Hornig/Lipkin cytokine study out now - press release

[MeSci]

Hopefully, the NIH will get their head out of their posterior orifice and fund the microbiome study.

Out of theirs and into ours!

We need a method of extending our gratitude to the authors of the study!

A sincere "Thank You" to The Hutchin's Family Foundation for making this study possible! Anyone know the best way to do this?

There was a thread about this, and groups set up here, but they seem to have fizzled out.

 

[Sidereal]

Twenty-four studies involving unstimulated measurements of cytokines in patients meeting DSM criteria for major depression were included in the meta-analysis; 13 for tumor necrosis factor (TNF)-α, 9 for interleukin (IL)-1β, 16 for IL-6, 5 for IL-4, 5 for IL-2, 4 for IL-8, 6 for IL-10, and 4 for interferon (IFN)-γ. There were significantly higher concentrations of TNF-α (p < .00001), weighted mean difference (WMD) (95% confidence interval) 3.97 pg/mL (2.24 to 5.71), in depressed subjects compared with control subjects (438 depressed/350 nondepressed). Also, IL-6 concentrations were significantly higher (p < .00001) in depressed subjects compared with control subjects (492 depressed/400 nondepressed) with an overall WMD of 1.78 pg/mL (1.23 to 2.33). There were no significant differences among depressed and nondepressed subjects for the other cytokines studied.

http://www.ncbi.nlm.nih.gov/pubmed/20015486

 

[Sasha]

Out of theirs and into ours!

 

[Sasha]

We need a method of extending our gratitude to the authors of the study!

A sincere "Thank You" to The Hutchin's Family Foundation for making this study possible! Anyone know the best way to do this?

There was a thread about this, and groups set up here, but they seem to have fizzled out.

I hesitate to suggest it after what just happened to our IOM card (let's not go there!) but an e-card from http://www.groupcard.com/ would be a brilliant thing to do for them. It's the very least we could do. And noncontroversial! What's not to like about this study?

Want to set one up, @August59 ?

Nice little feelgood project.

 

[user9876]

Re : what is going on later? Possibly not much of anything in respect of peripheral immune dysregulation. If, as mentioned by @Simon the cohort was 'enriched' by those from the XMRV study (selected as having viral onset) it's possible that the post 3 year pattern is actually more representative. As per the Dubbo studies, post viral cases may have an exaggerated and possibly prolonged immune response that does though eventually settle down.

It would be interesting to know how the XMRV cohort breaks down on the pre and post 3 year immune patterns. I'd also be curious to know if they'd received any treatments aimed at the presumed viral infection.

Does the pattern of transition over the 3 year barrier matter or signify something. Looking at table S7 in the supplementary material there is some correlation between illness duration and various cytokines but it is not that great. This leaves me wondering if the transition is gradual and linearish with duration or if it follows more of a logistic type pattern with a phase change around the 3 year mark. A scatter plot of duration vs the cytokine levels would be good.

But I guess my real question is would the form of that transition give a hint as to what is happening. For example, if the immune system was exhausted (whatever that means) would we expect one transition pattern vs some wider changes in the overall disease mechanism and cycle?

From a statistical perspective I also wonder about the sensitivity of the results to the 3 year threshold.

 

[Marco]

@user9876

Thanks. I hadn't noticed the supplmentary material.

All good questions and there isn't a lot of detail presented to dig much further but the fact that they use a Spearman rank order correlation to determine how the various cytokine levels co-vary with illness duration suggests to me that, for the highly significant results, they must have shown a more linear declining trend with duration (with two exceptions) rather than a step change at 3 years (otherwise a step change at 3 years followed by a flat pattern should yield a weak correlation between levels and illness duration).

 

[MeSci]

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?

I think that autoimmunity could switch off after a few years, if the cause goes away, e.g. due to treatment, pacing, resting, etc. The immune cells from which autoantibodies ultimately arise have a variable lifespan, which I think could be a couple of years. @Jonathan Edwards explained this in another thread; maybe he has already re-explained it here - I am still trying to catch up!

I used to get apparent early signs of infection - e.g. flu - early in my ME - and, like some other people, actually felt great at such times. It was as though the infection distracted my body from attacking me! Now I don't seem to get any such infections. But it can be so hard to tell, as PEM can be so similar to flu, etc.

