Innate Immune Changes in the Peripheral Blood

[Kati]

Technetium would not show lymphocytes. I guess some clever PET reagent might be better than Gallium, which probably shows mostly macrophages. The Japanese PET study this year might be something to get excited about and I am hoping it will be repeated. And Baraniuk's pictures of altered pathways in brain are also very interesting.

And of course, much important in performing these studies is the choice of the cohort. Picking anybody off the street VS picking patients using a strict definition VS picking only patients who meet the definitions and wear red socks.

 

[WillowJ]

I Do people with ME have more cells in their lymph nodes, or less? Sounds to me as if maybe at least some have more - tender swollen lymph nodes is even in the criteria I think. More lymphocytes in nodes, or gut lymphoid tissue would be a start - and a bit more solid than traffic.

Many of us have tender lymphs, particularly cervical and axillary, but fewer have swollen nodes. Does that make a difference? It would be cool if we could trace something going on with a tracer.

Lots of us have very unhappy GI systems, and I like your suggestion to look there.

 

[Jonathan Edwards]

In the absence of "exciting" markers, though, couldn't we use NKCC as a nonspecific marker for now, a lot like ANA is or has been used--doesn't mean a lot, particularly not anything highly specific, by itself, but could contribute to diagnosis? As a "this is a class of thing that is happening" kind of marker? (e.g. maybe it says there is inflammation?)

NK values could certainly be used just as a tag, with no interpretation, if the findings were consistent. The trouble with NK tests is that they are very susceptible to variation even in the same lab and unless it becomes clear that any lab can get the same spectrum of results in an ME population as other labs any day they choose then it is unclear that any particular NK test means anything reliable. And we come back to the fact, that Snow Leopard I think pointed out, that low NK values may simply be a result of doing less exercise or having a disturbed sleep pattern. Low NK values certainly would not in themselves indicate inflammation.

 

[WillowJ]

ok, thanks

 

[Gingergrrl]

I did an extensive review a while back and my opinion is that studies measuring (just) cortisol in these case/control studies are mostly worthless.

There is perhaps a link towards reduced vasopressin, which would also potentially explain the OI issues.

My overall conclusion was that any subtle disruptions in the HPA axis were not of primary importance and were a consequence of something else.

@Snow Leopard Could you explain about the link between reduced vasopressin and OI issues?

I posted in another thread that I had a blood test for vasopressin and my level was so low it was not measurable. However, I do not have DI, polyuria or polydipsia (the symptoms that are supposed to correlate with low vasopressin as I understood it.) But I do have OI and severe autonomic problems like tachycardia, low blood pressure, low blood volume, etc, and get short of breath with walking or the slightest exertion such as reaching my arms above my head. My cortisol is normal on blood, urine and ACTH stim tests so this did not seem to be related (although I do have Hashimoto's thyroid disease.) I would love to hear your thoughts on this (when you have time and energy of course!)

 

[Gingergrrl]

These values may be statistical anomalies but that does not make them biological anomalies. Red hair falls outside 95% of the human population but is not an 'anomaly'.

@Jonathan Edwards I am not sure if I understand this analogy b/c this seems more demographic versus functional. If everyone who had red hair was also sick with an illness that people without red hair did not have, then wouldn't it become more relevant? My NK cell functioning back in July was only 5 and I was told that a normal healthy person would have a score of at least 50 if not 100 on NK functioning. Is this incorrect in your opinion?

 

[Kati]

Technetium would not show lymphocytes. I guess some clever PET reagent might be better than Gallium, which probably shows mostly macrophages. The Japanese PET study this year might be something to get excited about and I am hoping it will be repeated. And Baraniuk's pictures of altered pathways in brain are also very interesting.

@Jonathan Edwards i think it is safe to say patients are more than willing to participate in research, even to risk getting a placebo so they have a chance to get the real drug, and would submit to a battery of tests including a 2 days exercise test in order to obtain biomarkers or help researchers helping us.

That said it is incredibly hard in my socialized health care system to obtain testing that is not usually done, especially if we have the ME diagnosis (you can be sure they don't call it ME). Asking for a brain MRI would not go far- i don't think my GP has the authority to order one. i would also get IV contrasts or radiotracers of all kinds in order to show proofs of illness.

The world out there is unbelievably rough for us patients. And I am a nurse.


ETA i would give spinal fluid, muscle biopsy (another one), bone marrow and more exercise testing for sake of advancing the field.

 

[Snow Leopard]

But I just wonder if anyone has ever done Gallium scans or something similar in ME? Gallium might not be the right tracer but something like that might show up.

I haven't seen any published studies like that. It might be possible that a Japanese group has done it, otherwise no...

@Snow Leopard Could you explain about the link between reduced vasopressin and OI issues?

