A systematic review and meta-analysis
Nelson, Maximillian J. PhDa,∗; Bahl, Jasvir S. BAppScia; Buckley, Jonathan D. PhDa; Thomson, Rebecca L. PhDa,b; Davison, Kade PhDa
Section Editor(s): NA.,
Medicine: October 2019 - Volume 98 - Issue 43 - p e17600
Research Article: Systematic Review and Meta-Analysis
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 < .001), HRtilt (SMD ± 95% CI = 0.92 ± 0.24, P < .001), HROR (0.50 ± 0.27, P < .001), and the ratio of low frequency power to high frequency power of HRVrest (0.39 ± 0.22, P < .001) were higher in ME/CFS patients compared to controls, while HRmax (MD ± 95% CI = –13.81 ± 4.15, P < .001), HR at anaerobic threshold (SMD ± 95% CI = –0.44 ± 0.30, P = 0.005) and the high frequency portion of HRVrest (–0.34 ± 0.22, P = .002) were lower in ME/CFS patients.
Conclusions: The differences in HR parameters identified by the meta-analysis indicate that ME/CFS patients have altered autonomic cardiac regulation when compared to healthy controls. These alterations in HR parameters may be symptomatic of the condition.
Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome
Authors: Ludovic Giloteaux, L., Goodrich, J.K., Walters, W.A., Levine, S.M., Ley, R.E., & Hanson, M.R.
Gastrointestinal disturbance is a common symptom of ME/CFS. This study examined the gut microbiota of ME/CFS patients and healthy controls.
These researchers found that ME/CFS patients have less biodiversity of gut microbiota compared with healthy controls. In addition, ME/CFS patients were more likely to have higher gut bacteria species which are reported as pro-inflammatory and less of those that are anti-inflammatory. There were also elevated levels of blood markers for microbial translocation (meaning that gut bacteria are found outside the gut) for ME/CFS patients than for healthy controls.
In summary, the results indicate imbalance or maladaptation of the gut microbiota in ME/CFS patients and an increased incidence of microbial translocation which may play a role in inflammatory symptoms of the illness.
A systematic review of cytokines in chronic fatigue syndrome/myalgic encephalomyelitis/systemic exertion intolerance disease (CFS/ME/SEID)
Authors: Corbitt, M., Eaton-Fitch, N., Staines, D., Cabanas, H., & Marshall-Gradisnik, S.
This literature review looked at whether there was a significant difference in cytokine levels between ME/CFS patients and healthy controls. The review examined 15 studies which met the criteria for further analysis.
Across the 15 studies, 64 cytokines were analysed. Despite moderate quality studies, results were inconclusive as to whether cytokines play a definitive role in ME/CFS other than “evidence of a concurrent inflammatory process.”
The review also identified several limitations in these studies, including that most of the studies analyses used the Fukuda criteria, which is very broad, and means that characteristics of the patient samples are likely to differ between studies.
The authors concluded that cytokines are unlikely to be useful as biomarkers for ME/CFS, and that more research is needed towards a diagnostic test and treatment for ME/CFS.
Epstein-Barr virus (EBV) reactivation and therapeutic inhibitors
Jonathan R Kerr
Journal of Clinical pathology – Vol 72, Issue 10
Epstein-Barr virus (EBV) is a ubiquitous human virus which infects almost all humans during their lifetime and following the acute phase, persists for the remainder of the life of the individual. EBV infects B lymphocytes leading to their immortalisation, with persistence of the EBV genome as an episome. In the latent phase, EBV is prevented from reactivating through efficient cytotoxic cellular immunity. EBV reactivates (lytic phase) under conditions of psychological stress with consequent weakening of cellular immunity, and EBV reactivation has been shown to occur in a subset of individuals with each of a variety of cancers, autoimmune diseases, the autoimmune-like disease, chronic fatigue syndrome/myalgic encephalitis and under other circumstances such as being an inpatient in an intensive care unit. Chronic EBV reactivation is an important mechanism in the pathogenesis of many such diseases, yet is rarely tested for in immunocompetent individuals. This review summarises the pathogenesis of EBV infection, EBV reactivation and its role in disease, and methods which may be used to detect it. Known inhibitors of EBV reactivation and replication are discussed, including drugs licensed for treatment of other herpesviruses, licensed or experimental drugs for various other indications, compounds at an early stage of drug development and nutritional constituents such as vitamins and dietary supplements.
