ME/CFS and Long Covid Research: 22 – 28 March 2022

April 1, 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 from Katrina Pears

ME/CFS Research Published 22 – 28 March 2022 

There have been four new ME/CFS studies and fourteen studies on Long Covid.  

We have highlighted two of the studies below:  

Paper two (2) is on endothelial dysfunction and altered endothelial biomarkers in long covid patients, which relates to the layer of cells lining blood vessels. We have most commonly seen studies of this nature coming from the research group in Austria, who have published several recent studies on endothelial dysfunction. 

This study looked at the endothelial function of 30 post covid patients, where 14 of these were then classified to have ME/CFS and 16 to have post-covid syndrome (PCS). However, I am rather confused as to how this classification can be made with not much detail given, as to my knowledge there is currently no agreed diagnostic criteria for PCS. It appears that patients are classed as having ME/CFS if they fit the criteria, but there is no detail to which criteria (i.e. IOM 2015 diagnostic criteria or Fukuda etc, see here), if not they have PCS. 

Nevertheless, the study did find differences between the two groups and healthy controls. Endothelial dysfunction exists in ME/CFS patients and some PCS patients but not healthy controls (although the differences are minimal when looking at the data). Further differences were found for a range of biomarkers studied, with elevated Endothelin-1 (ET-1)(an amino acid peptide secreted by vascular endothelial cells) levels being found in PCS patients only. 

I feel that much stronger case definitions are needed to make this a more robust study (as well as larger sample size), which would help address the discrepancy between findings, with only a subset of patients with PCS (5 out of 16) displaying endothelial dysfunction. This is particularly important as endothelial dysfunction has been widely reported in other studies (such as Østergaard, 2021; Charfeddine et al., 2022). 

Paper four (4) is on the lessons learnt from ME/CFS to help inform treatment practices for Long Covid, in the hope that the same mistakes are not made as currently this set of patients have not experienced the same level of stereotyping and exclusion from medical attention. The paper examines the differences experienced between the two groups of patients in terms due to: 

  • prevalence- owing to the large public awareness,  
  • aetiology of the illness- there is a clear defined onset and cause in Long Covid,  
  • biological markers of symptoms- where some with Long Covid have organ damage, and greater scientific interest to look for biomarkers, 
  • socio-political dimensions of illness- historical effect of ME/CFS in psychological spotlight. 

The paper concludes and recommends that research, policy and practice for Long Covid need to: (1) draw on the experiences from ME/CFS (e.g. graded exercise therapy (GET) recommendations), (2) the process needs to be two way where both conditions can inform the other in all aspects, (3) patient needs should be taken into account in education, and (4) disability policies needs to be reviewed. 

This paper highlights important points and comparisons between the two conditions. However, I feel many of us with ME/CFS would already be able to express our concerns with Long Covid being in the spotlight and where the differences and similarities lie. Furthermore, this paper does not explain how it will distribute its findings and recommendations to help address the concerns raised. 

You may also be interested in reading the Long Covid reference section several of the papers on treatments for Long Covid, these are papers: two (2), three (3) and four (4).  

ME/CFS Research References and Abstracts  

1. Pathway Phenotypes Underpinning Depression, Anxiety, and Chronic Fatigue Symptoms Due to Acute Rheumatoid Arthritis: A Precision Nomothetic Psychiatry Analysis 

Smesam HN, Qazmooz HA, Khayoon SQ, Almulla AF, Al-Hakeim HK, Maes M.  
J Pers Med. 2022 Mar 16;12(3):476. 


Rheumatoid arthritis (RA) is a chronic inflammatory and autoimmune disorder which affects the joints in the wrists, fingers, and knees. RA is often associated with depressive and anxiety symptoms as well as chronic fatigue syndrome (CFS)-like symptoms.  

This paper examines the association between depressive symptoms (measured with the Beck Depression Inventory, BDI), anxiety (Hamilton Anxiety Rating Scale, HAMA), CFS-like (Fibro-fatigue Scale) symptoms and immune-inflammatory, autoimmune, and endogenous opioid system (EOS) markers, and lactosylcer-amide (CD17) in RA.  

The serum biomarkers were assayed in 118 RA and 50 healthy controls. Results were analyzed using the new precision nomothetic psychiatry approach.  

We found significant correlations between the BDI, FF, and HAMA scores and severity of RA, as assessed with the DAS28-4, clinical and disease activity indices, the number of tender and swollen joints, and patient and evaluator global assessment scores.  

Partial least squares analysis showed that 69.7% of the variance in this common core underpinning psychopathology and RA symptoms was explained by immune-inflammatory pathways, rheumatoid factor, anti-citrullinated protein antibodies, CD17, and mu-opioid receptor levels.  

