The Symposium on Viruses in Chronic Fatigue Syndrome (ME/CFS) (May, 2008): Part I by Cort Johnson
Highlight on the HHV-6 Foundation
The HHV-6 Foundation produced both the International Conference on HHV-6 & 7 and the International Symposium on Viruses and CFS in Baltimore, Md in May, 2008. The IACFS/ME co-sponsored the events. Financial Support was provided by the CFIDS Association of America, the Whittemore-Peterson Institute, PANDORA, ProHealth and others. One of the most impressive aspects of the Symposium was the people who put it on. Created just a few years ago ,and led by Kristin Loomis Executive Director and Scientific Director Dharam Ablashi – the HHV-6 Foundation is clearly on a mission to make a difference.
The Foundation is constantly probing and cajoling researchers to examine the viral connections to disease. Many, perhaps most of the researchers presenting at the conference were indebted to the Foundation for assistance with materials or with direct testing. They assisted Birgitta Evengard and Kasuhiro Kondo with testing and persuaded others, such as Brigitte Huber to include HHV-6 in their studies. They played a major behind the scenes role in helping convince Roche to take on the Montoya/Valcyte study , funded significant parts of Stanford’s pre-trial efforts and lined up over a dozen outside collaborations for sophisticated testing.
The HHV-6 Foundation embodies the kind of creative activity that the private sector can be so good at and it was heartening to see them at work.
Finding ‘Waldo’: The Montoya Valcyte Chronic Fatigue Syndrome (ME/CFS) Study
J. G. Montoya. A randomized, double-blind, placebo-controlled trial on the use of Valganciclovir in patients with chronic fatigue syndrome (CFS) and elevated human herpesvirus and Epstein-Barr virus antibodies.
The Montoya team and Roche Pharmaceuticals have asked for some breathing room and the results from the Valcyte trial will not be provided here. Montoya presented some key results at the conference but he’s still in the middle of processing data that may affect how the study is perceived and he’s asked that the results not be posted wait until he’s finished.
The HHV-6 Foundation’s financial and administrative assistance allowed Montoya to characterize his patients to a much greater degree than usual. The Montoya team is currently engaged in pouring over pathogen, immune data, gene expression and exercise data in an attempt to figure just what kind of chronic fatigue syndrome (ME/CFS) patient this drug works the best on. Suffice it to say that some results were achieved and others were not. It was a small study and these are the most difficult kinds of studies to get statistically significant results from.
The Pharmaceutical drug companies were reportedly there in force with six people from Roche and others from three more drug companies. The Roche people and a group of chronic fatigue syndrome (ME/CFS) professionals meet for several hours Sunday night to decide what the next step will be. Based on who you talk to Roche is either enthusiastic or not about going following up with a larger study. (One problematic aspect of the present trial was its small size. By their very nature smaller sized studies increase the difficulty of getting a statistically ‘significant’ result. Much will undoubtedly depend on the results of Montoya’s analysis.
The appearance of the Pharmaceutical companies underscores the potential impact of the Montoya study. This study was never about just about treating EBV/HHV-6 infected ME/CFS patients; it was about illustrating that a chronic infection of some sort plays a major role in ME/CFS. Montoya’s success would embolden efforts to the duplicate his results with other pathogens. Montoya is reportedly already looking into other pathogen subsets.
Dr. Montoya began his presentation on a good note by lauding the work of Dr. Lerner, a longtime ME/CFS researcher, who’s done more to keep the antiviral question open in the minds of the research community than anyone else.
The ‘Sith’ Returns: Novel Herpesvirus Protein Linked to Chronic Fatigue Syndrome (ME/CFS) and Depression
K. Kondo. Identification of novel HHV-6 latent protein associated with mood disorders in CFS, depressive disorder, bipolar disorder and HHV-6 encephalopathy.
