Blood Products Advisory Committee Meeting Announcement (BPAC) December 14-15, 2010

[Cloud]

I believe it's been discussed before that Bell's patients are not really recovered. The "recovered" people have been able to figure out how to be somewhat functional but are in no way recovered.

I wonder who labeled them "recovered", how much the patients themselves agree with that status, and get their take on whatever improvements they have made.

The fact that some have made huge improvements over the years without treating an active retro-viral infection, is very significant.

 

[omerbasket]

Conclusions from Phase IIb



I think only the WPI found positives in the second round collected using the phlebotomy company.... That could be a danger sign for the WPI - except that, by and large, they identified the positives correctly.......

So it's more of a danger sign for everyone else, I think :Retro smile::Retro smile:

As far as I understand - the samples in phase IIb were from the same patients whose samples were used in phase IIa. And in phase IIa the CDC found all of the four to be positive for XMRV with two of the methods used.

Look at what Val wrote:
Phase IIa:

No positives found for any subject using a WB DNA/RNA test on any days.

No positives found for any subject using PBL DNA/RNA test on any days.

Positive (?- there's either a symbol or letter before this, but can't read it)XGAG PCRresults for Subjects 3 and 4 on Days 2 and 4. Sequenced XMRV.

Positive (looks like) off-PCR (pro) results for:
Subject 1 on Day 2, sequenced XMRV/MuLV (no results from Day 4, no explanation)
Subjects 2, 3 and 4 on Days 2 and 4, sequenced XMRV/MuLV
Notes:
-Plasma was ultracentrifuge pelleted prior to nucleic acid extraction
-All PCR positive samples tested negative for mouse mitochondrial DNA

Phase IIb:

Phase IIb CDC Results

Multiple Assays for XMRV and generic MLV

-Plasma ultracentrifuged before nucleic acid extraction

-Plasma assayed with nested RT-PCR for XMRV gag and envelope and quantitative RT-PCR for MLV gag and integrase

-WB and PBMC assayed with nested PCR for XMRV polymerase and quantitative PCR for MLV protease
All plasma and PBMCs samples from both days were negative

-Plasma RNA controls in range

-WB and PBMC genomic DNA controls in range

As far as I understand it - the CDC didn't use in the IIb stage the assays that found positives in the IIa stage. But in the IIa stage they found by a combination of two methods that ALL OF THE FOUR WERE POSITIVE. They even checked for contamination and did not find one.
I don't really understand why they haven't used in phase IIb the assays that found XMRV in phase IIa. Anyway, there is also the factor that we don't know what they were testing in phase IIa regarding the samples being plasma samples, PBMCs samples or whole blood samples.

By the way - they found an explanation for the "false positive" of the WPI. But why are they so sure that it's false? couldn't it be that this "pedigreed negative" is actually positive? It's the second time that the WPI find the same "pedigreed negative" to be positive. So it's possible that the WPI got a false positive. But it's also possible that this patient is actually positive!

 

[CBS]

CSB, thanks so much for the NCI info!! You "noted" that Coffin consults to NCI/DRP, right? (Save that man part, man!)

leela, in the intro slide to the BWG results, the presenter basically said they "really need" a reliable/valid blood test because that's most cost-effective for dealing with the blood supply, as well as for cheap, easy testing of individuals (us!).

I did see that Coffin consults with the DRP. I tend to view Coffin more as a conservative scientist who knows nothing more about CFS than what the CDC has told him and not as being "against us." I do hope that Alter pulled him aside after the meeting and shared a thought or two. Really glad to see Alter allude to the need for appropriate diagnosis.

As for "that part," I'd think of it as a something akin to a kidney donation. There's a reason we were given two (nature has a way of being redundant when it comes to the important stuff) but you don't need them both (I actually have it on good authority that you don't really need either of them - not kidneys) to keep going.

As for the blood supply, you'd need a test for XMRV/MLV's to clean it and keep out tainted donations. However, the blood collection agencies don't test for blood related cancers directly but those patients are permanently deferred (can't find a list but just spoke with a American Red Cross medical staff that confirmed this deferral):

No blood donations are accepted from patients with a history of hematological cancer (i.e., where the cancer affected blood cells), such as leukemia, lymphoma, Hodgkin's Disease, Mycosis Fungoides, Kaposi's Sarcoma, Multiple Myeloma, and Polycythemia Rubra Vera. Blood may also be refused from cancer patients who underwent a splenectomy or certain types of transplants, or who had cancer affecting any organ in the blood production system (e.g., liver cancer).

