this has not been thoroughly evaluated in ME/CFS.
Methods: A systematic database search for case-control literature was performed. Meta-analysis was performed to determine differences in HR parameters between ME/CFS patients and controls.
Results: Sixty-four articles were included in the systematic review. HR parameters assessed in ME/CFS patients and controls were grouped into ten categories: resting HR (RHR), maximal HR (HRmax), HR during submaximal exercise, HR response to head-up tilt testing (HRtilt), resting HR variability (HRVrest), HR variability during head-up tilt testing (HRVtilt), orthostatic HR response (HROR), HR during mental task(s) (HRmentaltask), daily average HR (HRdailyaverage), and HR recovery (HRR) Meta-analysis revealed RHR (MD±95% CI=4.14±1.38, P
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Journal of Epidemiological Research:International Peer-Reviewed and Open Access Journal for the epidemiological specialists
Home > Vol 5, No 1 (2019) > Lin
Incidence rates of brain cancer following an outbreak of Chronic Fatigue Syndrome
Cheng-Te Major Lin, Naji Younes, Paul H. Levine
Abstract
Previous studies utilizing data from the Nevada Cancer Registry suggested a transient increase in non-Hodgkin’s lymphoma (NHL) and brain cancer in northern Nevada following an outbreak of Chronic Fatigue Syndrome (CFS) in that area which was not seen in southern Nevada which had no reported CFS outbreaks. A subsequent study from the National Cancer Institute (NCI) using data from the NCI’s Surveillance, Epidemiology and End Results (SEER) Program and Medicare documented the association between CFS and NHL on a national basis but no other cancer association was seen. Since brain cancer has a younger age distribution than NHL, we returned to the Nevada Cancer Registry and used ten more years of data and additional analyses to determine if there was an association between CFS and brain cancer by age. This study confirmed the increased incidence of brain cancer following the outbreak in northern Nevada but not southern Nevada with the increase limited to the under 65 age group, thus explaining why the SEER-Medicare analysis only analyzing data in the 65 and above age group did not detect this association.
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The physiological timeline of post exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
L Hodges T Nielsen D Cochrane D Baken
First published: 08 January 2020 – Translational Sports Medicine.
https://doi.org/10.1002/tsm2.133
Abstract
With fatigue being such a dominant feature, it is important to define the timeline and its impact following exertion in individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This study aimed to investigate the physiological effects of repeated graded maximal exercise testing at 48 and 72 hours, along with analysing the reported time to recover from repeated graded exercise tests (PEM). ME/CFS (n = 16), age and gender matched controls (n=16) were randomly assigned to either a 48‐hour or 72‐hour protocol. Each participant completed a maximal incremental cycle exercise test on day one and again at either 48‐hours (48‐h) or 72‐hours (72‐h) later. Physiological responses were analysed at peak work rate (PWR). There were significant differences in both peak VO2 and workload (p<0.05) in the 48‐h ME/CFS group compared to the 48‐h controls in both test 1 and test 2. Significant differences in peak VO2 and workload were only demonstrated in test 2 in participants in the ME/CFS 72‐h group. There was a small but insignificant decrease in both peak VO2 and workload in the ME/CFS group at 48‐h. Interestingly those in the 72‐h ME/CFS protocol demonstrated an increase in workload (10 Watts), despite no change in VO2peak. Subjective data demonstrated the 48‐hour ME/CFS group reported significantly longer time to recover.
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RESEARCH ARTICLE (Open Access)
Contents Vol 11(4)
A neuro-inflammatory model can explain the onset, symptoms and flare-ups of myalgic encephalomyelitis/chronic fatigue syndrome
Angus Mackay 1
Journal of Primary Health Care 11(4) 300-307 https://doi.org/10.1071/HC19041
Published: 29 November 2019
Journal Compilation © Royal New Zealand College of General Practitioners 2019 This is an open access article licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License
Abstract
A neuro-inflammatory model is proposed to explain the onset, symptoms and perpetuation of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) via characteristic flare-ups (relapses). In this article, I explore the proposition that a range of triggers (intense physiological stressors such as severe viral infections, chemical toxin exposure or emotional trauma) in ME/CFS-predisposed people causes disruption in the neural circuitry of the hypothalamus (paraventricular nucleus), which induces a neuro-inflammatory reaction in the brain and central nervous system of ME/CFS patients, via over-active innate immune (glial) cells. Resulting dysfunction of the limbic system, the hypothalamus and consequently of the autonomic nervous system can then account for the diverse range of ME/CFS symptoms. Ongoing stressors feed into a compromised (inflamed) hypothalamus and if a certain (but variable) threshold is exceeded, a flare-up will ensue, inducing further ongoing neuro-inflammation in the central nervous system, thus perpetuating the disease indefinitely.
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• Published: 06 January 2020
Systematic review of randomized controlled trials for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)
Journal of Translational Medicine volume 18, Article number: 7 (2020) Cite this article
Abstract
Background
Although medical requirements are urgent, no effective intervention has been proven for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). To facilitate the development of new therapeutics, we systematically reviewed the randomized controlled trials (RCTs) for CFS/ME to date.
Methods
RCTs targeting CFS/ME were surveyed using two electronic databases, PubMed and the Cochrane library, through April 2019. We included only RCTs that targeted fatigue-related symptoms, and we analyzed the data in terms of the characteristics of the participants, case definitions, primary measurements, and interventions with overall outcomes.
Results
Among 513 potentially relevant articles, 55 RCTs met our inclusion criteria; these included 25 RCTs of 22 different pharmacological interventions, 28 RCTs of 18 non-pharmacological interventions and 2 RCTs of combined interventions. These studies accounted for a total of 6316 participants (1568 males and 4748 females, 5859 adults and 457 adolescents). CDC 1994 (Fukuda) criteria were mostly used for case definitions (42 RCTs, 76.4%), and the primary measurement tools included the Checklist Individual Strength (CIS, 36.4%) and the 36-item Short Form health survey (SF-36, 30.9%). Eight interventions showed statistical significance: 3 pharmacological (Staphypan Berna, Poly(I):poly(C12U) and CoQ10 + NADH) and 5 non-pharmacological therapies (cognitive-behavior-therapy-related treatments, graded-exercise-related therapies, rehabilitation, acupuncture and abdominal tuina). However, there was no definitely effective intervention with coherence and reproducibility.
Conclusions
This systematic review integrates the comprehensive features of previous RCTs for CFS/ME and reflects on their limitations and perspectives in the process of developing new interventions.
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J of Translational medicine 2020 Jan 6;18(1):4. doi: 10.1186/s12967-019-02184-z.
Reduced heart rate variability predicts fatigue severity in individuals with chronic fatigue syndrome/myalgic encephalomyelitis.
Escorihuela RM1, Capdevila L2, Castro JR3, Zaragozà MC4, Maurel S5, Alegre J6, Castro-Marrero J7.
Abstract
BACKGROUND:
Heart rate variability (HRV) is an objective, non-invasive tool to assessing autonomic dysfunction in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). People with CFS/ME tend to have lower HRV; however, in the literature there are only a few previous studies (most of them inconclusive) on their association with illness-related complaints. To address this issue, we assessed the value of different diurnal HRV parameters as potential biomarker in CFS/ME and also investigated the relationship between these HRV indices and self-reported symptoms in individuals with CFS/ME.
METHODS:
In this case-control study, 45 female patients who met the 1994 CDC/Fukuda definition for CFS/ME and 25 age- and gender-matched healthy controls underwent HRV recording-resting state tests. The intervals between consecutive heartbeats (RR) were continuously recorded over three 5-min periods. Time- and frequency-domain analyses were applied to estimate HRV variables. Demographic and clinical features, and self-reported symptom measures were also recorded.
RESULTS:
CFS/ME patients showed significantly higher scores in all symptom questionnaires (p < 0.001), decreased RR intervals (p < 0.01), and decreased HRV time- and frequency-domain parameters (p < 0.005), except for the LF/HF ratio than in the healthy controls. Overall, the correlation analysis reached significant associations between the questionnaires scores and HRV time- and frequency-domain measurements (p < 0.05). Furthermore, separate linear regression analyses showed significant relationships between self-reported fatigue symptoms and mean RR (p = 0.005), RMSSD (p = 0.0268) and HFnu indices (p = 0.0067) in CFS/ME patients, but not in healthy controls.
