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

March 4, 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 Katrina Pears

ME/CFS Research Published 22 – 28 February 2022 

There have been seven new ME/CFS studies and eleven studies on Long Covid this week.  

Despite there being a mix of studies this week, none of these were high quality biomedical studies which might add to our understanding of ME/CFS. 

We have highlighted two of the studies below:  

Paper four (4) looks at whether a tuberculosis infection (TB) increases the risk of developing CFS (term used in paper). The study was conducted by analysing the National Health Insurance Research Database of Taiwan, finding that TB infection is associated with an elevated risk of subsequent chronic fatigue syndrome. 

Despite this being the first study to investigate a potential link, these results are not too surprising as several underlying similar immunosignatures are shared between CFS and TB. For example; the similarities in the proinflammatory cytokine (small proteins involved in the immune system and blood cells). 

Interestingly, the study showed an increased risk in males, which could question whether chronic fatigue syndrome or chronic fatigue was being investigated as it might have been difficult to differentiate in this retrospective study.  

There is not much more we can learn from this pilot study as no laboratory analyses were performed but this study leads the ways for future studies examining the mechanisms involved in the link between CFS and TB. 

Paper six (6) caught my eyes solely due to the laboratory techniques used in the study, called Gas Chromatography–Mass Spectrometry (GCMS) which is a technique I am very familiar with having used this throughout my PhD studies. GCMS is a techniques where different chemicals in a sample are separated, identified and quantified. 

This study investigated an aerobic exercise intervention program for 46 male secondary school students. The study quantified several different parameters which were reported to improve following the intervention, as well as performing a urine metabolite analysis which uses GCMS.  

The GCMS technique was used to screen for several different compounds involved in important metabolic pathways. This approach revealed alterations in three out of the six metabolic pathways studied: 

  • putrescine (arginine and proline metabolism),  
  • 6-Phospho-D-Gluconate (starch and sucrose metabolism pathway),  
  • pentose (phosphate metabolism pathway).  

The authors propose that the lessening in fatigue symptoms and oxidative levels may be regulated by the altered metabolic pathways found. 

While I was personally interested in the paper due to the methods used, there are a number of questions over this study. 

  • This was a Chinese study and from reading the paper the description of symptoms does not fit with how we would describe ME/CFS. Which again makes me question whether the study was looking at students with chronic fatigue rather than ME/CFS. 
  • The study did not include anyone who had fatigue which caused an inability to exercise. 
  • No discussion of post-exertional malaise (PEM) after the intervention. 
  • It is also hard to believe that an exercise programme which was no less than 45 minutes three times a week for 12- weeks had positive outcomes on fatigue levels. It makes me tired just thinking about it! 

The conclusion of the paper was that “it is important to schedule daily exercise for high school students”. I think for that reason we can discount this study as adding to our knowledge of ME/CFS, as graded exercise therapy (GET)(not used in this study as it was an intense exercise technique) is no longer recommended for ME/CFS. Paper seven (7) in this roundup also expresses the harm that can be caused by GET. 

You may also be interested in reading the Editorial Article on post-infection fatigue syndromes (Paper 1 (one)) which Dr Charles Shephard has provided a comment for. 

ME/CFS Research References and Abstracts  

1. Editorial: Current Insights Into Complex Post-infection Fatigue Syndromes With Unknown Aetiology: The Case of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Beyond 

Francisco Westermeier, Eliana Mattos Lacerda, Carmen Scheibenbogen and Nuno Sepúlveda 

Front. Med., 24 February 2022  


No abstract available. Full article available online. 

Comment by Dr Charles Shephard available here

2. Platelet Storage Pool Deficiency and Elevated Inflammatory Biomarkers Are Prevalent in Postural Orthostatic Tachycardia Syndrome 

Gunning, W.T.; Kramer, P.M.; Cichocki, J.A.; Karabin, B.L.; Khuder, S.A.; Grubb, B.P.  

