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

alex3619 said:
At this point this paper is not leading to dangerous therapies. If however this paper is used as a justification for further papers, heading even deeper into psychobabble territory, then those papers might warrant deeper scrutiny.
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Agreed.

Right now this paper serves as weak evidence for issues following infections. It says nothing useful about ME. It does not even address ME except in name, which is a flaw that can be criticised even without data.
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To be fair to the authors, the paper itself does make clear that this only *might* be a model for ME/CFS - it is the follow-up reporting which overhypes this. Which is a problem that affects pretty much all scientific research. I just can't help feel that this paper is getting more than the usual amount of criticism because of its source rather than its contents.
 
Londinium said:
Agreed.



To be fair to the authors, the paper itself does make clear that this only *might* be a model for ME/CFS - it is the follow-up reporting which overhypes this. Which is a problem that affects pretty much all scientific research. I just can't help feel that this paper is getting more than the usual amount of criticism because of its source rather than its contents.
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Well given his previous comments we re allowed to be cynical and he’s not helped himself by hyping it up in the media.
 
Londinium said:
To be fair to the authors, the paper itself does make clear that this only *might* be a model for ME/CFS - it is the follow-up reporting which overhypes this. Which is a problem that affects pretty much all scientific research. I just can't help feel that this paper is getting more than the usual amount of criticism because of its source rather than its contents.
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Speaking solely for myself, the reasons I'm being critical of this paper is 1. I'm aware of it. I would be critical of any other paper where the hype far exceeds what the paper says but, for obvious reasons, this one is known to me, and 2. as NelliePledge touches on, authors of the paper are involved in the hype. It took a patient to actually get the senior author of the paper to admit, on air, that this study doesn't definitely look at CFS patients - I'd have more time for Pariante, and this paper, if there was actually an interview with him about this study where he corrects the hype unprompted.

Just because a problem is widespread shouldn't mean that we can't call out individual instances of that problem.
 
It is natural that the degree of scrutiny should be commensurate with the degree of publicity and the claims made for the paper.

It is perhaps unfortunate for the lead author, whom one would not wish to discourage, but orchestrated events have overtaken the normal approach.

And Pariante needs to state what is the synthesis of his apparently conflicting positions.
 
I have been wondering whether this trail was pre-registered and if so, what the plan was for data analysis. So far I have found this, which seems to be the plan with details of funding etc.
UK Research and Innovation
Persistent Fatigue Induced by Interferon-alpha: A New Immunological Model for Chronic Fatigue Syndrome
Lead Research Organisation: King's College London
Department Name: Psychological Medicine
https://gtr.ukri.org/projects?ref=MR/J002739/1
Funded Value:
£373,075
Funded Period:
Aug 12 - Aug 16 (I assume that's 2012 to 2016)
Funder:
MRC
Principal Investigator:
Carmine M. Pariante

Abstract

Chronic fatigue syndrome (CFS) is a medical condition in which patients feel persistently and overwhelmingly tired and run down, both physically and mentally. In addition, they have difficulty with concentration, flu-like symptoms and aches and pains. This condition interferes with daily life activity, and, in some patients, is profoundly disabling. Although many years of research have been conduced on CFS, we still do not know what is causing it.

One biological system that is involved in CFS is the "immune system", that is, the system dedicated to fight infections in our body. Indeed, in many cases CFS is triggered by an infection, but then the symptoms continue even after the infection has been eliminated. Specifically, infections are always accompanied by acute fatigue and flu-like symptoms, as a consequence of the infection-driven immune activation; however, in patients with CFS the immune activation and the associated fatigue and flu-like symptoms persist for months or years. Moreover, there is evidence that the immune system is in a state of "hyper-activity" in patients with CFS, as if they were fighting an infective agent, even though they do not have an ongoing infection.

