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From: TSS ()
Subject: Risk of variant Creutzfeldt– Jakob disease in France
Date: December 5, 2005 at 6:00 am PST

IJE vol.34 no.1 © International Epidemiological Association 2005; all rights reserved. International Journal of Epidemiology 2005;34:46–52

Advance Access publication 13 January 2005 doi:10.1093/ije/dyh374

Risk of variant Creutzfeldt–Jakob disease

in France

Marc Chadeau-Hyam* and Annick Alpérovitch

Accepted 6 October 2004

Background France has the second highest number of variant Creutzfeldt–Jakob disease

(vCJD) cases worldwide. Imports of bovine carcasses from the UK probably

constituted the main source of exposure of the French population to the bovine

spongiform encephalopathy (BSE) agent. Meat products consumed whilst

visiting the UK have also been considered as a possible source of exposure.

Methods We estimated the number of future vCJD cases in France using a simulation

approach. Both the distribution of the vCJD incubation period and the agedependent

susceptibility to the BSE agent were estimated from UK data. The

French epidemic was simulated by gender and birth-cohort from data on the

infectivity of UK bovine tissues and simulations of the French consumption of

infected beef products. We also used data on travel to the UK between 1980

and 1995.

Results We predicted 33 future cases of vCJD: 12 in the 1940–69 birth-cohort and 21 in

the post-1969 birth-cohort. No case was predicted in the pre-1940 cohort. Based

on our model, simulated vCJD cases occurred later in the older (1940–69) than

in the younger cohort (post-1969). Age at onset was stable in the post-1969

cohort and increased in the older cohort. The model predicted a small excess of

male patients. No case was attributed to travels in the UK.

Conclusions This modelling confirms that a large vCJD epidemic in France is very unlikely.

Since France (where 60% of the total British exports of bovine carcasses were

exported) has been highly exposed to the BSE agent, our results are reassuring

for most countries worldwide.

Keywords Epidemiology, vCJD, France, predictions, simulation, exposure to BSE agent,

birth-cohort

46

The data available indicate that the French population has been

highly exposed to the bovine spongiform encephalopathy (BSE)

agent from the early 1980s to the embargo on British beef, in

1996. France has the second highest incidence of variant

Creutzfeldt–Jakob disease (vCJD) worldwide. The number of

vCJD cases are, however, much lower in France than in the UK:

6 and 146, respectively at the time of this study (since, two

new cases occurred in France and five in the UK). Several

predictions of the vCJD epidemics in the UK have already been

published. While early studies predicted very large epidemics,

most recent studies predict that the number of future vCJD

cases in the UK should not be greater than a few hundreds.1–6

To date, models that were used to estimate the risk of vCJD in

the UK have not been applied to French data. Fitting models on

only 6 cases, key parameters such as the incubation period

distribution and the susceptibility to vCJD cannot be accurately

estimated. But recent studies on the epidemics in the UK

provided consistent estimates for these parameters.1–3 They can

be used to assess the risk of vCJD in France, assuming factors

that modulate these parameters to be similar in France and

the UK.

vCJD cases have two remarkable characteristics. First, they all

are homozygous for methionine at the codon 129 of the prion

protein (PRNP) gene.3,4 Therefore, predictions of vCJD

incidence only apply to this genotype which accounts for 40%

of both French and British populations. Second, about twothirds

of the vCJD cases are aged between 15 and 35 years; only

3 cases were older than 60 years. This age distribution raises the

issue of an age-dependant pattern in exposure, susceptibility

and/or incubation period. Modelling approaches require those

relations to be assessed and defined.

INSERM U 360, Hôpital La Salpêtrière, 75651 Paris Cedex 13, France.

