Deficient EBV-specific B- and T-cell response in patients with chronic fatigue syndrome.

[Woolie]

I have a modest proposal. Since grants often include money to cover publication costs, and many groups funded by NIH or CDC amount to government-funded lobbies for further funding, why not include an advertising disclaimer on all publications produced by this process?

This is maybe a bit off-topic, @anciendaze, but what you're describing is pretty much the open-access model of publication, which is where the academic/research world is heading. This is the model where the author pays a fee to the journal, and then readers can access the article free of charge. Many funding bodies require that findings from research they fund should be freely available, so they directly cover such fees.

Basically, if you can access and read an article without a journal subscription, then that article is open access - that is, the journal agreed, for a fee, to waive its right to charge readers to access the article. This fee is paid for by the authors.

Open access is not bad, and it doesn't mean low quality. It all depends on the journal. There are totally rubbish open access journals, rogues that will publish any old crap for a fee. Noone in the business takes these journals seriously. But there are also very high quality open access journals (like PlosONE). Also, most conventional journals now offer authors this option after they accept a paper - you can pay extra to make your article open access (note the key word "after acceptance"). These journals make a policy of not preferring papers on the basis of fees alone. This policy is important to their success; otherwise their status will plummet, and noone will want to read articles from them, let alone publish their own in them.

As readers, we want open access - we don't want articles about ME to be "behind a pay wall".

But your concerns about how to judge article quality are well placed. Here's my advice: an easy metric is to check the journal's Impact Factor, stated on the journal home page. Its not a complete guide, but generally, the higher the impact factor, the more rigorous the selection process, and the higher quality the articles. Anything above 2 is very respectable; anything above 6 is god-like.

 

[anciendaze]

@Woolie

In general I approve of open access, but that is not what I was aiming for. I was concerned that many publications have become no more than means of advertising how successful you have been at acquiring funding, not the quality of any result which might change the world. You will find information about the people employed and the equipment used, powerful allies of your group, etc., etc. This remains true even if the bottom line for patients is that any proposed advance in treatment will reach their level of the food chain after they are dead. (My repeated comments about the total lack of results, beyond acquiring funding and self promotion, from the PACE study might clue people in.)

I'm afraid the best predictor of future funding is simply past funding, and organizations actively promoting change are necessarily at a distinct disadvantage here. This is precisely how any bureaucracy likes things to remain.

 

[Woolie]

In general I approve of open access, but that is not what I was aiming for. I was concerned that many publications have become no more than means of advertising how successful you have been at acquiring funding, not the quality of any result which might change the world. You will find information about the people employed and the equipment used, powerful allies of your group, etc., etc. This remains true even if the bottom line for patients is that any proposed advance in treatment will reach their level of the food chain after they are dead. (My repeated comments about the total lack of results, beyond acquiring funding and self promotion, from the PACE study might clue people in.)

The peer review process is not perfect, sure. Stuff gets out there which is crap. Some of this is pure chance (who the reviewers were); some is due to different standards in different disciplines, and even different points of view/orientation in the same discipline. Hardly any of it is to do with where you got your funding. As a previously government-funded researcher, both here in New Zealand and before that in the US (NIH), I can assure you that its totally the other way around: once you get funding, you are under enormous pressure to produce something worthwhile out of that funding, and the journals you submit to do not offer you any smoother ride!

Sure, status might help you a bit. But status comes from a lot of sources, not just funding - including the institution you work in, and your previous publication history. The last one is in my opinion the single most important factor.

Desperation to publish is a factor for groups with funding, they're motivated to dress up their results in any way they can to get them out there and meet the goals of their proposal. But this is a ubiquitous problem in research/academia, we're all desperate to publish to keep our jobs, funding or no funding!

I'm afraid the best predictor of future funding is simply past funding...

You're right: a large predictor of future funding is previous funding. But there's probably a lot of things going on here. One might even be competency. For example, a large predictor of which students will get A's in a class is whether they got A's in previous classes. We don't automatically assume all teachers are just going on past marks!

