# Presentation: 709003

## Comparison of the transfusion risk for CJD vs. vCJD 

- Steven Anderson, Ph.D, MPP
- Office of Biostatistics & Epidemiology
- Center for Biologics Evaluation & Research
- U.S. Food & Drug Administration
- TSE Advisory Committee Meeting
- February 12, 2004

**Notes:**
Good Morning  My name is Steve Anderson and I am from the 
Office of Biostatistics and Epidemiology in the FDA’s Center for Biologics Evaluation and Research.

Much of what I am going to talk about has already been presented – so I will be brief with my presentation.

## CJD and vCJD – risk of transmission via blood

- Animal experiments have suggested that both Creutzfeldt-Jakob disease (CJD) and Bovine Spongiform Encephalopathy (BSE) can be transmitted via blood transfusion
- Humans
- CJD - Prion protein _not_ found in lymphoreticular system
- vCJD - Prion protein found in lymphoreticular  system - tonsils, appendix, lymph nodes and spleen

**Notes:**
Today I am going to talk about comparing the transfusion risk for vCJD and CJD transmission via blood.
The speakers that will follow will discuss the  animal experiments – which have suggested that both CJD and BSE can be transmitted via blood.

Of interest for Humans is that the CJD protein in infected individuals was not found in the lymphoreticular system and was mostly localized in neural tissues.
For vCJD, prion protein has been found in the lymphoreticular system –including tonsils – appendix, lymph nodes – and spleen.
Because of its localization extraneurally in humans the possibility of transfusion transmission has been thought to be more likely to occur for vCJD compared to CJD.
Until recently the risk of transfusion transmission of these agents has been thought to be theoretical. 
 But recent events may offer a new perspective on this issue. 

## I. vCJD: Possible vCJD transmission via human blood transfusion

- On Dec 17, 2003 U.K. reported a 69 year old male died of variant Creutzfeldt-Jakob disease  (vCJD) 6.5 years after transfusion
- Above recipient received RBCs from donor in 1996 that died 3 years later from vCJD

**Notes:**
As previous speakers have detailed.  
On Dec 17th the United kingdom reported a possible case of transfusion transmission of vCJD.  
The disease occurred in a 69 year old male 6.5 years after transfusion.  
The recipient had received Red Blood Cells from a donor in 1996 who had died 3 years later from vCJD.

## Study of vCJD donors and recipients

- Study in United Kingdom by National Surveillance Unit and National Blood Service
- Followed donations from 15 donors later diagnosed vCJD
- 48 Individuals received blood products from the 15 donors
- Whole blood, RBCs, plasma, platelets, etc.
- *Llewelyn, et al. Lancet, 2004.

**Notes:**
As Dr Will had discussed.  There has been a study being conducted in the United Kingdom by the National Surveillance Unit and National Blood Service.

The study has followed donations from 15 donors that were later diagnosed with vCJD.  

A total of 48 individuals had received blood products from the 15 donors  --
These products have included whole blood, RBCs, plasma, platelets, etc.

The recent case of vCJD announced in December was one of these 48 individuals that received products.

## Additional potential vCJD exposures via blood products in the U.K.

- 18 units of plasma from vCJD infected donors included in fractionated products prior to 1998
- Thousands of potential exposures
- vCJD has not been observed to date for these products

**Notes:**
In addition to the previous study of blood products.  

There are potential exposures that may have occurred prior to 1998   -  when 18 units of plasma from donors later diagnosed with vCJD were used in the manufacturing of fractionated products.

There could have been thousands of potential exposures since plasma from up to 60,000 donors may have been used in the manufacture of each batch of  products.

If agent was present it may have been diluted or partially removed during processing.

But no reports of vCJD from these products to date. 

