Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids

Abstract:

The latest worldwide prevalence rate projects that over 65 million patients suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), an illness with known effects on the functioning of the immune and nervous systems. We performed an extensive metabolomics analysis on the plasma of 52 female subjects, equally sampled between controls and ME/CFS patients, which delivered data for about 1750 blood compounds spanning 20 super-pathways, subdivided into 113 sub-pathways.

Statistical analysis combined with pathway enrichment analysis points to a few disrupted metabolic pathways containing many unexplored compounds. The most intriguing finding concerns acyl cholines, belonging to the fatty acid metabolism sub-pathway of lipids, for which all compounds are consistently reduced in two distinct ME/CFS patient cohorts. We compiled the extremely limited knowledge about these compounds and regard them as promising in the quest to explain many of the ME/CFS symptoms.

Another class of lipids with far-reaching activity on virtually all organ systems are steroids; androgenic, progestin, and corticosteroids are broadly reduced in our patient cohort. We also report on lower dipeptides and elevated sphingolipids abundance in patients compared to controls. Disturbances in the metabolism of many of these molecules can be linked to the profound organ system symptoms endured by ME/CFS patients.

Source: Germain A, Barupal DK, Levine SM, Hanson MR. Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids. Metabolites. 2020 Jan 14;10(1). pii: E34. doi: 10.3390/metabo10010034. https://www.ncbi.nlm.nih.gov/pubmed/31947545

A System Theoretic Investigation of Cortisol Dysregulation in Fibromyalgia Patients with Chronic Fatigue

Abstract:

Fibromyalgia Syndrome (FMS) and Chronic Fatigue Syndrome (CFS) are complex medical conditions with similar symptoms such as anxiety, fatigue, depression, headaches, muscle aches and joint pain. The etiology of both these syndromes is unknown. The objective of this study is to characterize FMS, both in the presence and in the absence of CFS, by analyzing variations in cortisol secretion patterns, timings, amplitudes, and the number of the underlying pulses as well as infusion and clearance rates.

The comparison is performed against matched healthy control subjects. We estimate the hormonal secretory events by deconvolving cortisol data using a two-step coordinate descent approach. The first step implements a sparse recovery approach to infer the amplitudes and the timings of the cortisol secretion events from limited cortisol hormone data. The main advantage of this method is estimating the cortisol secretory events using a system theoretic approach. The second step is to estimate the physiological system parameters (i.e. infusion and clearance rates). This approach has been verified on healthy individuals previously.

Our results show that the clearance rate of cortisol by the liver is relatively lower in patients as compared to the matched healthy individuals. This suggests that there is a relatively higher accumulation of serum cortisol in patients when compared to matched healthy subjects.

Source: Pednekar DD, Amin MR, Azgomi HF, Aschbacher K, Crofford LJ, Faghih RT. A System Theoretic Investigation of Cortisol Dysregulation in Fibromyalgia Patients with Chronic Fatigue. Conf Proc IEEE Eng Med Biol Soc. 2019 Jul;2019:6896-6901. doi: 10.1109/EMBC.2019.8857427. https://www.ncbi.nlm.nih.gov/pubmed/31947425

Low-dose naltrexone as a treatment for chronic fatigue syndrome

Abstract:

Naltrexone is used as an off-label treatment in low doses for several chronic immune-modulated disorders in many countries. Although only small-scale clinical trials have been performed, these suggest efficacy in several diseases including Crohn’s disease, fibromyalgia and Gulf War Illness. Despite numerous internet reports of response to low-dose naltrexone (LDN), no clinical trials exist in people with chronic fatigue syndrome. This condition is characterised by chronic profound fatigue, postexertional malaise, pain and autonomic and neurocognitive disturbances.

This series of three case reports compiled by people with long-term ill-health due to chronic fatigue syndrome shows the range of responses they observed when taking LDN, from life changing to a reduction in some symptoms only. Treatment doses ranged from 4 to 12 mg. Clinical trials may be warranted to explore the potential use of naltrexone in people with these debilitating illnesses which currently have no licensed treatments available.

