# Presentation: 312144

## Slide 1

## Blood-borne vCJD risk: in UK and other European populations

*Sheila M. Bird*
*MRC Biostatistics Unit, CAMBRIDGE*

## BSE cascade . . . to end 2004

**Human Dietary BSE exposure:** consider **UK** exports of bovine carcasses **(60% to France: C-H & A)**, **UK** exports of contaminated feed, **UK **exports of infected live-stock **[GBR III . . . ] **
-        **UK:**** ****France: **carcasses** other**** =  ****20:**** ****1: ****0.67  ****(% male?)**
**vCJD clinical cases**** (presumed dietary exposure: ****90m****/****161****)**
**       ****152:****    ****9:****   **Ireland (2), Italy (1), Saudi (1)
-                         Canada (1), USA (1)** = 7 . . .**
**Blood-borne vCJD exposure:**** **consider **UK:**** ****France:**** other **exports of pre/sub-clinical vCJDs, & of contaminated blood/products  . . .

## Brief history: 1980 - 1999

**BSE**{Nov. 1986} & **vCJD**
**BSE projections too low**: **maternal transmission** et vive la France
**vCJD projections: news**** ****& dietary BSE exposure by birth-cohort & gender**
**Geographical BSE Risk ******

## Slide 5

## BSE Controls after November 1986: infectivity highest in brain, spinal cord [& DRG]

**Slaughter-compensate ****& Feed Ban: Aug. 1988**
**SBO legislation** *(brain, spinal cord)***: Nov. 1989**
*        **additions/amendments . . .  **SVS inspections . . . *
**MRM from vertebral columns:  ended December 1995**
**vCJD announced: 20 March 1996**
**Recovery of head meat: ended March 1996**
**Over Thirty Month Scheme [OTMS]: April 1996**
**Real Feed Ban: 1 August 1996 [UK],**** ****January 2001[EU]**

## Remit: National CJD Surveillance Unit, 1990

**To alert to any changes in**
** ****age-specific incidence, occupational distribution, or dietary correlates of CJD**** **
**that might suggest humans were affected by exposure to BSE **
**Presentation, if it happened at all, was ****more likely to be**** ****atypical****, but could not be described in advance**

## Slide 8

## It’s official, mad cow disease can kill you!

**10 cases of variant CJD in UK**
- young age at onset
- longer clinical course
- distinctive neuropathology
- methionine homozygosity

## Slide 10

## April 1996: Ministry vets spurn calls to pass on data from dam-calf experiments . . . 10% maternal transmission risk within 6 months of BSE onset in dam BSE Inquiry: CMO letters 

## Nature, August 1996Transmission dynamics and epidemiology of BSE in British cattleAnderson RM, Donnelly CA et al.

- Sacred cows, science and uncertainties
*David CG Skegg*
**Mean BSE incubation period = 5 years**

## BSE incidence curve @ incubation period @ age-specific slaughter/export = BSE affected

***BSE incidence curve:**
**access to contaminated feed**
**maternal transmission?**
*other exposure?*
***Age-specific slaughter/export:**
**dairy or beef herd**
*BSE-infected?*

## BSE projections

**Back-calculation from clinical BSE cases ********  serious under-estimation of BSE infections**
**No under-reporting** of BSE cases after 1988
**No diversion** of BSE cases into **OTMS**
**No differential survival** *if BSE-infected*
**No exposure ****except maternal** after August 1996

## vCJD projections ~ news!

**Back-calculation from clinical vCJD cases *********** beware !***
**Projections reigned** **in: ****vast** to **< 1000 **to **. . . < 400**
**Dietary BSE exposure** **by birth-cohort:** **explains** **young**** ****age, anticipate male excess re dietary vCJD ****? . . . **** Valleron !**

## UK dietary exposure to BSE: infectivity from beef MRM & head meat

| Birth-cohort:                                           &               vCJDs
       Onsets before 2001 |    Median infectivity [Bo ID50s]
          |  |
| --- | --- | --- |
|  |   1980 - 1989 |  1990 - 1996 |
| Post-1969:      64 |       83,150 |      188,200 |
| 1940 – 1969:  47 |   161,900 |    190,600 |
| Pre-1940:         1
 |      39,300 |      47,200 |