CONCLUSIONS:
Our findings suggest that ANS dysfunction presenting as increased sympathetic hyperactivity may contribute to fatigue severity in individuals with ME/CFS. Further studies comparing short- and long-term HRV recording and self-reported outcome measures with previous studies in larger CFS/ME cohorts are urgently warranted.
PMID: 31906988
PMCID:PMC6943898
DOI:10.1186/s12967-019-02184-z
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Psychoneuroendocrinology – vol 113. March 2020, 104578
The role of low-grade inflammation in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) - associations with symptoms
Martin AJonsjöabfGunnar LOlssonabRikard WicksellcKjellAlvingdLindaHolmströmaeAnnaAndreassonfg
https://doi.org/10.1016/j.psyneuen.2019.104578Get rights and content
Highlights
Associations between inflammatory markers and common symptoms in ME/CFS.
Higher levels of markers were significantly associated with higher levels of symptoms.
Biological sex moderated several associations.
Abstract
Background
Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) often present with a range of flu-like symptoms resembling sickness behavior as well as widespread pain and concentration deficits. The aim of this study was to explore the association between inflammatory markers previously shown to be related to fatigue severity in ME/CFS and common ME/CFS symptoms post-exertional fatigue, impaired cognitive processing, musculoskeletal pain and recurrent flu-like symptoms, and the moderating effect of sex on these associations.
Methods
53 adult patients diagnosed with ME/CFS at a specialist clinic were included in the study. Fasting blood plasma was analyzed using the Olink Proseek Multiplex Inflammation panel (β-NGF, CCL11, CXCL1, CXCL10, IL-6, IL-7, IL-8, IL-10, IL-18, TGF-α, TGF-β-1 and SCF) and BioRad Human Cytokine Type 1 assay (TNF-α). Participants rated the average severity of symptoms (0–10) based on the 2011 International Consensus Criteria of ME/CFS during a structured clinical interview. Associations between inflammatory markers and symptom severity were analyzed using bivariate correlations and moderated regression analyses bootstrapped with 5000 repetitions.
Results and conclusions
Only β-NGF was associated with the fatigue severity measure. However, higher levels of CCL11, CXCL10, IL-7, TNF-α and TGF-β-1 were significantly associated with higher levels of impaired cognitive processing and musculoskeletal pain, and sex was a significant moderator for CXCL10, IL-7 and TGF-β-1. Future studies should investigate the relationship between inflammatory markers and key symptoms in ME/CFS in a longitudinal design in order to explore if and for whom low-grade inflammation may contribute to illness development.
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N. Eaton-Fitch, S. C. Johnston, P. Zalewski, D. Staines & S. Marshall-Gradisnik
Quality of Life Research (2020)
Abstract
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious and debilitating disorder associated with significant disruptions in daily life including. This study aimed to examine the impact of sociodemographic and patient symptom characteristics on health-related quality of life (HRQoL) of Australians with ME/CFS.
Methods
Self-reported data collected from 480 individuals diagnosed with ME/CFS were obtained between August 2014 and August 2018. This cross-sectional survey analysed sociodemographic, symptom characteristics and HRQoL according to the 36-Item Health Survey (SF-36). Multivariate linear regression models were used to determine ME/CFS symptoms associated with eight domains of HRQoL.
Results
Reported HRQoL was significantly impaired in ME/CFS patients across all domains compared with the general population. Scores were the lowest for physical role (4.11 ± 15.07) and energy/fatigue (13.54 ± 13.94). Associations with females, higher body mass index (BMI), employment status, cognitive difficulties, sensory disturbances and cardiovascular symptoms were observed in the physical functioning domain. Impaired pain domain scores were associated with high BMI, annual visits to their general practitioner, flu-like symptoms and fluctuations in body temperature. Reduced well-being scores were associated with smoking status, psychiatric comorbidity, cognitive difficulties, sleep disturbances and gastrointestinal difficulties.
Conclusion
This study provides evidence that ME/CFS has a profound and negative impact on HRQoL in an Australian cohort.
October 2019, Volume 119, Issue 10, pp 2375–2389| Cite as
Unexplained exertional intolerance associated with impaired systemic oxygen extraction
- Authors
- Kathryn H. MelamedMário Santos Rudolf K. F. Oliveira Mariana Faria Urbina Donna Felsenstein Alexander R. Opotowsky Aaron B. Waxman David M. Systrom
Purpose
The clinical investigation of exertional intolerance generally focuses on cardiopulmonary diseases, while peripheral factors are often overlooked. We hypothesize that a subset of patients exists whose predominant exercise limitation is due to abnormal systemic oxygen extraction (SOE).
Methods
We reviewed invasive cardiopulmonary exercise test (iCPET) results of 313 consecutive patients presenting with unexplained exertional intolerance. An exercise limit due to poor SOE was defined as peak exercise (Ca-vO2)/[Hb] ≤ 0.8 and VO2max < 80% predicted in the absence of a cardiac or pulmonary mechanical limit. Those with peak (Ca-vO2)/[Hb] > 0.8, VO2max ≥ 80%, and no cardiac or pulmonary limit were considered otherwise normal. The otherwise normal group was divided into hyperventilators (HV) and normals (NL). Hyperventilation was defined as peak PaCO2 < [1.5 × HCO3 + 6].
Results
Prevalence of impaired SOE as the sole cause of exertional intolerance was 12.5% (32/257). At peak exercise, poor SOE and HV had less acidemic arterial blood compared to NL (pHa = 7.39 ± 0.05 vs. 7.38 ± 0.05 vs. 7.32 ± 0.02, p < 0.001), which was explained by relative hypocapnia (PaCO2 = 29.9 ± 5.4 mmHg vs. 31.6 ± 5.4 vs. 37.5 ± 3.4, p < 0.001). For a subset of poor SOE, this relative alkalemia, also seen in mixed venous blood, was associated with a normal PvO2 nadir (28 ± 2 mmHg vs. 26 ± 4, p = 0.627) but increased SvO2 at peak exercise (44.1 ± 5.2% vs. 31.4 ± 7.0, p < 0.001).
Conclusions
We identified a cohort of patients whose exercise limitation is due only to systemic oxygen extraction, due to either an intrinsic abnormality of skeletal muscle mitochondrion, limb muscle microcirculatory dysregulation, or hyperventilation and left shift the oxyhemoglobin dissociation curve.
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European Journal of applied physiology
October 2019, Volume 119, Issue 10, pp 2375–2389| Cite as
Unexplained exertional intolerance associated with impaired systemic oxygen extraction
- Authors
- Kathryn H. MelamedMário Santos Rudolf K. F. Oliveira Mariana Faria Urbina Donna Felsenstein Alexander R. Opotowsky Aaron B. Waxman David M. Systrom
Purpose
The clinical investigation of exertional intolerance generally focuses on cardiopulmonary diseases, while peripheral factors are often overlooked. We hypothesize that a subset of patients exists whose predominant exercise limitation is due to abnormal systemic oxygen extraction (SOE).
Methods
We reviewed invasive cardiopulmonary exercise test (iCPET) results of 313 consecutive patients presenting with unexplained exertional intolerance. An exercise limit due to poor SOE was defined as peak exercise (Ca-vO2)/[Hb] ≤ 0.8 and VO2max < 80% predicted in the absence of a cardiac or pulmonary mechanical limit. Those with peak (Ca-vO2)/[Hb] > 0.8, VO2max ≥ 80%, and no cardiac or pulmonary limit were considered otherwise normal. The otherwise normal group was divided into hyperventilators (HV) and normals (NL). Hyperventilation was defined as peak PaCO2 < [1.5 × HCO3 + 6].
Results
Prevalence of impaired SOE as the sole cause of exertional intolerance was 12.5% (32/257). At peak exercise, poor SOE and HV had less acidemic arterial blood compared to NL (pHa = 7.39 ± 0.05 vs. 7.38 ± 0.05 vs. 7.32 ± 0.02, p < 0.001), which was explained by relative hypocapnia (PaCO2 = 29.9 ± 5.4 mmHg vs. 31.6 ± 5.4 vs. 37.5 ± 3.4, p < 0.001). For a subset of poor SOE, this relative alkalemia, also seen in mixed venous blood, was associated with a normal PvO2 nadir (28 ± 2 mmHg vs. 26 ± 4, p = 0.627) but increased SvO2 at peak exercise (44.1 ± 5.2% vs. 31.4 ± 7.0, p < 0.001).
