MEA Research Roundup

ME/CFS and Long Covid Research: 02 – 08 August 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).


The ME Association maintains a comprehensive index of published research on ME/CFS and Long Covid that is free to use and updated weekly.

Audio Commentary by Dr Katrina Pears

ME/CFS Research Published 2 – 8 August 2022 

Research has picked up again this week, there have been seven new ME/CFS studies and fourteen studies on Long Covid.  

We have highlighted two contrasting studies below: 

Paper four (4) is a fairly interesting small-scale in-vitro study (experimental work performed outside of a living organism, such as in a test tube) looking at endothelial cell function (layer of cells lining blood vessels) in Long Covid (referred to as post-COVID-19 syndrome, PCS in this study. This study looked at the blood of patients with or without ME/CFS and healthy controls. 

Given the recent evidence of endothelium dysfunction in ME/CFS, which we have previously reported in a research summary, this study looked at expanding this work to try and explain why this happens. This study screened for serum anti-endothelial cell autoantibodies (AECAs) and dysregulated cytokines. The study reported a number of findings, and found compared to healthy controls: 

  • Long Covid patients with ME/CFS have significantly increased AECA binding to endothelia cells,  
  • Long Covid patients without ME/CFS have enhanced release of molecules associated with vascular remodelling and significant promotion of angiogenesis (formation of new blood vessels), 
  • Long Covid patients with and without ME/CFS were shown to have different AECA content, which in turn had different functional effects on the endothelia cells. 

However, the two groups of Long Covid patients (with and without ME/CFS) had similar results for: 

  • reduced surface levels of several EC activation markers, 
  • induced release of molecules involved in inhibition of nitric oxide-mediated endothelial relaxation. 

With the increasing number of studies which are showing the prevalence of ME/CFS in Long Covid (see brief comment on paper two (2) below), it is interesting that this study formed its own classification for Long Covid patients with ME/CFS, which was based on the Canadian Consensus Criteria (CCC). It is hard to comment on the strength of the definition used in this study, when no international agreement has been reached yet, especially on how to clearly distinguish between Long Covid patients with and without ME/CFS. 

Paper seven (7) is a review article on chinese medicine, especially focusing on acupuncture and moxibustion. Moxibustion is a form of therapy that entails the burning of mugwort leaves, it is believed that doing this alongside acupuncture enhances healing. 

The study reviewed 51 previously published studies, finding varying results, where moxibustion and traditional Chinese medicine performed better when looking at the total effective rate score and moxibustion plus acupuncture is better in the fatigue total score. These results show the need for biological measurements in studies to get meaningful answers and not relying on questionnaires as interpretation of results can vary. Although the study does not seem to have a very wide breadth as a number of indicators could have been included, such as improvement in symptoms.  

To me it seems like from the outset of this study that the authors were in favour of these treatments, with the conclusion being “traditional Chinese medicine should be used more widely in the treatment of CFS”,  I do not think there is enough evidence in this study to support this claim. 

You may also be interested in reading paper two (2) which is a pre-print publication further showing the overlap of ME/CFS in Long Covid patients. The MEA also has a new free guide to Long Covid and ME/CFS which can be found here. Dr Charles Shepherd has provided a comment for this paper: 

“I’m sure that this will be the first of many research studies to confirm that infection with Covid-19 can cause persisting ill health (i.e., Long Covid) that often involves ME/CFS-type symptoms and in some cases an illness that is identical to ME/CFS (43% in this research study).” 

There are also a number of interesting papers in the Long Covid reference section

  • Paper two (2) is a very large study from the Netherlands looking at symptoms in the hope of establishing a core definition, however, it does not look at ME/CFS symptoms. 
  • Paper four (4) is a follow-up study on microclots in Long Covid by Pretorius et al. Two studies were published by this group last year (available here: one and two). 

ME/CFS Research References and Abstracts  

1. Post-COVID syndrome with fatigue and exercise intolerance: myalgic encephalomyelitis/chronic fatigue syndrome 

Renz-Polster H, Scheibenbogen C.  

Inn Med (Heidelb). 2022 Aug;63(8):830-839. German. 


Background: A sizable part of post-COVID syndrome meets the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A doubling of cases of ME/CFS within the next years is therefore projected. 

