Epidemiology of Variant CJD and Other Human TSEs Variant CJD

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The UK National CJD Surveillance Unit (NCJDSU), Edinburgh, was established by the Department of Health in 1990 following the Southwood Committee Report (www.cjd.ed.ac.uk). At its inception, the principal aim of the NCJDSU was to identify any changes in CJD in the United Kingdom, in the wake of the cattle BSE epidemic, that could indicate transmission of BSE to man. In 1996, the NCJDSU reported the emergence of a previously unrecognised form of CJD, known as variant CJD (vCJD) (Will et al., 1996). The NCJDSU continues with UK CJD surveillance, identifying all cases of human prion disease, along with associated research: particularly to examine risk factors for all UK cases of sporadic and variant CJD, to investigate the geographic distribution of CJD, to identify mechanisms of transmission of BSE to humans, to establish short and long term trends, to evaluate potential risks of onward transmission, to identify novel forms of human prion diseases and to evaluate case definitions and diagnostic tests.

Up to 31 December 2007, 166 cases of definite or probable vCJD had been identified in the United Kingdom. Figure 5.1 shows the number of cases of vCJD in the United Kingdom by year. Seventy-three (44%) of the 166 cases were women. The median age at onset of disease was 26 years and the median age at death 28 years (compared with 66 years for the median age at onset and 67 years for the median age at death for sporadic CJD). The youngest case was aged 12 years at onset, while the oldest case was aged 74 years. To date, no case of vCJD has been identified in the United Kingdom in individuals born after 1989. The age- and sex-specific mortality rates for vCJD over the time period 1 May 1995 to 31 December 2006 are shown in Fig. 5.2. The median duration of

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Fig. 5.1 The number of deaths per year of variant CJD in the United Kingdom

Age group (years)

Mortality rates calculcated using 2001 Census

Fig. 5.2 Age- and sex-specific mortality rates of vCJD in the United Kingdom from 1 May 1995 to 31 December 2006

Age group (years)

Mortality rates calculcated using 2001 Census

Fig. 5.2 Age- and sex-specific mortality rates of vCJD in the United Kingdom from 1 May 1995 to 31 December 2006

illness from the onset of first symptoms to death was 14 months (range 6-40) compared with the median duration of illness for cases of sporadic CJD, which was 4 months (range 1-74).

In addition to the 166 cases of vCJD in the United Kingdom, there have been 41 vCJD cases diagnosed elsewhere in the world (worldwide total = 207), a small proportion of which (6) have resided in the United Kingdom for greater than 6 months between 1980 and 1996, which is considered the at risk period in the United Kingdom for exposure to BSE in diet. After the United Kingdom, France has reported the greatest number of cases, 23, but modelling predicts a limited size to the epidemic, and with a lower total than for the United Kingdom (Alperovitch & Will, 2002).

There have been four cases of transfusion association vCJD infection to date, who received blood from people who went on to develop symptoms of vCJD. Three of these individuals developed clinical vCJD (one diagnosed in 2003 and two in 2006), while the fourth died from causes unrelated to vCJD, but was found on post-mortem examination to have abnormal prion protein present in the spleen and a lymph node (2004) (Llewelyn et al., 2004; Peden, Head, Ritchie, Bell, & Ironside, 2004; Wroe et al., 2006; HPA, 2007). There is no evidence of transmission of vCJD through plasma products, surgery or dental transmission, although a risk of transmission remains with each of these routes (Ward et al., 2006).

Results from modelling the underlying incidence of diagnoses and deaths indicate that the primary epidemic reached a peak in the year 2000 (NCJDSU Annual Report, www.cjd.ed.ac.uk). It is important to note that although a peak has been passed, it is possible that there will be future peaks, possibly in other genetic groups. There is also the possibility of ongoing person-to-person spread as seen with four cases of transfusion association vCJD infection to date, who received blood from earlier cases.

