1. Impact of vCJD on Haemophilia Practice
Dr Gerry Dolan
Nottingham Comprehensive Care Centre UK
Thank you. And good morning ladies and gentlemen. I'm presenting the experience as a hemophilia treater in one of the comprehensive care centers in the UK. And the basis of the talk is really to discuss how we as treaters responded to this information which was so elegantly outlined by Richard Knight.

2. The UK issue – late 1990s vCJD may be transmitted by blood products.
There may be a large number of infectious, asymptomatic individuals in the UK donor population.
Haemophiliacs in the UK treated with plasma-derived concentrates may have been exposed and continue to be exposed to transfusion transmitted
vCJD.
The whole issue came to light first in the late 1990s. And this is a summary of the information that we had to try and deal with. The information was the variant CJD may be transmitted by blood products without any clear proof. There may be a large number of infectious asymptomatic individuals in the UK donor population. And the hemophiliacs in the UK had been treated with large pool concentrates prepared from these donors.

3. The UK issue – 1990s
What can be done to minimise the risk to patients from this new TTI risk?
So, given this potential risk, was there anything that we could do to try and minimize the risk of this potential TTI, transfusion transmitted infection?

4. The UK issue – 1990s
History in haemophilia care of devastation caused by transfusion transmitted infection – HIV.
Difficulties caused by delayed acceptance of the risk of TTI and of delayed actions.
Potential to improve safety for patients.
This was in the background, which I won't have to outline to this audience of a very sorry history of TTI and hemophilia. And if I look back to the beginning of the HIV epidemic, there were clearly some difficulties there caused by a delayed acceptance of the fact that it was indeed a transfusion transmissible agent. And there were potential maneuvers that could have been adopted at that point to improve patient safety.

5. Incomplete knowledge The UK issue – 1990s
One of the biggest challenges that we had to actually decide what, if anything, we needed to do was a complete lack of clear data.

6. Meeting of UKHCDO in 1997 Spongiform Encephalopathy Advisory Committee
(SEAC)
Centre for Surveillance of CJD
The first thing we did was we convened a meeting. This was the United Kingdom Hemophilia Center director's organization and we had a meeting back in 1997 with key members of the Spongiform Encephalopathy Advisory Committee (SEAC) and the Centre for Surveillance for CJD to inform us of everything up to date of what we might do.

7. Meeting of UKHCDO in 1997 New Disease British Disease
Long incubation period  may be many infected blood donors
Experimental evidence for TTI
Large number of UK haemophilic population had received and were still treated with plasma products derived from UK donors.
This is a summary of where we got to. It's a clear consensus this was a new disease that we were dealing with. It was at that time and still is largely a British disease. It was a long incubation period therefore there might be many infected blood donors. And there was some experimental, and this was barely experimental, evidence for TTI. But probably a majority of patients in the UK at that time had received large pool concentrates and even probably importantly were still receiving them. This was still probably one of the major products that were being used at that time.

8. Reducing risk - 1
As soon as possible – stop using UK plasma-derived products.
Recombinant products treatment of choice.
Plasma-derived products – use non-European plasma  USA plasma sourced products preferred.
Our conclusion at the end of that meeting, it wasn’t uncontroversial, was that with immediate effect we stopped using British sourced plasma products where we could, where there was a choice. We reconfirmed the statement made in our therapeutic guidelines a couple years earlier, which was that recombinant products were the treatment of choice based on safety issues. That recommendation was not universally adopted nor accepted through the UK and there were a lot of local battles with public health doctors and commissioners because they, at that time probably quite rightly, said that we had no clear evidence upon which to base the recommendation. We knew that politically it was unlikely to happen. It was unlikely that it would be a change at that time and the pragmatic approach was that we should move to non-European sourced plasma products. That effectively meant that we were looking for USA plasma based products. And the reason for the term non-European was that cases of BSE had started to be reported in other countries in Europe and we knew that we had exported the contaminated animal feeding material which seems to have been responsible for BSE. And we've exported it largely to Europe.

