Amit K Saha, Brendan R Schmidt, Julie Wilhelmy, Vy Nguyen, Justin Do, Vineeth C Suja, Mohsen Nemat-Gorgani, Anand K Ramasubramanian and Ronald W Davis
Blood 2018 132:4874; doi: https://doi.org/10.1182/blood-2018-99-117260
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is arguably the last major disease we know almost nothing about. It is a multi-systemic illness of unknown etiology affecting millions of individuals worldwide, with the capacity to persist for several years. ME/CFS is characterized by disabling fatigue of at least 6 months, accompanied serious fatigue and musculoskeletal pain, in addition to impaired short-term memory or concentration, and unrefreshing sleep or extended post-exertional. While the etiology of the disease is still debated, evidence suggest oxidative damage to immune and hematological systems as one of the pathophysiological mechanisms of the disease. Erythrocytes are potent scavengers of oxidative stress, and their shape changes appreciably in response to oxidative stress and certain inflammatory conditions including obesity and diabetes. The shape of erythrocytes change from biconcave discoid to an ellipsoid due shear flow in microcapillaries that provides a larger specific surface area-to-volume ratio for optimal microvascular perfusion and tissue oxygenation establishing the importance not only of total hematocrit but also of the capacity for large deformations in physiology. Clinically, ME/CFS patients show normal arterial oxygen saturation but nothing much is known about microvascular perfusion. In this work, we tested the hypothesis that the erythrocyte deformability in ME/CFS is adversely affected, using a combination of biophysical and biochemical techniques.
We tested the deformability of RBCs using a high-throughput microfluidic device which mimics blood flow through microcapillaries. We perfused RBCs (suspension in plasma) from ME/CFS patients and from age and sex matched healthy controls (n=9 pairs of donors) through a high-throughput microfluidic platform of 5µm width and 3-5 µm height. We recorded the movement of the cells at high speed (4000 fps), followed by image analysis to assess the following parameters: entry time (time required by the cells to completely enter the test channels), average transit velocity (velocity of the cells inside the test channels) and elongation index (ratio of the major diameter before and after deformation in the test channel). We observed that RBCs from ME/CFS patients had higher entry time (~12%, p<0.0001), lower average transit velocity (~17%, p<0.0001) and lower elongation index (~14%, p<0.0001) as compared to RBCs from healthy controls. Taken together, this data shows that RBCs from ME/CFS patients have reduced deformability. To corroborate our findings, we also measured the erythrocyte sedimentation rate (ESR) for these donors which show that the RBCs from ME/CFS patients had lower (~40%, p<0.01) sedimentation rates.
To understand the basis for differences in deformability, we investigated the changes in the fluidity of the membrane using a lateral diffusion assay using pyrenedecanoic acid (PDA), and observed that RBCs from ME/CFS patients have lower membrane fluidity (~30%, p<0.01). Apart from the fluidity, Zeta potential measurements showed that ME/CFS patients had lower net negative surface charge on the RBC plasma membrane (~18%, p<0.0001). Higher levels of reactive oxygen species (ROS) in RBCs from ME/CFS patients (~30%, p<0.008) were also observed, as compared to healthy controls. Using scanning electron microscopy (SEM), we also observed changes in RBC morphology between ME/CFS patients and healthy controls (presence of different morphological subclasses like biconcave disc, leptocyte, acanthocyte and burr cells; area and aspect ratio; levels of RBC aggregation). Despite these changes in RBC physiology, the hemoglobin levels remained comparable between healthy donors and ME/CFS patients. Finally, preliminary studies show that RBCs from recovering ME/CFS patients do not show such differences in cellular physiology, suggesting a connection between RBC deformability and disease severity.
Taken together, our data demonstrates that the significant decrease in deformability of RBCs from ME/CFS patients may have origins in oxidative stress, and suggests that altered microvascular perfusion can be a possible cause for ME/CFS symptoms. Our data also suggests that RBC deformability may serve as a potential biomarker for ME/CFS, albeit further studies are necessary for non-specific classification of the disease.
Sleep problems and fatigue as predictors for the onset of chronic widespread pain over a 5- and 18-year perspective
Katarina Aili, Maria Andersson, Ann Bremander, Emma Haglund’ Ingrid Larsson and Stefan Bergman
BMC Musculoskeletal Disorders201819:390 https://doi.org/10.1186/s12891-018-2310-5
Received: 16 March 2018 Accepted: 19 October 2018 Published: 3 November 2018
Abstract
Background
Previous research suggests that sleep problems may be an important predictor for chronic widespread pain (CWP). With this study we investigated both sleep problems and fatigue as predictors for the onset of CWP over a 5-year and an 18-year perspective in a population free from CWP at baseline.
Methods
To get a more stable classification of CWP, we used a wash-out period, including only individuals who had not reported CWP at baseline (1998) and three years prior baseline (1995). In all, data from 1249 individuals entered the analyses for the 5-year follow-up and 791 entered for the 18-year follow-up. Difficulties initiating sleep, maintaining sleep, early morning awakening, non-restorative sleep and fatigue were investigated as predictors separately and simultaneously in binary logistic regression analyses.
Results
The results showed that problems with initiating sleep, maintaining sleep, early awakening and non-restorative sleep predicted the onset of CWP over a 5-year (OR 1.85 to OR 2.27) and 18-year (OR 1.54 to OR 2.25) perspective irrespective of mental health (assessed by SF-36) at baseline. Also fatigue predicted the onset of CWP over the two-time perspectives (OR 3.70 and OR 2.36 respectively) when adjusting for mental health. Overall the effect of the sleep problems and fatigue on new onset CWP (over a 5-year perspective) was somewhat attenuated when adjusting for pain at baseline but remained significant for problems with early awakening, non-restorative sleep and fatigue. Problems with maintaining sleep predicted CWP 18 years later irrespective of mental health and number of pain regions (OR 1.72). Reporting simultaneous problems with all four aspects of sleep was associated with the onset of CWP over a five-year and 18-yearperspective, irrespective of age, gender, socio economy, mental health and pain at baseline. Sleep problems and fatigue predicted the onset of CWP five years later irrespective of each other.
Conclusion
Sleep problems and fatigue were both important predictors for the onset of CWP over a five-year perspective. Sleep problems was a stronger predictor in a longer time-perspective. The results highlight the importance of the assessment of sleep quality and fatigue in the clinic.
