Posted by MERM on 6/26/2008, 12:46 pm, in reply to "HHV-6 and ME/CFS"
Testing can be an enormous, even insurmountable problem. In some clinical conditions, blood and spinal fluid show little HHV-6, even though the brain, on autopsy, is loaded with virus.
Comment: This last point is critical for ME/CFS. Brain biopsy is not an option, so how can we know if HHV-6 (HHV-6A) is causing a/the problem?
Overview of HHV-6 and Chronic Fatigue Syndrome Dr. Anthony Komaroff
Active infection with HHV-6 is more common in ME/CFS than in matched controls. In the opening overview, Dr. Komaroff reviewed the nine studies showing increased incidence of active infection, and the two studies that did not. He mentioned the different ways to assess active infection: PCR, IgM antibodies to HHV6 early antigen, cytopathic effect in culture, and viral isolation.
Overview of CFS Dr. A Komaroff
In this session Dr. Komaroff lists, in a very convincing way, the studies that are clearly abnormal in CFS. This may be an illness of different subsets, yet the data proving that it is real is incontrovertable. He reviewed the abnormal findings in CD8 cells, NK cells, Proteomics. Genomics, MRI, SPECT, autonomic nervous system, both sympathetic and parasympathetic, hypothalamic-pituitary axis, EEG, upregulation of pro-inflammatory cytokines.
In regard to HHV-6 Dr. Komaroff said that this agent is ¡°One infectious agent capable of triggering and perpetuating CFS.¡±
Comment: Is it possible that there are medical care providers who do not ¡°believe¡± in CFS?
HERV-K18 as a Risk Factor in CFS Dr. Huber
In this very interesting talk, Dr. Huber discussed HERV (human endogenous retro virus) K18. The presence of an endogenous retrovirus is not that exciting as it is estimated that 8% of the human genome is made up of HERV¡¯s. What is interesting is that this particular one is transactivated by both EBV and ¦Á interferon. What¡¯s more, the Env gene of this HERV encodes a superantigen. This latter fact is possible to become a dominant topic in the near future, as superantigens cause a massive T cell activation. Some diseases such as ¡°toxic shock syndrome¡± are known to be caused by superantigens (not the same one as we are discussing here). In this study three different groups of CFS patients were examined: Dr. Miller at Emory (interferon related), Dr. Levine in NYC (idiopathic), and recently with the EBV portion of Dubbo study. All showed a relationship leading to the conclusion that CFS risk may be related to specific HERV-K18 genotype in subsets of patients.
A Randomized, Double Blind, Placebo-controlled Study on the Use of Valganciclovir in Patients with CFS and Elevated HHV-6 and EBV Antibodies Dr. J.G. Montoya
This is the first report of the study since the good results from a pilot study were released a year ago January on the use of valgancyclovir. This drug is a competitive inhibitor of viral DNA polymerase, and while there were no serious adverse events during this trial, it should not be considered a completely benign medication. Anyone taking it should be followed carefully for toxicities.
The entry criteria for this study were elevated levels of anitbody to both EBV and HHV-6. Over 130 persons were screened, and thirty were in the study, 20 on drug and 10 on placebo. The entry antibody levels were as follows: HHV-6 IgG ¡Ý 640; EBV IgG ¡Ý 640, and EBV EA ¡Ý 160. There were many indicators used for end points, but discussion here revolved around only three: MFI-20 indicating fatigue severity, CDC SI relating to symptoms; and a global assessment of physical and cognitive functioning. The only value that improved to statistical significance was the cognitive portion of overall functioning. The other measures pointed to a positive trend but did not reach statistical significance.
Comment: A disappointing result overall, definitely not a ¡°home-run¡±. Furthermore, few CFS patients have these kinds of antibody titers from standard laboratories.
The Dubbo Infection Outcome Study Dr A Lloyd
This session was a further review of studies presented earlier, but clarifying new data. Essentially this study looks at ¡°nested¡± case-control studies of patients followed after acute infection with Epstein-Barr virus, Ross River virus and Q fever. As was presented earlier, all three infections had similar rates of illness resolution. Roughly 5% of each had fatigue and other symptoms at one year and this decreased somewhat by year two. The severity of acute illness was the best predictor of persisting illness.
Why do some resolve and some do not? The first hypothesis is due to persistence of the infecting agent. Their studies showed no evidence of persistence of EBV, RRV or Q fever, despite an aggressive search. Interestingly, IgM and IgG antibodies were of no use predicting in any of the three. Second hypothesis is that immunity was different with antigen-specific T cells and again no differences were found. Dr. Lloyd concluded that there was no aberrant immune response.
Cytokines in Post-Infective Fatigue Dr. Vollmer-Conna
This session continued the Dubbo findings from Dr. Lloyd¡¯s talk and looked at cytokine expression as a mechanism of symptom expression. She briefly reviewed the many inconsistent cytokine studies of the past. At the beginning of the Dubbo infections IL-1¦Â and Il-6 seemed to correlate with symptom severity, particularly fatigue. However the best association with symptom persistence was increased IFN¦Ã, and decreased Il-10.
Comment: The cytokine data does not look convincing in explaining symptom persistence. There was a large gap between symptom severity at onset and the increased IFN¦Ã/decreased Il-10. But these two talks tell us a great deal about what is going on .
Summary and Personal Comments about HHV-6 and Conference.
This summary was not presented at the conference, but represents my personal conclusions about the relationship between HHV-6 and ME/CFS. As always, every observer could come to different conclusions.
A) HHV-6 has two variants, A & B, and is a ubiquitous agent. It causes Roseolla in young children, and everybody is exposed to it at one time or another.
B) Roughly 1% of babies are born with the virus, most with it integrated into chromosomes and have high viral loads. It is not known yet if this will cause any problems. Because children do not usually develop ME/CFS until after age 10, we will have to wait another few years to get any early information on this point.
C) HHV-6, particularly HHV-6A has a strong association with many diseases of the central nervous system.
D) In ME/CFS, the only way to know if HHV-6 is important is to treat it with an effective antiviral, or prevent it with a vaccine. The antivirals currently available are only partially effective and vaccine is not available (Note- the relationship between human papilomavirus and cervical cancer was only shown when the vaccine was shown to prevent the cancer)
E) HHV-6 infects/resides in many tissues, including vascular endothelium, making it a good candidate for the variety of symptoms seen in ME/CFS.
F) HHV-6 is one of many infectious agents that can precipitate and/or perpetuate ME/CFS.
G) A trial of valgancyclovir was not very effective in reducing the fatigue and physical symptoms of ME/CFS. It did seem to help cognitive symptoms.
Bottom Line: Many of my patients will want to know if I will be using valgancyclovir in regular clinical practice. As of this time I do not plan to use it in patients with ME/CFS. I may consider testing some persons with RT-PCR and quantitative PCR for HHV-6, but this can be expensive and not covered by insurance.
In my practice, I plan to aggressively pursue the relationship between anaerobic threshold and mitochondrial function in some patients. For those of you hoping to hear that the valgancyclovir study was going to be the ¡°cure¡±, I am sorry. But do not give up hope. One of these days¡..
My thanks go to Andy Detwiler who financed this trip to the HHV-6 conference, paying for the airline tickets, hotels, and conference fees. For all those who are grateful for this information summarized here, please thank Andy. He wishes to encourage interested persons to get involved in one way or another.
I am in complete agreement ¨C if those interested in ME/CFS do not make it happen, it is not going to happen
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