This paper suggests that mood problems may be more a function of infection than behavior. Dr. Kondo identified a novel human herpesvirus-6 (HHV-6) protein that was present in Chronic Fatigue Syndrome (ME/CFS) patients with ‘psychological symptoms’ (whatever that means!) but not in healthy controls or ME/CFS patients without them. A serological study indicated that 71% of CFS patients with psychological symptoms and none of the health controls possessed the antibody against the SITH-1 protein (p<.0001).
The Sith were a malevolent force in George Lucas’ Star Wars and the name is an apt one. Once Kondo realized the protein changed cellular calcium levels he checked for and found it in bipolar depression/major depression patients and but not in a host of other diseases including fibromyalgia or multiple sclerosis. Fifty-three percent of depression and 78% of bipolar depression patients possessed the antibody.
Latent But Not Inactive. Intriguingly the SITH-1 protein is produced when HHV-6 is ‘latent’. Latency, it turns out, is a something of a misnomer; it simply means the virus is not replicating and eventually killing the cell and then spilling its virions by the millions into the bloodstream. Kondo’s study bears witness to the fact that viruses can be engaged in all sorts of damaging activities (such as generating damaging cytokines) that researchers have basically ignored. (A ‘latent’ central nervous system virus ,for instance, could prompt cells to produce immune agents called cytokines that are able to cause the kinds of symptoms found in ME/CFS).
HHV-6’s persistence in the cell could conceivably have worse long term effects than if it actually killed the cell. The death of an infected cell sparks an enormous immune response and usually, if all goes well, a complete resolution of the problem. HHV-6’s mole-like behavior in its latent state could allow it to run well below the immune response and conceivably alter the behavior of cells for decades. What might a process like that look like? – perhaps a mysterious chronic disease?
A Post-Infectious Mood Disorder Subset? Although Kondo’s study is very preliminary – the ground he’s opening – that a pathogen may be responsible for the mood disorders in some ME/CFS – is fascinating. Later in the conference Dr. White will note that the depression in ME/CFS is something of a puzzle and that they cannot predict in whom it will strike. Does this suggest some unknown biological factor – a latent central nervous system infection perhaps – could be a work? In another later talk Dr. Peterson will argue that ME/CFS patients with HHV-6 reactivation display neurological problems not seen in other patients.
This study, too, is very preliminary and many questions remain to be answered. Dr. Kondo needs to more fully characterize the protein and his findings need to be replicated in U.S patients. (The HHV-6 Foundation is attempting to do that right now). Is mood disorder in ME/CFS synonymous with an HHV-6 infection of the nervous system? Is depression more prevalent in acute onset ME/CFS patients? Can Kondo’s study be replicated in US patients? Much remains to be done.
A Foundation’s Focus. This kind of difficult to detect, smoldering’ infection is exactly what the HHV-6 Foundation is focused on. Dharam Ablashi, who co-discovered the HHV-6 virus in AIDS pateints while working as a virologist at the National Cancer Institute, warned that while the test probably won’t be available soon it could make a big difference when it does show up.
“It may take years to get the assay validated and into commercial production, but will be worth the wait. This assay could identify large numbers of patients with CNS dysfunction who could benefit from antiviral treatment. The HHV-6 Foundation is working hard to help scientists like Dr. Kondo develop better assays”.
All the more reason to contribute to the HHV-6 Foundation NOW.
Ancient Retrovirus Alive and Kicking in Chronic Fatigue Syndrome (ME/CFS) Patients?
B.T. Huber. EBV and IFN-a activation of the human endogenous retrovirus HERV-K18 and CFS
The Symposium was full of interesting research but none was more eye-catching than Brigette Huber’s study. Dr Huber presented evidence suggesting that a reactivated ancient retrovirus embedded in our genome may be active in chronic fatigue syndrome (ME/CFS) (and multiple sclerosis (MS)) patients.
About eight percent of our genome is comprised of broken up, degraded, useless bits of ancient retroviruses that many millennia ago somehow managed to claw their way in there and hang on for the ride. They’re almost all ‘dead’ but of these bits of defunct genetic material can ‘come alive’ the right circumstances and start producing proteins again. Most of them belong to the Human Endogenous Retrovirus K (HERV-K) family.