Source: Bolton MJ, Chapman BP, Van Marwijk H. Low-dose naltrexone as a treatment for chronic fatigue syndrome. BMJ Case Rep. 2020 Jan 6;13(1). pii: e232502. doi: 10.1136/bcr-2019-232502. https://www.ncbi.nlm.nih.gov/pubmed/31911410

Development of a conceptual framework to underpin a health-related quality of life outcome measure in paediatric chronic fatigue syndrome/myalgic encephalopathy (CFS/ME): prioritisation through card ranking

Abstract:

PURPOSE: Chronic fatigue syndrome (CFS)/myalgic encephalopathy (ME) is relatively common in children and is disabling at an important time in their development. This study aimed to develop a conceptual framework of paediatric CFS/ME using the patient-perspective to ensure that the content of a new outcome measure includes the outcomes most important to young people.

METHODS: We developed a child-centred interactive card ranking exercise that included health-related quality of life (HRQoL) outcomes identified from a previous review of the literature as well as qualitative work. Adolescents and their parents selected and ranked the outcomes most important to them and discussed each outcome in further detail. Adolescents were purposively sampled from a single specialist paediatric CFS/ME service in England. Interviews were audio recorded and transcribed verbatim, and thematic framework analysis was used to develop the final conceptual framework.

RESULTS: We interviewed 43 participants in which there are 21 adolescents, 12-17 years of age with mild-moderate CFS/ME and their parents (20 mothers and 2 fathers). ‘Symptoms’, ‘tiredness’, ‘payback and crashing’ and ‘activities and hobbies’ were ranked most important to improve by both children and parents. Children ranked ‘school’ higher than parents and parents ranked ‘mood’ higher than children. A youth- specific CFS/ME conceptual framework of HRQoL was produced that included 4 outcome domains and 11 subdomains: sleep, tiredness, problems concentrating, individual symptoms, fluctuation and payback, daily and general activities, participation in school, leisure and social life, mood, anxiety and self-esteem.

CONCLUSIONS: An interactive card ranking exercise worked well for adolescents aged 12-17 to elicit the most important outcomes to them and explore each domain in further detail. We developed a final conceptual framework of HRQoL that forms the basis of a new paediatric patient-reported outcome measure (PROM) in CFS/ME.

Source: Parslow RM, Anderson N, Byrne D, Haywood KL, Shaw A, Crawley E. Development of a conceptual framework to underpin a health-related quality of life outcome measure in paediatric chronic fatigue syndrome/myalgic encephalopathy (CFS/ME): prioritisation through card ranking. Qual Life Res. 2020 Jan 6. doi: 10.1007/s11136-019-02399-z. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31907870

Reduced heart rate variability predicts fatigue severity in individuals with chronic fatigue syndrome/myalgic encephalomyelitis

Abstract:

BACKGROUND: Heart rate variability (HRV) is an objective, non-invasive tool to assessing autonomic dysfunction in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). People with CFS/ME tend to have lower HRV; however, in the literature there are only a few previous studies (most of them inconclusive) on their association with illness-related complaints. To address this issue, we assessed the value of different diurnal HRV parameters as potential biomarker in CFS/ME and also investigated the relationship between these HRV indices and self-reported symptoms in individuals with CFS/ME.

METHODS: In this case-control study, 45 female patients who met the 1994 CDC/Fukuda definition for CFS/ME and 25 age- and gender-matched healthy controls underwent HRV recording-resting state tests. The intervals between consecutive heartbeats (RR) were continuously recorded over three 5-min periods. Time- and frequency-domain analyses were applied to estimate HRV variables. Demographic and clinical features, and self-reported symptom measures were also recorded.

RESULTS: CFS/ME patients showed significantly higher scores in all symptom questionnaires (p < 0.001), decreased RR intervals (p < 0.01), and decreased HRV time- and frequency-domain parameters (p < 0.005), except for the LF/HF ratio than in the healthy controls. Overall, the correlation analysis reached significant associations between the questionnaires scores and HRV time- and frequency-domain measurements (p < 0.05). Furthermore, separate linear regression analyses showed significant relationships between self-reported fatigue symptoms and mean RR (p = 0.005), RMSSD (p = 0.0268) and HFnu indices (p = 0.0067) in CFS/ME patients, but not in healthy controls.