AABB - http://www.aabb.org/resources/donation/Pages/donatefaqs.aspx

Screening tests performed are listed below:

• Hepatitis B surface antigen (HBsAg)
• Hepatitis B core antibody (anti-HBc)
• Hepatitis C virus antibody (anti-HCV)
• HIV-1 and HIV-2 antibody (anti-HIV-1 and anti-HIV-2)
• HTLV-I and HTLV-II antibody (anti-HTLV-I and anti-HTLV-II)
• Serologic test for syphilis
• Nucleic acid amplification testing (NAT) for HIV-1 and HCV
• NAT for West Nile virus (WNV) (this test is not required by the Food and Drug Administration [FDA], the organization responsible for federally regulating the blood supply)
• Anitbody test for Trypanosoma cruzi, the agent of Chagas' disease (this test is also not required by FDA)

If I were an FDA Blood Safety official my nightmare scenario would be a wide spread infectious retrovirus (5% of the population) with a long latency period but that is not detectable in the blood even though it is associated with numerous cancers and neuro-immune disorders. I hope that this is not where we are headed but I do hope that people at the FDA are losing some serious sleep over this.

Say this were the case, is the most manageable public policy then to deny the dangers and keep telling everyone that there is nothing to fear? I'm not much of a conspiracy theorist but simply from a practical stand point, I'd hate to be in charge of ensuring public safety when the truth was that 1/20 transfusions was going to infect a seriously ill or traumatized person. On the other hand, if this were the case, the autologous blood banking business would go through the roof.

 

[Cort]

Ok I probably am not getting most of it..could someone in a few sentencss tell me why Coffin is negative (as opposed to cautious) about xmrv, that is, how does that present itself?

Coffin found two people with CFS who appeared to have MLV's but his new test showed they actually had mouse DNA....That's one thing. THere was another researcher at the last Workshop who was going to report she had found another form of XMRV - which turned out to be contamination.....He's concerned more with Alter than the WPI, I think.

I think he's probing deeply but he's on the fence...If Alter can isolate the virus he will be fine....in lieu of that Coffin is fine...He didn't seem to have many problems with Judy's presentation I don't think.

 

[Cort]

As far as I understand it - the CDC didn't use in the IIb stage the assays that found positives in the IIa stage. But in the IIa stage they found by a combination of two methods that ALL OF THE FOUR WERE POSITIVE. They even checked for contamination and did not find one.

Interesting! Good catch! They didn't use the assay that worked the first time......in Phase IIB -- I would think they would have used the same assays throughout.....Maybe if they had about 20 more samples they could've used more assays for each stage.........

 

[leaves]

Thanks Cort, I appreciate it.

 

[Cort]

But why are they so sure that it's false? couldn't it be that this "pedigreed negative" is actually positive? It's the second time that the WPI find the same "pedigreed negative" to be positive. So it's possible that the WPI got a false positive. But it's also possible that this patient is actually positive!

We are counting on that sample being negative. I assume that its been tested many times by the WPI and its come up negative each time. We don't know though.

 

[eric_s]

Here's WPI

Remember samples are blinded and from someone who tested positively and this is newly drawn, never before stored blood at the WPI

They wrongly identified a negative control as positive - but think they can explain the area.

They were able to identify XMRV correctly in 3 of 4 positives - it wasn't easy, they could only do so on one day and they missed on one but the important thing is that by and large they identified the positive samples correctly - a big win

This suggests a) because the controls tested negative, their lab is not contaminating the samples
b) while its not always easy to find XMRV they can find it and in the right samples....

Their ability to identify the positives and controls correctly suggests

they are doing something right and the other labs are doing something wrong..

​

Its a good result.

It's a little sketchy because they missed on one control and XMRV is not easy to find - and, suggests that really, no one has a really good test for it yet.

It also kind of suggests that there were only five samples??? (Is that how they blind - throw ONE more sample in there?). That doesn't sound like a strong test...)

The salient fact is though, that, by and large the WPI picked out the controls from the positives and that is the acid test. It suggests to me that the WPI is doing some right the other labs are not and that the BWG should be very carefully going over the labs procedures - down to the smallest detail - to see what the WPI is doing differently.

To me this seems like a big win for the WPI

Sorry, but i can't be so positive about this. So far we've had phase 1, phase 2a and phase 2b. And in pahse 1 and phase 2b the WPI got a (presumably) false positive.

If they really are able to explain the false positive then the result is pretty good, but i wish they would not have so many false positives.

I don't see how you can say they were able to tell the positives from the controls in this case.

