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Learning CFS: the Lerner Antiviral Treatment Trial Succeeds

Comments

(Not on the Lerner study)

"An even vaguely healthy immune system should be able to keep babesia under control, for instance."

That's a confusing issue, to me; if a person has multiple (5) tick infections that have gone undx'd and untreated, then I can almost understand how EMV & CMV might reactivate - almost. But once they're detected & treated, you'd think the immune system would be considered at least somewhat healthy at that point...

Could (one of?) the especially confouding issue here be the presence of HLA DR1? (This can prevent a person's body from mounting a sufficient immune response against borrelia, even if that's the *only* infection.)

http://www.ncbi.nlm.nih.gov/pubmed/11532615

It's not likely the issue for a significant # of people, tho, since I think HLA DR1 occurrence rate is fairly low.
Don't know if this is of any interest to you. It's about the only biomedical study ever done in the Rep. of Ireland (the small adrenal glands is sometimes said to be from a hospital a few miles away from me in Dublin but I'm 98% it was done in England - the radiologist or radiographer is from where the authors used to work but by the time the work was published, the corresponding author had moved back to Ireland). We do try to do our bit in Ireland by raising money for research.

Fitzgibbon E, Whelto H, Smith T.

HLA DR class II antigens and post viral fatigue syndrome [abstract].

J Chronic Fatigue Syndr 1996;2:166.

166 JOURNAL OF CHRONIC FATIGUE SYNDROME
HLA-DR CLASS I1 ANTIGENS AND POST-VIRAL FATIGUE
SYNDROME.
E. J. Fitzgibbon, H. J. Whelton, and T. J. Smith.

Class I1 major histocompatibility complex (MHC) glycoproteins,
encoded by the HLA-D locus, are involved in the response of T
cells to antigen. Recent genetic studies suggest that there may be an
association of Post-Viral Fatigue Syndrome (PVFS) with particular
HLA types. The aim of this study is to investigate the role of
irnrnunogenetic factors in susceptibility to and development of
PVFS. The major specific goal is to determine if there is an association
between certain HLA-D antigen types and PVFS, specifically
HLA-DRB 1. For this study, a group of 48 unrelated Irish individuals
with clinically defined PVFS were analyzed. Polymerase chain
reaction (PCR) amplification of the second exon within the HLADRBl
gene was carried out using seven PCR primer sets.

These result in the differentiation of individuals into HLA-DR
haplotypes. Restriction enzyme digestion of the PCR products was
then carried out to further subdivide the genetic haplotypes of the
individuals. The allele frequencies obtained were compared to a
healthy British Caucasian control population. Statistical signifi- '
cance was estimated using the Chi-squared test with Yates correction.
The data suggests that there may be a negative association
between HLA-DR4 haplotypes PVFS (p < 0.001).

AUTHOR NOTE
T. J. Smith is affiliated with the National Diagnostics Centre, BioRcscarch
Ireland, University College Galway, Ireland.
E. J. Fitzgibbon is affiliated with the Department of Pharmacology,
University College Galway, Ireland.
H. J. Whelton and T. J. Smith are affiliated with the National Diagnostics ,
Centre, BioResearch Ireland,University Collegc Galway, Ireland.
It was a poster at the Belgium CFS conference in 1995. You won't find it on PubMed.
 
BTW -- I think someone said in this thread that patients with identified herpesvirus infections are automatically excluded from a CFS diagnosis. It that, in fact, true? Is that true of Drs Klimas, Petersen, and Montoya's patients?

Forgive (and correct) me if I've misinterpreted something. My fog is still a long way from cleared.
One person claimed it. I don't recall seeing it in studies when they were listing exclusions (although I don't swear it has never been there as my eyes can glaze over occasionally but there have certainly been many studies done using the Fukuda where they listed the exclusions and it wasn't there).
 
Firstly, let me say I found this study interesting.
And it's useful to have something in print. [Aside: It is frustrating that doctors such as Paul Cheney have published so little - unfortunately, that can mean other doctors are slow to take ideas on board].