## Dietary exposure to BSE: Cooper & Bird; Chadeau-Hyam & Alperovitch

| Birth-cohort:                                           &               vCJDs
Onsets before 2004
                   UK  France |    Median infectivity [Bo ID50s]
        |  |
| --- | --- | --- |
|  |        UK |  France |
| Post-1969:    89 3 |    271,350 |      14,350 |
| 1940 – 1969:58 3 |   352,500 |    16,400 |
| Pre-1940:       1  0
(+1 blood-borne) |      86,500 |      5,400 |

## 1940-1969 birth cohort: intrinsic            age-dependent susceptibility [Valleron]

| Period of birth | vCJD patients | ‘Best’: without age-susceptibility | Add: 0.06 exp.  decay after 
15 years |
| --- | --- | --- | --- |
| 1940– 1954  | 1 + 2 + 4 = 7 | 17 | 1 + 3 + 4 =  8 |
| - 1959 |                6 |   7 ( 4 – 13) |   7 ( 2 – 11) |
| 1960- 1964 |              13 | 11 ( 6 – 16) | 12 ( 7 – 18) |
| 1965- 1969 |              21 | 12 ( 8 – 17) | 19 (14 – 27) |

## Spectre of sub-clinical BSE infections:Differential by birth-cohort?Blood/operation-transmissible? 

## vCJD projections ~ latest

- Chadeau-Hyam & Alperovitch (Int. J. Epid.)
**BSE dietary exposure in**** UK: ****France****  = 20:****1**
**vCJD incidence UK: ****France ****= ****152:****9**** = 17:****1**** {dietary}**
**vCJD projections**** ****France**** = ****33 ****in total****  ****{Valleron/C & B: 0.06}**
**vCJD projections ****UK . . . ****“under 600”**
**    ****{****individual in 1940-69 birth cohort required more ****(* 1.5)**** infectious units to be infected than in post-1969 cohort. ****Also,**** ****note:**** ****species barrier ****re dietary BSE exposure****}**

## Rapid post-mortem BSE/TSE testing

**1999: Switzerland**
**(fallen stock & 5% normal slaughter ~ BSE tested); ****OTMS**
**2000: France & N. Ireland (risk stock), ****UK (OTMS);**** Swiss**
**2000: EU approved 3 BSE tests (out of 4: Nature, 1999)**
**2000: Geographical BSE Risk [GBR III = BSE likely, or confirmed at low level]**
**2001: EU’s Requirements for Statistically Authoritative BSE/TSE Surveys**

## Active BSE surveillance: 2001

-        **European Union**
**BSE positivity** ~ **10** to **15** times higher in **risk stock** than normal slaughter bovines aged over 30m
**THREE-SUM**  = # BSE positives in **risk stock**  +      # **clinical** **BSEs** **+** # BSE positives at **normal slaughter**

## Jan-Apr BSE surveillance in 2004: & BSE positive rate per 1 million tested

| Member
State

EU15-UK

# tested | Adult cattle 

36.2m | Clinical BSE 

       39                               

 | Risk stock:  & rate pmt

101*: 245

 414K | Normal kill: & rate pmt

  47:    16

   2,959K |
| --- | --- | --- | --- | --- |
|              UK
# tested |   4.9m | 40 | 104: 1140
   91K | Not applicable
{JW = “60”} |
| New MS
# tested |   5.6m | 0   |     6:     95
   63K |    6:     21
     285K |

## Late-stage BSE under-estimated: UK BSE infection incidence * 3 

**BSE testing in OTMS 2000**
- 40 BSE positives in 10,032 OTMS bovines aged    5 years+  **2700 BSE positives in OTMS, when UK had only 1400 clinical BSEs in 2000**
****** ****BSE infections * 3**

## Sheep scrapie (plus genotype)

## Active TSE surveillance in sheep: 2002

- 60,000 adult sheep & 6,000 fallen sheep per MS
**Genotyping**: **TSE positives** *[& 6 controls]*             **&  ‘random’ sample of 500 adult sheep**
**Early monitoring [year 1] . . . ****4 TSE positives**** in ****‘scrapie-resistant’ ARR/ARR**** sheep!       Re-appraisal of ****ARQ/ARQ**** genotype (accounted for ****515****/1310 positives: ****39%****)**

