ME Association regular research roundup

ME/CFS and Long Covid Research: 02 – 08 May 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

ME/CFS Research Published 2 – 8 May 2023 

There have been six new ME/CFS studies and sixteen new Long Covid studies this week. 

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

Paper three (3) is on orthostatic chronotropic incompetence (or intolerance), which is where there is an inability of the heart rate to increase to a degree proportionate with increased activity or demand. This piece of research is from the well-known research group van Campen and Visser who focus on orthostatic intolerance and cerebral blood flow studies.   

This is the first study which investigates the presence of chronotropic incompetence in tilt table testing in ME/CFS. It is commonly found that ME/CFS patients do not have hypotension or postural orthostatic tachycardia syndrome (POTS) during tilt table testing but are found to have reductions in the stroke volume index (SVI) which is not accompanied by the needed increase in heart rate. SVI is the relationship between cardiac output, heart rate and body surface area, giving the milliliters of blood per square meter of body surface area for each heartbeat. 

This study compared results pre-recorded in a database for 362 ME/CFS and 52 healthy controls. They found: 

  • following tilt-tabling testing compared to healthy controls, ME/CFS patients had a significantly lower SVI, and higher heart rate.  
  • When lying down both cohorts had a similar relationship between HR and SVI. 
  • During the tilt table test ME/CFS patients had a lower HR, with 37% of ME/CFS patients having an inadequate HR increase. Indicating chronotropic incompetence. 
  • Chronotropic incompetence was more common in more severely affected ME/CFS patients. 

As we would expect from this research group this is a well performed and thought-out novel study. Previously, we have found that their investigations lack in size, but this has been overcome in this research with using pre-existing results. This often has disadvantages if the data is not collected by the same researchers, due to slight variations in protocols (such as tilt table durations). This is hopefully less of a problem in this study as data was used from the clinic that the researchers work in, so hopefully they will oversee practices. 

It is likely that the presence of orthostatic chronotropic incompetence is higher in this study than would be found in the general ME/CFS population, as patients used were from a clinic accepting referrals from those with severe orthostatic symptoms. 

It is a shame that a more equal number of healthy controls was not used as this affects the comparison between cohorts and also there is no mention of the activity levels of the healthy controls, as those who live a sedentary life-style would be much more appropriate especially when looking at cardiac performance as activity effects stroke volumes.  

It goes without saying that there were more females than males who participated in this research, for the ME/CFS group there were 55 males and 307 females. It is a shame that no comparison between the two sexes was made, as with this size sample it should have been possible. 

It is hard to find many negatives with this study, these findings are novel and confirm another abnormality in the circulatory response to upright posture in ME/CFS. 

ME/CFS Research References and Abstracts  

1. Patient and clinician experiences of fibromyalgia, ME/CFS and medically unexplained 

Duda N, Maguire R, Gitonga I, Corrigan S. 

PsyArXiv [Preprint], 28 Apr 2023 


Objectives: Fibromyalgia (FM), Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and other syndromes with medically unexplained symptoms (MUS) pose significant healthcare challenges. We aimed to synthesize qualitative evidence regarding the experiences of persons with these conditions (PwC) and their healthcare professionals (HCPs).Methods & Measures: Databases were searched using terms relating to FM/ME/CFS/MUS, Experience and Qualitative research. Studies published between 2001-2021 concerning adult PwC or HCP perspectives were included and synthesized using Meta-Aggregation, with confidence established following the ConQual approach. 

Results: 143 studies were included, with 708 findings aggregated into 82 categories and 13 synthesized findings. PwC narratives reflected a range of themes concerning: The experience of symptoms; The patient journey; Identity loss and change; Managing chronic illness; Understanding and legitimacy; Support needs and experiences; Healthcare needs and experiences; and Managing the healthcare encounters. HCPs perspective themes included: Beliefs and attitudes towards patients; Sensemaking at the limits of medical knowledge; Consultation and management; The patient-clinician relationship; and Barriers and facilitators to care. 

Conclusion: Sensemaking challenges are at the core of the patient and clinician experience of MUS, FM and ME/CFS. While gaps in biomedical knowledge are clear, this review highlights the need to address the patient-clinician dynamic in the context of uncertainty. 

2. Modulation of Beta-Adrenergic Autoantibodies Over Time in Post-Viral ME/CFS is Related to Fatigue and Pain Symptoms 

Busch L, Schriek C, Paul M, Heidecke H.  

Isr Med Assoc J. 2023 Apr;25(4):259-264.  


Background: Myalgic encephalomyelits/chronic fatigue syndrome (ME/CFS) is an acquired disease with symptoms of fatigue and pain. In pathogenesis, the induction of autoantibodies (AAB) against G-protein coupled receptors (GPCR), such as β-adrenergic receptors (β-AdR), has been suspected. GPCR-AAB correlate with symptom severity and autonomic dysfunction in ME/CFS. Objectives: To describe symptoms and treatment of a patient presenting with infection-triggered ME/CFS demonstrating that levels of β-AdR-AAB underlie modulation over time, correlating with the severity of symptoms. 

