C-reactive protein, CRP

[Hutan]

We've discussed CRP on a number of threads. There are some hints of mildly raised CRP in ME/CFS and some suggestion that levels may track with fluctuations of illness severity. But, there are a lot of confounding factors. I'm going to link some of the papers and discussions here.

When completing the poll try to choose a range that reflects most of your CRP levels, rather than your highest ever level. If there is an odd one that you know was related to a specific infection unrelated to ME/CFS, ignore it.

 

[Hutan]

CRP measurement
First some background on the measurement from some of the discussions. Levels are often reported in mg/L. Sometimes levels are reported in mg/dL - to convert to mg/L, multiply by 10.

HS-CRP is high sensitivity CRP, obtained by a test that can accurately identify low levels. I think the reported levels are comparable with the standard CRP test, although there may be some differences in normal level ranges resulting from different tests.

Pearson et al notes that 95% of the population has a CRP less than 10mg/L:

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

So, over 10mg/L is not normal.

Pearson et al also notes that small differences in low levels of CRP have been found to be predictive of heart disease.

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.

Jonathan Edwards has commented here on CRP levels based on his experience as a rheumatologist:

<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)

 

[Hutan]

What does CRP do?
CRP is found in blood plasma and produced by the liver, is often said to be a marker of inflammation. It activates the complement system.
Wikipedia says

C-reactive protein (CRP) is an annular (ring-shaped) pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin-6 secretion by macrophages and T cells. Its physiological role is to bind to lysophosphatidylcholine expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the complement system via C1q.[5]

CRP is synthesized by the liver[6] in response to factors released by macrophages, T cells and fat cells (adipocytes).[7] It is a member of the pentraxin family of proteins.[6] It is not related to C-peptide(insulin) or protein C (blood coagulation).

But, as with most things, it is more complicated than that, for example:

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.

 

[Hutan]

What do studies in ME/CFS and related diseases tell us?

Association between C-reactive protein and chronic fatigue syndrome: a meta-analysis, 2017, Wang et al

This review found 7 studies. Selection criteria of participants looks to be loose, which is a problem.

Quality assessment of the seven included studies (Table 2) indicated medium quality of the included studies. Four studies showed greater baseline CRP levels in CFS patients as compared to that in controls, while no significant between-group difference was observed in the other four studies.

(4+4=7 is due to the Sulheim study having two case groups)

However, on subgroup analysis based on the type of specimen used for CRP test (plasma or serum), the method used for measurement of CRP (regular or high-sensitivi- ty CRP assay) and the age-group of the popula- tion (adults or teenagers), the heterogeneity was found to have reduced to some extent.

Meta-analysis revealed a mean difference (MD) of 0.39 μg/mL (95% CI: 0.15-0.64) in CRP levels between the CFS patients and healthy controls.

Woolie had this to say:

These results are pretty consistent, imo. When they isolated those studies that used high sensitivity CRP assays, every single one showed a trend towards higher CRP in the ME patients vs. controls.

The difference is pretty tiny, which suggests that it might be driven by a subset of patients.

One potential problem is that its unclear just from the paper whether all studies controlled for BMI. This is a pretty strong predictor of CRP levels so you need to control for that.

So, a small increase over healthy controls. But questions about how many people in the studies actually had ME/CFS. Also differences in BMI may account for the different mean CRPs, and there is the possible problem of the healthy controls being 'too healthy' as in not being representative of the range of CRP levels in normal people.

 

[Hutan]

That's me done for the moment, but hopefully I or other people can have a look at the other evidence we have on CRP levels in ME/CFS and related diseases. I think the conclusion I came to for the 2017 review may apply to a number of the studies.

 

[Ravn]

I've only been able to find 3 results, one was high (23) but that was during an acute infection.
The other two were reported as <1 and 1mg/L respectively, so nothing very spectacular to see (I ticked <1)

 

[Arnie Pye]

I've always been puzzled by the difference between CRP and CRP-HS.

In the CRP link it says :

When To Get Tested?
When your doctor suspects that you might be suffering from an inflammatory disorder (as with certain types of arthritis and autoimmune disorders or inflammatory bowel disease) or to check for the possibility of infection (especially after surgery)

In the CRP-HS link it says :

hs-CRP is being proposed as a method for predicting a healthy person’s risk of heart attack or other heart conditions.

If your hs-CRP result is at the high end of the normal range, it may suggest that you are at risk of developing cardiovascular (heart and blood vessel) disease and other heart conditions. People who seem to be healthy but who have hs-CRP results in the highest quarter of test results have 2 to 4 times the risk of developing blocked arteries, compared with those in the lowest quarter.

As far as I can tell (and I realise I could well be wrong), CRP gives an indication of how much inflammation a person has from multiple different possible sources e.g. infection or arthritis, and CRP-hs gives an indication of how high a risk a person has of cardiovascular disease.

