ME/CFS and Long Covid Research: 31 May – 06 June 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 Dr Katrina Pears

ME/CFS Research Published 31 May – 6 June 2022 

There have been five new ME/CFS studies and sixteen studies on Long Covid. 

We have highlighted two of the studies below: 

Paper one (1) looks at the two overlapping conditions ME/CFS and fibromyalgia (FM) and looks into determining potential autonomic and inflammatory mechanisms of pain and fatigue in these conditions. 

The study used several different techniques, including:  

  • inflammation biomarkers- CRP and ESR (Erythrocyte Sedimentation Rate and C-Reactive Protein), 
  • mediation analysis- quantifies the extent to which a variable causes an effect, and in this case helps to identify the mechanism responsible for pain and fatigue,  
  • hypermobility assessments, 
  • autonomic challenge- tilt table test. 

Unsurprisingly, the inflammation levels were higher in patients with ME/CFS and FM, the autonomic challenge amplified pain and fatigue compared to controls, and these finding together allow prediction of symptom severity. Mediation analysis proved a useful tool in this study allowing connections to be seen between degree of hypermobility, pain and the autonomic challenge.  

Unfortunately, we cannot access the full study to comment on the specific details, however, this study was small (60 ME/CFS/FM and 23 controls). It’s been a while since we have seen a study using both ME/CFS and FM patients, but the results do not distinguish between these groups which for two different but overlapping conditions probably decreases the validity of the results. This is the first time I have come across mediation analysis, therefore I do not know the effectiveness of this technique.  

Paper two (2) is on different metabolites (intermediate products of metabolic reactions) and metabolic pathways (series of chemical reactions starting with a substrate and ending with a product) from students who didn’t recover after having infectious mononucleosis. The title of the research is misleading as it does not mention ME/CFS but the study is definitely on the development of ME/CFS following infectious mononucleosis. There have been a number of research studies of this nature from the lead author Leonard Jason from DePaul University of late (such as; Jason et al., 2022a; Jason et al., 2022b) where they have researched the differing cytokine expression in ME/CFS and predictors for developing ME/CFS following infectious mononucleosis. 

In this current research, the authors found metabolite differences between patients that developed severe ME/CFS and controls, particularly alteration in:  

  • glutathione metabolism- important role in antioxidant defence, nutrient metabolism and regulation of cellular events,  
  • nucleotide metabolism- nucleic acids which are DNA and RNA are synthesised and degraded, 
  • TCA cycle- (tricarboxylic acid cycle, or krebs cycle or cirtic acid cycle) a series of chemical reactions to release energy in cellular respiration. 

The study confirmed their findings by using models and they could correctly identify between severe ME/CFS and controls. These findings also correlated with the previously reported findings showing pro-inflammatory cytokines (Jason et al., 2022a).  

This study definitely provides some interesting findings, however, it is limited by its scale (18 patients per group) and similar to other studies by this group the classification of severe ME/CFS is not ideal.  Again, severe ME/CFS was classified where patients had not recovered at a 6-month follow-up appointment and had more than one symptom listed in the case definition (as in other studies too: Jason et al., 2022a; Jason et al., 2022b; Jason et al., 2021), which really demeans severe ME/CFS for those who we would typically class as having severe ME/CFS. I do hope we see more research looking at metabolic pathways and also a justification from the authors of their classification of severe ME/CFS. 

 ME/CFS Research References and Abstracts  

1. Mechanistic factors contributing to pain and fatigue in fibromyalgia and me/cfs: autonomic and inflammatory insights from an experimental medicine study 

Eccles J, Thompson C, Thompson B, et al. 
Annals of the Rheumatic Diseases 2022;81:1719. 


Background: Fibromyalgia and ME/CFS are multifaceted conditions with overlapping symptoms(1); the pathoaetiological mechanisms are complex and debated(2), however there is a strong association with features of hereditary disorders of connective tissue (hypermobility) and autonomic and inflammatory abnormalities (1,2). 

Objectives: To determine potential autonomic and inflammatory mechanisms of pain and fatigue in fibromyalgia and ME/CFS 

Methods: After excluding participants with WCC higher than 10 (suggesting acute infection) baseline markers of inflammation (CRP and ESR) were available for 60 patients with confirmed diagnoses of Fibromyalgia and/ or ME/CFS and 23 matched controls. Participants then underwent full research diagnostic evaluation including a hypermobility assessment(1) and autonomic challenge (60 degree head up tilt, ISRCTN78820481). Subjective pain and fatigue were assessed before and after challenge (VAS). Linear regression models were used to explore predictors, with adjustment for confounders as appropriate. Mediation analyses (looking for mechanistic effects) were conducted according to the method of Hayes (3) and mediation considered significant if bootstrapped confidence intervals of the estimated indirect effect did not cross zero. In these mediation analyses predictor variable was group membership (patient or control), outcome variable was change in 1)pain and 2)fatigue induced by challenge and mediatiors 1)no of connective tissue features in hypermobility diagnostic criteria endorsed by participant; 2)baseline inflammatory markers. 

