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

[Andy]

if someone has all the symptoms of ME/CFS but no marked PEM they may still be substantially disabled

So this hypothetical person wouldn't have all the symptoms of ME/CFS, no matter how disabled they are. They absolutely do deserve effective research and treatment, but so do ME/CFS patients. Lumping all patients who report fatigue into one group when we have a symptom that can indicate a target group risks all of the confusion that we have suffered in the past.

 

[cfsandmore]

I think if the Fukuda group is moved into one of the other groups it changes the data dramatically. Jason et al needed three groups to produce a better statistically significant result.

 

[Medfeb]

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

I don't know why Jason used this definition of severity. And I agree with the comments above - severity can have a spectrum but that spectrum is not a function of what case criteria was used. And referring to Fukuda patients without PEM and at any level of severity as ME patients confounds research.

 

[Mithriel]

EBV was always known to have a prolonged course in some people, taking up to 2 years to be back to health. That was the way the common herd (us non medical people) thought of it.

Saying it is ME/CFS after 6 months must be because they think of it like Oxford no matter what definition they say is being used.

My own view is that when they discover what biological problem causes ME they may be able to diagnose it much sooner than 6 months but I am not convinced that Jason is being careful enough to distinguish ME from prolonged EBV.

 

[Wyva]

EBV was always known to have a prolonged course in some people, taking up to 2 years to be back to health. That was the way the common herd (us non medical people) thought of it.

Saying it is ME/CFS after 6 months must be because they think of it like Oxford no matter what definition they say is being used.

My own view is that when they discover what biological problem causes ME they may be able to diagnose it much sooner than 6 months but I am not convinced that Jason is being careful enough to distinguish ME from prolonged EBV.

Prolonged EBV? You mean acute infection for two years? Is there any source for that?

 

[Mithriel]

I don't know about acute infection but we just accepted that some people would be very ill, even to being bedbound for months then gradually get better.

In a similar way, prolonged giardiasis is being called ME but it can be prolonged without becoming ME. A friend had a few years with this but was completely recovered after that.

My worry is that if they call these prolonged recovery periods for infections ME then it will distort the statistics and make it seem as if most people recover from ME fairly quickly. Small step from that to thinking people do something wrong if thye do not recover and the exercise phobia of the psych brigade fits the bill nicely.

In my young days prolonged recovery from infections was just the way things could be and convalescence was an important part of that recovery. It might have been because antibiotics were still quite new so infections were treated very seriously.

 

[adambeyoncelowe]

Is there a circularity here?

Jason says patients who fit more than one set of criteria have more symptoms, and therefore have severe ME.

But a predictor for those people having more symptoms is... having more symptoms before they even get ME.

And not just any symptoms, but symptoms that would count towards an ME diagnosis.

Isn't it just the case that those pwME who have severe GI symptoms before and after diagnosis, merely have ME plus severe GI symptoms, rather than more severe ME itself?

It's the classic trap of attributing everything to ME once you diagnose someone. That increases the risk that other pathologies will be missed and misdiagnosis will occur.

So are the before-IM symptoms being controlled for? Couldn't these pre-existing severe GI symptoms be a confounding factor that makes the pattern he found meaningless?

I do respect Jason's work, but I think there are problems here, just as there were problems with the development of his PEM questionnaire.

As for s-ME, I think he should call this dv-ME or 'double-verified ME'. But PEM does need to be mandated when using the Fukuda criteria and I would want a clearer analysis of the differences between those diagnosed using Fukuda, IOM, ICC or a combination.

But all of this also requires a proper tool for assessing PEM.

 

[Mij]

In a similar way, prolonged giardiasis is being called ME but it can be prolonged without becoming ME. A friend had a few years with this but was completely recovered after that.

https://pubmed.ncbi.nlm.nih.gov/22316329/

Conclusion: After giardiasis enteritis at least 5% developed clinical characteristics and functional impairment comparable to previously described post-infectious fatigue syndrome.

 

[adambeyoncelowe]

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

Ah, I misread the results section. They don't confirm that the patients still have severe GI symptoms after diagnosis, but they do have them before IM and at the point of IM developing, so it's a fair bet.

Severe GI symptoms at the diagnosis stage would skew the results on the DSQ if not controlled for, as it does ask about those symptoms and uses them to help diagnose ME.

 

[Jonathan Edwards]

Prolonged EBV? You mean acute infection for two years? Is there any source for that?

I think @Mithriel raises an important point here that maybe we have tended to gloss over.

Prolonged fatigue after EBV is well recognised. I remember having it for about 6 months.
That is not due to prolonged active replication of EBV. Control of viral proliferation occurs within the first few weeks. Virus persists but then it does life long.

I also remember having something that might have been PEM - feeling terrible after having tried some gentle sporting activity.

However, I think a useful concept of ME is of an illness that goes on longer than this - in the sense that it is not consistent just with the 'tail-off' of a severe infection in the way that EBV fatigue is. In a way I think diagnosis of ME should be delayed longer when after EBV than if occurring without a major infective trigger.

