Learning CFS: the Lerner Antiviral Treatment Trial Succeeds

http://www.dovepress.com/subset-dir...us-patients-with-c-peer-reviewed-article-VAAT

 

It might clear up a small part of the confusion to pay careful attention to the title of the paper:
"Subset-directed antiviral treatment of 142 herpesvirus patients with chronic fatigue syndrome"

This paper is not about ALL CFS patients; it's about herpesvirus patients with chronic fatigue syndrome. This study only included patients with identified herpesvirus infections.

The paper states how those infections were identified:

"CFS patients were considered to have active EBV infection if there were elevated enzyme-linked immunosorbent assay (ELISA) serum antibodies to EBV IgM viral capsid recombinant peptide antigen VCA p18 (Diasorin, Stillwater, MN) and/or EBV early antigen EA-D, a 47 kDa recombinant polypeptide."

"HCMV infection was identified by elevated serum antibody titers to human fibroblast lysate HCMV strain AD69, IgM, or IgG by ELISA tests and elevated Copalis light-scatter HCMV IgM p52 recombinant protein, UL44, and HCMV CM2, UL44, and part UL57 recombinantprotein."

"HHV6 infection was identified by elevated IgMand IgG serum antibody titers >= 160 (LabCorp, Dublin, OH)."

What I got from the paper is that those of us who are identified as CFS patients AND who have only one active herpesvirus infection have an excellent chance of returning to a decent level of functionality using certain antivirals long-term, and that such long-term use of antivirals doesn't appear to cause serious problems during the course of treatment if proper monitoring and management are performed.

So, if you have been identified as NOT having a herpesvirus infection BY THE TESTS STATED, then you can draw no conclusion from this data about the use of antivirals for you. If you have been identified as herpesvirus-negative by other tests, you might want to get these tests to see if you are in one of the subsets on which this study reports. If you DO have a herpesvirus infection, this paper gives you a plan of attack.

None of this really explains to me why common latent infections reactivate in us and not in other people.

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.

If they have active EBV infection by definition they cant be CFS patients

 

Dr. Lerner is not testing his patients for classic signs of active EBV infection. The importance of high antibody levels to early antigens is a real grey area in Science - there is no agreement that this finding denotes disease and therefore it could not be excluded under Fukuda. This type of infection is not going to exclude anyone from being diagnosed with CFS under Fukuda because this type of EBV is not a 'recognized medical cause of fatigue' - Dr. Lerner is trying to make it one. Dr. Lerner is attempting to say that nonpermissive herpesvirus infections do cause disease and that disease happens to be called CFS.

If this kind of infection was an accepted cause of fatigue than physicians would be doing the tests and treating it like they would hepatitis or HIV but they're obviously not doing that. These patients come from all over the country and the world to see Dr. Lerner because he's doing these tests that pick up their abnormalities.

I don't think you're suggesting that we call people with CFS whose illness was triggered by granular fever or infectious mononucleosis and who never recovered - infectious mononucleosis patients - instead of CFS patients? That would out a nice chunk of CFS patients.

I would love to have PEM in there - for sure, that would have been nice - but I'm just not worried about that. Their functionality was in the pits. I'll assume that these peoples inability to function in a pre-treatment and Dr. Lerner's admonitions to them not to exercise was an indication of their PEM.

Active epstein barr infection is an exclusion factor under fukuda. Chronic epstein barr infection is largely asymptomatic.there are only two kinds of epstein Barr infection acute and chronic .


Epstein-Barr virus syndrome
In the early 1980s, patients with symptoms including fatigue, muscle pain, and depression were often diagnosed with chronic Epstein-Barr virus syndrome or chronic mononucleosis syndrome. [ 1 ] These patients had symptoms that suggested infection, such as low-grade fever, recurrent sore throat, and tender lymph nodes. Epstein-Barr virus (EBV), which causes acute mononucleosis, was considered a likely source. But researchers could not isolate EBV as the cause of the syndrome and, as yet, have not definitively identified any other infectious agents.

