PRION DISEASES BLOOD INFECTIVITY ISSUES Richard Knight NCJDSU

OUTLINE OF TALK INTRODUCTION VARIANT CJD : PRESENT POSITION BLOOD PRION RISK: EXPERIMENTAL EVIDENCE BLOOD PRION RISK: EPIDEMIOLOGICAL EVIDENCE UK TMER STUDY: SOME DETAILS CONCLUDING COMMENTS

PRION DISEASES BLOOD INFECTIVITY ISSUES INTRODUCTION

CJD : TYPES SPORADIC Worldwide? Cause ~50 GENETIC Aut DominantPRNP gene ~5 IATROGENIC Accidental Transmission ~5 VARIANT* UK + BSE 18# 1996 (1994) * ‘new variant CJD’ # in 2003 “Human BSE”

PRNP GENE (HUMAN CHROMOSOME 20) POLYMORPHISM AT CODON 129 MMMVVV PRNP ORF 129 M or V

CODON 129 POLYMORPHISM Normal data : 5 Caucasian Studies UK sCJD ( )

CODON 129 POLYMORPHISM Normal data : 5 Caucasian Studies UK vCJD (total Jan 2005) 130

PRION DISEASES BLOOD INFECTIVITY ISSUES VARIANT CJD : PRESENT POSITION

vCJD: CAUSE BSE & vCJD: IDENTICAL CAUSATIVE AGENTS BSE PASSED FROM CATTLE TO MAN IT PASSED IN DIET

UK vCJD CASES January Definite & Probable cases MEAN AGE ONSET : 28 (R : 12-74) MEDIAN AGE ONSET :26 MEDIAN DURATION :14 m (R : 6-40) M:F86:67 106NEUROPATHOLOGICALLY CONFIRMED 5ALIVE

VARIANT CJD UK 2004 : 153 cases AGE AT DEATH or PRESENT AGE BY DECADES

Variant CJD MEAN AGE AT ONSET HAS NOT CHANGED OVER TIME ? AGE-RELATED EXPOSURE ? AGE-RELATED INCUBATION PERIOD ? AGE-RELATED SUSCEPTIBILITY

vCJD : NON-UK : 15 (January 2005 UK : 153) FRANCE9 ITALY1 REPUBLIC of IRELAND1 USA1 CANADA1 SAUDI ARABIA1

VARIANT CJD: THE FUTURE

NUMBER OF DEATHS PER ANNUM OF vCJD IN THE UK ?

NUMBER OF ONSETS PER ANNUM OF vCJD : UK JAN 2005 ??

vCJD DEATHS in UK ~2000

CAUTION Could be other peaks related to MV & VV cases Could be other peaks related to other genetic factors Could be secondary (human-human) transmission cases

vCJD & the LRS PRE-CLINICAL INVOLVEMENT : THE EVIDENCE Appendicectomy vCJD onset Interval PrP Sc months POS years POS

LRS PrP IMMUNOCYTOCHEMISTRY ‘SURVEILLANCE’ Hilton DA et al J Path 2004 ANONYMISED SURGICAL SPECIMENS UK IMMUNOCYTOCHEMISTRY (KG9 & 3F4) FOR PrP Sc APPENDIX12,6743 POSITIVE

LRS PrP IMMUNOCYTOCHEMISTRY ‘SURVEILLANCE’ Hilton DA et al J Path 2004 APPENDIX12,6743 POSITIVE 83% of cases at operation PREVALENCE:237/million (95% CI: ) AGE:3,808 people (95% CI: ,128)

LRS PrP IMMUNOCYTOCHEMISTRY ‘SURVEILLANCE’ & OBSERVED CASES OF vCJD A DISCREPANCY ? LRS: AGE:3,808* vCJD CASES age group: 90(& in decline) ? FALSE POSITIVES IN THE LRS STUDY CLINICAL CASES ALL OF MM GENOTYPE ? GENOTYPES OF THE LRS STUDY POSITIVE CASES ? SUBCLINICAL CASES *95% CI: ,128