But having recently served on a government research funding board, there's lots of luck in it too - which experts are chosen to evaluate your proposal, and also how much critical evaluation there is in your field. You might be unlucky enough to straddle two disciplines in your research, one sympathetic to your work and the other critical. Result: mixed reviews, so no funding for you! In general, I have found that health-related applied Psychology proposals are not as rigorously critically evaluated as some other disciplines (now there's a point could be useful to know). Philosophers and cognitive scientists are the most brutally critical!

....and organizations actively promoting change are necessarily at a distinct disadvantage here. This is precisely how any bureaucracy likes things to remain.

You have a point here, although I would describe it differently. Its because grant proposals are reviewed by other researchers. And the more revolutionary an idea, the more likely it is to invite criticism from at least some reviewers. And since funding goes only to those proposals with consistent approval, the innovators lose out. In MECFS there are also other problems with definition and heterogeneity, which reviewers are likely to point out, and that's actually a fair criticism and one that's hard to address in our current state of knowledge (I personally like the subset approach, but not all agree...).

I'm just trying to give you a bit of a richer picture of what its really like out there. In MECFS, I don't think the real enemy is "bureaucracy", the establishment, the funding bodies, the researchers or even the doctors themselves. It is they way people have been taught to think in different disciplines and clinical professions. That's where we need to fight our war. The more we understand the enemy, the better!

@Jonathan Edwards might have some more insights to add here, and many others here who've been involved in applying for or evaluating grant proposals, reviewing journal articles etc, whose names I don't know.

(you're probably thinking now Woolie's sitting pretty, not much of an MECFS case, she even has a career!. That's true but past tense. Been bedbound for nearly two months now and am probably going to lose my job )

 

[anciendaze]

@Woolie

My own views may well be jaundiced by exposure to a government agency doing cutting-edge research, NASA. I actually warned that the Shuttle program was heading for disaster, and even specifically identified the tiles of the thermal protection system as the component that would fail next. I have since had to grapple with the problem of how otherwise intelligent, educated and hard-working people could constitute a dysfunctional organization which consumed literally billions of dollars in funding each year while inevitably moving in a direction which would leave the agency and country without a means of launching either humans or large payloads into space. This pretty well destroyed the raison d'être of the entire manned space program.

My personal exposure to lapses in reasoning by medical professionals seems to have begun long before yours, and during the time when I have been mostly confined to bed, but able to read, I have put considerable effort into exploring the way past innovations in medicine actually took place. My dismal conclusion is that medical innovators don't convince their opponents, they outlive them.

People regularly tell me the things I'm talking about are part of the bad old days of medicine, and all those institutional problems have been corrected. I have my doubts.

We aren't all that far from the day that Robert Koch presented evidence at a conference that TB was caused by mycobacterium tuberculosis, and Rudolf Virchow led a walkout by the majority of senior doctors. Virchow had previously spoken against Semmelweis' view that doctors were carrying the infectious agent of puerperal fever from autopsies to maternity patients -- without ever allowing Semmelweis himself to publish evidence in a journal. In terms of sociology Virchow's subject of cell biology remains a core part of medical curricula while Koch's bacteriology is something of a specialization. This despite the fact that you can't find a human who doesn't have more bacterial DNA than human DNA in his/her body. Koch and Pasteur were often bitterly opposed, and the subject of virology is yet another specialization which tends to be isolated from the rest of medicine, despite the existence of even active viruses passed through the germ line, like HHV6. You can't find humans without viruses, so you can't isolate virology from general medicine, though this is precisely the sociological effect.

I've had some experience with innovation in areas far from medicine. The chief thing I've learned is that you can't avoid making mistakes. Sometimes you have to do things precisely because the majority of people in the field, especially authorities, are convinced they will not work. You need to question common assumptions.

This is not going to make it through funding committees. It will not pass review by authorities, when the primary requirement for becoming an authority is that you are good at avoiding perceived mistakes, and shooting down ideas proposed by others, irrespective of your own ability to generate original ideas.

