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: 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 BSE Controls after November 1986: infectivity highest in brain, spinal cord [& DRG] Slaughter-compensate & Feed Ban: Aug SBO legislation (brain, spinal cord) : Nov 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 Its 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 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 incubation 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] Post-1969: 64 83, , 1969: , , 600 Pre-1940: 1 39, , 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: , , 1969: , , 400 Pre-1940: 1 0 (+1 blood-borne) 86, 500 5, 400 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 = = ( 4 13) 7 ( 2 11) ( 6 16) 12 ( 7 18) ( 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 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: EUs 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 *: K Normal kill: & rate pmt 47 : 16 2,959K UK # tested 4.9m : K Not applicable {JW = 60} New MS # tested 5.6m 0 6: 95 63K 6: K Late-stage BSE under-estimated: UK BSE infection incidence * 3 BSE testing in OTMS 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: ,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 Donors vCJD onset = 1999 [~ 3yrs] Recipients 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 Donors vCJD onset = ? end 2000 [ ~ 1.5 yrs] Recipients vCJD onset = no: sub/pre-clinical Dr.-alerted re recipients 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: , mainly aged 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 vCJD projections ~ latest Clarke & Ghani (J. Royal Society Interface) Projected UK Prevalent case numbers (2004+) infections:04 vCJD cases only 70 ( ) * Clinical & survey 133 ( 32 3780) 140 (36 10K) Sub-clinical carrier II 69 ( ) 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...