Research Digest 12/06/20

Welcome to the 49th 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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Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome
Authors: Schreiner P, Harrer T, Scheibenbogen C, Lamer S, Schlosser A, Naviaux R K, Prusty B K

Human herpesvirus (HHV) -6A and -6B are associated with several diseases involving mitochondrial dysfunction, including ME/CFS. This comprehensive laboratory study investigated potential infectious causes and molecular mechanisms behind mitochondrial dysfunction using HHV-6A reactivation as a model.

The study included serum samples from 25 ME/CFS patients (diagnosed according to the Canadian Consensus criteria) and 10 age- and sex-matched healthy controls who did not suffer from fatigue. 

The authors studied quantitative changes in cellular as well as mitochondrial proteomics upon HHV-6A reactivation, and found several significant alterations with close similarity to ME/CFS pathophysiology. The results show a serum-transferrable innate immune activity in ME/CFS patients that induces a state of low mitochondrial activity. The authors speculate that there could be a direct role for HHV-6 infection in the pathophysiology of ME/CFS.

The results suggest that alterations in mitochondrial architecture, to acquire a more M1-pro-inflammatory form of mitochondria, is an important characteristic feature in ME/CFS patients, and does not require direct viral infection in every cell. They conclude that HHV-6 reactivation in ME/CFS patients activates a multisystem, pro-inflammatory, cell danger response that protects against certain RNA and DNA virus infections but comes at the cost of mitochondrial fragmentation and severely compromised energy metabolism.

They suggest that future research should systematically evaluate potential factors affecting mitochondrial dynamics in a larger number of ME/CFS patients for their ability to induce a powerful antiviral state.
A systematic review of metabolomic dysregulation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis/Systemic Exertion Intolerance Disease (CFS/ME/SEID)

Author: Huth T K, Eaton-Fitch N, Staines D, Marshall-Gradisnik S

Metabolomics is the study of metabolites, small molecules produced during metabolism. This systematic review analyses metabolomics studies which compared metabolites in blood or urine samples in ME/CFS patients with healthy controls. The review included 11 studies: 10 studies analysed blood samples, and three studies analysed urine samples.

“Metabolites associated with the amino acid pathway were the most commonly impaired with significant results in seven out of the 10 studies. However, no specific metabolite was consistently impaired across all of the studies. Urine metabolite results were also inconsistent.” 

While none of the 11 studies were excluded due to a low-quality assessment score, the researchers noted that a lack of consistency in diagnostic criteria used to select patients, and in the methodology used to measure and compare metabolites, likely contributed to the lack of consistent results between studies. 

Metabolites are highly changeable. Confounding factors such as participant age, sex, diet, physical activity (and many others) can all impact metabolites, and the authors note that these could also contribute to inconsistent results between studies. 

The authors conclude that there is currently insufficient evidence to conclude that anomalies in metabolomics contribute to disease development in ME/CFS. 

The authors recommend that further research is done with a unified ME/CFS diagnostic criteria, metabolite analysis method, and better controls for confounding factors to yield more conclusive results.

The Development of a Consistent Europe-Wide Approach to Investigating the Economic Impact of Myalgic Encephalomyelitis (ME/CFS): A Report from the European Network on ME/CFS (EUROMENE)

Authors: Pheby D F H, Araja D, Berkis U, Brenna E, Cullinan J, de Korwin J D, Gitto L, Hughes D A, Hunter R M, Trepel D, Wang-Steverding X

EUROMENE is a collaborative research network formed in 2016 and which currently includes 22 European countries. The network aims to investigate research gaps and includes four key working groups: epidemiology, biomarkers and diagnostic criteria, clinical research, and socio-economics. 
This article provides an overview of the work of EUROMENE’s socio-economics working group into the development of a consistent Europe-wide approach to measuring the economic cost of ME/CFS. While the economic burden appears large, there are significant challenges which impede an accurate estimate, including lack of consistent case definition, very little accurate data on the incidence and prevalence of ME/CFS in Europe, failure to diagnose and variability within the ME/CFS patient population (e.g. presumably the economic cost would increase with increased illness severity). 
To improve the ability to accurately estimate the economic impact of ME/CFS, the EUROMENE working group make eight recommendations.

Use the Fukuda (CDC-1994) case definition alongside the Canadian Consensus Criteria (CCC).
A common symptom checklist which can be mapped onto the Fukuda and CCC should be used for case identification, to increase rates of diagnosis.
Improved epidemiological information concerning the proportion of severely affected people for accurate estimate of the impact of severity on economic burden.
Prevalence-based cost of illness studies should be carried out in different countries, to determine the overall cost burden.
A list of data items required for cost of illness studies should be collected by all countries.
The data items should be audited for cost-of illness studies to facilitate international comparisons.
The EuroQol-5D instrument should be used as a generic measure of health status and as a multi-attribute utility instrument to determine the relationship, if any, between disease severity and economic impacts.
Use purchasing power parities (PPP) in order both to make valid international comparisons and to collate meaningful statistics at a European level.

The authors conclude that the relationship between disease severity and economic impact should be a high priority for future research.

Heart Rate Thresholds to Limit Activity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients (Pacing): Comparison of Heart Rate Formulae and Measurements of the Heart Rate at the Lactic Acidosis Threshold during Cardiopulmonary Exercise Testing
Authors: van Campen C L M C, Rowe P C, Visser F C
It is thought that oxidative metabolism is impaired in ME/CFS. Pacing is a type of self-management strategy based on this theory which aims to prevent post-exertional malaise. One approach to pacing involves maintaining a heart rate below the anaerobic threshold (AT) during physical activities. This threshold can be accurately measured using a cardiopulmonary exercise test (CPET), although it can also be estimated from a formula defined as 55% of the age-specific predicted maximal heart rate.

The aim of the study was to compare estimates of the heart rate at the AT provided by the formulae, with the actual heart rate at the lactic acidosis threshold as determined by CPET. This study included 30 male and 60 female ME/CFS patients. Patients were diagnosed using both the Fukuda and International Consensus Criteria. The study examined several different formulae for predicting maximal age-specific heart rate. 

They found that there was a significant difference between the heart rate at AT predicted by the formulae and that measured by the CPET. This difference varied between 28 and 19 beats per minute (bpm) in male and between 6 and 23 bpm in female ME/CFS patients, depending on the formula used.

They conclude that heart rate thresholds generated by formulae in an attempt to help people with ME/CFS exercise below the anaerobic threshold do not reliably predict actual heart rates at the lactic acidosis threshold, as measured by a CPET. The authors conclude that formulae based on age-dependent predicted peak heart rate have a wide age-specific variability, and suggest that these formulae have a limited application in clinical practice.
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