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Carmine Pariante's MRC research award-Persistent fatigue induced by interferon-alpha
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New MRC info on this study
This study is not as originally described. It is still looking at fatigue in Hepatitis C Virus (HCV) patients treated with Interferon-alpha (IFN-alpha) but instead of looking at the fatigue during treatment, it's actually looking at post-treatment fatigue, which makes it a particularly interesting model for post-infectious CFS.
Certainly this ties in with the Dubbos study and theory of an initial cytokine stimulus provoking long-term fatigue.
Perhaps unsurprisingly given the study is based at Kings', they will be looking at psychological risk factors for fatigue too:
As before, this is not studying CFS directly but it could prove an intersting model, that would then need validating in CFS patients. One of the strengths of this approach is that they can collect prospective data on HCV patients pre-IFN-induced-fatige. However, the equivalent data for CFS patients can't be collected in the same way as they are already ill and fatigued so the comparison won't be direct.
Just to expand on the link with ME: They will also be looking at cortisol, another favourite of King's College researchers.
This study is not as originally described. It is still looking at fatigue in Hepatitis C Virus (HCV) patients treated with Interferon-alpha (IFN-alpha) but instead of looking at the fatigue during treatment, it's actually looking at post-treatment fatigue, which makes it a particularly interesting model for post-infectious CFS.
Certainly this ties in with the Dubbos study and theory of an initial cytokine stimulus provoking long-term fatigue.
Perhaps unsurprisingly given the study is based at Kings', they will be looking at psychological risk factors for fatigue too:
As before, this is not studying CFS directly but it could prove an intersting model, that would then need validating in CFS patients. One of the strengths of this approach is that they can collect prospective data on HCV patients pre-IFN-induced-fatige. However, the equivalent data for CFS patients can't be collected in the same way as they are already ill and fatigued so the comparison won't be direct.
Just to expand on the link with ME: They will also be looking at cortisol, another favourite of King's College researchers.
Best to use a new window, too, if the goal is to avoid attracting attention (as we figure they are here anyway, I'm not sure there's a point to this, but it could have value). Some web tracking programs allow one to see the last page a visitor was on prior to arriving at one's own page, even if not following a direct link.
Thanks oceanblue. This is interesting to me because my husband is starting a treatment trial at Kings with pegalated interferon and telaprovir for his Hep C in 2 days time. He had interferon (not pegalated) treatment 20 years ago but it failed to deal with the virus. Four years ago his liver failed and he was lucky enough to have a successful transplant, but of course the virus is now attacking his new liver.
The trial he is on is for patients who've had transplants. Treatment for them is more complicated as they are on an immune suppressant drug and the telaprovir will interact with that.
He had mild fatigue and flu-like symptoms for the 9 months he was on the interferon 20 years ago, but could still work full-time. He had no problems once the treatment ended. Hope it's the same this time round as I doubt we could cope with both of us ill with these symptoms!
I'm wondering if he'll be part of the MRC funded study.
I am amazed at the resources they have for dealing with Hep C patients at Kings - he has had tremendous care all along. The contrast with how they treat ME patients is huge.
Jenny
The trial he is on is for patients who've had transplants. Treatment for them is more complicated as they are on an immune suppressant drug and the telaprovir will interact with that.
He had mild fatigue and flu-like symptoms for the 9 months he was on the interferon 20 years ago, but could still work full-time. He had no problems once the treatment ended. Hope it's the same this time round as I doubt we could cope with both of us ill with these symptoms!
I'm wondering if he'll be part of the MRC funded study.
I am amazed at the resources they have for dealing with Hep C patients at Kings - he has had tremendous care all along. The contrast with how they treat ME patients is huge.
Jenny
Thanks Ocean 
I'm going to do 'my thang' on the laysummary of this study and figured it was better here than on the general MRC thread (which can be found here: http://forums.phoenixrising.me/show...es-ME-CFS-Research-Projects-Worth-£1-6m/page6).
I don't know if going through it like I do helps anyone else but I often find these days that it's the only way I can try and understand.
Additional information provided by MRC from their website here: http://www.mrc.ac.uk/Ourresearch/ResearchInitiatives/CFSME/index.htm : See MRC-funded Research Projects: or hit this link for a download of the pdf. file: 12 April 2012: http://www.mrc.ac.uk/consumption/id...dID=35295&dDocName=MRC008582&allowInterrupt=1
MR/J002739/1
PI: Dr Carmine Pariante, King's College London
Title: Persistent Fatigue Induced by Interferon-alpha: A New Immunological Model for Chronic Fatigue Syndrome
Start Date: 01/03/2012
End Date: 28/02/2015
Award Amount: 373,075.15
Lay Summary
All true. Of course you could argue (as some are) that 'CFS' ain't 'ME' but for the MRC and NIH they is - at least until such time as a specific and quantifiable difference can be found. And who knows? Perhaps immunological differences will be part of that puzzle-solving.