This project aims to understand exactly this process: how the infection and the acute immune activation evolve into CFS, and what are the risk factors that make this process occur in some individuals but not others. Clearly, trying to study this process in subjects experiencing naturally-acquired infections is very difficult, for the unpredictability of these events. In contrast, we want to model the development of CFS by studying a group of patients that have a pre-existing infection (chronic viral hepatitis C, HCV) and that receive a course of treatment (lasting months) with the immune activator, interferon-alpha (IFN-alpha). IFN-alpha is the treatment of choice for HCV infection. Because it activates the immune system, IFN-alpha also induces fatigue and flu-like symptoms in all patients. Moreover, and 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, for 6 months or even one year after the cessation of IFN-alpha. This phenomenon strikingly resembles CFS, which, as mentioned above, also persists after the infective/immune trigger has been eliminated. Therefore, we are proposing to use IFN-alpha as a model to understand how an immune trigger induces persistent fatigue even when the initial immune trigger is no longer present.

To do this, we will assess these patients throughout the many months of IFN-alpha treatment and at 6 months after cessation of treatment, in order to identify those with persistent "post-IFN-alpha-treatment" fatigue, and understand what biological and clinical changes lead to this outcome. Moreover, we will compare these patients with a group of patients with CFS and with a group of healthy individuals, conducting the same biological and clinical assessment. We will measure changes occurring in blood hormones that are relevant to the immune function, such as "cytokines" and "cortisol". In addition, we will asses changes in measures of well-being, including physical fitness, concentration, sleep and mood.

We are confident that creating and validating this model of CFS will generate a host of future studies aimed at improving the health of people with CFS. For example, we will be able to build a check-list of blood measures that could predict who will, and who will not, develop CFS; we will test novel treatments for "post-IFN-alpha-treatment" fatigue, facilitated by the fact that these patients are homogeneous in their clinical background, and then extend these treatments to patients with CFS; and, finally, we will truly understand what happens in the body during the development of CFS, and thus identify novel therapeutic approaches to interrupt this development.
Technical Summary
We propose to model chronic fatigue syndrome (CFS) by studying patients taking interferon-alpha (IFN-alpha) for chronic viral hepatitis C (HCV) infection. IFN-alpha treatment leads to acute fatigue in the majority of patients. Most importantly, a proportion of patients continue to experience persistent fatigue, together with other CFS-like-symptoms, for many months after the cessation of treatment, that is, in the absence of the pro-inflammatory stimulus. This phenomenon strikingly resembles CFS, which also persists after the viral/immune trigger has been eliminated.

In order to develop this as a model of CFS, in our three-year project we want to:
1) assess a cohort (n=100) of patients throughout the IFN-alpha treatment and at 6 months after cessation of treatment, and identify the group who develop the persistent post-treatment fatigue (expected n=50);
2) validate this model, by comparing the clinical and biomarkers profiles in patients who experience persistent post-treatment fatigue, patients with CFS (n=50), and healthy controls (n=50);
3) identify the risk factors and the biomarkers trajectories (before and during IFN-alpha treatment) that identify those patients who will later experience persistent post-treatment fatigue.

We will measure: fatigue, mood, and other CFS-like symptoms; medical and psychiatric history; childhood and recent stressors; social support; illness and treatment perceptions; physical fitness; quality of life; and occupational function. Moreover, we will measure blood biomarkers: serum cytokines; cortisol at awakening and during the day; and leukocytes gene expression.

The project will build onto an existing pilot study in HCV patients, an established collaboration with Liver Units across London, and the research-led clinical service for CFS patients at King's College Hospital. Thus, the project has great chances of success.

Planned Impact
Our research on chronic fatigue syndrome (CFS) will benefit health and biological scientists; policy makers; stakeholders in health care; the interested lay public (especially those with a personal investment in understanding CFS), and, finally, patients with CFS.

Social and health scientists will benefit from our data: we will explain the mechanisms underlying the development of chronic fatigue, offer novel aetiological hypotheses to be confirmed in CFS patients, identify a group who are particularly indicated to test novel therapeutic interventions, and suggest new potential biological targets for the pharmacological treatment of CFS.

