The ME Association ME/CFS (& Long Covid) Weekly Research Round-up

July 31, 2021

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).

All research relating to ME/CFS can be located in the ME Association: Index of ME/CFS Published Research. It is a FREE resource, available to anyone, and updated at the beginning of each month.

The Index provides an A-Z of published research studies, selected key documents and articles, listed by subject matter, on myalgic encephalomyelitis, myalgic encephalopathy, and/or chronic fatigue syndrome (ME/CFS).

You can use it to easily locate and read any research that you might be interested in regard to, e.g., epidemiology, infection, neurology, post-exertional malaise etc.

You can also find the Research Index in the Research section of the website together with a list of Research Summaries that provide more detailed lay explanations of the more interesting work that has been published to date.

ME/CFS Research Published 17 – 23 July 2021

Six new research studies on ME/CFS have been published during this period and we have also included five studies on Long Covid. We highlight two on ME/CFS from the selection below:

The first study (1) aimed to differentiate between groups of people with ME/CFS using samples from the ME/CFS Biobank (UKMEB).

  • Some of the problems in advancing ME/CFS research stem from the wide range of triggers. Trying to find subgroups formed the basis of this study, which looked at chronic herpesviruses infection.
  • It concluded that herpesviruses serology could distinguish subgroups of ME/CFS patients according to their disease trigger, but this finding is not robust and could be affected by the problem of multiple testing.

The fourth study (4) looked at establishing routine blood tests for the diagnosis of ME/CFS. It examined over 20 different routine blood test scores comparing each to healthy controls.

  • ME/CFS patients were found to have multiple differences in key blood indicators such as vitamin B12, potassium, and creatine kinase compared to healthy controls.
  • However, most of abnormal findings were believed to be of minor significance and the results could in part be due to taking supplements.
  • The low levels of creatine kinase and creatinine levels in the blood may suggest muscle damage and metabolic abnormalities in ME/CFS patients as well as low-grade inflammation.

ME/CFS Research References and Abstracts

1. Herpesviruses Serology Distinguishes Different Subgroups of Patients From the United Kingdom ME/CFS Biobank

Domingues TD, Grabowska AD, Lee JS, Ameijeiras-Alonso J, Westermeier F, Scheibenbogen C, Cliff JM, Nacul L, Lacerda EM, Mouriño H, Sepúlveda N. Front Med (Lausanne). 2021 Jul 5;8:686736.


The evidence of an association between Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and chronic herpesviruses infections remains inconclusive. Two reasons for the lack of consistent evidence are the large heterogeneity of the patients' population with different disease triggers and the use of arbitrary cut-offs for defining seropositivity.

In this work we re-analyzed previously published serological data related to 7 herpesvirus antigens.

Patients with ME/CFS were subdivided into four subgroups related to the disease triggers: S0-42 patients who did not know their disease trigger; S1-43 patients who reported a non-infection trigger; S2-93 patients who reported an infection trigger, but that infection was not confirmed by a lab test; and S3-48 patients who reported an infection trigger and that infection was confirmed by a lab test.

In accordance with a sensitivity analysis, the data were compared to those from 99 healthy controls allowing the seropositivity cut-offs to vary within a wide range of possible values.

We found a negative association between S1 and seropositivity to Epstein-Barr virus (VCA and EBNA1 antigens) and Varicella-Zoster virus using specific seropositivity cutoff. However, this association was not significant when controlling for multiple testing.

We also found that S3 had a lower seroprevalence to the human cytomegalovirus when compared to healthy controls for all cutoffs used for seropositivity and after adjusting for multiple testing using the Benjamini-Hochberg procedure. However, this association did not reach statistical significance when using Benjamini-Yekutieli procedure.

In summary, herpesviruses serology could distinguish subgroups of ME/CFS patients according to their disease trigger, but this finding could be eventually affected by the problem of multiple testing.

2. ME/CFS: When Suffering Is Multiplied

Komaroff, A.L. Healthcare 2021, 9, 919


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an illness defined predominantly by symptoms. Routine laboratory test results often are normal, raising the question of whether there are any underlying objective abnormalities. In the past 20 years, however, new research technologies have uncovered a series of biological abnormalities in people with ME/CFS. Unfortunately, many physicians remain unaware of this, and some tell patients that “there is nothing wrong” with them. This skepticism delegitimizes, and thereby multiplies, the patients’ suffering.

