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From: TSS ()
Subject: Source of Variant Creutzfeldt-Jakob Disease outside United Kingdom
Date: July 12, 2007 at 9:45 am PST

Source of Variant Creutzfeldt-Jakob Disease outside United Kingdom

Pascual Sanchez-Juan,*† Simon N. Cousens,‡ Robert G. Will,§ and Cornelia M. van Duijn*
*Erasmus Medical Center, Rotterdam, the Netherlands; †University Hospital “Marqués de Valdecilla,” Santander,
Spain; ‡London School of Hygiene and Tropical Medicine, London, UK; and §Western General Hospital,
Edinburgh, UK

We studied the occurrence of variant Creutzfeldt-Jakob disease (vCJD) outside the United
Kingdom in relation to the incidence of indigenous bovine spongiform encephalopathy (BSE) and
to the level of live bovines and bovine products imported from the UK during the 1980s and the
first half of the 1990s. Our study provides evidence that a country’s number of vCJD cases
correlates with the number of live bovines it imported from the UK from 1980 to 1990 (Spearman
rank correlation coefficient [rs] 0.73, 95% confidence interval [CI] 0.42–0.89, p<0.001). Similar
correlations were observed with the number of indigenous BSE cases (rs 0.70, 95% CI 0.37–
0.87, p = 0.001) and carcass meat imported from the UK from 1980 to 1996 (rs 0.75, 95% CI
0.45–0.89; p<0.001) Bovine imports from the UK may have been an important source of human
exposure to BSE and may have contributed to the global risk for disease.
In 1996 a new variant of Creutzfeldt-Jakob disease (vCJD) was described in the
United Kingdom (1). By September 2006, 196 cases had been reported worldwide; most
(162, 83%) occurred in the UK. Laboratory and epidemiologic studies provide strong
circumstantial evidence for a causal link between vCJD and the bovine spongiform
encephalopathy (BSE) epizootic in cattle (2,3) with the most likely route of primary human
infection being through dietary exposure to highly infected bovine tissues (3).
In recent years, vCJD has been identified in a number European countries with
indigenous outbreaks of BSE, including 20 cases of vCJD in France, 4 in Ireland, 2 in the
Netherlands, and single cases in Portugal, Italy, and Spain. A growing number of cases of
vCJD have also been identified in countries outside Europe that have minimal incidence of
BSE, including Japan, the United States, and Canada, and also in Saudi Arabia, a country in

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which BSE has not been identified (4). Several of the non-UK patients, notably 2 Irish, 1
Canadian, 2 American, and possibly the Japanese patient, may have been infected during
periods of residence in the UK, but most cases (28 of 34) occurring outside the UK were in
persons who had never visited the UK. Although vCJD cases have occurred in countries with
very low incidence of BSE, no cases have been reported in countries with higher incidence of
BSE, such as Switzerland (460 reported cases of BSE) and Germany (395 cases) (5). This
fact raises questions as to the source of infection in the vCJD cases outside the UK. Were the
patients exposed to indigenous cases of BSE or to infected bovine material imported from the
UK? An analysis of infection risk in France suggests that the most likely source of vCJD in
that country is imported infected material from the United Kingdom (6). In the Republic of
Ireland, the transmission of BSE to humans was estimated to be equally likely from
indigenous BSE or from UK imports (7). Given the apparently weak association between the
occurrence of indigenous BSE and vCJD in some countries, we studied the occurrence of
vCJD cases outside the UK in relation to the level of imported bovines and bovine products
from the UK during the 1980s and the first half of the 1990s.