I posted in another thread that I had a blood test for vasopressin and my level was so low it was not measurable. However, I do not have DI, polyuria or polydipsia (the symptoms that are supposed to correlate with low vasopressin as I understood it.) But I do have OI and severe autonomic problems like tachycardia, low blood pressure, low blood volume, etc, and get short of breath with walking or the slightest exertion such as reaching my arms above my head. My cortisol is normal on blood, urine and ACTH stim tests so this did not seem to be related (although I do have Hashimoto's thyroid disease.) I would love to hear your thoughts on this (when you have time and energy of course!)

I don't really have the time and energy to go into detail, but:
Vasopressin plays a key role in the regulation of blood pressure, see:
http://en.wikipedia.org/wiki/Vasopressin#Cardiovascular_system
https://www.google.com/search?q=vasopressin orthostatic hypotension

It is quite possible that there are issues apart from low vasopressin.

As far as the tests go, what is considered 'off the charts low', or 'normal', depends on the test and the judgement of the laboratory of what is high/low. Often the 'low' cortisol that CFS patients have, may be considered on the low edge of the normal range on many laboratory tests (hence why many physicians do not get too excited about it). A 'not measurable' level may also indicate issues with the test...

 

[Jonathan Edwards]

@Jonathan Edwards I am not sure if I understand this analogy b/c this seems more demographic versus functional. If everyone who had red hair was also sick with an illness that people without red hair did not have, then wouldn't it become more relevant? My NK cell functioning back in July was only 5 and I was told that a normal healthy person would have a score of at least 50 if not 100 on NK functioning. Is this incorrect in your opinion?

My point is that 'normal range' on a lab test result sheet IS purely demographic for most tests for most labs. It is the range of maybe 95% of results - which says nothing about whether being outside that range is unhealthy. It may be true that a normal healthy person is very likely to have a result of 50 or more but that does not mean that a result of less is 'unhealthy'. Just like having red hair it may be perfectly healthy.

What I agree seems to indicate that low NK values have something to do with being ill, with ME, is that the results so often seem to turn up low when done in certain labs. But the problem for me is that I am told that when other labs try to confirm this they get normal results. And even the labs that get low results seem to get low results on different NK tests.

So there seem to be two possibilities. One is that these tests are just too unreliable and that in fact low levels will turn up just as often in healthy people as in people with ME. So like red hair, the test is actually nothing to do with being ill. The other possibility is that the labs that get low results for PWME are not explaining clearly enough to other labs what you need to do to get the test to work in such a way that it gives reliably different results between healthy people and PWME. My understanding is that not long ago there was a formal attempt to do this and the results came out no different again.

Within path labs in the NHS, for instance, all tests in routine use would be subject to blinded quality control exercises. Labs would swap coded samples to see if other labs could indeed get consistent results without knowing what was wrong with the patients. Maybe the labs doing NK cell tests should do that on a regular basis. Whether or not low NK cell values really are more common in PWME the current situation seems to me to be letting the patients down. Basically nobody knows whether or not to take any notice of these tests and I think it is up to the labs doing the tests to sort out why we don't know. To be frank, it looks to me that PWME are being taken for a ride. This situation does not occur in the context of RA or diabetes - the tests pass the quality control requirements.

I can understand PWME wanting results on paper, but if the results are not worth the paper they are written on then it is not going to help the cause of proving ME is a physical disease by hanging on to them. Maybe I should get the UCL lab to set up some NK tests on coded samples from elsewhere, but I have been told that this has already been done in the UK, without consistent findings. I do not want to suggest wasting charity money if it has already been done without some new clue as what might have been done wrong.

 

[MeSci]

Many of us have tender lymphs, particularly cervical and axillary, but fewer have swollen nodes. Does that make a difference? It would be cool if we could trace something going on with a tracer.

Lots of us have very unhappy GI systems, and I like your suggestion to look there.

I get swollen - but not tender - cervical lymph nodes and submandibular glands. I get tender - but not swollen as far as I am aware - axillary lymph nodes.

I wonder if a poll has been done on this...

 

[MeSci]

I get swollen - but not tender - cervical lymph nodes and submandibular glands. I get tender - but not swollen as far as I am aware - axillary lymph nodes.

I wonder if a poll has been done on this...

I have started one here.

 

[duncan]

Dr. Edwards: "Within path labs in the NHS, for instance, all tests in routine use would be subject to blinded quality control exercises."

So these NK cell tests have not undergone such tests? Isn't that true for many tests done by specialty labs? And even when such stringent tests have been embraced, the reliability is still not guaranteed? An example might be the ELISA used for Lyme. According to some it has an accuracy rate of around 65% - some studies argue more, some less, but the reality is that likely more than a third of those tested who are told they don't have Lyme may in fact have it.