? SUBCLINICAL CASES / OTHER GENOTYPES 2004 CASE REPORT AUTOPSY IN KNOWN vCJD BLOOD RECIPIENT NO CLINICAL EVIDENCE OF vCJD IN LIFE OTHER CAUSE OF DEATH : died 5 years after blood transfusion NO NEUROPATHOLOGICAL FEATURES OF vCJD SPLEEN POSITIVE FOR PrP Sc INDIVIDUAL WAS PRNP-CODON 129 MV EVIDENCE OF BSE/vCJD INFECTION IN A NON-MM INDIVIDUAL* EITHER A PRECLINICAL CASE OR A SUBCLINICAL CASE Peden et al Lancet 2004*But not vCJD & cannot be certain of route

vCJD : CONCERN BSE CONTROLLED / DIET PROTECTED DIET-RELATED CJD : AWAIT OUTCOME ? SECONDARY IATROGENIC SPREAD (Especially with preclinical/subclinical cases) SURGERY & BLOOD

CJD & BLOOD: A RISK? EXPERIMENTAL EVIDENCE EPIDEMIOLOGICAL EVIDENCE

PRION DISEASES BLOOD INFECTIVITY ISSUES BLOOD PRION RISK: EXPERIMENTAL EVIDENCE

CJD & BLOOD SUMMARY OF EXPERIMENTAL DATA prior to 2002 INFECTIVITY MAY BE PRESENT IN BLOOD IN SOME MODELS CERTAINLY NOT ALWAYS PRESENT ANIMAL MODELS USUALLY NOT USING v or s CJD EVEN USING v or s CJD : PROBLEM OF ‘SPECIES BARRIER’ OFTEN WITH INTRA-CEREBRAL INNOCULATION DIFFERENTIAL COMPONENTS / FRACTIONS RISK PLASMA(WHOLE BLOOD)* BUFFY COAT(RED CELLS)* CRYOPRECIPITATEIV1 & IV4 I & II & IIIV * PROBLEMS WITH DILUTION

CJD & BLOOD SUMMARY OF EXPERIMENTAL DATA prior to 2002 PROCESSING STEPS REDUCE INFECTIVITY IV ROUTE < IC ROUTE5-7 x PRE-CLINICAL INFECTIVITY LOWER OR ABSENT

Hunter et al SHEEP BLOOD EXPERIMENTS SHEEP BSE BSE SHEEP SHEEP POS i/v blood SHEEP NATURAL SCRAPIE SHEEP SHEEP POS i/v blood TRANSMISSION OF SHEEP BSE BY WHOLE BLOOD TRANSMISSION BY IV TRANSFUSION OF A UNIT TRANSMISSION WITH CLINICAL PHASE DONATIONS TRANSMISSION WITH PRECLINICAL PHASE DONATIONS J Gen Virol 2002

CJD & BLOOD SUMMARY OF EXPERIMENTAL DATA POTENTIALLY CONCERNING BUT HOW MUCH OF THIS CAN BE EXTRAPOLATED TO HUMAN DISEASE AND USUAL CLINICAL PRACTICE ?

WHY BLOOD MIGHT NOT BE such A PROBLEM GENERALLY LOW TITRE OF INFECTIVITY PARTICULARLY LOW INFECTIVITY IN SPECIFIC COMPONENTS PROCESSING REDUCES INFECTIVITY PERIPHERAL ROUTE OF ADMINISTRATION IN CLINICAL PRACTICE RELATIVELY HIGH MORTALITY IN RECIPIENTS OF (HIGHEST RISK) LABILE COMPONENTS

