Myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) is a common and disabling condition with a paucity of effective and evidence-based therapies reflecting a major unmet need.
Cognitive behavioural therapy and graded exercise are of modest benefit for only some ME/CFS patients, and many sufferers report aggravation of symptoms of fatigue with exercise.
The presence of a multiplicity of pathophysiological abnormalities, in at least the subgroup of people with ME/CFS diagnosed with the current international consensus “Fukuda” criteria, points to numerous potential therapeutic targets. Such abnormalities include extensive data showing that at least a subgroup has a pro-inflammatory state, increased oxidative and nitrosative stress, disruption of gut mucosal barriers and mitochondrial dysfunction together with dysregulated bioenergetics.
In this paper, these pathways are summarised, and data regarding promising therapeutic options that target these pathways are highlighted; they include coenzyme Q10, melatonin, curcumin, molecular hydrogen and N-acetylcysteine. These data are promising yet preliminary, suggesting hopeful avenues to address this major unmet burden of illness.
The researchers reviewed invasive cardiopulmonary test results of 313 patients with unexplained exertional intolerance. The paper focuses mainly on a small subset of patients: “We identified a cohort of patients whose exercise limitation is due only to systemic oxygen extraction, due to either an intrinsic abnormality of skeletal muscle mitochondrion, limb muscle microcirculatory dysregulation, or hyperventilation and left shift the oxyhemoglobin dissociation curve” They indicate that these patients had a diagnosis of ME/CFS.
Unexplained exertional intolerance associated with impaired systemic oxygen extraction by Kathryn H Melamed, Mário Santos, Rudolf K F Oliveira, Mariana Faria Urbina, Donna Felsenstein, Alexander R Opotowsky, Aaron B Waxman, David M Systrom inEur J Appl Physiol Sep 6 pp 1-15 (2019) https://doi.org/10.1007/s00421-019-04222-6 [Epub ahead of print]
Review abstract:
PURPOSE: The clinical investigation of exertional intolerance generally focuses on cardiopulmonary diseases, while peripheral factors are often overlooked. We hypothesize that a subset of patients exists whose predominant exercise limitation is due to abnormal systemic oxygen extraction (SOE).
METHODS: We reviewed invasive cardiopulmonary exercise test (iCPET) results of 313 consecutive patients presenting with unexplained exertional intolerance. An exercise limit due to poor SOE was defined as peak exercise (Ca-vO2)/[Hb] ≤ 0.8 and VO2max < 80% predicted in the absence of a cardiac or pulmonary mechanical limit. Those with peak (Ca-vO2)/[Hb] > 0.8, VO2max ≥ 80%, and no cardiac or pulmonary limit were considered otherwise normal. The otherwise normal group was divided into hyperventilators (HV) and normals (NL). Hyperventilation was defined as peak PaCO2 < [1.5 × HCO3 + 6].
RESULTS: Prevalence of impaired SOE as the sole cause of exertional intolerance was 12.5% (32/257). At peak exercise, poor SOE and HV had less acidemic arterial blood compared to NL (pHa = 7.39 ± 0.05 vs.
7.38 ± 0.05 vs. 7.32 ± 0.02, p < 0.001), which was explained by relative hypocapnia (PaCO2 = 29.9 ± 5.4 mmHg vs. 31.6 ± 5.4 vs. 37.5 ± 3.4, p < 0.001). For a subset of poor SOE, this relative alkalemia, also seen in mixed venous blood, was associated with a normal PvO2 nadir (28 ± 2 mmHg vs. 26 ± 4, p = 0.627) but increased SvO2 at peak exercise (44.1 ± 5.2% vs. 31.4 ± 7.0, p < 0.001).
CONCLUSIONS: We identified a cohort of patients whose exercise limitation is due only to systemic oxygen extraction, due to either an intrinsic abnormality of skeletal muscle mitochondrion, limb muscle microcirculatory dysregulation, or hyperventilation and left shift the oxyhemoglobin dissociation curve.
