- Email: [email protected]
Bovine Spongiform Encephalopathy☆
Bovine Spongiform Encephalopathy☆ RG Will, Western General Hospital, Edinburgh, UK ã 2014 Elsevier Inc. All rights reserved.
Introduction BSE Clinical and Subclinical Infection The Origin of BSE Epidemiology Variant CJD Clinical and Subclinical Infection The Origin of vCJD Epidemiology
1 1 1 2 2 4 4 4 4
Introduction Bovine spongiform encephalopathy (BSE) is a prion disease of cattle, which was first identified in 1986, and has subsequently become a source of widespread concern for policymakers and public health. To date, more than 184 000 cases have been identified in the UK and more than 5000 cases in other countries, primarily, but not exclusively, in Europe. The origin of BSE is unknown, but may have been related to scrapie contamination of cattle feed, with amplification of the epidemic through within-species recycling of infection. Legislative measures, including restrictions on the feeding of ruminant protein to ruminants, has led to a marked decline in annual numbers of identified cases in all countries, and it is likely that the introduction and implementation of appropriate control measures will lead to the eradication of BSE. In 1996, a new form of human prion disease, variant Creutzfeldt–Jakob disease (vCJD), was identified in the UK, and epidemiological and laboratory data indicate that this disease is a zoonosis caused by infection with BSE, probably through past dietary exposure to infection. The human population in the UK and many European countries were exposed to significant titers of BSE infectivity over a period of years from about 1980, but the possibility of an extensive epidemic of vCJD has not materialized. There has been a relatively limited and declining annual mortality rate in the UK and, with the exception of France, only isolated cases in other, mainly European, countries. However, future outbreaks of vCJD, perhaps related to polymorphisms in the human prion protein gene (PRNP), cannot be excluded and concern for public health has continued with the demonstration of transmission of vCJD through blood transfusion. Accurate predictions of future numbers of cases are hampered by many uncertainties including the mean incubation period of human BSE infection and the prevalence of sub- or preclinical infection in exposed populations.
BSE Clinical and Subclinical Infection All prion diseases are degenerative conditions of the central nervous system and present with progressive and fatal neurological disorders. The clinical features of BSE include weight loss, reduced milk yield, ataxia and hyperesthesia, progressing to recumbency and death. Although there is a wide age range of affected cattle, the majority of cases are aged 4–6 years. Identification of clinically affected animals is critical to analysis of the epidemiology of BSE and for protection of public health, but depends on recognition of the clinical phenotype or active testing in abattoirs. As in other prion diseases, BSE has a protracted incubation period, in BSE a mean of about 5 years prior to the onset of clinical signs, and infectivity may be present in some tissues, particularly in the pre-terminal stages. However, the tissue distribution of infectivity in BSE is relatively restricted in comparison to other prion diseases such as sheep scrapie. Effective protection of public health depends on accurate case identification in the field or testing for the presence of disease in the abattoir to prevent clinically unrecognized cases entering the human food chain. Passive surveillance for BSE has proved to be a relatively inefficient strategy for case identification and varies by country according to available skills and resources and the size of the cattle population. Active testing for BSE in abattoirs by examination of the obex region of the brain stem for disease-associated prion protein (PrPSc) has proved to be a reliable method of identifying infected animals. This has allowed more precise information on the course of the BSE epidemic, although the costs of systematic testing of cattle populations are significant and the testing regimes in many countries are becoming less stringent with the decline in the number of identified cases. ☆
Change History: July 2014. RG Will updated Figures 1, 2, 3 and Table 1. Text updated in a number of places to provide up to date data.