Results: ESR and CRP were significantly higher in patients rather than controls, even after correcting for BMI, age and sex (B=5.15, t=2.05, p=0.044; B=1.77, t=2.15, p=0.044 respectively). Adjusted ESR and CRP correlated with both subjective fatigue (B=0.44, t=2.09, p=0.04; B=1.63, t=2.60, p=0.011) and pain severity (B=0.13, t=2.51, p=0.014; B=0.45, t=3.01, p=0.004) at baseline. Autonomic challenge amplified pain (B=14.20, t=2.87, p=0.005) and fatigue (B=31.48, t=5.95, p=<0.001) in patients to a significantly greater degree than controls, controlling for baseline levels. Baseline ESR and CRP also predicted challenge-induced increase in fatigue (B=0.78, t=370, p=<0.001; B=1.91, t=3.36, p=<0.001) and ESR challenge-induced increases in pain (B=0.46, t=2.35, p=0.021). 

Mediation analysis demonstrated that number of connective tissue features expressed in hypermobility criteria mediated the degree to which subjective pain was increased by the autonomic challenge (Bootstraped 95% CI of indirect effect do not cross zero, 0.1572 – 6.8171). ESR mediated the degree to which subjective fatigue was increased by the autonomic challenge (Bootstraped 95% CI of indirect effect do not cross zero,0.7541 – 7.3888). 

Conclusion: To our knowledge this is the first study to directly explore autonomic and inflammatory mechanisms of pain and fatigue in a combined population of Fibromyalgia and ME/CFS. This study this adds to the evidence-base of baseline inflammatory abnormalities in fibromyalgia and ME/CFS. It highlights their potential role in predicting symptom severity and their potential mechanistic role in autonomic induced pain and fatigue, suggesting future treatment strategies. 

2. Pre-illness data reveals differences in multiple metabolites and metabolic pathways in those who do and do not recover from infectious mononucleosis 

Jason LA, Conroy KE, Furst J, Vasan K, Katz BZ.  
Mol Omics. 2022 May 31. [Epub ahead of print.] 


Metabolic pathways related to energy production, amino acids, nucleotides, nitrogen, lipids, and neurotransmitters in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may contribute to the pathophysiology of ME/CFS.  

4501 Northwestern University college students were enrolled in a prospective, longitudinal study. We collected data before illness, during infectious mononucleosis (IM), and at a 6 month follow-up for those who recovered (N = 18) versus those who went on to develop ME/CFS 6 months later (N = 18).  

Examining pre-illness blood samples, we found significant detectable metabolite differences between participants fated to develop severe ME/CFS following IM versus recovered controls.  

We identified glutathione metabolism, nucleotide metabolism, and the TCA cycle (among others) as potentially dysregulated pathways.  

The pathways that differed between cases and controls are essential for proliferating cells, particularly during a pro-inflammatory immune response.  

Performing a series of binary logistic regressions using a leave-one-out cross-validation (LOOCV), our models correctly classified the severe ME/CFS group and recovered controls with an accuracy of 97.2%, sensitivity of 94.4%, and specificity of 100.0%.  

These changes are consistent with the elevations in pro-inflammatory cytokines that we have reported for patients fated to develop severe ME/CFS 6 months after IM. 

3. Systemic exertion intolerance disease associated to neuroendocrine dysfunction and cortical atrophy: a case report 

López-Amador N.  
Fam Pract. 2022 May 28:cmac060. [Epub ahead of print.] 


Background: Scarce evidence about the organic and functional abnormalities of systemic exertion intolerance disease (SEID) is found in literature and the pathophysiology is still unclear. 

Methods: Following the CARE Guidelines, this case report describes a patient with a 5-year history of nonspecific symptoms, lately recognized as SEID. 

Results: Low serum thyroid- and adrenocorticotropic stimulating hormone levels, and 24-h urinary cortisol excretion almost twice the upper limit were detected. Computed tomography scan found significant cortical atrophy. Low-dose modafinil improved the clinical outcome, added to nonpharmacologic approach. 

