Hornig/Lipkin cytokine study out now - press release

[RustyJ]

I wont know without doing some investigating. I suspect this might include biological drugs, that is things like antibodies, but there are lots of drugs that have been discussed over the years for this kind of thing. There are a wide range of cytokines involved, and this means we have many targets. With many targets comes many drugs, and potential drugs, and drugs overllooked by pharma because they didn't see a need for them.

If this study is replicated then you might see Pharma finally getting involved, but only for new or newer drugs. Repurposing old drugs will have to be researched with other funding.

Let me say again that this will probably require a drug combination, which may be why it has been so hard to find by chance. Also, the initial targets may be critical factors found in the cytokine network.

Whether this treatment will have any impact on long term patients is less certain. If immune exhaustion is the key then it might. If activated microglia is the key, then other treatments may be necessary, either on their own or in combination with the anti-cytokine treatments.

Suppressing cytokines may not work. Note, suppressed cytokine in later-stage patients and symptoms persist.

There is also the concern that there is a reason the cytokines are elevated, and by suppressing them, that agent may itself become more potent.

Another point to consider, I still have no colds or common infections after 25 years, so I am still in the early stage? I don't have any test results to support this, but it seems my cytokine profile may not have changed.

Do other later-stage patients still suffer from so-called cytokine storms (if that is what the 24hr attacks are)?

 

[adreno]

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.

The HPA might follow the same pattern as the cytokines - high activity in early stages followed by lower activity in later. Of course, leptin also inhibits the HPA, fitting the hypothesis of high leptin levels in advanced stages of ME/CFS.

 

[user9876]

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.

I keep thinking that scientific publishing should move on from the world of the printed page and instead provide data on web pages with appropriate (html 5 -d3) gadgets to allow the reader to view data in different ways. There can be a default for the printed page. But if we are talking about sharing data for others to understand these days we should be able to do so much better than static diagrams.

 

[user9876]

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.

I have seen people use small histograms for each bar in another histogram for the type of case used in this paper. In your example ideas of bi modal distributions would still be hidden.

 

[lansbergen]

Or does the cytokine reaction subside because an impasse is reached or the infection is driven into latency?

The immune system is complex. If one strategy leads to impasse it tries something else.

 

[Simon]

Only one out of the 51 immune proteins studied was elevated in all cases compared with controls, something that could happen by chance alone.

I didn't see the reference in the paper about all cases being higher than controls, but presume this applies to IFN-gamma in short duration cases.

But according to my maths, the chances of any one cytokine being higher in cases than controls (assume for the 52 short duration, and compared with matched controls) are:
0.5^52 x 51=1 x 10^-14 - or one in 100,000 billion
Maybe someone could check my maths but it looks like Peter White's 'chance alone' comment is a little off.

 

[Simon]

What does the study mean?
More detal later but I thought I'd highlight what the authors concluded:

Discussion

The presence of a specific immune profile early in the course of ME/CFS has important implications for the diagnostic process.

First, we were able to define a distinctive immune signature that differed from that of healthy controls. Integration of these immune markers with clinical findings will provide clinicians with a stronger framework for establishing an ME/CFS diagnosis, and, possibly, make it easier to rule out other conditions at an earlier time point...

Second, the restriction of this pattern of immune disturbances to short-duration as opposed to long-duration cases suggests that both the dysregulation of immune cell interactions (for example, faulty CD40L signaling leading to impaired T and B cell interactions) and the opportunities for intervention may be transient. Therapeutic strategies that specifically target abnormalities found in these early immune profiles may present novel but time-limited opportunities not only for remediation but potentially also for staving off the long-term, chronic decline associated with ME/CFS.

Prospective analyses that establish the diagnosis of ME/CFS at an early or incipient stage and follow the trajectory of immune responses over the course of illness are required to elucidate the clinical significance of these findings.

Delineation of immune profiles in well-characterized subjects with ME/CFS, both early and late in the course of illness, as we have presented here, provides a unique tool for the establishment of clinically relevant phenotypes and discovery of novel treatment targets.

If replicated in longitudinal studies, these data may provide a basis for early immunomodulatory intervention to prevent long-term, recalcitrant illness.

 

[Bob]

I keep thinking that scientific publishing should move on from the world of the printed page and instead provide data on web pages with appropriate (html 5 -d3) gadgets to allow the reader to view data in different ways. There can be a default for the printed page. But if we are talking about sharing data for others to understand these days we should be able to do so much better than static diagrams.

You might be interested in this...

Researchers: it's time to ditch the PDF
The PDF makes reading science research even more difficult and prevents a two-way conversation from taking place
11 February 2015
http://www.theguardian.com/higher-e.../feb/11/researchers-its-time-to-ditch-the-pdf

 

[user9876]

Suppressing cytokines may not work. Note, suppressed cytokine in later-stage patients and symptoms persist.

