ME/CFS and Long Covid Research: 03 – 09 May 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 3 – 9 May 2022 

Apologies for the delayed weekly research roundup, I have been taking a break for a few days. 

There have been a range of studies published in the past week, with five new ME/CFS studies and eighteen studies on Long Covid.  

We have briefly highlighted two of the studies below: 

Paper two (2) looks at neurovascular dysregulation and whether this contributes to exercise intolerance, where an oral dose of the drug pyridostigmine was given or a placebo after an intense exercise test. The drug pyridostigmine is used to improve muscle strength and is typically given to patients with certain muscle diseases.  

The study did find improvements when the drug was taken compared to the placebo, which leads the authors to conclude that neurovascular dysregulation is treatable in ME/CFS where there is acute exercise intolerance. Unfortunately, this paper is behind a paywall so we can not analysis this study any further. 

Paper three (3) is on cognitive behaviour therapy (CBT) and multi-convergent therapy (MCT). This was certainly not a strong study, where the use of CBT was compared to receiving “education and support” or “standard medical care”. We do not learn anything new from this and the research concludes that CBT has little evidence of leading to any significant changes in health. However, MCT saw much greater improvements in mood and performance. If you are interested in reading any further, the paper is free to access and provides several easily comparable tables on the three “treatments” received! 

ME/CFS Research References and Abstracts  

1. Aberrations in the cross-talks among redox, nuclear factor-κB and Wnt/catenin pathway signaling underpin Myalgic Encephalomyelitis and chronic fatigue syndrome 

Michael Maes, Marta Kubera and Magdalena Kotańska 
Frontiers in Psychiatry 13: 822382.   


There is evidence that chronic fatigue spectrum disorders (CFAS-D) including Myalgic Encephalomyelitis (ME), chronic fatigue syndrome (CFS) and chronic fatigue with physiosomatic symptoms including when due to comorbid medical disease are characterized by neuroimmune and neuro-oxidative biomarkers.  

The present study was performed to delineate the protein-protein interaction (PPI) network of CFAS-D and to discover the pathways, molecular patterns and domains enriched in their PPI network.  

We performed network, enrichment and annotation analysis using differentially expressed proteins and metabolics, which were established in CFAS-D patients.  

PPI network analysis revealed that the backbone of the highly connective CFAS-D network comprises NFKB1, CTNNB1, ALB, peroxides, NOS2, TNF, and IL6, and that the network comprises interconnected immune-oxidative-nitrosative and Wnt/catenin subnetworks.  

MultiOmics enrichment analysis shows that the CFAS-D network is highly significantly associated with cellular (antioxidant) detoxification, hydrogen peroxide metabolic process, peroxidase and oxidoreductase activity, IL10 anti-inflammatory signaling, and neurodegenerative, canonical Wnt, the catenin complex, cadherin domains, cell-cell junctions and TLR2/4 pathways; and the transcription factors NF-κB and RELA.  

The top-10 DOID annotations of the CFAS-D network include four intestinal, three immune system disorders, cancer and infectious disease.  

Custom GO term annotation analysis revealed that the CFAS-D network is associated with a response to a toxic substance, lipopolysaccharides, bacterium or virus.  

In conclusion, CFAS-D may be triggered by a variety of stimuli and their effects are mediated by aberrations in the cross-talks between redox, NF-κB, and Wnt/catenin signaling pathways leading to dysfunctions in multicellular organismal homeostatic processes. 

2. Neurovascular Dysregulation and Acute Exercise Intolerance in ME/CFS: A Randomized, Placebo-Controlled Trial of Pyridostigmine 

Joseph P, Pari R, Miller S, Warren A, Stovall MC, Squires J, Chang CJ, Xiao W, Waxman AB, Systrom DM  
Chest. 2022 May 5:S0012-3692(22)00890-X. [Epub ahead of print] 


Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by intractable fatigue, post-exertional malaise, and orthostatic intolerance, but its pathophysiology is poorly understood. Pharmacologic cholinergic stimulation was used to test the hypothesis that neurovascular dysregulation underlies exercise intolerance in ME/CFS. 

Research question: Does neurovascular dysregulation contribute to exercise intolerance in ME/CFS and can its treatment improve exercise capacity? 

Methods: Forty-five subjects with ME/CFS were enrolled in a single-center, randomized, double-blind, placebo-controlled trial. Subjects were assigned in a 1:1 ratio to receive a 60 mg dose of oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test (iCPET). A second iCPET was performed 50 minutes later. The primary end point was the difference in peak exercise oxygen uptake (VO2). Secondary end points included exercise pulmonary and systemic hemodynamics and gas exchange. 

