Hornig/Lipkin cytokine study out now - press release

[Sasha]

I really hope that the NIH/HHS gets an ear full about not funding the "Microbiome Study" and wasting funding on some of the other useless studies that were funded. Hopefully, the NIH will get their head out of their posterior orifice fund the microbiome study.

I think we need to be organising around this issue of funding and bombarding the NIH now with calls to increase their funding to ME/CFS research. Great time to do it!

 

[alex3619]

Lets not forget that this study confirmed, yet again, that interferon gamma was critical, with an odds ration of 104. Thats HUGE.

This is calculated in Table 2, with the following description:

Table 2. Final logistic regression model for association of plasma
cytokines and covariates with short-duration versus long-duration
ME/CFS.

Variable OR 95% CI P
IFNg 104.777 6.975–1574.021 0.001

 

[Forbin]

The hit-and-run scenario is mentioned in the release from Columbia below, so I assume it is sourced from the researchers.

The study supports the idea that ME/CFS may reflect an infectious “hit-and-run” event.
http://www.mailman.columbia.edu/new...e-chronic-fatigue-syndrome-biological-illness

Could it be that the "hit-and-run" aspect is inferred from not seeing any pathogens "run wild" at the 3 year point when the immune system becomes "exhausted?"

 

[msf]

I think you will find that it was editorializing, if the researchers had said it they would have used a quote. If you read the paper they talk about how chronic infection with HIV and HCV results in a similar pattern of cytokine exhaustion.

 

[Jonathan Edwards]

Just to be clear, you are saying that the modest changes in cytokine levels are likely to be biologically significant, as well as statistically significant? (Though the mean changes might be masking much bigger changes for substantial numbers of individuals).

I think they are likely to be biologically significant in the sense that these mean or median figure are likely to represent some sort of biological signalling relevant to the disease and therefore they reflect a real biological phenomenon. But, as you realise, that does not imply that these cytokines are themselves likely to be responsible for any symptoms. I personally think it is pretty unlikely that we are looking at the specific cause of symptoms here - and so I am completely unsurprised that PWME go on having symptoms while the cytokine levels go back to normal or below.

Perhaps more relevant to your question is that clearly it is likely that the raised median levels in the early group arise from a whole lot of fairly normal levels and a few rather high ones. So I am interpolating from the data that some individuals may have double or triple the normal level at least - which might be what one would expect from biologically significant in the individual case. So we have to think subsets, but we were already doing that. And so the data have the right 'look' to me on the basis of a guesstimate of dilution by normal levels.

What I have to say I am disappointed by is the fashion for presenting data like this as histograms with standard error bars (since these are not Gaussian populations I am not sure error bars are even sensible). I have never been able to get the feel from error bars as to what variation they imply. In my own lab I do not allow people to show me histograms of data like this. I need to see the individual results as data points so that I can see the shape of the scatter. When we are thinking subpopulations that seems to me crucial because we might see bimodality straight off.

 

[Sasha]

What I have to say I am disappointed by is the fashion for presenting data like this as histograms with standard error bars (since these are not Gaussian populations I am not sure error bars are even sensible). I have never been able to get the feel from error bars as to what variation they imply. In my own lab I do not allow people to show me histograms of data like this. I need to see the individual results as data points so that I can see the shape of the scatter. When we are thinking subpopulations that seems to me crucial because we might see bimodality straight off.

I've heard you say that before and it's very interesting. Perhaps it should be set as the new norm for displaying ME/CFS data. Do you think it worth your contacting Dr Hornig and Dr Lipkin, or maybe disseminating this idea some other way? It sounds like a powerful technique for thinking about subsetting and that's going to be crucial for us.

 

[Simon]

I think they are likely to be biologically significant in the sense that these mean or median figure are likely to represent some sort of biological signalling relevant to the disease and therefore they reflect a real biological phenomenon

Perhaps more relevant to your question is that clearly it is likely that the raised median levels in the early group arise from a whole lot of fairly normal levels and a few rather high ones. So I am interpolating from the data that some individuals may have double or triple the normal level at least - which might be what one would expect from biologically significant in the individual case. So we have to think subsets, but we were already doing that. And so the data have the right 'look' to me on the basis of a guesstimate of dilution by normal levels

Thanks. So average results not per se very exciting but the implicit high ones are?

What I have to say I am disappointed by is the fashion for presenting data like this as histograms with standard error bars (since these are not Gaussian populations I am not sure error bars are even sensible). I have never been able to get the feel from error bars as to what variation they imply. In my own lab I do not allow people to show me histograms of data like this

Yes, I much prefer seeing the data too (see this example), but the stats section did say the data was log-transformed and was then normal - though not sure that fully justifies the approach, out of my depth here.

 

[A.B.]

Perhaps more relevant to your question is that clearly it is likely that the raised median levels in the early group arise from a whole lot of fairly normal levels and a few rather high ones.

Is it possible to discard the hypothesis that the time point of immune exhaustion varies widely? The fast and slow patients would cancel each other out for the most part.

