The Problem(s) with "Inflammation"

[Hutan]

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.

I think for many of us, it's not the use of the word inflammation alone that would lead us to conclude that someone is 'completely stupid, mad, brain dead or malicious'. If someone is just using 'inflammation' as an alternative way of saying 'glial activation' or something, so long as they explain what they mean, it's just imprecise. We'd still read their paper and try to find something useful in it.

It's similar to how 'holistic' can be good and appropriate but most often in the context of ME/CFS is neither, and crops up in places where there are lots of unevidenced claims. 'Inflammation' is something of a red flag, a marker of problems and unreliable studies.

The use of the term 'inflammation' so often comes with nonsensical treatment offers. It's been something that people with a very loose grasp on biology have latched onto: 'stress' >'inflammation' > 'you need whatever diet or brain retraining or supplement that I have a financial interest in selling'. So often it is attached to papers that have p-hacked their way to finding some marginal differences in cytokines in a post-hoc subset of their ME/CFS cohort.

 

[Jonathan Edwards]

A point I have raised before is that although inflammation is a perfectly useful and appropriate term in some contexts, like staphylococcal infection, in the context of the hard to understand diseases we are no left with trying to explain there is a specific reason for it being misleading.

Inflammation describes a complex set of physiological changes that follow a stereotyped set of rules.
In the diseases we struggle to understand the problem is not so much that we do not know why a set of physiological rules has been activated but that the rules have been subverted and no longer behave as the original set.

Autoimmunity is a good example. It is not an immune response to the wrong antigen. It is a subversion of the normal rules of the immune response. You cannot explain it by invoking the normal rules. You have to dig deeper to fundamental interactions to see how they might be diverted.

ME/CFS is likely to be some sort of subversion of the rules of immune and nervous system homeostasis. If you try to explain it by invoking normal rule sets like those of inflammation you are almost certain to get nowhere. If you dig deeper there is a chance of finding an answer to why there is pain but no swelling or redness and so on.

 

[butter.]

Peripheral “classical” inflammation = swelling, heat, infiltration of neutrophils, increased CRP, etc.

Neuroinflammation (microglial inflammation) = microglia and astrocytes producing cytokines, reactive oxygen species, and signaling cascades, but without the classic peripheral signs.

(I talked to neurologists and neuroscientists in the past and they said it might be that 'classical inflammation' is actually part of 'neuroinflammation' - it's just in a very localized, diffuse manner and low grade. Not sure what to make of that.)

What makes matters even more complicated is that classical inflammation in the periphery, such as during an acute infection, might set the stage for multiple downstream problems. So even if there is no classical inflammation in ME/CFS during the chronic phase, classical inflammation might still have a role in triggering the illness through the acute/subacute stages and (maybe somewhat less likely - because it doesn't pop up in PEM studies) during phases of baseline deterioration.

To say inflammation is not relevant when 75% (?) of patients report an inflammatory event triggering the disease seems off to me.

To give an example of how it's really important to understand the temporal dynamics of disease:

Some studies suggest that high CRP in midlife is a risk factor for later developing AD, but once AD is established, CRP is often considered unexpectedly low or normal.

(https://www.sciencedirect.com/science/article/abs/pii/S0531556520303521)

I think something similar could be true for ME/CFS. I have very severe ME, I have non existent CRP since I am very severe, but I had increased CRP levels 10 -15 years ago as a mild/moderate patient regularly.

 

[Jonathan Edwards]

Neuroinflammation (microglial inflammation) = microglia and astrocytes producing cytokines, reactive oxygen species, and signaling cascades, but without the classic peripheral signs.

That illustrates nicely how these words just cause confusion. Inflammation is not the production of these things, it is the response to these things or the effects of these things. And it depends entirely on context.

If Kupffer cells produce cytokines there is no inflammation, there is increased production of acute phase proteins in nearby liver. Because Kupffer cells aren't outside vessels like other macrophages so there is no chemotactic gradient.

Every day of our lives our spleen is full of macrophages making cytokines, reactive oxygen species, and signalling cascades and nobody calls that inflammation. There aren't even any proper vessel walls in the spleen pulp so the rules for other tissues do not apply.

 

[butter.]

