Research Digest | Issue 103

Welcome to the 103rd edition of Emerge Australia’s Research Digest. The first edition of the year features studies that illuminate various aspects of research related to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-acute COVID-19 syndrome, as well as insights and experiences from those living with ME/CFS regarding healthcare services.

Contributing Digesters: Sarah, Solène, Shan and Ella

Digest Editor: Simone Eyssens

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Worsening symptoms is associated with larger cerebral blood flow abnormalities during tilt-testing in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)


Authors: van Campen CMC, Rowe PC & Visser FC (Stichting CardioZorg, The Netherlands).
Publication:  Medicina
Link: https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00323-1/fulltext

Previous studies have found that ME/CFS patients experience abnormal reduction in cerebral blood flow (CBF) during tilt testing. Studies have not previously examined the relationship between ME/CFS symptom severity and CBF reduction. The authors sought to examine whether there was a correlation between the severity of symptoms and the degree of CBF reduction during tilt testing.

110 ME/CFS patients (International Consensus Criteria (ICC)) were selected from the authors’ existing database. Patients had completed tilt testing and assessments of ME/CFS symptomology on the same day, and again at a subsequent follow-up. In addition, the authors combined the data from of two previous studies, which included 219 participants whose symptom severity had been defined by the ICC.

The authors found that of the 110 patients from their database, 71 were retested due to worsening symptoms. Within this group, the ICC disease severity changed, with a significant number of patients experiencing a more severe ICC disease rating, from 51% mild, 45% moderate and 4% severe at the initial visit, to 1% mild, 72% moderate and 27% severe at follow-up. In this group, the CBF reduction also changed, from 19% at the first test, to 31% at the follow-up. Of the 39 patients with stable disease, the severity of disease distribution and CBF reduction did not differ significantly between the initial visit and follow-up. When looking at the combined data from the two previous studies, the authors found that patients with mild, moderate, and severe disease experienced CBF reductions of 25%, 29%, and 33% respectively.

The authors conclude that there is a strong association between ME/CFS disease severity and percentage CBF reduction during tilt testing, with a more severe disease rating being associated with a larger reduction in CBF. The authors propose that this objective measure of confirming worsening symptoms may help to guide treatment and measure the effectiveness of therapies.

Dysregulations in hemostasis, metabolism, immune response, and angiogenesis in post‐acute COVID‐19 syndrome with and without postural orthostatic tachycardia syndrome: a multi‐omic profiling study

Authors: Mahdi A, Zhao A, Fredengren E, Fedorowski A, Braunschweig F, Nygren‐Bonnier M, … Ståhlberg M (Karolinska University Hospital, Sweden)
Publication: Scientific Reports
Link:https://doi.org/10.1038/s41598-023-47539-1

An estimated 30% of severely affected post-acute COVID-19 syndrome (PACS) patients experience postural orthostatic tachycardia syndrome (POTS) and present with microvascular endothelial dysfunction. To unravel the unknown pathological mechanisms underlying PACS with POTS, the authors applied an unbiased multi-omic approach to participants’ plasma to analyse cardio-metabolic proteins, pro-inflammatory cytokines/chemokines, and sphingolipids.

A total of 42 non-hospitalised patients with PACS (diagnosed according to the WHO definition) were recruited from the post-acute COVID-19 clinic at Karolinska University Hospital in Sweden. On average, participants had been unwell for 18 months. Participants were divided into 2 groups depending on the presence (PACS+POTS, 20 individuals) or absence (PACS-POTS, 22 individuals) of POTS, defined as (1) a persistent rise in heart rate of more than 30 beats/min, or (2) a heart rate inferior to 120 beats/min within 10 min of the tilt-up test. PACS patients were matched with 21 healthy individuals (healthy controls). There were no significant differences in symptom scores between the two PACS groups. Women were more represented than men in all groups.

Differential expression analysis of 700 plasma proteins showed that PACS patients had a clearly dysregulated plasma proteome with around 200 dysregulated proteins when compared to healthy controls. There were no significant differences in dysregulated proteins between the two PACS groups.

Gene ontology enrichment analysis revealed many significantly altered pathways in both PACS groups compared with healthy controls, including haemostasis, inflammation, amino acid metabolism, and apoptosis. Differential expression analysis of 36 cytokines showed similar cytokine dysregulation in both PACS groups, with 11 up-regulated cytokines compared to healthy controls. Differential expression analysis of 88 plasma sphingolipids showed 16 and 19 dysregulated lipids in PACS+POTS and PACS-POTS respectively, compared to healthy controls. Nevertheless, the authors found no significant difference in proteins, cytokines, or sphingolipids between PACS+POTS and PACS-POTS groups. Principal component analysis also failed to differentiate between these groups.

Collectively, this study suggests that the pro-inflammatory, proliferative and pro-coagulative state in PACS represents an important phenotype in the pathophysiology. Therefore, the resolution of inflammation and micro clots, combined with haemostasis correction, might alleviate PACS burden. The absence of distinctions between participants with and without POTS suggests that POTS may not be associated with the dysregulation of plasma proteins, cytokines, and sphingolipids observed in PACS.

