ME Association regular research roundup

ME/CFS and Long Covid Research: 04 – 10 July 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).

It’s been a slightly quieter week for research, with six new ME/CFS studies and nineteen new Long Covid studies this week.


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

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

Paper one (1) is a review of what we currently know about urinary biomarkers for ME/CFS. If a urine biomarker for diagnosing ME/CFS was to be found, this would be ideal as it involves non-invasive sampling.

This was a rigorous review which searched three different databases for research published between 1994 and 2022.

In summary, the review found:

  • Twenty-one previous investigations into urinary biomarkers.
  • All studies compared ME/CFS patients to healthy controls.
  • The majority of the studies (n=14) used the minimum diagnostic criteria for ME/CFS (i.e. Fukuda). Seven of the studies used the more rigorous diagnostic criteria of CCC or ICC.
  • In previous published research urinary outputs of those with ME/CFS were reported to change as follows: free cortisol (38.10%), carnitine (28.6%), iodine (4.76%), and the metabolome (42.86%).
  • Most studies measured different outcomes (such as; metabolites, amino acids) but urinary free cortisol was most commonly reported.
  • Meta-analysis was conducted on seven of the studies (where results from multiple studies are combined statistically to find a common result), all of the studies included reported on urinary free cortisol.
  • The levels of urinary free cortisol were significantly different between ME/CFS and controls, but the results were not comparable between studies (reduced levels in four of the studies and no significant difference in three of the studies), meaning that no conclusions could be drawn.

The review mostly focused on urinary free cortisol as the number of studies which reported on this allowed for comparisons to be made. However, additionally, creatinine levels were also investigated in six of the studies, with lower and higher levels being found in ME/CFS. This was also not found to be a suitable biomarker, due to its association with reduced kidney function as well as low levels being associated with depleted muscle mass (which may be caused by being bedbound). Further to this, reduced muscle mass has not yet been clinically established as a characteristic of ME/CFS and exertion levels have not been investigated in relation to this.

Also of note, of the studies included in this review, only one of them investigated urinary composition during PEM. It is interesting that more studies have not covered this, due to significant differences being found between ME/CFS patients and healthy controls following exercise and during PEM. We have recently reported on a study which investigated just this, but unfortunately it was too recent to have been included in the review (Glass et al., 2023, roundup comment).

Despite this review not being able to confirm urinary biomarkers which need further investigation, it was well-conducted and written. The review further shows the inconsistent evidence available when looking into metabolic and hormonal processes which could provide a biomarker. In addition it showed problems with the size of studies and methodological approaches used. Although it is disappointing it does not highlight future avenues or give recommendation into what should be investigated, such as specific metabolites.

You may also be interested in reading Paper five (5) which supports the use of Graded Exercise Therapy (GET) and Cognitive Behavioural Therapy (CBT) and openly criticises the recommendations made in the 2021 NICE Guideline on the ME/CFS. The ME Association and NICE have robustly defended the clinical recommendation, more about this can be read here.

In the Long Covid Reference section, you may also be interested in Paper two (2) which tries to find a genetic risk factor for Long Covid. Results suggest there is a genetic predisposition, more about this can be read here.

ME/CFS Research References and Abstracts (13 – 19 June)

1. A systematic review and meta-analysis of urinary biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Taccori A, Maksoud R, Eaton-Fitch N, Patel M, Marshall-Gradisnik S.

J Transl Med. 2023 Jul 5;21(1):440.


Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multifactorial illness that affects many body systems including the immune, nervous, endocrine, cardiovascular, and urinary systems. There is currently no universal diagnostic marker or targeted treatment for ME/CFS. Urine is a non-invasive sample that provides biomarkers that may have the potential to be used in a diagnostic capacity for ME/CFS. While there are several studies investigating urine-based biomarkers for ME/CFS, there are no published systematic reviews to summarise existing evidence of these markers. The aim of this systematic review was to compile and appraise literature on urinary-based biomarkers in ME/CFS patients compared with healthy controls.

Methods: Three databases: Embase, PubMed, and Scopus were searched for articles pertaining to urinary biomarkers for ME/CFS compared with healthy controls published between December 1994 to December 2022. The final articles included in this review were determined through application of specific inclusion and exclusion criteria. Quality and bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Case Control Studies. A meta-analysis according to Cochrane guidelines was conducted on select studies, in particular, those that investigate urinary free cortisol levels in ME/CFS patients compared to healthy controls using the program STATA 17.

