Research Roundup: ME/CFS Research Published 18-24 January 2022

January 28, 2022


The weekly research round-up includes recent publications about ME/CFS and Long Covid. We highlight the studies that have particularly caught our interest and follow these with the full list of publications together with their abstracts (summaries).

All research relating to ME/CFS can be located in the ME Association: Index of ME/CFS Published Research. It is a FREE resource, available to anyone, and updated at the beginning of each month.

The Index provides an A-Z of published research studies, selected key documents and articles, listed by subject matter, on myalgic encephalomyelitis, myalgic encephalopathy, and/or chronic fatigue syndrome (ME/CFS).

You can use it to easily locate and read any research that you might be interested in regard to, e.g., epidemiology, infection, neurology, post-exertional malaise etc.

You can also find the Research Index in the Research section of the website together with a list of Research Summaries that provide more detailed lay explanations of the more interesting work that has been published to date.

Audio Commentary on the Research Roundup

ME/CFS Research Published 18 – 24 January 2022 

Its been an interesting week for ME/CFS research with seven new studies as well as ten studies on Long Covid.  

We have highlighted two of the studies below:  

Paper one (1) is a pre-print and has not been peer-reviewed, but it analyses a large range of metabolic substances in 106 ME/CFS patients. The study results are consistent with previous research finding compromised energy metabolism and redox imbalance. The authors provide a one-summary sentence: 

Plasma levels of plasmalogens are decreased in patients with myalgic encephalomyelitis/chronic fatigue syndrome suggesting peroxisome dysfunction.” (Peroxisome is a membrane-bound organelle found in cells, playing a key role in oxidation of specific biomolecules, such as fatty acids and amino acids) 

Paper two (2) is a follow-on study from a research group in Austria, who study endothelium cells (layer of cells lining blood vessels). We have covered the background of this research in a previous research summary, which uses samples from the UK ME/CFS biobank.  

This additional study further shows the decrease in production of nitric oxide by the endothelium cells, which is needed for regulating blood flow throughout the body. The study suggests the enzyme involved in the endothelial dysfunction (nitric oxide synthase) may be involved in the pathophysiology of ME/CFS. 

You may also be interested in reading: 

  • Paper five (5) which concludes that “cognitive Behavioural Therapy may need to focus more on generalised worry in CFS”. 
  • Paper six (6) which shows that Covid patients with constitutional neuropsychiatric symptoms in the initial phases of illness are predictors for chronic fatigue syndrome. 
  • Paper seven (7) which proposes that “antibiotic use throughout life favours an intestinal microbiota composition which might be a risk factor for ME/CFS.”  
  • Paper ten (10) in the Long Covid reference section feature’s the research study from the recently published article in The Guardian, showing that people with certain antibody signatures are more at risk from Long Covid. 

ME/CFS Research References and Abstracts  

1. Evidence for Peroxisomal Dysfunction and Dysregulation of the CDP-Choline Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome 

Che X, Brydges CR, Yu Y, Price A, Joshi S, Roy A, Lee B, Barupal DK, Cheng A, Palmer DM, Levine S, Peterson DL, Vernon SD, Bateman L, Hornig M, Montoya JG, Komaroff AL, Fiehn O, Lipkin WI.  

medRxiv [Preprint]. 2022 Jan 11:2021.06.14.21258895.  

Abstract 

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease that is characterized by unexplained physical fatigue unrelieved by rest. Symptoms also include cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems.  

A syndrome clinically similar to ME/CFS has been reported following well-documented infections with the coronaviruses SARS-CoV and MERS-CoV. At least 10% of COVID-19 survivors develop post acute sequelae of SARS-CoV-2 infection (PASC). Although many individuals with PASC have evidence of structural organ damage, a subset have symptoms consistent with ME/CFS including fatigue, post exertional malaise, cognitive dysfunction, gastrointestinal disturbances, and postural orthostatic intolerance.  

These common features in ME/CFS and PASC suggest that insights into the pathogenesis of either may enrich our understanding of both syndromes, and could expedite the development of strategies for identifying those at risk and interventions that prevent or mitigate disease. 