Conclusions
We identified a cohort of patients whose exercise limitation is due only to systemic oxygen extraction, due to either an intrinsic abnormality of skeletal muscle mitochondrion, limb muscle microcirculatory dysregulation, or hyperventilation and left shift the oxyhemoglobin dissociation curve.
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Journal of Clinical Investigation
Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations
Alexandra H. Mandarano, Jessica Maya, Ludovic Giloteaux, Daniel L. Peterson, Marco Maynard, C. Gunnar Gottschalk, and Maureen R. Hanson
First published December 12, 2019
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease with no known cause or mechanism. There is an increasing appreciation for the role of immune and metabolic dysfunction in the disease. ME/CFS has historically presented in outbreaks, often has a flu-like onset, and results in inflammatory symptoms. Patients suffer from severe fatigue and post-exertional malaise. There is little known about the metabolism of specific immune cells in ME/CFS patients. To investigate immune metabolism in ME/CFS, we isolated CD4+ and CD8+ T cells from 53 ME/CFS patients and 45 healthy controls. We analyzed glycolysis and mitochondrial respiration in resting and activated T cells, along with markers related to cellular metabolism, and plasma cytokines. We found that ME/CFS CD8+ T cells have reduced mitochondrial membrane potential compared to healthy controls. Both CD4+ and CD8+ T cells from ME/CFS patients had reduced glycolysis at rest, while CD8+ T cells also had reduced glycolysis following activation. ME/CFS patients had significant correlations between measures of T cell metabolism and plasma cytokine abundance that differed from healthy control subjects. Our data indicate that patients have impaired T cell metabolism consistent with ongoing immune alterations in ME/CFS that may illuminate the mechanism behind this disease.
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Epidemiology and Community Health: Research report
Influence of sleep problems and co-occurring musculoskeletal pain on long-term prognosis of chronic low back pain: the HUNT Study
Eivind Schjelderup Skarpsno, Paul Jarle Mork, Tom Ivar Lund Nilsen,
Anne Lovise Nordstoga
Abstract
Background We investigated the influence of sleeplessness and number of insomnia symptoms on the probability of recovery from chronic low back pain (LBP), and the possible interplay between sleeplessness and co-occurring musculoskeletal pain on this association.
Methods The study comprised data on 3712 women and 2488 men in the Norwegian HUNT study who reported chronic LBP at baseline in 1995–1997. A modified Poisson regression model was used to calculate adjusted risk ratios (RRs) for the probability of recovery from chronic LBP at follow-up in 2006–2008, associated with sleep problems and co-occurring musculoskeletal pain at baseline.
Results Compared with persons without sleeplessness, persons who often/always experienced sleeplessness had a lower probability of recovery from chronic LBP (RR 0.65, 95% CI 0.57 to 0.74 in women and RR 0.81, 95% CI 0.69 to 0.95 in men). Although there was no clear evidence of statistical interaction between sleeplessness and co-occurring musculoskeletal pain, women and men who often/always experienced sleeplessness and had ≥5 additional chronic pain sites had RRs of recovery of 0.40 (95% CI 0.33 to 0.48) and 0.59 (95% CI 0.45 to 0.78), respectively, compared with persons without sleeplessness and 1–2 chronic pain sites.
Conclusion These findings suggest that preventing or reducing sleep problems among people with chronic LBP may have the potential of improving the long-term prognosis of this condition, also among those with several additional pain sites.
View Full Text
http://dx.doi.org/10.1136/jech-2019-212734
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Journal: Fatigue: Biomedicine, Health & Behavior
Low-dose naltrexone in the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Olli Polo,Pia Pesonen &Essi Tuominen
Received 13 Sep 2019, Accepted 11 Nov 2019, Published online: 19 Nov 2019
ABSTRACT
Background: Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a common medical condition that limits physical and cognitive functions, with no known effective medical treatment.
Methods: We report on the safety and effectiveness data accumulated in clinical practice when treating ME/CFS with low-dose naltrexone (LDN, 3.0 – 4.5 mg/day). The medical records from 218 patients who received ar diagnosis of ME/CFS and LDN treatment during 2010–2014 were retrospectively analyzed.
Results: Outcome data were available in 92.2% of patients with an average follow-up time of 1.7 years. A positive treatment response to LDN was reported by 73.9% of the patients. Most patients experienced improved vigilance/alertness and improved physical and cognitive performance. Some patients reported less pain and fever, while 18.3% of patients did not report any treatment response to LDN. Mild adverse effects (insomnia, nausea) were common at the beginning of the treatment. Neither severe adverse effects nor long-term adverse symptoms were reported.
Conclusions: The high frequency of treatment response and good safety profile observed in this retrospective open label study could prompt prospective controlled studies to confirm the feasibility of LDN in alleviating ME/CFS symptoms.
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Brain Behav Immun. 2019 Nov 20. pii: S0889-1591(19)30762-7. doi: 10.1016/j.bbi.2019.11.015.
Identification of actin network proteins, talin-1 and filamin-A, in circulating extracellular vesicles as blood biomarkers for human myalgic encephalomyelitis/chronic fatigue syndrome.
Eguchi A1, Fukuda S2, Kuratsune H2, Nojima J3, Nakatomi Y4, Watanabe Y5, Feldstein AE
1 Department of Gastroenterology and Hepatology, School of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; JST, PRETO, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan; Department of Pediatrics, University of California San Diego (UCSD), La Jolla, CA 92093, USA. Electronic address: [email protected].
2 Department of Health Welfare Sciences, Kansai University of Welfare Sciences, Kashiwara 582-0026, Japan; Department of Endocrinology, Metabolism and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8586, Japan; RIKEN, Center for Biosystems Dynamics Research, Kobe 650-0047, Japan.
3 Department of Laboratory Science, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
4 Nakatomi Fatigue Care Clinic, Osaka 541-0043, Japan.
5 Department of Endocrinology, Metabolism and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8586, Japan; RIKEN, Center for Biosystems Dynamics Research, Kobe 650-0047, Japan; RIKEN Compass to Healthy Life Research Complex Program, Kobe 650-0047, Japan.
6 Department of Pediatrics, University of California San Diego (UCSD), La Jolla, CA 92093, USA.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, debilitating disorder with a wide spectrum of symptoms, including pain, depression, and neurocognitive deterioration. Over 17 million people around the world have ME/CFS, predominantly women with peak onset at 30-50 years. Given the wide spectrum of symptoms and unclear etiology, specific biomarkers for diagnosis and stratification of ME/CFS are lacking. Here we show that actin network proteins in circulating extracellular vesicles (EVs) offer specific non-invasive biomarkers for ME/CFS. We found that circulating EVs were significantly increased in ME/CFS patients correlating to C-reactive protein, as well as biological antioxidant potential. Area under the receiver operating characteristic curve for circulating EVs was 0.80, allowing correct diagnosis in 90-94% of ME/CFS cases. From two independent proteomic analyses using circulating EVs from ME/CFS, healthy controls, idiopathic chronic fatigue, and depression, proteins identified from ME/CFS patients are involved in focal adhesion, actin skeletal regulation, PI3K-Akt signaling pathway, and Epstein-Barr virus infection. In particular, talin-1, filamin-A, and 14-3-3 family proteins were the most abundant proteins, representing highly specific ME/CFS biomarkers. Our results identified circulating EV number and EV-specific proteins as novel biomarkers for diagnosing ME/CFS, providing important information on the pathogenic mechanisms of ME/CFS.
Copyright © 2019 Elsevier Inc. All rights reserved.PMID:31759091 DOI:10.1016/j.bbi.2019.11.015
Research: REVIEW
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Understanding neuromuscular disorders in chronic fatigue syndrome
Yves Jammes, Frédérique Retornaz2
Abstract
Muscle failure has been demonstrated in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Neurophysiological tools demonstrate the existence of both central and peripheral fatigue in these patients. Central fatigue is deduced from the reduced amplitude of myopotentials evoked by transcranial magnetic stimulation of the motor cortex as well as by the muscle response to interpolated twitches during sustained fatiguing efforts. An impaired muscle membrane conduction velocity assessed by the reduced amplitude and lengthened duration of myopotentials evoked by direct muscle stimulation is the defining feature of peripheral fatigue. Some patients with ME/CFS show an increased oxidative stress response to exercise. The formation of lipid hydroperoxides in the sarcolemma, which alters ionic fluxes, could explain the reduction of muscle membrane excitability and potassium outflow often measured in these patients. In patients with ME/CFS, the formation of heat shock proteins (HSPs) is also reduced. Because HSPs protect muscle cells against the deleterious effects of reactive oxygen species, the lack of their production could explain the augmented oxidative stress and the consecutive alterations of myopotentials which could open a way for future treatment of ME/CFS.