We constructed a new endophenotype class comprising patients with very high immune-inflammatory markers, CD17, RA, affective and CF-like symptoms, and tobacco use disorder.  

We extracted a reliable and replicable latent vector (pathway phenotype) from immune data, psychopathology, and RA-severity scales. Depression, anxiety, and CFS-like symptoms due to RA are manifestations of the phenome of RA and are mediated by the effects of the same immune-inflammatory, autoimmune, and other pathways that underpin the pathophysiology of RA. 

2. Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS) 

Haffke, M., Freitag, H., Rudolf, G. et al.  
J Transl Med20, 138 (2022).  



Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS. 

Methods: We studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs).  

14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS.  

Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs.  

In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers. 

Results: Five of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding.  

A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs. 

Conclusion: A subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups. 

3. Impact of exercise vs cognitive therapy in athletes with chronic fatigue syndrome 

S. M. Divya Mary, N. Koushik Kumar, Nelson Arputharaj John, T. Neelamalar 
International Journal of Medical and Exercise Science 2022; 8(1) 


Background of the study: Athletes are exposed to traumatic events that lead to long term psychological and psychosomatic sufferings. After an athlete experience a traumatic event, squeal may include post traumatic stress disorder. In current past year PSTD prevalence was 3.5% among women it was 7.5% and in men it was about 3.6%.  

Methodology: A observational study is done with convenient sampling. Post Traumatic Stress Disorder DMS-5 was used as a measurement tool and their psychological and psychosomatic sufferings as an outcome measure.  

Athletes who have scored more than 5 in questionnaire were divided in two groups. Before starting the study they were assessed with PSTDDMS5 scale.  

The subjects were randomly assigned into group A & B. Group A were given behavioural therapy and aerobic exercise includes stepper exercise of 3weeks/session of 30mins/session. Group B were given behavioural therapy with aerobic exercise which includes daily brisk walking of 30 minutes before 8AM.  

All the 30 participants were made to meet the Psychologist weekly once to receive cognitive behavioral therapy of 12 visits of the whole study duration.  

Result: On comparing the pre and post test values of group A and group B on PSTD shows significant difference in the mean values of p≤0.001. Thus it has been proved that stepper aerobics exercise given in groups along with the music has greater significance.  

Conclusion: There was improvement in post traumatic stress in athletes of both groups. However stepper aerobics and cognitive behavioural therapy showed more significant improvement than aerobics exercise and cognitive behavioural therapy. 

4. Long Covid at the Crossroads: Comparisons and lessons from the treatment of patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) 

Hunt J, Blease C, Geraghty KJ.  
Journal of Health Psychology. March 2022. 

Whilst parallels have been drawn between Long Covid and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), there is a well-documented history of negative stereotyping and marginalisation of patients with ME/CFS.  

A socio-politically oriented comparison of scientific, clinical and societal responses to Long Covid and ME/CFS is thus important to prevent similar harms arising among Long Covid patients.  

We identify four reasons for injustices in the treatment of ME/CFS patients, and discuss the risk of Long Covid following a similar trajectory.  

We conclude with policy and practice recommendations to help prevent such injustices arising again, including consideration of critical reflexivity in medical education. 

Long-COVID Research References   

  1. Dyspnea in Post-COVID Syndrome following Mild Acute COVID-19 Infections: Potential Causes and Consequences for a Therapeutic Approach 
  1. Can drugs reduce the risk of long COVID? What scientists know so far 
  1. Drugmakers, scientists begin the hunt for long COVID treatments 
  1. Efficacy of Adaptogens in Patients with Long COVID-19: A Randomized, Quadruple-Blind, Placebo-Controlled Trial 
  1. Sex-Related Differences in Long-COVID-19 Syndrome 
  1. Sulodexide: A Benefit for Cardiovascular Sequelae of Long COVID Patients? 
  1. Rehabilitation of post-COVID patients with chronic fatigue and cognitive disorders syndromes 
  1. Long COVID-19: The Need for an Interdisciplinary Approach 
  1. The Impact of Long COVID-19 on Muscle Health 
  1. Global Trends and Research Hotspots in Long COVID: A Bibliometric Analysis 
  1. Serology Test Results and Other Important Characteristics of Patients With Persistent COVID-19 Symptoms 
  1. Long COVID syndrome and the lung-How long will it last? 
  1. Post-COVID-19 syndrome and humoral response association after one year in vaccinated and unvaccinated patients 
  1. Magnetic Resonance Imaging Confirmed Olfactory Bulb Reduction in Long COVID-19: Literature Review and Case Series 

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent



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