Neural mechanisms supporting the relationship between dispositional mindfulness and pain
Zeidan, Fadela,*; Salomons, Timb; Farris, Suzan R.a; Emerson, Nichole M.a; Adler-Neal, Adriennea; Jung, Youngkyooc; Coghill, Robert C.a,d
PAIN: December 2018 - Volume 159 - Issue 12 - p 2477–2485
doi: 10.1097/j.pain. 0000000000001344
Abstract
Interindividual differences in pain sensitivity vary as a function of interactions between sensory, cognitive–affective, and dispositional factors. Trait mindfulness, characterized as the innate capacity to nonreactively sustain attention to the present moment, is a psychological construct that is associated with lower clinical pain outcomes. Yet, the neural mechanisms supporting dispositional mindfulness are unknown. In an exploratory data analysis obtained during a study comparing mindfulness to placebo analgesia, we sought to determine whether dispositional mindfulness is associated with lower pain sensitivity. We also aimed to identify the brain mechanisms supporting the postulated inverse relationship between trait mindfulness and pain in response to noxious stimulation. We hypothesized that trait mindfulness would be associated with lower pain and greater deactivation of the default mode network. Seventy-six meditation-naive and healthy volunteers completed the Freiburg Mindfulness Inventory and were administered innocuous (35°C) and noxious stimulation (49°C) during perfusion-based functional magnetic resonance imaging. Higher Freiburg Mindfulness Inventory ratings were associated with lower pain intensity (P = 0.005) and pain unpleasantness ratings (P = 0.005). Whole brain analyses revealed that higher dispositional mindfulness was associated with greater deactivation of a brain region extending from the precuneus to posterior cingulate cortex during noxious heat. These novel findings demonstrate that mindful individuals feel less pain and evoke greater deactivation of brain regions supporting the engagement sensory, cognitive, and affective appraisals. We propose that mindfulness and the posterior cingulate cortex should be considered as important mechanistic targets for pain therapies.
Trait mindfulness, the innate capacity to nonreactively attend to the present moment, was associated with lower pain and brain mechanisms supporting self-referential processes.
aDepartment of Neurobiology and Anatomy, Wake Forest School of Medicine, Winston-Salem, NC, United States
bDepartment of Psychology, School of Psychology and Clinical Language Sciences, University of Reading, Reading, United Kingdom
cDepartment of Radiology, Wake Forest School of Medicine, Winston-Salem, NC, United States
dDepartment of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
Corresponding author. Address: Department of Neurobiology and Anatomy, Wake Forest School of Medicine, 1 Medical Center Boulevard, Winston-Salem, NC 27157, Unites States. Tel.: 336-716-4284; fax: 336-716-4534. E-mail address: [email protected] (F. Zeidan).
Received March 13, 2018 Received in revised form July 03, 2018 Accepted July 09, 2018
© 2018 International Association for the Study of Pain
Cell: 2018 Sep 6;174(6):1388-1405.e21. doi: 10.1016/j.cell.2018.08.041.
Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features.
Zmora N1, Zilberman-Schapira G2, Suez J2, Mor U2, Dori-Bachash M2, Bashiardes S2, Kotler E3, Zur M2, Regev-Lehavi D2, Brik RB2, Federici S2, Cohen Y2, Linevsky R2, Rothschild D3, Moor AE4, Ben-Moshe S4, Harmelin A5, Itzkovitz S4, Maharshak N6, Shibolet O6, Shapiro H2, Pevsner-Fischer M2, Sharon I7, Halpern Z8, Segal E9, Elinav E10.
Abstract
Empiric probiotics are commonly consumed by healthy individuals as means of life quality improvement and disease prevention. However, evidence of probiotic gut mucosal colonization efficacy remains sparse and controversial. We metagenomically characterized the murine and human mucosal-associated gastrointestinal microbiome and found it to only partially correlate with stool microbiome. A sequential invasive multi-omics measurement at baseline and during consumption of an 11-strain probiotic combination or placebo demonstrated that probiotics remain viable upon gastrointestinal passage. In colonized, but not germ-free mice, probiotics encountered a marked mucosal colonization resistance. In contrast, humans featured person-, region- and strain-specific mucosal colonization patterns, hallmarked by predictive baseline host and microbiome features, but indistinguishable by probiotics presence in stool. Consequently, probiotics induced a transient, individualized impact on mucosal community structure and gut transcriptome. Collectively, empiric probiotics supplementation may be limited in universally and persistently impacting the gut mucosa, meriting development of new personalized probiotic approaches.
PMID:30193112 DOI: 10.1016/j.cell.2018.08.041
Psychoneuroendocrinology: 2018 Dec 14. pii: S0306-4530(18)30196-3. doi: 10.1016/j.psyneuen.2018.11.032.
Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome.
Russell A1, Hepgul N2, Nikkheslat N3, Borsini A4, Zajkowska Z5, Moll N6, Forton D7, Agarwal K8, Chalder T9, Mondelli V10, Hotopf M11, Cleare A12, Murphy G13, Foster G14, Wong T15, Schütze GA16, Schwarz MJ17, Harrison N18, Zunszain PA19, Pariante CM20.
Abstract
The role of immune or infective triggers in the pathogenesis of Chronic Fatigue Syndrome (CFS) is not yet fully understood. Barriers to obtaining immune measures at baseline (i.e., before the trigger) in CFS and post-infective fatigue model cohorts have prevented the study of pre-existing immune dysfunction and subsequent immune changes in response to the trigger. This study presents interferon-alpha (IFN-α)-induced persistent fatigue as a model of CFS. IFN-α, which is used in the treatment of chronic Hepatitis C Virus (HCV) infection, induces a persistent fatigue in some individuals, which does not abate post-treatment, that is, once there is no longer immune activation. This model allows for the assessment of patients before and during exposure to the immune trigger, and afterwards when the original trigger is no longer present. Fifty-five patients undergoing IFN-α treatment for chronic HCV were assessed at baseline, during the 6-12 months of IFN-α treatment, and at six-months post-treatment. Measures of fatigue, cytokines and kynurenine pathway metabolites were obtained. Fifty-four CFS patients and 57 healthy volunteers completed the same measures at a one-off assessment, which were compared with post-treatment follow-up measures from the HCV patients. Eighteen patients undergoing IFN-α treatment (33%) were subsequently defined as having 'persistent fatigue' (the proposed model for CFS), if their levels of fatigue were higher six-months post-treatment than at baseline; the other 67% were considered 'resolved fatigue'. Patients who went on to develop persistent fatigue experienced a greater increase in fatigue symptoms over the first four weeks of IFN-α, compared with patients who did not (Δ Treatment Week (TW)-0 vs. TW4; PF: 7.1 ± 1.5 vs. RF: 4.0 ± 0.8, p = 0.046). Moreover, there was a trend towards increased baseline interleukin (IL)-6, and significantly higher baseline IL-10 levels, as well as higher levels of these cytokines in response to IFN-α treatment, alongside concurrent increases in fatigue. Levels increased to more than double those of the other patients by Treatment Week (TW)4 (p = 0.011 for IL-6 and p = 0.001 for IL-10). There was no evidence of an association between persistent fatigue and peripheral inflammation six-months post-treatment, nor did we observe peripheral inflammation in the CFS cohort. While there were changes in kynurenine metabolites in response to IFN-α, there was no association with persistent fatigue. CFS patients had lower levels of the ratio of kynurenine to tryptophan and 3-hydroxykynurenine than controls. Future studies are needed to elucidate the mechanisms behind the initial exaggerated response of the immune system in those who go on to experience persistent fatigue even if the immune trigger is no longer present, and the change from acute to chronic fatigue in the absence of continued peripheral immune activation.