Catalytic antibodies may contribute to demyelination in myalgic encephalomyelitis/chronic fatigue syndrome

Authors: Jensen MA, Dafoe ML, Wilhelmy J, Cervantes L, Okumu AN, Kipp L, … Davis RW (Stanford University, USA)
Publication: Biochemistry
Link: https://doi.org/10.1071/AH23106 

Multiple sclerosis (MS) is an autoimmune inflammatory disease affecting the central nervous system (CNS), characterised by symptoms of pain and impaired nerve communication from the demyelination caused by catalytic antibodies (antibodies with enzyme-like behaviour (Abzs)). There are considerable overlaps between MS and ME/CFS. MRI and PET studies have found physical abnormalities in the brain of ME/CFS patients, and ME/CFS shares symptoms of pain and impaired nerve communication that may be caused by the digestion of myelin basic protein (MBP). The aim of this study was to examine the role of Abzs in ME/CFS. 

Total plasma antibodies (Abs) were collected from 19 patients with ME/CFS (diagnosed using the Canadian Consensus Criteria), 19 healthy controls (HC), and 3 patients with MS to be used as an expected metric comparison. Samples were analysed to identify catalytic antibodies.

When added to bovine brain MBP substrate, 47% of ME/CFS Abs showed digestion, compared to 5% of HC. The authors suggest that those with ME/CFS whose Abs did not cleave MBP may have symptoms unrelated to myelin breakdown or that, similar to MS, there may be patterns of remission and relapse. The Abzs were shown to have serine protease-like activity. Three additional substrates (casein, a-lactalbumin, and lysozyme) were used to determine that breakdown was myelin-specific, not random proteolysis. Purification and size-exclusion assays proved that there was no protease involvement in the MBP breakdown. When the MS drug, glatiramer acetate (GA) was added to ME/CFS Abs + MBP assays, the breakdown of MBP was significantly reduced. GA was shown to be Abzs-specific and did not cause inhibition of general serine protease enzyme activity. Fractionated GA demonstrated the higher molecular weight fragments having greater potency.

The concentration of GA used in these assays far exceeds the general dosage used in MS (and thus what is proposed for usage in myelin-associated ME/CFS). However, demyelination has a long-term cumulative effect, and treatment with GA often takes 6 to 9 months before effects become apparent. As such, the authors believe that the higher dosage used in these assays accounts for these longer-term effects. The authors recommend that a prospective study be undertaken over a long period of time to discover whether there is a similar relapsing-remission pattern in ME/CFS as seen in MS.

‘We have no services for you...so you have to make the best out of it’: A qualitative study of myalgic encephalomyelitis/chronic fatigue syndrome patients’

Authors:Melby, L. & das Nair, R. (SINTEF, Norway)
Publication:Health Expectations
Link: https://www.abc.net.au/news/2023-12-08/dave-clark-on-living-with-chronic-fatigue-syndrome/103071294

The authors of this study sought to gain a comprehensive understanding of Norwegian ME/CFS patients’ experiences of dissatisfaction with healthcare services and to explore the reasons for this dissatisfaction.

The authors used in-depth interviews conducted in participants’ homes, lasting between 40 and 150 minutes, to gain an understanding of participants’ encounters with healthcare services as well as to assess participants’ reasons for satisfaction or dissatisfaction with these healthcare services. In total, 48 participants from 24 households in Norway participated in the interviews. This number included 37 individuals diagnosed with ME/CFS (25 females, 12 males, age range 10-59), in addition to family and household members.

The authors identified four key reasons why ME/CFS patients and their families experienced dissatisfaction with healthcare services. The first was nonexistent services, which involved study participants feeling as though they received a lack of practical help and information, or they were told effective treatment was not a possibility after receiving their ME/CFS diagnosis. The second reason was non-personalised services, where participants received healthcare services that were not adapted to their needs, resulting in these services being viewed as inappropriate or damaging. The third was slow services, where ME/CFS patients and their families believed they received services too late in their ME/CFS trajectory for these services to be useful. The fourth was inappropriate services, where participants believed the healthcare services they received, did not address their ME/CFS, and they felt sicker than they had previously.

The authors concluded that dissatisfaction with healthcare services that Norwegian ME/CFS patients and their families experienced may stem from a variety of factors including systemic issues such as bureaucracy within the healthcare industry, inadequate knowledge of ME/CFS leading to a lack of precise recommendations and uncertainty amongst healthcare professionals, poor personalisation and flexibility from healthcare services, healthcare providers’ disbelief in ME/CFS as a medical condition, and a lack of patient involvement in the design of healthcare services.

The authors note the importance of highlighting ME/CFS patients’ negative healthcare experiences in order to improve future services. The authors suggest that future research should investigate how ME/CFS patients can be involved in healthcare service design to help improve healthcare services.

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