* Corresponding author. E-mail: marc.chadeau@chups.jussieu.fr

RISK OF vCJD IN FRANCE 47

Dietary exposure to the BSE agent is the most likely cause of

vCJD. Products containing beef as mechanically recovered meat

(MRM) (burgers, sausages, etc.) are generally considered as

the major source of exposure as they could have been

contaminated with infectious nervous tissues. There were

three potential sources of BSE exposure in the French population:

(i) the consumption of contaminated French meat, (ii) the

consumption of contaminated British meat imported to France

and (iii) the consumption of contaminated British meat in the

UK whilst French travellers visited the UK. Previous studies

indicated that the exposure due to indigenous BSE was low.7–10

The aim of this study is to forecast the number of vCJD cases in

France based on exposure to BSE through British infected meat

and meat products which were imported to France or consumed

by French travellers during stays in the UK. Assessment of the

exposure of the French population to BSE was based on previous

studies by our group and others. We had already estimated the

French consumption of beef MRM contained in burgers and other

beef products. To investigate the observed age-dependent risk of

vCJD, consumptions were computed by birth-cohorts (pre-1940,

1940–69, post-1969) and gender.11 The present analysis also

required estimates of the infectivity in UK beef MRM by calendar

year, which were provided by Cooper and Bird.12

Methods

Exposure to the BSE agent through

consumption of UK beef MRM

Dietary exposure intensities to the BSE agent were expressed as

bovine oral ID50 (Bo-ID50), the oral dose required to cause

an infection in 50% of an exposed bovine population. Two

infectivity options were considered.12 Assuming an exponential

increase in infectivity in the last year of incubation with a

doubling time of 6 months (optimistic option), infected bovines

slaughtered 12 months before their onset were approximately

half (54%) as infectious as bovines with clinical signs. The

pessimistic option assumed that pre-clinical and clinical bovines

were equally infectious. The Monte Carlo simulation process

providing estimates of the infectivity titre per tonne of UK beef

MRM, for each calendar year from 1980 to 1995, has been

detailed by Cooper and Bird.12 Their study showed that the

infectivity titre of UK beef MRM increased exponentially

between 1980 and 1992, and then fell; in 1995, MRM

infectivity was approximately at the 1987–1988 level. In 1989,

a sharp but transitory drop in MRM infectivity was observed

when specified bovine offal (SBO) legislation was introduced in

the UK. These measures prevented potentially infectious

products from entering the human food chain.

Exposure to BSE agent through bovine

carcasses imported from the UK

In a previous study, we estimated by calendar year the total

quantity of beef MRM produced for human consumption in

France and the proportion of MRM produced from imported

bovine carcasses.11 To estimate the annual number of Bo-ID50

consumed due to imports, we simulated the infectivity titre

distribution in French MRM due to British imported bovines,

using the methodology developed by Cooper and Bird.12

Combining estimated individual consumption of products

containing MRM by age group and gender with the simulated

infectivity titre of French MRM, we first got the simulated

distribution of the individual exposure and then the total

population exposure to BSE by birth-cohort, calendar year and

gender.

Exposure to BSE whilst visiting the UK

This part of our study is detailed elsewhere.13 Briefly, to know

the proportion of blood donors who had travelled to the UK

from 1980 to 1996, the French Blood Transfusion Service

conducted a nationwide survey in 1999. Donors (n 16 191)

answered questions about dates and durations of their visits to

the UK during the critical years. About one-third of the French

donors had spent at least one day in the UK during the surveyed

period. Only 1.2% had spent more than six months in the UK.

Data from blood donors were extrapolated to the general

population, with adjustments which were necessary to take into

account the specific age and gender characteristics of the

donors. Based on these data, we simulated the distribution of

the number of weeks spent in the UK by French travellers and

we estimated exposure to BSE during those trips by birthcohort

and gender.

Estimation of the vCJD incidence in France

The approach we used is derived from the one described by

Cooper and Bird.3 The evolution of the health status of each

infected individual was simulated. Individuals were all

attributed a calendar year of infection and an incubation

period. Consequently, the size and the temporal pattern of

French vCJD epidemic could be described. To get distributions,

5000 independent epidemics were simulated.

The required number of infected individuals was not fixed

but set along the simulation runs. A run stopped once as many

cases as really observed in each birth-cohort by the end of 2003

were simulated. The year in which infection took place (y)

was randomly attributed according to the probability of

being infected at year y. That probability was assumed to be

proportional to the density of the exposure that year. Exposure

itself depended on gender g, birth-cohort c and on how

the individual was exposed (during trips to the UK or not): the

source of exposure s. Therefore, y was sampled simultaneously

with the three other parameters from their joint distribution

{ ˆPy,g,c,s}(y,g,c,s). Let (Ey,g,c,s)(i) denote the exposure intensity

simulated for iteration i, for given y, g, c and s, and (Py,g,c,s)(i) the

corresponding probability of getting infected. (Py,g,c,s)(i) was

estimated for given y, g, c, s with the exposure density:

Each infected individual was then randomly attributed a

combination of modalities for those four variables describing

how and when their infection occurred. Incubation periods

were sampled from a log-normal distribution whose parameters

were dependent on the birth-cohort c.3 Values were the ones

which provided the best fitting epidemic in the UK according to

a 2 criterion, namely a mean of 11 years (SD 1.5) for the

youngest cohort, and a mean of 26 years (SD 16.5) for the two

older cohorts. Finally, to know whether each onset was

observed or censored, the year of death from other reasons than

(Pˆ

y,g,c,s)(i)


(Ey,g,c,s)(i)

y,g,c,s(Ey,g,c,s)(i)

48 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY

vCJD was simulated according to French mortality rate by age,

gender, and calendar year (http://www.ined.fr). Simulated

individuals were only considered if (i) their onset led to an

epidemic which was compatible with observations and (ii) they

were susceptible, according to an age-related susceptibility

function s(a). We considered individuals aged 15 years old to

be totally susceptible [s(a) 1], thereafter, the susceptibility

exponentially decreased, with 6% decrease per year of age.2

Results

French exposure to BSE through imports

and travels to the UK

Figure 1 shows the total exposure of the French population by

birth-cohort and calendar year, assuming that pre-clinical

bovines were 54% as infectious as clinical BSE bovines

(optimistic option). In all cohorts, exposure peaked in 1993.

The pre-1940 birth-cohort was far less exposed than the two

younger cohorts. The exposure patterns of the 1940–69 and

post-1969 cohorts were similar, the 1940–69 cohort being,

however, more exposed. A direct interpretation of these figures

can be misleading because sizes of the cohorts were very

different and varied differently with time: while the population

in the oldest cohort decreased, it increased in the post-1969

cohort. In order to get size-independent results, exposure was

simulated for virtual birth-cohorts whose size was fixed to

105 individuals. That simulation indicated that individuals born

before 1940 had been as exposed to BSE as the younger ones

(Figure 2). Under the optimistic infectivity option, the French

population was exposed to 36 142 Bo-ID50 (Table 1).

During the same period, the exposure of the UK population

was equal to 710 350 Bo-ID50

12,13 (ratio UK/France: 20). As

expected, the exposure was roughly multiplied by two under

the pessimistic option, but the UK/France ratio remained

unchanged.

Travels to the UK accounted for only 2% of the French total

exposure to BSE.

Number of future vCJD cases in France

Under the optimistic infectivity option (Table 2), a total of

33 vCJD cases are expected:12 cases in the 1940–69 cohort and

21 cases in the post-1969 cohort. Only three cases were expected

to occur after 2020. No case was predicted in the pre-1940

cohort. Almost all simulated onsets, except three in the

1940–69 cohort, occurred in individuals infected between 1990

and 1995. The temporal distribution of onsets differed between

the two cohorts: while all expected vCJD onsets occurred before

2010 in the youngest cohort, 7 out of 12 onsets in the 1940–69

cohort were predicted to occur after 2010. We also found that

no onset was censored in the youngest cohort while three

onsets were censored in the 1940–69 cohort. According to our

simulation, the age at onset of the simulated vCJD cases in the

post-1969 cohort remained stable along time, whereas it

increased in the 1940–69 cohort. As a consequence of gender

differences in exposure to BSE, we predicted an excess of male

patients in both cohorts (around 60%). That proportion was

constant over time and consistent with French and British data,

which did not suggest any gender-related susceptibility

function. Simulations did not predict any case that could be

attributed to travels in the UK.

We also computed a crude estimate of the bovine-to-human

transmission barrier (T-barrier) in the genetically susceptible

population. As a consequence of the assumed age-dependent

susceptibility, an individual in the 1940–69 birth-cohort

required more (1.5) infectious units to be infected than an

individual from the post-1969 cohort. Indeed, the mean

estimated number of infectious units required to cause one

infection was around 280 for the youngest cohort and 420 for

the 1940–69 cohort. Confidence intervals were very large:

[167–1382] and [106–972] for the 1940–69 and post-1969

cohorts respectively. Under the pessimistic infectivity option,

the mean T-barrier roughly doubled.

