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Background and ObjectivesThe pathophysiology of chronic fatigue syndrome (CFS) and Q fever fatigue syndrome (QFS) remains elusive. Recent data suggest a role for neuroinflammation as defined by increased expression of translocator protein (TSPO). In the present study, we investigated whether there are signs of neuroinflammation in female patients with CFS and QFS compared with healthy women, using PET with the TSPO ligand 11C-(R)-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carbox-amide ([11C]-PK11195).MethodsThe study population consisted of patients with CFS (n = 9), patients with QFS (n = 10), and healthy subjects (HSs) (n = 9). All subjects were women, matched for age (±5 years) and neighborhood, aged between 18 and 59 years, who did not use any medication other than paracetamol or oral contraceptives, and were not vaccinated in the last 6 months. None of the subjects reported substance abuse in the past 3 months or reported signs of underlying psychiatric disease on the Mini-International Neuropsychiatric Interview. All subjects underwent a [11C]-PK11195 PET scan, and the [11C]-PK11195 binding potential (BPND) was calculated.ResultsNo statistically significant differences in BPND were found for patients with CFS or patients with QFS compared with HSs. BPND of [11C]-PK11195 correlated with symptom severity scores in patients with QFS, but a negative correlation was found in patients with CFS.DiscussionIn contrast to what was previously reported for CFS, we found no significant difference in BPND of [11C]-PK11195 when comparing patients with CFS or QFS with healthy neighborhood controls. In this small series, we were unable to find signs of neuroinflammation in patients with CFS and QFS.Trial Registration InformationEudraCT number 2014-004448-37.

Background The pathophysiology of chronic fatigue syndrome (CFS) and Q fever fatigue syndrome (QFS) remains elusive. Recent data suggest a role for neuroinflammation as defined by increased expression of translocator protein (TSPO). In the present study we investigated neuroinflammation in female CFS and QFS patients compared with healthy women, using Positron Emission Tomography (PET) with the TSPO ligand [11C]-PK11195. Methods The study population consisted of CFS patients (n = 9), QFS patients (n = 10), and healthy controls (n = 9). All subjects were women, matched for age (± 5 years) and neighbourhood, between 18 and 59 years of age, who did not use any medication other than paracetamol or oral contraceptives, and were not vaccinated in the last six months. None of the subjects reported substance abuse in the past 3 months or reported signs of underlying psychiatric disease on the Mini-International Neuropsychiatric Interview (MINI). All subjects underwent a [11C]-PK11195 PET scan and the [11C]-PK11195 binding potential (BPND) was calculated. Results No statistically significant differences in BPND were found for CFS patients or QFS patients when compared to healthy controls. BPND of [11C]-PK11195 positively correlated with symptom severity scores in QFS patients, but a negative correlation was found in CFS patients. Conclusions In contrast to what was previously reported for CFS, we found no significant difference in BPND of [11C]-PK11195 when comparing CFS or QFS patients to healthy neighbourhood controls. In this small series we were unable to find signs of neuroinflammation in patients with CFS and QFS. Trial registration EudraCT number: 2014-004448-37

Background Q fever fatigue syndrome (QFS) is characterised by a state of prolonged fatigue that is seen in 20% of acute Q fever infections and has major health-related consequences. The molecular mechanisms underlying QFS are largely unclear. In order to better understand its pathogenesis, we applied a multi-omics approach to study the patterns of the gut microbiome, blood metabolome, and inflammatory proteome of QFS patients, and compared these with those of chronic fatigue syndrome (CFS) patients and healthy controls (HC). Methods The study population consisted of 31 QFS patients, 50 CFS patients, and 72 HC. All subjects were matched for age, gender, and general geographical region (South-East part of the Netherlands). The gut microbiome composition was assessed by Metagenomic sequencing using the Illumina HiSeq platform. A total of 92 circulating inflammatory markers were measured using Proximity Extension Essay and 1607 metabolic features were assessed with a high-throughput non-targeted metabolomics approach. Results Inflammatory markers, including 4E-BP1 (P = 9.60–16 and 1.41–7) and MMP-1 (P = 7.09–9 and 3.51–9), are significantly more expressed in both QFS and CFS patients compared to HC. Blood metabolite profiles show significant differences when comparing QFS (319 metabolites) and CFS (441 metabolites) patients to HC, and are significantly enriched in pathways like sphingolipid (P = 0.0256 and 0.0033) metabolism. When comparing QFS to CFS patients, almost no significant differences in metabolome were found. Comparison of microbiome taxonomy of QFS and CFS patients with that of HC, shows both in- and decreases in abundancies in Bacteroidetes (with emphasis on Bacteroides and Alistiples spp.), and Firmicutes and Actinobacteria (with emphasis on Ruminococcus and Bifidobacterium spp.). When we compare QFS patients to CFS patients, there is a striking resemblance and hardly any significant differences in microbiome taxonomy are found. Conclusions We show that QFS and CFS patients are similar across three different omics layers and 4E-BP1 and MMP-1 have the potential to distinguish QFS and CFS patients from HC.

