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:

 

Yes, also it states that depression and stressful life events had no significance in the responses.

ETA: I basically just repeated your quote but from a different section of the paper, sorry! My brain is struggling this morning with all this going on.

 

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.

 

Maybe the hype is because the MRC wants to distract from its continued failure to fund good studies.

 

Here is the key quote from Michael Sharpe, and he has it wrong:

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.

https://twitter.com/user/status/1074604952939651073

 

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.

 

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)

 

Whose account was that?

 

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.

 

Full pdf is here: https://ac.els-cdn.com/S03064530183...t=1545044108_ac177765a8f65b4735ee8a38d9809ee4

 

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 ?

 

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.

 

I'm sure I was reading in ME charity newsletters 30 years ago or so that having ME was like having interferon-alpha.

 

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.

 

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.