Research Roundup: ME/CFS Research Published 16-22 October 2021

October 29, 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).


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

ME/CFS Research Published 16 – 22 October 2021  

It’s been a busier week for research, with seven new research studies on ME/CFS but ten studies on Long Covid. A large proportion of the papers I have reported on this week are preprints, therefore have not undergone peer review. 

We have highlighted two papers on ME/CFS from the selection below: 

Paper three (3) looks at the two overlapping conditions ME/CFS and Fibromyalgia (FM) and measures pain symptoms before and after exercise. The study conducts a systematic review and meta-analysis– which aims to merge the findings of many independent studies using statistical methods, therefore the authors did not conduct the research study themselves. 

Unsurprisingly, the authors conclude that exercise can increase pain felt by people with ME/CFS and FM, confirming that pain is an important part of post-exertional malaise (PEM). Some clarity is needed to quantify the pain levels before exertion, as pain is not only experienced with these conditions after exercise. 

Paper four (4) looks at cerebral blood flow (CBF- blood supply to the brain over time) after tilt table testing. Tilt table tests are the diagnostic test used for diagnosing orthostatic intolerance, such as postural tachycardia syndrome (POTS) (more information about this condition can be found here.) A tilt table test involves being led down for 20 minutes, before being tilted head up to 70 degrees for a maximum time of 30 minutes, while measurements such as heart rate and blood pressure are taken. 

This study looked at establishing when cerebral blood flow returns to normal after tilt table testing using 60 ME/CFS patients. 

The key points highlighted by the authors of this paper are: 

  • Cerebral blood flow in ME/CFS patients remains abnormal 5 minutes post-tilt test. 
  • Post cerebral blood flow abnormalities do not depend on hemodynamic (dynamics of blood flow) results and on end-tidal carbon dioxide pressures during the tilt-test. 
  • Post cerebral blood flow abnormalities are most severe in more severely diseased ME/CFS patients. 

These results have significance for energy management and the importance of lying down after a stressor in ME/CFS patients. Results from this study need further investigation to understand the mechanisms for delayed recovery of cerebral blood flow and the impact of post-exertional malaise (PEM). 

ME/CFS Research References and Abstracts  

1. Can Remote Patient Monitoring Be the New Standard in Primary Care of Chronic Diseases, Post-COVID-19? 

Muller AE, Berg RC, Jardim PSJ, Johansen TB, Ormstad SS.  
Telemed J E Health. 2021 Oct 19.  


Background: One lesson from the current COVID-19 pandemic is the need to optimize health care provision outside of traditional settings, and potentially over longer periods of time. An important strategy is remote patient monitoring (RPM), allowing patients to remain at home, while they transmit health data and receive follow-up services.  

Materials and Methods: We conducted an overview of the latest systematic reviews that had included randomized controlled trials with adult patients with chronic diseases. We summarized results and displayed these in forest plots, and used GRADE (Grading of Recommendations Assessment, Development, and Evaluation) to assess our certainty of the evidence.  

Results: We included 4 systematic reviews that together reported on 11 trials that met our definition of RPM, each including patients with diabetes and/or hypertension. RPM probably makes little to no difference on HbA1c levels. RPM probably leads to a slight reduction in systolic blood pressure, with questionable clinical meaningfulness. RPM probably has a small negative effect on the physical component of health-related quality of life, but the clinical significance of this reduction is uncertain. We have low confidence in the finding that RPM makes no difference to the remaining five primary outcomes.  

Conclusion: Most of our findings are consistent with reviews of other, broader definitions of RPM. The type of RPM examined in this review is as effective as standard treatment for patients with diabetes/hypertension. If this or other types of RPM are to be used for “long covid” patients or for other chronic disease groups post-pandemic, we need to understand why RPM may negatively affect quality of life. 

2. Evidence based care for people with chronic fatigue syndrome and myalgic encephalomyelitis 

Sharpe M, Chalder T, White P.  
Journal of General Internal Medicine. 2021 Oct 1. [Epub ahead of print] 


Chronic fatigue syndrome (CFS), sometimes referred to as myalgic encephalomyelitis (ME) and often as CFS/ME, is an illness characterized by disabling fatigue and other symptoms, typically worsened by activity.  

The main evidence-based treatments are rehabilitative in nature and include specific types of cognitive behavior therapy (CBT), and graded exercise therapy (GET).  

In this article we briefly review the evidence for their safety and effectiveness and propose that much of the controversy about them arises from misunderstandings about their nature and delivery. In particular, we emphasize that successful rehabilitation from CFS/ME does not indicate that the illness is not real.  

We recommend that rehabilitative treatment always be preceded by a thorough clinical assessment and delivered by appropriately trained therapists working in close collaboration with the patient.  

We conclude that properly applied rehabilitative treatments offer the best hope of safely improving fatigue and function for patients with CFS/ME. However, we also recognize the need for more research into the treatment of this neglected condition, especially for those most severely disabled by it. 