Methods: Using regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of 888 metabolic analytes in plasma samples of 106 ME/CFS cases and 91 frequency-matched healthy controls. 

Results: In ME/CFS cases, regression, Bayesian and enrichment analyses revealed evidence of peroxisomal dysfunction with decreased levels of plasmalogens. Other findings included decreased levels of several membrane lipids, including phosphatidylcholines and sphingomyelins, that may indicate dysregulation of the cytidine-5’-diphosphocholine pathway.  

Enrichment analyses revealed decreased levels of choline, ceramides and carnitines, and increased levels of long chain triglycerides (TG) and hydroxy-eicosapentaenoic acid.  

Elevated levels of dicarboxylic acids were consistent with abnormalities in the tricarboxylic acid cycle. Using machine learning algorithms with selected metabolites as predictors, we were able to differentiate female ME/CFS cases from female controls (highest AUC=0.794) and ME/CFS cases without self-reported irritable bowel syndrome (sr-IBS) from controls without sr-IBS (highest AUC=0.873). 

Conclusion: Our findings are consistent with earlier ME/CFS work indicating compromised energy metabolism and redox imbalance, and highlight new abnormalities that may provide insights into the pathogenesis of ME/CFS. 

One sentence summary: Plasma levels of plasmalogens are decreased in patients with myalgic encephalomyelitis/chronic fatigue syndrome suggesting peroxisome dysfunction. 

2. Decreased NO production in endothelial cells exposed to plasma from ME/CFS patients 

R. Bertinat, R. Villalobos-Labra, L. Hofmann, J. Blauensteiner, N. Sepúlveda, F. Westermeier 

Vascular Pharmacology, 2022, 106953 

Highlights 

  • ME/CFS-plasma reduced the ability of ECs to produce NO. 
  • Decreased NO production was linked to higher inhibitory phosphorylation of eNOS at Thr495 at the basal state. 
  • We provide new methodological approaches to study in vitro ED in ME/CFS. 

Abstract 

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by severe and persistent fatigue.  

Along with clinical studies showing endothelial dysfunction (ED) in a subset of ME/CFS patients, we have recently reported altered ED-related microRNAs in plasma from affected individuals. Inadequate nitric oxide (NO), mainly produced by the endothelial isoform of nitric oxide synthase (eNOS) in endothelial cells (ECs), is a major cause of ED.  

In this study, we hypothesized that plasma from that cohort of ME/CFS patients induces eNOS-related ED in vitro.  

To test this, we cultured human umbilical vein endothelial cells (HUVECs) in the presence of either plasma from ME/CFS patients (ME/CFS-plasma, n = 11) or healthy controls (HC-plasma, n = 12). Then, we measured the NO production in the absence or presence of tyrosine kinase and G protein-coupled receptors agonists (TKRs and GPCRs, respectively), well-known to activate eNOS in ECs.  

Our data show that HUVECs incubated with ME/CFS-plasma produced less NO either in the absence or presence of eNOS activators compared to ones in presence of HC-plasma.  

Also, the NO production elicited by bradykinin, histamine, and acetylcholine (GPCRs agonists) was more affected than the one triggered by insulin (TKR agonist).  

Finally, inhibitory eNOS phosphorylation at Thr495 was higher in HUVECs treated with ME/CFS-plasma compared to the same treatment with HC-plasma.  

In conclusion, this study in vitro shows a decreased NO production in HUVECs exposed to plasma from ME/CFS patients, suggesting an unreported role of eNOS in the pathophysiology of this disease. 

3. Review of the Midbrain Ascending Arousal Network Nuclei and Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and Postexertional Malaise (PEM) 

Baraniuk, J.N.  
Brain Sci. 2022, 12, 132.  

Abstract 

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS and Gulf War Illness (GWI) share features of post-exertional malaise (PEM), exertional exhaustion, or postexertional symptom exacerbation.  

In a two-day model of PEM, submaximal exercise induced significant changes in activation of the dorsal midbrain during a high cognitive load working memory task (Washington 2020) (Baraniuk this issue).  

Controls had no net change. However, ME/CFS had increased activity after exercise, while GWI had significantly reduced activity indicating differential responses to exercise and pathological mechanisms.  