I am frustrated with the lack of the data from the Holter Monitors at the end.

In the methods we get all this information about how it was scored:


It is even mentioned in the abstract:


But unless I missed something, we are given virtually no info on how the patients were at the end (and indeed aren't even given the data on the initial "total severity scores")



From the discussion:


From the introduction:
Great observation @Ill since 1989 - I've copied and pasted this and emailed it to Dr. Lerner and his team. I'll see what information I can gather from them and will report back.
 
Does this link in at all with the cardiac abnormalities Julia Newton talks about?

http://www.forums.aboutmecfs.org/sh...ponse-to-standing-in-Chronic-Fatigue-Syndrome

http://listserv.nodak.edu/cgi-bin/wa.exe?A2=ind1005E&L=CO-CURE&P=R143&I=-3&X=3CC0EE1C3F520304B4

(I know she doesn't mention viruses)
[Aside: I stopped studying biology aged 16 so tend to get a bit lost on cardiac issues]
Full paper now at: http://www.imet.ie/imet_documents/Impaired CV responses to standing in CFS.pdf
 
One person claimed it. I don't recall seeing it in studies when they were listing exclusions (although I don't swear it has never been there as my eyes can glaze over occasionally but there have certainly been many studies done using the Fukuda where they listed the exclusions and it wasn't there).
That is absolutely not true. In fact Dannybex I think it was posted material from the Fukuda definition specifically stating that EBV and herpesvirus infection were allowed.
 
That is absolutely not true. In fact Dannybex I think it was posted material from the Fukuda definition specifically stating that EBV and herpesvirus infection were allowed.
Just to be clear, you're not disagreeing with me, you're disagreeing with the suggestion that evidence of EBV is an exclusion.
 
While I applaud the efforts of Dr. Lerner and his team of volunteers, I found this paper to be very difficult to read and interpret. Much of the analysis was confusing and in some parts extraneous.

1. At its core, it is a case series of 142 patients and their treatment over time, rather than a clinical trial. There isn't a group really to compare people with as all were treated and the ones who stopped treatment weren't followed. In a trial, the high drop-out rate would be a concern -- when I initially read the paper, I thought everyone was followed for the full-time but it turns out many by week 18, about 30% of the initial 106 in group A had already dropped out in Table 3. We don't know what happened to these people. To be fair, the writers did default them to being "non-responders" which is acceptable.

2. Putting aside point 1, we can still get use the info on the people who were treated. I'm not convinced that people returned to "normal" or "near normal" life. From the article: " An EIPS of 0–5 is diagnostic of CFS. At EIPS values 6–10, patients no longer have CFS." At EIPS of 6, working 40 hours a week in a sedentary job, light limited housekeeping and social activities, with naps. Or at 7, without naps, does not strike me as a normal or near-normal life. I can appreciate improvement but don't call it normal. To me, near-normal is when you can do everything you want short of strenuous physical labor or exercise. Did people return to a similar job as the one they were doing before illness or did they need to downshift (i.e. they had no choice)? Also, it says that people had cognitive improvement but there is neither subjective nor objective evidence of this in the paper, other than the overall EIPS score (which doesn't talk about cognitive effects). Where is the immunologic data? Is this considered the same as the infectious disease measures?

3. In terms of the ID issues, we get a measure of titers (1:160) for HHV-6 but we don't get titer numbers for the other herpesviruses. It would be useful to know, even if those tests are based on Dr. Lerner's own lab tests. Also, Gerwyn's point about EBV has a point. Most people with positive EBV IgM, regardless of titers, would be considered under traditional medical standards to have an "active" or "very recent" EBV infection. IgM normally goes away pretty quickly after EBV mono. Now, it's true that maybe prior docs did not pay attention to IgM, didn't treat, or didn't test for it. My concern is how common is it for people with CFS to have positive IgMs (not IgG)? My impression, at least from people who have reported their results, is that it is not. Still interesting as these folks should get treated but just to put it into context.

