ME/CFS Research Published 24-30 May 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 by Dr Katrina Pears

ME/CFS Research Published 24 – 30 May 2022 

There have been seven new ME/CFS studies and fifteen studies on Long Covid. 

None of the research published this week particularly caught our eyes, but we have given details of two different studies below: 

Paper one (1) is a detailed review of the pathobiology to date on ME/CFS. The paper hypotheses that ME/CFS research may benefit by looking at the role of the innate immune system of the brain in greater depth. Specifically, the authors look into neuroglia cells, and the link to two common features in ME/CFS: post-exertional malaise (PEM) and reduced cerebral blood flow (CBF)

Glia or neuroglia cells are: 

  • non-neuronal cells (i.e. not nerves and do not produce electrical impulses) in the brain and nervous system (aka in central nervous system CNS),  
  • perform specific jobs at keeping the brain functioning,  
  • primary function is to support the neurons, 
  • there are a variety of subtypes of glial cells, including astrocytes, oligodendrocytes, and microglia, each of which is specialised for a particular function.  
  • (Singular is glial) 

The authors have provided a brief summary of their research, which helps shorten the lengthy reading of the full paper. The authors also provide a very good bite-sized tweet thread explaining  the steps in their review, which is definitely worth a read.  

It is a great shame that this is yet another review paper with no future biological studies. The evidence presented is limited by the small number of small-scale studies performed in this area which are rarely followed up with larger trials. Therefore, I hope the researchers use their evidence to conduct trials in this area, especially seeing as they recommend research should be in this area. 

Paper three (3) is a preprint study (has not undergone peer review so the science has not been verified) on the use of cytokines (small proteins involved in cell signalling) to diagnose conditions such as ME/CFS, post-treatment lyme disease (PTLD) and post-acute sequelae of Covid-19 (PACS). This study used models, specifically a decision tree model using a Classification and Regression Tree (CART) algorithm. 

Although the premise of this study is exciting as there is huge need to be able to distinguish between these conditions, I do not feel that this research is strong, especially given the one sentence abstract conclusion “proper classification of these inflammatory conditions with very similar symptoms is critical for proper diagnosis and treatment.” Furthermore, there is also a lot of information lacking, such as: 

  • recruitment of patients, 
  • details on patients (e.g. age, sex, duration of illness) 
  • classification criteria for ME/CFS, 
  • raw data of the cytokine levels for each group, 
  • no verification of results in the model with an independent cohort, 
  • very little detail on the cytokines found and their roles, 
  • details are lacking on how the three conditions can be characterised.  

In conclusion, I feel this research needs a lot more investigation to make a strong case for using cytokines to separate between ME/CFS, Lyme and Long Covid. 

You may also be interested in reading paper seven (7) on autoimmune characteristics in ME/CFS. 

ME/CFS Research References and Abstracts  

1. The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure 

Renz-Polster H, Tremblay ME, Bienzle D, Fischer JE.  
Front Cell Neurosci. 2022 May 9;16:888232. 

Abstract 

Although myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has a specific and distinctive profile of clinical features, the disease remains an enigma because causal explanation of the pathobiological matrix is lacking.  

Several potential disease mechanisms have been identified, including immune abnormalities, inflammatory activation, mitochondrial alterations, endothelial and muscular disturbances, cardiovascular anomalies, and dysfunction of the peripheral and central nervous systems.  

Yet, it remains unclear whether and how these pathways may be related and orchestrated.  

Here we explore the hypothesis that a common denominator of the pathobiological processes in ME/CFS may be central nervous system dysfunction due to impaired or pathologically reactive neuroglia (astrocytes, microglia and oligodendrocytes).  

We will test this hypothesis by reviewing, in reference to the current literature, the two most salient and widely accepted features of ME/CFS, and by investigating how these might be linked to dysfunctional neuroglia.  

From this review we conclude that the multifaceted pathobiology of ME/CFS may be attributable in a unifying manner to neuroglial dysfunction. Because the two key features – post exertional malaise and decreased cerebral blood flow – are also recognized in a subset of patients with post-acute sequelae COVID, we suggest that our findings may also be pertinent to this entity. 