3. Pain-related post-exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia: A systematic review and three-level meta-analysis 

Barhorst EE, Boruch AE, Cook DB, Lindheimer JB.  
Pain Med. 2021 Oct 20:pnab308. [Epub ahead of print.] 


Objective: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia (FM) are two debilitating, moderately comorbid illnesses in which chronic musculoskeletal pain symptoms are prevalent. These individuals can experience post-exertional malaise (PEM), a phenomenon where symptom severity is worsened 24hr or longer following physical stress, but the pain-related component of PEM is not well characterized. 

Design: Systematic review and meta-analysis. 

Methods: Case-control studies involving adults with ME/CFS or FM and measuring pain symptoms before and after exposure to a standardized aerobic exercise test were included. Hedges' d effect sizes were aggregated using random effects models and potential moderators were explored with meta-regression analysis. Results were adjusted for nesting effects using three-level modeling. 

Results: Forty-five effects were extracted from 15 studies involving 306 patients and 292 healthy controls. After adjusting for nesting effects, we observed a small-to-moderate effect indicating higher post-exercise pain in patients than controls (Hedges' d=0.42; 95% CI: 0.16, 0.67). The mean effect was significantly moderated by pain measurement timepoint (b = -0.19, z = -2.57, P = 0.01) such that studies measuring pain 8-72hr post-exercise showed larger effects (d = 0.71, 95% CI = 0.28-1.14) than those measuring pain 0-2hr post-exercise (d = 0.32, 95% CI = 0.10-0.53). 

Conclusions: People with ME/CFS and FM experience small-to-moderate increases in pain severity following exercise which confirms pain as a component of PEM and emphasizes its debilitating impact in ME/CFS and FM. Future directions include determining mechanisms of pain-related PEM and developing exercise prescriptions that minimize symptom exacerbation in these illnesses. 

4. Cerebral blood flow remains reduced after tilt testing in myalgic encephalomyelitis/chronic fatigue syndrome patients 

van Campen CLMC, Rowe PC, Visser FC.  
Clin Neurophysiol Pract 6: 245-255.  


Objective: Orthostatic symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may be caused by an abnormal reduction in cerebral blood flow. An abnormal cerebral blood flow reduction was shown in previous studies, without information on the recovery pace of cerebral blood flow. This study examined the prevalence and risk factors for delayed recovery of cerebral blood flow in ME/CFS patients. 

Methods: 60 ME/CFS adults were studied: 30 patients had a normal heart rate and blood pressure response during the tilt test, 4 developed delayed orthostatic hypotension, and 26 developed postural orthostatic tachycardia syndrome (POTS) during the tilt. Cerebral blood flow measurements, using extracranial Doppler, were made in the supine position pre-tilt, at end-tilt, and in the supine position at 5 min post-tilt. Also, cardiac index measurements were performed, using suprasternal Doppler imaging, as well as end-tidal PCO2 measurements. The change in cerebral blood flow from supine to end-tilt was expressed as a percent reduction with mean and (SD). Disease severity was scored as mild (approximately 50% reduction in activity), moderate (mostly housebound), or severe (mostly bedbound). 

Results: End-tilt cerebral blood flow reduction was -29 (6)%, improving to -16 (7)% at post-tilt. No differences in either end-tilt or post-tilt measurements were found when patients with a normal heart rate and blood pressure were compared to those with POTS, or between patients with normocapnia (end-tidal PCO2 ≥ 30 mmHg) versus hypocapnia (end-tidal PCO2 < 30 mmHg) at end-tilt. A significant difference was found in the degree of abnormal cerebral blood flow reduction in the supine post-test in mild, moderate, and severe ME/CFS: mild: cerebral blood flow: -7 (2)%, moderate: -16 (3)%, and severe :-25 (4)% (p all < 0.0001). Cardiac index declined significantly during the tilt test in all 3 severity groups, with no significant differences between the groups. In the supine post-test cardiac index returned to normal in all patients. 

Conclusions: During tilt testing, extracranial Doppler measurements show that cerebral blood flow is reduced in ME/CFS patients and recovery to normal supine values is incomplete, despite cardiac index returning to pre-tilt values. The delayed recovery of cerebral blood flow was independent of the hemodynamic findings of the tilt test (normal heart rate and blood pressure response, POTS, or delayed orthostatic hypotension), or the presence/absence of hypocapnia, and was only related to clinical ME/CFS severity grading. We observed a significantly slower recovery in cerebral blood flow in the most severely ill ME/CFS patients. 

Significance: The finding that orthostatic stress elicits a post-stress cerebral blood flow reduction and that disease severity greatly influences the cerebral blood flow reduction may have implications on the advice of energy management after a stressor and on the advice of lying down after a stressor in these ME/CFS patients. 

5. Chronic Fatigue Syndrome in Childhood Revisited: Not Common, But Not Unknown- Case Study and Literature Review 

Alison Leong, Rajeev Ramachandran, Sajini Mary Varughese, Lee Gan Goh 
BioPsychoSocial Medicine BMC. In review. Article Pre-print. ResearchSquare 


Lethargy is a common non-specific complaint to primary care and has a broad range of differentials.  