Policy makers will benefit from the evidence offered by our study: it will guide them in prioritising resources, in the difficult times ahead, by identifying important stages in the development of chronic fatigues and hence where and when to deliver screening and intervention programmes.

Stakeholders will benefit from understanding what happens to people while they are developing chronic fatigue: charities, non-governmental organisations, and regulatory bodies, all aimed at improving the clinical and social outcomes of CFS patients, will want to know how health, well-being, quality of life and occupational functioning is impacted by changes in biology and behaviour, and how these people can thus be helped.

Finally, the lay public, and especially patients and carers who have been personally touched by CFS, will benefit from all of our work: a non-stigmatising approach based on a sound biological basis, and an explanatory model that is not deterministic and that emphasises not only risk factors but also the protective factors that could be sought out.
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Key points I note from this:
They did not come anywhere near reaching the 100 patients, 50 with persistent fatigue target.
They have not reported on most of the things they said they would measure.
No mention anywhere of PEM in the description of CFS.
Their confidence that this is a valid model for CFS.
Very ambitious claims about usefulness in future screening and intervention programs.

Edit: Also described in this document from the MEA about MRC funded projects.
https://www.meassociation.org.uk/wp...04/Information-for-portfolio_FINAL-2-copy.pdf
 
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MEMarge said:
Their CEO is off, having surgery, so I suspect some of their other activities may be reduced for a while.
Hopefully they are concentrating on removing BPS info from their website.
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Sonya doesn’t do much aside from CMRC stuff recently it seems and that’s also cooling off as there’s no conference next year and they have many other staff, so I doubt it’s that. They are still keeping a Facebook page going, and discussing it with tweets isn’t any more Work than Facebook. They usually do both.
 
Not sure whether anyone else has noted here [apols if so, but these are the things that stood out for me], but a few limitations I noticed, that run contrary to the hyped media version presented:

First, we acknowledge that we can only speculate at this stage on whether or not the mechanisms underlying the persistence of fatigue in CFS and IFN-α induced PF are related.
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They didn't even measure IFN-a in the CFS pt group, either in vivo or in vitro. Maybe an in vitro challenge (like in the Lever et al 1988 study) should be their next step if they want to draw parallels?

The benefit of our proxy model is this opportunity to capture measures before and during the response to an early immune trigger,
which would be impossible to achieve in a CFS population within the remit of available resources.
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In addition, the differences between the HCV and CFS populations were such that it was not possible to recruit a matched CFS group (e.g. 80 vs. 31% males between groups). The healthy control group were therefore matched to the combined HCV and CFS group.
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Also of relevance, the CFS sample was recruited from a specialist service, and thus had an established diagnosis and long (average of 7 years) duration of illness, and as such were different from the PF groups that only had 6 months of post- IFN-α fatigue.
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There were also differences in fatigue "levels" between the groups:
In terms of fatigue severity (measured with the CFQ), there were significant differences between groups (p < 0.001), with CFS patients having the most severe symptoms (26.0 ± 0.6; p < 0.001 vs. all other groups) and the PF patients with an intermediate CFS-like phenotype (17.0±0.8; p < 0.001 vs. RF and controls), while RF and controls were, expectedly, the lowest and indistinguishable (10.6±0.5 and 11.6±0.3, respectively). The more severe fatigue in CFS patients than in the PF patients is understandable, considering that they had been referred to a specialist service for treatment, and the longer length of illness in this group (84±12 months in CFS vs. 6 months in the PF group).
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Note that they considered a CFQ score <18 to be "in the normal range".

Of note, our approach to categorise fatigue as ‘resolved’ (returned to the same level or lower than baseline), and ‘persistent’ (higher than baseline) may also attract some criticism given that this could mean that even a 1-point change on the CFQ can determine the classification. However, we believe this to be justified in order for us to focus on change in the individual in response to the trigger, where baseline fatigue is acknowledged, and in the context of additional changes in fatigue during IFN-α.
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chrisb said:
And Pariante needs to state what is the synthesis of his apparently conflicting positions.
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I think maybe Pariente needs to realise that if he wants to be taken seriously as an ME/CFS scholar he needs to make it clear what he thinks. As it is the impression we get is that t either he does not really know what he thinks and is muddled, or he is trying to please different people different ways - in publication and in popular comments.