2. Health secretary pledges more ME/CFS research as he reveals that relative has condition 

Ingrid Torjesen 
BMJ 2022;377:o1341 

Abstract 

Patients with myalgic encephalomyelitis (ME) can expect to see more research and support for the condition, which “has been neglected for far too long,” England’s health and social care secretary has said. 

Speaking at the launch of a report by the All Party Parliamentary Group on Myalgic Encephalomyelitis on 25 May,1 Sajid Javid revealed that one of his own relatives had had her life severely affected by ME, and he pledged to tackle the lack of research on the condition. He will co-chair a round table of international experts next month to help set this research strategy.2 

A lack of understanding about the condition and … (full text behind a paywall) 

3. Cytokine Hub Classification of PASC, ME-CFS and other PASC-like Conditions 

Bruce K. Patterson, Jose Guevara-Coto, Edgar B. Francisco, Ram Yogendra, Purvi Parikh, Rodrigo A Mora-Rodríguez, Javier Mora, Christopher Beaty, Gary Kaplan, Amiram Katz, Joseph A. Bellanti 
ResearchSquare [Preprint] 

Abstract  

Background: Post-acute sequelae of COVID-19 (PASC) is a growing healthcare and economic concern affecting as many as 10%-30% of those infected with COVID-19. Though the symptoms have been well-documented, they significantly overlap with other common chronic inflammatory conditions which could confound treatment and therapeutic trials.  

Methods: A total of 236 patients including 64 with post-acute sequelae of COVID-19 (PASC), 50 with myalgic encephalomyelitis-chronic fatigue syndrome (ME-CFS), 29 with post-treatment Lyme disease (PTLD), and 42 post-vaccine individuals with PASClike symptoms (POVIP) were enrolled in the study.  

We performed a 14-plex cytokine/chemokine panel previously described to generate raw data that was normalized and run in a decision tree model using a Classification and Regression Tree (CART) algorithm. The algorithm was used to classify these conditions in distinct groups despite their similar symptoms.  

Results: PASC, ME-CSF, POVIP, and Acute COVID-19 disease categories were able to be classified by our cytokine hub based CART algorithm with an average F1 score of 0.61 and high specificity (94%).  

Conclusions: Proper classification of these inflammatory conditions with very similar symptoms is critical for proper diagnosis and treatment. 

4. Fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome 

LucindaBateman 
Neurobiology of Brain Disorders (Second Edition) – Biological Basis of Neurological and Psychiatric Disorders – 2023, Pages 559-573 

Abstract 

Fibromyalgia (FM) and chronic fatigue syndrome, now called myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), are chronic multisystem illnesses manifest by widespread pain and pain amplification, chronic fatigue, impaired function, unrefreshing sleep, cognitive complaints, autonomic dysregulation, and chronic inflammation in the absence of well-established and clinically accessible objective markers. This chapter will discuss the similarities and differences, clinical presentation, historical context, case definitions, possible causes and pathogenesis, and common comorbid conditions of FM and ME/CFS. 

5. Chronic fatigue syndrome and occupational status: a retrospective longitudinal study 

Brian M Hughes, David Tuller 

Occupational Medicine, Volume 72, Issue 4, May 2022, Pages e1–e2 

Abstract 

No Abstract available- full content available online 

6. Electroacupuncture at BL15 attenuates chronic fatigue syndrome by downregulating iNOS/NO signaling in C57BL/6 mice 

Zhu Y, Wang J, Yao L, Huang Y, Yang H, Yu X, Chen X, Chen Y.  
Anat Rec (Hoboken). 2022 May 24. [Epub ahead of print.] 

Abstract 

Chronic fatigue syndrome (CFS) has a high incidence due to the increased pressure of daily life and work in modern society.  

Our previous clinical studies have found the effects of electroacupuncture (EA) on CFS patients, however, the mechanism of EA on CFS is still unknown. 

In this study, we investigated the effects of EA on cardiac function in a CFS mouse model to explore its underlying mechanism.  

The mice were randomly divided into three groups: control, CFS, and CFS mice receiving EA (CFS + EA).  

After behavioral assessments and echocardiographic measurement, blood and heart tissue of the mice were collected for biochemical tests, and then we evaluated the effects of EA on the CFS mouse model when nitric oxide (NO) levels were enhanced by l-arginine.  

The results showed that EA ameliorated the injured motor and cardiac function.  