Like the 'Sjorgen's/Not ME' Study on the general thread; here is an explicit acknowledgment that the immune system is in some way affecting/related to the chronic symptoms.
For this to be said (again) from UK researchers who have had their funding approved by the key government agency - is nothing short of bloody miraculous in my humble opine.
Perhaps worth noting here (as I did for the other study) that again the focus is on the immune system and we do hear of people diagnosed with the condition having had a viral infection of course.
Not everyone can remember or was told of a specific viral infection. Not everyone with 'CFS' will know therefore that or if a virus is responsible in some way for the symptoms.
But this research - and the other - are focusing a search on the immune system and it would seem reasonable to assume I think that most people with 'CFS' and experiencing the range of symptoms we endure might have a screwed immune system. Heck everyone might - but with different triggers perhaps?
The mention of the 'hyper-activity' within the immune system (or feelings that the immune system is in hyper-mode) is again interesting to see. The idea that the body is fighting against something that isn't there anymore - and is somehow 'stuck' on 'high' or something.
So it's fighting against the body? Against itself? Permanently or fluctuatingly on 'alert'? Triggered again and again by 'something'? Is the immune system itself revving up and leading us to 'relapse'? Interesting...
I digress
Well there we go
Ok. I think I understand. They have a clearly-defined patient cohort and trigger. They are going to simulate an immune response with a drug used in this case to treat Hep C.
Again it's more likely to result in a success (as well as being more efficient and cheaper) I would imagine than having to screen patients with 'CFS'.
Also as 'CFS' is not diagnosed until after six months it is not always evident what the trigger was - as has been mentioned.
Nonetheless it is disappointing perhaps as I'm sure we'd all like to have seen this - and the other - study looking specifically at 'CFS' patients in the initial phase and not 'merely' as a comparative cohort.
It is interesting that 'CFS' is being viewed as 'something that occurs post-infection to some people' i.e. it is a 'development'. You 'develop' CFS post-infection.
That's their working hypothesis I guess. Fine by me for the purposes of this study. Again - like the other study - we seem to be heading towards an autoimmune disease don't we? And - again like I said on the other thread - maybe this explains why Rituximab achieved such good results?
Anyway...
Ocean explains more about IFH-alpha above in the thread, I will need to go back through it I think.
So again they are assuming that the initial infection - the trigger - in Hep C has been treated effectively by IFN-alpha and that this is comparable to whatever the initial trigger was in patients who went on to develop 'CFS'.
Are patients - who have been treated for Hep C with IFN-alpha - candidates then for 'CFS' if the above symptoms post-treatment are observed? I guess they are.
But, again, the reasoning is that they know who had Hep C specifically and they know (or think it's reasonable to assume) that IFN-alpha treatment is leaving patients with 'CFS'-like symptoms: so that's the justification for the simulation.
A specific and defined cohort. Gotcha. And one that's ready to hand I guess. I suppose any cohort of patients who present with a specific viral infection, are treated and go on to develop the symptoms of CFS would have done; but they can control and observe and have to hand this lot.
And these researchers applied for the funding of course.
Gotcha. Would like some more detail about e.g. patient numbers, criteria and the tests that will be performed but I'm guessing none of them will come as a surprise and all will be consistent with other research enabling comparisons to be made.
Imagine being able to predict the likelihood of developing 'CFS'. Wow. I mean yes you need to accept that this is based on the hope their model 'works' of course. But imagine.
Ok. 'novel treatments'. Hmm... could be anything I suppose but I am assuming here we are talking about possible drug therapies? Don't know.
And the same with 'novel therapeutic approaches'. I suspect that means non-drug. Any ideas? I guess even they won't know until this initial research is complete and they can get to work on that aspect of it.
Have left the 'techy' stuff to Ocean
I'm going to do 'my thang' on the laysummary of this study and figured it was better here than on the general MRC thread (which can be found here: http://forums.phoenixrising.me/show...es-ME-CFS-Research-Projects-Worth-£1-6m/page6).
I don't know if going through it like I do helps anyone else but I often find these days that it's the only way I can try and understand.
Additional information provided by MRC from their website here: http://www.mrc.ac.uk/Ourresearch/ResearchInitiatives/CFSME/index.htm : See MRC-funded Research Projects: or hit this link for a download of the pdf. file: 12 April 2012: http://www.mrc.ac.uk/consumption/id...dID=35295&dDocName=MRC008582&allowInterrupt=1
MR/J002739/1
PI: Dr Carmine Pariante, King's College London
Title: Persistent Fatigue Induced by Interferon-alpha: A New Immunological Model for Chronic Fatigue Syndrome
Start Date: 01/03/2012
End Date: 28/02/2015
Award Amount: 373,075.15
Lay Summary
All true. Of course you could argue (as some are) that 'CFS' ain't 'ME' but for the MRC and NIH they is - at least until such time as a specific and quantifiable difference can be found. And who knows? Perhaps immunological differences will be part of that puzzle-solving.