It does not change my opinion, i still believe the positive studies were correct, but i'm not really happy about this result. Also i hope if Judy Mikovits said that the WPI's serology results are concordant with the NCI/Ruscetti's that this doesn't mean they also have a false positive there (like NCI/Ruscetti).

 

[Esther12]

Coffin found two people with CFS who appeared to have MLV's but his new test showed they actually had mouse DNA....That's one thing.

I didn't know that. That explains his scepticism a bit. What a mess this all still is.

 

[alex3619]

I'm not much of a conspiracy theorist but simply from a practical stand point, I'd hate to be in charge of ensuring public safety when the truth was that 1/20 transfusions was going to infect a seriously ill or traumatized person. On the other hand, if this were the case, the autologous blood banking business would go through the roof.

Hi CBS, there is an important factor that is missing in this argument. A friend of mine had a burst stomach ulcer a year or two ago. During the surgery he had 18 units of blood. Each of these probably came from a different donor. He is now very worried about XMRV since we have discussed the virus. Surgery sometimes requires a very great many units of blood from different donors. This might mean the risk of infection is very high, approaching certainty. It is so high in fact that it might explain most cases of CFS and XMRV infection. People with XMRV might be blood recipients, children of blood recipients, or partners of blood recipients.

Bye
Alex

 

[CBS]

Hi CBS, there is an important factor that is missing in this argument. A friend of mine had a burst stomach ulcer a year or two ago. During the surgery he had 18 units of blood. Each of these probably came from a different donor. He is now very worried about XMRV since we have discussed the virus. Surgery sometimes requires a very great many units of blood from different donors. This might mean the risk of infection is very high, approaching certainty. It is so high in fact that it might explain most cases of CFS and XMRV infection. People with XMRV might be blood recipients, children of blood recipients, or partners of blood recipients.

Bye
Alex

Alex,

Good point. Not terribly reassuring if you are a hemophiliac either. Has anyone done a review to determine if hemophiliacs get any of the suspected diseases more frequently?

 

[CBS]

Has anyone done a review to determine if hemophiliacs get any of the suspected diseases more frequently?

This is a first- I'm replying to my own quote:

Haemophilia. 2010 May;16(3):427-36. Epub 2009 Nov 11.
Malignancy in patients with haemophilia: a review of the literature.

Dunn AL.
Aflac Cancer Center and Blood Disorders Service/Children's Healthcare of Atlanta/Emory University, Atlanta, USA. amy.dunn@choa.org
Abstract

Haemophilia A and B are rare X-linked conditions. Elevated rates of HIV and hepatitis C related malignancies in these patients are well reported, however rates of other types of cancers are not. Therefore, a retrospective literature review of cancer in patients with haemophilia was conducted. A Medline search of articles from January 1966 to July 2009 utilizing the keywords haemophilia, leukaemia, malignancy, mortality, neoplasm and cancer was performed. The articles were reviewed and additional relevant publications were located from the references. Data on age, type and severity of haemophilia, HIV status, type of malignancy and outcomes were recorded as available. Thirty-two cases of leukaemia were identified as well as 159 malignant solid tumours. Specific incidence and prevalence rates could not be calculated due to the limited nature of the information available in the reports. Many types of malignancy have been reported in persons with haemophilia irrespective of infection with HIV and hepatitis C yet prevalence and incidence rates compared to the general population remain unknown. Patients with haemophilia can manifest non infectious related malignancies and symptomatic patients should be evaluated accordingly.

 

[George]

I would like to see detection in blood samples compared to detection in tissue samples.

If I recall correctly, the animal model study data detected XMRV in the testes during both the "acute" and "chronic" phases of infection. Add to that the findings of Ila Singh (as per the patent application) that:

It's clear that we need to stop messing around with just the blood and get down to business with finding the virus where it lives. I'd literally give my left nut to move this thing forward (but let's hope it doesn't come to that).

You are such a nut! (grins)

 

[George]

Yes, I guess the BWG will be looking for a blood test above all. Not sure how this works though if Singh and others indicate that XMRV mainly lurks in tissue (after the initial acute infection).

However, I do remember Dr Singh suggesting that if the subjects (Macaque monkeys in this case) were injected with something to stimulate the immune system (there is a word for this I have forgotten!), then the virus re emerges from the tissues and starts re-circulating in the blood.

So maybe the way forward for the BWG is to stimulate the immune systems of the patient group and see if they have better/more consistent luck at turning up positive results for XMRV in greater numbers in blood after this stimulation/injection.

Could you kindly volenteer to design the next phase of testing please. We need some logic and smarts injected into this crew!