Background Q fever fatigue syndrome (QFS) is a well-documented state of prolonged fatigue following around 20% of acute Q fever infections. It has been hypothesized that low grade inflammation plays a role in its aetiology. In this study, we aimed to identify transcriptome profiles that could aid to better understand the pathophysiology of QFS. Methods RNA of monocytes was collected from QFS patients (n = 10), chronic fatigue syndrome patients (CFS, n = 10), Q fever seropositive controls (n = 10), and healthy controls (n = 10) who were age- (± 5 years) and sex-matched. Transcriptome analysis was performed using RNA sequencing. Results Mitochondrial-derived peptide (MDP)-coding genes MT-RNR2 (humanin) and MT-RNR1 (MOTS-c) were differentially expressed when comparing QFS (− 4.8 log2-fold-change P = 2.19 × 10−9 and − 4.9 log2-fold-change P = 4.69 × 10−8), CFS (− 5.2 log2-fold-change, P = 3.49 × 10−11 − 4.4 log2-fold-change, P = 2.71 × 10−9), and Q fever seropositive control (− 3.7 log2-fold-change P = 1.78 × 10−6 and − 3.2 log2-fold-change P = 1.12 × 10−5) groups with healthy controls, resulting in a decreased median production of humanin in QFS patients (371 pg/mL; Interquartile range, IQR, 325–384), CFS patients (364 pg/mL; IQR 316–387), and asymptomatic Q fever seropositive controls (354 pg/mL; 292–393). Conclusions Expression of MDP-coding genes MT-RNR1 (MOTS-c) and MT-RNR2 (humanin) is decreased in CFS, QFS, and, to a lesser extent, in Q fever seropositive controls, resulting in a decreased production of humanin. These novel peptides might indeed be important in the pathophysiology of both QFS and CFS. Electronic supplementary material The online version of this article (10.1186/s12967-019-1906-3) contains supplementary material, which is available to authorized users.

Summary Background Q fever fatigue syndrome (QFS) is a state of prolonged fatigue following around 20% of acute Q fever cases. It is thought that chronic inflammation plays a role in its etiology. To test this hypothesis we measured circulating cytokines and the ex-vivo cytokine production in patients with QFS and compared with various control groups. Materials/methods Peripheral blood mononuclear cells (PBMCs), whole blood, and serum were collected from 20 QFS patients, 19 chronic fatigue syndrome (CFS) patients, 19 Q fever seropositive controls, and 25 age- and sex-matched healthy controls. Coxiella-specific ex-vivo production of tumor necrosis factor (TNF)α, interleukin (IL)-1β, IL-6, and interferon (IFN) was measured, together with a total of 92 circulating inflammatory proteins. Results PBMCs of QFS patients produced more IL-6 (P = 0.0001), TNFα (P = 0.0002), and IL-1β (P = 0.0005) than the various control groups when stimulated with Coxiella antigen. QFS patients had distinct differences in circulating inflammatory markers compared to the other groups, including higher concentrations of circulating IL-6 and IFNγ. Conclusion QFS patients showed signs of chronic inflammation compared to asymptomatic Q fever seropositive controls, CFS patients, and healthy controls, of which the monocyte-derived cytokines TNFα, IL-1β, and especially IL-6, are likely crucial components.