A retrospective outcome study of 42 patients with Chronic Fatigue Syndrome, 30 of whom had Irritable Bowel Syndrome. Half were treated with oral approaches, and half were treated with faecal microbiome transplantation, by JN Kenyon, Shelly Coe, Hooshang Izadi inHuman Microbiome Journal vol 13 August 2019 [https://doi.org/10.1016/j.humic.2019.100061]
Research abstract:
The gut microbiome comprises the community of microorganisms in the intestinal tract. Research suggests that an altered microbiome may play a role in a wide range of disorders including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Methods:
42 participants with ME/ CFS with Irritable Bowel Syndrome (IBS) were allocated into one of two groups, 21 were treated with standard oral approaches, which centred around various nutritional remedies, probiotics, prebiotics, dietary advice and lifestyle advice. The second group who had mostly failed using oral approaches, were treated with Faecal Microbiome Transplantation (FMT). Each patient received 10 Implants, each from a different screened donor, and the Implants were processed under anaerobic conditions. The transplant is delivered via a paediatric rectal catheter, which is inserted through the anus to reach the lower part of the sigmoid colon.
The results were assessed on a percentage basis before and after treatment, 0% being no improvement, 100% being maximum improvement. An exact non-parametric Mann-Whitney (one-tailed) test was used to compare medians from those on FMT compared with those receiving oral approaches only. On clinical experience over many years, the only way to judge improvement in Chronic Fatigue Syndrome as there is no test for Chronic Fatigue Syndrome, is my clinical assessment.
Results:
The median for the FMT group was found to be significantly higher compared to the oral treatment group (Mann-Whitney U=111.5, p=.003). Therefore, the FMT group improved to a greater extent (z=-2.761).
Conclusion:
This study shows that FMT is a safe and a promising treatment for CFS associated with IBS. Adequately powered randomised controlled trials should be carried out to assess the effectiveness of FMT in patients with CFS and IBS.
42 studies meta-analysed, testing 20 proteins between patients with CFS and controls
Patients had higher levels of 5 cytokines than controls (TNF, IL-2, IL-4, TGFb, CRP)
Group differences were not significant for 12 proteins
Results are heterogeneous but provide some support for an inflammatory role in CFS
Review abstract:
Immune dysfunction has been posited as a key element in the aetiology of chronic fatigue syndrome (CFS) since the illness was first conceived. However, systematic reviews have yet to quantitatively synthesise inflammatory biomarkers across the literature.
We undertook a systematic review and meta-analysis to quantify available data on circulating inflammatory proteins, examining studies recruiting patients with a CFS diagnosis and a non-affected control group.
Results were meta-analysed from 42 studies. Patients with CFS had significantly elevated tumour necrosis factor (ES = 0.274, p < 0.001), interleukin-2 (ES = 0.203, p = 0.006), interleukin-4 (ES = 0.373, p = 0.004), transforming growth factor-β (ES = 0.967, p < 0.001) and c-reactive protein (ES = 0.622, p = 0.019). 12 proteins did not differ between groups.
These data provide some support for an inflammatory component in CFS, although inconsistency of results indicates that inflammation is unlikely to be a primary feature in all those suffering from this disorder. It is hoped that further work will elucidate whether there are subgroups of patients with clinically-relevant inflammatory dysfunction, and whether inflammatory cytokines may provide a prognostic biomarker or moderate treatment effects.
Chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME) negatively impacts the quality of life for children with the condition. Although up to 2% of children have CFS/ME, the bulk of research investigates adults with CFS/ME. Using the PRISMA extension for a scoping review and the work of Arksey and O’Malley (2005), a scoping review was conducted of all relevant peer-reviewed research investigating nutrition, exercise, and psychosocial factors within a pediatric population diagnosed with CFS/ME.
Key themes found were nutrition and dietary components, exercise therapy, psychosocial factors, and multifaceted treatment. Nutrition was explored on its own as a tool to decrease symptoms; however, there were very few studies found to examine nutritional deficiency or treatment with those under the age of 18.
Graded exercise and resistance training improved fatigue severity and symptoms of depression in adolescents with CFS/ME. Research exploring psychosocial factors of CFS/ME presented attributes that could lead to being diagnosed as well as barriers to treatment. The multifaceted treatment undertaken typically consists of graded activities/exercise, cognitive behavioral therapy, nutritional advice, and family sessions. This has shown to increase school attendance and decrease the severity of the fatigue for adolescents.
