Review Predisposing and Precipitating Factors in Epstein–Barr Virus-Caused ME/CFS, 2025, Leonard Jason

[John Mac]

Full title:
Predisposing and Precipitating Factors in Epstein–Barr Virus-Caused Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

https://www.mdpi.com/2076-2607/13/4/702

Abstract
Long COVID following SARS-CoV-2 and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) following infectious mononucleosis (IM) are two examples of post-viral syndromes.

The identification of risk factors predisposing patients to developing and maintaining post-infectious syndromes may help uncover their underlying mechanisms.

The majority of patients with ME/CFS report infectious illnesses before the onset of ME/CFS, with 30% of cases of ME/CFS due to IM caused by the Epstein–Barr virus.

After developing IM, one study found 11% of adults had ME/CFS at 6 months and 9% had ME/CFS at 1 year. Another study of adolescents found 13% and 7% with ME/CFS at 6 and 12 months following IM, respectively.

However, it is unclear which variables are potential risk factors contributing to the development and maintenance of ME/CFS following IM, because few prospective studies have collected baseline data before the onset of the triggering illness.

The current article provides an overview of a study that included pre-illness predictors of ME/CFS development following IM in a diverse group of college students who were enrolled before the onset of IM.

Our data set included an ethnically and sociodemographically diverse group of young adult students, and we were able to longitudinally follow these youths over time to better understand the risk factors associated with the pathophysiology of ME/CFS.

General screens of health and psychological well-being, as well as blood samples, were obtained at three stages of the study (Stage 1—Baseline—when the students were well, at least 6 weeks before the student developed IM; Stage 2—within 6 weeks following the diagnosis of IM, and Stage 3—six months after IM, when they had either developed ME/CFS or recovered).

We focused on the risk factors for new cases of ME/CFS following IM and found factors both at baseline (Stage 1) and at the time of IM (Stage 2) that predicted nonrecovery.

We are now collecting seven-year follow-up data on this sample, as well as including cases of long COVID. The lessons learned in this prospective study are reviewed.

 

[forestglip]

We did not find any significant differences between those who developed ME/CFS versus those who recovered, on pre-illness baseline differences in stress, coping, anxiety, or depression.

We did find baseline pre-illness complaints of fatigue and deficiencies in IL-5 and IL-13 in the group that went on to develop severe ME/CFS versus those who recovered. Deficiencies in IL-5 and IL-13 before contracting IM may influence the immune response once the virus is contracted. For example, there is evidence in human and mouse models that IL-5 and IL-13 contribute to the pathology associated with ulcerative colitis.

In a network analysis study, we next examined groups of cytokines within each condition [recovered controls vs. severe ME/CFS] before developing IM. [...] The cytokines of those who went on to develop severe ME/CFS are highly clustered. [...] In the ME/CFS sample, the in silico-modeled cytokine-association patterns were also more interwoven, with less grouping into functional categorizations than in the healthy controls. The implication is that pathway activation is less discrete and more reflective of an ill-orchestrated immunologic response in those who developed ME/CFS.

Patients with stomach pain, bloating, and symptoms of an irritable bowel at pre-illness baseline, low levels of IL-13 and/or IL-5 at pre-illness baseline (previously discussed), and severe gastrointestinal symptoms at the time they contracted mononucleosis had a nearly 80% chance of developing severe ME/CFS six months following IM.

Baseline metabolomic predictors between recovered and severe ME/CFS:

Significant differences were observed for the following metabolites: S-adenosyl-L-methionine (part of one-carbon metabolism and is a methyl donor for epigenetic regulation), glutathione (part of glutathione metabolism), cysteine (an amino acid that participates in a variety of pathways, including glutathione metabolism), thiamine (modified and used as a cofactor in several TCA cycle enzymes), and N-acetyl-alanine (may have a role in protein signaling and post-translational modifications).

I'm not sure why the listed metabolites are different from the metabolites in Table 1, which are:

spermine
spermidine
ATP/dGTP
carbamoyl phosphate
glutathione disulfide
citrate/citrate(iso)
CDP

 

[Trish]

I recall from previous reports on this cohort they used Fukuda criteria, and their definition of severe ME/CFS was those with PEM, presumably diagnosed by the DePaul questionnaire, which is mainly about fatigue.
Please correct me if I have misremembered. I have no energy to look into this.

