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Written by thefreeprisoner
Transcribed by ‘thefreeprisoner’
January 15th 2010
Well thank you very much, it’s a great pleasure to be here.
We always try to find some place to go in January and February from upstate New York. [laughter] This is a wonderful place.
Let’s see if we can get our slides clicking here. So I have to turn this on… ahh there we are. It’s always a bit of a mystery.
[Slide:
Review of XMRV in Chronic Fatigue Syndrome
David S. Bell MD, FAAP
Clinical Assistant Professor,
University of New York at Buffalo,
Buffalo, New York]
I’d like to keep this informal and then after about 50 minutes we’re going to open it up for Questions and Answers, and any question is ok. There’s no question that’s silly or anything like that. I enjoy a huge variety of questions, but what I’m going to go through mainly is the new developments related to this virus XMRV.
Before I start I need to know is there anybody here who really doesn’t have any experience with Chronic Fatigue Syndrome and needs some education about the basics? So everybody’s a veteran, is that right? [laughter]
So that’s really interesting because many of the patients with Chronic Fatigue Syndrome go into their doctor and they’ll say “Well I’ve brought you this paper on the cytokines that’s been published” and a family doctor has no idea what a cytokine is. So many people with Chronic Fatigue Syndrome are very sophisticated in what they already understand in terms of what this illness is. So I’m going to just touch very briefly on some of the basics because we’ll be coming back to it.
[Slide:
Chronic Fatigue Syndrome Diagnostic Criteria: Centres for Disease
Activity-limiting fatigue
- 4 of 8 symptoms
- 1. Post-exertional malaise
- 2. Cognitive disturbance
- 3. Unrefreshing sleep
- 4. Recurrent sore throat
- 5. Lymph node pain
- 6. Recurrent muscle pain
- 7. Multi-joint pain
- 8. Headache
Absence of alternative explanation]
The current diagnostic criteria for CFS is really quite simple, even though on the internet people argue about it daily now for the past 25 years; it’s really very simple. The simplicity is that this illness restricts your activity. They used to say you have to have only 50% of your normal activity. Some people now would say well how do you measure 50% of activity? It almost doesn’t matter. In terms of what normal activity is, this illness restricts it. In addition, there are 8 very common symptoms, and you have to have 4 to meet the CDC criteria. And those symptoms are listed right up here.
And then the third part is that you have to have no obvious explanation for the fatigue and the other symptoms. So that it’s really quite simple. If you have somebody who comes into the office and their chart is this thick [holds hands about a foot apart] and you have no clue of what’s going on, they probably have Chronic Fatigue Syndrome. Those are the criteria that I put out 25 years ago, and I think that they’re still quite accurate. A lot of people with Chronic Fatigue Syndrome get enormous numbers of tests, and those tests cost an enormous amount of money, and those tests in general, for the most part they’re perfectly normal. This is interpreted by family physicians and specialists to mean that there is no disease present, and that’s a misinterpretation, and we’ll be coming back to that over and over again. Just because your standard laboratory tests are normal, does not mean that there’s no disease present.
[Slide: The Fatigue of CFS, ME, FM
Described as Exhaustion weakness
Concept of Orthostatic Intolerance
Concept of Pre-Syncope
Not Simple Tiredness
Not Anhedonia]
Now the fatigue of Chronic Fatigue Syndrome – it’s also called Myalgic Encephalomyelitis – the fatigue of Fibromyalgia as well – it not a true fatigue.
The fatigue as defined is a state of recovery. If you go out and run a marathon you will have fatigue. That is the process of recovery from that exertion. But that is exactly what does not happen in this illness. So fatigue is really the wrong word. This was misnamed right from the start. [you can virtually hear the nodding]
[laughter]
Whoopsie, I gave away my best slide there.
In fact, the fatigue is really described as an exhaustion or a weakness, but the true meaning of it is Orthostatic Intolerance. What that means is that people are not tolerating the ability to stand upright. So that when they’re standing upright they’re not able to maintain that position. Interestingly enough, most people with this illness when they’re walking around, they feel much better than if they’re standing still.
