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VARIANT CJD AN UPDATE DR. HESTER WARD National CJD Surveillance Centre Edinburgh, UK [email protected]

VARIANT CJD AN UPDATE DR. HESTER WARD National CJD Surveillance Centre Edinburgh, UK [email protected]

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VARIANT CJD

AN UPDATE

DR. HESTER WARD

National CJD Surveillance Centre

Edinburgh, UK

[email protected]

UK frequency of CJD

SINCE1985

< 1994n= 360

> 1995n= 513

Classicalsporadic

88% 67%

Geneticfamilial

7% 6%

Iatrogenic* 5% 5%

(new)Variant

--- 22%

* human growth hormone, human gonadotrophin, neurosurgery, depthelectrodes, corneal transplant, dura mater

Variant CJD

UK

114 definite & probable cases

• 89 definite cases- confirmed neuropathologically• 14 probable cases- died- no post mortem • 1 probable case- died- awaiting post mortem• 10 probable cases- alive

FRANCE: 3 definite & 2 alive probable cases

REPUBLIC OF IRELAND: 1 definite case

Variant CJD

AGE• Median age at onset : 26 years (range 12 - 74 years)• Median age at death : 28 years (range 14 - 74 years)

GENDER: 60 males : 54 females

DURATION OF ILLNES• Median: 13 months (range 6 - 39 months)

GENETICS: All tested = MM at codon 129 (n= 97)

vCJD ONSETS/YEAR- DEFINITE & PROBABLE

CASES (n=114)

05

101520253035

1994 1995 1996 1997 1998 1999 2000 2001

YEAR

NU

MB

ER

OF

CA

SE

S

vCJD DEATHS by YEAR- DEFINITE & PROBABLE CASES (n=104)

0

5

10

15

20

25

30

1995 1996 1997 1998 1999 2000 2001 2002

Courtesy of Nick Andrews, PHLS Statistics Unit, London

Quarter/Year

Inci

dence

02

46

810

12

o

oo o

o

o

o o

o

o

o

o

o

o

o

o

o

o o

o

o

o

o

o

o

oo

o

o o o

e

ee e

e

e

e e

e

e

e

e

e

e

e

e

e

e e

e

e

e

e

e

e

e e

e

e

ee

2/94 4/94 2/95 4/95 2/96 4/96 2/97 4/97 2/98 4/98 2/99 4/99 2/00 4/00 2/01 4/01

Figure1: Observed (-o-) and expected (-e-) quarterly incidence of vCJD onsets

Fitted underlying trend* (___) is given with its 95% confidence limits (...)

* includes adjustment for delay from onset to diagnosis

Geographical distribution of places of residence at onset of symptoms of vCJD cases (n=93)

Variant CJD - GEOGRAPHYDistribution of 51 variant CJD cases by region of residence in 1991

Standard region Population aged 16-54 at the1991 census (%)

Number (rate/million) ofvCJD cases

Scotland 2,684,004 ( 9) 8 (2.98)

Northern 1,592,257 ( 5) 5 (3.14)

North-West 3,293,814 (11) 6 (1.82)

Yorkshire & Humberside 2,567,630 ( 9) 7 (2.73)

Wales 1,461,006 ( 5) 2 (1.37)

West Midlands 2,749,699 ( 9) 1 (0.36)

East Midlands 2,121,678 ( 7) 4 (1.89)

East Anglia 1,072,018 ( 4) 1 (0.93)

South-West 2,379,370 ( 8) 3 (1.26)

South-East 9,469,745 (32) 14 (1.48)

Total 29,393,174 (100) 51 (1.74)

Variant CJD - GEOGRAPHY

Standard region Population (millions)aged 10 years andabove at the 1991census (%)

Number (rate/million) ofvCJD cases

“North” (North West,Yorkshire & Humberside,Northern, Scotland)

16.6 (35) 26 (1.57)

“South” (South West, SouthEast, Wales, West Midlands,East Midlands, East Anglia)

31.2 (65) 25 (0.80)

Total 47.8 (100) 51 (1.94)

Variant CJD - GEOGRAPHY

Number (rate/million) of vCJD cases by place ofresidence at 1st January 1991

Region Population aged10 years andabove at the1991 census First 51 cases Subsequent

casesTotal

“North” (NorthWest, Yorks &Humbs, Northern,Scotland)

16.6 million 26 (1.57) 19 (1.14) 45 (2.71)