 

[Utsikt]

I recall from previous reports on this cohort they used Fukuda criteria, and their definition of severe ME/CFS was those with PEM, presumably diagnosed by the DePaul questionnaire, which is mainly about fatigue.
Please correct me if I have misremembered. I have no energy to look into this.

I believe you’re correct.

They say this:

Students with “severe” ME/CFS (those who met > 1 set of criteria for ME/CFS) were compared to students who met a single set of criteria (“moderate” ME/CFS) and to those who recovered 6 months following IM

(…)

A consistent theme in our work has been differentiating patients who have what we have termed severe ME/CFS from those with moderate ME/CFS. Those with severe ME/CFS meet more than just the Fukuda criteria, which are less specific than other criteria for diagnosing ME/CFS.

 

[Yann04]

I recall from previous reports on this cohort they used Fukuda criteria, and their definition of severe ME/CFS was those with PEM, presumably diagnosed by the DePaul questionnaire, which is mainly about fatigue.
Please correct me if I have misremembered. I have no energy to look into this.

They used Fukuda, CCC, and IOM. Severe ME/CFS meant someone met more than one of those criteria. So I’m assuming those who met just one is mostly Fukuda.

 

[forestglip]

I don't have it in me to read these thoroughly right now, but I'm curious why this paper says IL-5 and IL-13 were lower, while the previous paper on the same cohort says IL-6 and IL-13 were lower.

Risks for Developing ME/CFS in College Students Following Infectious Mononucleosis: A Prospective Cohort Study, 2020, Jason et al

The former group was not different from the latter group at time 1 (prior to developing IM) in stress, coping, anxiety, or depression but were different in several behavioral measures and had significantly lower levels of IL-6 and IL-13.

 

[Utsikt]

Am I correct in saying that this ‘review’ is mostly just a summary of their previous work?

 

[forestglip]

Am I correct in saying that this ‘review’ is mostly just a summary of their previous work?

Appears that way, plus some information about what they plan in the future (e.g. study cohort in relation to long COVID).

 

[Dolphin]

ME Research UK:

Approximately 30% of ME/CFS cases associated with an infection are thought to be due to infectious mononucleosis – glandular fever, caused by the Epstein–Barr virus (EBV) – but not everyone who has an EBV infection develops ME/CFS. A study published in the journal "Microorganisms" investigated why this is the case.

Read more: https://bit.ly/4jIzgAx
Read more articles on EBV by ME Research UK here: https://bit.ly/42raddW

https://twitter.com/user/status/1914967626587029737

 

[forestglip]

We did find baseline pre-illness complaints of fatigue and deficiencies in IL-5 and IL-13 in the group that went on to develop severe ME/CFS versus those who recovered.

I don't have it in me to read these thoroughly right now, but I'm curious why this paper says IL-5 and IL-13 were lower, while the previous paper on the same cohort says IL-6 and IL-13 were lower.

Risks for Developing ME/CFS in College Students Following Infectious Mononucleosis: A Prospective Cohort Study, 2020, Jason et al

Yeah, I'm not sure why this review mentioned IL-5, but not IL-6 which was more significant. This is the relevant part of the study they're describing:

Complete data were available for 105 participants at all 3 time points (18 S-ME/CFS, 29 ME/CFS, 58 Recovered) (see Table 3).

There were significant time effects for IL-6 (P = .01), IFN-γ (P < .01), and TNF-α (P < .01), and close to significant differences for IL-13 (P = .015). There were significant group effects for IL-5 (P = .01), IL-12(p70) (P = .01), IL-13 (P < .01), and TNF-β (P < .01).

At time 1, the S-ME/CFS ["severe", met more than one case criteria] group had a significantly lower mean rank of cytokine expression than the Recovered group for IL-6 (P = .01) and IL-13 (P =< .01) and a close to significant difference for IL-5 (P = .02).

Additionally, the ME/CFS [met one or more criteria] group had a directionally lower mean rank of cytokine expression for IL-5 than the Recovered group (P < .03).

 

[forestglip]

And a note that the ME Research UK article posted above only mentions IL-5 and IL-3, the second of which isn't mentioned in either paper. I think it's a typo for IL-13.

Edit: I let them know and they very quickly fixed it.