One of the tests that we very commonly do in our office is we have a person stand still next to the examining table for 5, 10, 15 minutes or half an hour. And this we call the orthostatic testing and it’s been described by Dr David Streetman in great detail. Healthy people can stand for an hour. He did his normal values based on 90 healthy people. He had them stand for an hour without moving. After an hour many of them were somewhat tired and they would have some achiness in their legs and that’s normal. Chronic Fatigue Syndrome patients very rarely make it past 20 minutes. The severity of the illness is almost predictable by how soon it will be before the symptoms become overwhelming and that person becomes pre-syncopal — they have orthostatic intolerance and they have to lie down. Their pulse sometimes goes very high and their blood pressure goes through some changes, but this is in general called orthostatic intolerance, and it’s different from the fatigue which is present in 50% of the population.
It’s not simple tiredness and it’s not Anhedonia. Anhedonia is a psychiatric term which means that you have no motivation to go out and do things. Persons with Chronic Fatigue Syndrome would love to go out and do things but they just physically feel that they can’t do it. So in depression, because you’re depressed, you really don’t want to go out and go shopping at the mall but if you’re pushed to do that, frequently you’ll feel somewhat better. In Chronic Fatigue Syndrome if you try to go shopping at the mall, you actually don’t feel better, you feel worse.
It’s not a sleepiness. This is different from illnesses that are characterised by sleepiness, although a lot of patients will have hypersomnolance – they can sleep for 20 hours a day. In general the milder the illness, the more a person gets good or heavy sleep.
The psychiatric issue that’s been going on for years looks like this is characterised in this slide… as I understand it the web will not be able to see this slide and I guess I will be able to get away with that [laughter] I showed this slide in a lecture I gave in 1987 at the University of Rochester School of Psychiatry. The University of Rochester has a world famous School of Psychiatry and the auditorium was filled with interns and residents and I showed this slide, and silence… just silence. [lots of laughter]
It’s been a misperception that somehow this illness must be a psychiatric illness, and here’s where modern medicine has made a big mistake. Doctors are under the gun. If you go into the doctor and the doctor has no idea what’s going on with you, he’s got to come up with a diagnosis. In the old days he could say [shrugs shoulders] ‘I dunno what you got’ but now they can’t do that for some reason I don’t understand quite why. They will say “Well, I can’t find anything wrong. Your liver’s normal size. Your blood tests are fine. Therefore you must be depressed.”
And this is really quite unfortunate because psychiatric diagnoses have very strict criteria. If you’re depressed, you usually know you’re depressed. Depression has severe hopelessness; it has all these symptoms which are not part of Chronic Fatigue Syndrome. So for years there’s been this ongoing controversy – is this illness due to a psychiatric basis, and doctors have been kind of mystified. “I dunno what you have, but I don’t want to deal with you, so I want you to go to the psychiatrist.” This has very unfortunate consequences for the patients. Because this is what’s happening in the psychiatrist’s office. [laughter]
And really, when you’re trying to look at the specific… so in the University of Rochester they didn’t like this slide at all. [laughter] They were very negative about this slide. I was trying to say — you know, it’s just a joke — but psychiatrists really would have a difficult time explaining the theory of how a viral infection causes some inactivity and then that inactivity gets into a cycle which leads to orthostatic intolerance and these other things, because there is no model that explains it in the psychiatric literature.
Now that’s not to say that psychiatric disease cannot coexist with Chronic Fatigue Syndrome. This is a very important point. For those people who have Chronic Fatigue Syndrome and are depressed, well you’ve got to address that. And it’s actually fairly easy to address. The anti-depressants work very nicely on depression when it co-exists with Chronic Fatigue Syndrome. But it really doesn’t help the symptoms of Chronic Fatigue Syndrome much at all. Many people are reluctant to admit their depression because they then say well maybe the psychiatrist will…. but that’s a mistake, because if there’s depression going on, you’ve got to address it. This is no different than if you had Multiple Sclerosis or HIV disease or any other organic illness. If you get depressed because of your organic illness, that becomes fairly easy to treat as a part of the illness but it doesn’t remove the basic symptoms of Chronic Fatigue Syndrome.