Yes, it is important for any test to be as accurate as possible. But to have an immune function test offered by major labs - a test that has been fairly consistent in demonstrating a strong association with PWME - discarded because immunologists aren't in agreement what it signifies, seems to me emblematic of the indifference toward the sizable population this test seems to help characterize. If the test is offered, then it has merit in some circles, agreed? And not merely the patent holders to the test, or the labs that promote it - certainly there are many ME researchers who do support the utility of the test.

Dr. Edwards: "If the results are not worth the paper it is written on..."
...then shouldn't we be removing all such tests with questionable merit from the market, including the Lyme ELISA?

 

[ukxmrv]

The other area that is doing research into NK cells is infertility. Here is one research project

Who is organising and funding the research?

The study is being organised by Liverpool Women’s NHS Foundation Trust and the University of Liverpool.

http://www.intralipids.co.uk/our-re...t-using-assisted-reproductive-techniques.html

 

[Valentijn]

Patients (and i will speak for most of us) want proof of illness on paper. Because no one believes us including drs, employers, insurance companies and family members.

If looking at the research for ME/CFS, I think there's already pretty conclusive proof of biological illness, even if the actual pathology isn't understood yet. OI in ME patients has been pretty well documented for at least a couple decades now, and I don't think that anyone has ever tried to claim that swollen lymph nodes can be caused by psychological factors. This hasn't translated to a quick and easy blood test, but it really shouldn't have to.

The bigger issue is that certain groups have latched onto a psychogenic explanation and are 100% invested in it for various reasons. Insurance companies save a lot of money with the psychosomatic explanation. Governments avoid looking incompetent and/or responsible when ME/CFS is explained as being our own fault. BPS clinicians protect their reputations and careers by refusing to accept alternative explanations.

So on an individual basis, ME/CFS patients are trying to convince certain people of a biological cause for our disability when no amount or quality evidence would EVER get those people to acknowledge it. The only thing that will cause a change is when those insurance companies, governments, BPS clinicians, and others are no longer allowed to express such a view point regarding ME/CFS. They will have to be told that is no longer acceptable to treat the disease as imaginary or self-inflicted.

That would be easier if the governments were on our side, but most governments are already invested in being on the other side of the issue. If governments are going to change their attitude, it's going to require a certain amount of public outcry. And that public outcry is more likely to result when ME/CFS is better understood, and there's more rigorous research indicating a biological pathology.

So I don't think the solution is going to be every patient getting lab results showing some abnormality or another. I think progress is going to come from large and thoughtful studies which make very nice headlines for the general public, and which even the most ardent ME/CFS-denialist can't convincingly fault. With the lack of government support, those studies are not going to be easy to come by, but there has been a lot of progress lately with crowd-sourcing.

 

[Snow Leopard]

The other area that is doing research into NK cells is infertility. Here is one research project

In a subset of infertility cases, the NK cell level is often very high and there are other indicators at the same time, such as high ANA too. Apples and oranges at this stage.

 

[Jonathan Edwards]

So these NK cell tests have not undergone such tests? Isn't that true for many tests done by specialty labs? And even when such stringent tests have been embraced, the reliability is still not guaranteed? An example might be the ELISA used for Lyme. According to some it has an accuracy rate of around 65% - some studies argue more, some less, but the reality is that likely more than a third of those tested who are told they don't have Lyme may in fact have it.

Dear Duncan,
This is a very complicated issue and I think it is important not to confuse different aspects. Any test that is being offered as of clinical value should in my view have been subjected to quality control of the sort that at least used to be required in the NHS (much is now subcontracted so goodness knows what happens now). If by 'specialty lab' you mean something like an HIV lab then there should be quality control comparisons internationally between those labs.

I think the Lyme ELISA situation is something different. What is at issue here is whether or not a positive test can subsequently be confirmed by some more definitive measure, such as isolation of the organism, to indicate infection. I suspect the chief problem here is that much of the time no confirmation can be made, so the 'accuracy' of the test becomes a matter of debate. This is not what is at issue for NK tests. What is at issue for NK tests is whether a sample from a patient, split into five aliquots and sent to five labs will give the same result in all five labs relative to a normal population standard range. That is not very much to ask but if so far there is no agreement on what these tests show (irrespective of what they mean in terms of pathology) in a representative group of PWME then it looks as if it has not been met. An alternative possibility is that PWME in Australia have low NK values but PWME in the UK have a different disease with normal values, but if so it should be possible to demonstrate that clearly by a quality control exercise.

My view is simple. Tests that have not been through this basic sort of quality control are not suitable for clinical use.

But to have an immune function test offered by major labs - a test that has been fairly consistent in demonstrating a strong association with PWME - discarded because immunologists aren't in agreement what it signifies, seems to me emblematic of the indifference toward the sizable population this test seems to help characterize. If the test is offered, then it has merit in some circles, agreed? And not merely the patent holders to the test, or the labs that promote it - certainly there are many ME researchers who do support the utility of the test.