9. BPL and SNBTS  stop production of FVIII/FIX
Consequences
BPL and SNBTS  stop production of FVIII/FIX
Source and import USA plasma
Long delay and interruption of supply of other products FVII
FXI
The consequences of these decisions follow: the main manufacturers of plasma products in the UK, Bioproducts Limited and the Scottish National Blood Transfusion Service, stopped production of factor 8 and factor 9. It took them a long time to source and import USA plasma and so there was an interruption in supply and all the patients had to change product. For factor VIII, that really wasn’t much of a problem because there were plenty of other suppliers. For factor IX, it was a problem and there was some difficulty in getting volumes of USA based factor concentrate. But BPL is a fairly public spirited organization and they did produce niche products which weren't commercially very attractive, but were therapeutically useful, such as factor VII and factor XI concentrate. And these were no longer available; there was an interruption in supply.

10. Alarm among patients (1st wave)
Patient Response
Alarm among patients (1st wave)
Confidence undermined.
Increased pressure for recombinant products.
You can imagine the impact on patients when we went to them and said, we're having to change your blood products. Rightly or wrongly, many patients considered that UK plasma products were among the safest in the world. Many of the treaters felt that too. And now we were telling them, well, actually we're not going to use these products any more and we're going to use USA plasma. It was a big blow to the patients’ confidence-- as if we didn’t know what we were doing with these products. There was increased pressure for recombinant factor VIII and factor IX.

11. Impact
UKHCDO/Haemophilia Society – had for many years argued for the introduction of recombinant products – based on safety.
‘Failure of pathogen inactivation steps to deal with all infective agents and new/emerging pathogens’
vCJD
Now, our therapeutic guidelines, which were created probably around 1995, go back to the statement that we felt recombinant products were the treatment of choice. There wasn’t a lot of clear evidence-based data to justify that recommendation, but the arguments that we put forward were that it was clear evidence that the current virucidal techniques weren't effective for all infectious agents and there was the ever-present threat of new emerging pathogens. At some point HIV was a new pathogen. At some point HCV was a new pathogen. Many of my colleagues will remember that the public health doctors poured scorn on this and in particular this part here. What evidence did we have that there was any new infectious agent out there that could be transmitted by blood? Well, it didn't take long before that came sharply into focus.

12. Impact
Department(s) of Health – accepted the case for recombinant FVIII/IX for all children.
Children  recombinant products.
Adults  USA plasma-derived FVIII/IX.
And the immediate consequence in another impact on hemophilia care was, and I have to say not with good grace, the Department of Health accepted that recombinant products should be used for all children. Only four children and all adults would continue to receive plasma products.

13. The inevitable!
2000 BPL notified UKHDCO of batches of factor concentrate prepared in 1996/7 and used before 1998 – donor subsequently diagnosed with vCJD.
Many patients treated with these batches
? response
Given the story so far, you could probably have written this script concerning what happened next. A lot of patients have received these UK products; in 2000 we received the first notification from one of the manufacturers that batches of factor concentrate prepared back in 1996/97 and had been used before 1998 had been made from a donor who subsequently developed variant CJD. Because of the good tracking system of the UK, we can identify all of those recipients. And there were a lot of patients who had received these batches. So, the question was at that point, and this is an evolving story, what do we do with that information?

14. No clear evidence of vCJD transmitted by blood products but some experimental evidence.
No test for donor or recipient infection.
Long incubation period.
No treatment.
Just going back again, we were basing this decision on background where there was still no clear evidence of variant CJD transmission by blood products. We didn't have a test for either donors or recipients. This is a long incubation period so we wouldn't be able to tell clinically if anybody had any evidence of a disease and there was no treatment even if they were found to be positive.

15. Not tell patients v Tell them everything
Write to all patients irrespective of whether they had received implicated batches or not and ask if they wanted to know:-
1. Yes and discuss in person
2. Yes and inform by letter
3. No – don’t want to know.
Initially the challenge concerning informed patient choice was, did we tell them nothing on the grounds that we didn't have a test, we couldn't tell for certain there wasn’t any treatment, and risk that we would certainly disturb their peace of mind if we told them that they might be infected? Or did we tell them everything on the grounds that we should present information of this nature to our patients?
The official line originally was to tell them nothing, which we as hemophilia treaters were not happy with. In the true British fashion, we arranged a compromise which was that we'd write to all the patients who had received products and ask them if they wanted to know this information.
And they had three choices: Yes, they wanted to know and they wanted to see us face to face to discuss it. Yes, but I just wanted a letter with some information. And no, they didn't want to know. And surprising there still was a substantial number of patients, certainly in our center, who fell into this latter category.