Nonpermissive Infection - Certain host cells may lack essential factors for viral replication or may repress certain viral functions. Such cells are called nonpermissive cells and do not support viral replication

Essentially this means that in some cells the virus enters the cell and cant make new particles and reproduce

 

Speaking only as someone who's had chronic Lyme + bartonella, babesiosis, both kinds of ehrlichiosis & viral reactivations of CMV & EBV, the following concerned me: "There were 106 CFS patients who had negative IgM and IgG serum antibody titers to B. burgdorferi by Western blot and ELISA test, with antistreptolysin 0 titers ,400 units, and negative serum IgM and IgG antibody titers to B. microti and A. phagocytophila. These patients were categorized as Group A CFS."

So if you made no antibodies against borrelia (as those w/HLA DR1 may not), or against b.microti (again some produce no antibodies, plus other strains exist such as b.duncani, etc) you were put into a CFS group? No PCR or culture done for borrelia, no FISH for babesia of any kind?

"An additional 36 CFS patients had elevated serum antibody titers to B. burgdorferi, B. microti, A. phagocytophila, or antistreptolysin 0 . 400, and comprised Group B CFS."

What am I missing or otherwise not understanding? This is why it's so important to understand study design - in order to determine confidence level in the results... I'm not criticizing Lerner - just trying to understand logic in inclusion criteria...

btw, in addition to antibiotics & antiparasitics, I also took Valtrex during my treatment & both the EBV & CMV calmed back down nicely (tho I can occasionally feel EBV acting up).

 

Okay, am I perhaps stumbling over the difference between "active" infections and "non-permissive" infections? If we have "active" infections we're not ME/CFS patients, but ME/CFS patients could have the "non-permissive" infection Dr Lerner is talking about?

There are cells which are non permissive for EBV which are mainly epithelial.There are only two kinds of EBV infection .They are active and Latent.Active is an exclusion criteria and latent is mostly asymptomatic.

 

Re: why common latent infections reactivate in us (from Chia)"...during and after an initial infection, viruses often hide in our bodies by manipulating our Immune Systems and vulnerable cells. Research has demonstarted the presence of stable viral Genome on cells long after the initial infection - but the "True Viral Particle" is difficult to isolate. Once viral persistence is established and protected by our own cells, the Immune Response can only react to these Viral Particles with futility causing continuing or cyclical symptoms of me/cfs (virus "hide and seek"!)

(Also, Herpes 1&2, Chickenpox, EBV, CMV and HHV-6 are known to survive in our bodies - sometimes DESPITE a good immune response...as they don't kill their cell hosts. Our own cells actually protect them from the attack of the "Immune Response".
Ex: from the start of a virus infection, the Immune System fails to kill off the infected cells. Afterwards, the Immune Systems efforts are useless in destroying the virus and unintentionally continuing the flu-like symptoms. Periodically, the virus load in the cells will decrease as a resut of the immune response...you feel better for a few days or so, since the immune response subsides. Then, the virus grows back (like garden weeds) and the immune system reacts again. Since many infections behave this way, AV treatment should be/may need to be taken for years. (When you keep getting sick this may not be a new infection, but a relapse of the same infection when the th2 immune response is shifted to the th1 direction. Virus infecton is fought with the th2 response...the th1 side is sifted downward and the virus survives the immune attack and persists in the body.") Right? Makes perfect sense to me! ha! does this answer the question...or did I lose the question in looking for the answer? j

 

A nonpermissive infection seems to be a middle-ground between latent and active. Anyway, even a latent herpes infection can alter gene expression, and these are smart viruses. CMV is the largest virus known, producing 230 viral proteins. If that is a nonpermissive infection then it is partly active and some of those proteins are probably being produced. Also, again, it alters immune genes and down-regulates immune response even when latent.

Personally I think there has to be some genetic or pre-existing co-infection vulnerability in the CFS population if Learner is right, otherwise everyone carrying these viruses in latent form would get sick.

 

Hi Kurt,

I'm curious. I this the good news you said a few days ago that was coming this week, or do we have something else good to look forward to?

 

Hi Kurt,

I'm curious. I this the good news you said a few days ago that was coming this week, or do we have something else good to look forward to?

There have been several rumors back-channel and to be honest it is hard to know right now exactly when we will see the reports, if not this week then hopefully at least over the next one or two.