Antibodies to Human Herpesviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients
Authors: Jonas Blomberg, Muhammad Rizwan, Agnes Böhlin-Wiener, Amal Elfaitouri, Per Julin, Olof Zachrisson, Anders Rosén and Carl-Gerhard Gottfries
Institution: Section of Clinical Microbiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
Myalgic encephalomyelitis, also referred to as chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by myalgia and a sometimes severe limitation of physical activity and cognition. It is exacerbated by physical and mental activity. Its cause is unknown, but frequently starts with an infection. The eliciting infection (commonly infectious mononucleosis or an upper respiratory infection) can be more or less well diagnosed. Among the human herpesviruses (HHV-1-8), HHV-4 (Epstein-Barr virus; EBV), HHV-6 (including HHV-6A and HHV-6B), and HHV-7, have been implicated in the pathogenesis of ME/CFS. It was therefore logical to search for serological evidence of past herpesvirus infection/reactivation in several cohorts of ME/CFS patients (all diagnosed using the Canada criteria). Control samples were from Swedish blood donors. We used whole purified virus, recombinant proteins, and synthetic peptides as antigens in a suspension multiplex immunoassay (SMIA) for immunoglobulin G (IgG). The study on herpesviral peptides based on antigenicity with human sera yielded novel epitope information. Overall, IgG anti-herpes-viral reactivities of ME/CFS patients and controls did not show significant differences. However, the high precision and internally controlled format allowed us to observe minor relative differences between antibody reactivities of some herpesviral antigens in ME/CFS versus controls. ME/CFS samples reacted somewhat differently from controls with whole virus HHV-1 antigens and recombinant EBV EBNA6 and EA antigens. We conclude that ME/CFS samples had similar levels of IgG reactivity as blood donor samples with HHV-1-7 antigens. The subtle serological differences should not be over-interpreted, but they may indicate that the immune system of some ME/CFS patients interact with the ubiquitous herpesviruses in a way different from that of healthy controls.
Publication: Blomberg et al., Frontiers in Immunology, 2019 August 14; 10:1946
Comment by ME Research UK: Published recently in Frontiers in Immunology is a new study – funded partly by ME Research UK – from the late Prof. Jonas Blomberg in Sweden. The researchers looked for evidence of past infection with, or reactivation of, the human herpesviruses HHV-4 (also known as Epstein–Barr virus), HHV-6 and HHV-7, which have been implicated in the pathogenesis of ME/CFS. Immunoglobulin G reactivity levels to these viruses were similar in serum samples from patients and control subjects, indicating that none of these herpesviruses are more common or intense in ME/CFS patients than in the rest of the population. However, the researchers did find subtle differences in antibody reactivities to whole virus HHV-1 antigens and some recombinant HHV-4 antigens in ME/CFS samples, suggesting that the immune system of patients may interact
Physiol.Rep 2019 Jun; 7(11): e14138.Published online 2019 Jun 3. doi: 10.14814/phy2.14138
PMCID: PMC6546966 PMID: 31161646
Abnormal blood lactate accumulation during repeated exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome
Katarina Lien, 1 , 2 Bjørn Johansen, 3 Marit B. Veierød, 4 Annicke S. Haslestad, 1 Siv K. Bøhn, 1 Morten N. Melsom, 5 Kristin R. Kardel, 1 and Per O. Iversen 1 , 6
Author information Article notes Copyright and License information Disclaimer
Post‐exertional malaise and delayed recovery are hallmark symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Studies on repeated cardiopulmonary exercise testing (CPET) show that previous exercise negatively affects oxygen uptake (VO 2) and power output (PO) in ME/CFS. Whether this affects arterial lactate concentrations ([Laa]) is unknown. We studied 18 female patients (18–50 years) fulfilling the Canadian Consensus Criteria for ME/CFS and 15 healthy females (18–50 years) who underwent repeated CPETs 24 h apart (CPET 1 and CPET 2) with [Laa] measured every 30th second. VO 2 at peak exercise (VO 2peak) was lower in patients than in controls on CPET 1 (P < 0.001) and decreased in patients on CPET 2 (P < 0.001). However, the difference in VO 2peak between CPETs did not differ significantly between groups. [Laa] per PO was higher in patients during both CPETs (P interaction < 0.001), but increased in patients and decreased in controls from CPET 1 to CPET 2 (P interaction < 0.001). Patients had lower VO 2 (P = 0.02) and PO (P = 0.002) at the gas exchange threshold (GET, the point where CO 2 production increases relative to VO 2), but relative intensity (%VO 2peak) and [Laa] at GET did not differ significantly from controls on CPET 1. Patients had a reduction in VO 2 (P = 0.02) and PO (P = 0.01) at GET on CPET 2, but no significant differences in %VO 2peak and [Laa] at GET between CPETs. Controls had no significant differences in VO 2, PO or %VO 2peak at GET between CPETs, but [Laa] at GET was reduced on CPET 2 (P = 0.008). In conclusion, previous exercise deteriorates physical performance and increases [Laa] during exercise in patients with ME/CFS while it lowers [Laa] in healthy subjects.