Like the 'Sjorgen's/Not ME' Study on the general thread; here is an explicit acknowledgment that the immune system is in some way affecting/related to the chronic symptoms.
For this to be said (again) from UK researchers who have had their funding approved by the key government agency - is nothing short of bloody miraculous in my humble opine.
Perhaps worth noting here (as I did for the other study) that again the focus is on the immune system and we do hear of people diagnosed with the condition having had a viral infection of course.
Not everyone can remember or was told of a specific viral infection. Not everyone with 'CFS' will know therefore that or if a virus is responsible in some way for the symptoms.
But this research - and the other - are focusing a search on the immune system and it would seem reasonable to assume I think that most people with 'CFS' and experiencing the range of symptoms we endure might have a screwed immune system. Heck everyone might - but with different triggers perhaps?
The mention of the 'hyper-activity' within the immune system (or feelings that the immune system is in hyper-mode) is again interesting to see. The idea that the body is fighting against something that isn't there anymore - and is somehow 'stuck' on 'high' or something.
So it's fighting against the body? Against itself? Permanently or fluctuatingly on 'alert'? Triggered again and again by 'something'? Is the immune system itself revving up and leading us to 'relapse'? Interesting...
I digress
Well there we go
Ok. I think I understand. They have a clearly-defined patient cohort and trigger. They are going to simulate an immune response with a drug used in this case to treat Hep C.
Again it's more likely to result in a success (as well as being more efficient and cheaper) I would imagine than having to screen patients with 'CFS'.
Also as 'CFS' is not diagnosed until after six months it is not always evident what the trigger was - as has been mentioned.
Nonetheless it is disappointing perhaps as I'm sure we'd all like to have seen this - and the other - study looking specifically at 'CFS' patients in the initial phase and not 'merely' as a comparative cohort.
It is interesting that 'CFS' is being viewed as 'something that occurs post-infection to some people' i.e. it is a 'development'. You 'develop' CFS post-infection.
That's their working hypothesis I guess. Fine by me for the purposes of this study. Again - like the other study - we seem to be heading towards an autoimmune disease don't we? And - again like I said on the other thread - maybe this explains why Rituximab achieved such good results?
Anyway...
Ocean explains more about IFH-alpha above in the thread, I will need to go back through it I think.
So again they are assuming that the initial infection - the trigger - in Hep C has been treated effectively by IFN-alpha and that this is comparable to whatever the initial trigger was in patients who went on to develop 'CFS'.
Are patients - who have been treated for Hep C with IFN-alpha - candidates then for 'CFS' if the above symptoms post-treatment are observed? I guess they are.
But, again, the reasoning is that they know who had Hep C specifically and they know (or think it's reasonable to assume) that IFN-alpha treatment is leaving patients with 'CFS'-like symptoms: so that's the justification for the simulation.
A specific and defined cohort. Gotcha. And one that's ready to hand I guess. I suppose any cohort of patients who present with a specific viral infection, are treated and go on to develop the symptoms of CFS would have done; but they can control and observe and have to hand this lot.
And these researchers applied for the funding of course.
Gotcha. Would like some more detail about e.g. patient numbers, criteria and the tests that will be performed but I'm guessing none of them will come as a surprise and all will be consistent with other research enabling comparisons to be made.
Imagine being able to predict the likelihood of developing 'CFS'. Wow. I mean yes you need to accept that this is based on the hope their model 'works' of course. But imagine.
Ok. 'novel treatments'. Hmm... could be anything I suppose but I am assuming here we are talking about possible drug therapies? Don't know.
And the same with 'novel therapeutic approaches'. I suspect that means non-drug. Any ideas? I guess even they won't know until this initial research is complete and they can get to work on that aspect of it.
Have left the 'techy' stuff to Ocean
Thanks Ocean
Ok. I think I understand. They have a clearly-defined patient cohort and trigger. They are going to simulate an immune response with a drug used in this case to treat Hep C...
So again they are assuming that the initial infection - the trigger - in Hep C has been treated effectively by IFN-alpha and that this is comparable to whatever the initial trigger was in patients who went on to develop 'CFS'.
Are patients - who have been treated for Hep C with IFN-alpha - candidates then for 'CFS' if the above symptoms post-treatment are observed? I guess they are.
But, again, the reasoning is that they know who had Hep C specifically and they know (or think it's reasonable to assume) that IFN-alpha treatment is leaving patients with 'CFS'-like symptoms: so that's the justification for the simulation.
Ok. I think I understand. They have a clearly-defined patient cohort and trigger. They are going to simulate an immune response with a drug used in this case to treat Hep C...