KEYWORDS:
Chronic fatigue syndrome; Cytokines; Fatigue; Inflammation; Kynurenine; Tryptophan
PMID:30567628 DOI:10.1016/j.psyneuen.2018.11.032
Efficacy of Low-Dose Amitriptyline for Chronic Low Back Pain: A Randomized Clinical Trial.
JAMA Intern Med. 2018; 178(11):1474-1481 (ISSN: 2168-6114)
Urquhart DM; Wluka AE; van Tulder M; Heritier S; Forbes A; Fong C; Wang Y; Sim MR; Gibson SJ; Arnold C; Cicuttini FM
Importance: Antidepressants at low dose are commonly prescribed for the management of chronic low back pain and their use is recommended in international clinical guidelines. However, there is no evidence for their efficacy.
Objective: To examine the efficacy of a low-dose antidepressant compared with an active comparator in reducing pain, disability, and work absence and hindrance in individuals with chronic low back pain.
Design, Setting, and Participants: A double-blind, randomized clinical trial with a 6-month follow-up of adults with chronic, nonspecific, low back pain who were recruited through hospital/medical clinics and advertising was carried out.
Intervention: Low-dose amitriptyline (25 mg/d) or an active comparator (benztropine mesylate, 1 mg/d) for 6 months.
Main Outcomes and Measures: The primary outcome was pain intensity measured at 3 and 6 months using the visual analog scale and Descriptor Differential Scale. Secondary outcomes included disability assessed using the Roland Morris Disability Questionnaire and work absence and hindrance assessed using the Short Form Health and Labour Questionnaire.
Results: Of the 146 randomized participants (90 [61.6%] male; mean [SD] age, 54.8 [13.7] years), 118 (81%) completed 6-month follow-up. Treatment with low-dose amitriptyline did not result in greater pain reduction than the comparator at 6 (adjusted difference, -7.81; 95% CI, -15.7 to 0.10) or 3 months (adjusted difference, -1.05; 95% CI, -7.87 to 5.78), independent of baseline pain. There was no statistically significant difference in disability between the groups at 6 months (adjusted difference, -0.98; 95% CI, -2.42 to 0.46); however, there was a statistically significant improvement in disability for the low-dose amitriptyline group at 3 months (adjusted difference, -1.62; 95% CI, -2.88 to -0.36). There were no differences between the groups in work outcomes at 6 months (adjusted difference, absence: 1.51; 95% CI, 0.43-5.38; hindrance: 0.53; 95% CI, 0.19-1.51), or 3 months (adjusted difference, absence: 0.86; 95% CI, 0.32-2.31; hindrance: 0.78; 95% CI, 0.29-2.08), or in the number of participants who withdrew owing to adverse events (9 [12%] in each group; χ2 = 0.004; P = .95).
Conclusions and Relevance: This trial suggests that amitriptyline may be an effective treatment for chronic low back pain. There were no significant improvements in outcomes at 6 months, but there was a reduction in disability at 3 months, an improvement in pain intensity that was nonsignificant at 6 months, and minimal adverse events reported with a low-dose, modest sample size and active comparator. Although large-scale clinical trials that include dose escalation are needed, it may be worth considering low-dose amitriptyline if the only alternative is an opioid.
Trial Registration: anzctr.org.au Identifier: ACTRN12612000131853. PreMedline Identifier: 30285054
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Front. Pediatr., 08 January 2019 | https://doi.org/10.3389/fped.2018.00412
Estimating Prevalence, Demographics, and Costs of ME/CFS Using Large Scale Medical Claims Data and Machine Learning
Ashley R. Valdez1, Elizabeth E. Hancock1, Seyi Adebayo1, David J. Kiernicki1, Daniel Proskauer2, ohn R. Attewell3, Lucinda Bateman4, Alfred DeMaria Jr.5, Charles W. Lapp6, Peter C. Rowe7 and Charmian Proskauer8*
- 1Optum Enterprise Analytics, UnitedHealth Group, Minneapolis, MN, United States
- 2Optum Technology, UnitedHealth Group, Minneapolis, MN, United States
- 3Innovation, Research, and Development, UnitedHealth Group, Minneapolis, MN, United States
- 4Bateman Horne Center, Salt Lake City, UT, United States
- 5Bureau of Infectious Disease and Laboratory Sciences, Massachusetts Department of Public Health, Boston, MA, United States
- 6Hunter-Hopkins Center, Charlotte, NC, United States
- 7Children's Center Chronic Fatigue Clinic, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- 8Massachusetts ME/CFS & FM Association, Quincy, MA, United States
Metabolites 2018, 8(4), 90; https://doi.org/10.3390/metabo8040090
Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology
Arnaud Germain 1 David Ruppert 2, Susan M. Levine 1 and Maureen R. Hanson 1,*
1Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
2Department of Statistical Science and School of Operations Research and Information Engineering, Cornell University, Ithaca, NY 14853, USA
*
Received: 17 September 2018 / Revised: 30 November 2018 / Accepted: 4 December 2018 / Published: 6 December 2018
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease of enigmatic origin with no established cure. Its constellation of symptoms has silently ruined the lives of millions of people around the world. A plethora of hypotheses have been vainly investigated over the past few decades, so that the biological basis of this debilitating condition remains a mystery. In this study, we investigate whether there is a disturbance in homeostasis of metabolic networks in the plasma of a female 32-patient cohort compared to 19 healthy female controls. Extensive analysis of the 832-metabolite dataset generated by Metabolon®, covering eight biological classes, generated important insight into metabolic disruptions that occur in ME/CFS. We report on 14 metabolites with differences in abundance, allowing us to develop a theory of broad redox imbalance in ME/CFS patients, which is consistent with findings of prior work in the ME/CFS field. Moreover, exploration of enrichment analysis using www.MetaboAnalyst.ca provides information concerning similarities between metabolite disruptions in ME/CFS and those that occur in other diseases, while its biomarker analysis unit yielded prospective plasma biomarkers for ME/CFS. This work contributes key elements to the development of ME/CFS diagnostics, a crucial step required for discovering a therapy for any disease of unknown origin. View Full-Text
Keywords: ME/CFS; plasma; metabolomics; biomarkers; diagnostics
J Pain Res. 2018 Nov 21;11:2981-2990. doi: 10.2147/JPR.S169499. eCollection 2018.