Keywords: Elevated lactate, exercise intolerance, metabolism, oxygen uptake, post‐exertional malaise
Lyme disease: chronic illness is rare, say experts
BMJ 2019; 367 doi: https://doi.org/10.1136/bmj.l5975 (Published 10 October 2019)Cite this as: BMJ 2019;367:l5975
People who have had Lyme disease rarely develop chronic problems, experts have said, warning that those who seek treatment abroad believing their symptoms are a result of the infection may be putting themselves at risk.
There are around 1000 laboratory confirmed cases of Lyme disease in England and Wales annually, with an estimated 2000 more cases successfully treated in primary care without positive blood tests, said experts at a briefing on the disease at the Science Media Centre on 9 October.
Of these patients, fewer than one in 20 experience residual symptoms.
Effects of Smoking on Patients With Chronic Pain
A Propensity-weighted Analysis on the Collaborative Health Outcomes Information Registry
James S. Khan; Jennifer M. Hah; Sean C. Mackey
Abstract and Introduction
Tobacco smoking is associated with adverse health effects, and its relationship to pain is complex. The longitudinal effect of smoking on patients attending a tertiary pain management center is not well established. Using the Collaborative Health Outcomes Information Registry of patients attending the Stanford Pain Management Center from 2013 to 2017, we conducted a propensity-weighted analysis to determine independent effects of smoking on patients with chronic pain. We adjusted for covariates including age, sex, body mass index, depression and anxiety history, ethnicity, alcohol use, marital status, disability, and education. We compared smokers and nonsmokers on pain intensity, physical function, sleep, and psychological and mood variables using self-reported NIH PROMIS outcomes. We also conducted a linear mixed-model analysis to determine effect of smoking over time. A total of 12,368 patients completed the CHOIR questionnaire of which 8584 patients had complete data for propensity analysis. Smokers at time of pain consultation reported significantly worse pain intensities, pain interference, pain behaviors, physical functioning, fatigue, sleep-related impairment, sleep disturbance, anger, emotional support, depression, and anxiety symptoms than nonsmokers (all P < 0.001). In mixed-model analysis, smokers tended to have worse pain interference, fatigue, sleep-related impairment, anger, emotional support, and depression over time compared with nonsmokers. Patients with chronic pain who smoke have worse pain, functional, sleep, and psychological and mood outcomes compared with nonsmokers. Smoking also has prognostic importance for poor recovery and improvement over time. Further research is needed on tailored therapies to assist people with chronic pain who smoke and to determine an optimal strategy to facilitate smoking cessation.