## II. CJD and Blood epidemiology:   	CJD Donors and Recipients

- CJD
- Rare disease  -incidence ~ 1 per million population
- Occurs largely in individuals > 60 yrs old
- Long incubation period estimated at 4 – 40 yrs
-  CJD transmission via transfusion considered a low risk
- If risk was significant – might see increase in CJD rate annually
- CJD rate stable last 10 to 20 years

**Notes:**
Now turning to the epidemiolgical information of CJD and blood.

Creutzfeldt-Jakob disease is a rare disease with an incidence of approximately 1 million per population.  
The disease usually occurs in individuals 60 years of age or older.  
CJD is thought to have a long incubation period perhaps ranging from 4 years to as long as 40 years or more.  
The average incubation period is unknown.

The potential for CJD risk via transfusion has been considered a theoretical and low risk.
If the transfusion risk was significant one might expect to see an increase in the CJD rate annually or the disease might increasingly be seen in younger individuals.
However – in the last 10 or 20 years of surveillance for many countries – suggests that the incidence has been fairly stable.
Dr Sejvar also alluded to the CJD rate in the US as being stable over the last several years.

## ARC – CDC – NBDRC -                           CJD blood lookback study

- American Red Cross – CDC - National Blood Data Resource Center (NBDRC)–                 CJD transfusion lookback study
- Includes transfusions from 1959 to 2002
- 331 transfusion recipients who received blood from donors later diagnosed with CJD
- 116 of the recipients have lived >5 years post-transfusion
- 95 recipients (29%) still alive
**0 observed CJD infections to date**

**Notes:**
Dr. Sejvar had discussed the CJD lookback study which follows 
331 transfusion recipients who had received blood from donors later diagnosed with CJD

116 of the recipients have lived longer than 5 years  

To date there have been no CJD infections observed to date in these 331 individuals

## CJD and Transfusion Epidemiology Studies

- No observed association between CJD and Transfusion
- Study of 2,479 CJD patients  - Wilson, et al. BMJ 2000
-     from 5 case control studies

|  Location | # CJD patients |  Reference |
| --- | --- | --- |
|    Japan | 163 |     Kondo, et al. 1982 |
|     U.K. | 276 |     Harries-Jones et al., 1988 |
|     U.K. | 402 |     Esmonde et al, 1993 |
|     Europe | 719 |     Van Dujin et al, 1998 |
|     Australia | 919 |     Collins et al, 1999 |

**Notes:**

Dr. Seyvar also mentioned 7 case control studies.

Researchers in Canada examined 5 case control studies and looked at blood transfusions in CJD and control groups.  The researchers concluded that there wasn’t an observed association between CJD and transfusion.

The study was a recent review of a total of 2,470 CJD patients for                                                                         Japan, the United Kingdom, Europe and Australia.

## CJD studies in U.S. hemophilia populations

**CDC study of CNS tissues from 30 severe hemophilia patients – died with CNS symptoms after 1983**
**Received clotting factor & concentrates – 15 to 23 years**
**No indication of CJD** (Operskalski et al, Lancet 1995; 346:1224)
**Continuation of the CDC study**
**~12,000 hemophilia patients assessed for CJD**
**Neurologic tissue evaluated from additional ~ 10 decedents**
**No observed CJD to date**

**Notes:**

One might expect populations that frequently use blood or plasma derivatives                                                              might be at higher risk for contracting CJD, vCJD or potentially other human TSEs.

Dr. Sejvar also mentioned this CDC study of hemophilia patients in the United States
Autopsy examinations were done on up to 40 individuals who had died of CNS symptoms after  1983

Some 12,000 hemophilia patients were also examined.

To summarize the results thus far, CJD was not observed in any of the patients 

## Studies in U.K. hemophilia populations of vCJD and CJD

- U.K. retrospective postmortem study
- 33 hemophilia patients
- clotting factor concentrates (1962 – 1995)             for 3 to 27yrs
**No indication of vCJD or CJD** (Lee et al, Thromb Haemost 1998:80:909)

**Notes:**
A postmortem analysis of 33 hemophilia patients in the United Kingdom who received clotting factor concentrates
For 3 to 27 years.

Again neither vCJD nor CJD were observed in this study.         

Overall as Dr Sejvar alluded to – the weight of the evidence at this point for CJD transmission via blood suggests that the risk of such an occurrence is low  - and has not been observed in several studies.

