Persistent fatigue induced by interferon-alpha: A novel, inflammation-based, proxy model of Chronic Fatigue Syndrome, 2018, Pariante et al

This is very important, I think:
This lower KYN/TRP ratio in CFS (and the lack of association with PF) is somewhat in opposition to a study of somatization which observed higher levels of the KYN/TRP ratio (Maes et al., 2011). This evidence points again to a different biological underpinning of primarily psychiatric syndromes, such as depression and somatization, as opposed to CFS. This notion is further supported by the lack of an association, in our study, between PF and any of the classic, stress-related risk factors for psychiatric disorders. Targeting the kynurenine pathway, through antidepressants or nutritional interventions, may thus not be a relevant therapeutic strategy in CFS (Borsini et al., 2017).
Click to expand...
 
Jonathan Edwards said:
No, I think that is off target. These people are wanting to understand the biochemistry of depression. This particular study has always been about modelling CFS and I think that is what it really is about. I think it is useful research.
Click to expand...

If it was always meant to model CFS, then it is strange that the study is mostly concerned with comparing the two interferon treated groups, and barely examines similarities between the post-interferon persistent fatigue state and CFS. If it is not established that these two entities are similar then we can't draw any conclusions about CFS. They do seem similar in that the onset is related to immune activation, but a closer examination could reveal important differences, or confirm their similarity. Something as simple as symptom profiles and level of impairment would be very helpful to quickly get an idea of whether they are similar.

Instead, someone could be classified as having persistent fatigue with even 1 point change on the Chalder fatigue scale. I don't know how badly affected people can be after interferon, so maybe these people were likely to be significantly impaired and ill, but the authors left the door open to use people that were a tiny bit more tired than before as proxy model for CFS. While the conclusions appeal to me (that immune activation seems to cause CFS) I have to sadly admit that this is a poor study.
 
Last edited:
Esther12 said:
Looks like the Guardian's coverage includes comment from Sharpe, but it doesn't seem to be on their website yet:

https://www.pressreader.com/uk/the-guardian/20181217/281775630256669

"It may give us some clue down the line. If the thing is triggered by an abnormal or excessive immune response [and] if we could find a way to reduce that immune response, we might stop incident cases."

So if the thing is triggered by X, then if we found a way of stopping X we might stop the thing? Good to be able to have an expert explain that.
Click to expand...
Here is the key quote from Michael Sharpe, and he has it wrong:

Michael Sharpe, professor of psychological medicine at the University of Oxford, said the study added another piece to the puzzle about what might kick off CFS. “It does seem that something to do with the immune system may be a triggering event, [but] it doesn’t actually tell us why, when that trigger seems to have gone away, the person stays fatigued,” he said.
Click to expand...

The good thing about a prospective study, the design here, is that you look what happens first and then what happens afterwards. Since the immune activation happens first and the fatigue a long time later that’s good evidence that the immune activation could well to be causing fatigue.

Equally, the researchers measured psychosocial factors including childhood trauma before the interferon-alpha treatment started. And these factors did not predict predict subsequent fatigue.

Previously, psychosocial researchers have used weak evidence, such as that of pre-illness child trauma, as evidence that their psychosocial model was correct. It’s harder to argue that some people develop/maintain CFS after infection because of psychosocial issues (compared with those that don’t develop the illness) when there is no difference in psychosocial factors before the infection (Or immune activation). Why did these people who got CFS suddenly have psychosocial problems after an infection??

Together, the evidence indicates that immune activation may well play a causal role - and that psychosocial factors do not. I’ve no idea how Michael Sharpe came up with his argument, But the new evidence undermines his psychosocial theory of the illness.

 
Last edited:
Simon M said:
Together, the evidence indicates that immune activation may well play a causal role - and that psychosocial factors do not. I’ve no idea how Michael Sharpe came up with his argument, But the new evidence undermines his psychosocial theory of the illness.
Click to expand...

Even if depression was more common before interferon in the group that went on to develop persisent fatigue, it wouldn't support a psychosocial model any more than a biological one. Correlation is not causation. It would be plausible that both depression and persistent fatigue could be due to particular behaviour of the immune system.
 
In June, Scottish National Party MP Carol Monaghan led an emotional Westminster Hall debate into a common treatment, graded exercise therapy (Get), which is available on the NHS. She argued it was often damaging and in need of revision. Others defended the treatment.
Click to expand...

I don't remember any of the other MPs defending the treatment (not even the Minister who spoke at the end). There was a lot of anti-PACE discussion.
Where did the BBC get this from?

eta: need to check the Hansard, but I think a complaint/retraction of that line request might be in order.

eta2: as I thought; I've been thro the whole transcript and all references to GET are negative, there was absolutely no one who even vaguely defended it.....(unless you count Michael Sharpes email to Carol Monaghan)
 
Last edited:
Jonathan Edwards said:
... This particular study has always been about modelling CFS and I think that is what it really is about. I think it is useful research. I don't think anyone in this research group is interested in suggesting that continued fatigue after interferon is hysteria. Psychiatrists are desperate to have a biological basis to their work to make it legitimate. Even Simon Wessely tried to find one.
Click to expand...

As you have seen, a lot of us are struggling to see how this can be classed as good quality and useful work when Carmine Pariante goes on radio 4 and says some of the interferon patients developed CFS. Yet his abstract says they developed chronic fatigue and did not develop CFS, and he uses the Chalder nonsense questionnaire to assess fatigue. If he doesn't even understand what the condition he's trying to model is, how can he know if he's developed a useful model? Is it also a useful model for MS, since that is a chronically fatiguing condition too?

I would really like it to be a useful development that will increase understanding of ME, but I'm struggling here.
 