To date all the vCJD cases tested have been methionine homozygous at codon 129 of the prion protein gene. Follow-up studies on patients who developed Kuru or iatrogenic CJD (human-derived growth hormone recipients) suggest that individuals who were homozygous for methionine at codon 129 developed clinical disease sooner than heterozygote (MV) or valine homozygote (VV) individuals, who have appeared less susceptible with longer incubation periods, greater than 40 years in some cases (Cervenakova et al., 1998; Clarke & Ghani, 2005; Brandel et al., 2003; Huillard d'Aignaux et al., 2002). There is no reason to believe that vCJD would behave differently from other human prion disease, therefore, it is likely that those with non-methionine homozygous codon 129 genotypes will develop clinical disease and/or sub-clinical infection. However, the numbers of cases are unlikely to be greater than those seen for methionine homozygous individuals. Evidence to support this comes from three sources. First, while all clinical cases of variant CJD tested have been methionine homozygous, the second reported instance of transfusion-transmitted variant CJD infection (who did not develop clinical vCJD, but died of other causes) was shown to have heterozygous (MV) at codon 129. In addition, two of the three patients who tested positive for abnormal protein in a retrospective study of appendices have been shown to be valine homozygous (Ironside et al., 2006). Lastly, experimental data in mouse models also suggests that heterozygosity (MV) or valine homozygosity at codon 129 predisposes to a prolonged period of sub-clinical disease (Bishop et al., 2006).

There have been many studies published with the aim of estimating the number of clinical and sub-clinical cases of vCJD using mathematical modelling techniques. At the start of the vCJD epidemic, when uncertainties were greatest, the size of the epidemic was estimated to be in the millions (Ghani, Ferguson, Donnelly, Hagenaars, & Anderson, 1998). As the primary epidemic has progressed, the estimated number of clinical cases has reduced to less than 400 cases (Clarke & Ghani, 2005). However, from a public health viewpoint, it is not only the number of clinical cases that are of interest but also the number potentially infectious with sub-clinical or pre-clinical infection.

A key factor in determining the likelihood of onward transmission from person to person is estimating the prevalence of vCJD infection in the population. Without a simple diagnostic test, such as a blood test, this is difficult, complex and costly to undertake. A retrospective, tissue-based study using stored appendix and tonsil samples was performed to estimate the prevalence of vCJD in the United Kingdom. Three appendix samples out of a total of 12,674 samples tested were found to be positive for abnormal prion protein (Hilton et al., 2002, 2004). From these results mathematical modelling has predicted an estimate of between 3,000 and 5,000 infected people (95% CI: 520-13,440) in the United Kingdom, mainly in the 10-30-year age group. It is estimated that the majority of these will have sub-clinical infection (93-96%, 95% CI: 70-99%) with only 4-6% developing clinical disease (Clarke & Ghani, 2005). However, those with infection may (or may not) have the ability to transmit the disease through invasive medical procedures, such as surgery, dentistry and through blood transfusion.

A further study is underway by the UK Health Protection Agency, the National Anonymous Tonsil Archive study, which is gathering tonsils removed through routine surgery in the United Kingdom for testing for abnormal prion protein (3000 tonsil pairs are included from the National Prion Unit, London). Interim results of 0 confirmed positives out of 45,000 tonsils tested have not altered estimates in the prevalence of vCJD in the UK population, mainly because the relatively large numbers of those tested were in birth cohorts born after the peak of the BSE outbreak, that is they were not considered to be at high risk of exposure to BSE (www.seac.gov.uk/summaries/seac100_summary.pdf).

Risk Factors for Variant CJD

Early in the vCJD epidemic, three factors predisposing to the disease became evident: residence in the United Kingdom, methionine homozygosity at codon 129 of the prion protein gene and the relative young age of the individuals compared with sporadic CJD. In addition to these, a range of hypotheses were generated concerning risk factors relating to possible routes of exposure to the BSE agent, to predisposing factors or to other unrelated possible causes of the disease, such as exposure to organophosphates. Possible routes of exposure to the BSE agent included the most likely, which was through diet, and others such as surgery, medicines, including vaccines, certain occupations having contact with cattle, meat or products manufactured from cattle/meat (for example farmers, abattoir workers, butchers and laboratory workers) and contact with animals. Factors that were considered as predisposing factors included social class, ethnicity and urban/rural residence.

