Research Roundup

ME/CFS and Long Covid Research: 05 – 11 September 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 nine new ME/CFS studies and twenty-six new Long Covid studies this week.

We have also included the references which were missed in the previous week (29 August – 4 September) due to annual leave, in which there were four new ME/CFS papers.

We have highlighted one of the ME/CFS studies in more detail below:

Paper four (4) this week looks at the effect of end-tidal CO2 on cerebral blood flow during orthostatic stress.

  • End-tidal CO2 (PETCO2)– the level of carbon dioxide (CO2) that is released at the end of an exhaled breath. This measurement reflects the adequacy with which carbon dioxide is carried in the blood back to the lungs and exhaled.
  • Cerebral blood flow (CBF)– measurement of the rate of delivery of arterial blood to a capillary bed in the brain tissue, basically the blood flow to the brain which is important for healthy brain function. 
  • Orthostatic– an upright position. Common symptoms of orthostatic intolerance (OI) are light headedness, palpitations, fatigue, blurred vision, dizziness, exercise intolerance, chest discomfort, cognitive impairment, and occasionally syncope.

This was a retrospective study which used data already collected in a database for ME/CFS who had undergone tilt table testing due to suspected orthostatic intolerance. The study included 534 female patients with ME/CFS where all data needed was available (this can be broken down into 309 with normal heart rate and blood pressure during tilt table testing and 226 which were diagnosed with POTS). The healthy control group included 34 healthy controls.

The research found:

  • All patients with ME/CFS (both with and without POTS) had a significant relationship between CBF and PETCO2 in both supine (horizontal) and standing (at the of the end-tilt table test)
  • In patients with ME/CFS and healthy controls, relationships between the %CBF (percentage cerebral blood flow) change and the PETCO2 reduction were both significant.
  • The patient or healthy control status and PETCO2 was found to predicted CBF.
  • The contribution of PETCO2 to CBF changes was found to be limited, i.e. not found to be a casual factor (which was investigated as brain perfusion (a type of brain test that shows the amount of blood taken up in certain areas of your brain) is sensitive to changes in CO2 levels).
  • CO2 reactivity measured during orthostatic test testing was found to be similar in ME/CFS and healthy controls, and this is independent of any type of hemodynamic abnormality (i.e. orthostatic intolerance). However, this is dependent on age and disease severity.
  • It was found that the influence of CO2 changes on CBF changes is modest in female ME/CFS patients.

This piece of research is from the well-known research group van Campen and Visser who focus on OI and cerebral blood flow studies.  We often find their studies are small but significant and well thought out in order to test a theory. This study, however, has overcome sample size by using previous collected data, although this comes with other problems such as the reproducibility of methods between researchers. Furthermore, in using this sample group, all of the ME/CFS patients included may have been affected by a referral bias as all patients had suspected orthostatic intolerance. A few other things to note:

  • ME/CFS patients met the diagnostic criteria of Fukuda and the International consensus criteria.
  • The sample was female only due to the high prevalence in the female sex, as well as reported differences at a molecular level in other studies, but this is also a draw back as we don’t know if results would vary in males. With such a large sample size it is disappointing that a male to female comparison could not be made.
  • There was not an equal number of healthy controls which makes comparisons difficult. It is also disappointing that these were not sedentary.
  • The study included all levels of severity, apart from the very severe.

In conclusion, this was a slightly different style of research from this group (large and respective) as well as not aiding the significant results which we are used to seeing. However, the research does aid to our knowledge about cerebral blood flow in ME/CFS.  

ME/CFS Research References (5 – 11 September 2023)

1. Efficiency of comprehensive rehabilitation of chronic fatigue syndrome due to coronavirus infections COVID-19

Z.I. Adambaev, I.A. Kilichev, A.B. Nurzhonov, N.Yu. Khudoyberganov, and M.R. Niyazmetov.

BIO Web of Conferences 65, 05039 (2023)


The aim of the study was to study the effectiveness of complex rehabilitation in patients with chronic fatigue syndrome caused by coronavirus infections.

In 120 patients with a confirmed diagnosis of SARS-CoV-2 (COVID-19) aged 20-58 years, post-COVID syndrome or chronic fatigue syndrome was detected, 52 men and 68 women. Patients had asthenic, cognitive, vegetative manifestations, sleep disorders, smell and taste disorders, anxiety and depression.

Patients received drug therapy: succinic acid preparations, brain metabolic drugs, stimulating antidepressants, sleeping pills – melatonin and B vitamins, among other things, received micropolarization of the head and translingualneurostimulation.