That illustrates nicely how these words just cause confusion. Inflammation is not the production of these things, it is the response to these things or the effects of these things. And it depends entirely on context.

If Kupffer cells produce cytokines there is no inflammation, there is increased production of acute phase proteins in nearby liver. Because Kupffer cells aren't outside vessels like other macrophages so there is no chemotactic gradient.

Every day of our lives our spleen is full of macrophages making cytokines, reactive oxygen species, and signalling cascades and nobody calls that inflammation. There aren't even any proper vessel walls in the spleen pulp so the rules for other tissues do not apply.

That’s just how the phrase is currently used by, I would say, the majority (?) of researchers in the field. It might not be the most useful or correct term, but it is the one being used.

You can seek treatments for Malaria without renaming it or believing a HEPA Filter will solve the issue.

I think what is more relevant than the debate over whether we call it microglial activation versus neuroinflammation (or microglial inflammation) is 1. whether these processes (using misnomers currently) are actually relevant to the pathology and 2. what role plays classical inflammation during the early stages.

 

[hotblack]

The use of the term 'inflammation' so often comes with nonsensical treatment offers.

Agree with this and the comments from @MrMagoo and that this is part of a wider thing, not just ME/CFS but a general quackery and use of ‘inflammation’ as a term to justify it.

So we seem to have covered (i) questions over definition (ii) issues of reproducibility and mechanisms within ME/CFS (iii) good faith but imprecise use (iv) bad faith (or at best imprecise) use to bolster a paper, article or intervention.

 

[hotblack]

I think something similar could be true for ME/CFS. I have very severe ME, I have non existent CRP since I am very severe, but I had increased CRP levels 10 -15 years ago as a mild/moderate patient regularly.

But don’t we know that it is not universal? I had loads of blood tests early on because I was hospitalised for a serious infection and CRP was fine and was for those initial years.

Isn’t this part of the problem we’re talking about? Not just that these things are not universal in people with ME/CFS because they are regularly tested and we’re told we’re fine because they’re normal. But also people are familiar with being tested for ‘inflammatory markers’ so we sort of come to associate those with something being wrong, so people try to use the term to prove something is wrong?

 

[Jonathan Edwards]

That’s just how the phrase is currently used by, I would say, the majority (?) of researchers in the field. It might not be the most useful or correct term, but it is the one being used.

Except that when they got together they agreed that they didn't really know what they meant by it. And most biomedical researchers these days are going nowhere fast so following their buzzword jargon has nothing to commend it. It its use simply sends people round in circles then time to drop it - as I think was suggested when it was debated, in a review we looked at here.

 

[butter.]

But don’t we know that it is not universal? I had loads of blood tests early on because I was hospitalised for a serious infection and CRP was fine and was for those initial years.

Isn’t this part of the problem we’re talking about? Not just that these things are not universal in people with ME/CFS because they are regularly tested and we’re told we’re fine because they’re normal. But also people are familiar with being tested for ‘inflammatory markers’ so we sort of come to associate those with something being wrong, so people try to use the term to prove something is wrong?

I don't think we know that, my own case is actually quite exemplary of that. When I say I had increased CRP during mild/moderate ME - that's my retrospective assessment. I was sick but it was years before a formal diagnosis. It's impossible to know what might be prodromal or early/mild disease in any given patient. We have close to zero long-term follow up or epidemiological data available. We have no to very little knowledge about the natural progression of the disease(s). If you look at the AD example, the CRP dynamic is also not 'universal' probably, it's a trend and likely connected to genetic risk factors. Given all these complexities it's easy to see how people can come to certain conclusions prematurely.

I would also say it's not necessarily normal that you had a normal CRP while having a severe infection. (Same is true for me btw.)

 

[hotblack]

Given all these complexities it's easy to see how people can come to certain conclusions prematurely.

I see your point. And agree that saying we don’t know for sure is probably best. We also do not know that there is a prodromal or early phase or that there is a progression, many talk of sudden onset. And I think that is the argument, we have no evidence that inflammation or any of this is relevant. It may be, but lots of things may be. But that is a long way from the position that inflammation is conclusively part of ME/CFS and has been found, which is what I/we are pushing back on here isn’t it?