[Slide: Definitions
XMRV – Xenotropic Murine Retro Virus
More accurately: Xenotropic Murine Leukaemia Related Virus
Retrovirus – an RNA virus able to change to DNA within the cell and insert itself into the human genome
Xenotropic – able to jump species lines
Oncogenic – causes cancer]
OK, tonight we’re gonna be talking about XMRV. This was some of the interesting or exciting new information that’s come out.
XMRV stands for Xenotropic Murine Retrovirus. More accurately it’s Xenotropic Murine Leukaemia Related Virus. This is a fairly large family of retroviruses that XMRV is part of.
A retrovirus is a specific type of virus which is an RNA virus. Very small compared to other viruses. And it’s able to insert itself into the human chromosome and from there, it replicates itself and causes damage.
Xenotropic means that it’s able to jump species. Many years ago, back in the 1990s, this was thought to just never occurr among retroviruses and one of the big arguments in the HIV history was could this has come from the Simian Immonodeficiency Virus, or SIV. Did it actually jump species and become a human pathogen? Xenotropic means it definitely does. This was first described probably many years ago in the retrovirology in different animals and that’s where doctors have been able to study this for many years and it’s only recently become clear that this is a human pathogen.
Oncogenic means that it causes cancer. Now there are 3 human retroviruses, all of which cause cancer. HIV we know causes cancer. HTLV-1 clearly causes cancer. It used to be thought that HTLV-2 causes Cesary syndrome and leukaemias. That’s been called into question at this point. But XMRV also is now related to human malignancies.
[Slide: Dong B, Kim S, Hong S, Das Gupta J, Malthi K, Klein EA, Ganem D, Derisl JL, Silverman RH. [not sure about spelling; slide is a bit fuzzy]
A new human retrovirus associated with prostate cancer.
Hpc1 families with RNAse L activity
RNAse L degrades mRNA
XMRV more accurately MLV-RV (Murine Leukaemia Virus-Related Virus)
MLV – several families of RV proviruses]
The first recent paper on this virus was by Dr Silverman’s group in the Cleveland Clinic where he described families who had a specific immunologic abnormality called an RNAse L activity abnormality. He found in patients who had a very aggressive tuype of prostate cancer this virus. So there were a number of cases which he worked up and he published this about 5 years ago. And while there hasn’t been a huge number of papers on this in the ensuing 5 years, most retro-virologists have said — yes, this really looks like a human pathogen — because it’s present in prostate cancer.
[Slide: Schlaberg, R; Choe, DJ;
XMRV is present in malignant prostate epithelium and is associated with prostate cancer]
Here’s a second paper, this was published in PNAS, again high grade prostate cancer. Now there have been 2 papers published, one from Germany, where they have been unable to replicate the presence of this virus in prostate cancer. So there’s some discussion and debate going on, so the story’s not over as it’s regarding prostate cancer as well.
[Slide: Lombardi, VC; Ruscetti, FW; Gupta, JD; Plost, MA; Hagen, KS; Peterson, DL; Rusceni, SK; Bagni, RK; Petrow-Sadowski, C; Gold, B; Dean, M; Silverman, RH; Mikovits, JA
Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science, 8 October 2009; 10.1126/science.1179052]
This is the paper that came out 2 months ago. The first author Dr Vincent Lombardi, the second author Dr Frank Ruscetti, a very well known scientist who has worked for many years in this area, and then the final author is Dr Judy Mikovits who’s in the WPI. They baiscally started studying this 2 years ago and began to approach it very quietly. Nobody really knew quite what they were up to.