4. Figure 3 is somewhat confusing in that the EIPS for overall Group A patients is not 106. The number of group A patients declines over time and their make-up varies over time. For example, randomly taking week 48 and looking at table 3, there were 30 total group A and data for 28 responders. To my eye, this means there is only data on 2 (30-28) non-responders so the comparison is with a very small number. Most of the group A is made up heavily of responders as time goes on so why have the comparison this way?

Also what is with the missing lower standard deviation lines in Figure 3? I take it the blue point is the mean and there is an upper SD line but no lower?

Perhaps all this sounds harsh and I am grateful that the group published the data they did but I don't think that my questions are any different from what they would have received from some other journal. I'd appreciate any responses and hope that my questions will help them in the future.

3.
 
[Aside: It is frustrating that doctors such as Paul Cheney have published so little - unfortunately, that can mean other doctors are slow to take ideas on board].

Seconded here. I trust Cheney's early work but his claims of success later on without anything written (aside from some non-mainstream journals and a few conferences) has made me skeptical of them and his motives. I am prepared to change my opinion should he publish or be more transparent.
 
Hi

The problem that Cheney faces is that he is almost unpublishable. This is part of the prejudice about ME and CFS: since CFS doesn't exist then anyone who is making claims is a quack, and if they keep doing so they are a serial quack, and are best ignored. I think this was discussed in connection with Cheney in Oslers Web.

This is changing, and I hope much more research from Cheney and other marginalized doctors and researchers will get the attention it deserves in the future.

Bye
Alex

[Aside: It is frustrating that doctors such as Paul Cheney have published so little - unfortunately, that can mean other doctors are slow to take ideas on board].

Seconded here. I trust Cheney's early work but his claims of success later on without anything written (aside from some non-mainstream journals and a few conferences) has made me skeptical of them and his motives. I am prepared to change my opinion should he publish or be more transparent.
 
Hi

The problem that Cheney faces is that he is almost unpublishable. This is part of the prejudice about ME and CFS: since CFS doesn't exist then anyone who is making claims is a quack, and if they keep doing so they are a serial quack, and are best ignored. I think this was discussed in connection with Cheney in Oslers Web.

This is changing, and I hope much more research from Cheney and other marginalized doctors and researchers will get the attention it deserves in the future.

Bye
Alex
The Journal of CFS gave an outlet if somebody couldn't get an article published.

Now there is the Bulletin of the IACFS/ME.
 
Here's a mention of EBV in the Fukuda definition:

http://www.annals.org/content/121/12/953.full

In clinical practice, no additional tests, including laboratory tests and neuroimaging studies, can be recommended for the specific purpose of diagnosing the chronic fatigue syndrome. Tests should be directed toward confirming or excluding other etiologic possibilities. Examples of specific tests that do not confirm or exclude the diagnosis of the chronic fatigue syndrome include serologic tests for Epstein-Barr virus, retroviruses, human herpesvirus 6, enteroviruses, and Candida albicans; tests of immunologic function, including cell population and function studies; and imaging studies, including magnetic resonance imaging scans and radionuclide scans (such as single-photon emission computed tomography and posi-tron emission tomography) of the head.
 
The Journal of CFS gave an outlet if somebody couldn't get an article published.

Now there is the Bulletin of the IACFS/ME.
Paul Cheney was just one example. Byron Hyde is another who hasn't published much - since the early/mid 90s, possibly only twice (Isoprinosine papers - and there were lots of authors on that - and the SPECT scan and thyroid cancer paper). And he's got his own research charity, the Nightingale Research Foundation.
 
Hi

The problem that Cheney faces is that he is almost unpublishable. This is part of the prejudice about ME and CFS: since CFS doesn't exist then anyone who is making claims is a quack, and if they keep doing so they are a serial quack, and are best ignored. I think this was discussed in connection with Cheney in Oslers Web.



This is changing, and I hope much more research from Cheney and other marginalized doctors and researchers will get the attention it deserves in the future.