The results of treatment confirmed the effectiveness of the proposed conservative therapy. The neurological symptoms of post-COVID syndrome – chronic fatigue syndrome (CFS) were studied in 120 patients with a confirmed diagnosis of SARS-CoV-2 (COVID-19), aged 20-58 years.

Patients were examined according to the “Questionnaire for the detection of asthenia”, “Mini Mental State Assessment (MMSE)”, Sleep disorders were studied using the Epworth Sleepiness Scale, anxiety and depression were studied using the “Questionnaire for Determining Anxiety and Depression”.

The patients were divided into 2 groups: the main group (MG) – 69 patients and the control group (CG) – 51 patients. Patients with MG and CG received drug therapy: succinic acid preparations, brain metabolic drugs, stimulating antidepressants, sleeping pills – melatonin and B vitamins. And patients with MG, among other things, received micropolarization of the head and translingualneurostimulation.

2. Links between Serotonin Levels and Stress: Cortisol, Candida A./Mycetes, Omega 3/6 Ratio and Dysbiosis (Skatole/Indoxyl Sulfate) Role in Chronic Fatigue Syndrome (CFS) and Depression

Orlandoni, D.; Di Fede, G.; Mantovani, M.; Nava, C.R.; Tomasi, M.; Fusi, P.

Preprints 2023, 2023090253.


Intestinal microbiota attracts daily attention of a growing number of study which have attempted to link gut dysbiosIs with a variety of disease states: irritable bowel syndrome (IBS), inflamed bowel disease (IBD), Crohn's disease (CD), leaky gut syndrome (LGS), food intolerance, diabetes, metabolic syndrome, cancer, etc.

In our study we analyzed how intestinal dysbiosis may be related to chronic fatigue syndrome (CFS) and depression through the exchange of information through the gut-brain axis (GBA).

We studied 33 subjects, 13 males and 20 females, who reported CFS or/and depression: we investigated their salivary cortisol levels, blood serotonin, omega 3/6 ratio, intestinal dysbiosis (calculated on the urinary levels of indoxyl sulfate and skatole), and we looked for the presence of Candida a. or mycetes in the stool; the data accumulated with this research show a correlation between the presence of Candida a./miceti, indoxyl sulfate urine values beyond the physiological and low serotonin levels.

In addition, data analysis showed that the EPA/DHA values also show pro-inflammatory levels in case of dysbiosis and low serotonina levels. The relationship, however, with cortisol levels requires further research although this study showed a statistically significant positive correlation between these values, measured at specific times, and serotonin levels.

Aims: We investigated the relationship between stress (evaluated through the measurement of salivary cortisol levels) and gastrointestinal efficiency measured as a function of intestinal fermentative and putrefactive dysbiosis, evaluating the levels of urinary indoxyl sulfate in the first case (a possible correlation with the presence of Candida spp or Mycetes in the subjects feces was investigated), urinary skatole levels in the second one, in patients with chronic fatigue syndrome (SFC) and depression.

In these patients we also have studied omega 3/6 ratio, and finally we have analized the impact that the alteration of these parameters can have on the serotonin levels.

This research attemps to highlight the contact points, in some cases not so obvious, among these topics, contact points that, although they give us interesting indications, show the need to be further deepened by analyzing a larger amount of data.

3. Pre-pandemic activity on a myalgic encephalomyelitis/chronic fatigue syndrome support forum is highly associated with later activity on a long COVID support forum for a variety of reasons: A mixed methods study

Meyerson WU, Hoyle RH.

PLoS One. 2023 Sep 8;18(9):e0291173. 


Encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID share some clinical and social characteristics. We predicted that this would lead to an increased interaction between pre-pandemic members of an ME/CFS online support community and a long COVID community.

We performed a mixed-methods retrospective observational study of the Reddit activity of 7,544 users active on Reddit's long COVID forum. From among 1600 forums, pre-pandemic activity specifically on a ME/CFS forum is the top predictor of later participation on the long COVID forum versus an acute COVID support forum.

In the qualitative portion, motives for this co-participation included seeking mutual support and dual identification with both conditions. Some of this effect may be explained by pre-existing ME/CFS possibly being a risk factor for long COVID and/or SARS-CoV-2 infection being a cause of ME/CFS relapse.

The high rate of ME/CFS patients seeking mutual support on a long COVID forum speaks to the long-suffering experience of these patients not feeling heard or respected, and the hope of some ME/CFS patients to gain legitimacy through the public's growing recognition of long COVID.