Dr Huber’s study suggested that a small percentage of ME/CFS and MS patients may have a predilection for this zombie-like retroviral reactivation. She found that both MS and CFS patients (whose illness had been triggered by infectious mononucleosis) were at a higher relative risk for containing HERV-K18 variants known to induce superantigen activity.
Why would she check for this in ME/CFS? Because some facets of the disease look very much like a ‘superantigen’ is at work in the disease. Superantigens are proteins that are able to induce an overly broad immune (T-cell) response that depletes the immune system over time. Not long after Dr. Huber’s presentation Dr. Klimas reported that the immune findings in CFS are indeed what you’d expect in a chronically over-activated immune system.
HHV-6 – the Hidden Culprit? One intriguing scenario is the possibility that HERV-K18 activation could be the endpoint of an HHV-6 initiated viral cascade. HHV-6 is able to reactivate EBV and both HHV-6 and EBV trigger interferon production, all of which can trigger HERV-K18 activation. This means HHV-6 activity could turn on the HERV-K18 retrovirus in at least three ways; directly, by producing interferon, and by reactivating EBV.
We see yet another potential CFS/MS connection here as well and why not? Seventy-five percent of MS patients meet the criteria for CFS and fatigue is the often their most disabling symptom. There are, of course, major differences between the two diseases, but they also share grey matter atrophy, impaired cerebral glucose metabolism, altered autonomic nervous system activity, HHV-6 reactivation and altered patterns of brain activity.
This study is also quite preliminary. Most importantly Dr. Huber needs to actually show that HERV-K18 is indeed activated and contributing to the symptoms of ME/CFS. If it does we need to know which ME/CFS patients it is active in. Is it reactivated only in post-infectious mononucleosis (EBV) patients or is it also present in ME/CFS patients with HHV-6 reactivation. Dr. Huber’s subset, like Dr. Montoya’s may be fairly small.
Luckily after some ‘startup funding’ to get her going by the CFIDS Association of America she’s received an NIH grant to study these issues. Congratulations to her and congratulations to the CFIDS Association for getting the project off the ground.
A Smoldering Infection in the Heart? Chronic Fatigue Syndrome (ME/CFS) and Erythroviruses.
D. Lassner. Erthroviral myocarditis and fatigue like symptoms
Dr. Cheney has taken the field of cardiac dysfunction in ME/CFS and run with it. His idea (at least so far as I understand it) is that problems with energy production in heart cells, possibly related to ‘oxygen toxicity’, is impairing heart functioning – in particular – diastolic heart functioning in ME/CFS patients.
So far as I could tell, Dr. Lassner, a German cardiologist, has no acquaintance at all with Dr. Cheney’s work. Nor are his studies focused on CFS patients but they do suggest some intriguing parallels. The kind of heart disease Dr. Lassner is focused on, myocarditis, is accompanied by some very CFS-like symptoms (fatigue, lassisitude, flu-like symptoms) and some somewhat CFS-like symptoms (shortness of breath, chest pain). He noted that the myocarditis patients lacked ‘drive’ and had to take frequent breaks. Their systolic functioning was normal but their diastolic functioning was impaired and they often difficult to diagnose. (Dr. Cheney was was reportedly interested in the presentation but did not ask any questions).
It is Dr. Lassner’s contention that myocarditis – which is typically caused by a viral infection – is greatly under diagnosed and when it is diagnosed it’s frequently diagnosed incorrectly. Heart biopsies are the only way to tell which bug is present but they haven’t been done regularly in the US for 25 years. Dr. Lassner believes that uncovering what bug is present and treating it could save a substantial number of lives. Myocarditis, after all, is the leading non-accidental cause of sudden deaths in young adults.
His extensive biopsy research in Germany indicates that Parvovirus B-19 and HHV-6 infection are the two leading causes of viral myocarditis there, followed by enterovirus and EBV. The prognosis with treatment (IVIG-parvovirus, interferon-enterovirus), however, is very similar to that reported by ME/CFS physicians; improvement often followed by relapse once one is off the drug followed by improvement once one goes back on it.