Bye
Alex

Cheney may have his own reasons for not publishing but being "unpublishable" is an unsupported one. It might have been difficult in the past and some journals (like the big ones) might still have prejudices against CFS but there are many smaller ones that have published CFS papers -- in the past, Lerner has gotten published in In Vivo and the Annals of Internal Medicine, Dr. Chia and others in the Journal of Clinical Pathology, and also the Journal of Clinical Virology. Lesser known journals like Medical Hypotheses or Neuroendocrine Letters have also published on CFS, not to mention the new proliferation of online journals. One way to maybe increase your chances of publication is to submit to journals that have published on CFS before. Not to mention what Dolphin already brought up.

One big point of publishing is to get your information and knowledge out there, even if in a small journal, so others can see what you are doing/ thinking. This can sometimes inspire new ideas or collaborations. Presenting at conferences is good but getting something written, down in paper helps clarity and with legitimacy. In the US, in many situations, what you say has little weight compared to what is written down. Hence, people say "read the fine print."
 
I think Cheney could get published in a second in Medical Hypotheses. Marian Lemle, a mother with no research background, got an article on CFS published there and they publish some wild stuff. He's just not choosing to do it. He was the lead speaker of a big non CFS conference a couple of years ago. He may be controversial but he does have some standing - he could find a way. He probably couldn't get published in a reputable journal - unless he had a really rigorous, buttoned down, all bases covered paper, but he could get published somewhere.
 
While I applaud the efforts of Dr. Lerner and his team of volunteers, I found this paper to be very difficult to read and interpret. Much of the analysis was confusing and in some parts extraneous.

1. At its core, it is a case series of 142 patients and their treatment over time, rather than a clinical trial. There isn't a group really to compare people with as all were treated and the ones who stopped treatment weren't followed. In a trial, the high drop-out rate would be a concern -- when I initially read the paper, I thought everyone was followed for the full-time but it turns out many by week 18, about 30% of the initial 106 in group A had already dropped out in Table 3. We don't know what happened to these people. To be fair, the writers did default them to being "non-responders" which is acceptable.

2. Putting aside point 1, we can still get use the info on the people who were treated. I'm not convinced that people returned to "normal" or "near normal" life. From the article: " An EIPS of 0–5 is diagnostic of CFS. At EIPS values 6–10, patients no longer have CFS." At EIPS of 6, working 40 hours a week in a sedentary job, light limited housekeeping and social activities, with naps. Or at 7, without naps, does not strike me as a normal or near-normal life. I can appreciate improvement but don't call it normal. To me, near-normal is when you can do everything you want short of strenuous physical labor or exercise. Did people return to a similar job as the one they were doing before illness or did they need to downshift (i.e. they had no choice)? Also, it says that people had cognitive improvement but there is neither subjective nor objective evidence of this in the paper, other than the overall EIPS score (which doesn't talk about cognitive effects). Where is the immunologic data? Is this considered the same as the infectious disease measures?

3. In terms of the ID issues, we get a measure of titers (1:160) for HHV-6 but we don't get titer numbers for the other herpesviruses. It would be useful to know, even if those tests are based on Dr. Lerner's own lab tests. Also, Gerwyn's point about EBV has a point. Most people with positive EBV IgM, regardless of titers, would be considered under traditional medical standards to have an "active" or "very recent" EBV infection. IgM normally goes away pretty quickly after EBV mono. Now, it's true that maybe prior docs did not pay attention to IgM, didn't treat, or didn't test for it. My concern is how common is it for people with CFS to have positive IgMs (not IgG)? My impression, at least from people who have reported their results, is that it is not. Still interesting as these folks should get treated but just to put it into context.

4. Figure 3 is somewhat confusing in that the EIPS for overall Group A patients is not 106. The number of group A patients declines over time and their make-up varies over time. For example, randomly taking week 48 and looking at table 3, there were 30 total group A and data for 28 responders. To my eye, this means there is only data on 2 (30-28) non-responders so the comparison is with a very small number. Most of the group A is made up heavily of responders as time goes on so why have the comparison this way?