Front. Immunol. | doi: 10.3389/fimmu.2019.02545
Naltrexone restores impaired transient receptor potential melastatin 3 ion channel function in natural killer cells from myalgic encephalomyelitis/chronic fatigue syndrome patients
Helene Cabanas1, 2, 3, 4*, Katsuhiko Muraki4, 5, Donald Staines1, 2, 3, 4 and Sonya Marshall-Gradisnik1, 2, 3, 4
- 1School of Medical Sciences, Griffith Health, Griffith University, Australia
- 2National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute, Griffith University, Australia
- 3Menzies Health Institute, Griffith University, Australia
- 4National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Independent researcher, Australia
- 5School of Pharmacy, Aichi Gakuin University, Japan
Whole-cell patch-clamp technique was used to measure TRPM3 activity in Interleukin-2 (IL-2) stimulated and NTX-treated NK cells for 24 hours on sixteen age- and sex-matched healthy controls and CFS/ME patients, after modulation with pregnenolone sulfate (PregS), NTX and ononetin.
We confirmed impaired TRPM3 function in ME/CFS patients through electrophysiological investigations in Interleukin-2 (IL-2) stimulated NK cells after modulation with pregnenolone sulfate and ononetin. Importantly, TRPM3 channel activity was restored in IL-2 stimulated NK cells isolated from ME/CFS patients after incubation for 24 hours with NTX. Moreover, we demonstrated that NTX does not act as an agonist by directly coupling on the TRPM3 ion channel gating.
The opioid antagonist NTX has the potential to negate the inhibitory function of opioid receptors on TRPM3 in NK cells from CFS/ME patients, resulting in calcium signals remodelling, which will in turn affect cell functions, supporting the hypothesis that NTX may have potential for use as a treatment for CFS/ME. Our results demonstrate, for the first time, and based on novel patch clamp electrophysiology, potential pharmaco-therapeutic interventions in ME/CFS.
Keywords: Transient Receptor Potential Melastatin 3 (TRPM3), Naltrexone, Calcium, Opioid Receptor, Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, Natural killer cells (NK cells), Whole-cell patch clamp electrophysiology
Received: 07 Aug 2019; Accepted: 14 Oct 2019.
Exercise therapy for chronic fatigue syndrome – Cochrane amended review of the effectiveness of graded exercise therapy
Author: Larun, L., Brurberg, K.G., Odgaard‐Jensen, J., & Price, J.R.
Cochrane is an independent, international network of researchers, clinicians, patients, carers and others interested in health, which publishes systematic reviews of research into health interventions. Cochrane is very well-respected, and its reviews are highly influential.
The Cochrane review of exercise therapy for ME/CFS (Larun et al, 2017) has been the subject of a formal complaint about its science and methodology. This complaint led to an update of the review, which Cochrane has now published.
The updated review concludes that there is low-moderate certainty about the evidence that exercise therapy may alleviate some symptoms of ME/CFS, and recommends further research. The review acknowledges:
- The therapy’s long term effectiveness is uncertain due to a lack of follow-up in many studies.
- The risk of serious side effects and the effects of exercise therapy on pain, quality of life, and depression is uncertain, due either to lack of evidence or low quality evidence.
- Most studies are based on broader diagnostic criteria than are currently recommended for use and that “people diagnosed using other criteria may experience different effects.”
Importantly, Cochrane has committed to publish a full update of this review which will include the establishment of an independent advisory group which “will involve partners from patient-advocacy groups from different parts of the world”. Work will commence in 2020 and Emerge Australia has requested that they should be a part of this work.
Patients with Fibromyalgia and Chronic Fatigue Syndrome show increased hsCRP compared to healthy controls
Authors: Groven, N., Egil A.Fors, N.E, Reitanac, S.K,
ME/CFS and Fibromyalgia (FM) both have clinical aspects which resemble inflammatory disorders and, in both conditions, it is thought that the immune system may play a role. C-reactive protein (CRP) is a blood marker which measures inflammation. This study used a high-sensitivity CRP (hsCRP) test, which is more sensitive than standard CRP tests, to examine CRP levels in both conditions as compared to healthy controls.
Results showed hsCRP levels were significantly higher for both the ME/CFS and FM groups compared to healthy controls and there were no differences between the two patient groups.
Overall, the higher hsCRP levels suggest inflammation is present in ME/CFS and FM patients, which may contribute to symptoms as inflammation is a well-known cause for fatigue and pain. The researchers note that inflammation could be both a target for treatment, as well as a marker to monitor the effectiveness of treatment.
Editorial: Advances in ME/CFS Research and Clinical Care
Authors: Friedman, K.J., Bateman, K., Bested, A., & Nahle, Z.