A predictive algorithm to identify genes that discriminate individuals with fibromyalgia syndromediagnosis from healthy controls.
Lukkahatai N1, Walitt B2, Deandrés-Galiana EJ3, Fernández-Martínez JL3, Saligan LN2.
Abstract
OBJECTIVES:
Fibromyalgia syndrome (FMS) is a chronic and often debilitating condition that is characterized by persistent fatigue, pain, bowel abnormalities, and sleep disturbances. Currently, there are no definitive prognostic or diagnostic biomarkers for FMS. This study attempted to utilize a novel predictive algorithm to identify a group of genes whose differential expression discriminated individuals with FMS diagnosis from healthy controls.
METHODS:
Secondary analysis of gene expression data from 28 women with FMS and 19 age-and race-matched healthy women. Expression of discriminatory genes were identified using fold-change differential and Fisher's ratio (FR). Discriminatory accuracy of the differential expression of these genes was determined using leave-one-out-cross-validation. Functional networks of the discriminating geneswere described from the Ingenuity's Knowledge Base.
RESULTS:
The small-scale signature contained 57 genes whose expressions were highly discriminatory of the FMS diagnosis. The combination of these high discriminatory genes with FR higher than 1.45 provided a leave-one-out-cross-validation accuracy for the FMS diagnosis of 85.11%. The discriminatory genes were associated with 3 canonical pathways: hepatic stellate cell activation, oxidative phosphorylation, and airway pathology related to COPD.
CONCLUSION:
The discriminating genes, especially the 2 with the highest accuracy, are associated with mitochondrial function or oxidative phosphorylation and glutamate signaling. Further validation of the clinical utility of this finding is warranted.
KEYWORDS:
chronic pain; machine learning; medically unexplained symptoms; microarray
PMID:30538537 PMCID: PMC6255277 DOI:10.2147/JPR.S169499
Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy
Christina Mueller& Joanne C. Lin& Sulaiman Sheriff& Andrew A. Maudsley& Jarred W. Younger
Springer Science+Business Media, LLC, part of Springer Nature 2019
Brain Imaging and Behaviour https://doi.org/10.1007/s11682-018-0029-4
Abstract
Previous neuroimaging studies have detected markers of neuroin flammatio n in patients wit h Myalgi c Encephalo myelitis /Chronic Fatigue Syndrome (ME/CFS). Magnetic Resonance Spectroscopy (MRS) is suitable for measuring brain metabolites linked to inflamma tion, but has only been applied to discrete regions of interest in ME/CFS. We extended the MRS analysis of ME/CFS by capturing multi-voxel information across the entire brain. Additionally, we tested whether MRS-derived brain temperature is
elevated in ME/CFS patients. Fifteen women with ME/CFS and 15 age- and gender-matched healthy controls completed fatigue and mood symptom questionnaires and whole-brain echo-planar spectroscopic imagin g (EPSI). Choline (CHO), myo-inositol (MI), lactate (LAC), and N-acetylaspartate (NAA) were quantified in 47 regions, expressed as ratios over creatine (CR), an d compared
between ME/CFS patients and controls using independent-samples t-tests. Brain temperature was similarly tested between groups.
Significant between-group differences were detected in several regions, most notably elevated CHO/CR in the left anterior cingulate (p < 0.001). Metabolite ratios in seven regions were correlated with fatigue (p < 0.05). ME/CFS patients had increased temperature in the right insula, putamen, frontal cortex, thalamus, and the c erebellum (all p < 0.05), which was not attributable to increased body temperature or d iffe rences in cereb ral perfusion. Brain temperature increases converged with elevated LAC/CR in
the right insula, right thalamus, and cerebellum (all p < 0.05). We report metabolite and temperature abnormaliti es in ME/CFS patients in widely distributed regions. Our f indings may indicate that ME/CFS involves neuroinflammation.
Front. Pediatr., 15 February 2019 | https://doi.org/10.3389/fped.2019.00026
Impaired Health-Related Quality of Life in Adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Impact of Core Symptoms
Maria Roma, Colleen L. Marden, Marissa A. K. Flaherty, Samantha E. Jasion, Erica M. Cranston and Peter C. Rowe*
- Division of General Pediatrics and Adolescent Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
Study design: Cross-sectional study comparing individuals with ME/CFS referred to a tertiary care Chronic Fatigue clinic and HC. Eligible participants were age 10–30 years and met the Fukuda criteria for CFS. HC were eligible if they were age 10–30 years, with self-reported good, very good, or excellent general health. Pediatric HRQOL was measured using the PedsQL (Pediatric Quality of Life Inventory) and other validated instruments.
Results: We enrolled 55 consecutive ME/CFS patients (46 F) aged 10–23 years. From a pool of 69 potential HC we selected 55 with similar age and gender distribution for comparison. The total and subscale scores on the PedsQL and on all other measures of HRQOL indicated significantly worse function among those with ME/CFS (all P < 0.001). The self-reported frequency of post-exertional malaise (PEM) was significantly associated with the severity of impaired HRQOL (P < 0.001). Cognitive impairment had a weaker association with the PedsQL score (P = 0.02). Orthostatic intolerance was present in 96% of the ME/CFS population. Of the 55 who satisfied the Fukuda criteria, 47 (85%) also satisfied the IOM criteria for the diagnosis. Those meeting the IOM criteria had worse PedsQL total scores than those meeting just the Fukuda criteria (P < 0.001).
