The Problem(s) with "Inflammation"

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DHagen

Established Member (Voting Rights)
I hope that I have placed this question in an appropriate space and apologise in advance if, as seems likely, this has already been addressed and I have simply been unable to locate the relevant thread.

It seems that a recurrent objection expressed on S4ME to a great deal of ME research concerns "inflammation", with the S4ME consensus being that there has never been any documented "inflammation" associated with ME, while researcher after researcher and clinic after clinic bluntly assert that they have documented "inflammation" and that this "inflammation" is key to understanding ME. For both sides, the fact that their opposition is completely stupid, mad, brain dead, or malicious seems to be taken as self-evident.

All of this leaves me feeling a right idiot for not even being able to understand the point of disagreement. If there is anyone willing to take the time to explain at least the basics of the conflict to someone as dumb as I am, I would be exceedingly grateful. Is it a matter of how "inflammation" is defined? If so, why isn't this lack of an agreed upon definition for such a frequently used term a larger issue throughout medicine (or perhaps it is and I am simply unaware)? Is it a matter of interpreting specific data? If so, how comes it that the issue is spread so broadly across what appear to me to be profoundly different forms of evaluation?

Thanks in advance, and apologies for what must seem to many an unnecessary question.
 
It’s a great question and I look forward to the responses. My uneducated reading is inflammation is specifically about permeability of blood vessels, so tissues actually get inflamed. While a lot of what is talked about as inflammation is more inflammatory adjacent signals (like cytokines), so more messengers which may or may not cause inflammation of tissues.

This may be wrong :)
 
I think this has been discussed on various threads and @Jonathan Edwards has put out his views on why there is no evidence of inflammation in ME/CFS, I think the following post captures what has been said:
Jonathan Edwards said:
Someone has claimed that there is lots of inflammation in ME/CFS. That might seem to be a matter of meaning of 'inflammation', but it cannot be. There is no concept of inflammation that allows anyone on current evidence to say there is lots in ME/CFS. The original meaning is tissue physiology - no. Then you could allow surrogate biochemical markers like acute phase proetins and ESR - no. In fact the ESR is said to be unusually low in ME/CFS (doubtfully). Then you might stretch it to saying that any odd inflammatory cytokine that is raised means lots of inflammation. There are some reports of IL-8 being up but even more reports of TGF beta which is said to be anti-inflammatory. And who knows what these are doing, even if the results can be relied on?

I personally do not see how this statement can have been based on any evidence.
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I do actually think it would be good to have one "statement" or quick thread on this, so that it doesn't have to be discussed over and over again in different threads and we can just instead point to a reference when these things come up again.
 
DHagen said:
It seems that a recurrent objection expressed on S4ME to a great deal of ME research concerns "inflammation", with the S4ME consensus being that there has never been any documented "inflammation" associated with ME,
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I don't think this is an S4ME consensus. There is no S4ME consensus as far as I am aware. We all have different views. The objection to reference to inflammation is nearly always mine. The reasons are summarised in hotblack's post above and the bit of thread quoted by EndME.

I did my doctorate in inflammation and spent the rest of my career studying inflammation. It is defined as a tissue change mediated by blood vessels, with dilatation, fluid and protein exudation and cell emigration. It makes the part red, hot, swollen, painful and malfunctioning, although these things vary in degree (chronic inflammation is not very red and may be painless).

The problem with biomedical research since about 1990 is that increasingly it is done by people who do not have a wide background knowledge of all relevant fields - you only really get that from a full medical science preclinical course plus ongoing practical training in clinical applicability over a period of ten years. Most people who talk about inflammation in their papers would have no idea how to read a histology slide. It isn't easy. It takes years of practice. Most of them have never made a detailed examination of patients with inflammatory lesions. They just read about it in books.

So, yes, there is a pervasive problem with terms like inflammation being used by people who don't know what it means in practice. Biomedical research dogma is full of bullshit and far more so now than it was forty years ago. It is interesting to look at a journal like Annals of the Rheumatic Diseases (a professional clinical rheumatology journal with a strong science ethos) from 1965. Almost every paper in it is still relevant as an important new finding. If you look at an issue from 2025 you will be lucky to find a single paper that will stand the test of time.

In other words, for me, the 'opposition' is just ill-informed and careless about using words they do not understand. If anyone thinks that I am completely stupid, mad, brain dead, or malicious I am very happy to point out why I am not - as per above.
 
Jonathan wrote this also: (I forgot where, but I had saved this copy in my notes because I found it useful)
inflammation is a physiological change based on local blood vessel function that involves a change in calibre, permeability to water and solutes and cell diapedesis. It has been known since Roman times through the signs of: dolor, calor, rubor, tumor (and loss of function). In ME/CFS we can see from looking at the body and, most precisely, analysing tissue fluid content with MRI, that this occurs nowhere.

There is no inflammation.

As pointed out in our paper, there may be production of some cytokines that are often seen in inflammation but there is no production of others, and inflammation itself does not occur.