The role of bureaucracy in the area of medicine particularly concerning us on this forum is fairly simple: the same government agency (in the U.S. it is HHS) responsible for research is also responsible for disability payments. It is under constant pressure to reduce spending in the short term by denying disability benefits wherever possible without unacceptable political repercussions. Any time someone comes up with diagnostic criteria or biomarkers which would make it easier to classify ME/CFS patients as disabled this will inevitably lead to pointed questions from higher up. Nobody has to write memos directing people lower down the hierarchy to ignore these nuts. After a few episodes like the ones we have seen in the past 30 years every researcher will understand that such proposals should not be made unless they are backed by irrefutable evidence. Such evidence is not required for advice to treat patients with antidepressants, CBT or GET while telling them this is a personal problem of theirs.

 

[Woolie]

@anciendaze, You're hitting on some important issues here, and they're the human/discipline ones, to do with how people think in different disciplines, and how they respond to challenges to their point of view. Also the one about different burdens of proof for medical vs. psychological conditions.

My dismal conclusion is that medical innovators don't convince their opponents, they outlive them.

Yes, bad ideas aren't disproven, as many people might think, its more a process of slow attrition where one idea simply begins to gain more favour than another.

My personal exposure to lapses in reasoning by medical professionals seems to have begun long before yours, and during the time when I have been mostly confined to bed, but able to read,

After 25 years of being ill, and struggling on with my work and life despite huge losses in time (3 whole years at the onset - almost completely bedbound- then very big periods after that), I do feel offended by that statement. Also as an academic/researcher in cognitive neuroscience of some 28 years' standing, I think my exposure to "medical reasoning" goes back a long way too.

I'm less interested in the fact of these outrageous "lapses" as you call them; my interest is more on the reasons. But I think I might be alone in that, so I'll respectfully sign off from this conversation now.

 

[anciendaze]

After 25 years of being ill, and struggling on with my work and life despite huge losses in time (3 whole years at the onset - almost completely bedbound- then very big periods after that), I do feel offended by that statement. Also as an academic/researcher in cognitive neuroscience of some 28 years' standing, I think my exposure to "medical reasoning" goes back a long way too...

My apologies if I've offended you. Your experience parallels the last 23 years of mine, including being bedbound and struggling back, but my problems started much earlier, at a time when the ominous term chronic fatigue syndrome had not been invented. That statement was not intended to be patronizing, I simply noticed that you had been able to hold a job more recently. Prior to being thoroughly disabled I had many encounters with the medical profession which did nothing to help me in the struggle to maintain a career. The "lapses in reasoning" to which I was referring are much more apparent from the perspective of patients who do not benefit than from a general academic standpoint. The reference to reading while bedbound was simply intended as an explanation that I am self-educated in the field, not a claim of any authority. If my arguments will not stand by themselves, invoking authority will not save them.

My references to the not-so-ancient history of medicine have generally been chosen to avoid reference to living authorities. I am now old enough to have known people who had vagotomies at a time when a neuropsychiatric theory about peptic ulcers held sway. That controversy alone would have convinced me that the only way to falsify a theory of psychological causation is to invoke tests outside of psychology. This is not a good characteristic for any field of science.

 

[Sidereal]

Some interesting comments by Dr Fluge of the rituximab fame:

The long lag time from rapid initial B-cell depletion to start of the clinical response (2-8 months) is why we do not think elimination of EBV or CMV is the principle mechanism for symptom relief in our patients. In my work as a lymphoma oncologist, I have treated a few patients with chronic EBV infection, with moderate lymphadenopathy, night sweats and general symptoms for several years, and with no clear clinical benefit from valganciclovir.

In one patient, the B-cells in bone marrow and in lymph nodes were packed with EBV and she had a high EBV titer in her peripheral blood. When given rituximab, her symptoms waned in a few days after start of treatment – very different from what we see when treating ME/CFS patients.

http://simmaronresearch.com/2015/01/chronic-fatigue-syndrome-rituximab-fluge-mella/

 

[Woolie]

Hi @Sidereal, thanks for sharing this. I asked Jonathan Edwards about this, and his response was the same: He thinks the longer "incubation time" from rituximab to improvement in ME indicates a different mechanism of action.

It would seem to me tricky to read that much into times to respond, since the symptom severity and outcome measures are different for the different illnesses. But hell, I really don't know, I'm no doctor!