So again they are assuming that the initial infection - the trigger - in Hep C has been treated effectively by IFN-alpha and that this is comparable to whatever the initial trigger was in patients who went on to develop 'CFS'.
Are patients - who have been treated for Hep C with IFN-alpha - candidates then for 'CFS' if the above symptoms post-treatment are observed? I guess they are.
But, again, the reasoning is that they know who had Hep C specifically and they know (or think it's reasonable to assume) that IFN-alpha treatment is leaving patients with 'CFS'-like symptoms: so that's the justification for the simulation.
You probably realise this already, but just to clarify: the Hep C in this case isn't the trigger, the trigger is the IFN-alpha that creates an immune response comparable (in theory) to that seen in an infection. (See Dubbo studies on this.) As for tests for CFS and 'novel therapeutic approaches', I think that's just pie-in-the-sky that researchers seem to throw in to persuade funders to award grants. Don't hold your breath. But if they gain an insight into how immune activation can trigger long-term fatigue, that would be quite something.
hi Jenny, hope the treatment goes well. It seems cruel that your husband should be lucky enough to get a transplant only for it to be attacked by HCV again.
Normally studies like these like 'standard' patients with standard treatment so maybe your husband won't be in the Pariente trial - though it would be amazing if his treatment helped lead to a breakthrough in CFS. It is interesting how if you have the 'right' illness resources are more readily available.
Normally studies like these like 'standard' patients with standard treatment so maybe your husband won't be in the Pariente trial - though it would be amazing if his treatment helped lead to a breakthrough in CFS. It is interesting how if you have the 'right' illness resources are more readily available.
.
"Of particular relevance for this study, a considerable proportion of patients continue to experience debilitating persistent fatigue, and other symptoms that are similar to CFS"
.
Oh Really?? 'Persistent fatigue'. Back to 'Fatigue' again.
No progress for Myalgic Encephalomeyelitis (WHO ICD ME) research, then.
"Of particular relevance for this study, a considerable proportion of patients continue to experience debilitating persistent fatigue, and other symptoms that are similar to CFS"
.
Oh Really?? 'Persistent fatigue'. Back to 'Fatigue' again.
No progress for Myalgic Encephalomeyelitis (WHO ICD ME) research, then.
Given the background of Carmine Pariante/King's College what's a fair bet that this study won't find anything useful for Hep C patients, but try to blame it on psychological factors?
Another psychiatrist claiming to study immunity...
Another psychiatrist claiming to study immunity...
I know what you are saying Ember (I think), but the point is that in this model, treatment of the acute viral infection HPV with IFN-aplha stimulates an immune response that is believed to be comparable with 'CFS' - in so far as the immune system activation and the chronic symptomology.
'CFS' is diagnosed at the six-month stage and those who go on to develop 'CFS-like' symptoms following IFN-alpha do so at this point too - at least.
So the model is that 'Hey we can observe more readily what is happening in our patients post-IFN-alpha' and see if the immune stimulation is not only resulting, causing, the 'CFS-like' symptoms (which they believe it is) but biologically try and prove it as well as actually observing it.
And not only that, but biologically compare this profile with those patients otherwise diagnosed with 'CFS' and see if the two resemble one another.
One of the results of 'stimulation' of the immune system (whether by a virus or - in this case - IFN-alpha) is more generally known as 'inflammation' (hence the cytokine involvement).
And as you know it has long-been suggested that 'inflammation' plays another key role in 'CFS' (however you like to define it).
If they do - even in a small sub-set of patients* - then treatments post-treatment for IFN-alpha-induced 'CFS-like' symptoms could be applied similarly.
And a biomarker could be established. An immune biomarker. One that could also help predict patients who are in some way susceptible to post-viral infection 'CFS'.
The length of time a person who has been treated with IFN-alpha has the chronic effects is not really relevant. At least not to this model. And that's all it is - a model.
(*I actually think they will employ Fukuda and CCC as well as screening pre-study for immune-system abnormalities or at least to establish a base-line (cytokines and cortisol). Only a hunch mind but as well as applying and monitoring (and employing the other checks and balances mentioned in the Technical notes from Ocean), they will want to ensure that the 'CFS' cohort is as relevant as it can possibly be to the Hep C-treated cohorts.)
'CFS' is diagnosed at the six-month stage and those who go on to develop 'CFS-like' symptoms following IFN-alpha do so at this point too - at least.
So the model is that 'Hey we can observe more readily what is happening in our patients post-IFN-alpha' and see if the immune stimulation is not only resulting, causing, the 'CFS-like' symptoms (which they believe it is) but biologically try and prove it as well as actually observing it.
And not only that, but biologically compare this profile with those patients otherwise diagnosed with 'CFS' and see if the two resemble one another.
