prion diseases blood infectivity issues richard knight ncjdsu
TRANSCRIPT
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PRION DISEASESBLOOD INFECTIVITY ISSUES
Richard Knight NCJDSU
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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 DISEASESBLOOD INFECTIVITY ISSUES
INTRODUCTION
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CJD : TYPES
SPORADIC Worldwide ? Cause ~50
GENETIC Aut Dominant PRNP gene ~5
IATROGENIC Accidental Transmission ~5
VARIANT* UK + BSE 18#
1996 (1994)
* ‘new variant CJD’ # in 2003 “Human BSE”
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PRNP GENE (HUMAN CHROMOSOME 20)POLYMORPHISM AT CODON 129
MM MV VV
PRNP ORF
129
M or V
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CODON 129 POLYMORPHISM Normal data : 5 Caucasian Studies
UK sCJD (1990-1999)
0
10
20
30
40
50
60
70
80
MM VV MV
Normals
spCJD
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CODON 129 POLYMORPHISM Normal data : 5 Caucasian Studies
UK vCJD (total Jan 2005)
0
20
40
60
80
100
120
140
MM VV MV
Normals
vCJD
130
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PRION DISEASESBLOOD INFECTIVITY ISSUES
VARIANT CJD : PRESENT POSITION
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vCJD: CAUSE
BSE & vCJD: IDENTICAL CAUSATIVE AGENTS
BSE PASSED FROM CATTLE TO MAN
IT PASSED IN DIET
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UK vCJD CASES January 2005
153Definite & 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
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VARIANT CJD UK 2004 : 153 casesAGE AT DEATH or PRESENT AGE
0
10
20
30
40
50
60
70
0- 10- 20- 30- 40- 50- 60- 70+
BY DECADES
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Variant CJDMEAN AGE AT ONSET HAS NOT CHANGED OVER TIME
• ? AGE-RELATED EXPOSURE
• ? AGE-RELATED INCUBATION PERIOD
• ? AGE-RELATED SUSCEPTIBILITY
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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
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VARIANT CJD: THE FUTURE
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NUMBER OF DEATHS PER ANNUM OF vCJD IN THE UK
3
10 10
1815
28
2017 18
9
0
5
10
15
20
25
30
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004
?
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NUMBER OF ONSETS PER ANNUM OF vCJD : UK
810 11
1417
29
24
1714
5 4
0
5
10
15
20
25
30
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004
JAN 2005
? ?
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Figure 2c: Quadratic-exponential and plateau models for vCJD deaths incidence trend
0
2
4
6
8
10
12
Year
Dea
ths
Quadratic Model
Plateau Model
Observed data
vCJD DEATHS in UK
~2000
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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
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vCJD & the LRSPRE-CLINICAL INVOLVEMENT : THE EVIDENCE
Appendicectomy vCJD onset Interval PrPSc
1995 1995 8 months POS
1996 1998 2 years POS
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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
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LRS PrP IMMUNOCYTOCHEMISTRY ‘SURVEILLANCE’
Hilton DA et al J Path 2004
APPENDIX 12,674 3 POSITIVE83% of cases 10-30 at operation
PREVALENCE: 237/million (95% CI: 49-692)
10-30 AGE: 3,808 people(95% CI: 785-11,128)
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LRS PrP IMMUNOCYTOCHEMISTRY ‘SURVEILLANCE’&
OBSERVED CASES OF vCJD
A 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
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? 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 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
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vCJD : CONCERN
• BSE CONTROLLED / DIET PROTECTED• DIET-RELATED CJD : AWAIT OUTCOME
• ? SECONDARY IATROGENIC SPREAD(Especially with preclinical/subclinical cases)
• SURGERY & BLOOD
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CJD & BLOOD: A RISK?
• EXPERIMENTAL EVIDENCE
• EPIDEMIOLOGICAL EVIDENCE
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PRION DISEASESBLOOD INFECTIVITY ISSUES
BLOOD PRION RISK:
EXPERIMENTAL EVIDENCE
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CJD & BLOODSUMMARY 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 RISKPLASMA (WHOLE BLOOD)*
BUFFY COAT (RED CELLS)*
CRYOPRECIPITATE IV1 & IV4
I & II & III V
* PROBLEMS WITH DILUTION
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CJD & BLOODSUMMARY OF EXPERIMENTAL DATA
prior to 2002
• PROCESSING STEPS REDUCE INFECTIVITY
• IV ROUTE < IC ROUTE 5-7 x
• PRE-CLINICAL INFECTIVITY LOWER OR ABSENT
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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
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CJD & BLOODSUMMARY OF EXPERIMENTAL DATA
POTENTIALLY CONCERNING
BUT
HOW MUCH OF THIS CAN BE EXTRAPOLATED TO HUMAN DISEASE AND USUAL CLINICAL PRACTICE ?