Also what is with the missing lower standard deviation lines in Figure 3? I take it the blue point is the mean and there is an upper SD line but no lower?

Perhaps all this sounds harsh and I am grateful that the group published the data they did but I don't think that my questions are any different from what they would have received from some other journal. I'd appreciate any responses and hope that my questions will help them in the future.

3.
I think its good to point out the fairly high drop out rate - something I didn't really get upon reading the paper. I agree that the EIPS is not normal health or near normal health. What I was struck by was the average increase of two points or more on the EIPS scale.

With regard to the IgM data my understanding is that he is looking for IgM levels of early proteins (ie non-structural proteins) produced by EBV. He believes the EBV infection is a kind of active but incomplete infection; that is, EBV is producing the non-structural components of the virus but not the structural ones. Dr. Lerner would posit, I believe, that it would be quite uncommon for CFS patients to show high IgM levels to the proteins on the viral coat but common for them to show high Igm levels to proteins produced earlier in the life cycle of the virus. He believes that most physicians simply don't test for early antigens. I agree that it would have been very helpful to get antibody levels from the other viruses in the other paper and I'm not sure why they weren't there.
 
I've just been talking to a researcher and he pointed out several issues with the paper. One, is as Gerwyn said, you cannot divine cause and effect from a paper like this. Its absolutely imperative that a placebo-controlled study be done before you can say anything, anything at all really, about cause and effect.

This is a very stringent area because it involves making policy - it involves having institutions and government agencies - determine how how to treat CFS (or any other type of) patients. Its very difficult for paper a on CFS treatment (or treatment of any other diseases) to make any difference in the research world at large unless its placebo-controlled. In the research world you cannot say that CFS is caused by x or y factor if you con't use a placebo controlled group because you have to have one group that has the factor and gets better and one group that doesn't have the factor and doesn't get better and this paper didn't do that. That paper has not come forth yet.

Another issue was the lack of data on side effects. In order to balance cost and benefit researchers have to know how many people had side effects, what they were and how severe they were. These antiviral drugs has statistically been shown to produce certain level of side effects even in the patients they are helping. Information on side effects is another critical bit of data that the medical community needs to know in order to assess the effectiveness of a treatment.

Gerwyn also had a point about the journal the study was published in; my 'source' (who wishes to remain anonymous and who has CFS) does not believe there is a bias against getting CFS papers published - he believes good journals would love to publish groundbreaking work on CFS - that's the type of thing they live for - but that really good papers with really significant findings are rare. THe XMRV paper was a notable exception. Really good, rigorous papers, he felt, should be able to find their way to really good journals. he fact that this paper was not in a significant journal was not a strong point.

This doesn't mean that Dr. Lerner is wrong in his conclusions at all - it simply means that for the research community to take note of them much more rigorous studies need to be done - as he notes in the interview that he wishes to see done.

Doing a really rigorous study is very difficult and expensive but those studies are important because they do get noticed by the research community and they generally get built upon.

In light of the difficulty of us - laymen - reading and understanding scientific papers we're going to work on a "how to read a scientific paper' paper so that we can assess the strengths research papers. Anyone who wants to help out please PM or email me at phoenixcfs@gmail.com
 