Comments

Our model predicted a low vCJD incidence in the French

genetically susceptible population (methionine homozygous),

with a median estimate of 33 future clinical cases between 2004

and 2020. We found that two-thirds of the simulated vCJD

cases were expected in the post-1969 birth-cohort and the

remaining one-third in the 1940–69 cohort.

As six cases were not sufficient enough to get reliable estimates

for the key parameters of our model, their values were fixed to

the ones obtained by the modelling of the vCJD epidemics in the

UK. First, the incubation period was sampled from an agedependent

log-normal distribution whose parameters best fitted

Cooper’s model.3 Second, as proposed by others,1,2 we used an

age-dependent susceptibility function exponentially decreasing

after the age of 15 years. Previous modelling studies showed that

these assumptions and parameters were accurate enough to

predict the vCJD epidemics in the UK. As incubation period and

susceptibility are mainly related to biological mechanisms, UK

estimates are valid in other populations as well. However, a

sensitivity analysis (results not shown) indicated that our

conclusions remained stable while considering alternative values.

Assuming that vCJD was a consequence of eating

BSE-infected beef, we estimated dietary exposure intensities

to BSE by combining two categories of data: estimated

distributions of the French consumption of products containing

beef MRM, by birth-cohort and gender, and infectivity titre in

MRM produced from British bovines, expressed as number of

units of Bo-ID50. This methodology had been proposed to

predict vCJD incidence in the UK.3 Others used estimates of the

number of BSE-infected animals entering the human food

chain to quantify human exposure to BSE.1,2,4,5 Both

approaches resulted in comparable predictions. The advantage

of the latter methodology is that it required neither any

assumption about which types of beef products are infective nor

any data on the consumption of meat products which induced

serious uncertainties that have already been discussed.11,15 On

the another hand, our methodology, derived from Cooper and

Bird’s study, facilitates the discussion about age-dependent

exposure and/or incubation period.

To get an estimate of the French exposure to BSE during

stays in the UK, we extrapolated data from blood donors to the

general population. We adjusted for age distribution and sex

ratio differences between donors and the general population.

It is established that, on the average, French blood donors

have lower socioeconomic level than the general population.

Since the proportion of travellers increases with the

RISK OF vCJD IN FRANCE 49

Figure 1 Evolution of the French total dietary exposure to BSE in beef MRM produced from British carcasses, expressed in Bo-ID50 units, for

pre-1940 (a), 1940–69 (b), post-1969 (c) birth-cohorts, assuming preclinical bovines being 0.54 times less infectious than clinical bovines

(optimistic infectivity option)

(a)

(b)

(c)

socioeconomic level, this could have resulted in underestimating

the proportion of travellers in the general population.

Consequently, the number of vCJD cases due to infections whilst

travelling in the UK may be slightly higher than expected in our

analysis. But probably, no more than one French vCJD case

might be due to infections contracted in the UK.

Based on a previous analysis,10 the exposure due to BSEinfected

cattle in France was neglected in our model. This major

50 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY

Figure 2 Evolution of the French total dietary exposure to BSE in beef MRM produced from British carcasses (in Bo-ID50 units), for the three

birth-cohorts whose size is fixed to 105 individuals. Figures are based on 5000 simulation runs, under the optimistic infectivity option

Table 1 Total infectivity (in Bo-ID50 units) consumed in France and in the UK between 1980 and 1995, by birth-cohorts. Figures are based on

5000 simulation runs. Median values are reported

Optimistic infectivity option Pessimistic infectivity option

French British Ratio French British Ratio

Birth-cohorts exposure Exposure UK/France exposure Exposure UK/France

Pre-1940 5379 86 500 16.08 9456 138 000 14.59

1940–1969 16 412 352 500 21.48 28 948 560 500 19.36

Post-1970 14 351 271 350 18.91 25 612 457 700 17.87

Total 36 142 710 350 19.65 64 016 1 156 200 18.06

Table 2 Estimated incidence of vCJD linked to the importation of British bovines in France by birth-cohort. Figures are based on

5000 simulation runs, under the optimistic infectivity option. Mean values, (bold), median values, and [5th, 95th] percentiles are presented