The time point for diagnosis is a very easy cause of confusion. Leaving it to 6 months probably avoids including people who are in a post-infection tail-off, but even there for EBV and maybe Q fever the time point should perhaps be longer. At the same time one has to remember that those people who do develop ME have probably already flipped into the ME state long before 6 months - you just cannot know until you have the benefit of hindsight.

This is one of the reasons why diagnostic criteria are never as good as we would like them to be. They are very overrated. In RA we have possible, probable definite and classical categories of diagnostic criteria - which shows how complicated things are but probably does not help much.

 

[Hutan]

Leaving it to 6 months probably avoids including people who are in a post-infection tail-off, but even there for EBV and maybe Q fever the time point should perhaps be longer. At the same time one has to remember that those people who do develop ME have probably already flipped into the ME state long before 6 months - you just cannot know until you have the benefit of hindsight.

My two children and I had ME/CFS symptoms essentially immediately after an infection. Whatever state is an ME state, we "flipped into it" straight away. My daughter didn't have such severe symptoms and slowly, over a couple of years, returned to near normal health. I don't think she 'flipped out of it', it's just that her threshold for PEM gradually became higher.

I think post-viral fatigue syndrome (with PEM) and ME/CFS are the same things, there's just an arbitrary (but useful) time requirement for ME/CFS. In my experience, if there's a fundamental difference between the two, it's in the 'not getting better vs getting better', rather than the sickness itself.

I don't think a time requirement of longer than 6 months before ME/CFS after EBV and Q-fever is diagnosed is helpful. As the NICE Guideline committee seemed to acknowledge, the aim should be to recognise people who have PEM early, so that they can get some insight into how to manage their illness. There's no point trying to exclude people with

the 'tail-off' of a severe infection

if the 'tail-off' is actually the same as ME/CFS.

 

[Mij]

I don't think a time requirement of longer than 6 months before ME/CFS after EBV and Q-fever is diagnosed is helpful.

I see this as the same as saying drink 8 glasses of water a day. Where did 'they' come up with the number 8?

 

[LarsSG]

A good thread on statistical issues with this study:

 

[Simon M]

* The S-ME/CFS group is not selected on severity — but does it have any useful meaning? *

S-ME/CFS is not a selection of the most severe patients (it could have been)

S-ME/CFS defines individuals who meet more than one case definition. In practice, this means excluding ME/CFS patients who only meet Fukuda criteria.

The S-ME/CFS group was not significantly more fatigued not had worse SF-36 physical health [composite score] than regular MEcfs, though its DSQ score was significantly lower.

The authors have the data to select on severity

A "severe" category can only be created by classifying each patient on the basis of severity. While there is no universally agreed definition of severity in ME/CFS, all the ones I know of are based on levels of functioning (e.g. the SF 36 physical function scale, housebound/bedbound versus not and the NICE severity scale).

Yet to meet any of the ME/CFS criteria, people needed to "experience substantial reductions in occupational, educational or personal activities". This was defined as scoring at or below at least two of the three following subscale SF 36 subscale cut-offs: Role physical 50 or less; Social Functioning 62.5 or less; Vitality 35 or less.

The authors could have have defined a severe group on the basis of the same SF 36 subscales but with a lower cut-off score.

It would be interesting to see results of a genuine severe category created on such a basis.

Does the S-ME/CFS group have any useful meaning?

Looking at the results for questionnaires and cytokines, there is a trend with S-ME/CFS worse than regular ME/CFS which is worse than the recovered group — even though most of the differences are not statistically significant. So the S-ME/CFS category does seem to be a bit different.

Potentially, this is simply because IOM and CCC cases are, on average, more severely affected than those with just Fukuda i.e. these differences could just be reflecting a group difference in severity.

A. Is it all about PEM?

The neatest explanation would be that the regular ME/CFS cases, which only meet only one case definition, are Fukuda cases that simply lack PEM.

There are two problems with this:

1. I would be surprised of this research group missed such an obvious difference. If it was the case, I would have expected them to simply select on a mandatory requirement for PEM to define a PEM group (Versus no PEM).

2. Also, the DSQ assessment of PEM is debatable: many patients believe it simply measures exertional intolerance. So we can't be sure that the DSQ would allow a clean separation on PEM.

If we assume that S-ME/CFS is defined by presence of PEM, does that mean that after Mono people can either develop "true" ME or a different illness that is similar in many ways? That doesn't feel right to me.

B Is it a more subtle difference?

Fukuda-but-not-IOM

The surprising thing (to me) is that so many people meet Fukuda but not IOM criteria. If it isn’t simply down to PEM, what is the other explanation?

IOM = fatigue +3 mandatory symptoms, Fukuda is fatigue + any 4 of 8 possible symptoms.