This is something that the BPS people need to get right if they are ever going to have any credibility outside their own circle. They have to demonstrate they actually know what they mean. As a disinterested academic observer I am unimpressed.
 
Andy said:
Just because a problem is widespread shouldn't mean that we can't call out individual instances of that problem.
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We most definitely should highlight problems with the study. The question is how far should we go, given that despite the hype this study is not very relevant. If it starts gaining traction as though it were relevant, aside from poor reporting, then the need for more criticism will rise. The first I would be sure to mention is that Oxford should be retired, and any study using it has built-in obsolescence.

To me the comments that most disturb me are patients taking this hype at face value, often in the comments sections of newspaper articles reporting this. It is mildly disturbing to me that some in our community are vulnerable to this kind of hype. One actually said they were looking forward to a cure, clearly in reference to this research, and that this finally validates CFS is real. More and more reading forums are becoming scientifically literate, but many in the community are not.
 
alex3619 said:
To me the comments that most disturb me are patients taking this hype at face value, often in the comments sections of newspaper articles reporting this. It is mildly disturbing to me that some in our community are vulnerable to this kind of hype. One actually said they were looking forward to a cure
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I thought this too; with the interviewer emphasising that CP is Prof of Biological Psychiatry.
This research appears to be their answer to the call for more biological research into ME and on the surface it sounds as though it is. By openly criticising it feeds into the 'militant minority against research' narrative that they have previously successfully used to try and silence their critics.

I think (as some twitter posters are already doing) just pointing out that this is not a study of ME/CFS patients, and citing other more deserving research on the involvement of the immune system in research that actually uses pwME as subjects is the best way to counteract.

Unfortunately, getting the media to follow suit is another matter.
 
Also worrying is that there is a discussion of this trial on another forum where it is seen as adding to the evidence that vaccines are only a way for companies to make money and are making people sick. More immune activation, more fatigue so vaccine more immune activation more fatigue.
 
MEMarge said:
Their CEO is off, having surgery, so I suspect some of their other activities may be reduced for a while.
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If true, I'm sure we all wish Sonya all the very best and a fast and full recovery.

Perhaps we could ask @Action for M.E. that if you are going to respond to this study, you will take into full consideration the points raised in this thread and in the excellent blog by @sTeamTraen

Tagging in @phil_in_bristol
 
Hi - I've just got back from a holiday & I think AfME are probably on the festive break now, so not sure i can do much to influence! Whilst in Spain, i did see a notice from AfME saying that they had concerns about the fact that this is clearly NOT a study of ME/CFS patients, and that the criteria wasn't as robust as we should expect (essential , in my personal opinion).

I did speak to Carmine at the CMRC conference , as I wasn't happy, but he said: a) yes, he felt awful that these people were feeling so shit / wrecked for months after their treatment, and b) The study was basically being opportunistic - here we had (no need to recruit) patients that we could study the effects of & likelihood of post-in_alpha induced fatigue (as some would go on to develop chronic fatigue - yeah, not ME/CFS, but.....), so they could study cytokine levels etc before & after. So it was an opportunity to study the effects , & leaves questions un answered, but on balance, I think it's good it got studied. Carmine & his team clearly know there's something amiss (he may be a psychiatrist, but he certainly believes it's a physical disease!!!!). Btu of course no answers for sufferers here. & I was convinced ME/CFS was immune system dysfunction when i got ill a mere 21 years ago!!!!!

However, like most people, I'm surprised at the coverage in the press - shows what SMC influence exists, shocking - there's been 1000s of studies with more patients (this one had 18????), just not reported by the UK press as SMC wasn't interested. Absurd & unbalanced. SMC has too much influence. Hmmm.
 
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