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Research Digest 16/07/21

Welcome to the 73rd Emerge Australia Research Digest, where you will find summaries of some of the latest research and information about ME/CFS, with links to the complete articles.

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Content warning: Emerge Australia wishes to highlight that article 4 of this edition contains research about suicide in ME/CFS patients.

The Role of Prevention in Reducing the Economic Impact of ME/CFS in Europe: A Report from the Socioeconomics Working Group of the European Network on ME/CFS (EUROMENE)

Authors: Pheby DFH, Araja D, Berkis U, Brenna E, Cullinan J, de Korwin JD, … Wang-Steverding X (University of Warwick, UK)
Publication: Medicina

This report was compiled by Socioeconomics Working Group of the European Network on ME/CFS (EUROMENE), and aimed to evaluate the availability of preventative programmes for ME/CFS and the economic benefits of such programmes. 

The authors detailed the economic value of existing preventative health programmes such as immunisation programmes and fluoridation, with benefits seen in reduced healthcare spending, increased productivity, and improved quality of life. Barriers to implementing preventative programmes were found to include reluctance to change behaviour, and the cost of funding programmes. The authors determined that the effectiveness of a preventative programme for ME/CFS was dependent on whether there are modifiable risk factors for ME/CFS and the potential health and economic benefits of a prevention programme for ME/CFS.

The authors acknowledged that the pathogenesis of ME/CFS remains unknown, however suggested the most plausible hypothesis to be a combination of immunological and environmental factors. This was identified as including infections, a range of immunological factors, occupational exposures, psychological factors, child/adolescent specific factors, and other unknown risk factors. Risk factors for poorer prognosis were found to include old age, chronic illness, comorbid psychiatric disorder, baseline severity of fatigue and psychiatric morbidity, and lack of appropriate early management.

The authors conclude that the low number of identified modifiable risk factors for ME/CFS allowed little scope for primary preventative programmes, but that further research was needed into modifiable risk factors. 

However, the authors also conclude that secondary prevention programmes aimed at improving the early management of ME/CFS have the potential to reduce both the risk of severe prolonged disease and the economic impact of ME/CFS. Such programmes should target diagnostic delays and barriers to healthcare utilisation, such as the disbelief and doctors’ inadequate knowledge of ME/CFS.

Lymphoblastoid Cell Lines as Models to Study Mitochondrial Function in Neurological Disorders

Authors: Annesley SJ, Fisher PR (La Trobe University, Australia)
Publication: International Journal of Molecular Sciences
While neurological disorders are characterised by dysfunction within the brain, brain tissue is inaccessible for study. However, neurological and neurodegenerative disorders have also been associated with mitochondrial dysfunction. The authors argue that systemic mitochondrial dysfunction likely exists in many neurological disorders, making more accessible cells and tissues, such as blood lymphocytes, useful for characterising the diseases, measuring disease severity and as potential biomarkers. This paper reviews lymphoblastoid cell lines (LCL) studies in several neurological disorders, including ME/CFS.
Mitochondrial dysfunction has been proposed in ME/CFS based on peripheral tissue testing, including blood cells, muscle tissue, urine and saliva. Research utilising LCLs has demonstrated mitochondrial respiration defects, specifically in the final complex, Complex V. Due to the active proliferation of LCLs, metabolism (and therefore respiration) is increased, allowing differences between patients and controls to be more easily identified. 

ME/CFS patients also have increased activity of the Target of Rapamycin Complex 1 (TORC1), a stress sensing regulator. TORC1 is involved in upregulation of mitochondrial proteins, and may be a compensation mechanism for Complex V dysfunction. Research has shown that LCL TORC1 activity combined with mitochondrial function measures and frozen lymphocyte cell death rate assays are highly specific and sensitive for ME/CFS identification. However, further validation is required.
Due to LCLs high metabolic activity, the authors suggest that LCLs will be of benefit for ongoing research into mitochondrial activity in neurological disorders, such as ME/CFS. There are opportunities for this research to lead to diagnostic test development and identification of potential treatment targets.