Meanwhile, EA also inhibited increased expression of inducible nitric oxide synthase (iNOS) at heart tissue and the serum NO levels in mice subjected to sustained forced swimming stress.  

Furthermore, the NO level in serum increased with l-arginine administration, which blocked the effects of EA on CFS mice.  

This study suggested that EA could improve the motor function and cardiac function in CFS mice and its effects may be associated with the down-regulation of iNOS/NO signaling.  

7. Chronic Fatigue Exhibits Heterogeneous Autoimmunity Characteristics Which Reflect Etiology 

Danilenko, O.V.; Gavrilova, N.Y.; Churilov, L.P.  
Pathophysiology 2022, 29, 187-199 

Abstract 

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is considered to be associated with post-viral complications and mental stress, but the role of autoimmunity also remains promising.  

A comparison of autoimmune profiles in chronic fatigue of different origin may bring insights on the pathogenesis of this disease.  

Thirty-three patients with CFS/ME were divided into three subgroups. The first group included Herpesviridae carriers (group V), the second group included stress-related causes of chronic fatigue (distress, group D), and the third group included idiopathic CFS/ME (group I). Were evaluated thirty-six neural and visceral autoantigens with the ELISA ELI-test (Biomarker, Russia) and compared to 20 healthy donors, either without any fatigue (group H), or “healthy but tired” (group HTd) with episodes of fatigue related to job burnout not fitting the CFS/ME criteria.  

β2-glycoprotein-I autoantibodies were increased in CFS/ME patients, but not in healthy participants, that alludes the link between CFS/ME and antiphospholipid syndrome (APS) earlier suspected by Berg et al. (1999).  

In CFS/ME patients, an increase in levels of autoantibodies towards the non-specific components of tissue debris (double-stranded DNA, collagen) was shown.  

Both CFS and HTd subgroups had elevated level of autoantibodies against serotonin receptors, glial fibrillary acidic protein and protein S100. Only group V showed an elevation in the autoantibodies towards voltage-gated calcium channels, and only group D had elevated levels of dopamine-, glutamate- and GABA-receptor autoantibodies, as well as NF200-protein autoantibodies. Therefore, increased autoimmune reactions to the multiple neural antigens and to adrenal medullar antigen, but not to other tissue-specific somatic ones were revealed.  

An increase in autoantibody levels towards some neural and non-tissue-specific antigens strongly correlated with a CFS/ME diagnosis.  

Autoimmune reactions were described in all subtypes of the clinically significant chronic fatigue. Visceral complaints in CFS/ME patients may be secondary to the neuroendocrine involvement and autoimmune dysautonomia. CFS may be closely interrelated with antiphospholipid syndrome, that requires further study. 

Long-COVID Research References   

  1. Recommendations for the recognition, diagnosis, and management of long COVID 
  1. Long COVID in children and young people: uncertainty and contradictions 
  1. ‘Tell me about that colleague': long COVID, narrative medicine, and a remarkable conversation 
  1. Use of linked patient data to assess the effect of Long-COVID on system-wide healthcare utilisation 
  1. One Year Follow-Up of COVID-19 Related Symptoms and Patient Quality of Life: A Prospective Cohort Study 
  1. Cardiometabolic syndrome — an emergent feature of Long COVID? 
  1. The Impact of COVID Vaccination on Symptoms of Long COVID: An International Survey of People with Lived Experience of Long COVID 
  1. Epipharyngeal Abrasive Therapy (EAT) Has Potential as a Novel Method for Long COVID Treatment 
  1. Association between chemosensory impairment with neuropsychiatric morbidity in post-acute COVID-19 syndrome: results from a multidisciplinary cohort study 
  1. Neurological Sequelae of COVID-19 
  1. Clearance of Persistent SARS-CoV-2 RNA Detection in a NFκB-Deficient Patient in Association with the Ingestion of Human Breast Milk: A Case Report 
  1. Impaired Vagal Activity in Long-COVID-19 Patients 
  1. Long COVID after breakthrough SARS-CoV-2 infection 
  1. Long COVID and the Autonomic Nervous System: The Journey from Dysautonomia to Therapeutic Neuro-Modulation through the Retrospective Analysis of 152 Patients 
  1. Symptom burden correlates to impairment of diffusion capacity and exercise intolerance in long COVID patients 

Dr Katrina Pears
MEA Research Correspondent

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