ME Association regular research roundup

ME/CFS and Long Covid Research: 11 – 17 April 2023

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

There have been three new ME/CFS studies but twenty-one new Long Covid studies this week.

It’s been another quiet week, with none of the studies really catching our eyes this week. Therefore, we have briefly highlighted two of the ME/CFS studies:

Paper one (1) is a review article of exercise pathophysiology, i.e. exercise intolerance in ME/CFS and Long Covid.

This review doesn’t tell us anything new, the review finds the mechanisms of systemic blood flow, ventilatory control, hemodynamic and gas exchange derangements to be involved in exercise intolerance in both conditions. A few points to highlight:

  • Only one reference is cited which demonstrates the overlap between Long Covid and ME/CFS. We know of many strong research papers which have demonstrated the link to date, so it’s a shame more of these are not cited.
  • The review strongly supports the use of cardiopulmonary exercise testing (CPET) to investigate exercise intolerance and the main focus of the review is analysing studies where this has been done.
  • On first glance at the abstract you would think that the authors found deconditioning to be the cause of exercise intolerance in Long Covid. However, from reading the full review the authors strongly disprove this theory with CPET. Research that disproves the deconditioning theory, includes Singh et al., 2022 (for covid-19) and Systrom et al., 2021 (for ME/CFS).
  • There is a slightly hazy area over the recommendations for exercise, which doesn’t recommend graded exercise therapy, but does support CPET guided exercise prescriptions in rehabilitation efforts. Additionally, this group of researchers have previously recommended careful graded exercise (Systrom et al., 2021).
  • This is a review article, so no further investigating was carried out, but it also fits well with one of the Long Covid studies this week. This study finds impaired oxygen extraction to be associated with exercise tolerance in Long Covid (Paper two (2), Norweg et al., 2023). Unfortunately, this study also recommends exercise to treat Long Covid.

Paper three (3) reports results from a randomised, placebo-controlled trial using intranasal mechanical stimulation (INMEST) targeting nerve endings in the nasal cavity. This study was originally published as a preprint back in 2020, showing there were probably problems in the publishing process. Excitingly, the study reports a 30% reduction in symptoms scored after eight weeks of treatment, which would be significant for those with severe ME. The study also monitors the immune system over time, finding chronic immune activation, and looking into the immunology finds correlations of improvement in gut-homing immune cells and reduced inflammation.

This was obviously a small study, involving 23 females and 8 males, therefore more investigation is needed to support the findings and examine the mechanisms involved. However, these findings were probably limited as patients had to visit the clinic twice a week for eight weeks, which is a very energy demanding task.

You may also be interested in reading in the Long Covid reference section:

  • Paper three (3) which is on the pathophysiological factors of Long Covid, where the authors claim that endothelial dysfunction and microclots affect every organ system and together are the pathways for disease. Dr Charles Shepherd has provided a comment on this study.
  • Paper four (4) provides published data on AXA1125 which is being trialled for the treatment of Long Covid, showing improvement in fatigue symptoms, this study has also been covered by Sky news. We have previously covered some of the treatments being investigated for Long Covid in a research summary.

ME/CFS Research References and Abstracts 

1. Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-Acute Sequelae of SARS-CoV-2: More in Common Than Not?

Joseph P, Singh I, Oliveira R, Capone CA, Mullen MP, Cook DB, Stovall MC, Squires J, Madsen K, Waxman AB, Systrom DM.

Chest. 2023 Apr 11:S0012-3692(23)00502-0. [Epub ahead of print.]


Topic importance: Post-Acute Sequelae of SARS-CoV-2 (PASC) is a long-term consequence of acute infection from coronavirus disease 2019 (COVID-19). Clinical overlap between PASC and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been observed, with shared symptoms including intractable fatigue, postexertional malaise, and orthostatic intolerance. The mechanistic underpinnings of such symptoms are poorly understood.

Review findings: Early studies suggest deconditioning as the primary explanation for exertional intolerance in PASC. Cardiopulmonary exercise testing (CPET) reveals perturbations related to systemic blood flow and ventilatory control associated with acute exercise intolerance in PASC, which are not typical of simple detraining. Hemodynamic and gas exchange derangements in PASC have substantial overlap with those observed with ME/CFS, suggestive of shared mechanisms.

Summary: This review aims to illustrate exercise pathophysiologic commonalities between PASC and ME/CFS that will help guide future diagnostics and treatment.

2. Life changing response to successive surgical interventions on cranial venous outflow: A case report on chronic fatigue syndrome

Higgins JNP, Axon PR and Lever AML.

Front. Neurol. 14:1127702.