“South” (SouthWest, South East,Wales, WestMidlands, EastMidlands, EastAnglia)

31.2 million 25 (0.80) 21 (0.67) 46 (1.47)

Total (age/sexadjusted rate ratio)

47.8 million 51 (1.94) 40 (1.66) 91 (1.81)

Variant CJD- GEOGRAPHY

Dietary & Nutritional Survey of British Adults• 1986 - 1987• 2197 adults aged 16 to 64 years• weighed, 7 day dietary records

Household Food consumption & Expenditure Report• 1984 - 1986• 20, 000 households• One week records of all foods entering home for

consumption

Regional variations in weekly quantities of foods consumed (grams) measured in theperiod 1986-1987

Type of food Mean quantity per person in grams by region

Scotland Northern,North West,

Yorks &Humbs

East Midlands,East Anglia,

WestMidlands,

South Westand Wales

South East

Beef and veal 351 342 319 362

Burgers and kebabs 170 166 139 205

Sausages 147 136 142 143

Meat pies and pastries 251 284 243 237

Other meat products 170 201 197 215

Total 1089 1129 1040 1162

Data from the Nutritional Survey of British Adults

Regional variations in weekly quantities of foodsbrought into the home (grams) measured inthe period 1984-1986

Scotland North Yorks &Humbs

NorthWest

EastMids

WestMids

SouthWest

SouthEast/East

Anglia

Wales

Carcasemeat

325 362 359 377 373 392 395 382 355

Bacon 102 119 113 121 110 122 89 88 113

Poultry 158 192 174 199 175 212 196 205 191

Othermeat andmeatproducts

455 456 369 408 367 376 362 338 339

Total 1040 1129 1015 1105 1025 1102 1042 1013 998

Data from Household Food Consumption and Expenditure:1988

Scatterplot of cumulative, age-standardised vCJD incidence against weekly consumption of other meat and meat products (grams) by region (Household

Food Consumption and Expenditure: 1988) of cumulative, age-standardised vCJD incidence

against weekly consumption of other meat and meat products (grams) by region (dietary data from Household Food Consumption and Expenditure:1988)

vC

JD

sta

nd

ard

ise

d c

um

. in

cid

.

Other meat/meat products(grams)300 350 400 450

0

50

100

150

200

GEOGRAPHICALLY ASSOCIATED CASES (GACs) of vCJD

Geographically associated cases

Definition :

2 or more cases of probable or definite vCJD where preliminary investigations suggest there is an association between the cases because of:

a) Geographical proximity of residence at some time, either now or in the past;

b) Other link with the same geographic area, eg. attending the same school or work place or attending functions in the same area.

The Leicester cluster

5 cases of variant CJD lived in Leicestershire (population 870, 000)

Cumulative incidence: UK 1.5/ million Leicester 5.7/ million4/5 from Charnwood (142, 000): 28.2 / million

Kulldorff’s method- spatial scan statistic-Leicestershire- most likely cluster (p<0.004)No other significant clusters

(Cousens et al. Lancet 2001; 357: 1002- 1007)

The Leicester cluster

4/5 were reported to have bought meat from butchers who

processed whole carcass beasts & split the heads to

remove the brains for commercial purposes

Hypothesis- cases bought meat from butchers that split heads

Tested - control study- matched each case to 6 community controls

OR 15 (1.6- 139)

The Leicester cluster

If true: minimal incubation- between 10- 16years

Does this explain other cases in UK & in other countries?

BUT

Bias

Interview with butchers

Brain- where did it go?- food chain…..

Variant CJD- RISK FACTORS

TO DATE from case control study:

No evidence of increased risk of CJD associated with diet, surgery or occupation (although, some differences in

diet between cases & controls)

BUT- rare disease, recall bias, surrogate witnesses, small numbers, control recruitment

Size of the vCJD epidemic- predictions

1997: Cousens et al. Nature; 385: 197-198 (n=14 vCJD)

75- 80, 000

Back calculation

MM genotype

2000: Ghani et al. Nature; 406: 583- 584 (n= 55 vCJD)

63- 136 000

Scenario analysis (> 5 million combinations of parameters)

MM genotype

< 2 cases vCJD per infectious bovine

Size of the epidemic- predictions

2001: Huillard d’Aignaux et al. Science; 294: 1792- 1931 (n= 82)

• Clinical cases: hundreds - few thousands• Infected individuals: hundreds - millions, but long mean

incubation period & so die from competing causes• Close to peak of epidemic

• Back calculation- calc. number infected based on assumptions of when infected & incubation pd

• Exposure cut off- 1996• MM genotype

• ? not reassuring re. potential secondary spread

Size of the epidemic- predictions

2001: Valleron et al. Science 294: 1726- 1728 (n=97)• Total number of cases: 205 (upper limit 403)• Mean incubation pd: 16.7 yrs (12- 23)• Peak: 2000/ 2001• Bimodal age distribution

• Age at diagnosis= age at infection + incubation time.• Assuming age of infection parallels BSE epidemic-

incubation pd calc using deconvolution technique.