Objectives: Presentation of the current state of knowledge on ME/CFS. 

Materials and methods: Unsystematic review of the literature and of own contributions in research and patient care. 

Results and conclusions: ME/CFS is a neuroimmunological disease, mostly infection-induced, usually persisting throughout life.  

Clinically it is characterized by fatigue lasting at least 6 months and the defining core feature of exercise intolerance (post-exertional malaise, PEM). Exercise intolerance is defined as a worsening of symptoms after (even mild) everyday exertion, which usually begins after several hours or on the following day, is still noticeable at least 14 h after exertion, and often lasts for several days (up to weeks or longer).  

Furthermore, ME/CFS is characterized by pain, disturbances of sleep, thinking and memory, and dysregulation of the circulatory, endocrine, and immune systems.  

As a separate clinical entity, ME/CFS should be distinguished from chronic fatigue, which occurs as a symptom of a range of very different diseases.  

The diagnosis of ME/CFS is made clinically using established international diagnostic criteria and requires careful stepwise diagnosis to exclude other diagnoses.  

A causal therapy for ME/CFS has not been established; the focus is on symptoms relief, treatment of the often accompanying orthostatic intolerance, and assistance with anticipatory energy management (pacing). 

2. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is common in post-acute sequelae of SARS-CoV-2 infection (PASC): Results from a post-COVID-19 multidisciplinary clinic 

Bonilla H, Quach TC, Tiwari A, Bonilla AE, Miglis M, Yang P, Eggert L, Sharifi H, Horomanski A, Subramanian A, Smirnoff L, Simpson N , Halawi H, Sum-Ping O, Kalinowski A, Patel Z, Shafer R, Geng L. 

medRxiv [preprint] 


Background: The global prevalence of PASC is estimated to be present in 0·43 and based on the WHO estimation of 470 million worldwide COVID-19 infections, corresponds to around 200 million people experiencing long COVID symptoms. Despite this, its clinical features are not well defined.  

Methods: We collected retrospective data from 140 patients with PASC in a post-COVID-19 clinic on demographics, risk factors, illness severity (graded as one-mild to five-severe), functional status, and 29 symptoms and principal component symptoms cluster analysis. The Institute of Medicine (IOM) 2015 criteria were used to determine the ME/CFS phenotype.  

Findings: The median age was 47 years, 59.0% were female; 49.3% White, 17.2% Hispanic, 14.9% Asian, and 6.7% Black.  

Only 12.7% required hospitalization.  

Seventy-two (53.5%) patients had no known comorbid conditions.  

Forty-five (33.9%) were significantly debilitated.  

The median duration of symptoms was 285.5 days, and the number of symptoms was 12.  

The most common symptoms were fatigue (86.5%), post-exertional malaise (82.8%), brain fog (81.2%), unrefreshing sleep (76.7%), and lethargy (74.6%).  

Forty-three percent fit the criteria for ME/CFS.  

Interpretations: Most PASC patients evaluated at our clinic had no comorbid condition and were not hospitalized for acute COVID-19.  

One-third of patients experienced a severe decline in their functional status. About 43% had the ME/CFS subtype. 

3. Functional Vitamin B12 deficiency in Chronic Fatigue Syndrome 

Gregory Russell-Jones 

Int J Psychiatry 7(3): 153-158. 


Chronic Fatigue Syndrome/Myalgic encephalomyelitis (CFS/ME) is a complex chronic condition, characterized by periods of extreme fatigue, for which an underlying medical condition has previously not been identified.  

Many of the symptoms of CFS/ME, are, though, similar to those with vitamin B12 deficiency. In contrast to nutritional vitamin B12 deficiency, the majority of individuals with CFS have been shown to have functional vitamin B12 deficiency as well as functional vitamin B2 deficiency.  

This functional B12 deficiency occurred despite elevated serum B12 being found, and hence presents as Paradoxical vitamin B12 deficiency. As such, CFS due to functional B2 deficiency presents as Paradoxical B12 deficiency.  

Maintenance of vitamin B12 functional activity is critically dependent upon functional B2 sufficiency, and hence resolution of CFS there must first be resolution of functional B2 deficiency before treatment with vitamin B12 can be effective. 

