Predictors for Developing Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome following Infectious Mononucleosis, 2022, Jason et al

[Wyva]

Abstract


Background: About 10% of individuals who contract infectious mononucleosis (IM) have symptoms 6 months later that meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Our study for the first time examined whether it is possible to predict who will develop ME/CFS following IM.

Methods: We have reported on a prospectively recruited cohort of 4,501 college students, of which 238 (5.3%) developed IM. Those who developed IM were followed-up at six months to determine whether they recovered or met criteria for ME/CFS. The present study focuses on 48 students who after six months had a diagnosis of ME/CFS, and a matched control group of 58 students who had no further symptoms after their IM. All of these 106 students had data at baseline (at least 6 weeks prior to the development of IM), when experiencing IM, and 6 months following IM. Of those who did not recover from IM, there were two groups: 30 were classified as ME/CFS and 18 were classified as severe ME/CFS. We measured the results of 7 questionnaires, physical examination findings, the severity of mononucleosis and cytokine analyses at baseline (pre-illness) and at the time of IM. We examined predictors (e.g., pre-illness variables as well as variables at onset of IM) of those who developed ME/CFS and severe ME/CFS following IM.

Results: From analyses using receiver operating characteristic statistics, the students who had had severe gastrointestinal symptoms of stomach pain, bloating, and an irritable bowel at baseline and who also had abnormally low levels of the immune markers IL-13 and/or IL-5 at baseline, as well as severe gastrointestinal symptoms when then contracted IM, were found to have a nearly 80% chance of having severe ME/CFS persisting six months following IM.

Conclusions: Our findings are consistent with emerging literature that gastrointestinal distress and autonomic symptoms, along with several immune markers, may be implicated in the development of severe ME/CFS.

Open access: https://www.rehabiljournal.com/arti...drome-following-infectious-mononucleosis.html

 

[Andy]

From the paper,

"Those who met more than one case definition (i.e., the Fukuda and either the Canadian and/or Institute of Medicine criteria) were defined as having severe ME/CFS.".

 

[Trish]

Jason has made that crazy definition of severity in previous papers. I don't understand why he persists with it. It doesn't fit with any other researchers, severity scales or patient groups. I am increasingly concerned that Jason doesn't understand ME/CFS.

 

[Hutan]

"Those who met more than one case definition (i.e., the Fukuda and either the Canadian and/or Institute of Medicine criteria) were defined as having severe ME/CFS.".

Yes, that's bizarre. Especially coming from someone who has spent a lot of time working on ME/CFS, and specifically on diagnostic criteria.

 

[Hoopoe]

that crazy definition of severity

It might just be a convenient way to divide the patient sample into those with more and those with fewer symptoms. But yes, don't we have enough problems with odd definitions in the literature already?

 

[Hutan]

It's damn annoying, because prospective studies are rare and expensive, and Jason's one had a good chance to tell us something useful, including about possible predictors of severe ME/CFS.

This very odd definition of severe ME/CFS just muddies the water. It's not the first time I've been frustrated with how the data from that prospective study has been analysed and reported. You would think that a paper about a prospective study of ME/CFS, one aiming to predict severe ME/CFS, would at least tell us how many of the young people who developed ME/CFS at six months had it with a severity that resulted in them being unable to continue their studies, or required them to be mostly bedbound.

A number of studies12-14 have found that the Fukuda et al. criteria are broader and identify a larger group of patients, with less severity, than those identified by the Canadian Consensus or Institute of Medicine criteria. Therefore, participants who primarily only met the Fukuda et al.8 criteria were defined as having ME/CFS. Those who met more than one case definition (i.e., the Fukuda and either the Canadian and/or Institute of Medicine criteria) were defined as having severe ME/CFS. Those who met more than one case definition also scored worse on the DSQ than those who met only a single case definition for ME/CFS six months following IM.

"the Fukuda criteria are broader and identify a large group of patients, with less severity' - no it doesn't. The average severity may be lower than those identified with CCC or IOM - but that is quite a different thing.

Jason et al do say that those who met more than one case definition also scored worse on the DSQ. (The DSQ does take into account symptom severity and frequency.) But, where's the data to back that statement up? Instead of showing us the actual findings, the paper leaps on to developing a predictive index before they have made a clear case for the components of the index being relevant.

And

Our study for the first time examined whether it is possible to predict who will develop ME/CFS following IM.

isn't even true. The Dubbo study initially concluded that acute illness severity was predictive of ME/CFS following glandular fever. And then there was that ridiculous Cvecic 2019 paper that looked again at the Dubbo data and purported to suggest that being neurotic was predictive of developing ME/CFS - even though the data they presented didn't show that at all.

I just can't understand why the research coming out of this group is so bad. A useful report wouldn't be hard to do - it's like they have put in extra effort to make something that tells us nothing useful.

 

[ME/CFS Skeptic]

The paper states:

When we tried to use the statistical methods to predict the development of ME/ CFS following IM, the results were not significant, so in our analyses reported below, we focused on the severe ME/CFS group.

Perhaps the most notable finding is that it is quite difficult to predict who will get ME/CFS after EBV-infection, even if you have measures of symptoms, cytokines and the severity of infection.

On the other hand, we might simply need bigger samples.