Conclusion: To ascertain an accurate SEID diagnosis and treatment are a challenge in daily clinical practice, that must be engaged based in clear methods and good practice recommendations. Thus, family practitioners should be aware of this diagnosis. 

4. The Role of Kynurenine Pathway and NAD+ Metabolism in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome 

Dehhaghi, Mona et al.  
Aging and Disease vol. 13,3 698–711.  


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, complex, and highly debilitating long-term illness. People with ME/CFS are typically unable to carry out their routine activities.  

Key hallmarks of the disease are neurological and gastrointestinal impairments accompanied by pervasive malaise that is exacerbated after physical and/or mental activity.  

Currently, there is no validated cure of biomarker signature for this illness.  

Impaired tryptophan (TRYP) metabolism is thought to play significant role in the pathobiology of ME/CFS. TRYP is an important precursor for serotonin and the essential pyridine nucleotide nicotinamide adenine dinucleotide (NAD+). TRYP has been associated with the development of some parts of the brain responsible for behavioural functions.  

The main catabolic route for TRYP is the kynurenine pathway (KP). The KP produces NAD+ and several neuroactive metabolites with neuroprotective (i.e., kynurenic acid (KYNA)) and neurotoxic (i.e., quinolinic acid (QUIN)) activities.  

Hyperactivation of the KP, whether compensatory or a driving mechanism of degeneration can limit the availability of NAD+ and exacerbate the symptoms of ME/CFS.  

This review discusses the potential association of altered KP metabolism in ME/CFS.  

The review also evaluates the role of the patient’s gut microbiota on TRYP availability and KP activation.  

We propose that strategies aimed at raising the levels of NAD+ (e.g., using nicotinamide mononucleotide and nicotinamide riboside) may be a promising intervention to overcome symptoms of fatigue and to improve the quality of life in patients with ME/CFS.  

Future clinical trials should further assess the potential benefits of NAD+ supplements for reducing some of the clinical features of ME/CFS. 

5. Facts and myths about chronic fatigue syndrome 

Fink P, Skjernov M, Petersen LK, Forstrøm C, Rosendal M.  
Ugeskr Laeger. 2022 May 23;184(21):V12210943. [Article in Danish.] 


Contrary to its precursor, the new NICE guidelines for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) caution against graded exercise therapy for the severely ill, and cognitive behavioural therapy is only recommended for treating consequence of ME/CFS and not the condition itself.  

Instead, energy management is recommended. The recommendations are based on dismissing most current evidence from studies not using new diagnostic criteria introduced by NICE or not including patient viewpoints.  

As argued in this review, instead of a scientific approach, the committee attaches importance to a consensus-driven approach among a biased group of specialists and patients; many associated to the ME action community. 

Long-COVID Research References   

  1. Is the number of long-term post-COVID symptoms relevant in hospitalized COVID-19 survivors? 
  1. Recommendation for standardized medical care for children and adolescents with long COVID 
  1. High Prevalence of Both Previous Infection with SARS-CoV-2 and Persistent Symptoms 
  1. Is there a role for the adrenal glands in long COVID? 
  1. Treating Insulin Resistance with Intermittent Personalized Nutrition to Sustain Metabolic Health and Functioning Immune System for Risk Reduction of Viral Diseases Especially COVID-19 and Long-COVID 
  1. Application of Kampo Medicines for Treatment of General Fatigue Due to Long COVID 
  1. Long COVID-19 and achalasia: a possible relationship? 
  1. Sulodexide Significantly Improves Endothelial Dysfunction and Alleviates Chest Pain and Palpitations in Patients With Long-COVID-19: Insights From TUN-EndCOV Study 
  1. Practicalities for Exercise Prescription in Long-COVID-19 Rehabilitation. A Narrative Review 
  1. Symptoms and signs of long COVID: A rapid review and meta-analysis 
  1. Multi-organ impairment and Long COVID: a 1-year prospective, longitudinal cohort study 
  1. Outpatient Pulmonary Rehabilitation in Patients with Long COVID Improves Exercise Capacity, Functional Status, Dyspnea, Fatigue, and Quality of Life 
  1. Acute Neurologic Complications of COVID-19 and Postacute Sequelae of COVID-19 
  1. Generalizable Long COVID Subtypes: Findings from the NIH N3C and RECOVER Programs 
  1. A global systematic analysis of the occurrence, severity, and recovery pattern of long COVID in 2020 and 2021 
  1. Long COVID is associated with extensive in-vivo neuroinflammation on [18F]DPA-714 PET 

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent


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