A biomarker in low NK cell activity...

[gregh286]

Hi.
With 15/17 studies conducted for nkcc proving low in cfs V control......it seems it doesnt get much attention?

http://www.omicsonline.org/open-acc...ptom-severity-2155-9899-1000348.php?aid=59415

Moreover, low nk activity seems directly proportional to symptom severity...
Why should low nkcc create a fatigue condition? Infection re-occurance?

 

[Antares in NYC]

Very interesting point. I can accredit that as my NK cell count and function had decreased steadily in the last three years, my symptoms have worsened.

In addition to NK cell problems, two of my IgG subclasses (1 and 3) have come down to below normal levels i nthe same time period. Every test we do, it tics a bit lower.

Something's up.

 

[Bansaw]

http://www.omicsonline.org/open-acc...ptom-severity-2155-9899-1000348.php?aid=59415

Looks like Isoprinosine and Rintatolimod (Ampligen) inspired positive changes. I'm convinced that in many CFS people, the hypothalamus is not functioning properly due to stress and thats why Isoprinosine might be getting some results.

 

[Kyla]

@gregh286
isn't it low NK cell function (activity) as opposed to cell count?

 

[JohnnyD]

The study and/or overview is of NK cell activity (or function) not cell count. Big difference between the two. You might want to change your topic heading.

The study was done by Hemispherx in an attempt to identify a sub-group that responds to ampligen.

Cort has a blog on which he 'heard' that the CDC is developing an accessible NK cell function test.

http://www.cortjohnson.org/forums/t...get-increase-good-news-me-cfs-expansion.3465/

 

[gregh286]

Hi.
Yea i changed it.
I had been reading a lot on low nk cd57 count in chronic lyme disease beforehand.
So we have low nk counts in chronic lyme and in cfs both low activity and low count in many cases.

So...reposing the question....why should low nk cell activity create fatigue.

 

[duncan]

The low NK Cell Function is likely just another downstream effect. It, too, probably is a byproduct, as fatigue is.

 

[Jonathan Edwards]

Hi.
Yea i changed it.
I had been reading a lot on low nk cd57 count in chronic lyme disease beforehand.
So we have low nk counts in chronic lyme and in cfs both low activity and low count in many cases.

So...reposing the question....why should low nk cell activity create fatigue.

I don't think anyone is suggesting that low NK function causes fatigue directly. The low NK cell function might lead to immune problems that caused fatigue or immune problems might lead to both fatigue and low NK cell function, as Duncan suggest.

The difficulty right now is that the main people who reported this finding do not seem to be able to get the same result again, and nor do other people who have tried to repeat it. Some have and have published that but negative results rarely get published. The consensus from the researchers I have talked to is that this is not a consistent finding. And NK cell function is a very capricious thing to try and measure. Moreover, nobody is quite sure what it means in the standard assay because NK cells can tell if cells are yours or not and the assay uses somebody else's cells.

 

[Kyla]

I don't think anyone is suggesting that low NK function causes fatigue directly. The low NK cell function might lead to immune problems that caused fatigue or immune problems might lead to both fatigue and low NK cell function, as Duncan suggest.

The difficulty right now is that the main people who reported this finding do not seem to be able to get the same result again, and nor do other people who have tried to repeat it. Some have and have published that but negative results rarely get published. The consensus from the researchers I have talked to is that this is not a consistent finding. And NK cell function is a very capricious thing to try and measure. Moreover, nobody is quite sure what it means in the standard assay because NK cells can tell if cells are yours or not and the assay uses somebody else's cells.

The review posted here suggests it IS a consistent if you account for diagnostic criteria. ie - that the negative findings are in studies using broader fatigue criteria and mild patients.

I thought the issues in terms of using it as a biomarker were:
1) that it is not specific to ME
2) that there aren't a lot of labs equipped to test for it
3) that the test needs to be run within a few hours of taking the blood

I am not trying to challenge your expertise @Jonathan Edwards , just confused as what you are saying seems to run counter to what I have read and been told.
I know a number of ME specialists consider this test as a useful biomarker and say they find it universally in their patients.

 

[gregh286]

I don't think anyone is suggesting that low NK function causes fatigue directly. The low NK cell function might lead to immune problems that caused fatigue or immune problems might lead to both fatigue and low NK cell function, as Duncan suggest.

The difficulty right now is that the main people who reported this finding do not seem to be able to get the same result again, and nor do other people who have tried to repeat it. Some have and have published that but negative results rarely get published. The consensus from the researchers I have talked to is that this is not a consistent finding. And NK cell function is a very capricious thing to try and measure. Moreover, nobody is quite sure what it means in the standard assay because NK cells can tell if cells are yours or not and the assay uses somebody else's cells.

Thanks Jonathan. Yes the fickleness of measurement certainly create difficulties in replication of results.

It appears limited studies have been done on presumably easier to measure nkc counts in cfs V control.

 

[Jonathan Edwards]

The review posted here suggests it IS a consistent if you account for diagnostic criteria. ie - that the negative findings are in studies using broader fatigue criteria and mild patients.