Another Smoldering Infection? Could ME/CFS patients simply be undiagnosed myocarditis patients? It’s important to note that there are real differences between Dr. Lassner’s patients and the average chronic fatigue syndrome patient. When I asked Dr. Lassner if the myocarditis he saw could settle into a kind chronic non-progressive state (i.e. ME/CFS-like) he replied ‘No’ – without some sort of intervention the disease was slowly progressive. Furthermore X-rays should show inflammation in the heart – which has not been reported in ME/CFS.
In his talk, though, he said it was possible for a virus to persist without killing the cells it had infected. This suggests that the same kind of ‘smoldering infection’ Dr. Kondo found in nerve cells could occur in heart cells as well and brings the question whether ME/CFS patients have some sort of infection that alters heart cell functioning without killing them. A similar process may be occurring with regard to HHV-6 infection and epilepsy.
With regard to the diastolic dysfunction found most often found in ME/CFS patients. Dr. Lassner suggested that HHV-6 infection in the endothelial cells lining the blood vessels would be the most likely culprit. This is the type of infection, interestingly, Dr. Lassner felt was most likely to cause problems by altering cellular functioning rather killing cells. HHV-6 infected endothelial cells appear to secrete more pro-inflammatory cytokines which could result in constricted blood vessels, impaired capillary production and lead to reduced heart blood flows – all of which have been found in at least a subset of ME/CFS patients.
Amazingly he reported that 16/30 genes in his list of genes with abnormal expression were identical to Dr. Kerr’s genes identified as abnormal. This is an almost unbelievable overlap. Since we didn’t have the actual data it was difficult to tell exactly where the overlap occurred e.g. was it in the Kerr’s short list of up/downregulated genes in ME/CFS or in a more general list of genes that may contribute to the disease. We’ll have to wait for the paper.
The work by Dr. Lassner’s group led by Dr. Uwe Kühl and findings from two other German cardiology centers (where biopsies are done routinely) have prompted the American Heart Association to alter it’s approach to heart biopsy’s and it recently outlined scenario’s which it believes warrant them. . Biopsies, then, are coming back – at least for a few carefully selected types of cardiac patients in the US. They are probably still not an option, though, for most ME/CFS patients – even those with cardiac abnormalities. (Dr. Lerner quickly stopped doing biopsies in ME/CFS patients after they experienced excessive bleeding.)
Stress and Infection (= Chronic Fatigue Syndrome?)
J. Kerr. Stress and parvovirus B-19 associated arthritis and chronic fatigue.
It’s almost stressful how much ‘stress’ is popping around chronic fatigue syndrome (ME/CFS) research circles. Here Dr. Kerr examined people who’d come down with ME/CFS following a parvovirus infection. After looking at a range of factors, including stress, cytokines, cortisol, etc. he found that only a ‘stress index’ predicted which patients would come down with ME/CFS (and arthritis) after a parvovirus infection. An increased ‘stress index’ also was associated with increased levels of fatigue during the initial stages of the infection.
There is something of a catch here. The patients were asked to assess their negative life events after they got ill. It’s possible, given the high levels of stress these patients were already under that they more negatively viewed their stress levels before they got ill than they would have if they were healthy. However, Dr. Kerr noted that his attention was drawn to this issue by the significant number of patients who’d indicated they’d lost relatives, were overworking, had been exercising too much, had been in a car accident, etc. and this is not the first time this finding has shown up.
This finding suggests that poorly functioning stress response systems play a role in virally induced ME/CFS. Given the role the two stress response systems in the body; the HPA axis and sympathetic nervous system also play in modulating the immune response this is perhaps not so surprising. Dr. Kerr noted that stress has been shown to inhibit several aspects of the immune response including reduced NK cell activity and T-cell proliferation, reduced interferon Y levels and that it increases the likelihood of herpesvirus reactivation. It also increases the likelihood of one coming down with infection. He also noted that in 3 parvovirus ME/CFS patients with increased cytokine activity intravenous immunoglobulin IVIG therapy had been successful.