Minimal literature exploring CFS/ME within a prepubescent population presents the need for further research.
Introduction:
Dysfunction of the autonomic nervous system (ANS) is seen in chronic fatigue syndrome (CFS) and temporomandibular disorders (TMDs). Both conditions have poorly understood pathophysiology. Several brain structures that play a role in pain and fatigue, such as the insular cortex and basal ganglia, are also implicated in autonomic function.
Objectives:
ANS dysfunction may point to common neurophysiologic mechanisms underlying the predominant symptoms for CFS and TMD. No studies to date have investigated the combination of both conditions. Thus, our aim was to test whether patients with CFS with or without TMD show differences in brain responses to autonomic challenges.
Methods:
In this exploratory functional imaging study, patients with CFS who screened positive for TMD (n = 26), patients who screened negative for TMD (n = 16), and age-matched control participants (n = 10) performed the Valsalva maneuver while in a 3-T magnetic resonance imaging scanner. This maneuver is known to activate the ANS.
Results:
For all 3 groups, whole-brain F test showed increased brain activation during the maneuver in the superior and inferior frontal gyri, the left and right putamen and thalamus, and the insular cortex. Furthermore, group contrasts with small-volume correction showed that patients with CFS who screened positive for TMD showed greater activity in the left insular cortex as compared with patients who screened negative and in the left caudate nucleus as compared with controls.
Conclusion:
Our results suggest that increased activity in the cortical and subcortical regions observed during autonomic challenges may be modulated by fatigue and pain. ANS dysfunction may be a contributing factor to these findings, and further work is required to tease apart the complex relationship among CFS, TMD, and autonomic functions.
Knowledge Transfer Statement:
Brain activity related to activation of the autonomic nervous system in patients with chronic fatigue syndrome who screened positive for painful temporomandibular disorder was greater than in patients who screened negative; activity was seen in brain regions associated with autonomic functions and pain. These findings suggest that autonomic dysfunction may play a role in the pathophysiology of both conditions, explain some of the apparent comorbidity between them, and offer avenues to help with treatment.
Background: Cytokines in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis/ Systemic Exertion Intolerance Disease (CFS/ME/SEID) patients compared with healthy controls have been extensively studied. However, the evidence regarding whether a baseline difference between CFS/ME/SEID patients and the normal population remains unclear.
The aim of this study was to conduct a systematic review of the literature regarding cytokines in CFS/ME/SEID and whether there is a significant difference in cytokine levels between this patient group and the normal population.
Methods: Pubmed, Scopus, Medline (EBSCOHost), and EMBASE databases were searched to source relevant studies for CFS/ME/SEID. The review included any studies examining cytokines in CFS/ME/SEID patients compared with healthy controls. Results of the literature search were summarised according to aspects of their study design and outcome measures, namely, cytokines. Quality assessment was also completed to summarise the level of evidence available.
Results: A total of 16,702 publications were returned using our search terms. After screening of papers according to our inclusion and exclusion criteria, 15 studies were included in the review. All the included studies were observational case control studies. Ten of the studies identified measured serum cytokines in CFS/ME/SEID patients, and four measured cytokines in other physiological fluids of CFS/ME/SEID patients. The overall quality assessment revealed most papers included in this systematic review to be consistent.
Conclusions: Despite the availability of moderate quality studies, the findings of this review are inconclusive as to whether cytokines play any definitive role in CFS/ME/SEID, and consequently, they would not serve as reliable biomarkers. Therefore, in light of these results, it is recommended that further efforts toward a diagnostic test and treatment for CFS/ME/SEID continue to be developed in a range of research fields.
It is unclear whether the functional somatic syndromes share a common etiology or have distinct syndrome-specific mechanisms. This prospective population-based study assessed whether the same variables predict new onsets of self-reported Irritablebowel syndrome (IBS), Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM).