Cells 2022, 11, 774. 


A significant number of postural orthostatic tachycardia syndrome (POTS) patients have platelet delta granule storage pool deficiency (δ-SPD).  

The etiology of POTS is unknown but a number of laboratories, including ours, have reported elevations of G-protein-coupled adrenergic receptor and muscarinic acetylcholine receptor autoantibodies in POTS patients, detected by a variety of techniques, suggesting that the disorder is an autoimmune condition. Thus, it could also be considered an inflammatory disease.  

In a pilot study, we investigated a limited number of platelet-related cytokines and chemokines and discovered many that were elevated.  

This case–control study validates our pilot study results that POTS patients have an activated innate immune system.  

Plasma of 35 POTS patients and 35 patients with unexplained bleeding symptoms and categorized as “non-POTS” subjects was analyzed by multiplex flow cytometry to quantify 16 different innate immune system cytokines and chemokines. Electron microscopy was used to quantify platelet dense granules.  

Ten of 16 biomarkers of inflammation were elevated in plasma from POTS patients compared to non-POTS subjects, with most of the differences extremely significant, with p values < 0.0001.  

Of particular interest were elevations of IL-1β and IL-18 and decreased or normal levels of type 1 interferons in POTS patients, suggesting that the etiology of POTS might be autoinflammatory.  

All POTS patients had δ-SPD. With a growing body of evidence that POTS is an autoimmune disease and having elevations of the innate immune system, our results suggest a potential T-cell-mediated autoimmunity in POTS characteristic of a mixed-pattern inflammatory disease similar to rheumatoid arthritis. 

3. Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 3: “Energy System First Aid” for People With Postexertional Symptom Exacerbation 

Todd E. Davenport,  Staci R. Stevens, Jared Stevens, Christopher R. Snell, J. Mark Van Ness 



No abstract available. Full article available online 

4. How mycobacterium tuberculosis infection could lead to the increasing risks of chronic fatigue syndrome and the potential immunological effects: a population-based retrospective cohort study 

Yang, TY., Lin, CL., Yao, WC. et al.  

J Transl Med 20,99 (2022). 


Background: Chronic fatigue syndrome (CFS) has been shown to be associated with infections. Tuberculosis (TB) is a highly prevalent infectious disease. Patients with chronic fatigue syndrome and post-tuberculosis experience similar symptoms. Furthermore, chronic fatigue syndrome and tuberculosis share similar plasma immunosignatures. This study aimed to clarify the risk of chronic fatigue syndrome following the diagnosis of Mycobacterium tuberculosis infection (MTI), by analyzing the National Health Insurance Research Database of Taiwan. 

Methods: 7666 patients aged 20 years or older with newly diagnosed Mycobacterium tuberculosis infection during 2000–2011 and 30,663 participants without Mycobacterium tuberculosis infection were identified. Both groups were followed up until the diagnoses of chronic fatigue syndrome were made at the end of 2011. 

Results: The relationship between Mycobacterium tuberculosis infection and the subsequent risk of chronic fatigue syndrome was estimated through Cox proportional hazards regression analysis, with the incidence density rates being 3.04 and 3.69 per 1000 person‐years among the non‐Mycobacterium tuberculosis infection and Mycobacterium tuberculosis infection populations, respectively (adjusted hazard ratio [HR] = 1.23, with 95% confidence interval [CI] 1.03–1.47). In the stratified analysis, the Mycobacterium tuberculosis infection group were consistently associated with a higher risk of chronic fatigue syndrome in the male sex (HR = 1.27, 95% CI 1.02–1.58) and age group of ≥ 65 years old (HR = 2.50, 95% CI 1.86–3.38). 

Conclusions: The data from this population‐based retrospective cohort study revealed that Mycobacterium tuberculosis infection is associated with an elevated risk of subsequent chronic fatigue syndrome. 