Methods: At T1 and T2, GPCR-AAB were measured and questionnaires assessing symptom severity were completed. TSHDS-IgM-AAB were tested, and SF density was analyzed via skin probe. 

Results: At T2, elevated levels of β-AdR-AAB were found, corresponding with an aggravation of fatigue and pain symptoms. Elevated TSHDS-IgM-AAB were found, which corresponded with reduced fiber density from the skin probe. 

Conclusions: The levels of β-AdR-AAB in post-infectious ME/CFS can be modulated. Future studies might target interventions to reduce these AAB. 

3. Orthostatic chronotropic incompetence in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) 

C. (Linda) M.C. van Campen, Freek W.A. Verheugt, Peter C. Rowe, Frans C. Visser. 

IBRO Neuroscience Reports [In Press, Journal Pre-proof] 


  • Adults with ME/CFS experience a 3-fold greater reduction in cerebral blood flow during end-tilt tilt compared to healthy controls, confirming orthostatic intolerance. 
  • During tilt testing we found that in 134/362 (37%) patients with ME/CFS without POTS or hypotension, the heart rate increase was below the lower limit of the 95% prediction interval of the heart rate increase of controls, indicative of orthostatic chronotropic incompetence. 
  • These novel findings represent the first description of orthostatic chronotropic incompetence during tilt testing, confirming another abnormality in the circulatory response to upright posture in ME/CFS. 


Background: Orthostatic intolerance (OI) is a core diagnostic criterion in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The majority of ME/CFS patients have no evidence of hypotension or postural orthostatic tachycardia syndrome (POTS) during head-up tilt, but do show a significantly larger reduction in stroke volume index (SVI) when upright compared to controls. Theoretically a reduction in SVI should be accompanied by a compensatory increase in heart rate (HR). When there is an incomplete compensatory increase in HR, this is considered chronotropic incompetence.  

This study explored the relationship between HR and SVI to determine whether chronotropic incompetence was present during tilt testing in ME/CFS patients. 

Methods: From a database of individuals who had undergone tilt testing with Doppler measurements for SVI both supine and end-tilt, we selected ME/CFS patients and healthy controls (HC) who had no evidence of POTS or hypotension during the test.  

To determine the relation between the HR increase and SVI decrease during the tilt test in patients, we calculated the 95% prediction intervals of this relation in HC. Chronotropic incompetence in patients was defined as a HR increase below the lower limit of the 95th % prediction interval of the HR increase in HC. 

Results: We compared 362 ME/CFS patients with 52 HC. At end-tilt, tilt lasting for 15 (4) min, ME/CFS patients had a significantly lower SVI (22 (4) vs. 27 (4) ml/m2; p<0.0001) and a higher HR (87 (11) vs. 78 (15) bpm; p<0.0001) compared to HC. There was a similar relationship between HR and SVI between ME/CFS patients and HC in the supine position.  

During tilt ME/CFS patients had a lower HR for a given SVI; 37% had an inadequate HR increase. Chronotropic incompetence was more common in more severely affected ME/CFS patients. 

Conclusion: These novel findings represent the first description of orthostatic chronotropic incompetence during tilt testing in ME/CFS patients. 

4. Sex Differences in Hemodynamic Response to Exercise in Patients With Myalgic Encephalomyelitis: Insights From Invasive Cardiopulmonary Exercise Testing 

K. Wichmann Madsen, J. Squires, M.C. Stovall, S. Al-Zayer, C.-J. Chang, W. Xiao, R. Pari, P. Joseph, D.M. Systrom. 

American Journal of Respiratory and Critical Care Medicine 2023;207:A2995 


Abstract available online 

5. ME/CFS Pathophysiology Investigated by Invasive Cardiopulmonary Exercise Testing and Autonomic Function Testing 

J. Squires, K. Wichmann Madsen, M.C. Stovall, S. Al-Zayer, W. Xiao, C.-J. Chang, P. Novak, D.M. Systrom. 

American Journal of Respiratory and Critical Care Medicine 2023;207:A2996. 