It seems from the video of Professor Pariante's talk back in October that IL-6 and IL-10 were already a bit elevated in the patients who went on to develop persistent fatigue, even before they started taking interferon alpha. He draws attention to the fact the the levels of IL-6 and IL-10 subsequently returned to normal once the treatments stopped, even though those patients had developed persistent fatigue.

Does that make elevated IL-6 and IL-10 a risk factor for developing persistent fatigue if they just happen to be a bit high when something else stimulates the immune system? That they return to normal even after persistent fatigue takes hold suggests that their initial elevation was temporary and not chronic. I wonder if this could reflect the "one-two punch" concept that is sometimes talked about in ME; that is, something stimulates your immune system, and, before the system has time to return to baseline, something else stimulates it again.
 
Last edited:
Jonathan Edwards said:
As I thought.

I think this is internal MRC politics.

I think this press release is intended to tell the world that the MRC has known about ME all along and has had brilliant people working hard on it and still does and so there is no need for a 'second referendum' on some new plan dreamt up by the CMRC.

Pariente's work has always been of considerable interest and is an intelligent approach. However, we have known the main punch line for five years now and all it can possibly tell us is that ME might work in a rather similar way to interferon treatment.

Edit: the question is - who is trying to tell the world this?
Click to expand...
Yep I agree, I think there’s evidence of that with three top arthritis MRC scientists suddenly appearing in a USA patient funded collaboration study. Or in the light of an upcoming HOC debate some spin of how the MRC are funding really imprtant CFS research. If this had been a charity funded study not by a kings psychiatrist would this have had a mention ?
 
Jonathan Edwards said:
Pariente's work has always been of considerable interest and is an intelligent approach. However, we have known the main punch line for five years now and all it can possibly tell us is that ME might work in a rather similar way to interferon treatment.
Click to expand...


I'm assuming that they have not come up with a way to test the validity of their analogy. I worry that they take a label of fatigue and use that to assert equivalence rather than looking at whether all fatigue is the same and thus whether a comparison may be valid. (Same with depression as well).

If they have found interesting stuff for interferon then that may be interesting and worth exploring in ME but that is the question raised by the research.
 
Trish said:
Yet his abstract says they developed chronic fatigue and did not develop CFS, and he uses the Chalder nonsense questionnaire to assess fatigue. If he doesn't even understand what the condition he's trying to model is, how can he know if he's developed a useful model? Is it also a useful model for MS, since that is a chronically fatiguing condition too?
Click to expand...

I think people are being too nitpicking. I agree with Simon. The basic study here is useful in documenting the fact that a known immunological stimulus can cause a long term and severe illness characterised by fatigue. That may not be the same as CFS or ME but it shows that you do not need to postulate any psychological factors in the causation of an illness at least similar to ME in some respects. A small step but an important one.

I detect a certain reluctance by people to take this seriously - just a bit of fatigue or whatnot. I can assure everyone that interferon alpha induced fatigue can be every bit as debilitating as PWME describe. I had one patient who was devastated by interferon. Moreover, it did not work for him and he died of his Hepatitis after a couple of years of being unable to do anything for himself.

This is not a useful model for MS because we already know that MS is due to an immunological abnormality that we can identify pathologically and with imaging. There is no need to model MS to show that you can be paralysed permanently by an immune stimulus. We know that. And if interferon alpha induced illness makes it more plausible to put ME on a par with MS surely that is useful?

I have not looked at the recent abstract to see what data it contains. I suspect it shows some slight shifts in cytokines that do not take us much further. But the original observation that illness persists after interferon alpha in some people without any obvious inflammatory response long term is to me important. You do not need large numbers for this sort of finding. We know that it is a not insignificant minority and not just a rare quirk. I think maybe the biggest criticism one can make of the recent work is that it has not really told us anything more than we knew before the study started. But getting detailed documentation of phenomena like this from prospective studies is always worthwhile because sometimes it turns something important up.
 
Adrian said:
I'm assuming that they have not come up with a way to test the validity of their analogy. I worry that they take a label of fatigue and use that to assert equivalence rather than looking at whether all fatigue is the same and thus whether a comparison may be valid.
Click to expand...

I don't think we need the model to be valid beyond showing that an immune insult can produce long term disabling illness without any apparent structural pathological change. Sure, there is a big issue about different sorts of 'fatigue' but that criticism can be levelled at just about everyone in the field. I am not seeing anyone look at this in useful detail.
 
In conclusion, findings from this study support the hypothesis that abnormal immune mechanisms are important in CFS, but only early in the course of the illness, around the time of the trigger, rather than when the syndrome is established. Moreover, our study confirms the importance of the acute fatigue response to the trigger, rather than of the recovery period preceding the illness. Future research will need to examine the molecular mechanisms that underlie an exaggerated immune response and that are involved in the conversion from acute to persistent fatigue symptoms.
Click to expand...

I really don't understand how they can possibly reach these conclusions from this study. They have presumed that IFN-alfa-induced persistent fatigue after HCV is a good model of CFS, but then have demolished that by only being able to match one of the cytokines measured (IL-7).

All they've done is looked at persistent fatigue in HCV. To align this HCV-PF with CFS seems to completely misunderstand what CFS (and by inference ME) actually is. It is not "persistent fatigue". They claim to have looked at CFS prospectively, but clearly haven't at all. How can they make any assertions about what goes on "early in the course of the illness" when they haven't even looked at it? Are they assuming that the fatigue element of ME/CFS is somehow induced by IFN-alfa (or some similar unspecfied mechansim)?

I guess by this logic, my bowl of oranges is a good model for your bowl of apples because they are both roughly spherical objects.
 
You must log in or register to reply here.
Back
Top Bottom