Results: Twenty-three subjects were assigned to pyridostigmine and 22 to placebo. The peak VO2 increased after pyridostigmine but decreased after placebo (13.3 ± 13.4 mL/min vs. -40.2 ± 21.3 mL/min, P<0.05). The treatment effect of pyridostigmine was 53.6 mL/min (95% CI, -105.2 to -2.0). Peak versus rest VO2 (25.9 ± 15.3 mL/min vs. -60.8 ± 25.6 mL/min, P<0.01), cardiac output (-0.2 ± 0.6 L/min vs. -1.9 ± 0.6 L/min, P<0.05), and RAP (1.0 ± 0.5 mm Hg vs. -0.6 ± 0.5 mm Hg, P<0.05) were greater in the pyridostigmine group compared to placebo. 

Interpretation: Pyridostigmine improves peak VO2 in ME/CFS by increasing cardiac output and right ventricular filling pressures. Worsening peak exercise VO2, Qc, and RAP after placebo may signal the onset of post-exertional malaise. We suggest treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. 

3. The Relation of Pain, Fatigue, Disease Impact, and Psychological Factors with Physical Function in post-COVID-19 Syndrome, Fibromyalgia, and Chronic Fatigue Syndrome 

Giovanni Berardi, Saman Haider, Adam Janowski, Lesnak B. Joseph, Kazuhiro Hayashi, Dana L. Dailey, Ruth Chimenti, Laura Frey-Law, Kathleen Sluka 
The Journal of Pain 23 (5): 47 


This research sought to identify the relation of pain, fatigue, disease impact, and psychological factors with physical function in individuals with post-COVID-19 syndrome (post-COVID), fibromyalgia, chronic fatigue syndrome (CFS), and those with combined diagnoses of post-COVID, FMS, and/or CFS (multi-Dx).  

Individuals with post-COVID, fibromyalgia, or CFS were invited to complete an anonymous survey.  

The following patient-reported outcome measures were collected: PROMIS-Physical Function (PROMIS-PF), PROMIS-Pain Interference (PROMIS-PI), Pain Severity (NRS; 0-10), 2016 Fibromyalgia Diagnostic Criteria Survey (FSS), Fatigue Severity (NRS; 0-10), PROMIS-Fatigue, Multisensory Amplification Scale (MSAS), PROMIS-Sleep Disturbance (PROMIS-SD), PROMIS-Dyspnea Severity (PROMIS-DS), Symptom Impact Questionnaire-Revised (SIQR), Coping Strategies Questionnaire-Catastrophizing Subscale (CSQ-CAT), Tampa Scale of Kinesiophobia-11 (TSK-11), and Hospital Anxiety and Depression Scale (HADS).  

Stepwise multiple linear regressions examined relationships between symptoms, disease impact, and psychological factors on physical function in each cohort.  

Results show 707 individuals (294-males, 413-females) completed surveys including 203 post-COVID, 99 FMS, 87 CFS, and 318 multi-Dx.  

Physical function was impaired in each cohort (post-COVID: 40.7±8.6; FMS: 39.5±5.5; CFS: 39.5±7.2; multi-Dx: 39.3±5.5).  

Regression analyses were significant for post-COVID (R2=.668, p<.001), fibromyalgia (R2=.502, p<.001), CFS (R2=.663, p<.001), and multi-Dx (R2=.611, p<.001).  

Unique factors significantly predicted physical function in each cohort as follows: 1) Post-COVID – dyspnea (β=-.453, p<.001), fatigue (β=-.182, p=.003), pain interference (β=-.196, p=.007), anxiety (β=.138, p=.007), symptom impact (β=-.185, p=.026); 2) fibromyalgia – fatigue (β=-.470, p<.001), symptom impact (β=-.351, p<.001); 3) CFS – symptom impact (β=-.427, p<.001), anxiety (β=.328, p<.001), dyspnea (β=-.210, p=.007), fatigue (β=-.334, p<.001), sleep disturbance (β=.249, p=.002), kinesiphobia (β=-.200, p=.014); 4) multi-Dx – fatigue (β=-.350, p<.001), symptom impact (β=-.201, p<.001), sleep disturbance (β=-.183, p<.001), pain interference (β=-.181, p<.001).  

Disease impact and fatigue related to physical function in all cohorts while pain interference, dyspnea, sleep disturbance, and psychological factors had varying relationships with physical function among individuals with post-COVID, FMS, CFS, and multi-Dx.  

4. Development of a Mouse Model for Chronic Fatigue Syndrome 

Adam Janowski, Joseph Lesnak, Ashley Plumb, Lynn Rasmussen, Kathleen Sluka 
The Journal of Pain 23 (5): 12 


The purpose of this study was to develop a clinically relevant mouse model of CFS to allow for the testing of underlying mechanisms and development of novel treatment interventions.  

Mice were injected with either lipopolysaccharide (LPS) or Poly I:C systemically (0.1- 1.0 mg/kg LPS, i.p. or 0.6-6mg/kg Poly I:C) and compared to a vehicle control injection.  

To test for fatigue-like behaviors, we examined voluntary wheel running (VWR) and open field activity.  

To test for pain-like behaviors, muscle withdrawal thresholds (MWT) and mechanical sensitivity of the paw.  