Before 2003 2004–2005 2006–2010 2011–2020 After 2020

Birth-cohort No.of

period onsets Observed Simulated Simulated Simulated Simulated Simulated

Pre-1940 0 0.00 0 [0,0] 0.05 0 [0,1] 0.09 0 [0,1] 0.09 0 [0,1] 0.01 0 [0,0]

1940–69 3 3.00 3 [3,3] 1.17 1 [0,4] 3.08 3 [0,9] 4.49 4 [0,12] 3.14 3 [0,9]

Post-1969 3 3.00 3 [3,3] 12.57 11 [2,32] 8.82 8 [1,23] 0.04 0 [0,1] 0.00 0 [0,0]

assumption must be carefully discussed. Although available

estimates of the BSE epidemics in France were not perfectly

consistent, they indicated that exposure due to infected

French meat had probably been small.7–9 For the period

1987–2000/2001, estimates of the number of infected animals

varied from 7000 to 70 000 according to the assumptions

considered. The number of infected animals entering the food

chain comprised between 100 and 7600 in France, compared

with 3.3 million in the UK16 during the same period of time. On

the other hand, the data indicated that exports of British bovine

carcasses to France represented about 10% of the beef meat

consumption in the UK. Based on these figures, French infected

bovines could have been responsible for a very small percentage

of the total BSE exposure of the French population between

1987 and the early 2000s. A study suggested that the number of

BSE infections in France could have been much higher before

1987 than after.9 If confirmed, this result could lead to revisiting

some models of the BSE and vCJD epidemics. Another argument

which supports our assumption is the comparison between

estimated exposure and observed vCJD incidence: the ratio

between the exposure in the UK computed by Cooper and Bird

and that provided by our model (20:1) is consistent with the

current vCJD incidence ratio (21:1) between these countries.

However, if it was necessary to consider indigenous French

exposure to BSE in modelling, the temporal and age-sex

distributions of the predicted vCJD cases might be affected, but

not (or only very slightly) the predicted number of vCJD cases.

Indeed, while the key parameter defining epidemic size is

RISK OF vCJD IN FRANCE 51

the observed numbers of cases, estimates of the French

exposure are only involved in the description by gender, age,

and calendar year of simulated vCJD cases.

We set the end of the exposure period in 1995 as the embargo

on British beef was ordered at the beginning of 1996.

Afterwards, indigenous BSE constituted the unique source of

infection of the French population. A total of 1500 French

bovine carcasses were estimated to have entered the human

food chain after 1995.9 If all those carcasses had been used to

produce MRM, French exposure between 1996 and 2001 would

have represented less than 2% of the French total exposure.

Other limitations of these predictive models have been

already pointed out. Other genotypes at the PRNP gene codon

129 could be susceptible to the BSE agent with longer

incubation period. Indeed, in both iatrogenic CJD due to human

growth hormone treatment17 and Kuru,18,19 individuals

with the methionine-valine heterozygous genotype, which

represents about 50% of the French population, have longer

incubation periods than the methionine-methionine

homozygotes. As heterozygotes also have a lower susceptibility

to prion diseases, they should not contribute much to the vCJD

epidemics. Moreover, possible transmission of vCJD by blood

transfusion was suggested by recent case reports in the UK20,21

and iatrogenic transmission of vCJD through medical or surgical

procedures cannot be excluded. But, a series of effective

measures to reduce the risk of transmission of vCJD by infected

material and blood products were taken in France. In addition,

transfused individuals were banned from blood donation.

Predictions of the vCJD epidemics in the UK, France, and the

Republic of Ireland6 are consistent and reassuring. To date, the

best estimates of the number of future clinical cases were

between 200 and 400 cases in the UK, approximately 30 in

France and between one and two in the Republic of Ireland.

The Republic of Ireland had the second highest incidence of BSE

worldwide. Harney et al. estimated that exposure due to the

BSE epidemic in Ireland and exposure due to Irish imports from

the UK were equivalent.6 Our study suggests that, in France,

imports from the UK have represented the main source of

infection by the BSE agent and that exposure due to BSE in

French cattle plays a negligible role in the vCJD epidemic.

Data from Customs and Excise in the UK indicated that, over

the period 1980–1995, about 60% of the total exports of UK

bovine carcasses to the European Community (EC) countries

(about 2 million tonnes equivalent of carcasses) were exported

to France. Therefore, very few vCJD cases due to the past BSE

epidemics are expected in other EC countries, and worldwide.