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Brief Cognitive Behavioral Therapy For Chronic Pain
Results From a Clinical Demonstration Project in Primary Care Behavioral Health
Beehler, Gregory P. MA, PhD*,†; Murphy, Jennifer L. PhD‡,§; King, Paul R. PhD*,∥; Dollar, Katherine M. PhD¶; Kearney, Lisa K. PhD, ABPP¶,#; Haslam, Aaron PhD**; Wade, Michael MS¶; Goldstein, Wade R. MA*
The Clinical Journal of Pain: October 2019 - Volume 35 - Issue 10 - p 809–817
doi: 10.1097/AJP.0000000000000747
Abstract
Objectives:
Although cognitive behavioral therapy is an effective intervention for chronic pain, it is a lengthy treatment typically applied only in specialty care settings. The aim of this project was to collect preliminary effectiveness data for Brief Cognitive Behavioral Therapy for Chronic Pain (Brief CBT-CP), an abbreviated, modular form of treatment designed for use in primary care.
Methods:
A clinical demonstration project was conducted in which Brief CBT-CP was delivered to primary care patients by 22 integrated care providers practicing in the Primary Care Behavioral Health model of Veterans Health Administration primary care clinics. Brief measures were used at each appointment to collect patient-reported clinical outcomes.
Results:
One hundred eighteen patients provided sufficient data for analysis (male, 75%; mean age, 51.4 y). Multilevel modeling suggested that a composite measure of pain intensity and functional limitations showed statistically significant improvements by the third appointment (Cohen’s d=0.65). Pain-related self-efficacy outcomes showed a similar pattern of results but of smaller effect size (Cohen’s d=0.22). The exploratory analysis identified that Brief CBT-CP modules addressing psychoeducation and goal setting, pacing, and relaxation training were associated with the most significant gains in treatment outcomes.
Discussion:
These findings provide early support for the effectiveness of Brief CBT-CP when delivered by providers in every day Primary Care Behavioral Health settings. Results are discussed in relation to the need for additional research regarding the potential value of employing safe, population-based, nonpharmacological approaches to pain management in primary care.
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
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Bragee Clinics report
Signs of Intracranial Hypertension, Hypermobility and
Craniocervical Obstructions in patients with
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Björn Bragée , Anastasios Michos, Brandon Drum, Mikael Fahlgren, Robert
Szulkin, Bo C Bertilson
Division of Family Medicine and Primary Care,
Department of Neurobiology, Care Sciences
and Society, Karolinska Institutet, Stockholm, Sweden
Division of Family Medicine and Primary Care,Stockholm Health Care Services, Region
Stockholm, Huddinge, Sweden
ME center, Bragée Clinics, Stockholm, Sweden
Objective: To test the hypothesis that hypermobility and craniocervical obstructions is overrepresented in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and that a large portion of these patients may have a degree of intracranial hypertension explaining many of the symptoms of the ME/CFS syndrome.
Methods: This is a retrospective cross-sectional study, performed at a specialist clinic for referred patients with severe ME/CFS fulfilling the Canada Consensus Criteria. The first 272 consecutive patients with ME/CFS were invited, and 229 of these whom had signed the informed consent within six weeks were included. Hypermobility was assessed using the Beighton score. The position of cerebellar tonsils, the optic nerve sheath diameter and eyeball transverse diameter were measured in magnetic resonance imaging scans of the brain as measures correlated to intracranial hypertension. Findings of obstructions in the craniocervical junction and the cervical spine were assessed through MRI scans of the cervical spine. Radiological assessments were made by an experienced radiologist.
Results: 190 women with a mean age of 45 years and 39 males with a mean age of 44 years were included. Hypermobility was found in 111 (49%) of the patients. Of the 205 patients with brain MRI scanning, increased diameter of the optic nerve sheath was found in 112 patients (55%), signs of possible intracranial hypertension expressed as the quote of the diameter of optic nerve/eyeball transverse diameter in left or right side were present in 171 patients (83%), and values seen with more severe states of intracranial hypertension were found in 65 of the patients (32%). Obstruction in the foramen magnum by cerebellar tonsils under the McRae line was found in 115 patients (56%). Findings of obstruction of the cervical spinal canal were found in 100 of the 125 patients (80%) with cervical scans. There was a significant overrepresentation of signs of hypermobility, intracranial hypertension and obstructions in the cranio-cervical region compared with general population.
Conclusion: These findings, which confirms our hypothesis, may explain the widespread symptoms these patients express. If confirmed in further studies, new diagnostic and therapeutic approaches to this widespread neurological syndrome should be considered.
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From Cold Spring Harbor Laboratory
Perturbation of effector and regulatory T cell subsets in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Ece Karhan, Courtney Gunter, Vida Ravanmehr, Meghan Horne, Lina Kozhaya, Stephanie Renzullo, Lindsey Placek, Joshy George, View ORCID ProfilePeter N. Robinson, Suzannne D Vernon, Lucinda Bateman, Derya Unutmaz
doi: https://doi.org/10.1101/2019.12.23.887505
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder of unknown etiology, and diagnosis of the disease is largely based on clinical symptoms. We hypothesized that immunological disruption is the major driver of this disease and analyzed a large cohort of ME/CFS patient or control blood samples for differences in T cell subset frequencies and functions. We found that the ratio of CD4+ to CD8+ T cells and the proportion of CD8+ effector memory T cells were increased, whereas NK cells were reduced in ME/CFS patients younger than 50 years old compared to a healthy control group. Remarkably, major differences were observed in Th1, Th2, Th17 and mucosal-associated invariant T (MAIT) T cell subset functions across all ages of patients compared to healthy subjects. While CCR6+ Th17 cells in ME/CFS secreted less IL-17 compared to controls, their overall frequency was higher. Similarly, MAIT cells from patients secreted lower IFNgamma;, GranzymeA and IL-17 upon activation. Together, these findings suggest chronic stimulation of these T cell populations in ME/CFS patients. In contrast, the frequency of regulatory T cells (Tregs), which control excessive immune activation, was higher in ME/CFS patients. Finally, using a machine learning algorithm called random forest, we determined that the set of T cell parameters analyzed could identify more than 90% of the subjects in the ME/CFS cohort as patients (93% true positive rate or sensitivity). In conclusion, these multiple and major perturbations or dysfunctions in T cell subsets in ME/CFS patients suggest potential chronic infections or microbiome dysbiosis. These findings also have implications for development of ME/CFS specific immune biomarkers and reveal potential targets for novel therapeutic interventions.
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Scientific Reports MC6906377 2019; 9: 18817.
Published online 2019 Dec 11. doi: 10.1038/s41598-019-55473-4 PMCID: PMC6906377
PMID: 31827223
Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with Myalgic encephalomyelitis/Chronic fatigue syndrome
Alaa Ghali,1 Carole Lacout,1 Maria Ghali,2 Aline Gury,1 Anne-Berengere Beucher,1 Pierre Lozac’h,1 Christian Lavigne,1 and Geoffrey Urbanski (France)
Abstract
Elevated blood lactate after moderate exercise was reported in some of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We hypothesised that blood lactate could be also elevated in resting conditions. We aimed investigating the frequency of elevated lactate at rest in ME/CFS patients, and comparing characteristics of ME/CFS patients with and without elevated lactate. Patients fulfilling international consensus criteria for ME/CFS who attended the internal medicine department of University hospital Angers-France between October 2011 and December 2017 were included retrospectively. All patients were systematically hospitalised for an aetiological workup and overall assessment. We reviewed their medical records for data related to the assessment: clinical characteristics, comorbidities, fatigue features, post-exertional malaise (PEM) severity, and results of 8 lactate measurements at rest. Patients having ≥1 lactate measurement ≥2 mmol/L defined elevated lactate group. The study included 123 patients. Elevated (n = 55; 44.7%) and normal (n = 68; 55.3%) lactate groups were comparable except for PEM, which was more severe in the elevated lactate group after adjusting for age at disease onset, sex, and comorbidities (OR 2.47, 95% CI: 1.10–5.55). ME/CFS patients with elevated blood lactate at rest may be at higher risk for more severe PEM. This finding may be of interest in ME/CFS management.