I am sorry Duncan but that argument does not wash and I think it implies a judgement about motives that is best not made without due care. I agree with Valentijn's attribution of motives and the route to a solution above because I do think we have evidence of conflict of interest in the areas mentioned. But in this case it is me, someone who is definitely not indifferent to PWME - since what on earth would I be doing writing here if I was - saying that from what I have gathered from reading and talking to scientists I do not think the NK tests are ready for clinical use. There may be plenty of indifferent medics around, but that has nothing to do with the reason for my not using this test in a research study or even thinking it is promising enough to advise a charity to fund a further comparison study.

The fact that a test is offered means absolutely nothing about its merit I am afraid. Doctors frequently order tests thinking that they are helpful when in fact they make no difference to what they do. And doctors also make judgements about what to do on the basis of tests when there is no good reason to do so. If you do not even know if five aliquots of the sample would give the same result in five labs then it seems to me that it is hard to justify treating someone on the basis of it.

This is NOT a political issue. It is an issue about basic quality control. Like you want to know that when the garage says you need new brake pads you do actually need new brake pads. Immunologists who go to the trouble to repeat these tests would dearly love to get a positive result because then they could publish a paper and get sponsored to talk at a meeting in somewhere nice like California or Sydney. The student doing the assays will be desperate to get something to write up for her PhD. So if they find nothing it is not for want of trying, I can assure you! When there are real bogeymen out there I think it is a pity to go for those who would really quite like to help.

 

[ukxmrv]

In a subset of infertility cases, the NK cell level is often very high and there are other indicators at the same time, such as high ANA too. Apples and oranges at this stage.

I was just hoping to make the point that the UK NHS is beginning to look at tests for NK cells in one area (and who knows about the future if this ever takes off).

There is a blood test for NK cells being offered at a Surrey Hospital by a doctor who has part NHS and part private practice. I've taken this test there as a private patient.

I see in this link that the infertility doctor is working with Dr Bansal (who runs a CFS clinic). It's an interesting connection. I'm not aware of Dr Bansal offering the NK test to his CFS patients though.

http://www.epsomguardian.co.uk/news/10157110.Medical_pioneer_gets_leading_role_at_hospital/

(There are PWCFS being seen for infertility as well at Liverpool and other clinics)

 

[user9876]

What is at issue for NK tests is whether a sample from a patient, split into five aliquots and sent to five labs will give the same result in all five labs relative to a normal population standard range. That is not very much to ask but if so far there is no agreement on what these tests show (irrespective of what they mean in terms of pathology) in a representative group of PWME then it looks as if it has not been met. An alternative possibility is that PWME in Australia have low NK values but PWME in the UK have a different disease with normal values, but if so it should be possible to demonstrate that clearly by a quality control exercise.

If you sent samples to five different labs would you expect the same results given the sending time and conditions (i.e. being shaken in delivery truck, heat etc)?

I was wondering how stable results are anyway; for example, PWME often struggle in hot weather so could NK variations in Australia but not the UK be a function of how the body is coping with different environmental conditions (i.e. could the test detect ME in a given environment or just the body reacting to different conditions depending how control samples or normal population stats were produced).

 

[Jonathan Edwards]

If you sent samples to five different labs would you expect the same results given the sending time and conditions (i.e. being shaken in delivery truck, heat etc)?

I was wondering how stable results are anyway; for example, PWME often struggle in hot weather so could NK variations in Australia but not the UK be a function of how the body is coping with different environmental conditions (i.e. could the test detect ME in a given environment or just the body reacting to different conditions depending how control samples or normal population stats were produced).

Clearly if samples are being send long distance it is important to ensure that conditions are comparable but since these sorts of tests often involve samples spending a few hours in a delivery truck they need to be foolproof in that regard for routine use anyway.

If low NK results in Australia were due to struggling with hot weather then I guess they would not be telling us much about the ME itself. But that should be discoverable by labs swapping samples and seeing if it is the samples or the labs that makes the difference.

 

[duncan]

With all due respect, Dr. Edwards, politics pervade just about every nook and cranny of the ME/CFS community, including labs and the studies that support their use - or, alternatively, the lack of effort to replicate such studies. Moreover, financial concerns further impede meaningful progress, because tests are manufactured to generate profits, and even basic quality control can succumb to financial pressures. Fortunately, I like to think that is the exception to the rule.

As for the real bogeymen - yep, they're out there. I go to meet some in a couple of weeks, unfortunately with one less data point than I thought I had had at my disposal.

But thank you for your candor.

P.S. Why do you imagine the Lyme ELISA is mandated as a prerequisite to the Western Blot?