One of the results of 'stimulation' of the immune system (whether by a virus or - in this case - IFN-alpha) is more generally known as 'inflammation' (hence the cytokine involvement).
And as you know it has long-been suggested that 'inflammation' plays another key role in 'CFS' (however you like to define it).
If they do - even in a small sub-set of patients* - then treatments post-treatment for IFN-alpha-induced 'CFS-like' symptoms could be applied similarly.
And a biomarker could be established. An immune biomarker. One that could also help predict patients who are in some way susceptible to post-viral infection 'CFS'.
The length of time a person who has been treated with IFN-alpha has the chronic effects is not really relevant. At least not to this model. And that's all it is - a model.
(*I actually think they will employ Fukuda and CCC as well as screening pre-study for immune-system abnormalities or at least to establish a base-line (cytokines and cortisol). Only a hunch mind but as well as applying and monitoring (and employing the other checks and balances mentioned in the Technical notes from Ocean), they will want to ensure that the 'CFS' cohort is as relevant as it can possibly be to the Hep C-treated cohorts.)
Note that the study isn't intended to help Hep C patients, beyond the IFN-alpha treatment itself. The aim is to use it as a model of CFS to gain insights, then try to see if that model really does apply to CFS patients (though they won't be able to do that fully in this study).
Psychologists e.g. Ute Vollmer-Conna have done very interesting work on the role of immunity in CFS as part of the Dubbo studies.
However, this study is clearly looking at psychological factors, including: "psychiatric history; childhood and recent stressors; social support; illness and treatment perceptions", as well as immune markers such as cytokines.
This would tie in with the view of Wessely & Harvey (of King's), expressed in their paper Chronic fatigue syndrome: identifying zebras amongst the horses, that fatigue across a range of illnesses including MS, cancer and HIV/AIDS has a strong psychological basis and behavioural treatment is the answer. (Needless, to say, the references they quote to make this case don't really back up their argument.) Rona Moss Morris, now also at King's/Institute of Psychiatry, published a study claiming that developing CFS post glandular fever is down to psychological factors. It's a deeply flawed study.
So, cause for concern, but the study might also find that it's the severity of the symptoms (in response to IFN-alpha therapy) that determines the likelihood of post IFN-a fatigue, rather than psychological factors (Dubbo found acute illness severity, not psychological factors predicted CFS post EBV and other infections). Also, whatever he findings are, they will apply to IFN-a treatment and will then need confirming in CFS.
I am concerned at where this study is stabled, given King's/IoP's track record in this area, but I also think it's a very interesting model and well worth pursuing.
Psychologists e.g. Ute Vollmer-Conna have done very interesting work on the role of immunity in CFS as part of the Dubbo studies.
However, this study is clearly looking at psychological factors, including: "psychiatric history; childhood and recent stressors; social support; illness and treatment perceptions", as well as immune markers such as cytokines.
This would tie in with the view of Wessely & Harvey (of King's), expressed in their paper Chronic fatigue syndrome: identifying zebras amongst the horses, that fatigue across a range of illnesses including MS, cancer and HIV/AIDS has a strong psychological basis and behavioural treatment is the answer. (Needless, to say, the references they quote to make this case don't really back up their argument.) Rona Moss Morris, now also at King's/Institute of Psychiatry, published a study claiming that developing CFS post glandular fever is down to psychological factors. It's a deeply flawed study.
So, cause for concern, but the study might also find that it's the severity of the symptoms (in response to IFN-alpha therapy) that determines the likelihood of post IFN-a fatigue, rather than psychological factors (Dubbo found acute illness severity, not psychological factors predicted CFS post EBV and other infections). Also, whatever he findings are, they will apply to IFN-a treatment and will then need confirming in CFS.
I am concerned at where this study is stabled, given King's/IoP's track record in this area, but I also think it's a very interesting model and well worth pursuing.
I know Ember and it is but one of the concerns I personally have with the ICCME. If CFS and ME are triggered by some insult to the immune system - or maybe even if some of the predominate symptoms are the results of an immune-system insult - how can they diagnose 'ME' at ground zero?
I get a viral infection. I get treated. My symptoms don't clear up in the expected time-frame. Indeed they become chronic. I am diagnosed with PVFS.
Or in the above example. I have Hep C. I am treated. That treatment stimulates my immune-system (in the way that a virus might only it exaggerates the reaction) and instead of recovering, I develop chronic symptoms comparable to those primarily seen in CFS or ME.
Indeed, as I speculated above, someone who has been treated for Hep C with IFN-alpha could then be diagnosed with CFS or ME or PVFS. It's just that in this model they believe they know the cause can be seen and as a result can observe the immune system interactions and effects.
You need a demarcation line. A point in the sand. If only to rule out anything else. And how do you determine exactly WHEN the specific (?) symptoms for 'ME' or 'CFS' actually occurred?