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December 27, 2019
Comparison of Lemborexant With Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults With Insomnia DisorderA Phase 3 Randomized Clinical Trial
Russell Rosenberg, PhD1; Patricia Murphy, PhD2,3; Gary Zammit, PhD4; et alDavid Mayleben, PhD5; Dinesh Kumar, PhD3; Shobha Dhadda, PhD3; Gleb Filippov, MD, PhD3; Antonia LoPresti, MD3; Margaret Moline, PhD3
JAMA Netw Open. 2019;2(12):e1918254. doi:10.1001/jamanetworkopen.2019.18254
Key Points
Question Does lemborexant therapy effectively treat insomnia disorder in patients 55 years and older compared with placebo and zolpidem tartrate extended release therapy?
Findings In this randomized double-blind clinical trial of 1006 participants 55 years and older with insomnia disorder, lemborexant therapy significantly improved both latency to persistent sleep and sleep maintenance (wake-after-sleep onset and sleep efficiency) compared objectively via polysomnography with both placebo and zolpidem tartrate extended release therapy. Efficacy was also demonstrated on patient-reported end points of sleep onset, sleep efficiency, and wake-after-sleep onset for both doses of lemborexant compared with placebo.
Meaning Lemborexant therapy may provide an additional option for sleep onset and sleep maintenance difficulties in older patients with insomnia disorder.
Abstract
Importance Insomnia disorder is prevalent and associated with health risks in older adults; however, efficacy and safety issues with existing treatments create significant unmet needs in this patient population.
Objective To compare treatment with the orexin receptor antagonist lemborexant with placebo and zolpidem tartrate extended release in participants with insomnia disorder.
Design, Setting, and Participants The Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older With Insomnia Disorder (SUNRISE 1) clinical trial was a global randomized double-blind parallel-group placebo-controlled active-comparator phase 3 study conducted at 67 sites in North America and Europe from May 31, 2016, to January 30, 2018. Data analyses were conducted from January 31, 2018, to September 10, 2018. Participants were 55 years and older with insomnia disorder characterized by reported sleep maintenance difficulties and confirmed by sleep history, sleep diary, and polysomnography. Participants could have also had sleep onset difficulties.
Interventions Participants received placebo, zolpidem tartrate extended release (6.25 mg), or lemborexant (5 mg or 10 mg) for 1 month at bedtime.
Main Outcomes and Measures Paired polysomnograms were collected at baseline, the first 2 nights, and the last 2 nights of treatment. The primary end point was the change from baseline in latency to persistent sleep for lemborexant therapy vs placebo. Key secondary end points were changes from baseline in sleep efficiency and wake-after-sleep onset compared with placebo, and wake-after-sleep onset in the second half of the night compared with zolpidem therapy.
Results Among 1006 participants randomized (placebo, n = 208; zolpidem, n = 263; lemborexant 5 mg, n = 266; and lemborexant 10 mg, n = 269), 869 (86.4%) were women and the median age was 63 years (range, 55-88 years). Both doses of lemborexant therapy demonstrated statistically significant greater changes from baseline on objective sleep onset as assessed by latency to persistent sleep (log transformed) that was measured using polysomnography at the end of 1 month of treatment (nights 29 and 30) compared with placebo (primary end point for least squares geometric means treatment ratio vs placebo: for lemborexant 5 mg, 0.77; 95% CI, 0.67-0.89; P < .001; for lemborexant 10 mg, 0.72; 95% CI, 0.63-0.83; P < .001). For nights 29 and 30, as measured using polysomnography, the mean change from baseline in sleep efficiency (LSM treatment difference vs placebo for lemborexant 5 mg, 7.1%; 95% CI, 5.6%-8.5%; P < .001 and for lemborexant 10 mg, 8.0%; 95% CI, 6.6%-9.5%; P < .001) and wake-after-sleep onset (least squares mean treatment ratio vs placebo for lemborexant 5 mg, −24.0 min; 95% CI, −30.0 to −18.0 min; P < .001 and for lemborexant 10 mg, −25.4 min; 95% CI, −31.4 to −19.3 min; P < .001) were significantly greater for both doses of lemborexant therapy compared with placebo. Also, for nights 29 and 30, wake-after-sleep onset in the second half of the night (least squares mean treatment difference vs zolpidem for lemborexant 5 mg, −6.7 min; 95% CI, −11.2 to −2.2 min; P = .004 and for lemborexant 10 mg, −8.0 min; 95% CI, −12.5 to −3.5 min; P < .001) was significantly greater for both doses of lemborexant therapy compared with zolpidem therapy measured using polysomnography. Six participants (4 in the zolpidem group and 2 in the lemborexant 5 mg group) reported serious adverse events; none were treatment-related. Other adverse events were mostly mild or moderate in severity.
Conclusions and Relevance In this randomized clinical trial, lemborexant therapy significantly improved both sleep onset and sleep maintenance, including in the second half of the night, compared with both placebo and zolpidem measured objectively using polysomnography. Lemborexant therapy was well tolerated.
Trial Registrations ClinicalTrials.gov identifier: NCT02783729; EudraCT identifier: 2015-001463-39
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Transient receptor potential melastatin 2 channels are overexpressed in myalgic encephalomyelitis/chronic fatigue syndrome patients
Cassandra Balinas, Helene Cabanas, Donald Staines Sonya Marshall-Gradisnik
Journal of Translational Medicine volume 17, Article number: 401 (2019)
Abstract
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is hallmarked by a significant reduction in natural killer (NK) cell cytotoxicity, a mechanism tightly regulated by calcium (Ca2+). Interestingly, interleukin-2 (IL-2) increases NK cell cytotoxicity. Transient receptor potential melastatin 2 (TRPM2) ion channels are fundamental for Ca2+ signalling in NK cells. This pilot investigation aimed to characterise TRPM2 and CD38 surface expression in vitro on NK cells in ME/CFS patients. This investigation furthermore examined the pharmaceutical effect of 8-bromoadenosine phosphoribose (8-Br-ADPR) and N6-Benzoyladenosine-3′,5′-cyclic monophosphate (N6-Bnz-cAMP) on TRPM2 and CD38 surface expression and NK cell cytotoxicity between ME/CFS and healthy control (HC) participants.
Methods
Ten ME/CFS patients (43.45 ± 12.36) and 10 HCs (43 ± 12.27) were age and sex-matched. Isolated NK cells were labelled with fluorescent antibodies to determine baseline and drug-treated TRPM2 and CD38 surface expression on NK cell subsets. Following IL-2 stimulation, NK cell cytotoxicity was measured following 8-Br-ADPR and N6-Bnz-cAMP drug treatments by flow cytometry.
Results
Baseline TRPM2 and CD38 surface expression was significantly higher on NK cell subsets in ME/CFS patients compared with HCs. Post IL-2 stimulation, TRPM2 and CD38 surface expression solely decreased on the CD56DimCD16+ subset. 8-Br-ADPR treatment significantly reduced TRPM2 surface expression on the CD56BrightCD16Dim/− subset within the ME/CFS group. Baseline cell cytotoxicity was significantly reduced in ME/CFS patients, however no changes were observed post drug treatment in either group.
Conclusion
Overexpression of TRPM2 on NK cells may function as a compensatory mechanism to alert a dysregulation in Ca2+ homeostasis to enhance NK cell function in ME/CFS, such as NK cell cytotoxicity. As no improvement in NK cell cytotoxicity was observed within the ME/CFS group, an impairment in the TRPM2 ion channel may be present in ME/CFS patients, resulting in alterations in [Ca2+]i mobilisation and influx, which is fundamental in driving NK cell cytotoxicity. Differential expression of TRPM2 between NK cell subtypes may provide evidence for their role in the pathomechanism involving NK cell cytotoxicity activity in ME/CFS.