This editorial provides an overview of a collection of 24 articles on ME/CFS published in the journals Frontiers in Neurology and Frontiers in Pediatrics. The collection, published between September 2018 and July 2019, sought to explore new and rejuvenated areas of ME/CFS research, as well as whether there have been improvements in clinical care.
The editorial summarises the advances in ME/CFS research and clinical care over the last few decades, outlining the current lack of diagnostic methods and effective treatment for the illness and highlights the historical misunderstandings which patients have had to endure.
However, despite setbacks, advances are being made through the determination and compassion of those working in the field. The collection includes:
- Three papers which evaluated potential clinical biomarkers such as hand grip strength, 2-day, cardiopulmonary exercise, and tilt table testing for diagnosing postural orthostatic tachycardia syndrome (POTS).
- Current research into ME/CFS patient pathology including microbiome, neuroinflammation and cytokines, cardiovascular symptoms, and the establishment of biobanks to identify additional tissue abnormalities.
- Research into how ME/CFS affects adolescents and what treatment and support benefitted them the most.
NeuroImage: Clinical Volume 24, 2019, 102045
Intra brainstem connectivity is impaired in chronic fatigue syndrome
Author links open overlay panelLeighton RBarndenaZack YShanabDonald RStainesaSonyaMarshall-GradisnikaKevinFinegancTimothyIrelandcSandeepBhutac
https://doi.org/10.1016/j.nicl.2019.102045Get rights and content
RAS connectivity was detected in HC and CFS groups both during rest and tasks
Strong connections were active for CFS from hippocampus to midbrain and medulla.
RAS connectivity was diminished in CFS in the brainstem and to the hippocampus.
RAS nuclei generate oscillatory signals which facilitate thalamocortical signal coherence.
Impaired RAS affects cortical coherence necessary for attention, memory and problem solving.
In myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), abnormal MRI correlations with symptom severity and autonomic measures have suggested impaired nerve signal conduction within the brainstem. Here we analyse fMRI correlations to directly test connectivity within and from the brainstem. Resting and task functional MRI (fMRI) were acquired for 45 ME/CFS (Fukuda criteria) and 27 healthy controls (HC). We selected limited brainstem reticular activation system (RAS) regions-of-interest (ROIs) based on previous structural MRI findings in a different ME/CFS cohort (bilateral rostral medulla and midbrain cuneiform nucleus), the dorsal Raphe nucleus, and two subcortical ROIs (hippocampus subiculum and thalamus intralaminar nucleus) reported to have rich brainstem connections. When HC and ME/CFS were analysed separately, significant correlations were detected for both groups during both rest and task, with stronger correlations during task than rest. In ME/CFS, connections were absent between medulla and midbrain nuclei, although hippocampal connections with these nuclei were enhanced. When corresponding correlations from HC and ME/CFS were compared, ME/CFS connectivity deficits were detected within the brainstem between the medulla and cuneiform nucleus and between the brainstem and hippocampus and intralaminar thalamus, but only during task. In CFS/ME, weaker connectivity between some RAS nuclei was associated with increased symptom severity. RAS neuron oscillatory signals facilitate coherence in thalamo-cortical oscillations. Brainstem RAS connectivity deficits can explain autonomic changes and diminish cortical oscillatory coherence which can impair attention, memory, cognitive function, sleep quality and muscle tone, all symptoms of ME/CFS.
Effect of tai chi versus aerobic exercise for fibromyalgia: comparative effectiveness randomized controlled trial
BMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k851 (Published 21 March 2018) Cite this as: BMJ 2018;360:k851
Objectives To determine the effectiveness of tai chi interventions compared with aerobic exercise, a current core standard treatment in patients with fibromyalgia, and to test whether the effectiveness of tai chi depends on its dosage or duration.
Design Prospective, randomized, 52 week, single blind comparative effectiveness trial.
Setting Urban tertiary care academic hospital in the United States between March 2012 and September 2016.
Participants 226 adults with fibromyalgia (as defined by the American College of Rheumatology 1990 and 2010 criteria) were included in the intention to treat analyses: 151 were assigned to one of four tai chi groups and 75 to an aerobic exercise group.