BackgroundCytokine disturbances have been suggested to be associated with the Chronic Fatigue Syndrome/Myalgic encephalomyelitis (CFS/ME) for decades.MethodsFifty female CFS patients were included in a study on the effect of the interleukin-1-receptor antagonist anakinra or placebo during 4 weeks. EDTA plasma was collected from patients before and directly after treatment. At baseline, plasma samples were collected at the same time from 48 healthy, age-matched female neighborhood controls. A panel of 92 inflammatory markers was determined in parallel in 1 μL samples using a ‘proximity extension assay’ (PEA) based immunoassay. Since Transforming growth factor beta (TGF-β) and interleukin-1 receptor antagonist (IL-1Ra) were not included in this platform, these cytokines were measured with ELISA.ResultsIn CFS/ME patients, the ‘normalized protein expression’ value of IL-12p40 and CSF-1 was significantly higher (p value 0.0042 and 0.049, respectively). Furthermore, using LASSO regression, a combination of 47 markers yielded a prediction model with a corrected AUC of 0.73. After correction for multiple testing, anakinra had no effect on circulating cytokines. TGF-β did not differ between patients and controls.ConclusionsIn conclusion, this study demonstrated increased IL-12p40 and CSF-1 concentrations in CFS/ME patients in addition to a set of predictive biomarkers. There was no effect of anakinra on circulating cytokines other than IL-1Ra.Trial Registration: ClinicalTrials.gov Identifier:NCT02108210, Registered April 2014

Item does not contain fulltext BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is considered a diagnostic marker for chronic fatigue syndrome (CFS). OBJECTIVES: The aims of this study were to (i) compare POTS prevalence in a CFS cohort with fatigued patients not meeting CFS criteria, and (ii) assess activity, impairment and response to cognitive behavioural therapy (CBT) in CFS patients with POTS (POTS-CFS) and without POTS (non-POTS-CFS). METHODS: Prospective cohort study at the Radboud University Medical Centre in the Netherlands. Between June 2013 and December 2014, 863 consecutive patients with persistent fatigue were screened. Patients underwent an active standing test, filled out questionnaires and wore an activity-sensing device for a period of 12 days. RESULTS: A total of 419 patients with CFS and 341 non-CFS fatigued patients were included in the study. POTS prevalence in adult patients with CFS was 5.7% vs. 6.9% in non-CFS adults (P = 0.54). In adolescents, prevalence rates were 18.2% and 17.4%, respectively (P = 0.93). Adult patients with POTS-CFS were younger (30 +/- 12 vs. 40 +/- 13 years, P = 0.001) and had a higher supine heart rate (71 +/- 11 vs. 65 +/- 9 beats per min, P = 0.009) compared with non-POTS-CFS patients. Severity and activity patterns did not differ between groups. In patients with CFS, criteria for Systemic Exertion Intolerance Disease (SEID) were met in 76% of adults and 67% of adolescents. In these patients with CFS fulfilling the SEID criteria, the prevalence of POTS was not different from that in the overall CFS population. POTS-CFS adolescents had less clinically significant improvement after CBT than non-POTS-CFS adolescents (58% vs. 88%, P = 0.017). CONCLUSION: In adults with CFS, the prevalence of POTS was low, was not different from the rate in non-CFS fatigued patients and was not related to disease severity or treatment outcome. In POTS-CFS adolescents, CBT was less successful than in non-POTS-CFS patients. The evaluation of POTS appears to be of limited value for the diagnosis of CFS.