Nevertheless, as long as BSE and other forms of animal

transmissible spongiform encephalopathies are not eliminated,

surveillance of human prion diseases at both the national and

international levels remains necessary.

Acknowledgements

This study was funded by a grant from the Groupement

d’Intérêt Scientifique (GIS) ‘Maladies à prions’. M.C.-H.

participated in the study during his PhD which was funded by

the French Ministry of Education. We would also like to thank

Sheila Bird and Jason Copper for having provided the British

data required for our study.

KEY MESSAGES

• The French population may have been mainly exposed to the BSE agent through the consumption of

BSE-infected bovines which were imported from the UK.

• Thirty-three future vCJD cases are expected in the French population, with the upper bound at lower than 100 cases.

• Expected cases of vCJD are young: two-thirds of the simulated vCJD cases are expected in the post-1969

birth-cohort and the remaining one-third in the 1940–69 cohort. Cases in people born before 1939 are very

unlikely to occur.

• No gender-related susceptibility to the BSE agent can be outlined.

References

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IJE vol.34 no.1 © International Epidemiological Association 2005; all rights reserved. International Journal of Epidemiology 2005;34:52–53

Advance Access publication 13 January 2005 doi:10.1093/ije/dyh393

Commentary: The risk of variant

Creutzfeldt–Jakob Disease: reassurance

and uncertainty

RG Will

The annual number of deaths from variant Creutzfeldt–Jakob

Disease (vCJD) in the UK is currently on a decline.1

Epidemiological and laboratory evidence strongly supports the

hypothesis that vCJD is caused by human infection with bovine

spongiform encephalopathy (BSE) and the population risk of

developing this condition is likely to be proportional to the

extent of human exposure to BSE, presumptively through

contaminated meat products. The risk of vCJD in countries

other than the UK may be due to exposure to indigenous BSE,

import of infected animals, animal feed, and food products

from the UK, or exposure to BSE during travel to the UK in

the risk period 1980–1996. The paper by Chadeau-Hyam and

Alperovitch2 assesses these potential risks in France and

concludes that overall there may be a limited number of future

vCJD cases in the French population (33 cases from 2004–2020)

and that the main risk was through consumption of infected

bovines from the UK. Travel to the UK was assessed to account

for only 2% of BSE exposure and exposure to French cases of

BSE was not considered because this was judged to represent a

low risk. This paper and a similar study in Ireland3 suggest that

the number of future cases of vCJD may be very limited outside

the UK. There are, however, a number of important caveats.

To date all clinical cases of vCJD in which the prion protein

gene (PRNP) has been examined have been methionine

homozygotes, with no identified cases in the 68% of the

Caucasian population with the alternative valine homozygotes

or heterozygous genotypes. All predictive studies of vCJD to

date have overtly assumed that only methionine homozygotes

will be affected, but the possibility that infection with BSE can

occur in the other genetic backgrounds has been supported by

the recent publication of a presumed preclinical† case of vCJD

in a PRNP heterozygous blood transfusion recipient.4 If

heterozygotes can be infected with BSE it would be surprising

if valine homozygotes could not also be infected, although

Chadeau-Hyam and Alperovitch suggest that heterozygotes

(and presumably valine homozygotes) may have a lower

susceptibility to infection and may not add significantly to the

vCJD epidemic. Cattle are uniformly methionine homozygotes

and homology of prion protein types is thought to lead to

University of Edinburgh Teviot Place, Edinburgh EH8 9AG, Scotland, UK.

E-mail: r.g.will@ed.ac.uk

†The possibility of life-long infection without the development of disease

cannot be excluded.

http://ije.oxfordjournals.org/cgi/reprint/34/1/46?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=creutzfeldt&searchid=1133791738792_657&stored_search=&FIRSTINDEX=0&journalcode=intjepid

IJE vol.34 no.1 © International Epidemiological Association 2005; all rights reserved. International Journal of Epidemiology 2005;34:52–53

