ME/CFS Research Published 25 September – 1 October 2021

October 7, 2021

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.

It’s certainly been a busier week, with seven new research studies on ME/CFS but eleven studies on Long Covid. There are several interesting papers this week, we highlight two on ME/CFS from the selection below:  

The first paper (1) looks at finding a diagnostic test for ME/CFS as this is currently a major barrier, it is often acknowledged  that an early and accurate diagnosis will help the patient the most (see the recent report by Dr Bested at the IACFS/ME conference). 

This study used a statistical analysis of 250 female ME/CFS patients to establish whether grouping of patients and molecules in the blood could be found. The study found that 43% of patients have high levels of the circulating complement factor C1q,in particular in those with more pain symptoms. This molecule plays a role in the innate immune system where it protects against invading pathogens and clears dead cells. 

The authors hope that these findings can be used to direct further research, especially into finding diagnostic testing and treatments for ME/CFS. 

The fourth paper (4) looked at reviewing the evidence for using neuroimaging and dysautonomia evaluations to diagnose and find biomarkers. The authors found that while neuroimaging reveals morphological, connectivity, metabolic, and functional alterations this scarcely contributes to a diagnosis.  

However, dysautonomia (conditions caused by the autonomic nervous system, such as POTS) studies show more promise in supporting diagnosis and identifying biomarkers. The authors conclude that the evidence currently available points to the pathology (cause) of ME/CFS involving the autonomic nervous system (but not exclusively).  

You may also wish to read paper seven (7) in the Long-COVID reference section of this round-up. This paper looks at  which groups of phenotypes (physical properties) of long-COVID patients, for example in terms of medical conditions are more likely to lead to a COVID infection and new diagnoses of conditions. 

ME/CFS Research References and Abstracts  

1Complement Component C1q as a Potential Diagnostic Tool for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Subtyping 

Castro-Marrero J, Zacares M, Almenar-Pérez E, Alegre-Martín J, Oltra E.  J Clin Med. 2021 Sep 15;10(18):4171. 


Background: Routine blood analytics are systematically used in the clinic to diagnose disease or confirm individuals' healthy status. For myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disease relying exclusively on clinical symptoms for its diagnosis, blood analytics only serve to rule out underlying conditions leading to exerting fatigue. However, studies evaluating complete and large blood datasets by combinatorial approaches to evidence ME/CFS condition or detect/identify case subgroups are still scarce. 

Methods: This study used unbiased hierarchical cluster analysis of a large cohort of 250 carefully phenotyped female ME/CFS cases toward exploring this possibility. 

Results: The results show three symptom-based clusters, classified as severe, moderate, and mild, presenting significant differences (p < 0.05) in five blood parameters. Unexpectedly the study also revealed high levels of circulating complement factor C1q in 107/250 (43%) of the participants, placing C1q as a key molecule to identify an ME/CFS subtype/subgroup with more apparent pain symptoms. 

Conclusions: The results obtained have important implications for the research of ME/CFS etiology and, most likely, for the implementation of future diagnosis methods and treatments of ME/CFS in the clinic. 

2. A Comprehensive Examination of Severely Ill ME/CFS Patients 

Chang C-J, Hung LY, Kogelnik AM, Kaufman D, Aiyar RS, Chu AM Wilhelmy J, Li P, Tannenbaum L, Xiao W  Healthcare 2021, 9, 1290. 


One in four myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients are estimated to be severely affected by the disease, and these house-bound or bedbound patients are currently understudied.  

Here, we report a comprehensive examination of the symptoms and clinical laboratory tests of a cohort of severely ill patients and healthy controls.  

The greatly reduced quality of life of the patients was negatively correlated with clinical depression. The most troublesome symptoms included fatigue (85%), pain (65%), cognitive impairment (50%), orthostatic intolerance (45%), sleep disturbance (35%), post-exertional malaise (30%), and neurosensory disturbance (30%). Sleep profiles and cognitive tests revealed distinctive impairments.  

Lower morning cortisol level and alterations in its diurnal rhythm were observed in the patients, and antibody and antigen measurements showed no evidence for acute infections by common viral or bacterial pathogens.  

These results highlight the urgent need of developing molecular diagnostic tests for ME/CFS. In addition, there was a striking similarity in symptoms between long COVID and ME/CFS, suggesting that studies on the mechanism and treatment of ME/CFS may help prevent and treat long COVID and vice versa. 