PS: I'm asking because it seems to be common for patients to report either get less infections than normal, or to get more infections than normal, and there are reports of patients switching from the former to the latter at some point (even many years in) in their illness

 

[bertiedog]

Although CD57, a marker of premature immune senescence that is found to increase in later phases of some chronic viral infections such as HIV (44) or hepatitis C virus (HCV) (45), has been shown to be decreased in previous work in ME/CFS (46, 47), studies that control for duration of illness may provide additional clarity as to the potential contribution of mechanisms of immune exhaustion to the immune changes observed later in the course of ME/CFS.

My CD57 cells last year were 67 which was well below the reference range of 130-360. (I also got a diagnosis of Late Stage Lyme Disease) and I have been sick for 20 years or more.

Pam

 

[charles shepherd]

They were set up in the UK for the media to be able to approach scientific experts for quotes and explanations re scientific issues. There is a lot of controversy surrounding them generally as they tend to promote an establishment view of science rather than a range of informed views. But in terms of ME/CFS they were responsible for promoting misinformation in relation to the PACE trial which led, for example, to media headlines suggesting that 30% of patients 'recovered' after exercise etc. They promote the PACE trial literature from the point of view of the psych-lobby.

I was very surprised and concerned to find that this list of quotes on an item of quite complex immune function research had failed to include a single comment from a UK immunologist who is carrying out immune system research involving ME/CFS, or has an expert interest in the immunology of ME/CFS - such as Professor Jonathan Edwards at UCL.

Yet it did include three quotes from psychiatrists.

There are, in fact, a number of immunologists carrying out immune function research involving ME/CFS here in the UK - examples include Dr Amolak Bansal (funded by MEA Ramsay Research Fund), Professor Stephen Todryk (funded by AfME and MEA Ramsay Research Fund) and the NIH funded study currently taking place at the ME Biobank (funded by AfME, MEA Ramsay Research Fund,MERUK and a private MEA donor).

I will therefore be writing to the SMC to express my continuing concerns about the way in which they are presenting ME/CFS research study findings to the UK media.

Dr Charles Shepherd
Hon Medical Adviser, MEA

 

[charles shepherd]

I was very surprised and concerned to find that this list of quotes on an item of quite complex immune function research had failed to include a single comment from a UK immunologist who is carrying out immune system research involving ME/CFS, or has an expert interest in the immunology of ME/CFS - such as Professor Jonathan Edwards at UCL.

Yet it did include three quotes from psychiatrists.

There are, in fact, a number of immunologists carrying out immune function research involving ME/CFS here in the UK - examples include Dr Amolak Bansal (funded by MEA Ramsay Research Fund), Professor Stephen Todryk (funded by AfME and MEA Ramsay Research Fund) and the NIH funded study currently taking place at the ME Biobank (funded by AfME, MEA Ramsay Research Fund,MERUK and a private MEA donor).

I will therefore be writing to the SMC to express my continuing concerns about the way in which they are presenting ME/CFS research study findings to the UK media.

Dr Charles Shepherd
Hon Medical Adviser, MEA

UK BBC coverage today:

http://www.bbc.co.uk/news/health-31644618

 

[Marco]

It's worth bearing in mind also that buried amongst these averaged findings will be PWME whose illness didn't follow from a viral infection.

It's also clear (to me anyway) that the post 3 year findings suggest that the immune pattern seen prior to that are not necessary to sustain the symptoms. Stating the obvious of course but it does all point to the glial hypothesis. I don't see 'immune exhaustion' as a likely explanation for the change in pattern.

 

[Scarecrow]

They don't refer to the early immune profile as dysfunctional though do they? Is there any evidence that this profile is actually dysfunctional? The elevated cytokines found in the early immune profile are most of the ones you would expect to see in response to a viral infection. I would argue that the late immune profile is dysfunctional however. Not being able to produce the same cytokine levels as a healthy person is a clear dysfunction.

They say:

Network diagrams of intercytokine correlations revealed unusual regulatory relationships among cytokines in the short-duration ME/CFS group that were not apparent in either the long-duration case group or healthy controls

 

[Scarecrow]

So it's a small study, despite the fact that it's the largest study ever done in ME? Are psychiatrists ever tempted to live in the real world?

Well, not quite the largest. But definitely the largest one with any credibility.

 

[wdb]

What I have to say I am disappointed by is the fashion for presenting data like this as histograms with standard error bars (since these are not Gaussian populations I am not sure error bars are even sensible). I have never been able to get the feel from error bars as to what variation they imply. In my own lab I do not allow people to show me histograms of data like this. I need to see the individual results as data points so that I can see the shape of the scatter. When we are thinking subpopulations that seems to me crucial because we might see bimodality straight off.

Scatter charts sound like they could be very interesting, presumably they already have all the data they would need to do a scatter of level vs years ill. Do you think there is any possibility they could be persuaded to produce these or even release the raw data so that others could ?