 

[markmc20001]

If I were an FDA Blood Safety official my nightmare scenario would be a wide spread infectious retrovirus (5% of the population) with a long latency period but that is not detectable in the blood even though it is associated with numerous cancers and neuro-immune disorders. I hope that this is not where we are headed but I do hope that people at the FDA are losing some serious sleep over this.

Say this were the case, is the most manageable public policy then to deny the dangers and keep telling everyone that there is nothing to fear? I'm not much of a conspiracy theorist but simply from a practical stand point, I'd hate to be in charge of ensuring public safety when the truth was that 1/20 transfusions was going to infect a seriously ill or traumatized person. On the other hand, if this were the case, the autologous blood banking business would go through the roof.

Simply inexcusable to ruin millions of lives because the smartest people in the world can't figure out how to manage public policy or are trying to make some extra profit for health insurers. The consequences are just not worth the potential gains.

In fact, governments have put more time and money into hiding XMRV(with bogus psychological studies, discrediting scientists, and phony balony CFSAC meetings for 25 years) than it would have taken to fund real cures and research. These CDC characters, and UK characters, better come clean because everybody is watching now. Time to deal with reality.

 

[George]

Hi CBS, there is an important factor that is missing in this argument. A friend of mine had a burst stomach ulcer a year or two ago. During the surgery he had 18 units of blood. Each of these probably came from a different donor. He is now very worried about XMRV since we have discussed the virus. Surgery sometimes requires a very great many units of blood from different donors. This might mean the risk of infection is very high, approaching certainty. It is so high in fact that it might explain most cases of CFS and XMRV infection. People with XMRV might be blood recipients, children of blood recipients, or partners of blood recipients.

Bye
Alex

It's an intersting theory Alex. Since we get the first hard report for this illness in 1934 in a hospital. I think some of the first blood transfusion go back to like the 1600 but I think the first blood banks were in the early 1900's.

from Wikipedia - in the 1910s it was discovered that by adding anticoagulant and refrigerating the blood it was possible to store it for some days, thus opening the way for blood banks.

Possible mouse contamination at the time could have transfered virus to humans where it did a little dance and became the wonderful parasite we all know and love today!?!

 

[CBS]

More on Hemophelia & Cancer

Turns out, the hemophilia & neoplasm relationship is heavily confounded because of HIV and Hep C (liver cancer). The rates of transfusion contracted HIV and Hep C are declining. Apparently, there are no epidemiological studies of hemophilia and cancer newer than a cohort that spanned the years 1992 - 2001.

Cancer Treat Rev. 2009 Jun;35(4):374-7. Epub 2009 Feb 4.
Hemophilia and cancer: a new challenge for hemophilia centers.

Franchini M, Lippi G, Montagnana M, Targher G, Zaffanello M, Salvagno GL, Rivolta GF, Perna CD, Tagliaferri A.
Immunohematology and Transfusion Center - Department of Pathology and Laboratory Medicine, University Hospital of Parma, Parma, Italy. massimo.franchini@azosp.vr.it
Abstract

The improved life expectancy of hemophilia patients due to the advances in hemophilia care and factor replacement therapy has permitted to hemophiliacs to reach an older age. As a consequence, age-related diseases, such as cardiovascular disorders and cancer, have been increasingly recognized in such patients. In particular, the management of cancer in people with inherited hemorrhagic disorders represents a new challenge for physicians working in hemophilia centers. The few published literature data document that there is a close relationship between hemophilia and neoplasia. Indeed, the congenital bleeding tendency may influence the cancer in different ways, by interfering with its clinical presentation, diagnosis and treatment. These aspects, along with the epidemiology of cancer in hemophiliacs will be discussed in this review.

Without doing any sort of statistical analysis, the more recent studies cited in the above review do suggest a possible a trend towards a higher incidence of non-HIV and Hep C related cancers than would be expected in the general population.

"In the prospective cohort study conducted by Plug and colleagues on the mortality and causes of death in the Dutch hemophilia population during the decade 1992–2001, deaths from malignant neoplasm accounted for 22% of total deaths with a standardized mortality ratio (SMR, the ratio of the observed-to-expected mortality) of 1.5"

A 50% increase.

Interestingly, Soucie and colleagues, in a survey on the causes of deaths conducted in six US states among 2950 hemophiliacs during the period 1993–1995, found that 6% (14/236) of deaths were attributable to non-HIV- or liver-related cancers with a standardized mortality ratio of 2.2.

More than twice as many non-HIV and Hep C related cancers.

Might have something to do with hemophilia. It doesn't seem unreasonable to ask if HIV and Hep C aren't the only infectious agents in the blood supply.

