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

Following the appointment of a new research correspondent, we have relaunched the weekly research round-up which now includes recent publications about ME/CFS and Long Covid.

We highlight several 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 and available to anyone.

This extensive library of research is normally updated at the end of each month, but with the change in staff, it will be updated again by 01 June 2021.

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 01 May – 07 May 2021

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

Orthostatic intolerance (symptoms which occur upon standing and are relieved when reclining) is a commonly reported symptom in people with ME/CFS. Deconditioning (reduction in the body’s physical function as a result of physical inactivity) has been thought to play role in the development of orthostatic intolerance, and this theory was examined in the second paper (2). A robust investigation was conducted where healthy controls were compared to people with ME/CFS and by using cardiopulmonary exercise testing, the authors concluded that deconditioning does not cause orthostatic intolerance.

The third (3) study was about disease pathology in ME/CFS. It investigated the role of the autonomic nervous system in neck muscles because of the reported stiffness in these muscles. The study examined patients who had recovered from ME/CFS after undergoing local modulation of the cervical muscles. The authors concluded that recovery might be partly linked to improvements in the autonomic nervous system.

ME/CFS Research References and Abstracts

1. The efficacy and safety of moxibustion for chronic fatigue syndrome: A protocol for systematic review and meta-analysis.

Xue K, Wang Y, Wang X, et al.
Medicine. 2021 May;100(18):e25742.


Background: The pathogenesis of chronic fatigue syndrome (CFS) is not clear. The main purpose of treatment is to improve autoimmune function and relieve fatigue symptoms. Moxibustion is often used to treat diseases caused by low autoimmunity, especially in relieving fatigue symptoms. It is a superior therapy for CFS in traditional Chinese medicine. At present, there is a lack of the high-level clinical evidence to support the moxibustion in the treatment of CFS, so this study will systematically review and analyze the currently available randomized controlled trials to evaluate the efficacy and safety of moxibustion in the treatment of CFS.

Methods: We will systematically search PubMed, EMBASE, Cochrane library, Sinomed, CNKI, VIP, and Wanfang Database, and Chinese Clinical Trial Registry will also be searched. The time range for the search will be from database activation to March 31, 2021. The randomized controlled trials (RCTs) associated with moxibustion for CFS will be included, regardless of language.We will use the standard proposed in Cochrane Handbook 5.1.0 to assess the bias risk of a single RCT. The main outcome index of the study is Fatigue Assessment Instrument (FAI), secondary outcome indexes will include Fatigue Scale -14 (FS-14), Fatigue Severity Scale (FSS), Pittsburgh sleep quality index (PSQI), natural killer (NK) cells, interleukin- 2 (IL-2), T lymphocyte subsets (CD4+, CD8+), cure rate, total efficiency and adverse reactions. The random effect model meta was used to analyze the effect data of a single RCT. Heterogeneity will be measured by Cochran Q test and I-squared statistics. We will use 2 subgroup analyses to explore the source of heterogeneity. RCTs with high bias risk was excluded and adjustment effect model was used for sensitivity analysis to test the robustness of the meta-analysis results. The publication bias included in RCTs will be assessed by funnel plot and Egger test.

Results: This study will objectively and comprehensively evaluate the efficacy and safety of randomized controlled trials of moxibustion in the treatment of chronic fatigue syndrome, and the results will be submitted to peer-reviewed journals for publication.

Conclusion: This systematic review will provide clinicians with the latest high-quality evidence for the use of moxibustion in the treatment of chronic fatigue syndrome.

2. Deconditioning does not explain orthostatic intolerance in ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome)

van Campen, C, Rowe PC & Visser, FC.
Journal of Translational Medicine 19, 193 (2021).


Background: Orthostatic intolerance (OI) is a frequent finding in individuals with myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS). Published studies have proposed that deconditioning is an important pathophysiological mechanism in various forms of OI, including postural orthostatic tachycardia syndrome (POTS), however conflicting opinions exist. Deconditioning can be classified objectively using the predicted peak oxygen consumption (VO2) values from cardiopulmonary exercise testing (CPET). Therefore, if deconditioning is an important contributor to OI symptomatology, one would expect a relation between the degree of reduction in peak VO2during CPET and the degree of reduction in CBF during head-up tilt testing (HUT).