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Original Paper Published: 23 January 2020
The Prevalence of Pediatric Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in a Community-Based Sample
Child & Youth Care Forum (2020)Cite this article
Abstract
Background
Most pediatric prevalence studies of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have been based upon data from tertiary care centers, a process known for systematic biases such as excluding youth of lower socioeconomic status and those less likely to have access to health care. In addition, most pediatric ME/CFS epidemiologic studies have not included a thorough medical and psychiatric examination. The purpose of this study was to determine the prevalence of pediatric ME/CFS from an ethnically and sociodemographically diverse community-based random sample.
Method
A sample of 10,119 youth aged 5–17 from 5622 households in the Chicagoland area were screened. Following evaluations, a team of physicians made final diagnoses. Youth were given a diagnosis of ME/CFS if they met criteria for three selected case definitions. A probabilistic, multi-stage formula was used for final prevalence calculations.
Results
The prevalence of pediatric ME/CFS was 0.75%, with a higher percentage being African American and Latinx than Caucasian. Of the youth diagnosed with ME/CFS, less than 5% had been previously diagnosed with the illness.
Conclusions
Many youth with the illness have not been previously diagnosed with ME/CFS. These findings point to the need for better ways to identify and diagnose youth with this illness.
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Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids
by Arnaud Germain 1,Dinesh K. Barupal 2,Susan M. Levine 1 andMaureen R. Hanson 1,*
1
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
2
UC Davis Genome Center—Metabolomics, University of California, Davis, CA 95616, USA
*
Author to whom correspondence should be addressed.
Metabolites 2020, 10(1), 34; https://doi.org/10.3390/metabo10010034 (registering DOI)
Received: 20 December 2019 / Revised: 9 January 2020 / Accepted: 12 January 2020 / Published: 14 January 2020
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Abstract
The latest worldwide prevalence rate projects that over 65 million patients suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), an illness with known effects on the functioning of the immune and nervous systems. We performed an extensive metabolomics analysis on the plasma of 52 female subjects, equally sampled between controls and ME/CFS patients, which delivered data for about 1750 blood compounds spanning 20 super-pathways, subdivided into 113 sub-pathways. Statistical analysis combined with pathway enrichment analysis points to a few disrupted metabolic pathways containing many unexplored compounds. The most intriguing finding concerns acyl cholines, belonging to the fatty acid metabolism sub-pathway of lipids, for which all compounds are consistently reduced in two distinct ME/CFS patient cohorts. We compiled the extremely limited knowledge about these compounds and regard them as promising in the quest to explain many of the ME/CFS symptoms. Another class of lipids with far-reaching activity on virtually all organ systems are steroids; androgenic, progestin, and corticosteroids are broadly reduced in our patient cohort. We also report on lower dipeptides and elevated sphingolipids abundance in patients compared to controls. Disturbances in the metabolism of many of these molecules can be linked to the profound organ system symptoms endured by ME/CFS patients. View Full-Text
Keywords: ME/CFS; metabolomics; acyl cholines; steroids; dipeptides; lipids
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“Altered T cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)”
Principal Investigators: Liisa Selin (PhD), Anna Gil (PhD)
University of Massachusetts Medical School
Our understanding of the immunological defects present in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is severely lacking compared to other disorders, leading to a major barrier to research, diagnosis, and treatment. ME/CFS is a complex disorder affecting numerous organ systems and biological processes with studies focusing on changes in cytokines, metabolism, and identifying a potential causative infectious agent. In this pilot study, we propose to examine the role of a novel subset of immune cells, CD4+CD8+ T cells in the pathology of ME/CFS.
We recently discovered not only an increased frequency of this otherwise rare T cell in a group of ME/CFS patients we were studying, but also that they were highly activated producing unusual cytokines. We observed a difference in the activation profile of these cells in mild and severe cases of ME/CFS. In my long career of studying human T cell responses during viral infections I have never previously observed an increase in this cell type. We will examine the role they may play in the highly dysregulated immune response of ME/CFS patients. Much of the published data seems to suggest that ME/CFS may be preceded by infection, and the chronic manifestation of illness may represent an altered host response to infection, or an inability to resolve inflammation.
Based on our preliminary data, we will examine in a larger cohort, whether this unique subset of CD4+CD8+ T cells is increased in all ME/CFS donors, or does it only occur in a subgroup. We will also assess its role in mediating the disease by examining its frequency and alterations in its function in ME/CFS patients, manifesting either a mild or severe form of the disease as compared to healthy donors. Also, T cells have unique receptors (TCR) that they use to recognize foreign pathogens and eliminate them. Sometimes these TCR also inadvertently recognize self-proteins and lead to autoimmune diseases.
In our preliminary studies examining the TCR repertoire of the CD4+CD8+ population there was strong evidence they were expanded by recognizing an antigen. At this time, we do not know if this is a self or a pathogen antigen. We will therefore explore the TCR repertoire of this unique population of CD4+CD8+ T cells in order to find characteristics that will help us identify the potential antigen that is driving their expansion and activation. This would be a major step in the field potentially leading to the identification a specific infectious or autoimmune response that could be the main driver of the immunological basis of ME/CFS. Studying these unique cells (CD4+CD8+ T cells) in a larger population of ME/CFS patients has the potential to give us a biomarker (much needed for this disease) while giving us clues to the mechanisms driving the pathology of ME/CFS and thus therapy.
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Tick-Borne Encephalitis Virus, United Kingdom
Maya Holding; Stuart D. Dowall; Jolyon M. Medlock; Daniel P. Carter; Steven T. Pullan; James Lewis; Richard Vipond; Mara S. Rocchi; Matthew Baylis; Roger Hewson
Emerging Infectious Diseases. 2020;26(1):90-96.
Abstract
During February 2018–January 2019, we conducted large-scale surveillance for the presence and prevalence of tick-borne encephalitis virus (TBEV) and louping ill virus (LIV) in sentinel animals and ticks in the United Kingdom. Serum was collected from 1,309 deer culled across England and Scotland. Overall, 4% of samples were ELISA-positive for the TBEV serocomplex. A focus in the Thetford Forest area had the highest proportion (47.7%) of seropositive samples. Ticks collected from culled deer within seropositive regions were tested for viral RNA; 5 of 2,041 ticks tested positive by LIV/TBEV real-time reverse transcription PCR, all from within the Thetford Forest area. From 1 tick, we identified a full-length genomic sequence of TBEV. Thus, using deer as sentinels revealed a potential TBEV focus in the United Kingdom. This detection of TBEV genomic sequence in UK ticks has important public health implications, especially for undiagnosed encephalitis.
Introduction
The only tickborne flavivirus in the United Kingdom documented to cause disease in vertebrates is louping ill virus (LIV), a vivirus transmitted by the deer/sheep tick, Ixodes ricinus.[1] This tick species is the most abundant and widely distributed tick species in the United Kingdom and a known vector of Lyme borreliosis. LIV is most commonly detected in sheep, cattle, and red grouse and has been reported in Scotland, Wales, and England (primarily Cumbria, Devon, and North Yorkshire).[1] Humans are incidental hosts for LIV, and infection has been reported infrequently; ≈45 clinical cases have been linked to encephalitis during the past 85 years.[1,2] However, the short window of acute infection leads to uncertainty about whether suspected cases resulted from LIV infection or some other cause, although serologic analysis to analyze recent exposure through induction of IgM-specific responses, in combination with clinical symptoms, could inform a presumptive diagnosis. Human cases are mostly linked to occupational exposure, particularly in abattoir or farm workers and occasionally in laboratory staff.[2] Although the UK Animal and Plant Health Agency holds a database of confirmed diagnoses of LIV in livestock,[3,4] the distribution and regional prevalence of LIV has not been fully defined. Records of distribution and regional prevalence are based on voluntary submissions by farmers and veterinarians from symptomatic livestock,[1] from which private submissions are not integrated. Serologic analysis has been complicated; some animals received vaccination before its withdrawal.