I was fortunate to go to a conference in Reno in Feburary. From the audience, when Dr Mikovits was talking about cytokines, and she was obviously very excited about something but it wasn’t the cytokines she was describing. And so I didn’t find out what it was until October 8th when this paper appeared in Science.
Science as you know is an extremely reputable journal. They review these papers extremely carefully. Now, in the paper the first headline that most people take is that roughly 67% of patients had a test of their DNA done by what’s called PCR – Polymerase Chain Reaction – which was able to detect the viral sequences of XMRV. So this was 2/3 of the patients had this sequences present. And when they do that test on healthy controls it’s only 3 to 4%. So this represents one of the first ways of establishing whether or not an infection is important in the generation of an illness. You have a high percentage of people with the illness who have evidence of the virus and in healthy control people a very low incidence.
If you remember back in the days when this was thought to be due to Epstein-Barr Virus, well 95% of healthy people have antibodies to Epstein-Barr Virus, and yes if you’re sick you’ve got a 95% chance of having those antibodies, but that doesn’t mean that Epstein-Barr Virus virus caused the illness. In fact back in ’85 we did a study on a bunch of children and only half the children had the antibodies to Epstein-Barr Virus. And half of our patients with Chronic Fatigue Syndrome who were children had those antibodies. So that meant that Epstein-Barr Virus clearly couldn’t be the cause.
XMRV is in a totally different league. This is a disease that is pretty rare. In the Japanese literature, their healthy population of 1-2% has evidence of this virus, so in line with what the WPI found.
However, the PCR data by itself is not going to change the world. Many journals will not publish a paper based on just PCR data. The WPI realised that early, so they went ahead with several other technologies, one of which was to demonstrate that this virus was… they were able to infect other cells with it. And they were able to show under electron microscopy was budding viral particles that fit the description of XMRV and a number of other things they did, which made the paper extremely strong. This becomes very important, because people are quite ready to dismiss PCR data. But the other ancillary studies that the WPI did I think make this paper very strong.
[Slide: XMRV in CFS
Data Reported at CFSAC meeting
68/101 XMRV DNA positive
Of the other 33, 19 are XMRV antibody positive
30 of 33 had transmissible virus in the plasme
10 of the 33 had protein expression]
After the paper was published, they had 33 patients who were negative for the PCR. This data here was presented by Dr Dan Peterson at the Washington CFSAC meeting shortly after the publication of the Science paper. What they presented was that 19 of them had postiive antibodies to XMRV. What that means is that those patients have seen this virus and developed a resistance to it by the way of linking antibodies. 30 of the 33 had transmissible virus in the plasma. And this is extraordinary. If you take the plasma of these people with Chronic Fatigue Syndrome and then show that it can infect these tissue cultures, this is really quite extraordinary. Now there are a lot of questions here. How come they weren’t PCR postiive? These are questions that are normal at the beginning of a scientific breakthrough and it’s going to take the next 5 years to come up with all these answers. So quite legitimately you can say “How come these people have transmissible virus but they are PCR negative?” Let’s give that a bit of time and we’ll find out.
And then 10 of the 33 had protein expression. What that means is when you look in the cells, you can find that not only is the virus there, it is making copies of itself, it is actually replicating, it is doing things. We’ll come to that a little bit later as well. When you add it all up, all of the people involved in this study, 99 out of the 101 patients had some evidence of XMRV infection and this is an extraordinary number. Is that going to hold up in the future? I have no idea. I think that it’s quite possible that there are a number of people who will be negative for XMRV. We just don’t know that yet. We need to be patient. We need to let the scientists do their work and we will come up with those answers eventually.
[Slide: XMRV in CFS
Data reported at CFSAC meeting – 2
Implication:
no simple test now that will tell you if you have XRMV or if the virus is active in your system. And we need a good control study using all measures to accurately know control presence of the virus.