Chronic fatigue syndrome (CFS) is characterized by profound and disabling fatigue with no known somatic explanation. Cognitive behavioral therapy (CBT) has proven to be a successful intervention leading to a reduction in fatigue and disability. Based on previous neuroimaging findings, it has been suggested that central neural mechanisms may underlie CFS symptoms and play a role in the change brought on by CBT. In this randomized controlled trial we aim to further investigate the neural mechanisms that underlie fatigue in CFS and their change by CBT. We will conduct a randomized controlled trial in which we collect anatomical and functional magnetic resonance imaging (MRI) measures from female CFS patients before and after CBT (N = 60) or waiting list (N = 30) and compare these with measures from age and education matched healthy controls (N = 30). By including a large treatment group we will also be able to compare patients that benefit from CBT with those that do not. In addition, to further investigate the role of endocrine and immune biomarkers in CFS, we will determine cortisol and cytokine concentrations in blood, hair and/or saliva. This project creates an unique opportunity to enhance our understanding of CFS symptoms and its change by CBT in terms of neuroanatomical, neurofunctional, endocrinological and immunological mechanisms and can help to further improve future treatments strategies. Dutch Trial Register #15852. Registered 9 December 2013 ( http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4311 )

Contains fulltext : 152096.pdf (Publisher’s version ) (Open Access) BACKGROUND: Chronic fatigue syndrome (CFS) is a medically unexplained syndrome for which no somatic or pharmacological treatment has been proven effective. Dysfunction of the cytokine network has been suspected to play a role in the pathophysiology of CFS. The disturbances of the cytokine network detected in CFS patients are highly variable, in part due to the lack of adequate controls in many studies. Furthermore, all studies have been performed on peripheral venous blood of patients. As cytokines mainly act in tissues, for example, the brain, the information that can be derived from peripheral blood cells is limited. The information regarding the possible role of cytokines in the pathophysiology could come from intervention studies in which the activities of relevant cytokines are reduced, for example, reducing interleukin-1, interleukin-6 or tumor necrosis factor. In this study, the clinical usefulness of anakinra, an IL-1 antagonist, will be assessed in patients with CFS. METHODS/DESIGN: A randomized placebo-controlled, double-blind trial will be conducted. Fifty adult female patients meeting the Centers for Disease Control (CDC) criteria for CFS and without psychiatric co-morbidity will be included. After inclusion, patients will be randomized between treatment with anakinra (recombinant human interleukin-1 receptor antagonist) or placebo. Each group will be treated for 4 weeks. Outcome measures will be assessed at baseline, after 4 weeks of intervention, and 6 months after baseline assessment. The primary outcome measure will be fatigue severity at 4 weeks, measured with the validated Checklist of Individual Strength (CIS). Secondary outcome measures are functional impairment, physical and social functioning, psychological distress, pain severity, presence of accompanying symptoms, and cytokine and cortisol concentrations. DISCUSSION: This is the first randomized placebo-controlled trial that will evaluate the effect of interference with IL-1 on the experience of fatigue in patients with CFS. The results of this study may expand treatment options for patients with CFS, for whom graded exercise therapy and cognitive behavioral therapy are the only evidence-based interventions that exist at this moment. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02108210 . Clinicaltrials.gov registration date: 8 April 2014. EudraCT: 2013-005466-19.

Contains fulltext : 174722.pdf (Author’s version postprint ) (Closed access) Background: Interleukin-1 (IL-1), an important proinflammatory cytokine, is suspected to play a role in chronic fatigue syndrome (CFS). Objective: To evaluate the effect of subcutaneous anakinra versus placebo on fatigue severity in female patients with CFS. Design: Randomized, placebo-controlled trial from July 2014 to May 2016. Patients, providers, and researchers were blinded to treatment assignment. (ClinicalTrials.gov: NCT02108210). Setting: University hospital in the Netherlands. Patients: 50 women aged 18 to 59 years with CFS and severe fatigue leading to functional impairment. Intervention: Participants were randomly assigned to daily subcutaneous anakinra, 100 mg (n = 25), or placebo (n = 25) for 4 weeks and were followed for an additional 20 weeks after treatment (n = 50). Measurements: The primary outcome was fatigue severity, measured by the Checklist Individual Strength subscale (CIS-fatigue) at 4 weeks. Secondary outcomes were level of impairment, physical and social functioning, psychological distress, and pain severity at 4 and 24 weeks. Results: At 4 weeks, 8% (2 of 25) of anakinra recipients and 20% (5 of 25) of placebo recipients reached a fatigue level within the range reported by healthy persons. There were no clinically important or statistically significant differences between groups in CIS-fatigue score at 4 weeks (mean difference, 1.5 points [95% CI, -4.1 to 7.2 points]) or the end of follow-up. No statistically significant between-group differences were seen for any secondary outcome at 4 weeks or the end of follow-up. One patient in the anakinra group discontinued treatment because of an adverse event. Patients in the anakinra group had more injection site reactions (68% [17 of 25] vs. 4% [1 of 25]). Limitation: Small sample size and wide variability in symptom duration; inclusion was not limited to patients with postinfectious symptoms. Conclusion: Peripheral IL-1 inhibition using anakinra for 4 weeks does not result in a clinically significant reduction in fatigue severity in women with CFS and severe fatigue. Primary Funding Source: Interleukin Foundation and an independent donor who wishes to remain anonymous.