Tick-borne encephalitis virus (TBEV) is a closely related flavivirus that, although known to be less virulent than LIV for sheep,[5] causes a neurologic disease (tick-borne encephalitis [TBE]) after transmission to humans by infected ticks, producing clinical disease in an estimated one third of TBEV infections.[6] TBE typically has a biphasic course starting with a prodromal phase with influenza-like symptoms, followed by a symptom-free interval before neurologic disease occurs; neurologic disease ranges from mild meningitis to severe encephalitis with or without myelitis and spinal paralysis.[7] Three classic subtypes of TBEV are recognized: European (TBEV-Eu), Siberian, and Far Eastern. Two additional TBEV subtypes have recently been proposed: Baikalian subtype and the Himalayan subtype.[8] TBEV-Eu is the prevailing subtype in Western Europe where it is primarily transmitted by I. ricinus ticks and is maintained within forest and meadow biotypes in endemic foci. In the United Kingdom, TBE is considered an imported disease; opportunities for the virus to become established principally are limited because the UK climate was not thought to support the specific conditions required for enzoonotic cycles to be established for TBEV to become endemic.[9] However, changes in climate have affected the emergence, distribution, and abundance of I. ricinus in the United Kingdom;[10] thus, the risk for tickborne disease has increased.[11] A recent study provided evidence that co-infestation of tick larvae and nymphs occurs in small mammals in UK woodland.[12] The increasing range of TBEV in Western Europe was underscored recently when the Netherlands reported its first human case in 2016.[13] Moreover, retrospective serologic screening of deer serum samples and molecular analysis of questing ticks found evidence of TBEV circulation in the Netherlands as far back as 2010 and 2015.[13,14] Given the increasing possibility that TBEV could be circulating in the United Kingdom, Public Health England developed a surveillance program focusing on wild animals and ticks.
In TBEV-endemic areas in continental Europe, the prevalence of TBEV in questing ticks is low, rarely exceeding 1% even in regions where the incidence of human infections is high.[15] Therefore, instead of screening ticks directly, we used sentinel animals first to identify serologic evidence of TBEV to highlight sites for focused tick testing by specific TBEV detection using real-time reverse transcription PCR (rRT-PCR). Deer are proven as reliable sentinels for identifying areas where TBEV is present[13,15] because they have a limited home range, are available in large numbers, and are broadly dispersed within the surveillance areas. They also show long-lasting antibody responses after natural exposure to flaviviruses.[15,16]
For our study, collectors retrieved blood samples from deer culled in England and Scotland during February 2018–January 2019; when available, they also collected tick samples. We tested the blood samples for TBEV or LIV antibodies and the ticks for the presence of viral RNA by rRT-PCR.
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Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations
Alexandra H. Mandarano, Jessica Maya, Ludovic Giloteaux, Daniel L. Peterson, Marco Maynard, C. Gunnar Gottschalk, and Maureen R. Hanson
First published December 12, 2019 – Journal of clinical investigation
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease with no known cause or mechanism. There is an increasing appreciation for the role of immune and metabolic dysfunction in the disease. ME/CFS has historically presented in outbreaks, often has a flu-like onset, and results in inflammatory symptoms. Patients suffer from severe fatigue and post-exertional malaise. There is little known about the metabolism of specific immune cells in ME/CFS patients. To investigate immune metabolism in ME/CFS, we isolated CD4+ and CD8+ T cells from 53 ME/CFS patients and 45 healthy controls. We analyzed glycolysis and mitochondrial respiration in resting and activated T cells, along with markers related to cellular metabolism, and plasma cytokines. We found that ME/CFS CD8+ T cells have reduced mitochondrial membrane potential compared to healthy controls. Both CD4+ and CD8+ T cells from ME/CFS patients had reduced glycolysis at rest, while CD8+ T cells also had reduced glycolysis following activation. ME/CFS patients had significant correlations between measures of T cell metabolism and plasma cytokine abundance that differed from healthy control subjects. Our data indicate that patients have impaired T cell metabolism consistent with ongoing immune alterations in ME/CFS that may illuminate the mechanism behind this disease.
Graphical Abstract
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Medicine. 98(43):e17600, OCTOBER 2019
DOI: 10.1097/MD.0000000000017600
,
PMID: 31651868
Issn Print: 0025-7974
Publication Date: October 2019
Evidence of altered cardiac autonomic regulation in myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review and meta-analysis
Maximillian Nelson;Jasvir Bahl;Jonathan Buckley;Rebecca Thomson;Kade Davison;
Abstract Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition with no reliable diagnostic biomarkers. Studies have shown evidence of autonomic dysfunction in patients with ME/CFS, but results have been equivocal. Heart rate (HR) parameters can reflect changes in autonomic function in healthy individuals; however, this has not been thoroughly evaluated in ME/CFS.
Methods: A systematic database search for case-control literature was performed. Meta-analysis was performed to determine differences in HR parameters between ME/CFS patients and controls.
Results: Sixty-four articles were included in the systematic review. HR parameters assessed in ME/CFS patients and controls were grouped into ten categories: resting HR (RHR), maximal HR (HRmax), HR during submaximal exercise, HR response to head-up tilt testing (HRtilt), resting HR variability (HRVrest), HR variability during head-up tilt testing (HRVtilt), orthostatic HR response (HROR), HR during mental task(s) (HRmentaltask), daily average HR (HRdailyaverage), and HR recovery (HRR) Meta-analysis revealed RHR (MD±95% CI=4.14±1.38, P
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Journal of Epidemiological Research:International Peer-Reviewed and Open Access Journal for the epidemiological specialists
Home > Vol 5, No 1 (2019) > Lin
Incidence rates of brain cancer following an outbreak of Chronic Fatigue Syndrome
Cheng-Te Major Lin, Naji Younes, Paul H. Levine
Abstract
Previous studies utilizing data from the Nevada Cancer Registry suggested a transient increase in non-Hodgkin’s lymphoma (NHL) and brain cancer in northern Nevada following an outbreak of Chronic Fatigue Syndrome (CFS) in that area which was not seen in southern Nevada which had no reported CFS outbreaks. A subsequent study from the National Cancer Institute (NCI) using data from the NCI’s Surveillance, Epidemiology and End Results (SEER) Program and Medicare documented the association between CFS and NHL on a national basis but no other cancer association was seen. Since brain cancer has a younger age distribution than NHL, we returned to the Nevada Cancer Registry and used ten more years of data and additional analyses to determine if there was an association between CFS and brain cancer by age. This study confirmed the increased incidence of brain cancer following the outbreak in northern Nevada but not southern Nevada with the increase limited to the under 65 age group, thus explaining why the SEER-Medicare analysis only analyzing data in the 65 and above age group did not detect this association.
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The physiological timeline of post exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
L Hodges T Nielsen D Cochrane D Baken
First published: 08 January 2020 – Translational Sports Medicine.
https://doi.org/10.1002/tsm2.133
Abstract
With fatigue being such a dominant feature, it is important to define the timeline and its impact following exertion in individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This study aimed to investigate the physiological effects of repeated graded maximal exercise testing at 48 and 72 hours, along with analysing the reported time to recover from repeated graded exercise tests (PEM). ME/CFS (n = 16), age and gender matched controls (n=16) were randomly assigned to either a 48‐hour or 72‐hour protocol. Each participant completed a maximal incremental cycle exercise test on day one and again at either 48‐hours (48‐h) or 72‐hours (72‐h) later. Physiological responses were analysed at peak work rate (PWR). There were significant differences in both peak VO2 and workload (p<0.05) in the 48‐h ME/CFS group compared to the 48‐h controls in both test 1 and test 2. Significant differences in peak VO2 and workload were only demonstrated in test 2 in participants in the ME/CFS 72‐h group. There was a small but insignificant decrease in both peak VO2 and workload in the ME/CFS group at 48‐h. Interestingly those in the 72‐h ME/CFS protocol demonstrated an increase in workload (10 Watts), despite no change in VO2peak. Subjective data demonstrated the 48‐hour ME/CFS group reported significantly longer time to recover.
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RESEARCH ARTICLE (Open Access)
Contents Vol 11(4)
A neuro-inflammatory model can explain the onset, symptoms and flare-ups of myalgic encephalomyelitis/chronic fatigue syndrome
Angus Mackay 1
Journal of Primary Health Care 11(4) 300-307 https://doi.org/10.1071/HC19041
Published: 29 November 2019
Journal Compilation © Royal New Zealand College of General Practitioners 2019 This is an open access article licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License
Abstract
A neuro-inflammatory model is proposed to explain the onset, symptoms and perpetuation of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) via characteristic flare-ups (relapses). In this article, I explore the proposition that a range of triggers (intense physiological stressors such as severe viral infections, chemical toxin exposure or emotional trauma) in ME/CFS-predisposed people causes disruption in the neural circuitry of the hypothalamus (paraventricular nucleus), which induces a neuro-inflammatory reaction in the brain and central nervous system of ME/CFS patients, via over-active innate immune (glial) cells. Resulting dysfunction of the limbic system, the hypothalamus and consequently of the autonomic nervous system can then account for the diverse range of ME/CFS symptoms. Ongoing stressors feed into a compromised (inflamed) hypothalamus and if a certain (but variable) threshold is exceeded, a flare-up will ensue, inducing further ongoing neuro-inflammation in the central nervous system, thus perpetuating the disease indefinitely.