In both cases the same thing is being measured, but the CRP-hs test is just more accurate. So, I don't understand how measuring it more accurately can change what it indicates?

 

[Jonathan Edwards]

The Beentjes study looked at BMI (reported in the second draft I think) and there was not much difference. But I think we may also have to consider activity levels. The difference in CRP in ME/CFS looks to be very tiny. Quite a lot of plasma proteins shift with recumbency (albumin goes down). Moreover, CRP is about the most variable of all the proteins within an individual - changing a hundred fold during infection, which is why it is such as useful test. A slight shift with recumbency would be on the cards.

There is also the possibility that people with more responsive CRP (the people who go up to 200 rather than 40) are more likely to develop ME/CFS for reasons that have nothing to do with CRP itself.

These may all sound obscure explanations but if ME/CFS actually involved inflammation as a main mediator of symptoms the difference would be much much bigger. Levels in ME/CFS would be five times normal.

 

[Jonathan Edwards]

In both cases the same thing is being measured, but the CRP-hs test is just more accurate. So, I don't understand how measuring it more accurately can change what it indicates?

It doesn't. It is just that the ordinary test is too crude to measure the tiny constant shift in CRP that indicates a risk of heart disease in healthy-looking people. People with risk of heart disease have a slightly higher level even when they are well.

 

[hotblack]

Throughout testing early on in my illness and in some routine more recently all < 1 mg/L. Even when being really rather quite ill.

 

[AliceLily]

I was able to find 5 results for CRP.

2002 very severe ME: it just said <3mg/l

2012 severe ME: 1mg/l

2022 moderate ME: 37 (I had a urinary infection when this was taken)

2023 moderate ME: 1mg/l

2024 moderate ME: 2mg/l (Could be due to some throat/thyroid problems this year?)

Looking back through my GP notes I have had a lot of tests for CRP but couldn't see the results for many of them.

 

[InitialConditions]

I've been very consistently (5 results) between 1 and 1.6 mg/L.

 

[NelliePledge]

Only 2 tests 7 years apart 10 and 14.6 mg/l. Notably I’m seriously overweight so that’s likely to be contributing

 

[Yann04]

Somehow even though I’ve had dozens of bloodtests over the past couple years only a single one measured CRP. And it was the tiny level of >0.3 mg/dl.

Note that I was very mild back when this test was done and even though I got PEM, only aerobic exercise or partying would trigger it. And suprisingly all my creatine markers were way over range in that test. I don’t know if that’s a common thing in ME, or maybe it’s because I was doing graded exercise.

 

[Mij]

Mine were only tested once in 2001 when I was at my worst relapse from taking immunomodulators. I was preparing to test for the hypercoagulation theory for CFS

My homocysteine and CRP were all in the lower normal range.

 

[Mij]

I didn't check the box because I can't find my CRP values but from memory it was low.

Homocysteine was at 5.4 (ref range 5-15)

 

[Hutan]

This is from a 2018 prospective study of people infected with EBV:

(e.g. people infected with EBV had, on average, lower CRP than healthy controls at one month. But those who went on to still be fatigued at [6 month] followup had, on average, higher CRP than healthy controls at one month. It would be so good to see a scatter chart, with people meeting CFS criteria differentiated.)

If that result was borne out, it might be evidence for an unusual inflammatory response during the acute illness and/or the possibility @Jonathan Edwards mentioned:

There is also the possibility that people with more responsive CRP (the people who go up to 200 rather than 40) are more likely to develop ME/CFS for reasons that have nothing to do with CRP itself.

 

[perchance dreamer]

When my CRP was high, my P.A. recommended taking a folate supplement. I started on a 400 mcg quatrefolic capsule, and my next scheduled blood test showed a normal CRP. It's been normal since then.

 

[MrMagoo]

Really overweight, it’s always been 7, once it was 5 when I was quite unwell. Consistent over 20 years.

 

[Hutan]

Two different isoforms. I just found this in passing, I haven't looked into it.

Role of C-Reactive Protein at Sites of Inflammation and Infection

There is increasing evidence that CRP has a functional role in the inflammatory process. It is well established that CRP is an acute marker of inflammation and that its concentration increases in circulation during inflammatory events. CRP is deposited at sites of inflammation and tissue damage in both naturally occurring and experimental conditions (57). However, there is a raft of published data investigating CRP that does not consider its two different isoforms. Understandably, when some of these studies were conducted, the existence of two CRP isoforms was not well established and available antibodies would have been raised against the pentameric nCRP alone. Another issue with published data is that CRP localization is often investigated in only a narrow range of inflammatory conditions and tissue types. Although the mCRP isoform has been shown to be insoluble in plasma, it becomes localized in inflamed tissues and amplifies a pro-inflammatory response by a positive feedback loop (58).