4. Influence of end-tidal CO2 on cerebral blood flow during orthostatic stress in controls and adults with myalgic encephalomyelitis/chronic fatigue syndrome

van Campen CLMC, Rowe PC, Verheugt FWA, Visser FC.

Physiol Rep. 2023 Sep;11(17):e15639. 


Brain perfusion is sensitive to changes in CO2 levels (CO2 reactivity). Previously, we showed a pathological cerebral blood flow (CBF) reduction in the majority of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients during orthostatic stress.

Limited data are available on the relation between CO2 and CBF changes in ME/CFS patients. Therefore, we studied this relation between ME/CFS patients and healthy controls (HC) during tilt testing.

In this retrospective study, supine and end-tilt CBF, as measured by extracranial Doppler flow, were compared with PET CO2 data in female patients either with a normal heart rate and blood pressure (HR/BP) response or with postural orthostatic tachycardia syndrome (POTS), and in HC. Five hundred thirty-five female ME/CFS patients and 34 HC were included.

Both in supine position and at end-tilt, there was a significant relation between CBF and PET CO2 in patients (p < 0.0001), without differences between patients with a normal HR/BP response and with POTS.

The relations between the %CBF change and the PET CO2 reduction were both significant in patients and HC (p < 0.0001 and p = 0.0012, respectively). In a multiple regression analysis, the patient/HC status and PET CO2 predicted CBF.

The contribution of the PET CO2 to CBF changes was limited, with low adjusted R2 values. In female ME/CFS patients, CO2 reactivity, as measured during orthostatic stress testing, is similar to that of HC and is independent of the type of hemodynamic abnormality. However, the influence of CO2 changes on CBF changes is modest in female ME/CFS patients.

5. The Potential Role of Hypothalamic Phospholipid Liposomes in the Supportive Therapy of Some Manifestations of Post-COVID-19 Condition: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Brain Fog

Menichetti F.

J Clin Med. 2023 Aug 23;12(17):5478.


Post-COVID-19 condition (commonly known as Long COVID) is a heterogeneous clinical condition in which Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and brain fog stand out among the different clinical symptoms and syndromes.

Cerebral metabolic alterations and neuroendocrine disorders seem to constitute an important part of the pathophysiology of Post-COVID-19 condition (PCC).

Given the substantial lack of specific drugs and effective therapeutic strategies, hypothalamic phospholipid liposomes, which have been on the market for several years as adjuvant therapy for cerebral metabolic alterations resulting from neuroendocrine disorders, might represent a potential option in an overall therapeutic strategy that aims to control PCC-associated symptoms and syndromes. Their pharmacological mechanisms and clinical effects strongly support their potential effectiveness in PCC.

Our initial clinical experience seems to corroborate this rationale. Further controlled clinical research is warranted in order to verify this hypothesis.

6. Fatigue, chronic fatigue syndrome and migraine: Intersecting the lines through a cross-sectional study in patients with episodic and chronic migraine

Kumar H, Dhamija K, Duggal A, Khwaja GA, Roshan S.

J Neurosci Rural Pract. 2023 Jul-Sep;14(3):424-431. 


Objectives: Fatigue is a common symptom occurring in a variety of disorders. Chronic fatigue syndrome (CFS) is characterized by debilitating fatigue as the core symptom. The risk of CFS is nearly 1.5 times higher in migraine while headaches have been reported in 59% of cases with CFS. However, details of its occurrence and severity remain largely unexplored.

The primary objective of our study was to determine the occurrence and severity of fatigue and CFS in patients with episodic and chronic migraine. The secondary objectives were to define their relationship with other common comorbidities.

Materials and methods: 60 migraine patients (30 each, episodic [EM] and chronic migraine [CM]) were recruited from Neurology Outpatient Department, GIPMER a tertiary referral center in New Delhi, India. Patients' headache severity was analyzed using the Headache impact test-6 (HIT-6) score while fatigue and other migraine accompaniments were assessed using Fatigue severity scale (FSS), Chalder fatigue scale, CDC diagnostic criteria for CFS, American College of Rheumatology Diagnostic Criteria for fibromyalgia, Hamilton Depression Scale, the Generalized Anxiety Disorder 7-Item Scale, and Epworth sleepiness Scale (ESS). Comparative analysis was further done among migraine patients with and without fatigue and CFS.