Conclusions: HRQOL was substantially lower in an ambulatory population of adolescents and young adults with ME/CFS than for healthy controls in North America, consistent with reports from other continents. HRQOL was also lower in ME/CFS than has been described in children with asthma, diabetes mellitus, epilepsy, eosinophilic gastroenteritis, and cystic fibrosis. The findings of this study lend further support to the inclusion of PEM, cognitive impairment, and orthostatic intolerance as core symptoms of pediatric ME/CFS.
Metabolites 2018, 8(4), 90; https://doi.org/10.3390/metabo8040090
Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology
Arnaud Germain 1,David Ruppert 2,Susan M. Levine 1 andMaureen R. Hanson 1,*
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
Department of Statistical Science and School of Operations Research and Information Engineering, Cornell University, Ithaca, NY 14853, USA
Received: 17 September 2018 / Revised: 30 November 2018 / Accepted: 4 December 2018 / Published: 6 December 2018
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease of enigmatic origin with no established cure. Its constellation of symptoms has silently ruined the lives of millions of people around the world. A plethora of hypotheses have been vainly investigated over the past few decades, so that the biological basis of this debilitating condition remains a mystery. In this study, we investigate whether there is a disturbance in homeostasis of metabolic networks in the plasma of a female 32-patient cohort compared to 19 healthy female controls. Extensive analysis of the 832-metabolite dataset generated by Metabolon®, covering eight biological classes, generated important insight into metabolic disruptions that occur in ME/CFS. We report on 14 metabolites with differences in abundance, allowing us to develop a theory of broad redox imbalance in ME/CFS patients, which is consistent with findings of prior work in the ME/CFS field. Moreover, exploration of enrichment analysis using www.MetaboAnalyst.ca provides information concerning similarities between metabolite disruptions in ME/CFS and those that occur in other diseases, while its biomarker analysis unit yielded prospective plasma biomarkers for ME/CFS. This work contributes key elements to the development of ME/CFS diagnostics, a crucial step required for discovering a therapy for any disease of unknown origin.
Keywords: ME/CFS; plasma; metabolomics; biomarkers; diagnostics
International Journal of Immunopathology and Pharmacology Volume 33: 1–8 © The Author(s) 2019 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/2058738418820402 journals.sagepub.com/home/iji
Changes in the transcriptome of circulating immune cells of a New Zealand cohort with myalgic encephalomyelitis/ chronic fatigue syndrome
Eiren Sweetman1, Margaret Ryan2, Christina Edgar1, Angus MacKay1, Rosamund Vallings3 and Warren Tate1
Abstract Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a poorly understood disease affecting 0.2%–2% of the global population. To gain insight into the pathophysiology of ME/CFS in New Zealand, we examined the transcriptomes of peripheral blood mononuclear cells by RNA-seq analysis in a small well-characterized patient group (10 patients), with age/gender-matched healthy controls (10 control subjects). Twenty-seven gene transcripts were increased 1.5- to sixfold and six decreased three- to sixfold in the patient group (P < 0.01). The top enhanced gene transcripts, IL8, NFΚBIA and TNFAIP3, are functionally related to inflammation, and significant changes were validated for IL8 and NFΚBIA by quantitative polymerase chain reaction (qPCR). Functional network analysis of the altered gene transcripts (P < 0.01) detected interactions between the products related to inflammation, circadian clock function, metabolic dysregulation, cellular stress responses and mitochondrial function. Ingenuity pathway analysis (P < 0.05) provided further insights into the dysfunctional physiology, highlighting stress and inflammation pathways. This analysis provides novel insights into the molecular changes in ME/CFS and contributes to the understanding of the pathophysiological mechanisms of the disease.
Journal of Epidemiological Research 2019, Vol. 5, No. 1 ORIGINAL ARTICLES
Incidence rates of brain cancer following an outbreak of Chronic Fatigue Syndrome
Cheng-Te Major Lin1, Naji Younes1, Paul H. Levine∗2,3 1Milken Institute School of Public Health, The George Washington University, Washington, United States 2College of Public Health, University of Nebraska, NE, United States 3The National Cancer Institute, National Institutes of Health, MD, United States
Received: May 14, 2018 Accepted: July 30, 2018 OnlinePublished: August 24, 2018 DOI:10.5430/jer.v5n1p1 URL:https://doi.org/10.5430/jer.v5n1p1
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. KeyWords: Chronic Fatigue Syndrome, Brain cancer, Incidence, Nevada
To test or not to test? Laboratory support for the diagnosis of Lyme borreliosis: a position paper of ESGBOR, the ESCMID study group for Lyme borreliosis
R.B. Dessau et alPlumX Metrics
DOI: https://doi.org/10.1016/j.cmi.2017.08.025
Published online: September 05, 2017Accepted: August 29, 2017Received in revised form: August 26, 2017Received: April 5, 2017
Figures
Abstract
Background
Lyme borreliosis (LB) is a tick-borne infection caused by Borrelia burgdorferi sensu lato. The most frequent clinical manifestations are erythema migrans and Lyme neuroborreliosis. Currently, a large volume of diagnostic testing for LB is reported, whereas the incidence of clinically relevant disease manifestations is low. This indicates overuse of diagnostic testing for LB with implications for patient care and cost-effective health management.
Aim
The recommendations provided in this review are intended to support both the clinical diagnosis and initiatives for a more rational use of laboratory testing in patients with clinically suspected LB.
Sources
This is a narrative review combining various aspects of the clinical and laboratory diagnosis with an educational purpose. The literature search was based on existing systematic reviews, national and international guidelines and supplemented with specific citations.
Implications
The main recommendations according to current European case definitions for LB are as follows. Typical erythema migrans should be diagnosed clinically and does not require laboratory testing. The diagnosis of Lyme neuroborreliosis requires laboratory investigation of the spinal fluid including intrathecal antibody production, and the remaining disease manifestations require testing for serum antibodies to B. burgdorferi. Testing individuals with non-specific subjective symptoms is not recommended, because of a low positive predictive value.
Keywords:
Antibody testing, Borrelia burgdorferi, Laboratory diagnosis, Lyme borreliosis, Polymerase chain reaction, Serology
∗Key references for suggested further reading are 1, 2, 14, 15, 16, 19 and 39.
© 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd.