Naviaux et al. (1) report on a distinct metabolic signature present in patients who have myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) compared with healthy controls. Metabolic pathway analysis is a growing field of interest, and could offer relevant pathophysiological or diagnostic clues in complex illnesses such as CFS. However, reviewing the patient selection and statistical methods used, we have some concerns.

Few proven effective treatments exist for chronic fatigue syndrome (CFS). This randomized controlled trial evaluated the benefits and harms of anakinra, an interleukin-1–receptor antagonist, for wo...

Contains fulltext : 169723.pdf (Publisher’s version ) (Open Access) Fatigue is commonly reported in a variety of illnesses, and it has major impact on quality of life. Previously, it was thought that fatigue originates in the skeletal muscles, leading to cessation of activity. However, more recently, it has become clear that the brain is the central regulator of fatigue perception. It has been suggested that pro-inflammatory cytokines, especially interleukin-1 alpha (IL-1alpha) and interleukin-1 beta (IL-1beta), play a prominent role in the development of central fatigue, and several studies have been performed to elucidate the connection between inflammation and these central processes.In this narrative review, mechanisms of action of IL-1 are described, with special attention to its effect on the central nervous system. In addition, we present a summary of studies that (i) investigated the relationship between circulating IL-1alpha and IL-1beta and fatigue severity and/or (ii) evaluated the effect of inhibiting IL-1 on fatigue. We aim to improve the understanding of fatigue in both inflammatory and non-inflammatory illnesses, which could help develop strategies to treat fatigue more effectively.Reviewing the studies that have been performed, it appears that there is a limited value of measuring circulating IL-1. However, inhibiting IL-1 has a positive effect on severe fatigue in most studies that have been conducted.

The widespread introduction of highly active anti-retroviral therapy (HAART) has significantly reduced infectious complications in patients with human immunodeficiency virus (HIV) and improved overall survival. The use of HAART, however, has metabolic syndrome-like effects and increases the risk of (type 2) diabetes (DM).

Introduction Alzheimer’s disease is a debilitating condition, and the search for an effective treatment is ongoing. Inflammation, in reaction to amyloid deposition, is thought to accelerate cognitive decline. With tumor necrosis factor α being an important proinflammatory cytokine, a recent trial investigated the effect of the tumor necrosis factor α inhibitor etanercept after peripheral administration in patients with Alzheimer’s disease. Although there was no significant effect, others have claimed spectacular effects of etanercept after perispinal injection. In the present study, the central delivery of drugs with a large molecular weight was evaluated after injection in the cervical perispinal region in rats. If successful, this strategy might increase therapeutic options for patients with Alzheimer’s disease. Methods Nine male Sprague–Dawley rats were given injections of iodine-125–labeled cetuximab (146 kDa), etanercept (51 kDa), and anakinra (17 kDa). Each radioiodinated drug was injected in the perispinal region in two rats and into the dorsal tail vein in one rat. Directly after injection, the rats were placed in a head-down position for 3 minutes to direct blood flow into the valveless vertebral venous system. A single-positron emission computed tomography scan was acquired starting 5 minutes after injection, subsequently the rats were euthanized and bio-distribution was determined. Results Intracranial delivery of the radiolabeled drugs could not be visualized in all but one of the rats. Injected drugs accumulated locally in the perispinal region. Conclusions In this study, no evidence could be found for the delivery of drugs to the central nervous system after perispinal injection. Additional research is needed before this treatment can be used in patients with Alzheimer’s disease.