Methods:
The study included adults participating in the Dutch Lifelines population-based study who reported the presence/absence of IBS, CFS or FM at baseline and follow-up (N=152,180). They were screened at baseline for physical and psychological disorders, ociodemographic, psycho-social and behavioral variables. At follow-up (mean 2.4 years) we identified new onsets of each syndrome by self-report. We performed separate analyses for the three syndromes, including only those participants who, at baseline, were free of the relevant syndrome or its key symptom. LASSO logistic regressions were applied to identify which of the 102 baseline variables predicted new onsets of each syndrome.
Findings:
The numbers of new onsets were 1,595 (1.2%), 296 (0.2%) and 692 (0.5%) for IBS, CFS, and FM respectively. LASSO logistic regression selected 26, 7 and 19 predictors for IBS, CFS and FM respectively. Four predictors were shared by all three syndromes: somatic symptoms, disturbed sleep, recent chronic illness and negative health perception. Female sex, allergies, gastrointestinal disorders, high BMI and low alcohol consumption predicted both IBS and FM; recent stress predicted both IBS and CFS but 28 predictors were specific to a single syndrome. CFS was more distinct from IBS and FM, which predicted each other.
Interpretation:
Syndrome-specific predictors were more common than shared ones. Such specific predictors might form a better starting point to unravel the heterogeneous etiologies of these syndromes than the current approach based on symptom patterns. The close relationship between IBS and FM is striking and the shared role of allergies, gastrointestinal and other medical disorders and medications needs further investigation.
Myalgic encephalomyelitis, also referred to as chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by myalgia and a sometimes severe limitation of physical activity and cognition. It is exacerbated by physical and mental activity. Its cause is unknown, but frequently starts with an infection.
The eliciting infection (commonly infectious mononucleosis or an upper respiratory infection) can be more or less well diagnosed. Among the human herpesviruses (HHV-1-8), HHV-4 (Epstein-Barr virus; EBV), HHV-6 (including HHV-6A and HHV-6B), and HHV-7, have been implicated in the pathogenesis of ME/CFS.
It was therefore logical to search for serological evidence of past herpesvirus infection/ reactivation in several cohorts of ME/CFS patients (all diagnosed using the Canada criteria). Control samples were from Swedish blood donors. We used whole purified virus, recombinant proteins, and synthetic peptides as antigens in a suspension multiplex immunoassay (SMIA) for immunoglobulin G (IgG).
The study on herpesviral peptides based on antigenicity with human sera yielded novel epitope information. Overall, IgG anti-herpes-viral reactivities of ME/CFS patients and controls did not show significant differences. However, the high precision and internally controlled format allowed us to observe minor relative differences between antibody reactivities of some herpesviral antigens in ME/CFS versus controls.
ME/CFS samples reacted somewhat differently from controls with whole virus HHV-1 antigens and recombinant EBV EBNA6 and EA antigens. We conclude that ME/CFS samples had similar levels of IgG reactivity as blood donor samples with HHV-1-7 antigens. The subtle serological differences should not be over-interpreted, but they may indicate that the immune system of some ME/CFS patients interact with the ubiquitous herpesviruses in a way different from that of healthy controls.
Studies to ascertain a possible relationship between herpesviruses and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have relied heavily on classical approaches, specifically, serological examination for antibodies against virus proteins, primarily structural, and/or increases in viral load (1–21).
These data have been conflicting due in part to several features: the heterogeneity of the disease, high prevalence of the herpesviruses in the population since they can establish lifelong infections, and differences between laboratories. Two additional problems lead to conflicting data in serological studies: which viral antigens are to be used for detection, and what is the possible relationship, if any, of these viral antigens to ME/CFS?
These are important questions that must be addressed for any data to provide meaningful insight into the possible contribution of a virus to the pathophysiology of ME/CFS. Although the experimental techniques used in Blomberg’s serological study were appropriate, the selection of specific herpesviruses and viral antigens studied gives a limited view of the humoral response in ME/CFS.
The presence of a multiplicity of pathophysiological abnormalities, in at least the subgroup of people with ME/CFS diagnosed with the current international consensus “Fukuda” criteria, points to numerous potential therapeutic targets. Such abnormalities include extensive data showing that at least a subgroup has a pro-inflammatory state, increased oxidative and nitrosative stress, disruption of gut mucosal barriers and mitochondrial dysfunction together with dysregulated bioenergetics.