Results: The mean HIT-6 score was significantly higher in CM versus EM. The CM group had a higher mean FSS score (47.87 vs. 37.3 in EM; P = 0.004), a percentage of patients with severe fatigue (60% vs. 20% in EM; P = 0.004), and a higher percentage of patients with pathological fatigue (83.3% vs. 63.3% in EM; P = 0.04). Around 23.33% of CM patients fulfilled the criteria of CFS. Fatigue correlated positively with severity, frequency, attack duration and chronicity of the migraine episodes, along with depression, anxiety, and excessive daytime sleepiness.

Conclusion: Fatigue and related comorbid disorders are significantly more common in CM than in EM, expanding the morbidity of the condition and underscores the need to address these accompanying symptoms for devising a holistic treatment plan.

7. Developing and validating a brief screening scale for ME/CFS

Leonard A. Jason, Sage Benner, Jacob Furst & Paul Cathey.

Fatigue: Biomedicine, Health & Behavior.


Objective: The purpose of the current study was to develop and evaluate a brief screening instrument for ME/CFS. The current study identified 4 symptom items that identify those positive for the IOM ME/CFS case definition.

Study Design: A data set of over 2,000 patients with Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and over 350 controls were assessed for the 4-item DePaul Symptom Questionnaire-Brief (DSQ-Brief). All respondents also completed the longer 54-item DePaul Symptom Questionnaire (DSQ-1) as well as the 14-item DePaul Symptom Questionnaire-Short Form (DSQ-SF). These data sets were collected from multiple countries.

We also examined the DSQ-Brief, DSQ-1, and DSQ-SF with other chronic illness groups [Multiple Sclerosis (MS) and Post-Polio Syndrome (PPS)] and those with Long COVID. Random Forest comparisons were employed in these analyses.

Results: When contrasting ME/CFS from controls, high levels of accuracy occurred using the DSQ-1, DSQ-SF, and DSQ-Brief. High accuracy again occurred for differentiating those with ME/CFS from MS, PPS, and Long COVID using the DSQ-1 and DSQ-SF, but accuracy was less for the DSQ-Brief.

Conclusions: The DSQ-Brief had high sensitivity, meaning it could identify those with ME/CFS versus controls, whereas accuracy dropped with other chronic illnesses. However, it was possible to achieve better accuracy and identify those cases where misidentification occurred by administering the DSQ-SF or DSQ-1 following the DSQ-Brief. It is now possible to screen individuals for ME/CFS using the DSQ-Brief and in so doing, identify those who are most likely to have ME/CFS.

8. What Long COVID investigators can learn from four decades of ME/CFS research

Leonard A. Jason, Benjamin H. Natelson, Hector Bonilla, Zaki A. Sherif, Suzanne D. Vernon, Monica Verduzco Gutierrez, Lisa O’Brien, Emily Taylor.

Brain Behavior and Immunity Integrative, Volume 4, 2023, 100022.


Four decades of research in the field of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) have yielded lessons that may be instructive for those devising criteria to better comprehend Post-Acute Sequelae of SARS CoV-2 Infection (PASC) and Long COVID.

For instance, substantial effort has been devoted to defining classification systems, operationalizing methods, and developing instruments with adequate reliability and validity in the ME/CFS field.

The current article provides guidelines for developing a case definition for Long COVID and discusses the significance of psychometric issues and criterion variance, including how to specify symptoms, develop thresholds, subtypes, and exclusionary conditions. ME/CFS research could enhance our knowledge of Long COVID pathophysiology, early diagnosis, prognosis, and the identification of effective treatments.

9. Myalgic Encephalomyelitis-Chronic Fatigue Syndrome Common Data Element item content analysis

Slavin MD, Bailey HM, Hickey EJ, Vasudevan A, Ledingham A, Tannenbaum L, Bateman L, Kaufman DL, Peterson DL, Ruhoy IS, Systrom DM, Felsenstein D, Kazis LE.

PLoS One. 2023 Sep 12;18(9):e0291364


Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multisystem chronic disease estimated to affect 836,000-2.5 million individuals in the United States. Persons with ME/CFS have a substantial reduction in their ability to engage in pre-illness levels of activity. Multiple symptoms include profound fatigue, post-exertional malaise, unrefreshing sleep, cognitive impairment, orthostatic intolerance, pain, and other symptoms persisting for more than 6 months. Diagnosis is challenging due to fluctuating and complex symptoms. ME/CFS Common Data Elements (CDEs) were identified in the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) Common Data Element Repository. This study reviewed ME/CFS CDEs item content.

Methods: Inclusion criteria for CDEs (measures recommended for ME/CFS) analysis: 1) assesses symptoms; 2) developed for adults; 3) appropriate for patient reported outcome measure (PROM); 4) does not use visual or pictographic responses. Team members independently reviewed CDEs item content using the World Health Organization International Classification of Functioning, Disability and Health (ICF) framework to link meaningful concepts.