Female Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Idiopathic Chronic Fatigue: Comparison of Responses to a Two-Day Cardiopulmonary Exercise Testing Protocol

Authors: van Campen CLMC, Visser FC (Stichting CardioZorg, Netherlands)
Publication: Healthcare

Cardiopulmonary exercise testing (CPET) measures the severity of physical activity intolerance. Previous studies have found that most ME/CFS patients show similar or slightly lower peak volume oxygen consumption (VO2) compared to healthy controls on day-one of a CPET, whereas on day two ME/CFS patients have significantly lower VO2. This study aimed to examine exercise intolerance in a two-day CPET protocol in patients with ME/CFS compared to patients with idiopathic chronic fatigue (ICF). 

51 patients with ME/CFS (Fukuda criteria) and 50 patients with ICF participated. All participants were female (male results were reported in a separate study). Patients were excluded if they had severe ME/CFS (as defined by the International Consensus Criteria), there was an alternative explanation for their symptomology, or the two CPETs were not completed on consecutive days. Physical measurements, disease severity and duration were comparable between the two groups, however there was a higher rate of fibromyalgia in the ME/CFS group. 

Throughout the CPET, measurements were taken of VO2, volume of carbon dioxide released, oxygen saturation, blood pressure and heart rate. The authors found no significant differences in resting heart rate between the groups. VO2 and workload parameters declined significantly in the ME/CFS group from day-one to day-two, whereas the ICF group showed an increase on day-two. 

The authors recognised that not including healthy sedentary controls was a limitation of this study.

The authors conclude that the findings of lower VO2 at peak exercise in the ME/CFS group on day-two are suggestive of metabolic abnormalities, not deconditioning, and may represent early signs of post-exertional malaise. In contrast, the general improvement seen on day-two in the ICF group show a pattern similar to sedentary and healthy controls, which suggests the findings are ME/CFS specific.

Identifying and Managing Suicidality in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Authors: Chu L, Elliott M, Stein E, Jason LA (DePaul University, USA)    
Publication: Healthcare 
Patients with ME/CFS are at an increased risk of death by suicide than the general population. This article provided an overview of risk and protective factors for suicide in ME/CFS while also discussing a strategy for assessing suicidality and basic management of at-risk patients.

The risk factors for suicide in ME/CFS patients can be classified as those that are either common in the general population or other chronically ill patient groups (e.g. demographic and historical characteristics, sleep disturbances and chronic pain) or those that are unique or more prominent in patients with ME/CFS. Risk factors specific to ME/CFS include several symptoms of ME/CFS (such as post-exertional malaise and hypersensitivity to stimuli) that limit the patients’ function and contribute to social and physical isolation; the lack of disease-modifying treatments which can lead to feelings of frustration, disappointment, and hopelessness; and the stigmatisation of ME/CFS and the lack of knowledgeable healthcare professionals.
The authors recommended that healthcare professionals assess all patients with ME/CFS for suicide risk upon initial intake, and then occasionally through the years, using validated and standardised instruments. Healthcare professionals should pay extra attention to feelings of hopelessness, loneliness, disconnectedness from others, and being a burden to society, as these have been linked to increased suicide risk among the chronically ill. 
The authors also recommended that healthcare professionals incorporate both general management of suicidality as well as management of patient-specific factors. Ideally, patients with ME/CFS should be referred to mental health professionals who are familiar with ME/CFS or other chronic, disabling medical diseases, and who understand that common solutions for other patients might not be suitable for patients with ME/CFS. 

The authors conclude that more research is necessary to characterise the different elements of suicide risk in the ME/CFS patient population. Additionally, they recommend that screening and management should be tailored towards the individual patient rather than focussing on general guidelines.

Figure | Overall approach to evaluation and management of suicidality in individuals.

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