Interventions Participants were randomly assigned to either supervised aerobic exercise (24 weeks, twice weekly) or one of four classic Yang style supervised tai chi interventions (12 or 24 weeks, once or twice weekly). Participants were followed for 52 weeks. Adherence was rigorously encouraged in person and by telephone.
Main outcome measures The primary outcome was change in the revised fibromyalgia impact questionnaire (FIQR) scores at 24 weeks compared with baseline. Secondary outcomes included changes of scores in patient’s global assessment, anxiety, depression, self efficacy, coping strategies, physical functional performance, functional limitation, sleep, and health related quality of life.
Results FIQR scores improved in all five treatment groups, but the combined tai chi groups improved statistically significantly more than the aerobic exercise group in FIQR scores at 24 weeks (difference between groups=5.5 points, 95% confidence interval 0.6 to 10.4, P=0.03) and several secondary outcomes (patient’s global assessment=0.9 points, 0.3 to 1.4, P=0.005; anxiety=1.2 points, 0.3 to 2.1, P=0.006; self efficacy=1.0 points, 0.5 to 1.6, P=0.0004; and coping strategies, 2.6 points, 0.8 to 4.3, P=0.005). Tai chi treatment compared with aerobic exercise administered with the same intensity and duration (24 weeks, twice weekly) had greater benefit (between group difference in FIQR scores=16.2 points, 8.7 to 23.6, P<0.001). The groups who received tai chi for 24 weeks showed greater improvements than those who received it for 12 weeks
(difference in FIQR scores=9.6 points, 2.6 to 16.6, P=0.007). There was no significant increase in benefit for groups who received tai chi twice weekly compared with once weekly. Participants attended the tai chi training sessions more often than participants attended aerobic exercise. The effects of tai chi were consistent across all instructors. No serious adverse events related to the interventions were reported.
Conclusion Tai chi mind-body treatment results in similar or greater improvement in symptoms than aerobic exercise, the current most commonly prescribed non-drug treatment, for a variety of outcomes for patients with fibromyalgia. Longer duration of tai chi showed greater improvement. This mind-body approach may be considered a therapeutic option in the multidisciplinary management of fibromyalgia.
Trial registration ClinicalTrials.gov NCT01420640.
Clin Ther 2019 May;41(5):815-835.e6. doi: 10.1016/j.clinthera.2019.01.011. Epub 2019 Mar 6.
Treatment Avenues in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Split-gender Pharmacogenomic Study of Gene-expression Modules.
Jeffrey MG1, Nathanson L2, Aenlle K3, Barnes ZM4, Baig M5, Broderick G6, Klimas NG7, Fletcher MA3, Craddock TJA8.
Institute for Neuro-Immune Medicine, Nova Southeastern University, Ft. Lauderdale, FL, USA; College of Psychology, Nova Southeastern University, Ft. Lauderdale, FL, USA.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisymptom illness impacting up to 1 million people in the United States. As the pathogenesis and etiology of this complex condition are unclear, prospective treatments are limited. Identifying US Food and Drug Administration-approved drugs that may be repositioned as treatments for ME/CFS may offer a rapid and cost-effective solution.
Here we used gene-expression data from 33 patients with Fukuda-defined ME/CFS (23 females, 10 males) and 21 healthy demographically comparable controls (15 females, 6 males) to identify differential expression of predefined gene-module sets based on nonparametric statistics. Differentially expressed gene modules were then annotated via over-representation analysis using the Consensus Pathway database. Differentially expressed modules were then regressed onto measures of fatigue and cross-referenced with drug atlas and pharmacogenomics databases to identify putative treatment agents.
The top 1% of modules identified in males indicated small effect sizes in modules associated with immune regulation and mitochondrial dysfunction. In females, modules identified included those related to immune factors and cardiac/blood factors, returning effect sizes ranging from very small to intermediate (0.147 < Cohen δ < 0.532). Regression analysis indicated that B-cell receptors, T-cell receptors, tumor necrosis factor α, transforming growth factor β, and metabolic and cardiac modules were strongly correlated with multiple composite measures of fatigue. Cross-referencing identified genes with pharmacogenomics data indicated immunosuppressants as potential treatments of ME/CFS symptoms.