 

[ME/CFS Skeptic]

This has been noted already, but in this study of the 238 students who got Infectious Mononucleosis, 48 or 20% had a diagnosis of ME/CFS after 6 months. This is double from the 10% that has previously been reported.

I think it's also a bit surprising that only 18 out of those 48 (37%) met more than 1 case definition. I would expect that number to be higher (because all case definitions are similar).

 

[MSEsperanza]

The paper states:

Perhaps the most notable finding is that it is quite difficult to predict who will get ME/CFS after EBV-infection, even if you have measures of symptoms, cytokines and the severity of infection.

On the other hand, we might simply need bigger samples.

And/ or perhaps, at 6 months, it's still too difficult to differentiate between prolonged recovery and ME/CFS?

Or you have to look at other signs and symptoms?

 

[ME/CFS Skeptic]

It's damn annoying, because prospective studies are rare and expensive, and Jason's one had a good chance to tell us something useful, including about possible predictors of severe ME/CFS.

Looking at patients who meet multiple case definitions might not be such a bad idea given the problems with the Fukuda criteria. So it's mostly the term "severe ME/CFS" for this group that is misleading.

So perhaps we could come up with an alternative term that describes it better and then suggest this to Leonard Jason's team? I can't come up with something good at the moment except for: "strict ME/CFS"

 

[Andy]

So perhaps we could come up with an alternative term that describes it better and then suggest this to Leonard Jason's team? I can't come up with something good at the moment though except for: "strict ME/CFS"

"ME/CFS as defined by multiple definitions".

 

[Trish]

I think the main difference between Fukuda and other criteria is the central place of PEM, properly defined, not just post activity fatigue.
Perhaps separation into two groups could be on that basis, with the groups called 'chronic fatigue without PEM' and ME/CFS.

 

[petrichor]

The mean scores of the severe ME/CFS group vs non-severe vs recovered on various questionnaires can be seen in the original paper for the prospective cohort study here: https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8664491/. I've inserted some of the scores here if it's of interest to anyone (S-ME/CFS is severe ME/CFS, SF-36 and DSQ are both 100 point scales, 1st column is pre-IM, 2nd is during IM, 3rd is 6 mo. after):



I'm puzzled by how low the SF-36 Physical health scores are at time 1, pre-IM, before illness, because healthy college students should be scoring very well, but their scores seem much worse than the general population (eg. the scores mentioned in this study: https://jnnp.bmj.com/content/74/6/710). So maybe there's something I'm misunderstanding

 

[Trish]

Are the SF36 scores on the normalised scale where the population mean is set at 50?

 

[adambeyoncelowe]

Severe ME needs to be scored on symptom severity, not a proxy such as 'meeting two or more sets of criteria'.

Number of symptoms alone might not even be a good enough measure, because if those symptoms are all very mild, then even cumulatively, they might not amount to severe impairment.

 

[petrichor]

Are the SF36 scores on the normalised scale where the population mean is set at 50?

That's a good idea, maybe. But I don't see any mention of that in the paper, the other scales don't seem to be normalised, and I think you'd expect the 6 month ME/CFS scores to be lower in that case. So I'm confused

 

[MEMarge]

From the paper,

"Those who met more than one case definition (i.e., the Fukuda and either the Canadian and/or Institute of Medicine criteria) were defined as having severe ME/CFS.".

@Medfeb can you explain or understand why this definition is used by Jason? How do other US clinicians and researchers etc view his approach

 

[Aimossy]

Severe ME needs to be scored on symptom severity, not a proxy such as 'meeting two or more sets of criteria'.

Number of symptoms alone might not even be a good enough measure, because if those symptoms are all very mild, then even cumulatively, they might not amount to severe impairment.

I agree with this and think all ME/CFS needs a proper standardised measurement for severity that includes symptoms and disruption of activities of daily living.

 

[CRG]

I think the main difference between Fukuda and other criteria is the central place of PEM, properly defined, not just post activity fatigue.
Perhaps separation into two groups could be on that basis, with the groups called 'chronic fatigue without PEM' and ME/CFS.

Certainly with/without 'reported PEM' is a viable categorisation - but caution is needed to avoid introducing a prior discrimination i.e ME/CFS/not ME/CFS, when there is no prior pathophysiological evidence on which to base that discrimination.

PEM may turn out to be descriminatory as a proxy for pathophysiology, separating a majority of people who have an ME/CFS diagnosis and everyone else. but at this stage we have no clear evidence that it does - as such it remains a feature to be researched.

We also need to be aware of the 'true ME' trap - if someone has all the symptoms of ME/CFS but no marked PEM they may still be substantially disabled, still needing effective research and treatment - it would be poor science to not explore what the source of disease for that person was. We need to be prepared for research to take multiple directions with the potential for that to lead to attenuation of research focus. For pragmatic reasons sticking with a 'big tent' might be better than splitting up into small tribes.

 

[Trish]

I'm not suggesting people without PEM aren't sick and in need of research and care. I'm simply saying most current research and accepted definitions of ME/CFS require PEM, and having PEM makes any therapy including increasing activity harmful.

There must be some sort of difference in pathology that causes PEM, so people with PEM need to be researched as a separate group, not lumped in with those without PEM as if we all had exactly the same condition.

Also ME/CFS with PEM can in the same person at different stages be anything from mild to extremely severe. Pretending that those with mild ME are mild because they only fit one criteria is nonsense.