ME/CFS Research Published 12 – 18 December 2023

The weekly research round-up includes recent publications about ME/CFS and Long Covid. We highlight studies that have particularly caught our attention.

RESEARCH INDEX

The ME Association maintains a comprehensive index of published research on ME/CFS and Long Covid that is free to use and updated weekly.

VIEW THE ME/CFS AND LONG COVID RESEARCH INDEX

Audio Commentary by Dr Katrina Pears

It’s been an exceptionally busy week for research. There has been a huge variety in studies this week, with twelve new ME/CFS studies and thirty new Long Covid studies this week.

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

Paper eleven (11) is a preprint study (meaning the science has not been peer-reviewed and verified) which looks at circulating biomarkers which measure endothelial dysfunction (the endothelial is a layer of cells lining blood vessels) and inflammation alongside self-reported outcomes in ME/CFS and Long Covid. This study used 31 patients with ME/CFS, 23 with Long Covid and 31 healthy controls. A very large range of data was collected in this study and included

Outcome measures: Questionnaires were used which measured changes in perceived fatigue (Fatigue Impact Scale, FIS-40), sleep quality (Pittsburgh Sleep Quality Index, PSQI), anxiety and depression symptoms (Hospital Anxiety and Depression Scale, HADS), autonomic dysfunction symptoms (Composite Autonomic Symptom Score-31, COMPASS-31), frequency and severity of orthostatic symptoms (Orthostatic Grading Scale, OGS), and health-related quality of life (Short-Form Health Survey, SF-36).
Endothelial function markers: blood levels of soluble endothelin-1 (ET-1), thrombospondin-1 (TSP-1), vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), plasminogen activator inhibitor-1 (serpin E1/PAI-1), endothelial selectin, and adiponectin, as well as nitric oxide (NOX assessed as NO2 – + NO3 -).
Inflammatory cytokines/chemokines assays: blood levels of twelve cytokines/chemokines, namely IL-1β, IL-4, IL-6, IL-8, IL-10, IL-13, TNF-α, monocyte chemoattractant protein-1 (MCP-1/CCL2), interferon-gamma (IFN-γ), interferon gamma-induced protein-10 (IP-10/CXCL10), macrophage in ammatory protein-1-alpha (MIP-1α), and leptin.
Cardiovascular autonomic function: all patients were assessed by a standing test (10-minute NASA lean test (NLT)).

The study found that combining biomarkers of endothelial dysfunction and inflammation with outcome measures differentiate ME/CFS and Long COVID. The study also found:

The results confirm the presence of inflammation and endothelial dysfunction in Long Covid and ME/CFS.
Four ME/CFS patients (13%), 1 with long COVID (4%), and 1 healthy control (3%) with postural orthostatic tachycardia syndrome (POTS)
Compared to healthy controls, ME/CFS and long COVID subjects showed higher levels of ET-1 and VCAM-1, and lower levels of nitrites (NOx assessed as NO2- + NO3-). (All measures of endothelial function.)
ME/CFS patients also showed higher levels of serpin E1 (PAI-1) and E-selectin than did both long COVID and control subjects. (Measures of endothelial function.)
Long COVID patients had lower TSP-1 levels than did ME/CFS patients and healthy controls. (Measure of endothelial function.)
As for inflammation biomarkers, both long COVID and ME/CFS subjects had higher levels of TNF-α than did healthy controls.
Compared with controls, ME/CFS patients had higher levels of IL-1β, IL-4, IL-6, IL-10, IP-10, and leptin. (Inflammation markers.)
There were no associations found between outcome measures and inflammation biomarkers in Long Covid patients.
For the ME/CFS group, three negative associations were found between symptomatology and IL-8, IL-4, and IL-6 (Inflammation markers).
For the association between outcome measures and endothelial markers, the most relevant is that clinical symptoms were associated with VCAM-1 in long COVID patients and with ET-1 in the ME/CFS group.
The association between endothelial biomarkers and inflammatory variables was stronger in the ME/CFS cohort, compared with long COVID patients or healthy controls.
ME/CFS patients demonstrated a heightened inflammatory response, particularly in plasma cytokine/chemokine levels, and this likely plays a significant role in the development of endothelial dysfunction.
The results also suggest that ME/CFS and long COVID may have different origins of endothelial dysfunction, as long COVID patients lack the sustained high cytokine/chemokine levels that are observed in ME/CFS.
A range of different analyse was used, with one analysis (PCA) showing that endothelial biomarker data could correctly distinguish 51% of patients with ME/CFS from those with long COVID, but inflammatory biomarkers only classified 35% of patients. Whereas using a different type of analysis, discriminant analysis, provided much higher results classifying 85.9% of participants correctly, with the variables serpin-E1 (PAI-1), NOx, IL-1β, IL-6, and FIS-40 (four biomarker molecules and fatigue impact scale).
Statistical analysis supported differentiation between groups based on self-reported outcome measures and endothelial and inflammatory biomarkers.

This is one of the few studies where we have seen a combination of outcome measures and circulating biomarkers used, and the first where this has been done for ME/CFS and Long Covid. A few things to note about this study:

A huge amount of data and results is available in this paper, the patient characteristics alone are very detailed and take up 8 pages!
ME/CFS patients all meet the diagnosis under the International Consensus Criteria (ICC).
Long Covid patients had unexplained symptoms after a positive covid tests for over 3 months and met the 2021 WHO Clinical case definition.
Healthy controls were all sedentary.
The illness average illness duration of ME/CFS patients was 7.4 years compared to 2.1 years for the Long Covid patients. Therefore, these results could be down to illness duration alone.
As always the small sample size can limit the statistical power and impact the significance of the findings, therefore, in a larger sample size the significant findings may not be present.
Due to the sample size as well it is not possible to determine how results differ in male and female populations.
The use of self-reported outcome measures is prone to recall bias and over-reporting, as well this data only reflects the week prior to assessments. However, all data in this study was treated the same and reinforced with blood biomarkers.

There’s not much too dislike about this study, but there is a lot of data to be considered. It is refreshing to see a study that works towards providing objective biological data for differentiating ME/CFS patients from both individuals with long COVID and healthy sedentary controls.

You may also be interested in reading this week:

Paper six (6) from the well-known researchers van Campen, Rowe and Visser, which provides further evidence that symptom severity in ME/CFS may be related to changes in blood flow to the brain (cerebral blood flow) – which is exacerbated when moving from a lying or sitting position to standing (ie orthostatic intolerance).