These data plus findings of the midbrain and brainstem atrophy in GWI inspired a review of the anatomy and physiology of the dorsal midbrain and isthmus nuclei in order to infer dysfunctional mechanisms that may contribute to disease pathogenesis and postexertional malaise.  

The nuclei of the ascending arousal network were addressed. Midbrain and isthmus nuclei participate in threat assessment, awareness, attention, mood, cognition, pain, tenderness, sleep, thermoregulation, light and sound sensitivity, orthostatic symptoms, and autonomic dysfunction and are likely to contribute to the symptoms of postexertional malaise in ME/CFS and GWI. 

4. Direct Costs of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in Latvia 

D Araja, U Berkis, A Lunga, M Murovska 

Value in Health, VOLUME 25, ISSUE 1, SUPPLEMENT, S45, JANUARY 01, 2022 

Abstract 
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease of various etiologies, characterised by chronic fatigue not alleviated by rest, and multi-system disorder leading to deterioration in quality of life.  

There are not sufficient studies to reveal the economic impact of this disease on society, significantly due to the low level of diagnostic. Therefore, the aim of this research is to determine the approximate direct costs of ME/CFS to society in Latvia, assuming that these data could be suitable for other European countries too, and to consider possibilities to enhance diagnostic. 

5. Generalised worry in patients with Chronic Fatigue Syndrome following Cognitive Behavioural Therapy – a prospective cohort study in secondary care 

Michail Kalfas, Abigail Smakowski, Colette Hirsch, Fabio Simiao, Trudie Chalder 

Behavior Therapy, 2022, 

Highlights 

  • Generalised worry is highly prevalent in Chronic Fatigue Syndrome (CFS). 
  • Worry was linked with greater fatigue, anxiety and worse work and social adjustment. 
  • Avoidance behaviour mediated the association of worry with work and social adjustment. 
  • Cognitive Behavioural Therapy may need to focus more on generalised worry in CFS. 

Abstract 

Research has shown that generalised anxiety disorder is commonly associated with Chronic Fatigue Syndrome (CFS).  

This prospective cohort study aimed to investigate the prevalence of generalised worry in CFS patients and its relationship with fatigue, anxiety and social functioning, before and after Cognitive Behavioural Therapy (CBT).  

Our cohort consisted of 470 patients diagnosed with CFS who received CBT at a secondary care, specialist clinic.  

Patients completed self-report measures investigating levels of generalised worry, fatigue, work and social adjustment, anxiety and depression at baseline (pre-treatment), discharge from treatment, 3-month and 6-month follow up (post treatment).  

Analysis indicated a high prevalence of generalised worry (72.4%) at assessment. A significant reduction in worry following CBT (M=-3.42, p<.001, 95%CIs: 2.26, 4.57) was observed at discharge, which remained stable at follow-up. Severe baseline worriers had greater overall fatigue score (M=3.74, p=.026, 95%CIs: .33, 7.15) and worse overall work and social adjustment than mild worriers across time-points (M=5.42, p=.035 95%CIs: .27, 10.58). Avoidance behaviour mediated the association between generalised worry and work and social adjustment (95%bootstrap CIs: 013, .080).  

The majority of patients with CFS had comorbid generalised worry and severe worriers reported greater fatigue, anxiety and worse work and social adjustment. This suggests that CFS patients may benefit from targeting generalised worry during CBT. 

6. Chronic fatigue syndrome and cognitive deficit are associated with acute-phase neuropsychiatric manifestations of COVID-19: A 9-month follow-up study 

Mirfazeli, F.S., Sarabi-Jamab, A., Pereira-Sanchez, V. et al.  

Neurol Sci (2022).  

Abstract 

The prevalence of long-COVID symptoms is rising but it is not still possible to predict which patients will present them, and which types of symptoms they will present.  

We followed up 95 patients with confirmed COVID-19 for 9 months to identify and characterize long-COVID symptoms.  

Easy fatigability was the most common symptom (51.04%), followed by anxiety (38.54%), dyspnea (38.54%), and new-onset headache (38.54%).  