I thought the issues in terms of using it as a biomarker were:
1) that it is not specific to ME
2) that there aren't a lot of labs equipped to test for it
3) that the test needs to be run within a few hours of taking the blood

I am not trying to challenge your expertise @Jonathan Edwards , just confused as what you are saying seems to run counter to what I have read and been told.
I know a number of ME specialists consider this test as a useful biomarker and say they find it universally in their patients.

I tried to find out where this review comes from. The first author seems to be an oncologist in Philadelphia aged 70 who does not seem to figure in ME research as far as I know. The last author is the founder of Hemispherx. Hemispherx have a financial interest in there being faith in NKCC as relevant to ME. So they have a financial interest in writing what seems to be a balanced article on NKCC studies in ME that has a positive slant.

All I can say is that most of the major researchers I have met - at IiME meetings and elsewhere are doubtful that NK function is reproducibly different in ME. There was a study not so long ago in which one of the main proponents of this finding did not reproduce the finding. The problem is that it is no good just looking at published studies of NK function because negative studies will either not have been published or the NK findings will be just a line saying nothing was found in a paper focusing on something else.

This is really the whole point of setting up collaborative biobank projects now - to cross-check findings of this sort and come to some sort of agreed conclusion using blinded samples swapped between labs. If this were a finding that was found 'universally in patients' that would totally change the field of ME research overnight because it would mean that all people with ME had the same basis for their disease (something that very few people think likely) and with a consistent biomarker. The psychological theorists could be sent packing. This is just not the reality. I am afraid things do not add up.

The scientific community has an accepted mode of behaviour which is not to make a noise about inconsistent findings but rather just let them be forgotten. The problem with this finding is that nobody is sure whether or not it should be forgotten or taken seriously.

 

[duncan]

All the more reason a study utilizing a strictly defined cohort - ICC compliant? - to check the prevalence of low NK cell function levels in PWME would be a good enterprise.

 

[JohnnyD]

David Strayer is Hemisphx's Medical Director. I'm not sure what age 70 has to do with anything, you're not being discriminatory are you Jonathon? (just a little joke, I'm about retirement age myself)

"DAVID R. STRAYER, M.D. has acted as our Medical Director since 1986. He has served as Professor of Medicine at the Medical College of Pennsylvania and Hahnemann University from 1987 to 1998. Dr. Strayer is Board Certified in Medical Oncology and Internal Medicine with research interests in the fields of cancer and immune system disorders. He has served as principal investigator in studies funded by the Leukemia Society of America, the American Cancer Society, and the National Institutes of Health. Dr. Strayer attended the School of Medicine at the University of California at Los Angeles where he received his M.D. in 1972."

Hemispherx did a review of NK Cell function studies going back about 20 years, 17 papers I think and then did in-vitro studies on 15 patients who donated NK Cells and found that ampligen increased cell activity by 100%. I'm not aware of anyone trying to replicate ampligen's effect on NK activity.

The whole reason Hemishperx took a hard look at this is NK cell function is the primary marker that Dr. Peterson has been using for screening suitability to ampligen. Peterson claims 70% of his ampligen patients see significant improvement. A top, if not THE top, ME/CFS clinician and he has no financial interest in Hemispherx. From Cort's Simmaron blog:

"It’s one of the few drugs shown to increase NK cell activity. Dr. Peterson gave Ampligen a strong endorsement stating that it’s the only therapy he’s seen in his three decades of work that’s been able to return ME/CFS patients to full health. He gets about a 70% response rate (not all of which get such strong results.) - See more at: http://simmaronresearch.com/2015/11...tigue-syndrome-patients/#sthash.CuurcwEo.dpuf

Dr. Peterson distinguishes what he believes to be an archetypal ME/CFS patient from the others primarily by using one test – the natural killer (NK) cell functioning test. The International Consensus Criteria for ME considers post-exertional neuroimmune exhaustion or PENE to be the hallmark of ME and Dr. Hyde focuses on SPECT scans, but Peterson has found the NK cell functioning test to be the most definitive.

 

[Kyla]

I tried to find out where this review comes from. The first author seems to be an oncologist in Philadelphia aged 70 who does not seem to figure in ME research as far as I know. The last author is the founder of Hemispherx. Hemispherx have a financial interest in there being faith in NKCC as relevant to ME. So they have a financial interest in writing what seems to be a balanced article on NKCC studies in ME that has a positive slant.

All I can say is that most of the major researchers I have met - at IiME meetings and elsewhere are doubtful that NK function is reproducibly different in ME. There was a study not so long ago in which one of the main proponents of this finding did not reproduce the finding. The problem is that it is no good just looking at published studies of NK function because negative studies will either not have been published or the NK findings will be just a line saying nothing was found in a paper focusing on something else.

This is really the whole point of setting up collaborative biobank projects now - to cross-check findings of this sort and come to some sort of agreed conclusion using blinded samples swapped between labs. If this were a finding that was found 'universally in patients' that would totally change the field of ME research overnight because it would mean that all people with ME had the same basis for their disease (something that very few people think likely) and with a consistent biomarker. The psychological theorists could be sent packing. This is just not the reality. I am afraid things do not add up.