3. Turning a Corner in ME/CFS Research 

Pheby DFH, Friedman KJ, Murovska M, Zalewski P.  Medicina 2021, 57, 1012. 


This collection of research papers addresses fundamental questions concerning the nature of myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS), the problem of disbelief and lack of knowledge and understanding of the condition among many doctors and the origins of this problem, and its impact on patients and their families.  

We report briefly the growing knowledge of the underlying pathological processes in ME/CFS, and the development of new organizations, including Doctors with ME, the US ME/CFS Clinical Coalition and EUROMENE, to address aspects of the challenges posed by the illness.  

We discuss the implications of COVID-19, which has much in common with ME/CFS, with much overlap of symptoms, and propose a new taxonomic category, which we are terming post-active phase of infection syndromes (PAPIS) to include both.  

This collection of papers includes a number of papers reporting similar serious impacts on the quality of life of patients and their families in various European countries. The advice of EUROMENE experts on diagnosis and management is included in the collection. We report this in light of guidance from other parts of the world, including the USA and Australia, and in the context of current difficulties in the UK over the promulgation of a revised guideline from the National Institute for Health and Care Excellence (NICE).  

We also consider evidence on the cost-effectiveness of interventions for ME/CFS, and on the difficulties of determining the costs of care when a high proportion of people with ME/CFS are never diagnosed as such.  

The Special Issue includes a paper which is a reminder of the importance of a person-centred approach to care by reviewing mind–body interventions.  

Finally, another paper reviews the scope for prevention in minimizing the population burden of ME/CFS, and concludes that secondary prevention, through early detection and diagnosis, could be of value. 

4. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Neurological Entity? 

Gandasegui IM, Laka LA, Gargiulo P-Á, Gómez-Esteban J-C, Sánchez J-VL  Medicina 2021, 57, 1030 


 Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disorder of unknown physiopathology with multisystemic repercussions, framed in ICD-11 under the heading of neurology (8E49). There is no specific test to support its clinical diagnosis.  

Our objective is to review the evidence in neuroimaging and dysautonomia evaluation in order to support the neurological involvement and to find biomarkers serving to identify and/or monitor the pathology.  

The symptoms typically appear acutely, although they can develop progressively over years; an essential trait for diagnosis is “central” fatigue together with physical and/or mental exhaustion after a small effort.  

Neuroimaging reveals various morphological, connectivity, metabolic, and functional alterations of low specificity, which can serve to complement the neurological study of the patient.  

The COMPASS-31 questionnaire is a useful tool to triage patients under suspect of dysautonomia, at which point they may be redirected for deeper evaluation.  

Recently, alterations in heart rate variability, the Valsalva maneuver, and the tilt table test, together with the presence of serum autoantibodies against adrenergic, cholinergic, and serotonin receptors were shown in a subgroup of patients.  

This approach provides a way to identify patient phenotypes. Broader studies are needed to establish the level of sensitivity and specificity necessary for their validation.  

Neuroimaging contributes scarcely to the diagnosis, and this depends on the identification of specific changes. On the other hand, dysautonomia studies, carried out in specialized units, are highly promising in order to support the diagnosis and to identify potential biomarkers. ME/CFS orients towards a functional pathology that mainly involves the autonomic nervous system, although not exclusively. 

5Subcortical brain segment volumes in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome 

Addiego FM, Zajur K, Knack S, Jamieson J, Rayhan RU, Baraniuk JN.  Life Sci. 2021 Oct 1;282:119749. 


Aims: There is controversy about brain volumes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (CFS) and Gulf War Illness (GWI). Subcortical regions were assessed because of significant differences in blood oxygenation level dependent signals in the midbrain between these diseases. 

Materials and method: Magnetization-prepared rapid acquisition with gradient echo (MPRAGE) images from 3 Tesla structural magnetic resonance imaging scans from sedentary control (n = 34), CFS (n = 38) and GWI (n = 90) subjects were segmented in FreeSurfer. Segmented subcortical volumes were regressed against intracranial volume and age, then iteratively analyzed by multivariate general linear modeling with disease status, gender and demographics as independent co-variates. 

Key findings: The optimal model for all subjects used disease status and gender as fixed factors with independent variables eliminated after iteration. Volumes of anterior and midanterior corpus callosum were significantly larger in GWI than CFS. Gender was a significant variable for many segment volumes, and so female and male subjects were analyzed separately. CFS females had smaller left putamen, right caudate and left cerebellum white matter than control women. CFS males had larger left hippocampus than GWI males. Orthostatic status and posttraumatic distress syndrome were not significant covariates. 