Enteroviral Enigma No More?
J. Chia. The role of enteroviruses in myalgic encephalomyelitis/chronic fatigue syndrome
Besides his possibly groundbreaking work on chronic fatigue syndrome (ME/CFS) Dr. Chia turned out to wonderful guy as well. On that first lunch he headed right over to a table of patients and settled in. Hardly touching his food he readily answered everyone’s questions in detail. The day we weren’t so lucky; the the head table already had a place set aside for him and they quickly snatched him. But who could blame them? His work is making many rethink their assumptions about pathogens in this field.
Dig Deeper: An Interview with Dr. Chia
He started out with a case report.
Case Report #1 – A patient with an infection came to see him. Over time she recovered nicely but six months later she was back another different infection. This time she fell apart and after three months she was hospitalized. Gamma globulin (IVIG) injections helped. She improved and while after four months she still had fatigue, muscle pain, irritable bowel syndrome she was able to be active 3-4 hours a day.
Two months later she relapsed severely. A stomach biopsy revealed she had an enteroviral infection. At lunch Dr. Chia says he sees this pattern again and again – a patient comes in with an infection and is apparently cured only to severely relapse (come down with ME/CFS) after another different infection. Something in that first infection appears to set these patients up for the knockout punch when the next infectious episode occurs. Dr. Chia is an infectious disease specialist so he’s in an excellent position to observe infectious onset cases of CFS.
The Enteroviral Enigma. Dr. Chia’s goal here in this talk was to illustrate why some of the enteroviral studies of the past had failed. Enteroviruses have long been suspected in ME/CFS and the research started off with a bang with early studies showing increased levels of enteroviral DNA in a significant portion of ME/CFS patients. Attempts to replicate those studies had mixed results, though, and a once promising field of inquiry languished until Dr. Chia came on the scene.
Dr. Chia has looked at this situation closely – too closely for a brain addled and increasingly writing challenged CFS patient such as myself to follow closely or even perhaps accurately. Hopefully this summary is more or less accurate.
As late as 1995 a blinded, controlled study indicated that 41% of ME/CFS patient’s vs. 2% of controls had enterovirus RNA in their serum.
Then if my understanding is correct something seemingly innocuous happened: one of the top researchers in the field (Robart) patented a new method to measure enteroviral RNA. The new test, which swept the field, created a new, and Dr. Chia believes, improper baseline.
Essentially the test was unable to detect enteroviral RNA below a certain number of copies. Unfortunately many ME/CFS patients had lower RNA levels than the test could indicated but still much higher levels than healthy (or even as Dr. Chia will demonstrate) unhealthy controls.
Trouble From the Top – In 1995 the leader of the NIH program, Stephen Strauss, reported in an editorial that he was unable to find any enterovirus in his patients. Strauss never published his results but his high profile as the leader of the NIH’s CFS effort put a substantial damper on the field. Dr. Chia believes Strauss’s results were correct but that he used the wrong test.
When Dr. Chia used an updated version of the Robart (Chemicon) test to which a new primer had been added the enteroviruses were back; he found 38% of CFS patients vs. only 4% of the controls were positive. As disease severity increased so did the percentage of those infected – 70% of bedridden patients had it but only 12% of higher energy patients were positive.
That result apparently convinced Dr. Chia to dig deeper and he began doing his stomach biopsies where he found much the same results; high percentages of positive patients (57%) and low percentages of positive controls (5%). Again the degree of infection seemed to match the severity of illness; only 25% of the ME/CFS patients with substantial infection were able to work but 54% of patients with lesser infection were.
Short-term course of antivirals (interferon a/ interferon y) that resulted in significant improvements (but also generally a relapse following cessation of the drugs) suggested that the bugs were contributing significantly to the disease.