The findings from our analysis suggest that ME/CFS symptoms are perpetuated by immune dysregulation that may be approached via immune modulation-based treatment strategies.
Copyright © 2019. Published by Elsevier Inc.
Neurosci Biobehav Rev. 2019 Dec;107:69-83. doi: 10.1016/j.neubiorev.2019.08.011. Epub 2019 Aug 26.
Inflammatory proteins are altered in chronic fatigue syndrome-A systematic review and meta-analysis.
Strawbridge R1, Sartor ML2, Scott F2, Cleare AJ2.
Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK. Electronic address: Becci.firstname.lastname@example.org.
Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
Immune dysfunction has been posited as a key element in the aetiology of chronic fatigue syndrome (CFS) since the illness was first conceived. However, systematic reviews have yet to quantitatively synthesise inflammatory biomarkers across the literature. We undertook a systematic review and meta-analysis to quantify available data on circulating inflammatory proteins, examining studies recruiting patients with a CFS diagnosis and a non-affected control group. Results were meta-analysed from 42 studies. Patients with CFS had significantly elevated tumour necrosis factor (ES = 0.274, p < 0.001), interleukin-2 (ES = 0.203, p = 0.006), interleukin-4 (ES = 0.373, p = 0.004), transforming growth factor-β (ES = 0.967, p < 0.001) and c-reactive protein (ES = 0.622, p = 0.019). 12 proteins did not differ between groups. These data provide some support for an inflammatory component in CFS, although inconsistency of results indicates that inflammation is unlikely to be a primary feature in all those suffering from this disorder. It is hoped that further work will elucidate whether there are subgroups of patients with clinically-relevant inflammatory dysfunction, and whether inflammatory cytokines may provide a prognostic biomarker or moderate treatment effects.
Copyright © 2019 Elsevier Ltd. All rights reserved.
CFS; Chronic fatigue syndrome; Inflammation; ME/CFS; Meta-Analysis; Systematic review
BMC Neurology December 2019, 19:275
A logistic regression analysis of risk factors in ME/CFS pathogenesis
- Eliana M. LacerdaKeith Geraghty Caroline C. Kingdon Luigi Palla Luis Nacul
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease, whose exact cause remains unclear. A wide range of risk factors has been proposed that helps understanding potential disease pathogenesis. However, there is little consistency for many risk factor associations, thus we undertook an exploratory study of risk factors using data from the UK ME/CFS Biobank participants. We report on risk factor associations in ME/CFS compared with multiple sclerosis participants and healthy controls.
This was a cross-sectional study of 269 people with ME/CFS, including 214 with mild/moderate and 55 with severe symptoms, 74 people with multiple sclerosis (MS), and 134 healthy controls, who were recruited from primary and secondary health services. Data were collected from participants using a standardised written questionnaire. Data analyses consisted of univariate and multivariable regression analysis (by levels of proximity to disease onset).
A history of frequent colds (OR = 8.26, P <= 0.001) and infections (OR = 25.5, P = 0.015) before onset were the strongest factors associated with a higher risk of ME/CFS compared to healthy controls. Being single (OR = 4.41, P <= 0.001), having lower income (OR = 3.71, P <= 0.001), and a family history of anxiety is associated with a higher risk of ME/CFS compared to healthy controls only (OR = 3.77, P < 0.001). History of frequent colds (OR = 6.31, P < 0.001) and infections before disease onset (OR = 5.12, P = 0.005), being single (OR = 3.66, P = 0.003) and having lower income (OR = 3.48, P = 0.001), are associated with a higher risk of ME/CFS than MS. Severe ME/CFS cases were associated with lower age of ME/CFS onset (OR = 0.63, P = 0.022) and a family history of neurological illness (OR = 6.1, P = 0.001).
Notable differences in risk profiles were found between ME/CFS and healthy controls, ME/CFS and MS, and mild-moderate and severe ME/CFS. However, we found some commensurate overlap in risk associations between all cohorts. The most notable difference between ME/CFS and MS in our study is a history of recent infection prior to disease onset. Even recognising that our results are limited by the choice of factors we selected to investigate, our findings are consistent with the increasing body of evidence that has been published about the potential role of infections in the pathogenesis of ME/CFS, including common colds/flu.