Heterogeneity is the name of the game when it comes to ME/CFS. Whilst ME/CFS is considered to be a symptom-based diagnosis, notably including post-exertional malaise (PEM), the core symptoms often mask a complex reality – the disease can widely vary from person-to-person (heterogeneity). From severity and duration to comorbidities and underlying pathophysiology, there are many areas where differences can occur.
This raises a critical question: should future treatments be tailored to specific phenotypes (disease presentations) rather than treating ME/CFS as a monolith?
A recent study reinforces this need, suggesting that individuals with ME/CFS following SARS-CoV-2 infection (i.e. those with long COVID meeting ME/CFS diagnostic criteria) exhibit different immunological signatures compared to those with “idiopathic” ME/CFS.
Defining the “Elephant in the Room”: Idiopathic ME/CFS
The study compares long COVID-ME/CFS (LC-ME/CFS) with “idiopathic” ME/CFS, but the latter term is potentially confusing and left undefined within the paper.
- What is “idiopathic”? “Idiopathic” typically denotes a condition arising from an unknown cause. Yet its application here is unclear and potentially inconsistent.
- The logic gap
If idiopathic ME/CFS is intended to describe cases where the underlying cause remains unknown (where the sequence of biological events leading to disease onset is not fully understood) then LC-ME/CFS would also fall under this category. Although the initial trigger (SARS-CoV-2 infection) is known, the precise mechanisms by which it leads to ME/CFS remain incompletely characterised, despite evidence of physiological disturbances.
Alternatively, if idiopathic ME/CFS refers to cases in which the trigger itself is unknown, then individuals with recognised precipitating events – such as Epstein-Barr virus (EBV) or influenza – would be excluded from this group. Further complicating matters, the “idiopathic” cohort may include individuals with unrecognised/unconfirmed prior COVID-19 infection. This may affect study findings.
- The likely story
In practice, the study likely contrasts confirmed LC-ME/CFS with a large heterogeneous “non-COVID” ME/CFS group that includes both cases with known non-COVID triggers and those with unidentified triggers. Whilst this comparison may still yield useful insights, it is inherently imperfect and should be interpreted with caution.
Where conditions converge
Long COVID is an umbrella term for prolonged symptoms following COVID-19 infection, making it a broad, non-specific diagnosis. ME/CFS, in contrast, is a specific clinical condition with clearly defined criteria.
Because long COVID can include individuals who meet ME/CFS diagnostic criteria, it is unsurprising that “long COVID studies” show overlapping findings with “ME/CFS studies”. Examples of this overlap include immune disturbances and oxidative stress. In a cohort trial led by former ME Research UK-funded researcher Prof. Dr. Scheibenbogen, 10-20% of long COVID patients met ME/CFS Canadian Consensus Criteria, and even those who did not meet criteria a great deal of symptom and pathophysiological overlap, which includes the presence of several autoantibodies.
The study
A total of 20 participants were enrolled for this study. Analysis of peripheral blood mononuclear cells (PBMCs), i.e. immune cells, collected 12 months after acute COVID-19 infection from 10 female individuals with LC-ME/CFS meeting Canadian Consensus criteria was done. This data was compared against 10 individuals who had recovered from SARS-CoV-2 infection and publicly available datasets of idiopathic ME/CFS patients.
Findings
There is strong evidence for immune dysfunction in ME/CFS, and it is no different in this study as it demonstrated immune changes in both LC-ME/CFS and idiopathic ME/CFS. However, there were interesting differences and emphases between the groups across a wide range of immune cells:
- In LC-ME/CFS, immune dysregulation was widespread: There was a notable loss of naïve (fresh and ready for action) and specialised T cells, and evidence of T cell exhaustion (a state where T cells are chronically stimulated and become so overworked that they eventually stop functioning properly). Additionally, there was impaired natural killer (NK) cell function, changes in monocytes and plasma cells, and hyperactivation of B cells, platelets and neutrophils.
This pattern reflects both immune system depletion and hyperactivation – essentially, a highly stressed system.
- Idiopathic ME/CFS, in contrast, showed subtler changes: Whilst T cells were activated and B cells and platelets were dysregulated, immune cells – MAIT (a type of T cell) and NK cells – were not reduced. There were also no signs of T cell exhaustion.
In other words, immune system activation was present without the pronounced depletion seen in LC-ME/CFS.
They additionally identified upregulation of the FOXP3 gene (a marker for a type of T cell) in idiopathic ME/CFS but not in LC-ME/CFS.
- Key difference: LC-ME/CFS shows a “double hit” of immune cell depletion AND hyperactivation, whereas idiopathic ME/CFS shows activation without the same level of cell loss.
The researchers mentioned Galectin-9–TIM-3 (immune checkpoint important for regulating immune system) as a potential mechanistic explanation for the immune cell loss observed in LC-ME/CFS.
Limitations and future questions
- Small sample size: There were only 10 individuals with LC-ME/CFS in this study, the findings would need to be replicated in a larger cohort
- Females only: The study focused exclusively on females, therefore sex-specific differences were not explored.
- The “Time Since Infection” Factor: This raises a crucial question. Does all ME/CFS start with the intense depletion seen in the LC-ME/CFS group, only to settle into the “idiopathic” profile over several years? The researchers state “Longitudinal follow-up and direct comparisons with pre-pandemic ME/CFS cohorts matched for illness duration will be required to disentangle time-since-infection-dependent immune alterations from convergent chronic disease mechanisms.”
- The idiopathic issue: It would have been useful if the paper defined idiopathic ME/CFS, without clear definitions one cannot know for certain what is being compared, which can affect interpretation of results.
Conclusions
They conclude “Overall, our findings suggest that while both LC-ME/CFS and idiopathic ME/CFS share some immune system abnormalities, the immune landscapes of the two groups diverge in several important aspects, particularly regarding T cell exhaustion, NK cell dysfunction, and the overall activation status of B cells and platelets. These differences underscore the need for a more nuanced understanding of the immunological underpinnings of these two subtypes of ME/CFS, which may ultimately inform more targeted therapeutic strategies.”
Nevertheless, it is worth noting that different studies can produce different results. In a different study that was focused on “ME cases that were triggered before the emergence of SARS-CoV-2”, T cell exhaustion was noted in participants. This would suggest greater similarity between LC-ME/CFS and ME/CFS with other triggers. Therefore, the differences observed in the present study would need to be validated further.