Introduction: Mechanisms underlying exercise and orthostatic intolerance in myalgic encephalomyelitis/chronic 
fatigue syndrome (ME/CFS) have been uncovered by invasive cardiopulmonary exercise testing (iCPET) and 
autonomic function testing (AFT), but the relationships between the two are not known. This study aims to determine 
if there is overlap of cardiovascular and respiratory pathophysiology in patients who have undergone both 
Methods: Between January 2017 and April 2022, 62 patients were identified with a contemporary iCPET and 
AFT. Key variables from the iCPET included peak oxygen uptake (pVO2), cardiac output (pQc), right atrial pressure 
(pRAP), and systemic oxygen extraction (Ca-vOy/Hgb) at peak exercise. Key variables from the autonomic testing 
included epidermal and sweat gland small fiber neurite density, electrochemical skin conductance, and change in 
heart rate (AH) and end tidal carbon dioxide (AETCO2) from supine to upright during the tilt table test 
Results: All 62 patients demonstrated preload failure (pRAP < 6.5mmHg). Of this group, 54 patients (87.1%) fulfilled NAM criteria for ME/CFS, with 32 testing positive (59.3%) for small fiber neuropathy (SFN) using either morphological and/or functional testing. Significant correlations were found between pVOg and both AH (r=-0.439. P<0.05) and AETCO, (r=0.474, P<0.05) during TTT. The same tilt table variables were found to be significantly correlated with pQc (r=-0.365, P<0.05 and r=0.351, P<0.05) from the iCPET. It should be noted that 8 of the ME/CFS SFN patients (25%) fulfilled diagnostic criteria for postural orthostatic tachycardia syndrome (POTS) based on the tilt table test. 
Conclusion: Decreased oxygen uptake and cardiac output at peak exercise during iCPET correlated with a greater change in heart rate and ETCO from supine to upright during TTT. There appears to be significant overlap of cardiopulmonary pathophysiology in ME/CFS underlying exercise and orthostatic symptoms. 

6. Post-acute Sequelae of SARS Co-V2 and Chronic Fatigue/Myalgic Encephalitis Share Similar Pathophysiologic Mechanisms of Exercise Limitation 

S. Jothi, G. Claessen, M. Insel, S. Kubba, E. Howden, S.-R. Carmona, F.P. Rischard. 

American Journal of Respiratory and Critical Care Medicine 2023;207:A6470 


Abstract available online 

6. Uplifts and hassles are related to worsening in chronic fatigue syndrome A prospective study 

Fred Friedberg, Jenna L. Adamowicz, Patricia Bruckenthal, Maria Milazzo, Sameera Ramjan, Xiaoyue Zhang, Jie Yang. 

Research Square [Preprint] 


Background: Limited published data suggests that absence of uplifts (minor pleasant events) is associated with clinical worsening in patients with chronic fatigue syndrome (CFS). The current study aimed to assess the relation of illness worsening to the trajectories of social and non-social uplifts and hassles in a six-month prospective study in CFS.  

Methods: Participants were primarily in their 40s, female, white, and ill for over a decade. All participants (N=128) met criteria for CFS. The interview-based global impression of change rating was used to classify individual outcomes as improved, unchanged, or worsened at six- month follow-up. Uplifts and hassles, both social and non-social, were assessed with the Combined Hassles and Uplifts Scale (CHUS). The CHUS was administered weekly in online diaries over six months. Linear mixed effect models were utilized to examine linear trends for hassles and uplifts.  

Results: No significant differences were found between the three global outcome groups for age, sex, or illness duration; however, work status was significantly lower for the non-improved groups (p<0.001). Nonsocial hassles intensity showed an increasing slope for the worsened group (p=.03) and a decreasing slope (p=0.05) for the improved group. For the worsened group, a downward trend was found for frequency of non-social (p=0.01) uplifts. 

Conclusion: Individuals with worsening as compared to improving illness in CFS show significantly different six-month trajectories for weekly hassles and a deficit in uplifts. This may have clinical implications for behavioral intervention. 

Long-COVID Research References  

  1. Long COVID: a review and proposed visualization of the complexity of long COVID 
  1. Long-COVID and its Physical and Neurological Symptoms in Adults: A Systematic Review 
  1. Use of symptom-guided physical activity and exercise rehabilitation for COVID-19 and other postviral conditions 
  1. ‘I'm still here, I'm alive and breathing': The experience of Black Americans with long COVID 
  1. COVID-19, post-acute COVID-19 syndrome (PACS, “long COVID”) and post-COVID-19 vaccination syndrome (PCVS, “post-COVIDvac-syndrome”): Similarities and differences 
  1. Long Covid: conceptualizing the challenges for public health 
  1. Co-production of a feasibility trial of pacing interventions for Long COVID 
  1. Perceived Cognitive Deficits in Patients With Symptomatic SARS-CoV-2 and Their Association With Post-COVID-19 Condition 
  1. Pulmonary circulation abnormalities in post-acute COVID-19 syndrome: dual-energy CT angiographic findings in 79 patients 
  1. A Narrative Review on the Potential Role of Vitamin D3 in the Prevention, Protection, and Disease Mitigation of Acute and Long COVID-19 
  1. Long COVID in people living with HIV 
  1. Long COVID: a review and proposed visualization of the complexity of long COVID 
  1. Viral persistence, reactivation, and mechanisms of long COVID 
  1. Forming a Consensus Opinion on Long COVID Support Mechanisms and Interventions Using a Modified Delphi Approach 
  1. Efficacy of cognitive behavioral therapy targeting severe fatigue following COVID-19: results of a randomized controlled trial 
  1. Corona With Lyme: A Long COVID Case Study 

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent
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