Original Research ARTICLE Front. Pediatr., 21 February 2019 | https://doi.org/10.3389/fped.2019.00021
Long Term Follow up of Young People With Chronic Fatigue Syndrome Attending a Pediatric Outpatient Service
Katherine S. Rowe*
- Department of General Medicine, Royal Children's Hospital, Melbourne, VIC, Australia
Methods: A cohort observational study of 784 young people, mean age 14.6 (6–18) years, with ME/CFS diagnosed at a specialist pediatric hospital and receiving regular care, was conducted with follow-up for a mean 8 (range 1–21) years after onset. Baseline symptoms, history, depression and anxiety questionnaires were available from 418. The remaining 366, did not have similar standardized baseline information. Questionnaires requested functional rating, persistent symptoms, duration of illness if “recovered,” social engagement and school/work attendance. Feedback was sought regarding management, support services, useful information, helpful interventions or personnel and use of alternative therapies. Reported recovery and function were compared with baseline information and between the two groups.
Results: Follow-up data were returned from 81.8%. There was no significant difference in functional score (if reported recovery) or illness duration related to provision of baseline data. The mean duration of illness was 5 (range 1–15) years in the 50% who reported recovery. By 5 years 38% and by 10 years 68% reported recovery. At 10 years the mean functional score was 8/10 (range 2–10) with 5% scoring <6. Depression, anxiety or severity of illness at diagnosis was not predictive of non-recovery. Designing and monitoring their own management plan that included educational, social, physical and enjoyable activities, as well as having symptom management and understanding professionals were highly valued. However, remaining engaged in an education system that flexibly accommodated their illness and aspirations was consistently reported as crucial for long term functioning.
Conclusions: ME/CFS in young people has a mean duration of 5 years (1–15) with 68% reporting recovery by 10 years. All improved functionally with 5% remaining very unwell and a further 20% significantly unwell. There were no obvious baseline predictors for recovery. However, depression, anxiety, orthostatic intolerance and to a lesser extent pain at follow up were identified as hampering recovery or function. Supportive professionals, remaining engaged in education and management strategies were identified as helpful.
Front. Pediatr., 21 January 2019 | https://doi.org/10.3389/fped.2018.00435
The Importance of Accurate Diagnosis of ME/CFS in Children and Adolescents: A Commentary
Keith James Geraghty* and Charles Adeniji
- Division of Population Health, Health Services Research and Primary Care, Centre for Primary Care, University of Manchester, Manchester, United Kingdom
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic illness that causes a range of debilitating symptoms. While most research has focused on adults, the illness also presents in children and adolescents. Many physicians find it difficult to diagnose the illness. In this commentary paper, we discuss a range of salient themes that have emerged from our ongoing research into the prevalence of ME/CFS in children and adolescents. We discuss reasons why pediatric prevalence estimates vary widely in the literature, from almost 0% to as high as 3%. We argue that there is considerable misdiagnosis of pediatric cases and over-inflation of estimates of pediatric ME/CFS. Many children and teenagers with general fatigue and other medical complaints may meet loose diagnostic criteria for ME/CFS. We make recommendations for improving epidemiological research and identifying pediatric ME/CFS in clinical practice.
Introduction
Children and adolescents with suspected myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) regularly present with persistent fatigue, sleep disturbance, and an array of other symptoms, such as headaches and cognitive difficulties (1). ME/CFS is noted for being a major cause of long-term school absence and has profound negative ramifications for social development, educational achievement, and future employment (2, 3). The illness is associated with co-morbid anxiety and depression (4). It is known that children with chronic health problems exhibit higher rates of distress, anxiety, and depression (5). Taking these factors together, it is vital that young patients with this illness are correctly identified, so that they might receive a speedy diagnosis and appropriate medical care and social support.
Epidemiological studies report a wide range of prevalence estimates of ME/CFS in this age group. Some estimates are as low as 0.1% (6), while others suggest rates of 2.6% (7); and rates for CFS-like illness go as high as 4.4% (8). Girls are at greater risk of developing ME/CFS, particularly post-puberty (9). This wide spread in prevalence estimates appears to result from researchers using different diagnostic criteria to classify cases and applying different methods to sample and identify cases, such as postal or telephone questionnaires, community-based surveys, and clinical interviews. Given the general lack of consistency in methodologies applied, inconsistency in prevalence estimates is not surprising. However, such inconsistency suggests a problem with the methods used to identify young ME/CFS sufferers. It is clear, with estimates as low as 0.1% and as high as 3–4%, many young patients are being misdiagnosed, either under or over. Misdiagnosis in this vulnerable group has profound implications, since a false positive diagnosis may lead to inappropriate labeling of a child with ME/CFS and improper intervention with treatment (10), while under-diagnosis might mean a child or teen not receiving the care they require. If researchers are unable to reliably identify pediatric cases of ME/CFS, how confident can we be that clinicians are able to diagnose cases at the clinic level? We know doctors often find it difficult to diagnose ME/CFS and adult sufferers commonly wait an average of 5 years for a diagnosis (11).
Initiating Care of a Patient With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Charles W. Lapp*
- Hunter-Hopkins Center PLLC, Charlotte, NC, United States
The approach to any complex problem is to break it down into small steps, and ME/CFS is no exception. The first office visit should be devoted to a history of the present illness, a physical examination, and collection of exclusionary laboratory tests. On follow-up the differential diagnosis and a treatment plan can be addressed. Many individuals with ME/CFS have been humiliated or dismissed by other providers, so one will need to be as non-judgmental as possible and acknowledge that ME/CFS is not a psychological condition but a real illness. They need reassurance that you will work with them to seek a unifying diagnosis and prioritize management.
Metabolites 2018, 8(4), 90; doi:10.3390/metabo8040090
Article
Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology
Arnaud Germain 1,David Ruppert 2,Susan M. Levine 1 and Maureen R. Hanson 1,*
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
Department of Statistical Science and School of Operations Research and Information Engineering, Cornell University, Ithaca, NY 14853, USA
Received: 17 September 2018 / Accepted: 4 December 2018 / Published: 6 December 2018
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease of enigmatic origin with no established cure. Its constellation of symptoms has silently ruined the lives of millions of people around the world. A plethora of hypotheses have been vainly investigated over the past few decades, so that the biological basis of this debilitating condition remains a mystery. In this study, we investigate whether there is a disturbance in homeostasis of metabolic networks in the plasma of a female 32-patient cohort compared to 19 healthy female controls. Extensive analysis of the 832-metabolite dataset generated by Metabolon®, covering eight biological classes, generated important insight into metabolic disruptions that occur in ME/CFS. We report on 14 metabolites with differences in abundance, allowing us to develop a theory of broad redox imbalance in ME/CFS patients, which is consistent with findings of prior work in the ME/CFS field. Moreover, exploration of enrichment analysis using www.MetaboAnalyst.ca provides information concerning similarities between metabolite disruptions in ME/CFS and those that occur in other diseases, while its biomarker analysis unit yielded prospective plasma biomarkers for ME/CFS. This work contributes key elements to the development of ME/CFS diagnostics, a crucial step required for discovering a therapy for any disease of unknown origin.