Chronic fatigue syndrome (CFS) should be considered when there is persistent fatigue affecting function and post- exertional malaise six months or longer and initial workup is not suggestive of other organic causes; it is a debilitating condition that would benefit from diagnosis and treatment.  

We present an adolescent with CFS, the disease timeline, its impact and outcome. 

6. Effects of The Prolong Life With Nine Turn Method (Yan Nian Jiu Zhuan) Qigong On Brain Functional Changes in Patients With Chronic Fatigue Syndrome in Terms of Fatigue and Quality of Life 

Fangfang Xie, Ziji Cheng, Yuanjia Gu, Ziying Chen, Chaoqun Xie, Fei Yao, Yanli You 
BMC Palliative Care BMC Series. In review. Article Pre-print. ResearchSquare 


Background: Chronic fatigue syndrome (CFS) is characterized by persistent fatigue, which often leads to physical and psychological damage. The prolong life with nine turn method (PLWNT) Qigong is considered one of the complementary treatments for improving symptoms in patients with CFS. However, the neurophysiological relevance of these effects remains poorly understood. In this study, we used functional magnetic resonance imaging (fMRI) to study the effects of PLWNT intervention on the neural circuits in subjects with CFS. 

Methods: Thirty four CFS patients were randomly divided into a PLWNT group (who received Qigong exercises) and a control group (who received cognitive behavioral therapy, CBT). Both groups were taught by a highly qualified professor at the Shanghai University of Traditional Chinese Medicine once a week and were supervised online during the remaining 6 days at home, over 12 consecutive weeks. We calculated the regional rs-fMRI index ALFF for all subjects. To study the changes of the brain network, we used the brain regions with significant differences in ALFF as the regions of interest for whole-brain FC analysis. The MFI-20 and SF-36 were used for clinical symptom assessment to explore the possible correlation between the rs-fMRI indicators and clinical variations. 

Results: The ALFF values of the right superior frontal gyrus (SFG), and left median cingulate gyrus (DCG) were increased, whereas those of the left middle occipital gyrus (OG), right middle OG and left middle temporal gyrus (MTG) were decreased in CFS patients. The FC values between the DCG and middle temporal gyrus (MTG), and those between the left OG and the right OG were enhanced. In addition, the SF-36 were positively with the left OG (r=0.542), SFG(r=0.517) and DCG(r=0.533), MFI-20 were negatively with the left OG (r=-0.583), SFG(r=-0.542) and DCG(r=-0.578). These results were all corrected by FWE (voxel level p < 0.001, cluster level p < 0.05). 

Conclusion: In conclusion, PLWNT can relieve the fatigue symptoms of CFS patients and improve their quality of life. CFS patients have abnormal regional spontaneous neuronal activity and abnormal functional connections between regions after PLENT intervention. The study was approved by the Ethics Committee of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine (Ethics Approval Number: 2018-043), and registered in the American Clinical Trial Registry (12/04/2018), Registration Number is NCT03496961. 

7. Idiopathic combined adrenocorticotropin and growth hormone deficiency mimicking chronic fatigue syndrome 

Tokumasu K, Ochi K, Otsuka F 
BMJ Case Reports CP 2021;14:e244861. 


A 42-year-old man who had suffered from severe fatigue for 5 years was diagnosed as having chronic fatigue syndrome (CFS) and fibromyalgia. 

 Endocrinological workup using combined anterior pituitary function tests showed that the patient had adrenocorticotropin hormone (ACTH) deficiency, with a normal pituitary MRI.  

Treatment with a physiologic dose of oral hydrocortisone replacement physically ameliorated his general fatigue.  

A secondary workup using a growth hormone-releasing peptide-2 test revealed that he also had growth hormone (GH) deficiency, and GH replacement therapy was started. His muscle pain and depression were improved by the therapy.  

Here, we present a rare case of combined deficiency of ACTH and GH in a middle-aged man with severe general fatigue. This case report aims to raise awareness of combined deficiency of ACTH and GH as a differential diagnosis of CFS and its mimics. 

Long-COVID Research References   

  1. Molecular Insights into SARS-CoV2-Induced Alterations of the Gut/Brain Axis 
  1. The immunology of asymptomatic SARS-CoV-2 infection: what are the key questions? 
  1. Age and subtle cognitive impairment are associated with long-term olfactory dysfunction after COVID-19 infection 
  1. Hand grip strength before and after SARS-CoV-2 infection in community-dwelling older adults 
  1. Long COVID syndrome-associated brain fog 
  1. Patterns of cardiac involvement in patients with long COVID syndrome using cardiovascular magnetic resonance 
  1. Children with Long Covid: Co-producing a specialist community public health nursing response 
  1. Long-COVID: neurological manifestations and management 
  1. The spectre of long covid 
  1. Cardiac involvement in the long-term implications of COVID-19 

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent


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