One of the things that might be possible following the above study perhaps because - if things pan-out as they hope - then they could be able to predict those patients whose immune systems are more likely to go on to develop CFS or ME.
If they are able to predict onset THEN you might be able to have a criteria with an immediate ability to diagnose. I just can't see it myself but there we go.
Whether or not CFS/ME clears-up after six months is debatable isn't it? And this study isn't looking at that.
If it does work though it might throw some light on the reasons why some people are debilitated far longer than others.
It might also serve to explain (I'm stretching) why relapses and remittances are occurring. Are we in some way more susceptible to viral insults once our immune systems have been knocked off-kilter in some way?
Do our immune systems react perhaps more slowly in coming down off the ceiling but are more twitchy and determined to get back up there again at the first sign of 'danger'?
I think it's all about being able to apply a model and once (and if) that model can be applied to people diagnosed with CFS/ME then we might have a biomarker that can be used to help explain more in terms of duration. Hell they might one day be able to predict how long we are likely to remain in such a state!
Wouldn't that be something.
I get a viral infection. I get treated. My symptoms don't clear up in the expected time-frame. Indeed they become chronic. I am diagnosed with PVFS.
Or in the above example. I have Hep C. I am treated. That treatment stimulates my immune-system (in the way that a virus might only it exaggerates the reaction) and instead of recovering, I develop chronic symptoms comparable to those primarily seen in CFS or ME.
Indeed, as I speculated above, someone who has been treated for Hep C with IFN-alpha could then be diagnosed with CFS or ME or PVFS. It's just that in this model they believe they know the cause can be seen and as a result can observe the immune system interactions and effects.
You need a demarcation line. A point in the sand. If only to rule out anything else. And how do you determine exactly WHEN the specific (?) symptoms for 'ME' or 'CFS' actually occurred?
One of the things that might be possible following the above study perhaps because - if things pan-out as they hope - then they could be able to predict those patients whose immune systems are more likely to go on to develop CFS or ME.
If they are able to predict onset THEN you might be able to have a criteria with an immediate ability to diagnose. I just can't see it myself but there we go.
Whether or not CFS/ME clears-up after six months is debatable isn't it? And this study isn't looking at that.
If it does work though it might throw some light on the reasons why some people are debilitated far longer than others.
It might also serve to explain (I'm stretching) why relapses and remittances are occurring. Are we in some way more susceptible to viral insults once our immune systems have been knocked off-kilter in some way?
Do our immune systems react perhaps more slowly in coming down off the ceiling but are more twitchy and determined to get back up there again at the first sign of 'danger'?
I think it's all about being able to apply a model and once (and if) that model can be applied to people diagnosed with CFS/ME then we might have a biomarker that can be used to help explain more in terms of duration. Hell they might one day be able to predict how long we are likely to remain in such a state!
Wouldn't that be something.
Sorry to come in so late in this discussion but I've been a little tied up lately.
Plus points (point).
Less likely to be a heterogenous population with at least the presence of objective biomarkers.
Negative points.
The emphasis on fatigue.
Fatigue is a common symptom associated with a wide range of illnesses or resulting from treatments that modulate the immune system (interferon alpha or some chemotherapy regimes). There is no mystery here. Fatigue is one element of 'sickness behaviour' resulting from inflammation :
and Danzer and colleagues have proposed a standard list of inflammatory markers to improve consistency in identifying inflammatory disorders that lead to such 'sickness behaviour' :
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919277/
What does appear to distinguish ME/CFS from other fatigue states is PEM although similar adverse responses to exercise (or other stressors) also occur in mitochondrial diseases and mastocytosis (resulting from mitochondrial disorder and mast cell proliferation respectively).
Even with a relatively unique symptom such as PEM, the underlying mechanisms may be very different.
Perhaps all these states lead to oxidative stress/cytokine induced 'fatigue' but I don't see how this advances our knowledge any?
More generally as regards this MRC funded tranche of projects, I really don't see anything particularly new there.
Perhaps the best I can say for them is that the MRC may have been suffering from 'not invented here' syndrome and they may look more favourably on any positive results that they funded. At least they can't write them off due to poor methodology.
Plus points (point).
Less likely to be a heterogenous population with at least the presence of objective biomarkers.
Negative points.
The emphasis on fatigue.
Fatigue is a common symptom associated with a wide range of illnesses or resulting from treatments that modulate the immune system (interferon alpha or some chemotherapy regimes). There is no mystery here. Fatigue is one element of 'sickness behaviour' resulting from inflammation :
and Danzer and colleagues have proposed a standard list of inflammatory markers to improve consistency in identifying inflammatory disorders that lead to such 'sickness behaviour' :
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919277/
What does appear to distinguish ME/CFS from other fatigue states is PEM although similar adverse responses to exercise (or other stressors) also occur in mitochondrial diseases and mastocytosis (resulting from mitochondrial disorder and mast cell proliferation respectively).