Case Report #2. At this point Dr Chia showed a graph of a patient’s progress over a course of treatment. Her functional levels started off low and with the die-off prompted by IFN-y gamma treatment fell she got even less functional but eventually rebounded strongly and with the addition of Valtrex she was she able to return to full-time work. Several months after going off Valtrex she relapsed severely returning to lowest level of functioning Putting her back on Valtrex a second time helped but not to the extent it did before.
Proving Viral Causality – It’s not easy to prove the infections found in ME/CFS cause or even contribute to the disease. Higher than normal pathogen loads suggest they might but do not prove that they do. The only really effective way to prove that X pathogen is responsible for all or part of Y disease is to identify the pathogen, hit it with the appropriate drugs, determine that its either declined or disappeared and then show improvement by measuring functionality, symptoms, aerobic respiration, immune status, etc. (all in the appropriate placebo controlled, double-blinded fashion).
Unfortunately those kinds of trials are very expensive and very rare in ME/CFS. With regards to enteroviruses just identifying the pathogen can be problematic. When asked if he checked to see if the enterovirus had disappeared after his patients had gotten better on the anti-virals Dr. Chia said it had with the proviso even when the patients were ill it sometimes took several attempts to find it.
(Chronic fatigue syndrome (ME/CFS) patients who have had upper endoscopies in the past can send biopsy samples to Chia for analysis. Kristen Loomis reported that the HHV-6 Foundation has been sending samples from ME/CFS patients to Dan Hartmann at Georgetown University Hospital, and has found enterovirus or HHV-6, in most of these samples. HHV-7, CMV and parvovirus B-19 have also been found.)
Better Antivirals Needed. There is strong anecdotal (and some study) evidence that antivirals can dramatically assist a subset of patients but what the research world responds to rigorously delineated treatment trials. Those are much more difficult to do when you have less than stellar detection methods. Its rather remarkable that diagnostic difficulties plague many of the pathogens (HHV-6, enteroviruses, borrelia (Lyme) in question in ME/CFS. This is why the finding better tests is the chief goal of the HHV-6 Foundation.
Another problem with the infections in ME/CFS is the general lack of efficacy of many of the antiviral drugs. They all help or even cure some patients but overall their performance is unsatisfactory. Some work fine only to have the patients relapse afterwards. Some patients that appear to be good targets for a drug do not respond while poor targets sometimes do.
Dig Deeper: Antiviral Drugs in Chronic Fatigue Syndrome (ME/CFS)
(One Montoya study found that, yes, ME/CFS patients with increased antibody titers did respond significantly better than those with low titers – a very important finding – but there where still those patients with high antibodies who had no response to the drug and patients with low titers who responded well; hence Dr. Montoya’s continuing attempts to find ‘Waldo’).
There are also toxicity problems and most are expensive. Some require long duration treatments that patients cannot afford or are unwilling to try. Both Dr. Chia and Dr. Peterson vigorously asserted that more effective as well as less toxic antiviral drugs are greatly needed.
Dig Deeper: See Part II of the Symposium Overview for future antiviral drugs
Waiting on Technology – Indeed Dr. Chia wrote in his abstract that the “Development of antiviral drugs specific for enterovirus replication is of paramount importance”. In fact the definitive assessment of the enteroviruses role in ME/CFS awaits the creation of drugs able to fully knock it out. His abstract ends by stating that ‘controlled trials with future antiviral drugs will likely provide the ultimate evidence for the pathogenic role of EV in ME/CFS’.
Once again, ME/CFS patients are waiting on the technology. This is all the more reason, of course, to ensure that organizations that are funding cutting edge research like the HHV-6 Foundation, the Whittemore-Peterson Institute, the CFIDS Association of American, MERUK and others are well funded. And even more reason to aggressively go after the golden egg of research funding – the National Institutes of Health – in the U.S.
Thanks to the HHV-6 Foundation and PANDORA for their assistance in attending the Baltimore Conference, thanks to Tom Hennessey for getting me back and forth several times from DC (and as always thanks to my brother for his twisted but still much appreciated hospitality. Thanks to the HHV-6 Foundation for their comments on this paper).