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

Comments on the Younger video:
I like that he uses the name ME/CFS.

74 women with ME/CFS and 31 female healthy controls
2.35 mins - chart of CRP results. He's using mg/dL.
He says: below 0.3 mg/dL healthy; 0.3-1.0 mild inflammation; 1.0-3.0 moderate inflammation; >3.0 severe inflammation
(so >10 mg/L is moderate inflammation or more)

There's an overlap, but there certainly does seem to be more CRP in the ME/CFS group. None have CRP in Younger's 'healthy' range and the majority have moderate to severe range.

Younger says, 'well, what next? I can't really do a paper showing these scatter plots'. To which I say, 'why not? we have seen papers of much less value than a paper like that would be'.

Younger starts posing questions - is higher CRP associated with higher levels of fatigue, or greater overall severity of illness, or who also has fibromyalgia? - and says 'we need to test that'. Yes, but surely he has that data already? I mean, if a participant comes in for a study and blood is collected, surely you would collect basic information such as current fatigue level, and overall illness severity category? He actually says that he does collect that information. In which case, if you have your database set up fairly well, that sort of analysis is something you can do in 5 minutes or less. Surely Younger knows the answers to the questions he is posing, for his sample group, although he says that he needs to do the analyses.

Seriously, at this point, we need reliable data from sizeable cohorts so we know what the clues are. I don't understand why he wouldn't find an honours student from somewhere to do the analyses and put the paper together. It's not difficult.

He raises the possibility that the people with only mildly elevated CRP were having a good day, and notes that people don't come in on very bad days. So, he wants to get continuous CRP measurement.

He then mentions that the healthy controls may have abnormally high CRP as a result of the pandemic (not necessarily Covid-19 infections, but also vaccinations and exposure to other diseases as social contact resumed). He mentions that they kept bringing in healthy controls and had to exclude them because their CRP levels were pathologically high! That is quite a concern. I mean, you can't conclude that the ME/CFS CRP results are abnormal if you had a policy of excluding people who reported that they were healthy and symptom-free but had high levels of CRP.... I think it might throw into question other results Younger has reported about inflammatory markers.

Next edition is about continuous CRP monitoring.
 
Hutan said:
He says: below 0.3 mg/dL healthy; 0.3-1.0 mild inflammation; 1.0-3.0 moderate inflammation; >3.0 severe inflammation
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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?
 
I have found the literature on CRP levels confusing and contradictory.

For what it is worth, my CRP levels, in mg/L, had a reported normal range of <5mg/L. Since illness onset, my levels have been from 6 to 20, and usually 10 or more. My GP remains completely unimpressed by a level of, for example, 15 mg/L, suggesting that some people just have naturally mildly elevated levels and it doesn't mean anything.

(sorry, edited, I don't know what to conclude)
 
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wigglethemouse said:
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
Click to expand...
From what I can see, Labcorp's levels have a reference 4:
Pearson TA, Mensah GA, Alexander RW et al. Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: A Statement for Healthcare Professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003 Jan 28; 107(3);499-511.

Pearson et al says:
The distribution of the logarithm of hs-CRP level is a normal distribution, and the nontransformed values are skewed toward the higher values, with most populations showing >95% of subjects with hs-CRP values of <10 mg/L. There seems to be population-to-population consistency in this, though as previously stated, data for racial and ethnic populations are limited
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So, over 10mg/L is not normal.

It also talks about levels of CRP being predictive of cardiovascular diseases giving that list of <1.0mg/L, 1.0-3.0, >3 mg/L. It relates to low, medium and high risk of cardiovascular disease. So, I think it is wrong to interpret those levels as indicators of abnormal levels of inflammation. It's just if your CRP is chronically over 3 mg/L, you have a higher chance of cardiovascular disease.
 
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So, given the above, if we convert Jarred Younger's CRP ranges to mg/L:
<3 mg/L is healthy; 3-10 mg/L indicates mild inflammation; 10-30 mg/L indicates moderate inflammation and >30 mg/L indicates severe inflammation.

That seems to be in line with the population data and the evidence on cardiovascular disease risk, so I think his categories are ok.
 
Hutan said:
So, given the above, if we convert Jarred Younger's CRP ranges to mg/L:
<3 mg/L is healthy; 3-10 mg/L indicates mild inflammation; 10-30 mg/L indicates moderate inflammation and >30 mg/L indicates severe inflammation.

That seems to be in line with the population data and the evidence on cardiovascular disease risk, so I think his categories are ok.
Click to expand...

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.
 
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?
 
chillier said:
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?
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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.

chillier said:
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?
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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.
 
Jonathan Edwards said:
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.
Click to expand...

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.
 
Jonathan Edwards said:
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.
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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.
 
mango said:
"031 - Air Quality Can Affect Chronic Fatigue and Pain

Here are some new results from our lab showing poor air quality may increase ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) fatigue and pain. This report is being prepared by graduate student Chloe Jones and is being submitted for peer-review now. - Jarred Younger"
Click to expand...

Now published:

Association Between Chronic Pain and Fatigue Severity with Weather and Air Pollution Among Females with [ME/CFS], 2024, Jones et al (Thread)
 
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