4. Serum of Post-COVID-19 Syndrome Patients with or without ME/CFS Differentially Affects Endothelial Cell Function In Vitro 

Flaskamp L, Roubal C, Uddin S, Sotzny F, Kedor C, Bauer S, Scheibenbogen C, Seifert M.  

Cells. 2022; 11(15):2376. 


A proportion of COVID-19 reconvalescent patients develop post-COVID-19 syndrome (PCS) including a subgroup fulfilling diagnostic criteria of Myalgic encephalomyelitis/Chronic Fatigue Syndrome (PCS/CFS).  

Recently, endothelial dysfunction (ED) has been demonstrated in these patients, but the mechanisms remain elusive.  

Therefore, we investigated the effects of patients’ sera on endothelia cells (ECs) in vitro. PCS (n = 17), PCS/CFS (n = 13), and healthy controls (HC, n = 14) were screened for serum anti-endothelial cell autoantibodies (AECAs) and dysregulated cytokines.  

Serum-treated ECs were analysed for the induction of activation markers and the release of small molecules by flow cytometry. Moreover, the angiogenic potential of sera was measured in a tube formation assay.  

While only marginal differences between patient groups were observed for serum cytokines, AECA binding to ECs was significantly increased in PCS/CFS patients.  

Surprisingly, PCS and PCS/CFS sera reduced surface levels of several EC activation markers. PCS sera enhanced the release of molecules associated with vascular remodelling and significantly promoted angiogenesis in vitro compared to the PCS/CFS and HC groups.  

Additionally, sera from both patient cohorts induced the release of molecules involved in inhibition of nitric oxide-mediated endothelial relaxation.  

Overall, PCS and PCS/CFS patients′ sera differed in their AECA content and their functional effects on ECs, i.e., secretion profiles and angiogenic potential. We hypothesise a pro-angiogenic effect of PCS sera as a compensatory mechanism to ED which is absent in PCS/CFS patients. 

5. Mechanism of acupuncture and moxibustion in treatment of chronic fatigue syndrome from perspective of intestinal flora 

Li CR, Sun ZR, Wang YL, Yang Y, Sun WB, Qu YY, Wang QY, Yang TS.  

Zhongguo Zhen Jiu. 2022 Aug 12;42(8):956-60. [Article in Chinese] 


Intestinal flora dysbiosis may play an important role in the occurrence and development of chronic fatigue syndrome (CFS), which may induce the inflammatory response and metabolic disturbance of patients with CFS.  

Acupuncture and moxibustion may achieve anti-fatigue effect by affecting the diversity and quantity of intestinal flora, improving intestinal barrier function, and regulating brain-gut peptides. 

6. In Schizophrenia, Chronic Fatigue Syndrome- and Fibromyalgia-Like Symptoms are Driven by Breakdown of the Paracellular Pathway with Increased Zonulin and Immune Activation-Associated Neurotoxicity 

Maes M, Andrés-Rodríguez L, Vojdani A, Sirivichayakul S, Barbosa DS, Kanchanatawan B.  

CNS Neurol Disord Drug Targets. [Epub ahead of print.] 


Background: A meaningful part of schizophrenia patients suffer from physiosomatic symptoms (formerly named psychosomatic) which are reminiscent of chronic fatigue syndrome and fibromyalgia (FF) and are associated with signs of immune activation and increased levels of tryptophan catabolites (TRYCATs). 

Aims: To examine whether FF symptoms in schizophrenia are associated with breakdown of the paracellular pathway, zonulin, lowered natural IgM responses to oxidative specific epitopes (OSEs); and whether FF symptoms belong to the behavioral-cognitive-physical-psychosocial-(BCPS)-worsening index consisting of indices of a general cognitive decline (G-CoDe), symptomatome of schizophrenia, and quality of life (QoL)-phenomenome. 

Methods: FF symptoms were assessed using the Fibromyalgia and Chronic Fatigue Rating scale in 80 schizophrenia patients and 40 healthy controls and serum cytokines/chemokines, IgA levels to TRYCATs, IgM to OSEs, zonulin and transcellular/paracellular (TRANS/PARA) molecules were assayed using ELISA methods. 