3. Illness-related cognition, distress and adjustment in functional stroke symptoms, vascular stroke, and chronic fatigue syndrome

Jones, A, Smakowski, A, Hughes, A, David, AS & Chalder, T European Journal of Health Psychology.


Background: High rates of psychological distress are reported in functional conditions and vascular stroke but there is limited understanding of how patients with functional neurological symptoms in stroke settings respond to symptoms.

Aims: This study compared patients with functional stroke symptoms to those with vascular stroke and chronic fatigue syndrome (CFS).

Methods: A prospective cohort of fifty-six patients with functional stroke symptoms were age-sex matched to patients with vascular stroke and CFS. Analysis of variance compared groups on cognitive and behavioural responses to symptoms, psychological distress and functioning. Sensitivity analyses controlled for known confounders. The proportions of clinical anxiety and depression were compared between groups.

Results: The functional stroke symptom group had a higher proportion of clinical anxiety cases compared to the CFS group, and a higher proportion of clinical depression cases compared to the vascular stroke group. Patients with functional stroke symptoms reported the highest rate of ‘damage beliefs’ and ‘all-or-nothing’ behaviours and greater symptom focussing and resting behaviour than patients with vascular stroke.

Limitations: Larger cohorts and a longitudinal design would strengthen study findings.

Conclusion: Compared to patients with vascular stroke or CFS, patients with functional stroke symptoms show a somewhat distinct profile of illness-related beliefs, behaviours, and cognitions, as well as higher rates of clinical anxiety . Understanding such group differences provides some insights into aetiology and cognitive-behavioural responses. Appropriate support and referrals should be available to patients with functional stroke symptoms to address distress and reduce likelihood of severe impairment.

4. Evaluating Routine Blood Tests According to Clinical Symptoms and Diagnostic Criteria in Individuals with ME/CFS

Baklund IH, Dammen T, Moum TÅ, Kristiansen W, Duarte DS, Castro-Marrero J, Helland IB, Strand EB. J Clin Med. 2021 Jul 14;10(14):3105.


There is a lack of research regarding blood tests within individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and between patients and healthy controls. We aimed to compare results of routine blood tests between patients and healthy controls.

Data from 149 patients diagnosed with ME/CFS based on clinical and psychiatric evaluation as well as on the DePaul Symptom Questionnaire, and data from 264 healthy controls recruited from blood donors were compared.

One-way ANCOVA was conducted to examine differences between ME/CFS patients and healthy controls, adjusting for age and gender. Patients had higher sedimentation rate (mean difference: 1.38, 95% CI: 0.045 to 2.714), leukocytes (mean difference: 0.59, 95% CI: 0.248 to 0.932), lymphocytes (mean difference: 0.27, 95% CI: 0.145 to 0.395), neutrophils (mean difference: 0.34, 95% CI: 0.0 89 to 0.591), monocytes (mean difference: 0.34, 95% CI: 0.309 to 0.371), ferritin (mean difference: 28.13, 95% CI: -1.41 to 57.672), vitamin B12 (mean difference: 83.43, 95% CI: 62.89 to 124.211), calcium (mean difference: 0.02, 95% CI: -0.02 to 0.06), alanine transaminase (mean difference: 3.30, 95% CI: -1.37 to -7.971), low-density lipoproteins (mean difference: 0.45, 95% CI: 0.104 to 0.796), and total proteins (mean difference: 1.53, 95% CI: -0.945 to 4.005) than control subjects.

The patients had lower potassium levels (mean difference: 0.11, 95% CI: 0.056 to 0.164), creatinine (mean difference: 2.60, 95% CI: 0.126 to 5.074) and creatine kinase (CK) (mean difference: 37.57, 95% CI: -0.282 to 75.422) compared to the healthy controls. Lower CK and creatinine levels may suggest muscle damage and metabolic abnormalities in ME/CFS patients.

Conclusion: Results of several routine blood tests of ME/CFS patients differed from those healthy controls. Our findings particularly highlight that decreased creatinine and CK levels may indicate greater muscle damage and metabolic disturbances in ME/CFS patients and is worthy of future studies. This is also true of results that may indicate a possible low-grade inflammation in ME/CFS patients.

5. Shadow Burden of Undiagnosed ME/CFS on Society: Retrospective and Prospective-In Light of COVID-19

Araja D, Berkis U, Lunga A, Murovska M. J Clin Med. 2021 Jul 6;10(14):3017.


Background:Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a poorly understood, complex, multisystem disorder, with severe fatigue not alleviated by rest, and other symptoms, which lead to substantial reductions in functional activity and quality of life.