Thanks Cort - interesting
Another issue was the lack of data on side effects. In order to balance cost and benefit researchers have to know how many people had side effects, what they were and how severe they were. These antiviral drugs has statistically been shown to produce certain level of side effects even in the patients they are helping. Information on side effects is another critical bit of data that the medical community needs to know in order to assess the effectiveness of a treatment.
There may need to be more information.
But for anyone who didn't read the paper we were given:
Toxicity
At 4–6 week visits, recorded entries were made for abnormal
white blood cells, platelet counts, aminotransferases, participation
in a smaller, randomized, blinded, placebo-controlled
trial, weight gain or loss, substitution of famciclovir for
valacyclovir, and any changes in dosage of valganciclovir,
valacyclovir, or famciclovir.30
Toxicity
After beginning valacyclovir (or famciclovir) or valganciclovir
there were two to 10 weeks with worsening initial
symptoms, decreased EIPS, and increased syncope, palpitations,
chest pain, and muscle pain. These transiently worsening
symptoms are Jarisch-Herxheimer reactions. At these
times CFS patients were usually afebrile and CBC, AST,
ALT, and creatinine remained normal. No patient had serious
toxicity. Transient increases in aminotransferases were
seen with valganciclovir. Aminotransferase abnormalities
resolved with modifications in administration of valganciclovir.
There was no serious toxicity among groups A or B
CFS patients. Fourteen Group A CFS patients with EBV
received famciclovir for a mean of 0.88 years. The mean
baseline EIPS value for these patients was 3.9, and the 24
three-month interval EIPS value was 5.89 for the patients, all
of whom received valacyclovir for portions of their antiviral
treatment. The value of famciclovir in CFS illness cannot be
estimated from these data.
Gerwyn also had a point about the journal the study was published in; my 'source' (who wishes to remain anonymous and who has CFS) does not believe there is a bias against getting CFS papers published - he believes good journals would love to publish groundbreaking work on CFS - that's the type of thing they live for - but that really good papers with really significant findings are rare. THe XMRV paper was a notable exception. Really good, rigorous papers, he felt, should be able to find their way to really good journals. he fact that this paper was not in a significant journal was not a strong point.
Well, generally, I've heard it said that it's hard to get in two big UK journals, the BMJ and the Lancet.

"Chronic Fatigue Syndrome: Editorial Bias in the British Medical Journal" by Goudsmit EM,
Stouten B. can be read at: http://freespace.virgin.net/david.axford/JCFS.pdf
I think there has been little change with the BMJ since then.

She did one on the Lancet it also.
Editorial bias in the Lancethttp://freespace.virgin.net/david.axford/lanbias1.htm

I think there may also be problems with the big, big medical journals in the US.
But one can probably get into the "medium" ones? Has this one got an impact factor?

In light of the difficulty of us - laymen - reading and understanding scientific papers we're going to work on a "how to read a scientific paper' paper so that we can assess the strengths research papers. Anyone who wants to help out please PM or email me at phoenixcfs@gmail.com
Of course, if anyone wants to link to articles that already exist, that could be useful also.
 
1. At its core, it is a case series of 142 patients and their treatment over time, rather than a clinical trial. There isn't a group really to compare people with as all were treated and the ones who stopped treatment weren't followed. In a trial, the high drop-out rate would be a concern -- when I initially read the paper, I thought everyone was followed for the full-time but it turns out many by week 18, about 30% of the initial 106 in group A had already dropped out in Table 3. We don't know what happened to these people. To be fair, the writers did default them to being "non-responders" which is acceptable.
Take Table 3, copy/paste it into a spreadsheet. It is the data for Group A total and Group A responders.
Use formulas to calculate N and EIPS (mean) for Group A non-responders. For N, that would be Group A total minus Group A responders. You can also calculate the mean EIPS.

You get the Group A non-responder group of N=27 whose mean EIPS goes from 3.77 at time=0 (N=27) to 6.45 at time=24 (6 years) (N=1). Wow, it "looks" like the non-responders improved their EIPS score even more than the responders!! But "responder" is defined as a patient with at least a change of 1 on the EIPS and "non-responder" as less than a change of 1 on the EIPS. So the non-responders after 6 years supposedly "look" like they improved their EIPS from 3.77 to 6.45, which is an increase of 2.68 points, but they're defined as patients who improved less than 1 point. Does this look like it makes absolutely no sense?! Well, it makes sense that it doesn't make sense because it's totally not legit to compare the EIPS over time of subsets of different N patients dropping out over time. Most of that increase in EIPS score is from drop outs to 5% of the original patient base. Which interestingly happens to look like the statistic I've seen that about 5% of CFS patients get well.

Of course, please feel free to point out if I've made any errors.