 

[Gijs]

Of course P. White et al. has a conflict of interest in these new findings. It appears that ME/CFS patients are flush with cytokines until around the three-year mark, at which point the immune system shows evidence of exhaustion and cytokine levels drop,” says Dr. Hornig.

If this hold up White et al. are responsable for damaging patiënts with CBT and GET! Also they are responsable for mental abuse!

 

[August59]

It's worth bearing in mind also that buried amongst these averaged findings will be PWME whose illness didn't follow from a viral infection.

It's also clear (to me anyway) that the post 3 year findings suggest that the immune pattern seen prior to that are not necessary to sustain the symptoms. Stating the obvious of course but it does all point to the glial hypothesis. I don't see 'immune exhaustion' as a likely explanation for the change in pattern.

I think the phrase "immune exhaustion" (probably not the best phrase to use) still represents immune dysfunction. This dysfunction IMO will eventually be linked to "Gut Dysbiosis", since the majority of the immune system is located in the gut, "CNS" abnormality and/or both.

I'm not sure if the HPA axis dysfunction is more prevalent in early stage or late stage, but for me it was late stage (around the 4 year mark) and it went all to hell. Cognitive impairment became much worse at this time as well and bringing almost all the hormones back within normal levels had very little impact. Cortical rhythm is still off, therefore so is my sleep (which is why it is 6 am and it will be bedtime in an hour).

The microbiome study needs to be funded now!

 

[August59]

PS: I'm asking because it seems to be common for patients to report either get less infections than normal, or to get more infections than normal, and there are reports of patients switching from the former to the latter at some point (even many years in) in their illness

This is the one thing that has baffled me! Since I became ill in 2005 I have not had a cold, flu, respiratory infection, sinus infection, fever blister or even a fever since then. My EBV EA, VCA and EBNA titres were all very high along with HHV6. How long they had been elevated or if they are still elevated I have know idea as I can't get any doctor to even do the test again. Can't afford to back to a ME/CFS doctor, nor travel to go to one!

 

[Valentijn]

But, as you realise, that does not imply that these cytokines are themselves likely to be responsible for any symptoms. I personally think it is pretty unlikely that we are looking at the specific cause of symptoms here - and so I am completely unsurprised that PWME go on having symptoms while the cytokine levels go back to normal or below.

Hence we could be having some underlying dysfunction, which directly creates some symptoms plus directly triggers some cytokine responses, which in turn generate some additional indirect symptoms.

Hypothetically, at some point our immune system (or part of it) then hoists the white flag to surrender, and goes off somewhere for a long nap. At that point those cytokines drop again, and the symptoms generated by the cytokines recede. But the symptoms directly caused by the underlying dysfunction remain, because the underlying dysfunction remains.

Additionally, perhaps certain physiological stressors such as normal infections or exertion could continue to nudge the napping immune system back into action from time to time, triggering relapses or shifts in symptoms.

Does any of this sound like a plausible explanation? If so, what sort of mechanism would be capable of creating this sort of situation? Auto-immunity doesn't seem likely - that doesn't take a break after a few years. On-going infection would allow for the cytokine symptoms to be replaced or superceded by symptoms of the infection itself (assuming there are any) - but it would have to be a relatively benign infection to not do more obvious harm when unchecked by the immune system. Or does the cytokine reaction subside because an impasse is reached or the infection is driven into latency?

Lots of interesting possibilities, but I know bugger-all about the immune system

 

[Bob]

Lipkin is interested in the hit-and-run theory. I assume this is because he's a pathogen hunter and he's been unable to detect any convincing patterns of pathogens, so far, that he would usually expect to see in an infectious disease.

All it means is that there is a microbial trigger for the illness. i.e. Perhaps a pathogen (or a variety of pathogens) is involved in triggering the illness, but it becomes undetectable after initial infection, but leaves a lasting biological effect?

I suppose this could also be the case for many other diseases with unknown cause (e.g. Parkinson's, MS, Alzheimer's, schizophrenia.) We simply don't know what mechanism triggers or drives the illness, so it seems sensible to entertain various concepts.

I'm convinced that Lipkin is open minded and wishes to carry out a comprehensive investigation into ME, and will follow any research leads. He's not dogmatic, so he's not just pursuing one specific theory, as far as I understand.

Part of the reason that he's looking at the gut microbiome is because he's not found any pathogens in the blood plasma or cerebro spinal fluid. (He's detected a couple of viruses but there was no difference between patients and controls.)

He's also looking for pathogens in blood cells.

Basically, he's covering it from all angles and the hit-and-run theory is one of those angles.

He's looking for viruses, bacteria and fungi in the gut microbiome. Something unexpected might turn up. And he's also looking at immune markers in the same patients (e.g. cytokines) to see if any changes in the gut correspond to changes in cytokine levels. He's done similar research for autism, and has uncovered some leads.

And he plans to do a proteome study of CFS patients, which may prove to be very interesting. (I think Dr Hornig may have started this already). And there's more that he's either planning, or has already started, but I'm hopeless at remembering it all. And I get the feeling that he's only told us a fraction of what he's up to.