Due to the unclear aetiology, treatment of patients is complicated, but one of the initial problems is the insufficient diagnostic process. The increase in the number of undiagnosed ME/CFS patients became specifically relevant in the light of the COVID-19 pandemic.

The aim of this research was to investigate the issues of undiagnosed potential ME/CFS patients, with a hypothetical forecast of the expansion of post-viral CFS as a consequence of COVID-19 and its burden on society.

Methods:The theoretical research was founded on the estimation of classic factors presumably affecting the diagnostic scope of ME/CFS and their ascription to Latvian circumstances, as well as a literature review to assess the potential interaction between ME/CFS and COVID-19 as a new contributing agent.

The empirical study design consisted of two parts: The first part was dedicated to a comparison of the self-reported data of ME/CFS patients with those of persons experiencing symptoms similar to ME/CFS, but without a diagnosis. This part envisaged the creation of an assumption of the ME/CFS shadow burden “status quo”, not addressing the impact of COVID-19.

The second part aimed to investigate data from former COVID-19 patients' surveys on the presence of ME/CFS symptoms, 6 months after being affected by COVID-19. Descriptive and analytical statistical methods were used to analyse the obtained data.

Results: The received data assumed that the previously obtained data on the ME/CFS prevalence of 0.8% in the Latvian population are appropriate, and the literature review reports a prevalence of 0.2-1.0% in developed countries.

Regarding the reciprocity of ME/CFS and COVID-19, the literature review showed a lack of research in this field. The empirical results show quite similar self-esteem among ME/CFS patients and undiagnosed patients with longstanding disease experience, while former COVID-19 patients show a significantly lower severity of these problems.

Notably, “psychological distress (anxiety)” and “episodic fatigue” are significantly predominant symptoms reported by former COVID-19 patients in comparison with ME/CFS patients and undiagnosed patients prior to the COVID-19 pandemic.

The results of our analysis predict that the total amount of direct medical costs for undiagnosed patients (out-of-pocket payments) is more than EUR 15 million p.a. (in Latvia), and this may increase by at least 15% due to the consequences of COVID-19.

Conclusions: ME/CFS creates a significant shadow burden on society, even considering only the direct medical costs of undiagnosed patients-the number of whom in Latvia is probably at least five times higher than the number of discerned patients. Simultaneously, COVID-19 can induce long-lasting complications and chronic conditions, such as post-viral CFS, and increase this burden.

The Latvian research data assume that ME/CFS patients are not a high-risk group for COVID-19; however, COVID-19 causes ME/CFS-relevant symptoms in patients. This increases the need for monitoring of patients for even longer after recovering from COVID-19's symptoms, in order to prevent complications and the progression of chronic diseases.

In the context of further epidemiological uncertainty, and the possibility of severe post-viral consequences, preventive measures are becoming significantly more important; an integrated diagnostic approach and appropriate treatment could reduce this burden in the future.

6. The Therapeutic Effect Of Sports On Relieving Chronic Fatigue

Xiutao Yu Rev Bras Med Esporte 27 (3) • Jul-Sep 2021


Introduction: Chronic fatigue syndrome (CFS) is a group of long-term fatigue; the rest is difficult to achieve. At the same time, it is accompanied by corresponding physical dysfunction and psychological and mental symptoms. It is very meaningful to find exercise countermeasures to cope with chronic fatigue syndrome actively.

Object: This article analyzes the current students’ CFS to realize the cognition of the disease. At the same time, it analyzes the effect of sports on the treatment of chronic fatigue to help students formulate related sports programs.

Method: The article conducts a related questionnaire survey and analysis of students and analyzes CFS and exercise status symptoms.

Results: Generally, students with CFS did not actively participate in sports and had poor physical fitness, especially muscle endurance and cardiopulmonary function. However, students who actively participate in sports training basically do not have CFS.

Conclusion: CFS students should strengthen physical exercise and improve the CFS situation through exercise.

Long-COVID Research References

  1. A role for T-cell exhaustion in Long COVID-19 and severe outcomes for several categories of COVID-19 patients
  2. The prolonged effects of COVID-19. A new “threat”?
  3. Post-COVID-19 Syndrome: Leveraging the Patient Perspective and Technological Innovations to Enable the Delineation of Effective Treatments
  4. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact
  5. Long covid-mechanisms, risk factors, and management

Katrina Pears, Research Correspondent, ME Association

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