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PRION DISEASES BLOOD INFECTIVITY ISSUES

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.

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PRION DISEASES BLOOD INFECTIVITY ISSUES

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  1. PRION DISEASESBLOOD INFECTIVITY ISSUES Richard Knight NCJDSU

  2. 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

  3. PRION DISEASESBLOOD INFECTIVITY ISSUES INTRODUCTION

  4. CJD : TYPES SPORADIC Worldwide ? Cause ~50 GENETICAut Dominant PRNP gene ~5 IATROGENICAccidental Transmission ~5 VARIANT*UK + BSE 18# 1996 (1994) * ‘new variant CJD’ # in 2003 “Human BSE”

  5. PRNP GENE (HUMAN CHROMOSOME 20)POLYMORPHISM AT CODON 129 MM MV VV 129 PRNP ORF M or V

  6. CODON 129 POLYMORPHISMNormal data : 5 Caucasian Studies UK sCJD (1990-1999)

  7. CODON 129 POLYMORPHISMNormal data : 5 Caucasian Studies UK vCJD (total Jan 2005) 130

  8. PRION DISEASESBLOOD INFECTIVITY ISSUES VARIANT CJD : PRESENT POSITION

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

  10. UK vCJD CASES January 2005 153 Definite & Probable cases MEAN AGE ONSET : 28 (R : 12-74) MEDIAN AGE ONSET : 26 MEDIAN DURATION : 14 m (R : 6-40) M:F 86:67 106 NEUROPATHOLOGICALLY CONFIRMED 5 ALIVE

  11. VARIANT CJD UK 2004 : 153 casesAGE AT DEATH or PRESENT AGE BY DECADES

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

  13. vCJD : NON-UK : 15(January 2005 UK : 153) • FRANCE 9 • ITALY 1 • REPUBLIC of IRELAND 1 • REPUBLIC of IRELAND 1 • USA 1 • CANADA 1 • SAUDI ARABIA 1

  14. VARIANT CJD: THE FUTURE

  15. NUMBER OF DEATHS PER ANNUM OF vCJD IN THE UK ?

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

  17. vCJD DEATHS in UK ~2000

  18. 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

  19. vCJD & the LRSPRE-CLINICAL INVOLVEMENT : THE EVIDENCE Appendicectomy vCJD onset Interval PrPSc 1995 1995 8 months POS 1996 1998 2 years POS

  20. LRS PrP IMMUNOCYTOCHEMISTRY ‘SURVEILLANCE’Hilton DA et al J Path 2004 ANONYMISED SURGICAL SPECIMENS UK IMMUNOCYTOCHEMISTRY (KG9 & 3F4) FOR PrPSc APPENDIX 12,674 3 POSITIVE

  21. LRS PrP IMMUNOCYTOCHEMISTRY ‘SURVEILLANCE’Hilton DA et al J Path 2004 APPENDIX 12,674 3 POSITIVE 83% of cases 10-30 at operation PREVALENCE: 237/million (95% CI: 49-692) 10-30 AGE: 3,808 people (95% CI: 785-11,128)

  22. LRS PrP IMMUNOCYTOCHEMISTRY ‘SURVEILLANCE’&OBSERVED CASES OF vCJDA DISCREPANCY ? LRS: 10-30 AGE: 3,808* vCJD CASES 10-30 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: 785-11,128

  23. ? SUBCLINICAL CASES / OTHER GENOTYPES2004 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 PrPSc • 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

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

  25. CJD & BLOOD: A RISK? • EXPERIMENTAL EVIDENCE • EPIDEMIOLOGICAL EVIDENCE

  26. PRION DISEASESBLOOD INFECTIVITY ISSUES BLOOD PRION RISK: EXPERIMENTAL EVIDENCE

  27. CJD & BLOODSUMMARY OF EXPERIMENTAL DATAprior to 2002 • INFECTIVITY MAY BE PRESENT IN BLOOD IN SOME MODELS CERTAINLYNOT 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)* CRYOPRECIPITATE IV1 & IV4 I & II & III V * PROBLEMS WITH DILUTION

  28. CJD & BLOODSUMMARY OF EXPERIMENTAL DATAprior to 2002 • PROCESSING STEPS REDUCE INFECTIVITY • IV ROUTE < IC ROUTE 5-7 x • PRE-CLINICAL INFECTIVITY LOWER OR ABSENT

  29. Hunter et al SHEEP BLOOD EXPERIMENTS SHEEP BSE BSE SHEEP SHEEPPOS 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

  30. CJD & BLOODSUMMARY OF EXPERIMENTAL DATA POTENTIALLY CONCERNING BUT HOW MUCH OF THIS CAN BE EXTRAPOLATED TOHUMAN DISEASE ANDUSUAL CLINICAL PRACTICE ?

  31. WHY BLOOD MIGHT NOT BEsuchA 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

  32. PRION DISEASESBLOOD INFECTIVITY ISSUES BLOOD PRION RISK: EPIDEMIOLOGICAL EVIDENCE

  33. 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

  34. CJD & BLOOD : CASE-CONTROL STUDIESNO EVIDENCE THAT BLOOD IS A RISK FACTOR FOR sCJD • USA* 38 1973 • JAPAN 60 1982 • USA 26 1985 • USA* 18 1993 • UK 155 1993 • EU 405 1998 • AUSTRALIA 241 1999 • META-ANALYSIS (3 studies) 178 1996 • EU 341 2000 • SYSTEMATIC REVIEW 2479 2000 * BT not specifically mentioned

  35. CJD & BLOODEPIDEMIOLOGICAL EVIDENCE : A CAUTION MUCH OF THE EVIDENCERELATES TO SPORADIC CJD & VARIANTCJD MIGHT BEHAVE DIFFERENTLY

  36. PRION DISEASESBLOOD INFECTIVITY ISSUES UK TMER (Transfusion Medicine Epidemiological Review) SOME DETAILS

  37. TMER1997 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

  38. TMER GENERAL RESULTS

  39. 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

  40. USE OF BLOOD DONATIONS FROM vCJD CASES • 50 RECIPIENTS OF COMPONENTS: • Red cells 27 • Leucodepleted red cells 12 • 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

  41. TMER LABILE COMPONENTS

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

  43. RECIPIENTS OF LABILE BLOOD COMPONENTS DONATED BY vCJD CASESDEAD: 33/50 • AGE AT DEATH: • Mean: 64 Median: 68 Range: 17-99 • (6/50 <50)

  44. TMER TWO SPECIFIC CASES

  45. TWO INSTANCES OF POSSIBLE BLOOD TRANSMISSION OF vCJD INFECTIONIN 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

  46. TMER A POSSIBLE CASE OF TRANSMISSIONLlewelyn et al 2004 1996 62 YEAR OLD SURGERY 5 units RBCs • 1 unit : 24 yr old : ONSET OF vCJD 3yrs 4 months later • Donor vCJD later confirmed by neuropathology • 68 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

  47. 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

  48. 2004 CASE REPORT 2ND POSSIBLE BLOOD TRANSFUSION CASEPeden 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 PrPSc • CODON 129 MV

  49. FOOTNOTE FRACTIONATED BLOOD PRODUCTS

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