Methods and results: In 22 healthy controls and 199 ME/CFS patients were included. Deconditioning was classified by the CPET response as follows: %peak VO2 ≥ 85% = no deconditioning, %peak VO2 65–85% = mild deconditioning, and %peak VO2 < 65% = severe deconditioning. HC had higher oxygen consumption at the ventilatory threshold and at peak exercise as compared to ME/CFS patients (p ranging between 0.001 and < 0.0001). Although ME/CFS patients had significantly greater CBF reduction than HC (p < 0.0001), there were no differences in CBF reduction among ME/CFS patients with no, mild, or severe deconditioning. We classified the hemodynamic response to HUT into three categories: those with a normal heart rate and blood pressure response, postural orthostatic tachycardia syndrome, or orthostatic hypotension. No difference in the degree of CBF reduction was shown in those three groups.

Conclusion: This study shows that in ME/CFS patients orthostatic intolerance is not caused by deconditioning as defined on cardiopulmonary exercise testing. An abnormal high decline in cerebral blood flow during orthostatic stress was present in all ME/CFS patients regardless of their %peak VO2 results on cardiopulmonary exercise testing.

3. Possible involvement of the autonomic nervous system in cervical muscles of patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS)

Matsui T, Hara K, Iwata M, Hojo S, Shitara N, Endo Y, Fukuoka H, Matsui M, Kawaguchi H.  BMC Musculoskelet Disordorders. 2021 May 5;22(1):419


Background: Patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) sometimes present with stiffness of the cervical muscles. To investigate the pathophysiology of ME/CFS, this observational study compared patients with versus without recovery from ME/CFS through local modulation of the cervical muscles.

Methods: Over a period of 11 years, a total of 1226 inpatients with ME/CFS who did not respond to outpatient care were enrolled in this study. All patients received daily cervical muscle physical therapy during hospitalization. Self-rated records documenting the presence or absence of ME/CFS, as well as the representative eight symptoms that frequently accompany it at admission and discharge, were compared. Pupil diameter was also measured to examine autonomic nervous system function involvement.

Results: The recovery rate of ME/CFS after local therapy was 55.5%, and did not differ significantly by sex, age strata, and hospitalization period. The recovery rates of the eight symptoms were variable (36.6-86.9%); however, those of ME/CFS in the symptom subpopulations were similar (52.3-55.8%). The recovery rates of all symptoms showed strong associations with that of ME/CFS (p < 0.001). The pupil diameter was more constricted in the ME/CFS-recovered patients than in the ME/CFS-unrecovered patients in the total population and the subpopulations stratified by sex, age, and hospitalization period.

Conclusions: There was a strong association between the recovery of ME/CFS and other related whole-body symptoms. The recovery of ME/CFS may be partly linked to amelioration of the autonomic nervous system in the cervical muscles.

4. Validation of the Bath CRPS Body Perception Disturbance Scale

Brink AFT, Halicka M, Vittersø AD, Jones HG, Stanton TR, Bultitude JH.
J Pain. 2021 May 5:S1526-5900(21)00215-7


The Bath Complex Regional Pain Syndrome Body Perception Disturbance Scale (“B-CRPS-BPDS”) measures alterations in body perception. We assessed its internal consistency, known group validity, construct validity, and associations with demographic and clinical characteristics. We also evaluated changes in, and baseline predictors of B-CRPS-BPDS scores at follow-up.

We included people with CRPS (N=114) and pain-free controls (N=69). People with CRPS obtained higher scores than pain-free controls on all B-CRPS-BPDS items, except the item on attention. Because this item also had an insufficient corrected item-total correlation, we propose a revised B-CRPS-BPDS (r-B-CRPS-BPDS) excluding this item.

The internal consistency of the r-B-CRPS-BPDS was good. The r-B-CRPS-BPDS showed a large positive relationship with “motor neglect-like symptoms”, indicating good construct validity. The r-B-CRPS-BPDS showed positive relationships with pain intensity, fear of movement, depression, and upper limb disability. There were no independent relationships with handedness, affected side, affected limb, disease duration, CRPS severity score, tension, anger, fatigue, confusion, and vigour. Finally, r-B-CRPS-BPDS scores did not consistently change over time.