Given the amount of evidence for vCJD – difficult to say much about the magnitude of transfusion transmission -  the risk may be small or it may not be – but difficult to say.                                                                     

## Comparison between data for vCJD and CJD

- U.K. study – vCJD transfusion infection
- 48 recipients of product
- 15 recipients survived > 5 years
- 1 presumptive vCJD infection (Dec 23, 2003)
- National Blood Data Resource Center (NBDRC) and CDC – CJD transfusion lookback study
- 331 transfusion recipients
- 116 recipients survived > 5 years
- 0 observed infections to date

**Notes:**
As a risk assessment person we often evaluate and compare groups of data for our risk analyses.

We did try to compare the United Kingdom vCJD study to the CJD lookback study in the United States to see if 
There were any inferences we could draw from the two studies

Of interest to us were those recipients that survived longer than 5 years after transfusion – which may have provided some time for the disease to incubate

As mentioned by Dr. Will the recipient who later acquired vCJD surveved 6.5 years post-transfusion and was in this >5 years group.

A significant percentage of transfused individuals do not survive beyond one or two years  - largely because 
Of high risk medical conditions or severe illness

## Incubation period Iatrogenic transmission of CJD

- Incubation periods for iatrogenic CJD
- Tissues -  Cornea / EEG – 16 months
- Within or close proximity to brain
- Human growth hormone – 4.5 years
- Injectable – intramuscularly
- Assumed similar to the infusion route for blood

**Notes:**

Is 5 years an appropriate place to draw the line?

Looking at some of the incubation periods for iatrogenic transmissions 

Implantation of some tissues have some of the shortest incubation periods – 
I show information here for corneas with a minimal incubation time of 16 months – but implanted near or in close proximity to nervous system tissue such as the brain.

Injectables like growth hormone have a minimal incubation period of more than 4 years – 
So choosing a cutoff of surviving 5 years post-transfusion or longer seems reasonable

Evaluating those two groups in the next slide 

## Comparison ofRecipients surviving >5yrs post transfusion                    of blood products from CJD/vCJD patients

- Percentage of recipients surviving longer than 5 years post-transfusion in two groups was similar
- vCJD = 15 out of 48      or    31.3%
- CJD  = 116 out of 331   or       35%

**Notes:**

This comparison of survival in the two groups  - 5 years beyond transfusion it seems they are similar in this respect.

In this case about 31% for vCJD even though it was a much smaller group 
Was similar to CJD at 35%.

But it was difficult to do comparisons much beyond this.

## Comparison ofRecipients surviving >5yrs post transfusion                    of blood products from CJD/vCJD patients

|  | Infection | Non-Infection |
| --- | --- | --- |
| vCJD | 1 | 14 |
| CJD | 0 | 116 |

- Given the relatively small size of each group
- it is difficult to say much about  the two groups
**Except that additional data and research are needed**

**Notes:**

Difficult to say much about the two groups

I had set up a 2 x 2 table but because we are looking at a 1 and a Zero in the Infection column 
And as an analytical person those numbers jump out at you

It’s difficult to say whether the vCJD is due to a confounding factor such as infection via a foodborne route or some other route of exposure
 or whether it is in fact due to vCJD transmission by transfusion – it could certainly be the case

As the vCJD case has been characterized it is a possible case – and given the circumstances that seems most appropriate.

One strong conclusion that we can draw from this work is that further data and research 
are needed to draw a more robust conclusion about any potential trend in the data.

## Challenges for comparing vCJD and CJD infection rates

- Caveats and challenges for comparing    vCJD and CJD data:
- Size (N) of groups is small
- Incubation period is long
- Survival duration post-transfusion often exceeds incubation period

**Notes:**

Certainly there are many caveats to drawing any general conclusions from these data.

Even though there is accumulating information for CJD one can argue that more data are needed.
Challenges are that the current study groups are small
The incubation period of the disease is long 
Survival beyond 5 years is only around 30% and further limits ability to study the situation.

At the beginning I said I would keep it relatively brief

Thank you