5. Evaluation of a training programme to enable MSK physiotherapists to identify individuals with CFS symptoms post-COVID19 

J. Breach, O. Ledbetter, L. Mould 

Physiotherapy P14 VOLUME 114, SUPPLEMENT 1, E178, FEBRUARY 01, 2022 


Purpose: It is reported there are currently 1.1 million people suffering from long COVID symptoms, with 830,000 of these reporting that has an impact on their day to day life. One of the primary symptoms reported is fatigue.  

As part of our COVID rehabilitation programme, Nuffield Health physiotherapists were involved in triaging participants for suitability for the programme. As previous research from the ME/CFS population indicates that exercise could be detrimental to individuals with fatigue by inducing post-exertional malaise, it was imperative they felt confident in being able to identify individuals with CFS-type symptoms to assess their suitability for the programme. 

The aim of this project is to evaluate the effectiveness of the training programme in improving individual confidence in being able to identify individuals with chronic fatigue symptoms. 

Methods: The training was devised following an extensive review of the current literature surrounding fatigue in both LongCovid and ME/CFS and delivered via a blended offering of online modules, webinars, interactive virtual classrooms, and discussion groups. It included being able to recognise signs of post viral fatigue, especially PEM as well as other symptoms such as cognitive issues, sleep disturbance and reduced functional capacity as detailed in the NICE draft guidelines for ME/CFS 2021. The importance of this was emphasised by discussing evidence surrounding exercise and chronic fatigue and potential for harm if not managed appropriately by considering the symptom response to activity. An Introduction to energy envelope theory for pacing was also presented. 

The effectiveness of the training was evaluated by an anonymised survey. Physiotherapists were asked to rate their levels of confidence before and after the training in regard to assessing participants for inclusion in the programme based on their fatigue symptoms, plus to provide comments on the training content. 

Results: Average confidence 8/10 

Improvement of 56% after training 


Positive: I felt confident to exclude all with CFS… 

I think it is a case of getting on with it putting it into practice 

Negative: I feel that as msk physios this is beyond the scope of what we should be doing… 

As MSK physios we are not experts in many of the fields listed. i.e., CFS 

Conclusion(s): The training did result in good improvement in confidence in screening for CFS symptoms. However, the feedback did include some individuals feeling this is beyond their current scope of practice as msk physios, highlighting a need for ongoing support. This is understandable due to the evolving picture of Long Covid symptoms being different to the usual caseload of msk physiotherapists. However, to meet the growing need of rehabilitation for those suffering with Long Covid, it is imperative to support therapists in expanding their scope of practice to contribute to the recovery from the pandemic. 

Impact: The findings will influence the ongoing support given to MSK physiotherapists to upskill in the area of chronic fatigue assessment and management to meet the demand Long Covid will be placing on rehabilitation. This is imperative to support individual therapists to expand their scope of practice beyond the usual MSK caseload. 

6. Differential Metabolites and Metabolic Pathways Involved in Aerobic Exercise Improvement of Chronic Fatigue Symptoms in Adolescents Based on Gas Chromatography–Mass Spectrometry 

Zhao, S.; Chi, A.; Wan, B.; Liang, J.  

Int. J. Environ. Res. Public Health2022, 19, 2377 


Studies have found that the prevalence of chronic fatigue syndrome (CFS) in adolescents has continued to increase over the years, affecting learning and physical health. High school is a critical stage for adolescents to grow and mature. There are inadequate detection and rehabilitation methods for CFS due to an insufficient understanding of the physiological mechanisms of CFS.  

The purpose of this study was to evaluate the effect and metabolic mechanisms of an aerobic running intervention program for high school students with CFS.  

Forty-six male high school students with CFS were randomly assigned to the exercise intervention group (EI) and control group (CFS). Twenty-four age- and sex-matched healthy male students were recruited as healthy controls (HCs).  

The EI group received the aerobic intervention for 12 weeks, three times a week, in 45-min sessions; the CFS group maintained their daily routines as normal.  