Results: 119 ME/CFS CDEs (measures) were reviewed and 38 met inclusion criteria, yielding 944 items linked to 1503 ICF meaningful concepts. Most concepts linked to ICF Body Functions component (b-codes; n = 1107, 73.65%) as follows: Fatiguability (n = 220, 14.64%), Energy Level (n = 166, 11.04%), Sleep Functions (n = 137, 9.12%), Emotional Functions (n = 131, 8.72%) and Pain (n = 120, 7.98%). Activities and Participation concepts (d codes) accounted for a smaller percentage of codes (n = 385, 25.62%). Most d codes were linked to the Mobility category (n = 69, 4.59%) and few items linked to Environmental Factors (e codes; n = 11, 0.73%).

Discussion: Relatively few items assess the impact of ME/CFS symptoms on Activities and Participation. Findings support development of ME/CFS-specific PROMs, including items that assess activity limitations and participation restrictions. Development of psychometrically-sound, symptom-based item banks administered as computerized adaptive tests can provide robust assessments to assist primary care providers in the diagnosis and care of patients with ME/CFS.

ME/CFS Research References (29 August – 4 September 2023)

1. A synthetic data generation system for myalgic encephalomyelitis/chronic fatigue syndrome questionnaires

2. Long-term symptom severity and clinical biomarkers in post-COVID-19/chronic fatigue syndrome: results from a prospective observational cohort

3. A synthetic data generation system for myalgic encephalomyelitis/chronic fatigue syndrome questionnaires

4. How post-infection status could lead to the increasing risks of chronic fatigue syndrome and the potential mechanisms: A 17-year population based Cohort study

Long-COVID Research References (5 – 11 September 2023)

  1. Unveiling the Mysteries of Long COVID Syndrome: Exploring the Distinct Tissue and Organ Pathologies Linked to Prolonged COVID-19 Symptoms
  2. Effect of physical activity on long COVID fatigue: an unsolved enigma
  3. SARS-CoV-2 reservoir in post-acute sequelae of COVID-19 (PASC)
  4. Headache in COVID-19 and Long COVID: to Know Facts for Clinical Practice
  5. Predictive models of long COVID
  6. Cognitive disengagement syndrome in pediatric patients with long COVID: associations with mood, anxiety, and functional impairment
  7. The role of myocardial perfusion imaging in predicting myocardial ischemia in patients diagnosed with long COVID
  8. Structural and functional impairments of skeletal muscle in patients with post-acute sequelae of SARS-CoV-2 infection
  9. Post-COVID symptoms are associated with endotypes reflecting poor inflammatory and hemostatic modulation
  10. Hydroxychloroquine as ‘Potential Treatment Option’ for Persistent Immune Dysregulation in Long COVID: Revisiting Its New Use as a ‘Versatile’ Molecule!
  11. The global challenges of the long COVID-19
  12. Long-Covid and Pain: Pathophysiology and Management
  13. Impaired parasympathetic function in long-COVID postural orthostatic tachycardia syndrome – a case-control study
  14. Neutrophil Extracellular Traps and Long COVID
  15. Long COVID: A Molecular, Cellular and Histopathology Overview
  16. Determinants of the onset and prognosis of the post-COVID-19 condition: a 2-year prospective observational cohort study
  17. Severity of neurological long-COVID symptoms correlates with increased level of autoantibodies targeting vasoregulatory and autonomic nervous system receptors
  18. Neuroimmunological Effect of Vitamin D on Neuropsychiatric Long COVID Syndrome: A Review
  19. Reactive gliosis and neuroinflammation: prime suspects in the pathophysiology of post-acute neuroCOVID-19 syndrome
  20. Exploring the mechanisms of long COVID: Insights from computational analysis of SARS-CoV-2 gene expression and symptom associations
  21. Analyzing the Interplay between COVID-19 Viral Load, Inflammatory Markers, and Lymphocyte Subpopulations on the Development of Long COVID
  22. Social Stigma in Children with Long COVID
  23. Long-term complications after infection with SARS-CoV-1, influenza and MERS-CoV – lessons to learn in long COVID?
  24. Examination of autoantibodies to type I interferon in patients suffering from long COVID
  25. COVID-19 and Long COVID: Disruption of the Neurovascular Unit, Blood-Brain Barrier, and Tight Junctions
  26. Long COVID: Clinical Findings, Pathology, and Endothelial Molecular Mechanisms

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent
Shopping Basket