Significance: CFS and GWI were appropriate “illness controls” for each other. The different patterns of adjusted segment volumes suggested that sexual dimorphisms contributed to pathological changes. Previous volumetric studies may need to be reevaluated to account for gender differences. The findings are framed by comparison to the spectrum of magnetic resonance imaging outcomes in the literature. 

6Differences in Dietary Intake Among Healthy Volunteers and Myalgic Encephalomyletitis/ Chronic Fatigue Syndrome Patients 

Al-Ani S, Herra L, Hill A, Neslson I, Yang S, Turner S, Zambell, Walitt B, Nath A.  

Jounral of the Academy of Nutrition and Dietrics 232 (10): 124 


Describe differences in dietary intake between patients with Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome and healthy volunteers. 

7Electroacupuncture improves cognitive function by inhibiting NF-κB activity in rats with chronic fatigue syndrome 

Feng CW, Qu YY, Sun ZR, Wang YL, Zhang P, Wang QY, Lin WJ, Zhang L, Yang TS.  Zhen Ci Yan Jiu. 2021 Sep 25;46(9):775-81. [Article in Chinese.]  

Objective: To observe the effect of electroacupuncture (EA) on the expression of NF-κB p65 in hippocampus and the morphology of hippocampus in rats with chronic fatigue syndrome (CFS), so as to explore its mechanism in improving cognitive dysfunction of CFS. 

Methods: Forty-eight SD rats were randomly divided into control, model, EA and inhibitor groups (n=12 in each group). The CFS model was established by multi-factor compound stress stimulation method. Rats of the EA group received EA (50 Hz, 1 mA) at “Baihui” (GV20), Emotional Area I and bilateral Sensory Area for 30 min, once daily for 15 days. For rats in the inhibitor group, pyrrolidine dithiocarbamate (100 mg·kg-1·d-1) was injected intraperitoneally, once a day for 15 days. Learning and memory ability was evaluated by Morris water maze test. HE staining was used to observe the morphology of hippocampus. Western blot was used to determine the expression level of NF-κB p65 in hippocampus. 

Results: After mode-ling, the general status score was increased (P<0.01), the escape latency was prolonged(P<0.01), the times of crossing the platform was decreased(P<0.01), and the expression level of NF-κB p65 in hippocampus tissue was significantly increased (P<0.05) in the model group compared with the control group. Compared with the model group, the general status score was decreased (P<0.01), the escape latency was shortened(P<0.01), the times of crossing the platform was increased(P<0.01), and the expression level of NF-κB p65 in hippocampus tissue was significantly decreased (P<0.05) in the EA and inhibitor groups. HE staining showed that in the model group, the hippocampal nerve cells were arranged disorderly, the structure was loose, and the number of apoptotic bodies and inflammatory cells was significantly increased. The degree of tissue damage of the EA and inhibitor groups was milder than that of the model group. 

Conclusion: EA can improve the cognitive function in CFS rats, which may be associated with its effect in inhibiting the expression of NF-κB and reducing the inflammation response in hippocampus. 

Long-COVID Research References   

  1. Incidence, co-occurrence, and evolution of long-COVID features: A 6-month retrospective cohort study of 273,618 survivors of COVID-19 
  1. Characterising long COVID: a living systematic review 
  1. Recovery Focused Nutritional Therapy across the Continuum of Care: Learning from COVID-19 
  1. Association between Long COVID and Overweight/Obesity 
  1. Long COVID in a prospective cohort of home-isolated patients 
  1. Design, validation and implementation of the post-acute (long) COVID-19 quality of life (PAC-19QoL) instrument 
  1. Evolving phenotypes of non-hospitalized patients that indicate long COVID 
  1. Cohort profile: a national, community-based prospective cohort study of SARS-CoV-2 pandemic outcomes in the USA-the CHASING COVID Cohort study 
  1. Long COVID or post COVID-19 syndrome 
  1. Central Nervous System Outcomes of COVID-19 
  1. Fatigue in post-acute sequelae of SARS-CoV2 (PASC) treated with oxygen-ozone autohemotherapy – preliminary results on 100 patients 

Katrina Pears, Research Correspondent, ME Association  



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