The outcome measures included fatigue symptoms and oxidation levels. Keratin was extracted from the nails of all participants, and the oxidation level was assessed by measuring the content of 3-Nitrotyrosine (3-NT) in the keratin by ultraviolet spectrophotometry. All participants’ morning urine was collected to analyze urinary differential metabolites by the GC-MS technique before and after the intervention, and MetaboAnalyst 5.0 was used for pathway analysis.  

Compared with before the intervention, the fatigue score and 3-NT level in the EI group were significantly decreased after the intervention. The CFS group was screened for 20 differential metabolites involving the disruption of six metabolic pathways, including arginine biosynthesis, glycerolipid metabolism, pentose phosphate pathway, purine metabolism, β-alanine metabolism, and arginine and proline metabolism.  

After the intervention, 21 differential metabolites were screened, involved in alterations in three metabolic pathways: beta-alanine metabolism, pentose phosphate metabolism, and arginine and proline metabolism.  

Aerobic exercise was found to lessen fatigue symptoms and oxidative levels in students with CFS, which may be related to the regulation of putrescine (arginine and proline metabolism), 6-Phospho-D-Gluconate (starch and sucrose metabolism pathway), and Pentose (phosphate metabolism pathway) 

7. Is It Useful to Question the Recovery Behaviour of Patients with ME/CFS or Long COVID? 

Vink, M.; Vink-Niese, F.  

Healthcare2022, 10, 392.  


For the last few decades, medical guidelines have recommended treating patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with graded exercise therapy (GET) and cognitive behavioural therapy (CBT). Moreover, doctors have questioned the recovery behaviour of these patients and stimulated them to follow these treatments so that they would be able to go back to work.  

In this article, we reviewed trials of GET and CBT for ME/CFS that reported on work status before and after treatment to answer the question of whether doctors should continue to question the recovery behaviour of patients with ME/CFS.  

Our review shows that more patients are unable to work after treatment than before treatment with CBT and GET. It also highlights the fact that both treatments are unsafe for patients with ME/CFS. Therefore, questioning the recovery behaviour of patients with ME/CFS is pointless.  

This confirms the conclusion from the British National Institute for Health and Care Excellence (NICE), which has recently published its updated ME/CFS guideline and concluded that CBT and GET are not effective and do not lead to recovery.  

Studies on CBT and GET for long COVID have not yet been published. However, this review offers no support for their use in improving the recovery of patients with an ME/CFS-like illness after infection with COVID-19, nor does it lend any support to the practice of questioning the recovery behaviour of these patients. 

Long-COVID Research References   

  1. Chronic cerebral aspects of long COVID, post-stroke syndromes and similar states share their pathogenesis and perispinal etanercept treatment logic 
  1. A multi-disciplinary rehabilitation approach for people surviving severe COVID-19-a case series and literature review 
  1. Multiple early factors anticipate post-acute COVID-19 sequelae 
  1. Implication of COVID-19 on Erythrocytes Functionality: Red Blood Cell Biochemical Implications and Morpho-Functional Aspects 
  1. Neural Dysregulation in Post-Covid Fatigue 
  1. Long COVID 12 months after discharge: persistent symptoms in patients hospitalised due to COVID-19 and patients hospitalised due to other causes—a multicentre cohort study 
  1. Long-term follow-up of dynamic brain changes in patients recovered from COVID-19 without neurological manifestations 
  1. Outpatient Pulmonary Rehabilitation in Patients with Long COVID Improves Exercise Capacity, Functional Status, Dyspnea, Fatigue, and Quality of Life 
  1. Neurological manifestations of long-COVID syndrome: a narrative review 
  1. A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications 
  1. Long-term immunologic effects of SARS-CoV-2 infection: leveraging translational research methodology to address emerging questions 

 Katrina Pears, Research Correspondent, ME Association  

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent



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