CONCLUSIONS: Our findings suggest that ANS dysfunction presenting as increased sympathetic hyperactivity may contribute to fatigue severity in individuals with ME/CFS. Further studies comparing short- and long-term HRV recording and self-reported outcome measures with previous studies in larger CFS/ME cohorts are urgently warranted.

Source: Escorihuela RM, Capdevila L, Castro JR, Zaragozà MC, Maurel S, Alegre J, Castro-Marrero J. Reduced heart rate variability predicts fatigue severity in individuals with chronic fatigue syndrome/myalgic encephalomyelitis. J Transl Med. 2020 Jan 6;18(1):4. doi: 10.1186/s12967-019-02184-z. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943898/ (Full article)

Systematic review of randomized controlled trials for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)

Abstract:

BACKGROUND: Although medical requirements are urgent, no effective intervention has been proven for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). To facilitate the development of new therapeutics, we systematically reviewed the randomized controlled trials (RCTs) for CFS/ME to date.

METHODS: RCTs targeting CFS/ME were surveyed using two electronic databases, PubMed and the Cochrane library, through April 2019. We included only RCTs that targeted fatigue-related symptoms, and we analyzed the data in terms of the characteristics of the participants, case definitions, primary measurements, and interventions with overall outcomes.

RESULTS: Among 513 potentially relevant articles, 55 RCTs met our inclusion criteria; these included 25 RCTs of 22 different pharmacological interventions, 28 RCTs of 18 non-pharmacological interventions and 2 RCTs of combined interventions. These studies accounted for a total of 6316 participants (1568 males and 4748 females, 5859 adults and 457 adolescents). CDC 1994 (Fukuda) criteria were mostly used for case definitions (42 RCTs, 76.4%), and the primary measurement tools included the Checklist Individual Strength (CIS, 36.4%) and the 36-item Short Form health survey (SF-36, 30.9%). Eight interventions showed statistical significance: 3 pharmacological (Staphypan Berna, Poly(I):poly(C12U) and CoQ10 + NADH) and 5 non-pharmacological therapies (cognitive-behavior-therapy-related treatments, graded-exercise-related therapies, rehabilitation, acupuncture and abdominal tuina). However, there was no definitely effective intervention with coherence and reproducibility.

CONCLUSIONS: This systematic review integrates the comprehensive features of previous RCTs for CFS/ME and reflects on their limitations and perspectives in the process of developing new interventions.

Source: Kim DY, Lee JS, Park SY, Kim SJ, Son CG. Systematic review of randomized controlled trials for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). J Transl Med. 2020 Jan 6;18(1):7. doi: 10.1186/s12967-019-02196-9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943902/ (Full article)

An Adrenalectomy Mouse Model Reflecting Clinical Features for Chronic Fatigue Syndrome

Abstract:

Chronic fatigue syndrome (CFS) is one of the most intractable diseases and is characterized by severe central fatigue that impairs even daily activity. To date, the pathophysiological mechanisms are uncertain and no therapies exist. Therefore, a proper animal model reflecting the clinical features of CFS is urgently required.

We compared two CFS animal models most commonly used, by injection with lipopolysaccharide (LPS from Escherichia coli O111:B4) or polyinosinic: polycytidylic acid (poly I:C), along with bilateral adrenalectomy (ADX) as another possible model. Both LPS- and poly I:C-injected mice dominantly showed depressive behaviors, while ADX led to fatigue-like performances with high pain sensitivity.

In brain tissues, LPS injection notably activated microglia and the 5-hydroxytryptamine (HT)1A receptor in the prefrontal cortex and hippocampus. Poly I:C-injection also remarkably activated the 5-HT transporter and 5-HT1A receptor with a reduction in serotonin levels in the brain. ADX particularly activated astrocytes and transforming growth factor beta (TGF-β) 1 in all brain regions.

Our results revealed that LPS and poly I:C animal models approximate depressive disorder more closely than CFS. We suggest that ADX is a possible method for establishing a mouse model of CFS reflecting clinical features, especially in neuroendocrine system.