Lyme Disease Emergence After Invasion of the Blacklegged Tick
Ixodes scapularis, Ontario, Canada, 2010-2016
Manisha A. Kulkarni; Isha Narula; Andreea M. Slatculescu; Curtis Russell
Emerging Infectious Diseases. 2019;25(2):328-332.
Abstract
Analysis of surveillance data for 2010–2016 in eastern Ontario, Canada, demonstrates the rapid northward spread of Ixodes scapularis ticks and Borrelia burgdorferi, followed by increasing human Lyme disease incidence. Most spread occurred during 2011–2013. Continued monitoring is essential to identify emerging risk areas in this region.
Introduction
Lyme disease (LD) is the most reported vectorborne disease in North America, where it is caused by Borrelia burgdorferi sensu stricto and principally transmitted by the blacklegged tick (Ixodes scapularis).[1] With northward expansion of I. scapularis tick populations from endemic areas in the United States, LD is rapidly emerging in parts of central and eastern Canada.[2–4] Although several studies have mapped blacklegged tick populations across Canada and developed models to predict future spread of ticks and LD risk,[2,3] little is known about the extent of human LD in relation to tick vector distributions at a fine geographic scale. We examined spatiotemporal trends in the occurrence and expansion of I. scapularis ticks, B. burgdorferi–infected ticks, and human LD cases over a 7-year period to elucidate the process of LD emergence in eastern Ontario, Canada.
Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods
Michael B. VanElzakker*, Sydney A. Brumfield and Paula S. Lara Mejia
- Division of Neurotherapeutics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
Front. Pediatr., 21 February 2019 | https://doi.org/10.3389/fped.2019.00021
Long Term Follow up of Young People With Chronic Fatigue Syndrome Attending a Pediatric Outpatient Service
Katherine S. Rowe*
- Department of General Medicine, Royal Children's Hospital, Melbourne, VIC, Australia
Methods: A cohort observational study of 784 young people, mean age 14.6 (6–18) years, with ME/CFS diagnosed at a specialist pediatric hospital and receiving regular care, was conducted with follow-up for a mean 8 (range 1–21) years after onset. Baseline symptoms, history, depression and anxiety questionnaires were available from 418. The remaining 366, did not have similar standardized baseline information. Questionnaires requested functional rating, persistent symptoms, duration of illness if “recovered,” social engagement and school/work attendance. Feedback was sought regarding management, support services, useful information, helpful interventions or personnel and use of alternative therapies. Reported recovery and function were compared with baseline information and between the two groups.
Results: Follow-up data were returned from 81.8%. There was no significant difference in functional score (if reported recovery) or illness duration related to provision of baseline data. The mean duration of illness was 5 (range 1–15) years in the 50% who reported recovery. By 5 years 38% and by 10 years 68% reported recovery. At 10 years the mean functional score was 8/10 (range 2–10) with 5% scoring <6. Depression, anxiety or severity of illness at diagnosis was not predictive of non-recovery. Designing and monitoring their own management plan that included educational, social, physical and enjoyable activities, as well as having symptom management and understanding professionals were highly valued. However, remaining engaged in an education system that flexibly accommodated their illness and aspirations was consistently reported as crucial for long term functioning.
Conclusions: ME/CFS in young people has a mean duration of 5 years (1–15) with 68% reporting recovery by 10 years. All improved functionally with 5% remaining very unwell and a further 20% significantly unwell. There were no obvious baseline predictors for recovery. However, depression, anxiety, orthostatic intolerance and to a lesser extent pain at follow up were identified as hampering recovery or function. Supportive professionals, remaining engaged in education and management strategies were identified as helpful.
Diagnostic sensitivity of 2-day cardiopulmonary exercise testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Maximillian J. Nelson, Jonathan D. Buckley, Rebecca L. Thomson, Daniel Clark, Richard Kwiatek and Kade Davison
Journal of Translational Medicine201917:80
https://doi.org/10.1186/s12967-019-1836-0
Published: 14 March 2019
Abstract
Background
There are no known objective biomarkers to assist with the diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A small number of studies have shown that ME/CFS patients exhibit an earlier onset of ventilatory threshold (VT) on the second of two cardiopulmonary exercise tests (CPET) performed on consecutive days. However, cut-off values which could be used to differentiate between ME/CFS patients have not been established.
Methods
16 ME/CFS patients and 10 healthy controls underwent CPET on a cycle-ergometer on 2-consecutive days. Heart rate (HR), ventilation, ratings of perceived exertion (RPE) and work rate (WR) were assessed on both days.
Results
WR at VT decreased from day 1 to day 2 and by a greater magnitude in ME/CFS patients (p < 0.01 group × time interaction). No interaction effects were found for any other parameters. ROC curve analysis of the percentage change in WR at VT revealed decreases of − 6.3% to − 9.8% provided optimal sensitivity and specificity respectively for distinguishing between patients with ME/CFS and controls.
Conclusion
The decrease in WR at VT of 6.3–9.8% on the 2nd day of consecutive-day CPET may represent an objective biomarker that can be used to assist with the diagnosis of ME/CFS.