A European Union (EU) surveillance network, established in 1993, ensures
prospective surveillance for CJD by using standard methods (8) in 18 European countries and
the United States, Canada, Israel, and Australia. By August 24, 2006, 32 cases of vCJD had
been identified in these countries (excluding the UK) (Table 1). Two more cases had been
identified in countries outside the surveillance network, Japan and Saudi Arabia. Casepatients
in Canada (n = 1), the United States (n = 2), Ireland (n = 2), and possibly Japan
(n = 1) were considered as likely to have been infected during periods of residence in the UK.
Data on indigenous BSE cases detected by both passive and active surveillance were
obtained from the World Organization for Animal Health webpage
( (5). The number of live cattle and the tonnage of
carcass meat exported from the UK were derived from UK Custom and Excise Data (9).
We included in our analysis all countries covered by the EU surveillance network.
Because exposure was expressed as a total amount rather than per capita, we based the
analysis on number of vCJD cases rather than rates. We plotted the incidence of vCJD
(number of cases) by country against the following factors: 1) number of cases of indigenous
BSE, 2) number of live bovines imported from the United Kingdom from 1980 to 1990, and

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3) tonnage of carcass meat imported from the United Kingdom from 1980 to 1996. For the
last 2 plots, we used logarithmic scales to improve visualization of the data.
We have included carcass meat data until 1996, when all UK bovine imports were
banned by the EU. However, for live bovine imports we limited our analysis to the period
1980–1990. In 1990 the EU restricted live bovine exports from the UK to animals <6 months
of age and required that the importing country must ensure that any imported cattle from the
UK were slaughtered at <6 months of age (10). For the correlation analyses, we included only
the non-UK vCJD patients who are thought likely to have acquired infection outside the UK.
A factor likely to be important for BSE exposure is the temporal distribution of UK exports.
The number of BSE-infected cattle entering the human food supply is estimated to have
peaked in the UK around 1989 (7), although with respect to exports, peak exposure may have
been later, around 1992–1993. For example, 85% of Germany’s imports of UK carcass meat
between 1980 and 1990 were before 1988. In contrast, 70% of the livestock imports to the
Netherlands were from 1987 through 1990. To account for this fact, we weighted the number
of live bovines and the carcass meat tonnage imported each year by the size of the UK BSE
epizootic that year (reported clinical cases) and normalized the data by the maximum number
of BSE cases detected in a year during the epizootic. Nonparametric Spearman rank
correlation coefficients (rs) were calculated to evaluate whether evidence of a correlation
between exposure and outcome existed.


Figure 1 shows a scatter plot of the number of cases of indigenous BSE in non-UK
countries and the number of non-UK vCJD cases per country. Although the confidence
intervals (CIs) are wide, evidence of a correlation between these 2 variables (rs 0.70, 95% CI
0.37–0.87, p = 0.001) exists in the countries belonging to the EU network (Table 2). When
we included in our analysis Japan and Saudi Arabia, the only 2 countries outside the EU
network in which vCJD cases have been detected, the correlation coefficient fell to 0.55 (95%
CI 0.17–0.79, p = 0.008) (Table 2). Non-UK vCJD cases in EU network countries were also
correlated with the number of live bovine imports from the UK (Figure 2; rs 0.73, 95% CI
0.42–0.89, p<0.001) and the amount of carcass meat imported from the UK (Figure 3; rs 0.75,
95% CI 0.45–0.89, p<0.001). Including Japan and Saudi Arabia produced similar results (live
bovines rs 0.65, 95% CI 0.31–0.84; carcass meat rs 0.73, 95% CI 0.45–0.88) (Table 2).

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We evaluated whether our findings were dependent on the data from France, which
has the largest number of non-UK cases, by repeating the analyses excluding France.
Evidence remained that all 3 exposures were correlated with vCJD incidence (Table 2). We
also repeated the analysis including the 6 cases detected outside the UK but thought to have
been acquired in the UK. The inclusion of these cases resulted in a reduction in all 3
correlation coefficients (Table 2).


Live bovine and carcass meat imports from the United Kingdom during the 1980s and
the first half of the 1990s correlate with the numbers of vCJD cases in countries outside the
United Kingdom. This finding suggests that live bovine and/or carcass meat imports from the
UK may have been an important source of exposure in at least some of the countries in which
vCJD has been detected. These results are consistent with an analysis of data from France,
which suggested that UK bovine imports were likely to have been a more important source of
infection than indigenous BSE (6). Thus, a proportion of cases observed to date outside the
UK may have been acquired through imports from the UK rather than by the patients’
exposure to indigenous BSE. The inclusion in the analysis of the 6 non-UK case-patients
thought to be infected in the UK reduced all 3 correlation coefficients, as one would expect if
the supposition that they were infected in the UK is correct.