Source: Lee JS, Jeon YJ, Park SY, Son CG. An Adrenalectomy Mouse Model Reflecting Clinical Features for Chronic Fatigue Syndrome. Biomolecules. 2020 Jan 1;10(1). pii: E71. doi: 10.3390/biom10010071. https://www.mdpi.com/2218-273X/10/1/71 (Full article)

Neuroinflammation, Oxidative Stress, and Neurogenesis in a Mouse Model of Chronic Fatigue Syndrome, and the Treatment with Kampo Medicine

Abstract:

The diagnosis of chronic fatigue syndrome (CFS) is mainly symptom-based, and the etiology is still unclear. Here, we evaluated the pathological changes in the brain of a mouse model of CFS and studied the effects of Kampo medicine.

A mouse model of CFS was established through six repeated injections of Brucella abortus (BA) every two weeks for a period of 12 weeks. Neuroinflammation was measured by estimating interleukin (IL)-1β, IL-6, and interferon-gamma (IFN-γ), and oxidative stress by nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE) 6 weeks after the last injection. Hippocampal neurogenesis was evaluated through Ki-67, doublecortin (DCX), and 5-bromodeoxyuridine (BrdU) assays. The effects of Kampo medicines (Hochuekkito (TJ-41) and Hachimijiogan (TJ-7)) on neuroinflammation during CFS were studied.

The wheel-running activity of mice was decreased by about 50% compared to baseline at 6 weeks after the last BA injection. The levels of IL-1β, IL-6, 3-NT, and 4-HNE were increased in both the cortex and the hippocampus of CFS mice at 6 weeks after the last BA injection. Hippocampal neurogenesis was unchanged in CFS mice. Treatment with TJ-41 and TJ-7 reduced the expressions of IL-1β, IL-6, and IFN-γ in the hippocampus but not in the cortex.

The results of the present study indicate that neuroinflammation and oxidative stress play important roles in the pathogenesis of CFS. The data further suggest that treatment with TJ-41 and TJ-7 could help reduce the inflammation associated with CFS in the hippocampus, but failed to improve the symptoms in CFS mice.

Source: He Q, Sawada M, Yamasaki N, Akazawa S, Furuta H, Uenishi H, Meng X, Nakahashi T, Ishigaki Y, Moriya J. Neuroinflammation, Oxidative Stress, and Neurogenesis in a Mouse Model of Chronic Fatigue Syndrome, and the Treatment with Kampo Medicine. Biol Pharm Bull. 2020;43(1):110-115. doi: 10.1248/bpb.b19-00616. https://www.jstage.jst.go.jp/article/bpb/43/1/43_b19-00616/_article (Full article)

The role of low-grade inflammation in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) – associations with symptoms

Abstract:

BACKGROUND: Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) often present with a range of flu-like symptoms resembling sickness behavior as well as widespread pain and concentration deficits. The aim of this study was to explore the association between inflammatory markers previously shown to be related to fatigue severity in ME/CFS and common ME/CFS symptoms post-exertional fatigue, impaired cognitive processing, musculoskeletal pain and recurrent flu-like symptoms, and the moderating effect of sex on these associations.

METHODS: 53 adult patients diagnosed with ME/CFS at a specialist clinic were included in the study. Fasting blood plasma was analyzed using the Olink Proseek Multiplex Inflammation panel (β-NGF, CCL11, CXCL1, CXCL10, IL-6, IL-7, IL-8, IL-10, IL-18, TGF-α, TGF-β-1 and SCF) and BioRad Human Cytokine Type 1 assay (TNF-α). Participants rated the average severity of symptoms (0-10) based on the 2011 International Consensus Criteria of ME/CFS during a structured clinical interview. Associations between inflammatory markers and symptom severity were analyzed using bivariate correlations and moderated regression analyses bootstrapped with 5000 repetitions.

RESULTS AND CONCLUSIONS: Only β-NGF was associated with the fatigue severity measure. However, higher levels of CCL11, CXCL10, IL-7, TNF-α and TGF-β-1 were significantly associated with higher levels of impaired cognitive processing and musculoskeletal pain, and sex was a significant moderator for CXCL10, IL-7 and TGF-β-1. Future studies should investigate the relationship between inflammatory markers and key symptoms in ME/CFS in a longitudinal design in order to explore if and for whom low-grade inflammation may contribute to illness development.