Front. Endocrinol., 20 March 2018 | https://doi.org/10.3389/fendo.2018.00097
Higher Prevalence of “Low T3 Syndrome” in Patients With Chronic Fatigue Syndrome: A Case–Control Study
Begoña Ruiz-Núñez1,2*, Rabab Tarasse1, Emar F. Vogelaar3, D. A. Janneke Dijck-Brouwer1 and Frits A. J. Muskiet1
- 1Department of Laboratory Medicine, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands
- 2Healthy Institute, Madrid, Spain
- 3European Laboratory of Nutrients, Bunnik, Netherlands
ORIGINAL RESEARCH |2 APRIL 2019
B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial
Øystein Fluge, MD, PhD; Ingrid G. Rekeland, MD; Katarina Lien, MD; Hanne Thürmer, MD, PhD; Petter C. Borchgrevink, MD, PhD; Christoph Schäfer, MD; Kari Sørland, RN; Jörg Aßmus, PhD; Irini Ktoridou-Valen, MD; Ingrid Herder, MD; Merethe E. Gotaas, MD; Øivind Kvammen, MD; Katarzyna A. Baranowska, MD, PhD; Louis M.L.J. Bohnen, MD; Sissel S. Martinsen, RN; Ann E. Lonar, RN; Ann-Elise H. Solvang, RN; Arne E.S. Gya, RN; Ove Bruland, PhD; Kristin Risa, MSc; Kine Alme, MSc; Olav Dahl, MD, PhD; Olav Mella, MD, PhD
Abstract
Background:
Previous phase 2 trials indicated benefit from B-lymphocyte depletion in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Objective:
To evaluate the effect of the monoclonal anti-CD20 antibody rituximab versus placebo in patients with ME/CFS.
Design:
Randomized, placebo-controlled, double-blind, multicenter trial. (ClinicalTrials.gov: NCT02229942)
Setting:
4 university hospitals and 1 general hospital in Norway.
Patients:
151 patients aged 18 to 65 years who had ME/CFS according to Canadian consensus criteria and had had the disease for 2 to 15 years.
Intervention:
Treatment induction with 2 infusions of rituximab, 500 mg/m2 of body surface area, 2 weeks apart, followed by 4 maintenance infusions with a fixed dose of 500 mg at 3, 6, 9, and 12 months (n = 77), or placebo (n = 74).
Measurements:
Primary outcomes were overall response rate (fatigue score ≥4.5 for ≥8 consecutive weeks) and repeated measurements of fatigue score over 24 months. Secondary outcomes included repeated measurements of self-reported function over 24 months, components of the Short Form-36 Health Survey and Fatigue Severity Scale over 24 months, and changes from baseline to 18 months in these measures and physical activity level. Between-group differences in outcome measures over time were assessed by general linear models for repeated measures.
Results:
Overall response rates were 35.1% in the placebo group and 26.0% in the rituximab group (difference, 9.2 percentage points [95% CI, −5.5 to 23.3 percentage points]; P = 0.22). The treatment groups did not differ in fatigue score over 24 months (difference in average score, 0.02 [CI, −0.27 to 0.31]; P = 0.80) or any of the secondary end points. Twenty patients (26.0%) in the rituximab group and 14 (18.9%) in the placebo group had serious adverse events.
Limitation:
Self-reported primary outcome measures and possible recall bias.
Conclusion:
B-cell depletion using several infusions of rituximab over 12 months was not associated with clinical improvement in patients with ME/CFS.
Published: Ann Intern Med. 2019.
DOI: 10.7326/M18-1451
©2019 American College of Physicians
Front. Pediatr., 22 March 2019
Chronotropic Intolerance: An Overlooked Determinant of Symptoms and Activity Limitation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?
Todd E. Davenport1,2*, Mary Lehnen1, Staci R. Stevens2, J. Mark VanNess2,3, Jared Stevens2 and Christopher R. Snell2
- 1Department of Physical Therapy, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA, United States
- 2Workwell Foundation, Ripon, CA, United States
- 3Department of Health, Exercise, and Sport Sciences, College of the Pacific, University of the Pacific, Stockton, CA, United States
April 2019, Volume 34, Issue 2, pp 385–415| Metabolic Brain Disease
Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop?
- Gerwyn Morris,Michael Maes,Michael Berk,Basant K. Puri
A model of the development and progression of chronic fatigue syndrome (myalgic encephalomyelitis), the aetiology of which is currently unknown, is put forward, starting with a consideration of the post-infection role of damage-associated molecular patterns and the development of chronic inflammatory, oxidative and nitrosative stress in genetically predisposed individuals. The consequences are detailed, including the role of increased intestinal permeability and the translocation of commensal antigens into the circulation, and the development of dysautonomia, neuroinflammation, and neurocognitive and neuroimaging abnormalities. Increasing levels of such stress and the switch to immune and metabolic downregulation are detailed next in relation to the advent of hypernitrosylation, impaired mitochondrial performance, immune suppression, cellular hibernation, endotoxin tolerance and sirtuin 1 activation. The role of chronic stress and the development of endotoxin tolerance via indoleamine 2,3-dioxygenase upregulation and the characteristics of neutrophils, monocytes, macrophages and T cells, including regulatory T cells, in endotoxin tolerance are detailed next. Finally, it is shown how the immune and metabolic abnormalities of chronic fatigue syndrome can be explained by endotoxin tolerance, thus completing the model.
Systematic Review of the Efficacy and Safety of Gabapentin and Pregabalin for Pain in Children and Adolescents
Oluwaseun Egunsola, PhD; Claire E. Wylie, PhD; Kate M. Chitty, PhD; Nicholas A. Buckley, MD
Anesth Analg. 2019;128(4):811-819.
Abstract
The barriers to opioid use in some countries necessitate the need to identify suitable alternatives or adjuncts for pain relief. The gabapentinoids (gabapentin and pregabalin) are approved for the management of persistent pain in adults, but not in children. Searches were conducted in Embase, Medline, Scopus, and Web of Science up until November 2017, for randomized controlled trials that investigated the analgesic effects of gabapentin or pregabalin in children and adolescents <18 years of age. A total of 7 publications were identified, 5 regarding gabapentin as prophylactic postsurgical pain relief for either adenotonsillectomy (n = 3) or scoliosis surgery (n = 2), and 1 for gabapentin treatment of chronic regional pain syndrome/neuropathic pain. One study investigated the efficacy of pregabalin as a treatment for fibromyalgia. Based on the studies' primary outcomes alone, neither of the chronic pain studies involving gabapentin and pregabalin showed significant efficacy compared with amitriptyline or placebo, respectively. Two of the prophylactic gabapentin studies for adenotonsillectomy and idiopathic scoliosis surgery reported significantly fewer children requiring analgesia and lower opioid requirement, respectively, compared with placebo. Two of the identified clinical trials (conducted by the same first author) on the efficacy of gabapentin for prophylactic postadenotonsillectomy pain relief were omitted from narrative synthesis due to clear evidence of fabricated data. Overall, this review identified a paucity of evidence for the analgesic effect and safety of gabapentinoids in children. We also suggest audit of any current evidence-based practice and clinical guidelines that have cited the research studies with fabricated data.