Recognition of similarities between chronic fatigue syndrome and idiopathic intracranial hypertension (IIH) has raised suggestions that they might be connected, with chronic fatigue syndrome representing a mild version of IIH, sharing many of its symptoms, but without the signature features of elevated intracranial pressure that characterize the complete syndrome.

A further development of this idea factors in the effects of a cerebrospinal fluid leak, a known complication of IIH, to explain cases where symptoms seem out of proportion to the apparent physiological disturbance. Cranial venous outflow obstruction has been proposed as the pathological substrate.

We describe a patient with multiple symptoms, including headache and disabling fatigue, in which this model guided investigation and treatment. Specifically, CT and catheter venography identified focal narrowings of both jugular and the left brachiocephalic veins.

Treatment of brachiocephalic obstruction was not feasible. However, in separate surgical procedures, relief of jugular venous obstruction produced incremental and significant clinical improvements which have proven durable over the length of follow-up.

We suggest that investigating chronic fatigue syndrome under this model might not only bring benefit to individual patients but also will provide new insights into IIH and its relationship with spontaneous intracranial hypotension.

3. Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and optimizing disease tolerance

Lucie Rodriguez, Christian Pou, Tadepally Lakshmikanth, Jingdian Zhang, Constantin Habimana Mugabo, Jun Wang, Jaromir Mikes, Axel Olin, Yang Chen, Joanna Rorbach, Jan-Erik Juto, Tie Qiang Li, Per Julin, Petter Brodin.

Oxford Open Immunology, 2023;, iqad003.


Myalgic encephalomyelitis, ME, previously also known as chronic fatigue syndrome (CFS) is a heterogeneous, debilitating syndrome of unknown etiology responsible for long-lasting disability in millions of patients worldwide.

The most well-known symptom of ME is post-exertional malaise, but many patients also experience autonomic dysregulation, cranial nerve dysfunction and signs of immune system activation. Many patients also report a sudden onset of disease following an infection.

The brainstem is a suspected focal point in ME pathogenesis and patients with structural impairment to the brainstem often show ME-like symptoms. The brainstem is also where the vagus nerve originates, a critical neuro-immune interface and mediator of the inflammatory reflex which regulate systemic inflammation.

Here we report the results of a randomized, placebo-controlled trial using intranasal mechanical stimulation (INMEST) targeting nerve endings in the nasal cavity, likely from the trigeminal nerve, possibly activating additional centers in the brainstem of ME-patients and correlating with a ∼30% reduction in overall symptom scores after eight weeks of treatment.

By performing longitudinal, systems-level monitoring of the blood immune system in these patients, we uncover signs of chronic immune activation in ME, as well as immunological correlates of improvement that center around gut-homing immune cells and reduced inflammation.

The mechanisms of symptom relief remains to be determined, but transcriptional analyses suggest an upregulation of disease tolerance mechanisms. We believe that these results are suggestive of ME as a condition explained by a maladaptive disease tolerance response following infection.

Long-COVID Research References

  1. Low vitamin D levels are associated with Long COVID syndrome in COVID-19 survivors
  2. Exercise Intolerance Associated with Impaired Oxygen Extraction in Patients with Long COVID
  3. Long COVID: pathophysiological factors and abnormalities of coagulation
  4. Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot study
  5. Long-term outcomes of different rehabilitation programs in patients with long COVID syndrome: a cohort prospective study
  6. Aged brain and neuroimmune responses to COVID-19: post-acute sequelae and modulatory effects of behavioral and nutritional interventions
  7. Prevalence of long COVID complaints in persons with and without COVID-19
  8. Long COVID in the context of social determinants of health
  9. Neural dysregulation in post-COVID fatigue 
  10. NETosis induction reflects COVID-19 severity and Long COVID: insights from a two-center patient cohort study in Israel
  11. Employment outcomes of people with Long Covid symptoms: community-based cohort study
  12. Long COVID and rehabilitation
  13. Unique immune and inflammatory cytokine profiles may define long COVID syndrome
  14. A review of cytokine-based pathophysiology of Long COVID symptoms
  15. Risk factors for post-COVID-19 condition (Long Covid) in children: a prospective cohort study
  16. Post-Acute Sequelae of SARS-CoV-2 (PASC): Musculoskeletal Conditions and Pain
  17. Chronic Disease Self-Management of Post-Acute Sequelae of COVID-19 Among Older Adults: A Mixed-Methods Analysis
  18. Lung diffusing capacities for nitric oxide and carbon monoxide at rest and post-walking in long COVID
  19. A Review of Neurological Symptoms in Long COVID and Clinical Management
  20. Changes in the State of Vital Systems with Long COVID-19
  21. Digital Interventions for Treating Post-COVID or Long-COVID Symptoms: Scoping Review

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent
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