IOM and Fukuda non-fatigue symptoms

IOM: 1. Post-exertional malaise, 2. Sleep problems 3. Cognitive impairment and/or orthostatic intolerance.

Fukuda: Any four of eight symptoms. 1. Post-exertional malaise, 2. Sleep problems 3. Cognitive impairment (memory/concentration difficulties). 4 Sore throat. 5 Lymph-node pain 6. Muscle pain 7. Joint pain 8. New or different headaches.

There are two ways somebody could meet Fukuda but not IOM criteria:

— they simply don’t have all three IOM symptoms (sleep or cognitive issues, as well as PEM)

— They have all three IOM criteria but don’t meet the study’s symptom severity and frequency thresholds for them (the method section makes no mention of any thresholds for Fukuda). In other words, they are milder IOM cases.

Conclusion
As things stand, I can't see what we learn from the S-MEcfs category results.

It would be useful to have more data from the authors on the differences between the S-MEcfs group and other MEcfs cases and to see an analysis that really was based on severity. Plus seeing the results for all ME/CFS cases combined.

 

[Simon M]

One long-term illness or two after mono?

I had thought it unlikely that there were two different illnesses triggered by mon: MEcfs and something else that looks a lot like it. @Jonathan Edwards thinks that's probably what's happening.

[MEcfs vs ] the 'tail-off' of a severe infection in the way that EBV fatigue is...
Those people who do develop ME have probably already flipped into the ME state long before 6 months [- you just cannot know until you have the benefit of hindsight].

It's an interesting idea and would be easier to explore if there had been a longer follow-up in this study. I think Dubbo followed up on cases for up to 2 years. This study only looked at six months, and there has been no mention of further follow-up.

Here's what we might see at follow-up:

Assuming MEcfs has a very low recovery rate, most recovery will be of the 'other' illness (a prolonged post-viral state). So an increasing proportion of those still ill would then be 'true' mecfs cases. Perhaps they would have a slightly different set of symptoms and be more severe. Maybe the S-MEcfs group is picking up more of these. If so, the recovery rate from this group would be lower than that for others.

Certainly, for Long Covid, the ONS data shows a high recovery rate initially and then a large group who have had it for more than a year. It's not easy to interpret this, though, as, in addition to recovery, there are new waves of Covid. But we might be seeing something similar there: one group where people gradually recover and the second group who have a more persistent illness.

Maybe we should ask if there will be a longer follow-up for this study.

 

[wigglethemouse]

I had thought it unlikely that there were two different illnesses triggered by mon: MEcfs and something else that looks a lot like it.

Other diseases such as MS and Lupus can be triggered by EBV, not only PVFS and ME/CFS, so you would expect different categories of symptoms. I imagine it can take many years for these other diseases to be diagnosed, so in the meantime they could have multiple symptoms and meet the Fukada criteria.

I've not read the series of papers so don't know if this aspect of EBV causing multiple diseases is taken into consideration.

 

[DigitalDrifter]

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.

Similarly I believe that those who experience LTSE should be categorized as a different group and researched separately.

 

[Simon M]

Other diseases such as MS and Lupus can be triggered by EBV, not only PVFS and ME/CFS, so you would expect different categories of symptoms. I imagine it can take many years for these other diseases to be diagnosed, so in the meantime they could have multiple symptoms and meet the Fukada criteria.

I don't know about Lupus, but my understanding of MS is that the main link is with EBV, not mono. The latest evidence seems to be that EBV infection is a necessary initial step for MS, but that the disease develops sometime later. As opposed to the case with ME/CFS where the infection starts a serious illness and while its nature morphs, there is no recovery from that point. So I wouldn't expect to see MS symptoms in people six months after mono.

 

[Mithriel]

Most people I know with MS believe their symptoms started years before they became sick enough to be diagnosed. Strange occasions when they kept dropping things or staggering for a few seconds.

 

[bobbler]

A good thread on statistical issues with this study:

Hmm. I haven't had a chance to read through all the study, but I'm not sure all the criticism is correct on this one. If it is what I think it is study-wise then it is unusual in that it is 'organic' and longitudinal scanning of students - they can't guarantee who gets EBV and from there what condition they end up in/with over time. Almost more like a census.

So the numbers used aren't chosen, but should increase over time. And because you are wanting it to be longitudinal and there may be different types then getting as much data from many angles before they get it and at relevant snaphots to when they catch it is needed. Because as people collect up then you can't 'go back' and collect something you didn't before. If someone has off the scale cytokines (or anything else) they need to know whether it is a huge increase for that person or it was high at baseline.

There is a lot of merit in knowing horse vs cart comparisons, timing of things and not having to assume prior based on patterns found 'after'.

As others have said I'm pretty sure this isn't the end of the research or being presented as a 'trial conclusion', but will give a lot of detail at the micro-level to back up patient lived experience/observations etc.

But yeah, I'm going to be interested at wording of what is presented in here claims-wise because that's the differentiator, is this data so far findings and ideas so far from that, or 'more'.