Advance Access publication 13 January 2005 doi:10.1093/ije/dyh393

Commentary: The risk of variant

Creutzfeldt–Jakob Disease: reassurance

and uncertainty

RG Will

The annual number of deaths from variant Creutzfeldt–Jakob

Disease (vCJD) in the UK is currently on a decline.1

Epidemiological and laboratory evidence strongly supports the

hypothesis that vCJD is caused by human infection with bovine

spongiform encephalopathy (BSE) and the population risk of

developing this condition is likely to be proportional to the

extent of human exposure to BSE, presumptively through

contaminated meat products. The risk of vCJD in countries

other than the UK may be due to exposure to indigenous BSE,

import of infected animals, animal feed, and food products

from the UK, or exposure to BSE during travel to the UK in

the risk period 1980–1996. The paper by Chadeau-Hyam and

Alperovitch2 assesses these potential risks in France and

concludes that overall there may be a limited number of future

vCJD cases in the French population (33 cases from 2004–2020)

and that the main risk was through consumption of infected

bovines from the UK. Travel to the UK was assessed to account

for only 2% of BSE exposure and exposure to French cases of

BSE was not considered because this was judged to represent a

low risk. This paper and a similar study in Ireland3 suggest that

the number of future cases of vCJD may be very limited outside

the UK. There are, however, a number of important caveats.

To date all clinical cases of vCJD in which the prion protein

gene (PRNP) has been examined have been methionine

homozygotes, with no identified cases in the 68% of the

Caucasian population with the alternative valine homozygotes

or heterozygous genotypes. All predictive studies of vCJD to

date have overtly assumed that only methionine homozygotes

will be affected, but the possibility that infection with BSE can

occur in the other genetic backgrounds has been supported by

the recent publication of a presumed preclinical† case of vCJD

in a PRNP heterozygous blood transfusion recipient.4 If

heterozygotes can be infected with BSE it would be surprising

if valine homozygotes could not also be infected, although

Chadeau-Hyam and Alperovitch suggest that heterozygotes

(and presumably valine homozygotes) may have a lower

susceptibility to infection and may not add significantly to the

vCJD epidemic. Cattle are uniformly methionine homozygotes

and homology of prion protein types is thought to lead to

University of Edinburgh Teviot Place, Edinburgh EH8 9AG, Scotland, UK.

E-mail: r.g.will@ed.ac.uk

†The possibility of life-long infection without the development of disease

cannot be excluded.

greater efficiency of prion protein conversion. However, studies

in transgenic mice indicate that this phenomenon is not always

predictable.5

The pathogenesis of vCJD is different from other forms of

human prion disease with higher levels of disease associated

prion protein and infectivity in peripheral lymphoreticular

tissues,6 raising the possibility of secondary transmission of

infection via blood transfusion, plasma products, or through

contaminated surgical instruments. The identification of a case

of possible transfusion transmitted vCJD7 and the case of

presumed preclinical infection in a transfusion recipient

indicate that secondary transmission of vCJD may already be a

reality. Measures to minimize the risks of transmission of vCJD

through this route, including deferral of transfusion recipients

and donor deferral related to residence in the UK, have been

introduced and should reduce the risk of recycling of infection.

If these measures are fully implemented, the expectation is that

the risk of future cases of secondary vCJD may be limited, on

the assumption that geographical areas at risk of vCJD are

aware of this risk. It is important to underline that the efficiency

of transmission of an agent adapted to a species is usually

greater than transmission of a prion between species.

The paper by Chadeau-Hyam and Alperovitch suggests that

risk of BSE exposure in France was largely related to imports

from the UK, but this may not be true in other European

countries. The numbers of cases of BSE in these countries are far

less than the UK (numbered in hundreds of cases or less, rather

than over 180 000 cases in the UK) indicating a significantly

lower risk of exposure to indigenous BSE. The first cases of

BSE were identified in some countries through the introduction

of active abattoir testing in 2000/2001 and this also resulted

in a significant increase in the number of identified cases

(http://www.oie.int/eng/en_index.htm). Passive surveillance of

BSE may have missed cases identified through clinical signs alone

and there is uncertainty about the true extent of human BSE

exposure in the 1990s in some countries. Measures to minimize

human exposure to BSE were introduced more than 10 years

after the UK in some countries and there is a possibility that cases

of vCJD related to exposure to indigenous BSE may appear later

than in the UK or France. If the predictions in the paper by

Chadeau-Hyam and Alperovitch are correct, the numbers of such

cases are likely to be limited but the recent evidence suggesting

secondary transmission of vCJD underlines the importance of

maintaining surveillance for human prion disease.