Results: Twenty-one studies were included in this review. All of the studies investigated urinary-based markers in ME/CFS patients compared with healthy controls. The reported changes in urinary outputs include urinary free cortisol (38.10%), carnitine (28.6%), iodine (4.76%), and the metabolome (42.86%). In most cases, there was minimal overlap in the main outcomes measured across the studies, however, differences in urinary free cortisol between ME/CFS patients and healthy controls were commonly reported. Seven studies investigating urinary free cortisol were included in the meta-analysis. While there were significant differences found in urinary free cortisol levels in ME/CFS patients, there was also substantial heterogeneity across the included studies that makes drawing conclusions difficult.

Conclusions: There is limited evidence suggesting a consistent and specific potential urinary-based biomarker for ME/CFS. Further investigations using more standardised methodologies and more stringent case criteria may be able to identify pathophysiological differences with diagnostic potential in ME/CFS patients compared with healthy controls.

2. Overall comorbidities in functional neurological disorder: A narrative review

Carle-Toulemonde G, Goutte J, Do-Quang-Cantagrel N, Mouchabac S, Joly C, Garcin B.

Encephale. 2023 Jul 4: S0013-7006(23)00086-6. [Epub ahead of print.]


Introduction: The importance to assess and include the frequent comorbidities in the personalised care management plan of patients with functional neurological disorders (FND) has arisen through the years. FND patients are not only complaining from motor and/or sensory symptoms. They also report some non-specific symptoms that participate to the burden of FND. In this narrative review, we aim to better describe these comorbidities in terms of prevalence, clinical characteristics and their variability depending on the subtype of FND.

Methods: The literature was searched for on Medline and PubMed. The search was narrowed to articles between 2000 and 2022.

Results: Fatigue is the most common symptom reported in relation to FND (from 47 to 93%), followed by cognitive symptoms (from 80 to 85%). Psychiatric disorders are reported in 40 to 100% FND patients, depending on the FND subtype (functional motor disorder [FMD], functional dissociative seizures [FDS]…) but also on the type of psychiatric disorder (anxiety disorders being the most frequent, followed by mood disorders and neurodevelopmental disorders). Stress factors such as childhood trauma exposure (emotional neglect and physical abuse predominantly) have also been identified in up to 75% of FND patients, along with maladaptive coping strategies. Organic disorders are commonly reported in FND, such as neurological disorders (including epilepsy in FDS [20%] and FMD in Parkinson's Disease [7%]). Somatic symptom disorders including chronic pain syndromes are frequently associated to FND (about 50%). To be noted, recent data also suggest a high comorbidity between FND and hypermobile Ehlers Danlos Syndrome (about 55%).

Conclusion: Put together, this narrative review highlights the high burden of FND patients, not only due to somatosensory alterations but also by considering the frequent comorbidities reported. Thus, such comorbidities must be taken into consideration when defining the FND personalised care management strategy for the patients.

3. Chronic inflammation, neuroglia dysfunction, and plasmalogen deficiency as a new pathobiological hypothesis addressing the overlap between post-COVID-19 symptoms and myalgic encephalomyelitis/chronic fatigue syndrome

Chaves AM, Braniff O, Angelova A, Deng Y, Tremblay MÈ.

Brain Res Bull. 2023 Jul 7:110702. [Epub ahead of print.]


  • Plasmalogens (Pls) are lipids containing a vinyl-ether bond in their glycerol backbone.
  • Pls have antioxidant properties and are important for curved membrane assemblies.
  • Post-COVID-19 symptoms are highly prevalent and share several features with ME/CFS.
  • Pls depletion is a shared biological hallmark of ME/CFS and acute COVID-19 syndrome.
  • Pls replacement is a promising tool against neuroinflammation in these two conditions.


After five waves of COVID-19 outbreaks, it has been recognized that a significant portion of the affected individuals developed long-term debilitating symptoms marked by chronic fatigue, cognitive difficulties (“brain fog”), post-exertional malaise, and autonomic dysfunction.

The onset, progression, and clinical presentation of this condition, generically named post-COVID-19 syndrome, overlap significantly with another enigmatic condition, referred to as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Several pathobiological mechanisms have been proposed for ME/CFS, including redox imbalance, systemic and central nervous system inflammation, and mitochondrial dysfunction. Chronic inflammation and glial pathological reactivity are common hallmarks of several neurodegenerative and neuropsychiatric disorders and have been consistently associated with reduced central and peripheral levels of plasmalogens, one of the major phospholipid components of cell membranes with several homeostatic functions.

Of great interest, recent evidence revealed a significant reduction of plasmalogens contents, biosynthesis, and metabolism in ME/CFS and acute COVID-19, with a strong association to symptom severity and other relevant clinical outcomes. These bioactive lipids have increasingly attracted attention due to their reduced levels representing a common pathophysiological manifestation between several disorders associated with aging and chronic inflammation. However, alterations in plasmalogen levels or their lipidic metabolism have not yet been examined in individuals suffering from post-COVID-19 symptoms.