Copyright © 2019. Published by Elsevier Ltd.

Source: Jonsjö MA, Olsson GL, Wicksell RK, Alving K, Holmström L, Andreasson A. The role of low-grade inflammation in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) – associations with symptoms. Psychoneuroendocrinology. 2019 Dec 26;113:104578. doi: 10.1016/j.psyneuen.2019.104578. [Epub ahead of print] https://www.sciencedirect.com/science/article/pii/S0306453019313198?via%3Dihub (Full article)

Results of the feasibility phase of the managed activity graded exercise in teenagers and pre-adolescents (MAGENTA) randomised controlled trial of treatments for chronic fatigue syndrome/myalgic encephalomyelitis

Editor’s Comment: Graded exercise therapy (GET) has been widely discredited as a treatment for ME/CFS. It has caused permanent damage in some patients. Exercise of any type is not recommended for severely ill patients, as it can cause significant harm. No exercise program should be undertaken that employs a structured incremental increase in exercise for patients at any level of illness. ME/CFS is a highly variable disease that can fluctuate unpredictably between exacerbations and remissions, which prohibits a goal-oriented exercise regimen.

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) also known as myalgic encephalomyelitis (ME) is relatively common in young people and causes significant disability. Graded exercise therapy (GET) and activity management are recommended by the National Institute for Health and Care Excellence (NICE) despite a limited evidence-base for either treatment in paediatric CFS/ME. This paper reports on feasibility and acceptability measures from the feasibility phase of the ongoing MAGENTA randomised controlled trial (RCT) investigating GET versus activity management for young people with CFS/ME.

METHODS: Setting: Three specialist secondary care National Health Service (NHS) Paediatric CFS/ME services (Bath, Cambridge and Newcastle).Participants: Young people aged 8-17 years with a diagnosis of mild to moderate CFS/ME. Young people were excluded if they were severely affected, referred to cognitive behavioural therapy (CBT) at initial assessment or unable to attend clinical sessions.Interventions: GET and activity management delivered by physiotherapists, occupational therapists, nurses and psychologists. Families and clinicians decided the number (typically 8-12) and frequency of appointments (typically every 2-6 weeks).Outcome Measures: Recruitment and follow-up statistics. We used integrated qualitative methodology to explore the feasibility and acceptability of the trial processes and the interventions.

RESULTS: 80/161 (49.7%) of eligible young people were recruited at two sites between September 2015 and August 2016, indicating recruitment to the trial was feasible. Most recruitment (78/80; 97.5%) took place at one centre. Recruitment consultations, online consent and interventions were acceptable, with less than 10% in each arm discontinuing trial treatment. Response rate to the primary outcome (the SF36-PFS at 6 months) was 91.4%. Recruitment, treatment and data collection were not feasible at one centre. The site was withdrawn from the study.In response to data collected, we optimised trial processes including using Skype for recruitment discussions; adapting recruiter training to improve recruitment discussions; amending the accelerometer information leaflets; shortening the resource use questionnaires; and offering interventions via Skype. These amendments have been incorporated into the full trial protocol.

CONCLUSIONS: Conducting an RCT investigating GET versus activity management is feasible and acceptable for young people with CFS/ME.

TRIAL REGISTRATION: ISRCTN23962803 10.1186/ISRCTN23962803, date of registration: 03 September 2015.

© The Author(s). 2019.

Source: Brigden A, Beasant L, Gaunt D, Hollingworth W, Mills N, Solomon-Moore E, Jago R, Metcalfe C, Garfield K, Wray C, Trist A, Vilenchik V, Grayson C, Crawley E. Results of the feasibility phase of the managed activity graded exercise in teenagers and pre-adolescents (MAGENTA) randomised controlled trial of treatments for chronic fatigue syndrome/myalgic encephalomyelitis. Pilot Feasibility Stud. 2019 Dec 19;5:151. doi: 10.1186/s40814-019-0525-3. eCollection 2019. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924066/ (Full article)