A case-control study was carried out comparing the frequency of certain risk factors (including dietary, medical, surgical, occupational) in vCJD cases with the frequency in people without CJD ("controls''). The methodology of this study has been described in detail previously (Ward et al., 2006). The results showed that reported frequent consumption of beef and beef products thought likely to contain mechanically recovered or head meat, or both, including burgers and meat pies, was associated with increased risk of vCJD. There was no evidence of socio-economic differences between cases and controls to explain these findings. However, reported consumption of chicken was also more frequent in cases than controls, which may be explained by recall bias (relatives of cases remembering more detail than relatives of controls), that it was a chance finding, or there was circumstantial evidence that some chicken and pork products contained beef mechanically recovered meat. The study found no evidence of a high proportion of cases in the study being infected through occupational exposure, including farming, veterinary medicine, meat and catering industries and medical and laboratory workers, or through reported animal, pesticide or fertiliser exposure since 1980. The reported exposure of cases and controls to medical, surgical and related risk factors was similar, except for a small group of minor operations for which cases reported more frequent exposure. This possibly due to underreporting by relatives of controls. The findings of this study provide evidence supporting the dietary hypothesis as the main route of transmission of BSE to humans in the primary VCJD epidemic. However, they do not exclude the possibility of further "waves'' of the epidemic occurring due to other risks, such as, through blood transfusion and surgery.

Cooper and Bird (2002a, 2002b, 2002c) attempted to quantify the UK dietary exposure to BSE using national surveys on diet and nutrition. They based their work on the assumption that the most likely exposure to dietary BSE was through beef mechanically recovered meat (MRM) and head meat used in burgers, sausages and other meat products. Approximately 90% of MRM and 80% of head meat was reportedly used in the production of burgers. The time period between 1980 and 1996 is considered the greatest ''at risk'' period for exposure to BSE in the diet in the United Kingdom. The highest consumption overall was in males in the 1940-1969 birth cohort, followed by the post-1969 and the pre-1940 cohorts. Although exposure through the dietary route explains to some extent the relatively young age of vCJD cases, an increased susceptibility and/or shorter incubation period is also needed to account fully for the age distribution.

The geographical distribution of cases of vCJD has remained of interest in terms of determining possible common exposures and so helping to elucidate possible risk factors. It was observed that individuals living in 1991 in the ''North'' of the country (Scotland, North, Yorkshire and Humberside, North West) were about one and a half times more likely to have developed vCJD than individuals who were living in the ''South'' (Wales, West Midlands, East Midlands, East Anglia, South West, South East). The rate ratio controlling for age and sex is 1.55 (95% CI, 1.14,2.12). The difference remains when the analysis is adjusted for socio-economic status, urban/rural mix and population density. Although regional variations in diet might explain these observed differences, results of dietary analyses were inconsistent (Cousens, 2001).

The Leicestershire cluster of five cases remains the only statistically significant cluster of cases to date. The results of the investigation of the cause of the Leicestershire cluster revealed that local butchers split bovine heads and removed the brains, which was an old-fashioned, but legal, practice at the time. The same knives and other instruments that were used to split the head and remove the brains were also used to obtain cuts of meat from the rest of the carcass, which may have resulted in cross-contamination of the cuts of meat with the BSE agent, which has highest titres in the brain and central nervous system (www.hpa.org.uk/cdr/archives/2001/cdr1201.pdf). Investigations in other areas did not reveal any suggestion of similar practices as a cause of cases.

If we assume that the dietary transmission BSE was virtually removed in the United Kingdom by measures put in place by 1996, the remaining question is whether there will be further cases as a result of secondary transmission. The tissue distribution of vCJD beyond neural tissue (mainly lymphoreticular tissues) means that the secondary transmission of vCJD through invasive medical procedures, transfusion of blood components and plasma products, dentistry and organ and tissue transplantation remains a possibility and a concern. Mathematical models to predict the chances of self-sustaining epidemics from secondary transmission have been undertaken. Some scenarios involving blood transfusion have revealed that self-sustaining epidemics were possible, but, biologically implausible and, therefore, unlikely. Public health interventions, such as leucodepletion, were effective (Clarke, Will, & Ghani, 2007). Other models also predicted that vCJD would not become endemic by blood transfusion alone (Dietz et al., 2007). Scenarios involving surgery showed that self-sustaining epidemics were possible and that key factors determining the scale of the epidemic were the number of times an instrument was re-used, the infectivity and the effectiveness of cleaning of the instruments (Garske, Ward, Clarke, Will, & Ghani, 2006).

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