The Learner study is certainly good news for people who test positive on the indicated herpes tests.

 

This study looked at activity of HCMV during the latent stage. Just an interesting point of reference, if Learner if finding nonpermissive infections (or theorizes that is what he sees), then that goes beyond the latent stage. But what strikes me from this study (below) is that if one herpes virus in LATENT stage can manipulate the immune system to allow it to persist, then is that like opening a door to other infections? What else will that immune manipulation allow to proliferate?

Journal of Virology, April 2004, p. 4054-4062, Vol. 78, No. 8
0022-538X/04/$08.00+0 DOI: 10.1128/JVI.78.8.4054-4062.2004
Copyright 2004, American Society for Microbiology. All Rights Reserved.
Impact of Human Cytomegalovirus Latent Infection on Myeloid Progenitor Cell Gene Expression
Barry Slobedman,1,* J. Lewis Stern,1, Anthony L. Cunningham,1 Allison Abendroth,1 Davide A. Abate,2 and Edward S. Mocarski2
Centre for Virus Research, Westmead Millennium Institute and University of Sydney, Westmead, New South Wales 2145, Australia,1 Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford University, Stanford, California 943052

Received 5 August 2003/ Accepted 13 January 2004

Herpesviruses establish lifelong latent infections in their hosts. Human cytomegalovirus (CMV) targets a population of bone marrow-derived myeloid lineage progenitor cells that serve as a reservoir for reactivation; however, the mechanisms by which latent CMV infection is maintained are unknown. To gain insights into mechanisms of maintenance and reactivation, we employed microarrays of 26,900 sequence-verified human cDNAs to assess global changes in cellular gene expression during experimental CMV latent infection of granulocyte-macrophage progenitors (GM-Ps). This analysis revealed at least 29 host cell genes whose expression was increased and six whose expression was decreased during CMV latency. These changes in transcript levels appeared to be authentic, judging on the basis of further analysis of a subset by semiquantitative reverse transcription-PCR. This study provides a comprehensive snapshot of changes in host cell gene expression that result from latent infection and suggest that CMV regulates genes that encode proteins involved in immunity and host defense, cell growth, signaling, and transcriptional regulation. The host genes whose expression we found altered are likely to contribute to an environment that sustains latent infection.

 

If they have active EBV infection by definition they cant be CFS patients

Then I must be misunderstanding the text of the Fukuda definition:

"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."

???

 

Then I must be misunderstanding the text of the Fukuda definition:

"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."

???

i,m afraid that you are epstein barr infection is a known medical cause for fatigue .

 

epstein barr infection is a known medical cause for fatigue .

That is not true. Almost everyone with EBV is asymptomatic. That leaves two possible diagnoses, 1. infectious mononucleosis (glandular fever) or 2. CFS. There is no such diagnosis as "fatigue caused by chronic EBV."

 

That is not true. Almost everyone with EBV is asymptomatic. That leaves two possible diagnoses, 1. infectious mononucleosis (glandular fever) or 2. CFS. There is no such diagnosis as "fatigue caused by chronic EBV."

Active epstein barr infection is a known cause of fatigue.Active epstein barr infection mirrors CFS but does not cause it

 

Yeah.... but WHY does it happen to us and not others? What about you and I is different from our neighbors who don't have ME/CFS. I know, I know... if we knew that we'd be way ahead of the game. But I'm not giving up looking for that answer even in the unlikely event that all my symptoms completely clear up with antiviral treatment.

There are many good clues to that difference. Most CFS patients are pathological detoxifiers, for example. And we have a host of gene abnormalities including immune, adrenal, methylation, etc. Full genomic profiling is becoming less an less expensive, one company says they will have a $100 full genomic profile test by the end of the year. That is the entire human genome for a given patient. I think the answers are coming.

 

I think Gerwyn is talking about mono, which is not CFS, people get over mono. But a certain percent does go on to acquire CFS so even if not a cause it can be a trigger for CFS.

however, Learner looked at other herpes viruses as well, and at multiple herpes, co-infections, etc. His argument is not reliant only on EBV.

 

Active epstein barr infection is a known cause of fatigue.Active epstein barr infection mirrors CFS but does not cause it

There is no such thing apart from mononucleosis/glandular fever, which is not what these patients had.

