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Research Digest 26/11/21

Welcome to the 79th 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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Herpesviruses Serology Distinguishes Different Subgroups of Patients From the United Kingdom Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Biobank

Authors: Domingues TD, Grabowska AD, Lee J-S, Ameijeiras-Alonso J, Westermeier F, Scheibenbogen C, … Sepúlveda N (London School of Hygiene and Tropical Medicine, UK)
Publication: Frontiers in Medicine

As many ME/CFS report an infection at onset of their illness, herpesviruses, such as Epstein-Barr virus (EBV), have been considered likely causes of ME/CFS due to their high prevalence in adults. However, serological studies have produced contradictory results. This study re-analyses UK ME/CFS Biobank data by dividing patients into four subgroups according to infection and non-infection triggers. The authors also performed a sensitivity analysis between ME/CFS and each herpesvirus.
Two hundred and twenty-six adult patients with ME/CFS (Fukuda criteria and Canadian Consensus Criteria) and 99 healthy controls were included in the study. Plasma concentrations of IgG antibodies for multiple viruses were obtained. ME/CFS patients were grouped according to their infection status at onset: the patient didn’t know if they had an infection at onset (S0), they didn’t have an infection at onset (S1), they did have an infection at onset but this wasn’t confirmed through testing (S3with a lab test (S2), they did have an infection at onset and it was confirmed through testing (S4with a test (S3).  
There was a significant difference in disease severity between the infection at onset (S2 and S3) groups and the non-infection at onset (S0 and S1) groups. 30% of those in S2 and S3 had severe ME/CFS, compared with 9% in the S0 and S1 groups.
Sub-group analysis showed a negative association between those with a reported non-infection trigger and seropositivity to EBV (VCA and EBNA1 antigens) and Varicella-Zoster virus when using specific seropositivity cut-off levels. This was not significant when the impact of multiple testing was controlled. There was a lower seroprevalence of human cytomegalovirus in the S3 subgroup compared to controls for all seropositivity cut-off levels and after adjusting for multiple testing, however this was not statistically significant.
The authors conclude that ME/CFS subgroups could be distinguished according to disease triggers using herpesviruses serology but the impact of multiple testing should be considered. To assist with future research, the authors encourage the detailed and accurate collection of infection-trigger data, and their sensitivity-like approach to cut-off levels to account for differences between laboratories and serological kits.


A Comprehensive Examination of Severely Ill ME/CFS Patients

Authors: Chang C-J, Hung L-Y, Kogelnik AM, Kaufman D, Aiyar RS , Chu AM, Wilhelmy J, Li P, Tannenbaum L, Xiao W, Davis RW (Stanford University, USA)
Publication: Healthcare

Approximately one in four ME/CFS patients are house-bound or bed-bound and are severely affected by the disease. This population is often understudied, in part due to the difficulties these patients experience in attending health care facilities. This study aimed to compare severe ME/CFS patients with healthy controls through examination of symptoms and laboratory tests.
Twenty severely ill ME/CFS patients (International Consensus Criteria) and 10 healthy volunteers were included in the study. Participants were age 18-70, and the severely ill ME/CFS patients spent more than 14 hours per day reclined or sedentary, and had low physical functioning. All participants provided blood samples for testing and antigen and antibody analysis. Questionnaires evaluated quality of life, health status and symptoms. Daily activity, sleep profile and cognitive capacity were also monitored through wearable activity trackers, sleep profile study, and EEG. Blood samples were also used to identify molecular signatures with results reported elsewhere.
The authors found that the severely ill ME/CFS group had significantly lower physical and social functioning and quality of life scores compared to healthy controls and ME/CFS patients generally.  However role limitations due to emotional problems were less significantly impacted, and mental health scores from severely ill patients were similar to the general ME/CFS patient population. The significantly reduced quality of life scores found in the severely ill group were negatively correlated with clinical depression.
The most troublesome symptoms reported were fatigue (85%), pain (65%), cognitive impairment (50%), orthostatic intolerance (45%), sleep disturbance (35%), post-exertional malaise (30%), and neurosensory disturbance (30%). Sleep profiles and cognitive tests revealed distinctive impairments, and lowered morning cortisol and altered diurnal rhythm were also observed.
The authors conclude that these findings highlight the urgent need for further research into severely ill ME/CFS patients. The authors recommend research focus on further identification of sleep and cognitive abnormalities and autoantibodies. The authors note the significant similarities between ME/CFS and post-COVID conditions, and propose that this highlights the need for greater understanding of the mechanisms of ME/CFS, in order to treat and prevent long COVID conditions. 


Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome

Authors: Paul BD,  Lemle MD, Komaroff AL, Snyder SH (Johns Hopkins University School of Medicine, USA)
Publication: PNAS         

Some survivors of acute COVID-19 continue to experience symptoms months later. While in some cases these symptoms may be due to organ damage from COVID-19, in others there is no apparent organ damage. Where there is no organ damage the condition has come to be known as long COVID-19, and has  symptoms similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), including fatigue, shortness of breath, cognitive dysfunction. This review highlights that besides similar clinical presentation, long COVID-19 and ME/CFS patients also have comparable biological abnormalities.
The authors speculate that a redox imbalance can explain the symptoms of long COVID-19 and ME/CFS. Acute COVID-19 is linked to a redox imbalance, as is common in viral infections. The redox imbalance is partially induced by the accumulation of reactive oxygen and nitrogen species (ROS/RNS) as a result of the entry of the virus via angiotensin converting enzyme 2 receptor. For ME/CFS, many studies reported that biomarkers of redox imbalance differ from healthy controls and correlate with the severity of symptoms. Finally, prooxidants levels are elevated while small molecule antioxidant levels are reduced in both acute COVID-19 and ME/CFS.
The redox imbalance found in both long COVID-19 and ME/CFS can in turn be linked to inflammation and energy metabolic deficits. Systemic inflammation and neuroinflammation occur in both acute COVID-19 and ME/CFS. Inflammation and redox imbalance are bidirectionally linked, in that inflammation generates ROS/RON and redox imbalance generates further inflammation. Viral infections trigger mitochondrial dysfunction, which in turn also triggers inflammation. Mitochondrial dysfunction and thus impaired energy metabolism have been found in both acute COVID-19 and ME/CFS. In addition, the nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome, is activated by both mitochondrial dysfunction and oxidative stress.

Figure 1: The interactions between redox imbalance, mitochondrial dysfunction, chronic inflammation and related symptoms.


Health, Wellbeing, and Prognosis of Australian Adolescents with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Case-Controlled Follow-Up Study

Authors: Josev EK, Cole RC, Scheinberg A, Rowe K, Lubitz L, Knight SJ (Royal Children’s Hospital, Australia)
Publication: Journal of Clinical Medicine

This study was  a follow-up of a group of Australian adolescents who had been newly diagnosed with ME/CFS, and was conducted over a mean period of 2 years post-diagnosis. The study aimed to examine changes over time to health and psychological wellbeing; track symptomatology of ME/CFS and whether paediatric patients continued to fulfil the ME/CFS diagnostic criteria over time; and to determine which baseline health and psychological wellbeing aspects were predictors of ME/CFS criteria fulfilment at follow-up.
Participants for this study were drawn from a previous wider study of newly diagnosed patients. Thirty-four participants were included in this follow-up study, 17 adolescents with ME/CFS (Canadian Consensus Criteria adapted for paediatric cases) and 17 healthy controls. Participants completed the same questionnaires at follow-up that were completed in the original study, as well as an additional questionnaire regarding symptoms experienced in the past 3 months.
At baseline (in the original study), the ME/CFS group reported significantly greater fatigue and pain, and worse health related quality of life and sleep quality than healthy controls. At follow-up, the ME/CFS group reported significant improvement in these measures, though the patient group’s fatigue, pain and health related quality of life were still significantly worse than healthy controls. At baseline, the ME/CFS group reported higher levels of anxiety than healthy controls, however the ME/CFS group’s anxiety levels was significantly reduced at follow up such that there was no significant difference between groups. There was no significant difference between the groups in sleep hygiene or depression.
At follow-up, 11 of the 17 ME/CFS participants continued to fulfil ME/CFS criteria, and 3 participants identified as having ME/CFS without continuing to fulfil the criteria. No baseline variables of health and psychological wellbeing were found to be significant predictors of fulfilment of ME/CFS diagnostic criteria at follow-up.
The authors conclude that this study highlights the need for early identification and targeted treatment for at least two years post-diagnosis. Due to the frequency of reports of pain at follow-up, the authors recommend this include clinical multidisciplinary strategies targeting pain relief and management. The authors recommend future research utilise multiple follow-up time points over a longer time period to reflect the fluctuating nature of symptoms and illness severity over time of ME/CFS.


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