PRION DISEASES BLOOD INFECTIVITY ISSUES BLOOD PRION RISK: EPIDEMIOLOGICAL EVIDENCE

CJD & BLOOD REASSURANCE FROM CJD SURVEILLANCE CJD HAS NOT BEEN REPORTED IN AN ‘AT HIGH RISK’ INDIVIDUAL (ONE EXPOSED TO REPEATED BLOOD / BLOOD PRODUCTS) FOR EXAMPLE : HAEMOPHILIA

CJD & BLOOD : CASE-CONTROL STUDIES NO EVIDENCE THAT BLOOD IS A RISK FACTOR FOR sCJD USA* JAPAN USA USA* UK EU AUSTRALIA META-ANALYSIS (3 studies) EU SYSTEMATIC REVIEW * BT not specifically mentioned

CJD & BLOOD EPIDEMIOLOGICAL EVIDENCE : A CAUTION MUCH OF THE EVIDENCE RELATES TO SPORADIC CJD & VARIANT CJD MIGHT BEHAVE DIFFERENTLY

PRION DISEASES BLOOD INFECTIVITY ISSUES UK TMER (Transfusion Medicine Epidemiological Review) SOME DETAILS

TMER 1997 SURVEILLANCE SYSTEM : NCJDSU & UK NBServices VARIANT CJD vCJD cases (>17) : names to relevant Blood Service NBS searches for records of donations (1980+) Identification of all components & their fate Recipient names to NCJDSU NCJDSU checks surveillance records for named recipients ‘Reverse Study’: tracing donors of blood given to vCJD cases SPORADIC CJD Concurrent study on same lines

TMER GENERAL RESULTS

TMER : vCJD – BLOOD DONORS Total number of vCJD cases in the UK: 153 Number with donor records traced: 20 Number from whom components actually issued: 16 Recipients identified from these 16 components where recipient & component information available: 50 Additionally: 9 vCJD individuals have donated to 23 plasma pools From which 174 products have been manufactured

USE OF BLOOD DONATIONS FROM vCJD CASES 50 RECIPIENTS OF COMPONENTS: Red cells27 Leucodepleted red cells12 Buffy-coat reduced red cells 2 Fresh frozen plasma 4 Whole blood 2 Cryo-depleted plasma 1 Cryoprecipitate 1 Platelets 1 9 DONORS : 23 PLASMA POOLS : 174 PRODUCTS

TMER LABILE COMPONENTS

RECIPIENTS OF LABILE BLOOD COMPONENTS DONATED BY vCJD CASES STILL ALIVE : 17/50 AGE OF ALIVE RECIPIENTS: Mean: 65 Median: 70 Range:30-88 (4/17 < 50)

RECIPIENTS OF LABILE BLOOD COMPONENTS DONATED BY vCJD CASES DEAD: 33/50 AGE AT DEATH: Mean: 64 Median: 68 Range: (6/50 <50)

TMER TWO SPECIFIC CASES

TWO INSTANCES OF POSSIBLE BLOOD TRANSMISSION OF vCJD INFECTION IN HUMANS CLINICAL vCJD IN A RECIPIENT* Onset 6.5 years after transfusion Llewelyn et al Lancet 2004 RES ABNORMAL PrP (not vCJD) IN A RECIPIENT* (Died 5 years after transfusion) Peden et al Lancet 2004 * DONORS DEVELOPED vCJD

TMER A POSSIBLE CASE OF TRANSMISSION Llewelyn et al YEAR OLDSURGERY 5 units RBCs 1 unit : 24 yr old : ONSET OF vCJD 3yrs 4 months later Donor vCJD later confirmed by neuropathology YEARS OLD 6.5 years after transfusion Relatively typical clinical illness of vCJD Died after 13 months of illness Neuropathologically confirmed vCJD (typical appearances) Codon 129 MM

A POSSIBLE CASE OF TRANSMISSION ? A STATISTICAL ANALYSIS THE PROBABILITY OF RECORDING A CASE OF vCJD IN THIS RECIPIENT POPULATION (from vCJD donors) IN THE ABSENCE OF TRANSFUSION-TRANSMITTED INFECTION (i.e. from BSE in diet) 1:15 000* –1:30 000** * Crude data** Taking account of ages of recipients