There was no association between COVID-19 severity in the acute phase and the number of long-COVID symptoms (F(1,93) = 0.75, p = 0.45), and cognitive function (MoCA) scores (F(1,90) = 0.073, p = 0.787) at follow-up.  

Being female (F(1,92) =  − 2.27, p = 0.02), having a higher number of symptoms (F(1,93) = 2.76, p = 0.0068), and experiencing constitutional neuropsychiatric symptoms (F(1,93) = 2.529, p = 0.01) in the acute phase were associated with having chronic fatigue syndrome at follow-up.  

Moreover, constitutional neuropsychiatric symptoms in the acute phase were associated with a lower MoCA score (F(1,93) = 10.84, p = 0.001) at follow-up.  

Specific clinical presentations such as constitutional neuropsychiatric symptoms in the acute phase might be predictors of debilitating long-COVID symptoms such as chronic fatigue syndrome and cognitive deficits. 

7. The Gut Microbiome in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) 

König RS, Albrich WC, Kahlert CR, Bahr LS, Löber U, Vernazza P, Scheibenbogen C, Forslund SK.  

Front Immunol. 2022 Jan 3;12:628741 

Abstract 

Myalgic encephalomyelitis (ME) or Chronic Fatigue Syndrome (CFS) is a neglected, debilitating multi-systemic disease without diagnostic marker or therapy. Despite evidence for neurological, immunological, infectious, muscular and endocrine pathophysiological abnormalities, the etiology and a clear pathophysiology remains unclear.  

The gut microbiome gained much attention in the last decade with manifold implications in health and disease.  

Here we review the current state of knowledge on the interplay between ME/CFS and the microbiome, to identify potential diagnostic or interventional approaches, and propose areas where further research is needed. We iteratively selected and elaborated on key theories about a correlation between microbiome state and ME/CFS pathology, developing further hypotheses.  

Based on the literature we hypothesize that antibiotic use throughout life favours an intestinal microbiota composition which might be a risk factor for ME/CFS.  

Main proposed pathomechanisms include gut dysbiosis, altered gut-brain axis activity, increased gut permeability with concomitant bacterial translocation and reduced levels of short-chain-fatty acids, D-lactic acidosis, an abnormal tryptophan metabolism and low activity of the kynurenine pathway.  

We review options for microbiome manipulation in ME/CFS patients including probiotic and dietary interventions as well as fecal microbiota transplantations.  

Beyond increasing gut permeability and bacterial translocation, specific dysbiosis may modify fermentation products, affecting peripheral mitochondria.  

Considering the gut-brain axis we strongly suspect that the microbiome may contribute to neurocognitive impairments of ME/CFS patients.  

Further larger studies are needed, above all to clarify whether D-lactic acidosis and early-life antibiotic use may be part of ME/CFS etiology and what role changes in the tryptophan metabolism might play. An association between the gut microbiome and the disease ME/CFS is plausible. As causality remains unclear, we recommend longitudinal studies.  

Activity levels, bedridden hours and disease progression should be compared to antibiotic exposure, drug intakes and alterations in the composition of the microbiota. The therapeutic potential of fecal microbiota transfer and of targeted dietary interventions should be systematically evaluated. 

Long-COVID Research References   

  1. Female Sex Is a Risk Factor Associated with Long-Term Post-COVID Related-Symptoms but Not with COVID-19 Symptoms: The LONG-COVID-EXP-CM Multicenter Study 
  1. Persistent Exertional Intolerance After COVID-19: Insights From Invasive Cardiopulmonary Exercise Testing 
  1. Trigger point injections and dry needling can be effective in treating long COVID syndrome-related myalgia: a case report 
  1. Post-acute neurological consequences of COVID-19: an unequal burden 
  1. Long COVID-19: Objectifying most self-reported neurological symptoms 
  1. Self-reported olfactory and gustatory dysfunctions in COVID-19 patients: a 1-year follow-up study in Foggia district, Italy 
  1. Covid-19: How Europe is approaching long covid 
  1. Long COVID-19: Objectifying most self-reported neurological symptoms 
  1. Long covid in children and adolescents 
  1. Immunoglobulin signature predicts risk of post-acute COVID-19 syndrome 

Dr Katrina Pears
MEA Research Correspondent

  

  

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