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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
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PRION DISEASESBLOOD INFECTIVITY ISSUES
BLOOD PRION RISK:
EPIDEMIOLOGICAL EVIDENCE
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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
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CJD & BLOOD : CASE-CONTROL STUDIES NO 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
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CJD & BLOODEPIDEMIOLOGICAL EVIDENCE : A CAUTION
MUCH OF THE EVIDENCE RELATES TOSPORADIC CJD
&
VARIANT CJD MIGHT BEHAVE DIFFERENTLY
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PRION DISEASESBLOOD INFECTIVITY ISSUES
UK TMER (Transfusion Medicine Epidemiological Review)
SOME DETAILS
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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
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TMER
GENERAL RESULTS
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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 componentswhere recipient & component information available: 50
• Additionally:9 vCJD individuals have donated to 23 plasma poolsFrom which 174 products have been manufactured
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USE OF BLOOD DONATIONS FROM vCJD CASES
•50 RECIPIENTS OF COMPONENTS:Red cells 27Leucodepleted red cells 12Buffy-coat reduced red cells 2Fresh frozen plasma 4Whole blood 2Cryo-depleted plasma 1Cryoprecipitate 1Platelets 1
•9 DONORS : 23 PLASMA POOLS : 174 PRODUCTS
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TMER
LABILE COMPONENTS
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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)
0
1
2
3
4
5
6
Num
ber
<1
1 - <
2
2 - <
3
3 - <
4
4 - <
5
5 - <
6
6 - <
7
7 - <
8
8 - <
9
9 - <
10
10+
Years since transfusion
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0
2
4
6
8
10
12
14
16
18
20
< 1
1 -
<2
2 -
<3
3 -
<4
4 -
<5
5 -
<6
6 -
<7
7 -
<8
8 -
<9
9 -
<10
> 1
0
Interval from transfusion to death (years)
Num
ber
RECIPIENTS OF LABILE BLOOD COMPONENTS RECIPIENTS OF LABILE BLOOD COMPONENTS DONATED BY vCJD CASESDONATED BY vCJD CASES
DEAD: 33/50DEAD: 33/50
AGE AT DEATH:
• Mean: 64 Median: 68 Range: 17-99
• (6/50 <50)
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TMER
TWO SPECIFIC CASES
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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
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TMER A POSSIBLE CASE OF TRANSMISSION
Llewelyn 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
2002 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
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A POSSIBLE CASE OF TRANSMISSION ?
A STATISTICAL ANALYSIS
THE PROBABILITY OF RECORDING A CASE OF vCJDIN THIS RECIPIENT POPULATION (from vCJD donors)
IN THE ABSENCE OF TRANSFUSION-TRANSMITTEDINFECTION (i.e. from BSE in diet)
1:15 000* –1:30 000**
* Crude data ** Taking account of ages of recipients
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2004 CASE REPORT 2ND 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 PrPSc
• CODON 129 MV
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FOOTNOTE
FRACTIONATED BLOOD PRODUCTS
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RECIPIENTS OF PLASMA PRODUCTS MANUFACTURED FROM DONATIONS
FROM INDIVIDUALS WHO DEVELOPED VCJD
• 9 blood donors who developed vCJDcontributed 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 exposureprecautions to reduce risk of further transmission
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Ongoing process See web-site
www.hpa.org.uk/infections/topics-az/cjd/blood-products.htm
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PRION DISEASESBLOOD INFECTIVITY ISSUES
CONCLUDING COMMENTS
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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
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vCJD - BLOOD DONORSYear Death
Total vCJD cases
Total eligible to
donate
Number reported by relatives to be blood
donors
Number registered with
UKBTS
Number with
donations* 1995 3 3 0 - -
1996 10 10 2 1 1
1997 10 10 2 2 2
1998 18 18 4 2 2
1999 15 13 3 2 1
2000 28 23 3 3 2
2001 20 19 2 1 1
2002 17 17 5 3 2
2003 18 16 7 4 4
2004 9 9 0 1 1
Alive 5 5 0 1 0
Total 153 143 28 20 16
*donors found on BTS system for whom components were actually issued (eg some donors were registeredbut did not make any donations).
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Survival of live recipients (n=17) of components from vCJD Survival of live recipients (n=17) of components from vCJD donors according to interval between transfusion and onset of donors according to interval between transfusion and onset of
clinical symptoms in donor (up to 31/12/2004)clinical symptoms in donor (up to 31/12/2004)
0
5
10
15
20
-1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Time from transfusion to onset of clinical symptoms in donor (years)
Rec
ipie
nt S
urvi
val (
year
s)
RBC/WB RBC(LD) Plasma
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vCJD - BLOOD DONORSYear Death
Total vCJD cases
Total eligible to
donate
Number reported by relatives to be blood
donors
Number registered with
UKBTS
Number with
donations* 1995 3 3 0 - -
1996 10 10 2 1 1
1997 10 10 2 2 2
1998 18 18 4 2 2
1999 15 13 3 2 1
2000 28 23 3 3 2
2001 20 19 2 1 1
2002 17 17 5 3 2
2003 18 16 7 4 4
2004 9 9 0 1 1
Alive 5 5 0 1 0
Total 153 143 28 20 16
*donors found on BTS system for whom components were actually issued (eg some donors were registeredbut did not make any donations).
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-0.8 1.2 3.2 5.2 7.2 9.2 11.2 13.2 15.2 17.2 19.2
Time from transfusion to onset of clinical symptoms in donor (years)
Rec
ipie
nt s
urvi
val t
o de
ath
(yea
rs)
RBC/WB RBC(LD) RBC(BCD) Plasma Cryo Platelets
0
2
4
6
8
10
12
14
16
18
CJDcase
20
Survival to death for recipients of vCJD components (n=33)
PrP positivityin spleen
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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 dosesingle dose factor VIII, IX, antithrombin, where 1 vial of product has been implicated.
• MEDIUM: Substantial quantities necessary to surpass thresholdseveral infusions of IgG.large doses of 4.5% Albumin.
• Low: Likelihood of surpassing threshold can be ignoredAlbumin 20%.Factor VIII where albumin excipient, but not plasma concentrate has been implicated.IM human Ig prophylaxis against Hep A, anti-D.
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Recipients of plasma products manufactured from donations
from individuals who developed vCJD ACTION
• HIGH: Batches being tracedRecipients 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
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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