Pre-Illness Data reveals Differences in Multiple Metabolites and Metabolic Pathways in Those Who Do and Do Not Recover from IM, 2022, Jason et al

Pre-Illness Data reveals Differences in Multiple Metabolites and Metabolic Pathways in Those Who Do and Do Not Recover from Infectious mononucleosis

https://pubs.rsc.org/en/Content/ArticleLanding/2022/MO/D2MO00124A

Leonard Jason, Karl Conroy, Jacob Furst, Karthik Vasan and Ben Katz

Abstract
Metabolic pathways related to energy production, amino acids, nucleotides, nitrogen, lipids, and neurotransmitters in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may contribute to the pathophysiology of ME/CFS.

4,501 Northwestern University college students were enrolled in a prospective, longitudinal study. We collected data before illness, during Infectious Mononucleosis (IM), and at a 6 month follow-up for those who recovered versus (N=18) versus those who went onto develop ME/CFS 6 months later (N=18).

Examining pre-illness blood samples, we found significant detectable metabolite differences between participants fated to develop severe ME/CFS following IM versus recovered controls. We identified glutathione metabolism, nucleotide metabolism, and the TCA cycle (among others) as potentially dysregulated pathways. The pathways that differed between cases and controls are essential for proliferating cells, particularly during a pro-inflammatory immune response. Performing a series of binary logistic regressions using a leave-one-out cross-validation (LOOCV), our models correctly classified the severe ME/CFS group and recovered controls with an accuracy of 97.2%, sensitivity of 94.4%, and specificity of 100.0%.

These changes are consistent with the elevations in pro-inflammatory cytokines that we have reported for patients fated to develop severe ME/CFS 6 months after IM.

 

Going by recent papers from Jason, 'severe ME/CFS' just means that the person meets two or more ME selection criteria.

 

Great to see these results.

I had hoped there would be people somewhere doing the same in relation to Covid 19, there was such an opportunity to look at a whole population in the early stages of the pandemic and then follow up over several years.

 

This will turn out to b a very important paper. I can already see how people sleep on it and its vast implications. Mitochondrial dysfunction predates what people consider their trigger.

 

I found a copy of the paper at:

https://0x0.st/oaF3.pdf

 

here is an quote from the paper:

we selected three major ones including the Fukuda et al. criteria,(15) the Canadian Consensus Criteria,(16) and the Institute of Medicine criteria(17). 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.

 

Thanks, as I suspected. I am really concerned about this rebranding of the term 'severe ME'. For patients, and many other people, severe ME denotes a certain, serious, level of impairment; if this attempt to redefine it catches on I can easily see it used by anybody who wants to downplay the severity of a patients suffering.

"Severe ME? That just means you meet two selection criteria, it doesn't mean you can't work or need those benefit payments."

And what happens if you are a severe (by the 'old' definition) patient who happens to only meet one definition? Are you then reclassified as moderate? mild? even less deserving?

 

I'm curious, is MS defined as serve, moderate or mild?

I personally prefer relapsing-remitting because we can go from mild, moderate or severe within a week.

 

A copy of the paper can be found here : https://0x0.st/oaF3.pdf

 

I've got mixed feelings about this study (I've only read the abstract and the comments here, especially from Hutan).

Strengths
1. It's a prospective study.

The great thing about this study is that it collected Baseline data before people developed glandular fever, and then recovered or developed ME CFS.

2. The study used strict (Bonferroni) statistical correction for multiple comparisons. That decreases the chances that these are chance findings.

3. The metabolic differences are consistent with (though don't prove) the pro-inflammatory cytokine changes previously found in the same cohort.

Weaknesses
1. It's a small study, with only 18 people in each group (recovered/developed "severe" ME/CFS).

2. As many others have pointed out, there's no good rationale for the study's definition of "severe" as meeting two different criteria. I'm pretty sure this was not specified in the study design. So I'm guessing it popped up when they started data analysis, which is a little concerning.

It would be interesting to see results for the full recovered versus ME/CFS cohorts.

3. Are the metabolic differences clinically significant?

Looking at table 1, the absolute differences in mean metabolite levels are rather small. Is there any evidence that these have any clinical meaning?

Although spermine does play a role in a pro-inflammatory response, like spermidine, it also plays an essential role in all animal and plant cells. It's a leap to say that these small differences are connected to a difference in cytokine responsiveness and an ability to fight infections.

That's the nature of metabolites: the role of many of them isn't well understood and they often have multiple roles. That gives researchers a lot of scope to link metabolites to many different biological processes. Whether or not those links are important in the real world.

 

It seems like a large sample size (4,501), so you’d think that the fact that half of the college age participants who came down with infectious mononucleosis (18/36) went on to develop ME/CFS would be a headline in and of itself.

Even if it were confined to “college age” participants, if that proportion were confirmed, you’d think it would be a pretty big deal.

[Not that I’m suggesting EBV is the sole cause of ME/CFS].

 

Somehow news that MS is largely caused by mono barely made the news either. It did get some coverage but considering that this is identifying the cause, you'd think there would be major interest. So no surprise this doesn't get much interest.

I'm not sure what's going on as this should be major news and maybe lots are happening in secret, behind closed doors, but even in medical news and forums this seems to have gotten very little interest and isn't moving the needle much on anything, as if the idea is so unappealing that most don't want it to be true.

There's something about medicine and rejecting the germ theory of disease that just continues to plod along, like they have to believe that illness must exactly match injury, if it doesn't, ignore. Only a severe infection can cause severe illness, mild infections must only cause minor, temporary, problems. It's really hard to understand other than from the endless obsession with blaming everything on psychology instead.

 

The two groups of 18 are just the "severe" ME patients and 18 matched controls selected for this specific metabolic investigation. Their previous paper showed 23% meeting any one of the three criteria and 8% more than one criteria at six months. Still a lot, but not 50%.