Our results demonstrate the utility of the r-B-CRPS-BPDS for measuring body perception disturbances in CRPS.

Perspective: This article evaluates the validity of the Bath Complex Regional Pain Syndrome Body Perception Disturbance Scale (“B-CRPS-BPDS”) in CRPS and assesses relationships with demographic and clinical variables. The proposed revised B-CRPS-BPDS appears to be a valid measure of body perception disturbances in CRPS.

5. COVID-19 symptoms over time: comparing long-haulers to ME/CFS

Jason LA, Islam MF, Conroy K, Cotler J, Torres C, Johnson M & Mabie B.
(2021) Biomedicine, Health & Behavior



Our objective was to determine which symptoms among long-hauler COVID-19 patients change over time, and how their symptoms compare to another chronic illness group.


278 long-haulers completed two symptom questionnaires at one time point, with one recounting experiences during the first two weeks of their illness, an average of 21.7 weeks prior. We used a comparison group of 502 patients diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Participants completed a standardized symptom questionnaire and a list of additional CDC COVID-19 symptoms.


Over time, the long-haulers reported an overall reduction of most symptoms including unrefreshing sleep and post-exertional malaise, but an intensification of neurocognitive symptoms. When compared to ME/CFS, the COVID-19 sample was initially more symptomatic for the immune and orthostatic domains but over time, the long-haulers evidenced significantly less severe symptoms than those with ME/CFS, except in the orthostatic domain. Among the COVID-19 long haulers, several neurocognitive symptoms got worse over time, whereas improvements occurred in most other areas.


These types of differential patterns of symptoms over time might contribute to helping better understand the pathophysiology of those reporting prolonged illness following COVID-19.

6. “Pacing does help you get your life back”: The acceptability of a newly developed activity pacing framework for chronic pain/fatigue

Antcliff D, Keenan AM, Keeley P, Woby S, McGowan L. Musculoskeletal Care. 2021 May 6.


Objectives: We have developed and feasibility tested an activity pacing framework for clinicians to standardise their recommendations of activity pacing to patients with chronic pain/fatigue. This study aimed to explore the acceptability and fidelity to this framework in preparation for a future trial of activity pacing.

Design: Acceptability and fidelity were explored using semi-structured interviews. Data were analysed using framework analysis.

Participants: Patients who attended a rehabilitation programme for chronic pain/fatigue underpinned by the framework, and clinicians (physiotherapists and psychological wellbeing practitioners) who led the programmes.

Results: Seventeen interviews were conducted, involving 12 patients with chronic pain/fatigue and five clinicians. The framework analysis revealed four deductive themes: (1) Acceptability of the activity pacing framework, (2) Acceptability of the feasibility study methods, (3) Processes of change and (4) Barriers and facilitators to activity pacing; and one inductive theme: (5) Perspectives of patients and clinicians.

Conclusions: The activity pacing framework appeared acceptable to patients and clinicians, and adherence to the framework was demonstrated. Processes of behaviour change included patients’ regulation of activities through activity pacing. Barriers to pacing included work/social commitments and facilitators included identifying the benefits of pacing on symptoms. Different perspectives emerged between clinicians and patients regarding interpretations of symptom-contingent and quota-contingent strategies. The framework recognises fluctuations in symptoms of chronic pain/fatigue and encourages a quota-contingent approach with flexibility. Future work will develop a patient friendly guide ahead of a clinical trial to explore the effects of pacing.

Long-COVID Research References and Abstracts

1. Neurological and cognitive sequelae of Covid-19: a four-month follow-up

Mattioli F, Stampatori C, Righetti, F, Sala E, Tomasi, C, De Palma G
Journal of Neurology (2021).


Central and peripheral nervous system involvement during acute COVID-19 is well known. Although many patients report some subjective symptoms months after the infection, the exact incidence of neurological and cognitive sequelae of COVID-19 remains to be determined.

The aim of this study is to investigate if objective neurological or cognitive impairment is detectable four months after SARS-CoV-2 infection, in a group of patients who had mild–moderate COVID-19.