16. Impact on patients Considerable concern may be infected with vCJD
recombinant products not available
This news caused considerable concern. Some patients in particular were very disturbed by this news. I can think of several patients in our center, in particular parents of children, older children who'd received plasma products in the past, and were on recombinant now and who were being very careful with their diet to ensure that they didn't expose themselves to any dodgy meat products. These patients were now were being told that they may have received contaminated material through factor VIII. The notification and the reaction to the notification undoubtedly increased the pressure and changed the political debate somewhat that our original recommendations should be adopted.

17. Recombinant for all
Undoubtedly increased political pressure to fund recombinant coagulation factor concentrates in the UK.
From April 1st 2005 – all patients with haemophilia A and B will be treated with recombinant products.
And from April the first of this year, all patients in the UK will be treated with recombinant factor VIII or factor IX. It's been a staged process over the past 3 years. The decision came about 3 years ago, but from April the first this situation should at least be partly resolved.

18. Unresolved issue
If these recipients of UK pooled plasma products have been exposed to vCJD – what risk do they pose to others?
But we still had a problem here. If these recipients of UK pool plasma products had been exposed to variant CJD, what risk did they pose to others? Is it all generally older patients with joint disease or with other complications of hemophilia, those who are likely to require invasive procedures?

19. ‘Guidance’ Department of Health
Advisory Committee on Dangerous Pathogens
Spongiform Encephalopathy Advisory Committee
Risk assessment conducted by Det Norske Veritas Consulting.
That guidance has come from the Department of Health, using expert advisory committees that Richard Knight discussed, the Department of Health Advisory Committee on Dangerous Pathogens and the Spongiform Encephalopathy Advisory Committee. There was a risk assessment which was partly conducted by this organization and their conclusions were undoubtedly influenced a little bit by the link with transfusion variant CJD but no definite proof. And I won't discuss this in details because Richard already has. The risk assessment they performed was very complex and very detailed and I don't intend to go into here and I actually don't think I have the ability to explain all the different complex contortions, but I will summarize and say that it was based on largely theoretical concerns. It was based on a kind of worst case scenario.

20. ‘Guidance’
Patient 1 receiving blood during an operation in 1997 –died of VCJD 6 years later.
Patient 2 – received blood from donor who subsequently developed vCJD. Patient died of other causes but at autopsy PrPsc in spleen.

21. Categorisation of patients at risk
1. Symptomatic patients
2. Asymptomatic patients at risk from familial forms of CJD linked to genetic mutations.
3. Asymptomatic patients potentially at risk from iatrogenic exposure.
They categorized patients according to perceived risk. All of our patients fell into this category - asymptomatic patients potentially at risk from iatrogenic exposure. And the interest that we had was what were the recommendations for how we handled the potential for these individuals to infect other patients.

22. Precautions Single use instruments where possible.
All procedures performed in operating theatre.
Procedures should be performed at the end of list.
Minimum healthcare personnel involved.
Liquid repellent operating gown over a plastic apron.
Mask,goggles or full-face visor.
Some of the recommendations were fairly generic using common sense approach, using single instruments where possible. Even minor procedures should be performed in a controlled environment rather than patients being operated on in the middle of a theater lest they should be operated at the end using some protection for the operators.
It is not that difficult to institute such measures in most modern hospitals. The problem is that it does raise the level of concern among more uninformed people - surgeons, theater staff, and this sort of things stigmatizes patients. The biggest concern really is what you do with those who are undergoing procedures which are categorized as high and medium risk procedures?