ETA: I couldn't find any papers on CFS and hemophilia. My guess is that unexplained fatigue and PEM in hemophilia patients is assumed to be explained by having hemophilia "with elements that do not respond to the standard therapy."

Also - Would the methods presently used to kill HIV in donated blood also kill XMRV? This question has been asked on the forums before. I'll keep looking.

 

[CBS]

From the World Federation of Hemophilia (WFH)


Interesting that this (April 2010 - http://www.wfh.org/2/9/9_1_Statements_Advisories.htm):

April 2010
XMRV and Chronic Fatigue Syndrome (CFS)
The World Federation of Hemophilia is closely following scientific developments with regard to XMRV. The decision by Canadian health authorities to defer blood donors who have had chronic fatigue syndrome (CFS) is a precautionary measure taken when there is incomplete information about XMRV. All indications are that an enveloped virus such as XMRV is not a threat to plasma-derived products, such as clotting factor concentrates, as it would be inactivated by current pathogen reduction processes. The action in Canada ensures that recipients of fresh blood products (red cells, platelets, fresh frozen plasma) will also not be at risk. Furthermore the supply of donated blood should not be affected as most people with symptoms of CFS were not eligible to be blood donors even before this decision. For more information, please contact the Canadian Hemophilia Society, a national member organization of the WFH, at chs@hemophilia.ca

Appears to have been changed to this (May 2010):

May 2010

Volume 9, Number 1

XMRV donor deferrals
Canadian and Australian authorities have imposed indefinite deferrals on potential blood donors who have had a medical diagnosis of chronic fatigue syndrome (CFS). There have been some reports that CFS patients may be infected with xenotropic murine leukemia virus-related virus (XMRV) and the deferrals aim to keep XMRV out of the blood supply as it may be transmitted through blood. At this time, there is no proof that XMRV causes CFS and studies have reached conflicting conclusions regarding XMRV infection in CFS patients. The decisions to defer have been made out of an abundance of caution in a time of uncertainty. An enveloped virus such as XMRV is not a threat to plasma-derived products, such as clotting factor concentrates, as it would be inactivated by current pathogen reduction processes.

Nothing about potential risks in fresh blood.

And what changed between the April and May statements?

I suspect that this is an uneasy topic in the hemophilia world.

 

[urbantravels]

Unlike whole blood and other blood products, plasma can be "cleaned up" between donor and recipient. This is why you can sell plasma but you can't sell your whole blood.

The reason why volunteer blood donations are the norm, rather than paying people to donate blood, has nothing to do with saving money - blood agencies could easily pay people to donate blood without affecting the bottom line much, the costs of providing blood products are concentrated elsewhere. But if there was a monetary incentive to give blood, they'd get the "wrong kind of people" giving blood - i.e. donors who would have a motivation to lie about their risk factors.

 

[omerbasket]

We are counting on that sample being negative. I assume that its been tested many times by the WPI and its come up negative each time. We don't know though.

If that's a sample taken from the same person, and that person have ME/CFS and was found negative by the WPI overy and overy in the past - it's possible that he was actually positive but the virus stayed out of his peripheral blood - or that it was in the peripheral blood but in levels that are below there level of detection of the WPI's assays - and that now he has higher levels of the virus in the blood and therefore he is found to be positive. The same about antibodies - maybe he stopped producing them then, for some reasons, and now he is producing them. It seems quite stupid, also, to use just one "pedigreed negative". I mean, the likelyhood of having 100% positives (in reality) while thinking you have 100% negatives in the "negative controls" when you use just one negative controls are much much higher than if you use, for exapmle, 20 "negative controls". And the best would be to take these controls from a group of completely healthy people who comes from a place without a known out break of ME/CFS and/or XMRV.
I mean, again, this "false positive" might show the WPI in a bad-light - but it's very possible that they are actually correct in diganosing him as XMRV positive.

By the way, the fact that john coffin thinks he found 2 persons that were diagnosed as MLV positive with mouse DNA is:
a) Probably a problem in the sentence, cause it seems very odd that a human being would have a mouse DNA... So I guess that he found mouse DNA in their blood samples.
b) Telling us nothing - because just as it could be a contaminant that came from the lab who found this person to be MLV positive, it can come from the lab of Dr. Coffin when he got to check the samples. Actually, if by some way the samples were taken from the WPI or the NCI - that declared that they have never worked with mouse in their labs - the chance of Dr. Coffin being the one infecting the samples, given that he, if I'm not mistaken (and correct me if I am) works a lot with mouse, is much higher.