PRION DISEASESBLOOD 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 DISEASESBLOOD INFECTIVITY ISSUES

INTRODUCTION

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”

PRNP GENE (HUMAN CHROMOSOME 20)POLYMORPHISM AT CODON 129

MM MV VV

PRNP ORF

129

M or V

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

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

PRION DISEASESBLOOD 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 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

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

Variant CJDMEAN 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)

• FRANCE 9

• ITALY 1

• REPUBLIC of IRELAND 1

• REPUBLIC of IRELAND 1

• USA 1

• CANADA 1

• SAUDI ARABIA 1

VARIANT CJD: THE FUTURE

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

?

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

? ?

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

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 LRSPRE-CLINICAL INVOLVEMENT : THE EVIDENCE

Appendicectomy vCJD onset Interval PrPSc

1995 1995 8 months POS

1996 1998 2 years POS

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

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)

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

? 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

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 DISEASESBLOOD INFECTIVITY ISSUES

BLOOD PRION RISK:

EXPERIMENTAL EVIDENCE

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

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

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 & BLOODSUMMARY 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 DISEASESBLOOD 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* 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

CJD & BLOODEPIDEMIOLOGICAL EVIDENCE : A CAUTION

MUCH OF THE EVIDENCE RELATES TOSPORADIC CJD

&

VARIANT CJD MIGHT BEHAVE DIFFERENTLY

PRION DISEASESBLOOD 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 componentswhere recipient & component information available: 50

• Additionally:9 vCJD individuals have donated to 23 plasma poolsFrom which 174 products have been manufactured

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

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)

0

1

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6

Num

ber

<1

1 - <

2

2 - <

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3 - <

4

4 - <

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5 - <

6

6 - <

7

7 - <

8

8 - <

9

9 - <

10

10+

Years since transfusion

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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)

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 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

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

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

FOOTNOTE

FRACTIONATED BLOOD PRODUCTS

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

Ongoing process See web-site

www.hpa.org.uk/infections/topics-az/cjd/blood-products.htm

PRION DISEASESBLOOD 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 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).

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

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).

-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

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.

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

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