 

[Bob]

..if I mentioned 'cytokines' to my GP, she would roll her eyes and sigh.

I think that's even worse than the blank stare.

 

[Bob]

I used to get apparent early signs of infection - e.g. flu - early in my ME - and, like some other people, actually felt great at such times. It was as though the infection distracted my body from attacking me! Now I don't seem to get any such infections. But it can be so hard to tell, as PEM can be so similar to flu, etc.

I've had that in an acute stage as well, after a major relapse. My symptoms were rapidly fluctuating between obvious infection symptoms (e.g. temperature, sweating, no appetite) and the ME symptoms. It's actually impossible to explain the difference because, although there was a clear difference in the subjective experience, when attempting to explain the symptoms in each phase, they appear to be almost the same. But the fact that the ME symptoms were turning themselves on and off rapidly, suggests that it could be straightforward to switch off ME symptoms, at least in a subset of cases, if only we understood the mechanism. Or perhaps this may only apply to the early/acute phases of the illness.

 

[Sidereal]

I used to get apparent early signs of infection - e.g. flu - early in my ME - and, like some other people, actually felt great at such times. It was as though the infection distracted my body from attacking me! Now I don't seem to get any such infections. But it can be so hard to tell, as PEM can be so similar to flu, etc.

Same here. Back when I was still getting infections I felt much better in the initial stages of an infection. Although symptoms of sickness behaviour and ME sound the same on paper, they seem to almost cancel each other out in my case.

 

[MeSci]

Are there symptom changes and different phases to the illness or are symptoms constant? Within this question it may be that a lot of symptoms are constant but some change. I've noted that people do talk about different symptoms when they are first ill or perhaps more varied symptoms that settle into more of a pattern but then occasional changes.

I also wonder about people who have a gradual onset where symptoms are initially occasional after a particularly busy time but then something like a virus triggers a much worse state where symptoms are much more severe and there all the time.

One thing I wonder about the 3 year thing is it a gradual change over time with a crossing point at 3 years or is it more of a phase change around the 3 year mark. I noted they said:

For cytokines that differed between short- and long-duration groups, levels were correlated with duration of illness, and in the expected direction: inverse correlations with duration of illness for cytokines that were increased in the short-duration group, and positive correlations for the two cytokines with reduced levels in the short-duration group (CD40L and PDGFBB) (table S7).

But I wasn't sure if that meant correlation by duration within each of the groups or whether it was across the groups.

I had a few symptoms in early illness that disappeared later, and some that appeared later, but most have been fairly constant.

I can definitely relate to this:

"I also wonder about people who have a gradual onset where symptoms are initially occasional after a particularly busy time but then something like a virus triggers a much worse state where symptoms are much more severe and there all the time."

It has occurred to me that the findings from the study could actually help us to pinpoint the start of the illness 'proper'. But for that to happen, everyone would have to have a cytokine profile done say, once a year, even if they haven't observed any obvious signs of illness, as occasional symptoms tend to be brushed aside and forgotten by busy people.

 

[alex3619]

But the fact that the ME symptoms were turning themselves on and off rapidly, suggests that it could be straightforward to quickly switch off ME symptoms, at least in a subset of cases, if only we understood the mechanism.

That is what has been giving me hope for many many years. However its likely the mechanism is a network of things, and what we see as symptoms is the outcome of a complex interplay of factors, a symphony of disharmony if you will. What notes will play counterpoint to that, and how rapidly will they need to change?

We need a static core pattern to attack. We are not really there yet.

 

[A.B.]

I also wonder about people who have a gradual onset where symptoms are initially occasional after a particularly busy time but then something like a virus triggers a much worse state where symptoms are much more severe and there all the time.

I think there may still be an infection involved in gradual onset cases. My mother had an infectious onset CFS that eventually resolved, even though she never fully regained her energy. I was infected by her shortly afterwards, but it cleared without complications. A few years later I had gradual onset CFS without apparent cause. I had actually forgotten about this co-infection and was only reminded of it today. Somewhere between this and the onset I also had a hepatitis B vaccination.