These findings come with several important caveats. First, they are based on small
numbers of vCJD cases. Even a small number of additional non-UK cases in the future could
alter the findings substantially. Furthermore, we have not performed multivariable analyses to
determine which of the 3 exposures of interest were correlated with vCJD incidence because
we were concerned that the small number of cases might lead to unreliable results. Second,
the analyses of imports are based on UK Customs and Excise data, not all of which been
validated by importing countries. Even if these data are reasonably accurate, the actual level
of BSE infection entering the human food chain in importing countries cannot be estimated
because many important unknown variables exist, such as the age distribution of imported
live bovines, the age at slaughter of these animals, the culinary habits in each country, and the
possibility that some of the UK imports may have been re-exported to other countries. Third,
indigenous BSE-infected cattle entering the food supply will have gone undetected until the
introduction throughout the EU of the active abattoir testing program for BSE in 2000/2001;
even now, cattle in the early stages of infection are unlikely to be detected. Furthermore, the

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efficiency of BSE surveillance varies from country to country: underascertainment is likely in
those countries with limited or no active testing programs.
It is noteworthy that none of the 162 UK patients with vCJD identified up to
September 2006 were born after 1989, the year in which the specified bovine offal ban was
introduced to minimize human exposure to BSE; however, 2 of the 34 non-UK vCJD casepatients
were born after 1989. Measures equivalent to the UK ban on specified bovine offals
were not introduced in many continental European countries until 2000.
Despite these caveats, our results suggest that, globally, imports from the UK may
have been an important source of infection and for some countries may even have been the
main source. If this is so, our findings have several implications. Past UK exports may be the
major determinant of the current incidence of vCJD outside the UK. The greatest volume of
these exports was to France, the Netherlands, and Ireland. Thus, initially at least, we might
expect the largest number of vCJD cases to occur in these countries. However, exposure to
BSE through imports from the UK ceased in 1996, and exposure to indigenous BSE is likely
to have continued at some level until the measures introduced in 2000. Thus, the proportion
of vCJD cases due to exposure to indigenous BSE may increase with time.


We specially thank our colleagues from the European and Allied Countries Collaborative Study Group
of CJD (EUROCJD) and our international colleagues for the data on vCJD incidence included in this article.
The EUROCJD surveillance system is funded by the Directorate General for Health and Consumer
Affairs (2003201) and the Neuroprion Network of Excellence (FOOD-CT-2004-506579). National CJD
surveillance is supported in the Netherlands by the Dutch Ministry of Health Welfare and Sports. P.S.-J. was
supported by the grant Wenceslao Lopez Albo from the Marques de Valdecilla Institute for Formation and
Research of the Fundación Pública Marqués de Valdecilla.
Dr Sánchez-Juan is a consultant neurologist. Since 2004 he has been coordinating the Dutch CJD
surveillance system at the Department of Epidemiology and Biostatistics, Erasmus MC, Rotterdam, the
Netherlands. His main research interests are prion diseases and the genetic epidemiology of neurodegenerative



IT will be interesting, with time, what the answer for the increase in sporadic CJD in the USA, with unknown phenotype strain growing, and it's relationship, with the BASE and or atypical BSE TSE in USA cattle. ...

1997 TO 2006. SPORADIC CJD CASES TRIPLED, with phenotype
of 'UNKNOWN' strain growing. ...

18 January 2007 - Draft minutes of the SEAC 95 meeting (426 KB) held on 7
December 2006 are now available.


64. A member noted that at the recent Neuroprion meeting, a study was
presented showing that in transgenic mice BSE passaged in sheep may be more
virulent and infectious to a wider range of species than bovine derived BSE.

Other work presented suggested that BSE and bovine amyloidotic spongiform
encephalopathy (BASE) MAY BE RELATED. A mutation had been identified in the


There is a growing number of human CJD cases, and they were presented last
week in San Francisco by Luigi Gambatti(?) from his CJD surveillance

He estimates that it may be up to 14 or 15 persons which display selectively
SPRPSC and practically no detected RPRPSC proteins.

sporadic CJD, and the UK BSE nvCJD only hypothesis

see full text ;

kindest regards,

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