## Rapid post-mortem PrP testing: in humans?

## Probable blood-borne vCJD transmission: “study-detected”

**Donation = March 1996**
**Donor’s vCJD onset = 1999  **[~ 3yrs]
**Recipient’s vCJD onset = autumn 2002** [6.5yrs]
**Recipient death** (undiagnosed) = **autumn 2003**
**vCJD-blood recipient**** = MM, born pre-1940**

## Probable blood-borne vCJD transmission: “autopsy-detected”

**Donation = ? mid 1999**
**Donor’s vCJD onset = ? end 2000 **[ ~ 1.5 yrs]
**Recipient’s vCJD onset = no: ****sub/pre-clinical**
- “***Dr.****-****alerted re recipient’s status: medico-legal”             ***
**PM-detected** **non-clinical vCJD =  July 2004 **[5yrs]
**vCJD blood-recipient =**** MV, born pre-1940**

## Testing for abnormal prion in human tonsil/appendix/spleen 

## Abnormal PrP in tonsil/appendix

**Unlinked Anonymous Testing of stored tissue: 1995-99, mainly aged 10 - 30 years at operation.**
-    **Positive ****in 1****st**** 8,000** **tested** . . .
**Finally,  ****3 Positive**** in 12,674 tested (****two**** atypicals . . .)**
*vCJD-projections-prior: ****expected 1 in 40,000****  *
**Conflict:**** ****vCJD cases**** ********  ****surveillance**
**     **
**   ****National tonsil collection started in 2004 . . . **

## vCJD projections ~ latest

- Clarke & Ghani (J. Royal Society Interface)
**                                      ****Projected UK            Prevalent**
**                                ****case numbers (2004+)    infections:04**
**vCJD cases only             70 ( 10 -     190)         ***
**Clinical**** & survey         133 ( 32 –  3780)     140 (36 –10K)**
**Sub-clinical carrier II    69 (10 -      190)   5000 (1K-13K)**
**Wider genetic susceptibility . . . **
**? Sub-clinical BSE infection transmissible by blood**

## Limit human-to-human vCJD & acquire key data

**Rural analogy ******** now consider**
***Attributable***** testing for abnormal prion at:**
**Tonsillectomy**
**Appendicectomy etc**
*** ****Autopsy under 55 years of age**
**& *****Permission-in-life***** for post-mortem testing in *****alerted*****   at-vCJD-risk patients **

## Limit human-to-human vCJD & acquire key data  rural analogy

**Experimental BSE/scrapie transfusion risks in 20+ sheep = 10% to 20%**
**Humans’ vCJD blood transfusion risk to **
**5-year survivors =**
**2/17**** or 2/ (17- ****5 {no autopsy}****)**
**= ****2/17**** (about ****10%****) to ****2/12 (about 17%)**

## Acquire key data: without consent at autopsy

**Test for subclinical vCJD at autopsy (sv/A)**
**[sv/A: by age-group, sex and ****genotype**** ******** ****prevalence****]**
**If subclinical vCJD, ****alert**** recipient-networks (blood, products, tissues, surgical, needle-stick, maternal)**
**Recipient-networks: ****a) prevent onward transmission, **
**b) contribute key data**** to document *****their *****exposure risk**

## Acquire key data about ‘transmission-risk’

***Permission-in-life***** for post-mortem testing in *****alerted***** **
**at-vCJD-risk patients (BMJ list,**** ****30 March 1996):**
**Blood transfusion recipients; ****Blood product recipients**
**Tissue recipients; Surgical “recipients”**
**Needle-stick BSE/vCJD/subclinical vCJD “recipients”**
**Child born within y years of vCJD death in mater/pater**
**Sexual risk . . .  **
***PM-detected****** subclinical vCJD in those vCJD-exposed at least 5 years previously / ******# PM-ed and/or ******who were vCJD-exposed at least 5 years previously ******= “sv5/PM5”***

## Detectability & Affordability

**A worse case (10% transmission risk):** **500,000** **tests** **on operative tissue**  **100 sub-clinical vCJDs** (10 donors, 40 recipients, **10 survive 5 years, ****1**)  **one avoidable** (blood-borne) **vCJD transmission**
**Even if screening cost £200 a tissue . . . cost is a** **10****th****  only of OTMS to prevent one cattle-human vCJD**
**IF transmission risks were 100 times less** **(0.1% versus 10%)**, **not even £1000 million would suffice for their reduction . . .**

## Slide 38