Measurements were assessed before and up to 1 week after injection of LPS or Poly I:C.  

Differences in voluntary running wheel data were assessed using mixed model analysis for differences between dose, time and an interaction between dose and time.  

Differences in open field parameters, MWT, and paw sensitivity between groups were assessed using repeated measures ANOVAs.  

Running wheel activity was reduced after injection of either LPS or Poly I:C (χ2=15.4; p=0.003).  

LPS reduced running wheel activity on days 1-3 for the 1.0 mg/kg dose of LPS and on Day 1 for Poly I:C when compared to vehicle (p<0.001).  

Lower doses of LPS showed faster recovery to baseline.  

For the open field testing, LPS reduced in distance travelled (F=9.1; p<0.001), increase in time standing still (F=6.5, p=0.001) but not time in center (F= 1.1, p=0.36) 24h after infection.  

Post-hoc testing (Tukey's test) showed a significant difference between the vehicle and the 1.0 mg/kg group of LPS (p=0.001).  

Similar reductions were observed for the 6 mg/kg group of Poly I:C (p<0.001). For pain behaviors, there was no difference between groups in the MWT or paw sensitivity (p>0.05) for either LPS or Poly I:C.  

These results show that a single injection of an infectious agent reduces physical activity and exploratory behavior, but does not produce pain behaviors. 

5. Cognitive behaviour therapy, multi-convergent therapy, and the mood and cognitive performance of chronic fatigue syndrome patients 

Smith AP and Thomas M 
World Journal of Pharmaceutical and Medical Research 8(5): 58-65 


Background: Cognitive Behaviour Therapy (CBT) has been recommended as a suitable treatment for chronic fatigue syndrome (CFS). However, recently it has been suggested that the efficacy of CBT is limited, and there is little evidence that it changes objective outcomes.  

Objectives: The aim of the present analyses were to determine whether group CBT changed the mood and cognitive performance of CFS patients. CBT was compared to two conditions from the same study, namely education and support and standard medical care. Further analyses compared these conditions with a longitudinal study of untreated CFS patients, healthy controls and those having Multi-Convergent Therapy (MCT).  

Methods: CFS patients were referred to a pain management clinic and randomly assigned to CBT (N=53), education and support (N=49) or standard medical care (N=49). Mood and cognitive performance were measured pre-treatment and again at six and twelve months post-treatment. Comparisons were also made with a sample of untreated CFS patients (N = 195) and those who had participated in a study of MCT (N=35).  

Results: At baseline, the CFS patients showed the usual differences from healthy controls, namely a more negative mood, slower reaction times, and impaired recall and sustained attention. Analyses of the post-treatment data revealed little evidence of CBT leading to significant changes. In contrast, MCT was associated with significant improvements in mood and performance.  

Conclusions: Group CBT leads to a significant reduction in subjective symptoms but does not improve cognitive performance, whereas individual MCT does improve mood and performance 

Long-COVID Research References   

  1. Evidence mapping and review of long-COVID and its underlying pathophysiological mechanism 
  1. The long-COVID-19 in older adults -facts and conjectures 
  1. Long COVID and neuropsychiatric manifestations (Review) 
  1. Post-acute COVID-19 is characterized by gut viral antigen persistence in inflammatory bowel diseases 
  1. Clinical, radiological, and transbronchial biopsy findings in patients with long COVID-19: a case series 
  1. Long-Term Cardiovascular Effects of COVID-19: Emerging Data Relevant to the Cardiovascular Clinician 
  1. Long-COVID post-viral chronic fatigue and affective symptoms are associated with oxidative damage, lowered antioxidant defenses and inflammation: a proof of concept and mechanism study 
  1. Prevalence of vitamin D deficiency among patients attending Post COVID-19 follow-up clinic: a cross-sectional study 
  1. Case Report: Therapeutic and immunomodulatory effects of plasmapheresis in long-haul COVID 
  1. Aromatherapy blend of thyme, orange, clove bud, and frankincense boosts energy levels in post-COVID-19 female patients: A randomized, double-blinded, placebo controlled clinical trial 
  1. Caring for the carers: understanding long covid in our diverse healthcare workforce 
  1. Long COVID: aiming for a consensus 
  1. Long COVID: A proposed hypothesis-driven model of viral persistence for the pathophysiology of the syndrome 
  1. Improvement in Long-COVID Symptoms Using Acupuncture: A Case Study 
  1. Post-COVID Condition in Adults and Children Living in the Same Household in Italy: A Prospective Cohort Study Using the ISARIC Global Follow-Up Protocol 
  1. Psychiatric disorders in Post-acute COVID-syndrome (PDPACS): Recommendations for health care professionals 
  1. Exploring trajectory recovery curves of post-COVID cognitive symptoms in previously hospitalized COVID-19 survivors: the LONG-COVID-EXP-CM multicenter study 
  1. Autonomic dysfunction in long-COVID syndrome: a neurophysiological and neurosonology study 

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent



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