Data on the export of meat, cattle, and cattle feed from the

UK are available from UK Customs and Excise for the period

1980–1995 and have been used as a component in the analysis

of geographical BSE risk carried out by the European

Commission for some countries. Although not verified by all

importing countries, the data on UK exports suggests that in the

1980s and early 1990s cattle and cattle feed were exported to

countries outside Europe, including South East Asia. Recycling

of infection within the cattle population may have taken

place in countries with a meat and bone meal industry and

re-exporting may have taken place. The risk of BSE is not

restricted to those countries in which BSE has already been

identified and one recommendation of a joint meeting of the

OIE/FAO/WHO in 2002 was that all countries should carry out

a risk assessment for BSE.8

One remarkable finding in the paper by Chadeau-Hyam and

Alperovitch is the extent of population exposure to BSE

infection with an estimate, using pessimistic assumptions, of

more than 64 000 bovine ID 50s in France and more than a

million ID 50s in the UK. This contrasts with the limited number

of predicted cases of vCJD in France and recent analyses in the

UK, which forecast hundreds rather than thousands of future

cases.9 This mismatch between exposure and disease is

unexplained. A barrier to transmission between species is well

recognised10 in prion disease and it is possible that transmission

between bovines and humans is very inefficient, with the

implication that the currently limited number of cases of vCJD

may be related to a rare exposure to a very high infectious dose.

This might also explain the fact that to date only one case has

been identified in any affected family. There is also the possibility

that there are genetic factors outside PRNP that influence the

likelihood of infection11 and that the proportion of susceptible

individuals in the population is restricted. There is also the

possibility of a co-factor, which increases the likelihood of

infection, e.g. concurrent bowel disease or dental procedures at

the time of exposure, but there is, as yet, no evidence of this. If

the mismatch between exposure to infection and the likelihood

of developing disease is maintained, the reassurance from the

paper by Chadeau-Hyam and Alperovitch may prove to be

justified, provided appropriate measures are taken to protect

public health in countries with BSE or vCJD.

References

1 Andrews NJ, Farrington CP, Ward HJT et al. Deaths from variant

Creutzfeldt-Jakob disease in the UK. Lancet 2003;361:751–52.

2 Chadeau-Hyam M, Alpérovitch A. Risk of variant Creutzfeldt–Jakob

disease in France. Int J Epidemiol 2005;34:46–52.

3 Harney MS, Ghani AC, Donnelly CA, McConn Walsh R, Walsh M,

Howley R, Brett F, Farrell M. vCJD risk in the Republic of Ireland.

BMC Infect Dis 2003;3:28–37.

4 Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW. Preclinical

vCJD after blood transfusion in a PRNP codon 129 heterozygous

patient. Lancet 2004;364:527–29.

5 Barron RM, Thomson V, Jamieson E, et al. Changing a single amino

acid in the N-terminus of murine PrP alters TSE incubation time

across three species barriers. EMBO 2001;20:5070–78.

6 Hilton DA, Sutak J, Smith MEF et al. Specificity of lymphoreticular

accumulation of prion protein for variant Creutzfeldt–Jakob disease.

J Clin Pathol 2004;57:300–02.

7 Llewelyn CA, Hewitt PA, Knight RSG et al. Possible transmission of

variant Creutzfeldt–Jakob disease by blood transfusion. Lancet 2004;

363:417–21.

8World Health Organisation, Food and Agricultural Organisation,

Office International des Epizooties. Technical Consultation on BSE:

public health, animal health and trade, 2002.

9 Boelle P-Y, Thomas G, Valleron A-J, Cesbron J-Y, Will R. Modelling

the epidemic of variant Creutzfeldt-Jakob disease in the UK based on

age characteristics: updated, detailed analysis. Stat Methods in Med Res

2003;12:221–33.

10 Prusiner SB, Scott M, Foster D et al. Transgenic studies implicate

interactions between homologous PrP isoforms in scrapie prion

replication. Cell 1990;63:673–86.

11 Stephenson DA, Chotti K, Ebeling C et al. Quantitative trait loci

affecting prion incubation time in mice. Genomics 2000;69:47–53.

RISK OF vCJD IN FRANCE 53

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