Reference Module in Biomedical Research
http://dx.doi.org/10.1016/B978-0-12-801238-3.02540-X
1
2
Bovine Spongiform Encephalopathy
Infectivity in prion diseases is not restricted to the central nervous system and may involve peripheral tissues, particularly in the lymphoreticular system, in which the agent replicates during the incubation period prior to neuroinvasion and clinical disease. In order to minimize human exposure to infection from preclinical or unrecognized clinical cases, many countries have introduced a ban on certain bovine tissues from entering the human food chain from apparently healthy cattle. A ‘specified bovine offal’ ban was introduced in the UK in 1989 and an extended list of tissues, the ‘specified risk materials’ in other European countries in 2000. Implementation and enforcement of these measures is essential to protect public health in countries with a significant risk of human exposure to BSE. The original list of proscribed tissues was based on information from previous studies in sheep scrapie, but experimental pathogenesis studies have subsequently provided information on the tissue distribution of infectivity in BSE during the incubation period and in the clinical phase. Infectivity in BSE can be identified in tonsil at 10 months after challenge, in terminal ileum after 6–18 months, in the dorsal root ganglia at 32 months, with clinical onset and involvement of brain at 35 months. Many tested tissues have been negative by bioassay in mice and a restricted range of tissue by similar studies in cattle, indicating that the anatomical distribution of BSE is relatively restricted in comparison to other prion diseases such as sheep scrapie. A more extensive tissue involvement in BSE, including involvement of sciatic nerve, has been suggested by the development of more sensitive techniques for the identification of either PrPSc or infectivity.
The Origin of BSE BSE was first identified in the UK in 1986 and epidemiological investigation indicated that the disease was a common source epidemic caused by infection in cattle feed in the form of meat and bone meal. This hypothesis has been strongly supported by the decline in the BSE epidemic in the UK about 5 years after a ban on feeding ruminant protein to cattle and the effectiveness of similar measures in other countries. The original hypothesis was that the initial source of infection was sheep scrapie, which had been inadvertently included in cattle feed, and that sufficient levels of infection had been present to cross the ‘species barrier’ between sheep and cattle. Circumstantial evidence of a change in the production methods for meat and bone meal in the 1970s provided an explanation for the timing of the initial cases and the subsequent extensive epidemic was attributed to subsequent recycling of infected cattle tissues to cattle. An alternative hypothesis for the origin of BSE is that this was due to the development of spontaneous disease in a single animal, which was used in the production of meat and bone meal and recycling of infection within the cattle population resulted in an epidemic. The true origin of BSE is unknown and will probably never be established with certainty. However, any hypothesis must be consistent with the origin of BSE in the UK rather than any other country. The UK had a large sheep population, a high incidence of scrapie, and a practice of feeding meat and bone meal to calves. If spontaneous BSE actually occurs, by analogy with sporadic CJD, the probability of a spontaneous case will be proportionate to the size of the cattle population and that in the UK was smaller than some other countries such as the USA, Australia, and New Zealand, and the latter two countries are believed to be free of classical scrapie and BSE.
Epidemiology The first cases of BSE in the UK probably occurred in the early 1980s and the subsequent epidemic peaked in 1992 and then declined as a result of the ban on feeding ruminant protein to ruminants, introduced in the UK in 1988 (Figure 1). At its peak, more
Figure 1 Annual number of cases of BSE identified in the UK. Data from OIE Website.
