News From Jarred Younger / Neuroinflammation, Pain, and Fatigue Laboratory at UAB, From Aug 2020

LabCorp in the US has the bars set at 0.3mg/L, 1mg/L, and 3mg/L. Dr Younger has 0.3mg/dL, 1mg/dL, and 3mg/dL.
LabCorp Review of hsCRP test : https://www.labcorp.com/tests/related-documents/L1097
LabCorp hsCRP test : https://www.labcorp.com/tests/120766/c-reactive-protein-crp-high-sensitivity-cardiac-risk-assessment

The UK ME Biobank paper I referenced earlier also used mg/L for an average of 2 for ME/CFS and 1 for HC.

Am I missing something - I listened to the start of the video again and I'm sure he says his results are mg/dL?

 

Younger's description of levels are reasonable. Except that for thirty years I worked with something more like.

In mg/L
<1 definitely no evidence of inflammation
1-2 probably OK
2-5 a little suspicious of inflammation but for many people can be taken as normal (note that the problem is that different people have markedly different CRP responses)
5-20 definitely some inflammation and it may be quite severe but for some people mild
20-50 inflammation that needs serious attention
>50 worrying, may be acute sepsis
>150 very likely acute sepsis

It is very hard to convey exactly how one uses the test because of this near tenfold range of responsiveness between individuals. One person's 10 mg/L is another person's 60mg/L.

But also note that the cardiovascular risk data relate to much lower levels
<1 mg/L is low risk
1 mg/L is moderate risk
3mg/L is high risk (not 30mg/L)

If the CureME data had an average level of 2 it was 2mg/L, which for Younger is healthy. I haven't seen Younger's data.

 

Younger is showing CRP in mg/L.
The normal controls are not a healthy population. Almost all should be below 3 and the majority below 2.

We seem to be back to an indication that people with ME/CFS may have slightly raised CRP suggestive that there probably isn't any actual inflammation (if there was at least some would have had levels of 20 mg/L in the CureME cohort) but there may be some cytokine production somewhere.

It looks as if Younger may have got his units muddled too.

 

Something I think we may have not twigged to is that low level inflammation might be a risk factor for developing ME/CFS, just as acute infection is.

So the diagram goes:


Inflammation + ?? >>> ME/CFS

Not

ME/CFS >>> inflammation

This is my central worry with the Beentjes paper.

 

My CRP level was <1 according to a blood test done on a visit on one of my worst ever days of ME/CFS, and the only other one where I can see the values on my records also show <1. I am housebound and largely bedbound.

 

Just checked and my CRP levels have always been well under 1 mg/L, measured 3 or 4 times over the last decade.

In the beentjes paper they report an increase of 1.3 units in male ME and 0.6 in female ME cohorts (It looks like CRP is measured in mg/L in the UK biobank just by googling UK biobank biomarkers).

I didn't see in the paper where they report on whether it's a subset of the population with elevated CRP or slight shift in the entire population, maybe that was in their second revision?

One thing I've wondered is that a sore throat and sore/tender/enlarged lymph nodes is a very common ME symptom, and a symptom I have a great deal of the time. My ignorant question - do these symptoms imply of local inflammation of some sort (too subtle to alter CRP levels?) - if not inflammation what causes these symptoms?

 

I don't think we know the scatter pattern. All that was said was that only a tiny percentage had levels above the chosen normal range.

Things get complicated here @chillier !! Inflammation is defined as an increase in vascular calibre, permeability to water and solutes and whitecell emigration. There are all sorts of variants on this. CRP is linked only to the variants driven by interleukin 6. In lupus you can have organ destruction by inflammation mediated by complement dysfunction without any rise in CRP.

Things are particularly peculiar for lymph nodes, which are normally full of white cells and receive white cells through lymphatics as well as across blood vessel walls. In viral infection lymph nodes become activated but they do not get the sort of white cell inflammation, dominated initially by polymorphs, that occurs in other tissues. In staphylococcal infection you can get lymphadenitis with pus and polymorphs but that is something different.

The bottom line is that analysing what is going on in terms of 'inflammation' is something that no competent inflammation scientist would attempt because inflammation covers a vast range of overlapping pathways and events. For each illness we want to know exactly which pathways. That is how inflammation research was built in the late 1970s and early 1980s by people with a deep understanding of both tissue structure (history) and biochemistry - people like John Vane and Salvador Moncada. I was fortunate enough to train in a department of that sort but sadly most of that broad understanding has gone.

Another problem is that IL-6 can be triggered by macrophage activation that is not part of inflammation. The most potent signal is likely to be Kupfer cell activation in liver sinusoids. Kipper cells are macrophages but weirdly they do not migrate into the tissue. They function sitting inside venules on the endothelium. Most of the CRP rise in rheumatoid arthritis may be due to Kipper cell activation rather than any of the inflammation in the joints.

In Castleman's disease there is huge IL-6 production and massive lymphadenopathy but not really any inflammation. I am not sure we know why.

So we have to unpick and unpick and unpick.

But I am struck by this discussion that it does seem likely that there is some connection between IL-6 and ME/CFS. It may be the opposite way round to what we think though.

 

Very interesting thank you for your response! Lots I want to ask about that but I'll restrain myself (such as how Kupffer cells would get activated in the first place - long range IL-1 signals?).

With respect to the microclots, since they supposedly contain fibrin and serum amyloid A, which I understand can also be acute phase proteins along with CRP - I wonder if it's plausible they could be a normal indication of a recent inflammatory episode. Ie they have a longer half life than something like CRP in the blood, but do not in themselves actually cause any of the symptoms in ME/long covid.

 

Kupffer cells (interesting to see how spellchecker handles that!) get activated through various surface receptors for immune complexes, other material attached to complement, lipopolysaccharide on bacteria (CD14 complex), other toll-like receptor ligands and probably through cytokines like TNF, IL-2 and gamma interferon.

Yes, I wondered if the micro clot phenomenon was just picking up a rise in fibrinogen and amyloid acute phase protein levels, which can aggregate when incubated with Thioflavine T.

 

I've just checked and my CRP was normal last year. (<1)

 

https://www.youtube.com/watch?v=sD1_6ZOxaA8

 

I personally think this is a more likely explanation, assuming Younger's result stands. Things like allergies or chronic stress have been previously identified as risk factors. ME/CFS patients on average may have had higher ambient inflammation level even before they got sick, not as the result of ME/CFS.