The scientific community has an accepted mode of behaviour which is not to make a noise about inconsistent findings but rather just let them be forgotten. The problem with this finding is that nobody is sure whether or not it should be forgotten or taken seriously.

Thanks for clarifying @Jonathan Edwards
I see what you are saying, but I agree with @duncan that this should mean all the more that someone should set up a proper study with strict diagnostic criteria (or comparisons between criteria), and controls (and maybe stratify the results by illness duration)

At some point this seems like circular reasoning to say that there are no consistent findings for 100% of patients but then also that the group is heterogenous and we don't know how to subgroup. If it was found to be consistent (and different from controls) even in a large subset of patients wouldn't that be a good way to identify a subgroup?

I know OMI considers this a marker, and one of their doctors has made public comments to that effect: "...virtually every patient has profoundly low natural killer cell function..."
http://forums.phoenixrising.me/inde...reatments-j-rehmeyer.35830/page-2#post-564197

Maybe it would be useful for iime to exchange info with OMI?

Nancy Klimas also considers it a biomarker.
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0010817
and i think there was some talk that the IOM report almost included it as one, but I can't remember where I read that at the moment.

Maybe these groups are seeing/selecting different patients, but that does seem like even more reason to find out if it is consistent and/or a subgroup.

 

[alex3619]

Why should low nkcc create a fatigue condition? Infection re-occurance?

This might be the wrong question. We do not know if its causal, a consequence, a parallel issue, or co-causal. It appears important, but exactly why still eludes us.

 

[heapsreal]

Any anatomy book will say that the job of nk cells is to kill cancer cells and viruses. So if nk function or numbers are low can increase our risk of cancers and chronic viral infections .

Griffith university(phanu) have done many studies reproducing their results show low nk function in cfsme compared to controls. A few years back they completed a study of cfsme vs controls over an 18 month period with testing at the beginning and then 6 monthly. Low nk function was a consistent finding but they were also testing nk bright and nk dim cells and found that cfsme patients had consistently lownk bright cell function .

Theres enough good studies showing low nk function in cfsme and should be a biomarker in diagnosing cfsme. Other markers could also be used to help diagnose cfsme.

 

[medfeb]

Nancy Klimas also considers it a biomarker.
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0010817
and i think there was some talk that the IOM report almost included it as one, but I can't remember where I read that at the moment.

The IOM report noted that

"Sufficient evidence supports the finding of immune dysfunction in ME/CFS (SEID). Specifi- cally, the committee’s literature search yielded data demonstrating poor NK cell cytotoxic- ity (NK cell function, not number) that correlates with illness severity in ME/CFS (SEID) patients and could serve as a biomarker for the severity of the disease, although it is not specific to ME/CFS (SEID)." ​

At an August CFSAC presentation on the IOM report, Dr. Klimas stated (from the CFSAC minutes)

"The evidence does show that natural killer (NK) cell dysfunction discriminates from normal very well. The evidence does not show, however, that the average doctor has access to the sophisticated type of testing required to measure NK cell function."

"Dr. Fletcher expressed disappointment over the lack of biomarkers in the case definition. Dr. Klimas said that NK cells came close to being designated as biomarkers because they stand out in the literature as the biomarker with the best evidence. The issue is that the laboratories to which most primary care physicians have access to do not perform the test well. As far as other biomarkers, more large-end studies are needed.
​

One of the main issues that I've heard is that because the test is of NK cell function, the speed with which the test is performed after the blood draw is critical. Most commercial labs are not set up to get the sample from draw to processing so quickly. I can imagine there are also other issues.

Dr. Ermias Belay of CDC told CFSAC "about the addition of a pilot study of NK cell function testing." (also from the August CFSAC minutes)

 

[heapsreal]

I'd say the studies that dont show low nk function in cfsme are probably done by the UK psychobabblers with some crap criteria which takes patients with multiple conditions other than cfsme . An attempt to discredit cfs biological research and keep it as a psych condition ? ?

 

[Gingergrrl]

My NK cell function done at OMI was 5 and six months later was 6. Have not tested it again and still not sure how it relates.

 

[heapsreal]

My NK cell function done at OMI was 5 and six months later was 6. Have not tested it again and still not sure how it relates.

What do they class as normal range for the testing? Im guessing each lab may have different reference ranges or different units of measurement .

Testing i had shows ranges from 13.8 to 34.8 as normal. Results i had was a 1, 6 and one test i had was 51 but i was on an interferon inducer at the time . During all these tests i also had nk bright cell testing which was low even when i had the high nk function. Nk bright cell range is 5 to 15 as normal. I had results of .93, 1, 1.95 and a 4.32.

What does it mean?
Nk cells aren't doing their job very well of killing cancer cells and viruses. Maybe other mechanisms in the immune system take over but its not normal. Maybe this is putting extra strain on the immune system???