Results: A large part (42.3%) of the variance in the total FF score was explained by the regression on the PARA/TRANS ratio, pro-inflammatory cytokines, IgM to zonulin, IgA to TRYCATs (all positively) and IgM to OSEs (inversely). There were highly significant correlations between the total FF score and G-CoDe, symtopmatome, QoL phenomenome and BCPS-worsening score. FF symptoms belong to a common core shared by G-CoDe, symtopmatome, and QoL phenomenome. 

Discussion: The physio-somatic symptoms of schizophrenia are driven by various pathways including increased zonulin, breakdown of the paracellular tight-junctions pathway, immune activation with induction of the TRYCAT pathway, and consequent neurotoxicity. It is concluded that FF symptoms are part of the phenome of schizophrenia and BCPS-worsening as well. 

7. Acupuncture and moxibustion for chronic fatigue syndrome: A systematic review and network meta-analysis 

Fang Y, Yue BW, Ma HB, Yuan YP.  

Medicine (Baltimore). 2022 Aug 5;101(31):e29310.  


Background: Research into acupuncture and moxibustion and their application for chronic fatigue syndrome (CFS) has been growing, but the findings have been inconsistent. 

Objective: To evaluate the existing randomized clinical trials (RCTs), compare the efficacy of acupuncture, moxibustion and other traditional Chinese medicine (TCM) treatments. 

Data sources: Three English-language databases (PubMed, Embase, Web of Science, and The Cochrane Library) and 4 Chinese-language biomedical databases (Chinese Biomedical Literature Database, VIP Database for Chinese Technical Periodicals, China National Knowledge Infrastructure, and Wanfang) were searched for RCTs published from database inception through August 2021. 

Study selection: RCTs include acupuncture, moxibustion, traditional Chinese herbal medicine, western medicine and no control. 

Data extraction and synthesis: Data were screened and extracted independently using predesigned forms. The quality of RCTs was appraised with the Cochrane Collaboration risk of bias tool. We conducted a random-effects network meta-analysis within a frequentist framework. We assessed the certainty of evidence contributing to network estimates of the main outcomes with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. 

Main outcomes and measures: The primary outcomes were the overall response rate and FS-14 scale. 

Results: A total of 51 randomized controlled trials involving 3473 patients with CFS were included in this review. Forty one studies indicate low risk or unknown risk, and the GRADE scores of the combined results show low levels. Among the main indicators, traditional Chinese medicine therapies have excellent performance. However, the overall response rate is slightly different from the results obtained from the Fatigue Scale-14 total score. Moxibustion and traditional Chinese medicine (Odds ratios 48, 95% CrI 15-150) perform better in the total effective rate, while moxibustion plus acupuncture (MD 4.5, 95% CrI 3.0-5.9) is better in the FS-14 total score. 

Conclusions: The effect of acupuncture and moxibustion in the treatment of CFS was significantly higher than that of other treatments. Traditional Chinese medicine should be used more widely in the treatment of CFS. 

Long-COVID Research References   

  1. Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches 
  1. Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study 
  1. Long COVID: which symptoms can be attributed to SARS-CoV-2 infection? 
  1. Prevalence of symptoms, comorbidities, fibrin amyloid microclots and platelet pathology in individuals with Long COVID/Post-Acute Sequelae of COVID-19 (PASC) 
  1. Cognitive Complications of COVID-19 Infection 
  1. A Review of Respiratory Post-Acute Sequelae of COVID-19 (PASC) and the Potential Benefits of Pulmonary Rehabilitation 
  1. Complementary and Alternative Medicine for Long COVID: Scoping Review and Bibliometric Analysis 
  1. Long COVID symptomatology after twelve months and its impact on quality of life according to initial COVID-19 disease severity 
  1. Post-acute COVID-19 syndrome and gut dysbiosis linger beyond 1 year after SARS-CoV-2 clearance 
  1. Mast cell activation syndrome and the link with long COVID 
  1. Returning to work and the impact of post COVID-19 condition: A systematic review 
  1. COVID-19 and Therapeutic Apheresis 
  1. Long-haul COVID: healthcare utilization and medical expenditures 6 months post-diagnosis 
  1. Clinical, sociodemographic and environmental factors impact post-COVID-19 syndrome 

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent
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