Even with a relatively unique symptom such as PEM, the underlying mechanisms may be very different.
Perhaps all these states lead to oxidative stress/cytokine induced 'fatigue' but I don't see how this advances our knowledge any?
More generally as regards this MRC funded tranche of projects, I really don't see anything particularly new there.
Perhaps the best I can say for them is that the MRC may have been suffering from 'not invented here' syndrome and they may look more favourably on any positive results that they funded. At least they can't write them off due to poor methodology.
Marco I think you are missing the point (or I am).
The difference here is that there are no biological markers that can be applied to a patient cohort with 'fatigue' and other predominant 'CFS-like' symptoms within a CFS/ME cohort of patients that are clearly defined and readily available.
If they can identify such markers in the Hep C contingent and apply the same model to patients with 'CFS' then we have a comparable marker or set of markers but something tangible.
Nobody is doubting that 'fatigue' all on it's own isn't a common symptom across the board. But in this Hep C (or rather IFN-alpha-treated cohort) they specifically go on to develop 'CFS-like' debilitation including severe fatigue as a result (or the majority appear to).
And 'fatigue' IF it is the result of immune system dysfunction; IF this study is able to apply the model to 'CFS' - it may also apply to other conditions too e.g. Multiple Sclerosis.
CFS is an amalgam of many different 'triggers' and some folk in the 'pot' may not even have anything like an immune profile developed by this model. Some may well do - and that's the hypothesis being worked on here:
That primarily any Viral Trigger leads in some cases post-resolution to CFS and that in HPV following treatment by a naturally occurring Immune Trigger (same as is triggered by a viral infection but to a more significant effect i.e. a stimulant) i.e. IFN-aplha leads to CFS-like symptoms INCLUDING fatigue.
If specifically it is shown that IFN-alpha is causing those symptoms or the interaction of this stimulant with other parts of the immune system this model should be able to demonstrate that. But they felt unable to use 'CFS' patients specifically - for the reasons you mention.
If they can model the Hep C-lot and match it to the CFS-lot then they might be able to see what is leading to the symptoms (at least in so far as immune-system contribution) and that includes inflammation i.e. cell inflammation including neurological inflammation.
Of course both studies are equated ME with CFS synonymously because in so far as the MRC/NICE and for that matter the NIH are concerned they are the same condition.
These studies COULD help us to quantify significant differences in the general population currently and in the future diagnosed with 'CFS'. Isn't that something we would all welcome? Might it not lead to more targeted and effective treatments?
When the MRC announced it was setting aside 'ring-fenced'/'specific' funding for research into CFS/ME it asked for research applications. Of the applications it received the interest was such and the quality judged to be such that they increased the allocation of funds.
Not one of the grants was for e.g. 'Quantification of the differences between ME and CFS' and I don't recall the MRC requesting applications for such. And yet some people seem to think these studies are crap because they are not focusing on their own preferred 'ME' as being somehow different to CFS/ME.
If all this funding were spent in trying (again) to define a cohort of 'ME' and then to look at the cause of all those symptoms (presuming they are fundamentally different to 'CFS') - it would not be sufficient to get anywhere near the MRC's objectives.
I have yet to really look at the other studies Marco but there is one (?) looking into mitochodria. That might be the one that considers best the PEM and muscle weakness we all experience. I think though it is beyond the remit of these two studies (Hep C and Sjorgen's) that appear most controversial.
The difference here is that there are no biological markers that can be applied to a patient cohort with 'fatigue' and other predominant 'CFS-like' symptoms within a CFS/ME cohort of patients that are clearly defined and readily available.
If they can identify such markers in the Hep C contingent and apply the same model to patients with 'CFS' then we have a comparable marker or set of markers but something tangible.
Nobody is doubting that 'fatigue' all on it's own isn't a common symptom across the board. But in this Hep C (or rather IFN-alpha-treated cohort) they specifically go on to develop 'CFS-like' debilitation including severe fatigue as a result (or the majority appear to).
And 'fatigue' IF it is the result of immune system dysfunction; IF this study is able to apply the model to 'CFS' - it may also apply to other conditions too e.g. Multiple Sclerosis.
CFS is an amalgam of many different 'triggers' and some folk in the 'pot' may not even have anything like an immune profile developed by this model. Some may well do - and that's the hypothesis being worked on here:
That primarily any Viral Trigger leads in some cases post-resolution to CFS and that in HPV following treatment by a naturally occurring Immune Trigger (same as is triggered by a viral infection but to a more significant effect i.e. a stimulant) i.e. IFN-aplha leads to CFS-like symptoms INCLUDING fatigue.