Bovine Spongiform Encephalopathy
3
than 30 000 clinical cases were identified annually by passive surveillance, although it is likely that there was under-ascertainment of cases, particularly in the early years of the epidemic and before the introduction of an active abattoir testing program. In addition, mathematical models suggest that at least 1 000 000 preclinically infected cattle may have entered the human food chain in the 1980s prior to the introduction of measures to minimize human exposure to BSE. To date, more than 40 000 affected cattle born after the introduction of the ruminant feed ban have been identified, indicating that this measure was not fully enforced. There is no good evidence of alternative vertical or lateral routes of transmission in BSE. A likely explanation for these cases is that meat and bone meal was still being fed to other species such as pigs and poultry and that cross contamination in feed mills resulted in continuing cattle exposures. A reinforced feed ban, prohibiting the feeding of meat and bone meal to any farmed species, was introduced in 1996 and only 178 cases of BSE born after this date have been identified, possibly linked to importation of animal feed. An experimental challenge study in BSE has shown that as little as 1 mg of infected brain is sufficient to cause infection by the oral route. It is of note, however, that the BSE epidemic continues to decline and in 2013 there were only 3 cases in the UK. Live cattle and bovine products, including cattle feed, were exported from the UK in the 1980s and early 1990s and from other European countries in later years. It is likely that the risk of cattle exposure to BSE has a widespread geographical distribution. BSE was identified in Ireland in 1989, in Portugal and Switzerland in 1990, in France in 1991, and has subsequently been identified in all original member states of the European Union (EU). A ban on feeding ruminant protein to ruminants was introduced in the EU in 1994 and an SRM ban in 2000, although some countries introduced these measures earlier. In contrast to the UK, the passive surveillance system appears to have been relatively inefficient in identifying cases of BSE in most countries (with the exception of Switzerland), and it was with the introduction of a mandatory abattoir testing program in 2000–01 that some countries first identified indigenous BSE (e.g., Denmark, Germany, Italy, and Spain), with resulting extensive public concern. It is likely that cases of BSE may not have been identified in preceding years and the true size of BSE outbreaks in some counties, although limited in relation to the size of the UK epidemic, is unknown. In recent years, there has been a decline in the number of cases in all European countries (Figure 2), underlining the importance of introducing and enforcing measures to prevent the recycling of infection within cattle populations. Cases of BSE have been found in small numbers in non-European countries, including Canada (19), Israel (1), Japan (36), and the USA (3, including 1 that originated in Canada). Despite the limited numbers of these cases, their identification has had important implications for trade. The possibility that risk of BSE may have been widely disseminated has resulted in a recommendation that all countries carry out a risk assessment, taking into account the possibility of importation of relevant risk materials and the possibility of recycling infection within cattle populations. Active abattoir testing for BSE can be an efficient means of identifying cases of BSE, but the precise populations to be tested, that is, normal slaughter, fallen stock, casualty animals, etc., and the numbers of required tests in specific populations are controversial. In the EU in 2005 over 10 000 000 cattle were tested at a cost of 45 euros per test, with 561 positives. New and atypical forms of BSE have been identified through the active testing programs, Cases of a novel form of BSE defined by a differential neuropathology and biochemical prion protein characteristics, H and L type bovine spongiform encephalopathy, were first recognized in Italy, and subsequently a small number of cattle with brain prion protein characteristics different from both the Italian cases and BSE itself have been found, mainly in Europe. The total number of atypical BSE cases identified is currently
Figure 2 Annual number of cases of BSE identified in some European countries. Data from OIE Website.
4
Bovine Spongiform Encephalopathy
over 60 and the majority are in the older age groups (>10 years) and most had no clinical signs. The origin of these cases is unknown and the implications for human health, if any, are uncertain.
Variant CJD Clinical and Subclinical Infection vCJD presents clinically with psychiatric symptoms, including depression and withdrawal, followed after a mean of 6 months by progressive ataxia and cognitive impairment, associated with involuntary limb movements. The mean survival is 14 months. vCJD affects younger age groups than in sporadic Creutzfeldt–Jakob disease (sCJD) with a mean age at death of 29 years (range 16–74 years), and it has been proposed that this may be related to either age-related susceptibility or variation in dietary exposure by age. All tested definite and probable clinical cases have been methionine homozygotes at codon 129 of the human prion protein gene (PRNP). The pathogenesis of vCJD is distinct from other human prion diseases as there is evidence of significant involvement of peripheral tissues and in particular the lymphoreticular system, including lymph nodes, spleen, appendix, and tonsil, in addition to the central nervous system. Infectivity is also present in peripheral nerves and large intestine and PrPSc in enteric plexus, adrenal, ileum, and skeletal muscle. Infectivity may be present in some peripheral tissues during the incubation period and act as a source of potential secondary iatrogenic infection, for example, through blood transfusion. The prevalence of sub- or preclinical infection has not been established with certainty in any population, but anonymized screening of appendectomy specimens in the UK has led to estimates that there may be a minimum prevalence of infection of 493 per million, translating to about 30 000 individuals in the age group 10–30 years who are currently infected, taking account of the age distribution of those from whom specimens were sourced. Positive appendix specimens were found in all codon 129 genotype, suggesting that individuals of all genetic backgrounds may be susceptible to infection with BSE.