A cohort of 120 health care workers previously affected by COVID-19 was examined 4 months after the diagnosis by means of neurological and extensive cognitive evaluation and compared to a group of 30 health care workers who did not have COVID-19 and were similar for age and co morbidities.

At 4-month follow-up, 118/120 COVID-19 cases had normal neurological examination, two patients had neurological deficits. COVID-19 patients did not show general cognitive impairment at MMSE. In COVID-19 cases the number of impaired neuropsychological tests was not significantly different from non-COVID-19 cases (mean 1.69 and 1 respectively, Mann–Whitney p = n.s.), as well as all the mean tests’ scores.

Anxiety, stress, and depression scores resulted to be significantly higher in COVID-19 than in non-COVID-19 cases. The results do not support the presence of neurological deficits or cognitive impairment in this selected population of mild–moderate COVID-19 patients four months after the diagnosis. Severe emotional disorders in patients who had COVID-19 in the past are confirmed.

2. Post-COVID syndrome: Incidence, clinical spectrum, and challenges for primary healthcare professionals

Pavli A, Theodoridou M, Maltezou, HC
Archives of Medical Research. 2021 May 4:S0188-4409(21)00081-3


Post-COVID syndrome also known as long COVID refers to symptoms persisting for more than three weeks after the diagnosis of COVID-19. We reviewed the current evidence on post-COVID syndrome, focusing on its clinical manifestations and addressing the challenges for its management in primary healthcare.

The incidence of post-COVID syndrome is estimated at 10-35%, while for hospitalized patients it may reach 85%. Fatigue is the most common symptom reported in 17.5-72% of post-COVID cases, followed by residual dyspnea with an incidence ranging from 10-40%. Mental problems, chest pain, and olfactory and gustatory dysfunction may affect up to 26%, 22% and 11% of patients, respectively. More than one third of patients with post-COVID syndrome have pre-existing comorbidities, hypertension and diabetes mellitus being the most common.

Beyond the prolonged duration of symptoms, the scarce published data indicate that most patients with post-COVID syndrome have a good prognosis with no further complications or fatal outcomes reported. Given the clinical spectrum of patients with post-COVID syndrome, most of them will be managed by primary healthcare professionals, in conjunction with pre-existing or new co-morbidities, which, in turn, may increase the burden of COVID-19 on primary healthcare.

In conclusion approximately 10% of patients with COVID-19 may have symptoms persisting beyond three weeks, fulfilling the criteria of post-COVID syndrome. Primary healthcare professionals have a key role in the management of patients with post-COVID syndrome. Research is needed to elucidate the pathogenesis, clinical spectrum, and prognosis of post-COVID syndrome.

3. Post-COVID-19 Syndrome: Theoretical Basis, Identification, and Management

Scordo KA, Richmond, MM, Munro, N. AACN Advanced Critical Care 2021


As COVID-19 continues to spread, with the United States surpassing 29 million cases, health care workers are beginning to see patients who have been infected with SARS-CoV-2 return seeking treatment for its longer-term physical and mental effects.

The term long-haulers is used to identify patients who have not fully recovered from the illness after weeks or months. Although the acute symptoms of COVID-19 have been widely described, the longer-term effects are less well known because of the relatively short history of the pandemic.

Symptoms may be due to persistent chronic inflammation (e.g., fatigue), sequelae of organ damage (e.g., pulmonary fibrosis, chronic kidney disease), and hospitalization and social isolation (e.g., muscle wasting, malnutrition).

Health care providers are instrumental in developing a comprehensive plan for identifying and managing post–COVID-19 complications. This article addresses the possible etiology of post viral syndromes and describes reported symptoms and suggested management of post-COVID syndrome.

4. Recognizing the Clinical Sequelae of COVID-19 in Adults: COVID-19 Long-Haulers

Leviner S.
Journal for Nurse Practitioners. 2021 May 7.


As the numbers of acute SARS-CoV-2 infections continue to rise, we are learning that symptoms do not resolve quickly in all patients. While it is not clear why some patients experience persistent symptoms, these individuals suffer. Long-hauler is the term that is associated with these persistent symptoms and a review of the literature provides information to nurse practitioners working in primary care about symptomatology, risk factors, and resources for disease management.

Katrina Pears, Research Correspondent, ME Association

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