DNA by PCR
Viral infectivity
Detection of viral proteins
Antibody to the XMRV envelope]
Now there are a number of implications to these findings, and one is that there is no simple test which is a gold standard for XMRV infection. I guess if you had a culture assay which showed the growth of this virus in tissue culture, yes I would consider that a gold standard. If you were able to say that your laboratory has no sources of contamination and you can grow this virus in a tissue culture from your patient sample, yes I would say that’s a gold standard but that’s a very difficult and expensive set of tests to do. There’s no way that the PCR is a gold standard at this point. Why is that? We don’t know. Could it be that the primers are not the best primers? There are lots of technical reasons why there may be a better test down the road.
So, when people are saying “I want a test to see whether I’ve got XMRV” you know, I want that test too. But I think it’s still a little bit early to say yes we have a test that is the right cost, the right specificity and that the clinicians will know how to interpret it. I think we are some time off from having those criteria met. Now if somebody wanted to go and get the test, it’s quite expensive. I would say no insurance company is going to cover it. If you want it for your own intellectual curiosity to know about it, you can go ahead and get it. But for my patients I’m not encouraging them to do that, because I think that we need to know a little more about this virus and about the testing procedures before this becomes a standard part of medical care.
[Slide: A New Virus for Old Diseases?
John M Coffin, Tufts University
www.scienceexpress.org/9October2009
10.1126/Science.1181349]
At the CFSAC meeting, I had the good fortune to meet a Dr John Coffin who wrote a little piece in the same issue of Science magazine that the original paper was published in. John is one of the great virologists. He’s been there during all of the AIDS research. He is just about as knowledgeable as you can get on retroviral diseases and he has been speaking to the committee advising the Department of Health and Human Services and he was giving his comments as an outsider. He was not one of the authors of that original study. And he said something which is just the right perspective. What he said was that as a first paper; the paper by Lombardi and others, it’s as good as it gets. You can’t have a better first paper. But it’s only a first paper. I think that’s a perspective that we need to keep. It’s very difficult because for people who have Chronic Fatigue Syndrome they lived for year after year after year of people disrespecting the illness itself. So patients are legitimately saying “I don’t want to wait any more. I want this to be the end. I want this to be declared the cause of Chronic Fatigue Syndrome.” Unfortunately it doesn’t quite work that way and you’re going to have to struggle through a little longer.
[Slide: Erlwein O, Kaye S, McClure M, Weber J, Will G, Collier D, Wessely S, Clear A.
Failure to detect the novel Retrovirus XMRV in Chronic Fatigue Syndrome.
PLoS ONE.
E8519. doi: 10.1371/journal.pone.0008519]
Now just a few weeks ago there was a paper published in the journal PLOS which tested 186 stored samples from a group in London.
[Slide: Erlwein et al.
186 Patient stored samples
Nested PCR
XMRV or MLV not detected]
They used a technique called Nested PCR and they were not able to find XMRV in a single one of the patients. This has caused again a great stir. There has been a number of editorials that have come out saying ‘Here we go again.’ This is very difficult for patients because patients don’t want to have to go through this controversy. However, science has to come up with the answer.
One of the things that’s happened in Chronic Fatigue Syndrome is that historically, there have been a lot of theories, and a lot of the theories have been incorrect. So somebody will come out and they’ll say “This illness is caused by a magnesium deficiency getting into the amygdala part of the brain” and it’s a very nice theory, and then after a period of time that theory begins to fall away and then something else comes up. So there have been a lot of theories presented.
In my experience, I enjoy studing these theories for several reasons. One is that I learn a lot of medicine and the second is that I practise a technique which has been very useful to me. And that is I give the theory the benefit of the doubt. And I say ok, let’s say that this theory is correct, then what means is this and this. And then I wait to see how long it is before that theory falls apart in my own set of reasoning. And in general the theories fall apart very quickly. Because this is a very complex disease. You have to be able to explain why children get it in equal sex ratios. Why do [in] adults more women than men get it? Why do some people get better without treatment, up to 80%? Why do some people get disastrous symptoms in this area? So when you look at all these symptoms, these theories tend to fall apart fairly soon.