Here, we proposed a pathobiological model for post-COVID-19 and ME/CFS based on their common inflammation and dysfunctional glial reactivity, and highlighted the emerging implications of plasmalogen deficiency in the underlying mechanisms.

Along with the promising outcomes of plasmalogen replacement therapy (PRT) for various neurodegenerative/neuropsychiatric disorders, we sought to propose PRT as a simple, effective, and safe strategy for the potential relief of the debilitating symptoms associated with ME/CFS and post-COVID-19 syndrome.

4. System and methods to determine ME/CFS & Long Covid disease severity using wearable sensor & survey data

Sun, Y.

Thesis, Bachelor of Science, The University of Utah


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with high probability of misdiagnosis and significant unmet medical needs that affects as many as 2.5 million people in the U.S. and causes enormous burden for patients, their caregivers, the healthcare system and society. Between 84 to 91 percent of ME/CFS patients are not yet diagnosed [6, 19], and at least one-quarter of ME/CFS patients are house- or bedbound at some point in their lives [12, 13]. The impact of ME/CFS to the U.S. economy, is about $17 to $24 billion in medical bills and lost income from lost household and labor force productivity per year [7, 13].

Current widely used diagnosis methods of ME/CFS and other diseases with similar clinical symptoms like Long COVID [6, 21] are highly dependent on patients’ self reporting [4, 5] and standardized survey, which are not optimal for medical diagnosis. In a joint study with The Bateman Horne Center (BHC)1, we designed and developed a system prototype that was able to stably collect terabytes of inertial measurement unit (IMU) time-series data, and analyzed multiple candidate parameters derived from them that could be used as reliable biomarkers for ME/CFS and other diseases with similar clinical symptoms.

Utilizing our system prototype, MetaProcessor, we conducted grouped t-tests on data collected from the EndoPAT study group (55 recruited, 51 participated, 30 ME/CFS, 15 Long COVID, 6 healthy control) to evaluate the predictive power of Upright Position Time (UpTime), Hours of Upright Activity (HUA), and Steps/Day. Through statistical analysis, we were able to assert the following for ME/CFS versus healthy control:

1. UpTime yielded a low p-value of 0.00004, indicating a significant difference between the groups and demonstrating its potential as a reliable measure for differentiating ME/CFS from healthy control populations.

2. HUA had a p-value of less than 0.00004, suggesting it could also serve as a useful measure for distinguishing ME/CFS from healthy control groups.

3. Steps/Day, x-axis and y-axis, had p-values of 0.01059 and 0.08665, respectively, indicating that step count may be relevant for differentiating ME/CFS individuals from healthy controls, but step count alone may not be sufficient to reliably distinguish between these groups.

 In a linear regression analysis, we found a moderately positive correlation between UpTime and HUA with r 2 = 0.68. Overall, we can confidently conclude that UpTime is a superior overall predictor due to its objective nature and the lowest p-values observed across all groups.

5. Anomalies in the review process and interpretation of the evidence in the NICE guideline for chronic fatigue syndrome and myalgic encephalomyelitis

White P, Abbey S, Angus B, Ball HA, Buchwald DS, Burness C, Carson AJ, Chalder T, Clauw DJ, Coebergh J, David AS, Dworetzky BA, Edwards MJ, Espay AJ, Etherington J, Fink P, Flottorp S, Garcin B, Garner P, Glasziou P, Hamilton W, Henningsen P, Hoeritzauer I, Husain M, Huys AML, Knoop H, Kroenke K, Lehn A, Levenson JL, Little P, Lloyd A, Madan I, van der Meer JWM, Miller A, Murphy M, Nazareth I, Perez DL, Phillips W, Reuber M, Rief W, Santhouse A, Serranova T, Sharpe M, Stanton B, Stewart DE, Stone J, Tinazzi M, Wade DT, Wessely SC, Wyller V, Zeman A.

J Neurol Neurosurg Psychiatry. 2023 Jul 10:jnnp-2022-330463. [Epub ahead of print.]


Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disabling long-term condition of unknown cause. The National Institute for Health and Care Excellence (NICE) published a guideline in 2021 that highlighted the seriousness of the condition, but also recommended that graded exercise therapy (GET) should not be used and cognitive-behavioural therapy should only be used to manage symptoms and reduce distress, not to aid recovery. This U-turn in recommendations from the previous 2007 guideline is controversial.

We suggest that the controversy stems from anomalies in both processing and interpretation of the evidence by the NICE committee.