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• Published: 06 January 2020
Systematic review of randomized controlled trials for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)
Journal of Translational Medicine volume 18, Article number: 7 (2020) Cite this article
Abstract
Background
Although medical requirements are urgent, no effective intervention has been proven for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). To facilitate the development of new therapeutics, we systematically reviewed the randomized controlled trials (RCTs) for CFS/ME to date.
Methods
RCTs targeting CFS/ME were surveyed using two electronic databases, PubMed and the Cochrane library, through April 2019. We included only RCTs that targeted fatigue-related symptoms, and we analyzed the data in terms of the characteristics of the participants, case definitions, primary measurements, and interventions with overall outcomes.
Results
Among 513 potentially relevant articles, 55 RCTs met our inclusion criteria; these included 25 RCTs of 22 different pharmacological interventions, 28 RCTs of 18 non-pharmacological interventions and 2 RCTs of combined interventions. These studies accounted for a total of 6316 participants (1568 males and 4748 females, 5859 adults and 457 adolescents). CDC 1994 (Fukuda) criteria were mostly used for case definitions (42 RCTs, 76.4%), and the primary measurement tools included the Checklist Individual Strength (CIS, 36.4%) and the 36-item Short Form health survey (SF-36, 30.9%). Eight interventions showed statistical significance: 3 pharmacological (Staphypan Berna, Poly(I):poly(C12U) and CoQ10 + NADH) and 5 non-pharmacological therapies (cognitive-behavior-therapy-related treatments, graded-exercise-related therapies, rehabilitation, acupuncture and abdominal tuina). However, there was no definitely effective intervention with coherence and reproducibility.
Conclusions
This systematic review integrates the comprehensive features of previous RCTs for CFS/ME and reflects on their limitations and perspectives in the process of developing new interventions.
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J of Translational medicine 2020 Jan 6;18(1):4. doi: 10.1186/s12967-019-02184-z.
Reduced heart rate variability predicts fatigue severity in individuals with chronic fatigue syndrome/myalgic encephalomyelitis.
Escorihuela RM1, Capdevila L2, Castro JR3, Zaragozà MC4, Maurel S5, Alegre J6, Castro-Marrero J7.
Abstract
BACKGROUND:
Heart rate variability (HRV) is an objective, non-invasive tool to assessing autonomic dysfunction in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). People with CFS/ME tend to have lower HRV; however, in the literature there are only a few previous studies (most of them inconclusive) on their association with illness-related complaints. To address this issue, we assessed the value of different diurnal HRV parameters as potential biomarker in CFS/ME and also investigated the relationship between these HRV indices and self-reported symptoms in individuals with CFS/ME.
METHODS:
In this case-control study, 45 female patients who met the 1994 CDC/Fukuda definition for CFS/ME and 25 age- and gender-matched healthy controls underwent HRV recording-resting state tests. The intervals between consecutive heartbeats (RR) were continuously recorded over three 5-min periods. Time- and frequency-domain analyses were applied to estimate HRV variables. Demographic and clinical features, and self-reported symptom measures were also recorded.
RESULTS:
CFS/ME patients showed significantly higher scores in all symptom questionnaires (p < 0.001), decreased RR intervals (p < 0.01), and decreased HRV time- and frequency-domain parameters (p < 0.005), except for the LF/HF ratio than in the healthy controls. Overall, the correlation analysis reached significant associations between the questionnaires scores and HRV time- and frequency-domain measurements (p < 0.05). Furthermore, separate linear regression analyses showed significant relationships between self-reported fatigue symptoms and mean RR (p = 0.005), RMSSD (p = 0.0268) and HFnu indices (p = 0.0067) in CFS/ME patients, but not in healthy controls.
CONCLUSIONS:
Our findings suggest that ANS dysfunction presenting as increased sympathetic hyperactivity may contribute to fatigue severity in individuals with ME/CFS. Further studies comparing short- and long-term HRV recording and self-reported outcome measures with previous studies in larger CFS/ME cohorts are urgently warranted.
PMID: 31906988
PMCID:PMC6943898
DOI:10.1186/s12967-019-02184-z
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Psychoneuroendocrinology – vol 113. March 2020, 104578
The role of low-grade inflammation in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) - associations with symptoms
Martin AJonsjöabfGunnar LOlssonabRikard WicksellcKjellAlvingdLindaHolmströmaeAnnaAndreassonfg
https://doi.org/10.1016/j.psyneuen.2019.104578Get rights and content
Highlights
Associations between inflammatory markers and common symptoms in ME/CFS.
Higher levels of markers were significantly associated with higher levels of symptoms.
Biological sex moderated several associations.
Abstract
Background
Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) often present with a range of flu-like symptoms resembling sickness behavior as well as widespread pain and concentration deficits. The aim of this study was to explore the association between inflammatory markers previously shown to be related to fatigue severity in ME/CFS and common ME/CFS symptoms post-exertional fatigue, impaired cognitive processing, musculoskeletal pain and recurrent flu-like symptoms, and the moderating effect of sex on these associations.
Methods
53 adult patients diagnosed with ME/CFS at a specialist clinic were included in the study. Fasting blood plasma was analyzed using the Olink Proseek Multiplex Inflammation panel (β-NGF, CCL11, CXCL1, CXCL10, IL-6, IL-7, IL-8, IL-10, IL-18, TGF-α, TGF-β-1 and SCF) and BioRad Human Cytokine Type 1 assay (TNF-α). Participants rated the average severity of symptoms (0–10) based on the 2011 International Consensus Criteria of ME/CFS during a structured clinical interview. Associations between inflammatory markers and symptom severity were analyzed using bivariate correlations and moderated regression analyses bootstrapped with 5000 repetitions.
Results and conclusions
Only β-NGF was associated with the fatigue severity measure. However, higher levels of CCL11, CXCL10, IL-7, TNF-α and TGF-β-1 were significantly associated with higher levels of impaired cognitive processing and musculoskeletal pain, and sex was a significant moderator for CXCL10, IL-7 and TGF-β-1. Future studies should investigate the relationship between inflammatory markers and key symptoms in ME/CFS in a longitudinal design in order to explore if and for whom low-grade inflammation may contribute to illness development.
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- Open Access Published: 22 January 2020
N. Eaton-Fitch, S. C. Johnston, P. Zalewski, D. Staines & S. Marshall-Gradisnik
Quality of Life Research (2020)
Abstract
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious and debilitating disorder associated with significant disruptions in daily life including. This study aimed to examine the impact of sociodemographic and patient symptom characteristics on health-related quality of life (HRQoL) of Australians with ME/CFS.
Methods
Self-reported data collected from 480 individuals diagnosed with ME/CFS were obtained between August 2014 and August 2018. This cross-sectional survey analysed sociodemographic, symptom characteristics and HRQoL according to the 36-Item Health Survey (SF-36). Multivariate linear regression models were used to determine ME/CFS symptoms associated with eight domains of HRQoL.
Results
Reported HRQoL was significantly impaired in ME/CFS patients across all domains compared with the general population. Scores were the lowest for physical role (4.11 ± 15.07) and energy/fatigue (13.54 ± 13.94). Associations with females, higher body mass index (BMI), employment status, cognitive difficulties, sensory disturbances and cardiovascular symptoms were observed in the physical functioning domain. Impaired pain domain scores were associated with high BMI, annual visits to their general practitioner, flu-like symptoms and fluctuations in body temperature. Reduced well-being scores were associated with smoking status, psychiatric comorbidity, cognitive difficulties, sleep disturbances and gastrointestinal difficulties.
Conclusion
This study provides evidence that ME/CFS has a profound and negative impact on HRQoL in an Australian cohort.
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