23. Precautions Surgical instruments
High and medium risk procedures CNS, posterior eye
lymphoid
olfactory epith
DESTROY instruments
So, these recommendations are what do we do with the surgical instruments in this situation? And any operation on the central nervous system, any operation on the posterior eye and lymphoid tissue also olfactory epithelium. It's difficult here. You know, if you take lymphoid tissue, what does that mean? Clearly obviously lymph nodes and things like that, but it does involve gut lymphoid tissue and there are some paradoxes here where lymphoid tissue is categorized as high and medium risk yet bone and bone marrow is categorized as low risk. But the upshot is that if anything is happening in these areas, then the instruments should be destroyed.

24. Precautions Endoscopy CNS GI and olfactory if biopsy performed
Quarantine/destroy
The biggest struggle we have now is what to do with endoscopy? Because of this caveat that lymphoid tissue exists through the gut, if your endoscoping a patient, then you might be contaminating that endoscope. They've refined the advice to say that if any biopsy of the gut or the olfactory epithelium is concerned, then that endoscope
has to be quarantined. Now, you can imagine the discussions that take place when we go to our endoscopy service and say Well, if you endoscope one of our patients who is categorized in this category 3 area, then you've got to quarantine your $100,000 dollar instrument and not use it again on anybody else. But the people who were giving us guidance said, but these guidelines should not affect the quality of patient care. It doesn't match up. And in many centers around the UK, there's a sort of degree panic and at the moment endoscopy is not being performed in some circumstances unless it's a real emergency.

25. Other initiatives Research/surveillance Autopsy
Recipients of potentially contaminated products.
There are other initiatives. Considering that this is a fairly well defined population, we have good records for all hemophiliacs in the UK. So, we have a model of patients who have potentially received this infectious agent by a transfusion transmission root. And at the moment there is an initiative to try and set up a surveillance program on all these patients who we know have received products. There's also an autopsy study which is being linked with that at the moment. As far as we're aware has only been two autopsies performed with no evidence of variant CJD.

26. Impact of vCJD in Haemophilia care in UK
Caused great anxiety and distress to patients in the UK.
Potential to severely reduce the quality of medical and surgical care to all patients.
So, the impact of this potential transfusion transmitted infection in hemophilia here in the UK is that it has caused great anxiety and distress to patients. The biggest fear we have is it has the potential to severely impair the quality of medical and surgical care for our patients.

27. Impact of vCJD in Haemophilia care in UK
Massive increase in extra clinics, administration and record keeping for haemophilia centre staff.
Potential to stigmatise the haemophilic population (again)
On a slightly more selfish front, it's caused a massive increase in the workload for the hemophilia centers. This is a big administrative exercise to retrace, often at a time when records were maybe not quite so good as they are now, and track down all the patients, and not just the severes. Any patient who has received plasma products. So, for the bigger centers, that's hundreds and hundreds of patients. We've got to track them all down and keep very clear records. And again, harking back to the HIV epidemic, making sure that you don't fall out of line with the party line that's being adopted in the UK at the moment. The biggest fear is that if this is an uncontrolled advice and implementation of guidelines then it has the potential to stigmatize the hemophilic population again.

28. Impact of vCJD in Haemophilia care in UK
The Recombinant for all programme should ensure that this will not happen again.
The, Ending on a slightly lighter note, this recombinant-for-all program has been a success in discussion and reasoning with our healthcare providers. And the fact that from April 1st all hemophiliacs will only be treated with recombinant products should stop, should partly stop this process from happening again. The difficulty is that there are many patients who have been told that, no you haven't received an implicated batch of product yet, but if there are any more notifications that we come across, and there probably will be, then we'll have to revisit the issue at that time. The interesting aspect is that I've given this talk from the UK perspective. I haven't clear ideas of what other countries are doing with respect to this variant CJD issue. We know other countries in Europe have actually had clinical cases of variant CJD among their general population. vCJD may exist in the donor population. We know that the manufacturers of the British pool plasma products exported those products to other countries. As far as I'm aware, those countries have done a risk assessment. And we all know that risk assessment is an imprecise science. Their conclusions were that they have not adopted the view that the risk is as high as we have in the UK. So, I'll end it there. Thank you for your attention.