 

[alex3619]

Really interesting, snowathlete.

I had EBV and recovered in 3 weeks. Then I relapsed and couldn't recover the second time, developing CFS, which fits "an impaired ability to control early steps of EBV reactivation" to a dime.

The next obvious question: Does anyone know what can boost the "EBV-specific B- and T-Cell memory response?"

This is about understanding WHY the problem occurs and dealing with that. There is no way to boost subtypes. Any treatment would be a blunt instrument unless it addresses the cause. I do not expect that simple supplements will fix this. It may be genetic, epigenetic, or viral.

What can be done with supplements, perhaps, is to support other anti-EBV pathways. This would not fix the problem however.

Now once we understand the mechanism there may indeed be things we can do.

 

[alex3619]

Second, these patients generally do not show antibodies to EBV nuclear antigen. This strongly suggests to me that the virus is manipulating immune response to protect itself. If the virus is capable of exploiting clonal expansion of B-cells, without lytic replication, any replication of viral DNA must be taking place in one of several "latent" phases. Infected cells could then produce more infected cells via mitosis. The common finding that ME/CFS patients exhibit polyclonal expansion of B-cells makes me think this is in fact taking place.

This is my suspicion also.

 

[alex3619]

Can you tell me more about this, @heapsreal? I thought that vaccines only worked preventitively. So once the horse was bolted, so to speak, they were no good?

Actually I don't think they are "no good" just limited. There is also the issue that we have some kind of depletion of relevant B cells - so immunization might have a flawed effect.

There is risk of course from adjuvants inducing further immune issues.

A vaccine would clearly present to the immune system a target. That would increase surveillance and response. A vaccine will take several weeks to really kick in. Acute infections are about hours or days. Hence it will always arrive too late. Yet for chronic infections this is not the case. Its not like it resolves within a few weeks.

Immunotherapy can be vastly more complicated than just vaccination, and can be very very expensive. I do not recall reading the paper (doh, yet another with memory issues) but such therapies often involve removing cells, training them, and then transfusing them back. Very difficult, very costly.

 

[alex3619]

@Woolie, @anciendaze , my own position on this is that you are both right. You are discussing different aspects of the same beast. This is not a simple issue. It is layered, multifactorial, and deep. The debate is even expanded by politics and funding issues. Its not just government that produces funding distortions, but private firms. That can be direct, or indirect. Economic theory, social and political ideology ... this is a complex mix of unreason at many levels, and not easy to distil into simple concepts. If it were simple it would have been solved long ago I suspect.

Society and organizations are supposed to (in theory) have checks and balances. Sadly we not only have a lack of transparency and corrective mechanisms in many cases, but corrective mechanisms such as the fourth estate (media) are failing due to economic viability and a change of culture. Political systems are supposed to be the final overarching corrective mechanism, but they fail regularly on even simple issues. These are not simple issues.

I would also like to point out that reviewer pools for research and grants can be limited or distorted. If a subgroup in the research field gets some dominance then they can pass favourable reviews to chosen projects, and cut out the competition. This does not have to be deliberate either, but due to how they reason about these issues.

The CBT/GET get researchers are a small but highly influential group. Their own theories lack decent substantiation, and lack validity testing, but their influence goes way outside their own group. Such insular groups can be academically successful for a long time, and often review each other for grants or publication, but in the end unless they are correct they become discredited. They can claim they wear a suit of gold all they want, but in the end someone will famously point out they are naked (to borrow from the story The Emperors New Clothes).

 

[Woolie]

Immunotherapy can be vastly more complicated than just vaccination, and can be very very expensive. I do not recall reading the paper (doh, yet another with memory issues) but such therapies often involve removing cells, training them, and then transfusing them back. Very difficult, very costly.

Yep, this is pretty much what it was (heapsreal posted the article link somewhere in the thread above).

 

[heapsreal]

Can you tell me more about this, @heapsreal? I thought that vaccines only worked preventitively. So once the horse was bolted, so to speak, they were no good?

Probably not really a vaccine as such, wrong terminology from me. Somehow they turn on a stronger T cell response to ebv. Still early days with research to know.