• Exposure cut off: 1990• Exponential decrease in susceptibility >15 years of age

Size of the epidemic- predictions2002: Ferguson et al. Nature 9 January 2002; DOI 10.1038/nature 709

Predictions of future cases of vCJD based on BSE infection of British sheep

• Bovine BSE only: Upper 95% CIs: 50 000- 100 000 vCJD cases

• Bovine + ovine BSE: Upper 95% CIs: 150, 000 vCJD cases (BSE endemic in national flock)

• Past exposure to BSE in UK: majority from cattle

• On- going exposure to BSE: sheep greater than cattle- reduce risk up to 90%- age at slaughter & SRM controls

Many assumptions: epidemiology based on scrapie & experimental BSE in sheep, tissue infectivity during incubation

Size of the epidemic- predictions

Conclusions

Much uncertainty, esp incubation period, risk from sheep

Only based on MM genotypes (40% of population)

? not necessarily reassuring if considering secondary spread

Transfusion Medicine Epidemiology Review (TMER)

Joint project between National Blood Service & NCJDSU

AIM: to investigate whether any evidence that CJD, including vCJD, may be transmitted via blood supply

TMER- vCJD

TMER• All definite + probable cases vCJD- reported to

transfusion service of relevant country (England, Wales, Scotland & Northern Ireland)

• If a donor- trace fate of all donations- recipient details passed to NCJDSU

Reverse TMER• vCJD cases (& matched controls) who have received

blood transfusions- details passed to BTS• Details of donors passed back to NCJDSU

TMER- vCJD

RESULTS (April 2001)

(n= 87 vCJD cases)

TMER

8 cases vCJD were blood donors- 22 recipients between 1981- 1999

None have developed CJD to date- 9 have died from other causes

None have registered as blood donors

TMER- vCJD

Reverse TMER

4 cases of vCJD received blood components (117- 1 case 103 of these)

111 donors- none have developed CJD to date

National CJD Surveillance Unit, UK

Director & Neuropathology- Professor J. Ironside

Neurology-

Professor R.G. Will & Dr. R. Knight

Protein Biochemistry-

Dr. M. Head

Genetics- Mr. M. Bishop

CSF Biochemistry-

Dr. A. Green

Epidemiology-

Dr. H. Ward

Care co-ordinator-

Dr. B. Weller

Blood transmission studies: on going

Tests of CJD

Blood/ urine

Screening vs. diagnostic

DIAGNOSTIC CRITERIA FOR vCJD

I A Progressive neuropsychiatric disorder

B Duration of illness > 6 months

C Routine investigations do not suggest an alternative diagnosis

D No history of potential iatrogenic exposure

E No evidence of a familial form of TSE

II A Early psychiatric symptomsa

B Persistent painful sensory symptomsb

C Ataxia

D Myoclonus or chorea or dystonia

E Dementia

III A EEG does not show the typical appearance of sporadic CJD c

(or no EEG performed)

B Bilateral pulvinar high signal on MRI scan

IV A Positive tonsil biopsyd

DEFINITE: I A and neuropathological confirmation of vCJD

(spongiform change and extensive PrP deposition with florid plaques, throughout the cerebrum and cerebellum)

PROBABLE: I and 4/5 of II and III A and III B

OR

I and IV Ad

POSSIBLE: I and 4/5 of II and III A

a depression, anxiety, apathy, withdrawal, delusions.

b this includes both frank pain and/or dysaesthesia.

c generalised triphasic periodic complexes at approximately one per second.

d tonsil biopsy is not recommended routinely, nor in cases with EEG appearances typical of sporadic CJD, but may be useful in suspect cases in which the clinical features are compatible with vCJD and MRI does not show bilateral pulvinar high signal.

e spongiform change and extensive PrP deposition with florid plaques, throughout the cerebrumand cerebellum.