2004 CASE REPORT 2 ND POSSIBLE BLOOD TRANSFUSION CASE Peden et al 2004 AUTOPSY IN KNOWN vCJD BLOOD RECIPIENT DIED 5 YEARS AFTER TRANSFUSION NO CLINICAL EVIDENCE OF vCJD IN LIFE OTHER CAUSE OF DEATH NO NEUROPATHOLOGICAL FEATURES OF vCJD SPLEEN POSITIVE FOR PrP Sc CODON 129 MV

FOOTNOTE FRACTIONATED BLOOD PRODUCTS

RECIPIENTS OF PLASMA PRODUCTS MANUFACTURED FROM DONATIONS FROM INDIVIDUALS WHO DEVELOPED VCJD 9 blood donors who developed vCJD contributed to 23 plasma pools from which 174 plasma products manufactured UK CJD Incidents Panel (part of UK Health Protection Agency) developed model of risk assessment This allows calculation of a dose of product as a threshold beyond which certain measures taken: inform individual of exposure precautions to reduce risk of further transmission

Ongoing process See web-site

PRION DISEASES BLOOD INFECTIVITY ISSUES CONCLUDING COMMENTS

UK CASES OF VARIANT CJD IN DECLINE BUT CONCERNS MUST REMAIN VARIANT CASES APPEARING IN DIFFERENT COUNTRIES OVER TIME, INCREASING EVIDENCE THAT BLOOD IS A POTENTIAL RISK AND NOW 2 POSSIBLE INSTANCES OF ACTUAL TRANSMISSION PERHAPS INCREASING CONCERN OVER PRECLINICAL/SUBCLINICAL CASES OF vCJD UK TMER STUDY CONTINUES TO COLLECT DATA THE UK & OTHER COUNTRIES HAVE TAKEN MANY PRECAUTIONARY MEASURES CONCERNING CJD & REVIEW THESE CONSTANTLY AS KNOWLEDGE INCREASES

vCJD - BLOOD DONORS *donors found on BTS system for whom components were actually issued (eg some donors were registered but did not make any donations).

Survival of live recipients (n=17) of components from vCJD donors according to interval between transfusion and onset of clinical symptoms in donor (up to 31/12/2004)

vCJD - BLOOD DONORS *donors found on BTS system for whom components were actually issued (eg some donors were registered but did not make any donations).

Survival to death for recipients of vCJD components (n=33) PrP positivity in spleen

RECIPIENTS OF PLASMA PRODUCTS MANUFACTURED FROM DONATIONS FROM INDIVIDUALS WHO DEVELOPED vCJD ‘AT RISK’ THRESHOLD At risk threshold definition: ≥1% potential risk of infection (on top of the general dietary risk in UK population) HIGH: Threshold surpassed after a very small dose single dose factor VIII, IX, antithrombin, where 1 vial of product has been implicated. MEDIUM: Substantial quantities necessary to surpass threshold several infusions of IgG. large doses of 4.5% Albumin. Low: Likelihood of surpassing threshold can be ignored Albumin 20%. Factor VIII where albumin excipient, but not plasma concentrate has been implicated. IM human Ig prophylaxis against Hep A, anti-D.

Recipients of plasma products manufactured from donations from individuals who developed vCJD ACTION HIGH: Batches being traced Recipients treated as ‘at risk’ for public health purposes MEDIUM: Efforts to trace batches To assess potential additional risk & to determine if public health precautions to be taken LOW: Batches not being traced Individuals not informed

Recipients of plasma products manufactured from donations from individuals who developed vCJD Public health measures for those at risk Not to donate blood Not to donate tissues or organs To tell clinicians treating them so special precautions can be taken with instruments etc To tell family in case of emergency treatment