 

lucky for us...sickofcfs, we finally have some good docs who are trying to find the answer to that queston...and they will. (imo...it's genetic) and as long as nobody comes along to tell me that I DON't really have me/cfs...I'll be just fine. jackie

 

sure epstein barr symptoms mirror the symptoms of CFS as defined by FUKUDA as long as PEM is not used.in reality however if there is a medical reason for the fatigue such as epstein Barr infection then a formal diagnosis of CFS cannot be given

That didn't really address my question, but others have answered it.

So thanks.

 

There is no such thing apart from mononucleosis/glandular fever, which is not what these patients had.

We dont know what the patients had.Learner chose to measure IgG levels with all the viruses save EBV.He considered EBV to be active if IGm levels were raised

Patients were evaluated by EIPS with consensus of
physician and patient. An EIPS of 05 is diagnostic of CFS.
At EIPS values 610, patients no longer have CFS. An effect
size of 0.8 is significant. A CFS patient was considered a
responder to antiviral treatment if the change in EIPS effect
size was 1. A CFS patient was considered a nonresponder
to antiviral treatment if the effect size was ,1 (Figure 2).

someone was a responder if the change in the Eips scale was as little as one.The dianosis of CFS was based on the Eips scale value which was agreed with the patient less than 5 is cfs. More than 5 not CFS. I really dont see how things could be made more subjective.If they had a certain level of disability then they had CFS. That is not a diagnostic method that is used by anyone else that I have ever heard of.Coupled with the lack of a placebo where self limiting infections are involved and unequal numbers in group B(with much higher overt pathology) I,m not realy suprised that it took two years from initial presentation (2008) to publication.Jason told us that Fukuda itself is a highly unreliable tool for diagosing ME/cfs.In my view diagnosing ME,cfs in this manner adds a whole new dimension to this unreliability. I am also concerned that the study was published in a journal owned by one of the researchers.The peer review process of this journal is the subject of controversy to put it mildly.If people find antiviral therapy useful then i am really glad.There are however a number of reasons for that.

If the viruses in question are active(raised IgG) when normally latent then something has brought them out of latency.We dont know if the EBV was active because the IgG level was not measured.I agree that active viruses need to be treated as co pathogens and hopefully people will feel better as a result.That does not mean that these pathogens are in any way causative.the last data I read said that about 90% of Americans had been exposed to cyclomegalovirus.that makes the 4% of XMRV paltry in comparison.

 

This

"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.

"

indicates that you can have positive EBV, retroviral, HHV-6, enteroviral and Candida tests and still fit the definition of CFS - which is a good thing because a considerable portion of patients do have positive test results.

he dianosis of CFS was based on the Eips scale value which was agreed with the patient less than 5 is cfs. More than 5 not CFS. I really dont see how things could be made more subjective.

I don't understand the focus on diagnosis - there was little focus on diagnosis in this paper; the focus was on the average 2+ mean increased rate of progress according to the EPIS scale. The question of where Dr. Lerner places a diagnosis of CFS on his scale really has very little bearing on the outcome of the study.

I don't see how the criteria for who's a responder matters either. The responders made up 75% of the patients - it was a large group of people. What matters to me is that those people moved up the scale rather dramatically - they improved greatly.

If the viruses in question are active(raised IgG) when normally latent then something has brought them out of latency.We dont know if the EBV was active because the IgG level was not measured.I agree that active viruses need to be treated as co pathogens and hopefully people will feel better as a result.That does not mean that these pathogens are in any way causative.the last data I read said that about 90% of Americans had been exposed to cyclomegalovirus.

I don't know if Dr. Lerner cares if EBV is 'active' in the sense that you mean. If he cared about that - if his years of studying these patients had indicated that traditional measures of EBV activity was the pertinent he would have measured it - but that's not what he found. He found other measures were important and those were the ones he used. The scientific community was all over 'active' EBV at one time - it doesn't appear to make a difference in CFS.

Most people have been exposed to EBV, HHV6 and CMV. The question here is do they have the kind of nonpermissive infection that Dr. Lerner has found in these patients and if they do - how important is it to their health.