To say inflammation is not relevant when 75% (?) of patients report an inflammatory event triggering the disease seems off to me.

What is your definition of an inflammatory event? If we said infectious then I think people would agree. But infectious does not automatically equal inflammatory in my understanding?

 

[butter.]

I see your point. And agree that saying we don’t know for sure is probably best. We also do not know that there is a prodromal or early phase or that there is a progression, many talk of sudden onset. And I think that is the argument, we have no evidence that inflammation or any of this is relevant. It may be, but lots of things may be. But that is a long way from the position that inflammation is conclusively part of ME/CFS and has been found, which is what I/we are pushing back on here isn’t it?


What is your definition of an inflammatory event? If we said infectious then I think people would agree. But infectious does not automatically equal inflammatory in my understanding?

I see your point. And agree that saying we don’t know for sure is probably best. We also do not know that there is a prodromal or early phase or that there is a progression, many talk of sudden onset. And I think that is the argument, we have no evidence that inflammation or any of this is relevant. It may be, but lots of things may be. But that is a long way from the position that inflammation is conclusively part of ME/CFS and has been found, which is what I/we are pushing back on here isn’t it?


What is your definition of an inflammatory event? If we said infectious then I think people would agree. But infectious does not automatically equal inflammatory in my understanding?

Infection always (?) leads to classical inflammation. Is that right, @Jonathan Edwards? And if not, it's only because the immune system doesn't detect it?

 

[MrMagoo]

In general conversation, I find asking “what is it that’s inflamed” helps, because nobody can ever answer.

 

[Jonathan Edwards]

Infection always (?) leads to classical inflammation. Is that right, @Jonathan Edwards?

No, there are a variety of organisms that can infect us with essentially no inflammatory response - nematodes for instance. The HIV virus does not cause inflammation until secondary events occur. There are human retroviruses that get incorporated without any obvious pathology as far as I am aware.

But it isn't that relevant. ME/CFS is what we call the process that is often a sequel to an infection. The infective event isn't ME/CFS. Any more than strep throat is rheumatic fever.

 

[butter.]

No, there are a variety of organisms that can infect us with essentially no inflammatory response - nematodes for instance. The HIV virus does not cause inflammation until secondary events occur. There are human retroviruses that get incorporated without any obvious pathology as far as I am aware.

But it isn't that relevant. ME/CFS is what we call the process that is often a sequel to an infection. The infective event isn't ME/CFS.

I think I understand what you are saying, but that seems quite arbitrary? I understand that's part of the current diagnostic criteria of course, but that might be a mistake.

It’s a bit like an electrical short circuit and a house fire: of course the short circuit isn’t the fire itself, but the fire wouldn’t exist without it. Ignoring the short circuit as “not relevant” might lead to missing the (potential) causal link?

ME/CFS may not be the infection itself (not even that seems absolutely certain) but it can be the direct consequence of immune and metabolic changes set in motion by that infection?

 

[Jonathan Edwards]

It’s a bit like an electrical short circuit and a house fire: of course the short circuit isn’t the fire itself, but the fire wouldn’t exist without it. Ignoring the short circuit as “not relevant” might lead to missing the (potential) causal link?

But nobody is ignoring anything as irrelevant. We think genes contribute to ME/CFS but they in themselves do not constitute ME/CFS. We think infections contribute but they do not constitute ME/CFS.

I think you are missing the point that what we call a disease and what we suspect is the basis of a syndrome is the segment of a causal pathway network that is common to all in a clinical group. Tuberculosis is partly caused by alcoholism, poor living conditions and infected classmates but when we talk of tuberculosis we are referring to being infected with M tuberculosis. Sometimes the common segment tracks back to a gene - like haemophilia. But for diabetes all sorts of causal inputs converge on a single common segment, which is glucose intolerance.

It is conceivable the inflammatory events are a necessary component of ME/CFS at least early on. It is quite plausible that events that are often associated with inflammation but are not themselves inflammatory, like a rise in CRP production are a necessary component. But so far we don't have much evidence for either.

 

[hotblack]

I’m not sure it’s being ignored, more perhaps a case of asking what is the mechanism that keeps it going?

So in the fire analogy a spark may trigger it but to understand and extinguish the fire you need to understand different mechanisms.