If specifically it is shown that IFN-alpha is causing those symptoms or the interaction of this stimulant with other parts of the immune system this model should be able to demonstrate that. But they felt unable to use 'CFS' patients specifically - for the reasons you mention.
If they can model the Hep C-lot and match it to the CFS-lot then they might be able to see what is leading to the symptoms (at least in so far as immune-system contribution) and that includes inflammation i.e. cell inflammation including neurological inflammation.
Of course both studies are equated ME with CFS synonymously because in so far as the MRC/NICE and for that matter the NIH are concerned they are the same condition.
These studies COULD help us to quantify significant differences in the general population currently and in the future diagnosed with 'CFS'. Isn't that something we would all welcome? Might it not lead to more targeted and effective treatments?
When the MRC announced it was setting aside 'ring-fenced'/'specific' funding for research into CFS/ME it asked for research applications. Of the applications it received the interest was such and the quality judged to be such that they increased the allocation of funds.
Not one of the grants was for e.g. 'Quantification of the differences between ME and CFS' and I don't recall the MRC requesting applications for such. And yet some people seem to think these studies are crap because they are not focusing on their own preferred 'ME' as being somehow different to CFS/ME.
If all this funding were spent in trying (again) to define a cohort of 'ME' and then to look at the cause of all those symptoms (presuming they are fundamentally different to 'CFS') - it would not be sufficient to get anywhere near the MRC's objectives.
I have yet to really look at the other studies Marco but there is one (?) looking into mitochodria. That might be the one that considers best the PEM and muscle weakness we all experience. I think though it is beyond the remit of these two studies (Hep C and Sjorgen's) that appear most controversial.
Hi Firestorm
I wouldn't rule out me missing the point.
I'm still a little tied up at the mo' so haven't looked at this in sufficient detail and can't respond as fully as I would like.
Having said that, I now conceded that the literature notes that 'exercise intolerance' is associated with IFN a treatment (which may equate to PEM) and some of the effects of IFN a treatment with HIV are also suggestive (endothelial dysfunction, cardiac arhythmias etc).
My concern is that immune markers in ME/CFS are inconsistent even using a cohort elected by 'tight' criteria such as the CCC. What does appear to be consistent is the finding of low grade inflammation/oxidative stress.
My intuition, for what its worth is that ME/CFS is a 'state' with many and various triggers which may include a viral etiology.
Lets suppose they identify an immune signature associated with IFN a treatment (like raised IFN a?) and search for this signature in a ME/CFS cohort.
They may find this signature in say 25% of the cohort.
How should this be interpreted?
That this immune pattern is not strongly associated with ME/CFS as its only detected in one quarter of the cohort (the usual argument against pathogens in ME/CFS)?
That 25% of the cohort only have ME/CFS and the remainder are ideopathic fatigue?
That the 25% are a subset associated with a viral onset (fair enough - I've no problem with splitting)? and the remainder do have ME/CFS but not of viral onset origin?
In which case, what value is the IFN a associated immune marker if other routes can lead to the same state of low grade inflammation/oxidative stress.
What additional diagnostic value or treatment options would this offer?
It would have been nice to have seen an expanded rationale for this and the other studies beyond even the additional information provided which might better answer questions such as these.
As it stands, you may be right about its potential but its hard to tell.
Cheers
Marco
I wouldn't rule out me missing the point.
I'm still a little tied up at the mo' so haven't looked at this in sufficient detail and can't respond as fully as I would like.
Having said that, I now conceded that the literature notes that 'exercise intolerance' is associated with IFN a treatment (which may equate to PEM) and some of the effects of IFN a treatment with HIV are also suggestive (endothelial dysfunction, cardiac arhythmias etc).
My concern is that immune markers in ME/CFS are inconsistent even using a cohort elected by 'tight' criteria such as the CCC. What does appear to be consistent is the finding of low grade inflammation/oxidative stress.
My intuition, for what its worth is that ME/CFS is a 'state' with many and various triggers which may include a viral etiology.
Lets suppose they identify an immune signature associated with IFN a treatment (like raised IFN a?) and search for this signature in a ME/CFS cohort.
They may find this signature in say 25% of the cohort.
How should this be interpreted?
That this immune pattern is not strongly associated with ME/CFS as its only detected in one quarter of the cohort (the usual argument against pathogens in ME/CFS)?
That 25% of the cohort only have ME/CFS and the remainder are ideopathic fatigue?
That the 25% are a subset associated with a viral onset (fair enough - I've no problem with splitting)? and the remainder do have ME/CFS but not of viral onset origin?
In which case, what value is the IFN a associated immune marker if other routes can lead to the same state of low grade inflammation/oxidative stress.
What additional diagnostic value or treatment options would this offer?
It would have been nice to have seen an expanded rationale for this and the other studies beyond even the additional information provided which might better answer questions such as these.
As it stands, you may be right about its potential but its hard to tell.
Cheers
Marco