So the need is to construct a model that includes the mediators we think are involved but does not invoke some rag-bag concept of a package deal of events that people like to use as a buzz word but is not relevant.
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It’s pretty safe to assume that the vast majority of papers talking about “inflammation” in ME/CFS are talking about handfuls of cytokines that have been broadly dumped in the “pro-inflammatory” bucket, without any further characterization of what those cytokines actually do and in what part of the body. It’s even further confounded by the fact that many cytokines in the “pro-inflammatory” bucket actually inhibit each other.

There are a ton of findings that show differential cytokine levels in ME/CFS vs. healthy controls. We have very very few, arguably none, that actually show those differences consistently across studies, let alone any that have been coherently tied to a mechanism/cell type that’s actually producing them.
 
Is this why researchers become too focused or convinced that there is inflammation in the brain and spinal cord based on the term encephalomyelitis?

Are there subsets of pwME that have some form of inflammation based on testing who are misdiagnosed and have something else?
 
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duncan said:
I've a link to a layman's explanation of neuroinflammation from the American Brain Foundation.
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That is very typical of the confused dogma. If you read it carefully it doesn't add up. One minute it talks of redness heat and so on then it talks of the body's reaction to injury. Which is it?

There was a neurology conference some years back where they discussed what they meant by neuro-inflammation and decided nobody knew and that it was probably a bad term. But it seems to have been ignored.

Neuroinflammation is often taken to equate to evidence of microglial activation. That is not inflammation as originally defined and is much better referred to as microglial activation.
 
jnmaciuch said:
There are a ton of findings that show differential cytokine levels in ME/CFS vs. healthy controls. We have very very few, arguably none, that actually show those differences consistently across studies, let alone any that have been coherently tied to a mechanism/cell type that’s actually producing them.
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Yeah that’s the other aspect of this isn’t it, beyond definition of what inflammation is, it’s reproducibility and mechanism. Even if we could agree on what inflammation means we couldn’t say for sure everyone with me/cfs has it let alone why.

I guess that applies to a lot of claims.
 
Mij said:
Is this why researchers become too focused or convinced that there is inflammation in the brain and spinal cord based on the term encephalomyelitis?
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I think historically that is a big part of it. But of course the encephalomyelitis referred to the acute viral illness, not the long term problem afterwards, where there is nothing to suggest inflammation. It turned out that the interpretation of the acute illness as encephalitis was probably wrong too.
 
hotblack said:
It’s a great question and I look forward to the responses. My uneducated reading is inflammation is specifically about permeability of blood vessels, so tissues actually get inflamed. While a lot of what is talked about as inflammation is more inflammatory adjacent signals (like cytokines), so more messengers which may or may not cause inflammation of tissues.

This may be wrong :)
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I have always wondered how this ties into encephalitis with the brain being beyond the bb barrier (unless this is my ignorance of anatomy) How can "itis" always be about inflammation and thus about blood vessels if there are no such vessels relevant to encephalitis (again this may be pure ignorance on my part). (I mean the term/phenomenon encephalitis per se , not the question of whether it really applies to ME).
 
Mij said:
Do some subsets of pwME actually have some form of inflammation based on testing?
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Not that I am aware of. Some people with ME/CFS will have evidence of inflammation because they have some other problem but nothing so far has indicated that ME/CFS includes inflammation. The very slightly higher CRP levels in a few cases giving a slightly higher mean in the Beentjes study doesn't look as if it reflects actual tissue inflammation.
 
richie said:
I have always wondered how this ties into encephalitis with the brain being beyond the bb barrier (unless this is my ignorance of anatomy) How can "itis" always be about inflammation and thus about blood vessels if there are no such vessels relevant to encephalitis (again this may be pure ignorance on my part).
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Oh, the brain blood vessels are perfectly capable of dilating, becoming permeable and letting out water protein and white cells. Which is why people with encephalitis or neurolupus go into coma with raised intracranial pressure. The blood brain barrier is just a difference in the permeability properties when the brain is uninflamed.
 
I just want to take a moment to thank everyone, and especially Jonathan Edwards, for taking the time to write such thorough and illuminating responses.This has already been enormously helpful for my understanding of the lack-of-understanding, and I am so very glad that it seems others are benefiting as well.
 
You seem very confident.

That is reassuring.

Can yu recall being as confident and being possibly wrong relative to neuroinflammation? Since your involvement with ME/CFS on this forum and, in theaory, about other diseases that might be related?
 
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Not a scientist, but I get irrationally annoyed by “inflammation” being bandied around as the latest buzzword. It’s practically a red flag for someone about to offload an opinion based mainly on reading The Daily Mail health page (other peddlers of click bait unscientific rubbish are available).
I think Jonathan has explained the science behind it. On the media/culture side of things which is more my area, it’s becoming ubiquitous. I use Mounjaro (skinny jabs/fat jabs) everyone is saying how they’ve reduced “inflammation” personally I don’t know what they’re on about, it’s made me slimmer but I wasn’t “inflamed” I was fat.
 
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