The committee:

(1) created a new definition of CFS/ME, which ‘downgraded' the certainty of trial evidence;

(2) omitted data from standard trial end points used to assess efficacy;

(3) discounted trial data when assessing treatment harm in favour of lower quality surveys and qualitative studies;

(4) minimised the importance of fatigue as an outcome;

(5) did not use accepted practices to synthesise trial evidence adequately using GRADE (Grading of Recommendations, Assessment, Development and Evaluations trial evidence);

(6) interpreted GET as mandating fixed increments of change when trials defined it as collaborative, negotiated and symptom dependent;

(7) deviated from NICE recommendations of rehabilitation for related conditions, such as chronic primary pain and

(8) recommended an energy management approach in the absence of supportive research evidence.

We conclude that the dissonance between this and the previous guideline was the result of deviating from usual scientific standards of the NICE process. The consequences of this are that patients may be denied helpful treatments and therefore risk persistent ill health and disability.

6. Nutrient Therapy for the Improvement of Fatigue Symptoms

Barnish M, Sheikh M, Scholey A.

 Nutrients. 2023; 15(9):2154. 


Fatigue, characterised by lack of energy, mental exhaustion and poor muscle endurance which do not recover following a period of rest, is a common characteristic symptom of several conditions and negatively impacts the quality of life of those affected. Fatigue is often a symptom of concern for people suffering from conditions such as fibromyalgia, chronic fatigue syndrome, cancer, and multiple sclerosis.

Vitamins and minerals, playing essential roles in a variety of basic metabolic pathways that support fundamental cellular functions, may be important in mitigating physical and mental fatigue.

Several studies have examined the potential benefits of nutrients on fatigue in various populations. The current review aimed to gather the existing literature exploring different nutrients’ effects on fatigue.

From the searches of the literature conducted in PubMed, Ovid, Web of Science, and Google scholar, 60 articles met the inclusion criteria and were included in the review. Among the included studies, 50 showed significant beneficial effects (p < 0.05) of vitamin and mineral supplementation on fatigue.

Altogether, the included studies investigated oral or parenteral administration of nutrients including Coenzyme Q10, L-carnitine, zinc, methionine, nicotinamide adenine dinucleotide (NAD), and vitamins C, D and B.

In conclusion, the results of the literature review suggest that these nutrients have potentially significant benefits in reducing fatigue in healthy individuals as well as those with chronic illness, both when taken orally and parenterally. Further studies should explore these novel therapies, both as adjunctive treatments and as sole interventions.

Long-COVID Research References

  1. Detrimental effects of COVID-19 in the brain and therapeutic options for long COVID: The role of Epstein–Barr virus and the gut–brain axis
  2. Genome-wide Association Study of Long COVID
  3. Psychiatric symptoms in Long-COVID patients: a systematic review
  4. Understanding How Post-COVID-19 Condition Affects Adults and Health Care Systems
  5. Fatigue in Post-Acute Sequelae of Coronavirus Disease 2019
  6. Altered brain connectivity in Long Covid during cognitive exertion: a pilot study
  7. Long COVID Clinical Phenotypes up to 6 Months After Infection Identified by Latent Class Analysis of Self-Reported Symptoms
  8. Long COVID, the Brain, Nerves, and Cognitive Function
  9. Supporting Students With COVID and Long COVID in the School Setting: Best Practices Utilizing an Interdisciplinary Framework
  10. Long COVID: An approach to clinical assessment and management in primary care
  11. Approaches towards menstrual cycle disorder therapy in reproductive-aged women with long COVID
  12. Antihistamines improve cardiovascular manifestations and other symptoms of Long-COVID attributed to Mast Cell Activation
  13. Role of Vitamin D Supplementation for Symptoms and Lung Function Improvement in Long COVID Patient
  14. Long COVID: what is known and what gaps need to be addressed
  15. Correlation between Hepatocyte Growth Factor (HGF) with D-Dimer and Interleukin-6 as Prognostic Markers of Coagulation and Inflammation in Long COVID-19 Survivors
  16. Apolipoprotein E (ApoE) ε4 Genotype (ApoE rs429358—ApoE rs7412 Polymorphisms) Is Not Associated with Long COVID Symptoms in Previously Hospitalized COVID-19 Survivors
  17. The Avon Longitudinal Study of Parents and Children – a resource for COVID-19 research: questionnaire data capture July 2021 to December 2021, with a focus on long COVID
  18. Carotid body dysregulation contributes to the enigma of long COVID

Imbalanced brain connectome: A possible link behind functional somatic disorders, multiple chemical sensitivity, and long COVID patients

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent
Shopping Basket