 

[Bob]

It has occurred to me that the findings from the study could actually help us to pinpoint the start of the illness 'proper'. But for that to happen, everyone would have to have a cytokine profile done say, once a year, even if they haven't observed any obvious signs of illness, as occasional symptoms tend to be brushed aside and forgotten by busy people.

Someone, somewhere, is doing a longitudinal study on a large number of healthy students to see what immune changes occur when they first get ill. But I can't remember the details. It's it Montoya perhaps? Edit: it's Lenny Jason. (Thanks @Scarecrow)

 

[Bob]

I think there may still be an infection involved in gradual onset cases. My mother had an infectious onset CFS that eventually resolved, even though she never fully regained her energy. Just today I learned that I was infected by the same thing (I had forgotten because it seemed harmless), but didn't develop CFS until a few years later. Maybe it wasn't the Hep B vaccine after all.

I think it's Byron Hyde who says that gradual onset is actually usually sudden onset but the patient isn't aware of when they first became ill. e.g. when carefully studying the case history, he can usually identify an infection whereby problems started however subtle the symptoms were at the time. Sometimes the infection can be during childhood, with some resulting mild or short-lived ME-like symptoms, but full-blown ME doesn't become apparent until adulthood.

As an alternative possibility, I think that Jonathan Edwards has said that an initial infection might be a red herring e.g. that the patient is unaware that they are already ill with ME (i.e. with no obvious symptoms) when they get the (apparently) precipitating infection. The precipitating infection provokes/amplifies the existing (but previously hidden) ME, such that the ME symptoms suddenly become apparent. (I might be putting words into Jonathan Edwards' mouth - hopefully he'll correct me if I am.)

In both these scenarios, there may be no meaningful distinction between (apparent) gradual or sudden onset ME.

 

[Scarecrow]

It's it Montoya perhaps?

Leonard Jason.

 

[Scarecrow]

I think it's Byron Hyde who says that gradual onset is actually usually sudden onset but the patient isn't aware of when they first became ill. e.g. when carefully studying the case history, he can identify an infection whereby problems started however subtlety. As an alternative possibility, I think that Jonathan Edwards has said that initial infection might be a red herring e.g. that the patient is already ill when they get the apparently precipitating infection, and the infection provokes the existing illness such that the symptoms suddenly become apparent. In both these scenarios, there may be no meaningful distinction between (apparent) gradual or sudden onset.

Both scenarios seem to apply to me. The Jonathan Edwards scenario followed Byron Hyde, except that obviously the second scenario wasn't totally 'out of the blue'.

 

[Bob]

Dr Hornig has said that they have already embarked on a longitudinal study for a subset of the patients in this study, following them over the course of a year or more, to watch the changes in the immune system. I don't know any further details. It could be interesting.

 

[msf]

Monkey pox? Just kidding, I assume you mean Lyme. This is pure speculation, but when I googled Lyme and CD40L I found this paper:

http://www.ncbi.nlm.nih.gov/pubmed/8683101

From what I can get from it, it seems to suggest that the immune response to Lyme does not involve CD40L. This seems to be unusual.

So this might possibly fit the bill for the early stage of the illness, where CD40L didn't correlate with the other cytokines, but it doesn't seem likely to for the late stage, where CD40L apparently did correlate with the other cytokines. Of course, the Lyme study was done in acute disease, so it would be interesting if they found did the same study in late-stage Lyme.

As I said, this is complete speculation from a layman, these issues seem to be too complex for most doctors to get a handle on, never mind the patients.

 

[cigana]

Monkey pox? Just kidding, I assume you mean Lyme. This is pure speculation, but when I googled Lyme and CD40L I found this paper:

http://www.ncbi.nlm.nih.gov/pubmed/8683101

From what I can get from it, it seems to suggest that the immune response to Lyme does not involve CD40L. This seems to be unusual.

As I said, this is complete speculation from a layman, these issues seem to be too complex for most doctors to get a handle on, never mind the patients.

Also complete speculation, but it's interesting that IFN-gamma is particularly raised in the acute phase of Lyme http://www.ncbi.nlm.nih.gov/pmc/articles/PMC201073/