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.

 

[Bob]

"Only one out of the 51 immune proteins studied was elevated in all cases compared with controls, something that could happen by chance alone."

Maybe someone could check my maths but it looks like Peter White's 'chance alone' comment is a little off.

Yes, I noticed that as well. I wouldn't know how to do the maths but I'd imagine that those results suggest the opposite of what Peter White has claimed re "chance alone". It seems like a potentially significant result to me. Although, I suppose if we are to consider the potential heterogeneity of the cohort then perhaps it's not such a significant result as it first appears.

 

[RustyJ]

I have read some reports of higher rates of 'recovery' in the first 3-4 years. One came out of South Australia more than 15 years ago, from memory. After 3-4 years rates fell away quite dramatically in the that survey. It is odd that for all the money spent on epidemiological studies that this point was confirmed. It would have helped cohort selection decades ago.

 

[Daisymay]

Following the supposedly impartial SMC briefing of Hornig et al results it is timely to draw attention to Professor Malcolm Hooper's article of September 2013, "The Role of the Science Media Centre and the Insurance Industry in ME/CFS: the facts behind the fiction" http://tinyurl.com/ppxyl9y

 

[RustyJ]

I didn't see the reference in the paper about all cases being higher than controls, but presume this applies to IFN-gamma.

But according to my maths, the chances of any one cytokine being higher in cases than controls (assume for the 52 short duration, and compared with matched controls) are:
0.5^52 x 50=1 x 10^-14 - or one in 100,000 billion
Maybe someone could check my maths but it looks like Peter White's 'chance alone' comment is a little off.

I think he's applying the PACE rule here.

 

[RustyJ]

Following the supposedly impartial SMC briefing of Hornig et al results it is timely to draw attention to Professor Malcolm Hooper's article of September 2013, "The Role of the Science Media Centre and the Insurance Industry in ME/CFS: the facts behind the fiction" http://tinyurl.com/ppxyl9y

It seems like the SMC response was a little panicked. I really think they overplayed their hand.

 

[user9876]

Yes, I noticed that as well. I wouldn't know how to do the maths but I'd imagine that those results suggest the opposite of what Peter White has claimed re "chance alone". It seems like a potentially significant result to me. Although, I suppose if we are to consider the potential heterogeneity of the cohort then perhaps it's not such a significant result as it first appears.

Given White's ignorance of stats demonstrated in his PACE write ups I wouldn't trust his comments.

Don't any such calculations assume something about the underlying distributions of cytokines? Of course if you assume a normal distribution then there is a "chance alone" that someone will have a negative number of cytokines!

 

[wdb]

Peter White - Only one out of the 51 immune proteins studied was elevated in all cases compared with controls, something that could happen by chance alone.

I'd like to know if there is even one measure used on the PACE trial for which every single case was elevated compared with controls. I bet there isn't

 

[user9876]

Given most studies collect data on duration of illness I wonder if it would be possible for those who have done previous cytokine studies to reinterpret them in light of this work?

My guess is that none of the data is publicly accessible?

 

[aimossy]

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.

@Jonathan Edwards

I'm trying to understand. So a couple of these cytokines are high enough to reflect that some physiological problem is definitely going on somewhere in the body and these cytokine results in short duration do reflect this quite clearly? So even though the cytokines themselves are not at levels to cause symptoms ( I read that they don't correlate with symptoms) these findings are adequately reflective of something going on biologically elsewhere to make this very significant? Any chance you could give a 101 how we know these could reflect that something else is happening. I'm trying to understand how the difference between short duration and healthy controls is enough to show this to doctors and researchers.

I had thought that the increase compared to controls in short duration and then the drop in long duration was also significant. Do you think this paper will be taken notice of really seriously in the medical community?

 

[RustyJ]

Anyone find it ironic that this study would never have happened if it weren't for XMRV. Or the further irony that it took private funding.

Since these findings were known then, why has it taken so long for this to get published?

 

[alex3619]

Suppressing cytokines may not work. Note, suppressed cytokine in later-stage patients and symptoms persist.

This is about playing a tune. Not just suppression. We might actually want to enhance some cytokines. That tune might have to be modified as we improve.

If some other cause is involved then suppression will fail, that I do not disagree, though it might modify symptoms. However if its immune exhaustion then the right cytokine pattern might break any self reinforcing seppoint. This is potentially valid in either stage of the disease, what separates them, in a simple interpretation, is the immune exhaustion.

All this remains speculation of course. We need a lot more research. Viral or autoimmune causes may require other additional treatments.