The Origin of vCJD The hypothesis of a causal link between BSE and vCJD is supported by a range of evidence. The clinical and pathological phenotypes are remarkably consistent and distinct from previous experience. The characteristic neuropathological findings, including widespread deposition of florid plaques of PrPSc, have not been recognized previously in human prion disease, and review of archive tissues in a number of countries has failed to identify any case with the typical pathological phenotype prior to the identification of vCJD in the UK. Retrospective review of deaths certified under a range of rubrics and review of neuropathology in a limited number of these cases have failed to identify past cases of unrecognized vCJD. This evidence strongly suggests that vCJD is a new disease. Laboratory studies have demonstrated that the infectious agent in vCJD is almost identical to the BSE agent in terms of incubation period and brain lesion distribution in experiments carried out on wild-type and transgenic mice. The biochemical characteristics of the PrPSc deposited in the brain in vCJD are similar to BSE and distinct from other human prion diseases. Macaque monkeys inoculated experimentally with BSE develop florid plaques similar to those in vCJD. These studies indicate that the BSE agent is the cause of vCJD. It has been proposed that BSE-infected humans through past dietary exposure, probably to high-titer bovine tissues and, in particular, spinal cord, dorsal root ganglia, and products containing mechanically recovered meat. Direct evidence of this hypothesis is lacking, not least because of the difficulties in investigating exposures that may have taken place years or even decades in the past. Furthermore, details of dietary history are necessarily obtained from surrogate witnesses because of the cognitive impairment that develops in vCJD. A case–control study comparing dietary exposures in cases of vCJD and age-matched population controls is consistent with increased risk through past oral intake of food products likely to have contained high levels of BSE infectivity, but the potential biases in this study compromise any firm conclusions. It is however of note that the mortality rate of vCJD is approximately double in the north when compared to the south of the UK, and this may reflect regional differences in past dietary exposures. Neither descriptive analyses nor case–control studies have provided evidence of any plausible alternative route of BSE exposure in vCJD cases, including past occupation or previous surgery. The occurrence of a novel form of human prion disease, vCJD, in a country with a potentially new risk factor, BSE, first raised the possibility that these conditions were linked. Importantly, data from a harmonized system for surveillance of CJD in Europe indicated, in 1996, at the time vCJD was first found in the UK, that similar cases had not been identified in other countries. Improved efficiency of surveillance in the UK was therefore unlikely to explain the identification of this new disease. Subsequently, cases of vCJD have been found in other countries, but the fact that some of the cases occurred in countries with a very limited risk of exposure to indigenous BSE and had a history of residence in the UK during the time of maximal human exposure to BSE supports the concept that BSE is indeed the cause of vCJD.
Epidemiology Up to June 2014, 177 cases of vCJD have been identified in the UK, all but three of which are presumed to be related to past dietary exposure to BSE. The annual number of deaths from vCJD in the UK peaked in 2000 with 28 cases and has subsequently declined to
Bovine Spongiform Encephalopathy
5
Figure 3 Number of vCJD deaths per annum (UK).
Table 1
Country UK France Rep. of Ireland Italy USA Canada Saudi Arabia Japan Netherlands Portugal Spain Taiwan
Number of vCJD cases per country (June 2014) Total number of primary cases (number alive)
Total number of secondary cases: blood transfusion (number alive)
Residence in UK >6 months during period 1980–96
174(0) 27(0) 4(0)
3(0)
177 1 2
2(0) 4a(0) 2(0) 1(0)
0 2 1 0
1b(0) 3(0) 2(0) 5(0) 1(0)
0 0 0 0 1
a
The third US patient with vCJD was born and raised in Saudi Arabia and has lived permanently in the United States since late 2005. According to the US case report, the patient was most likely infected as a child when living in Saudi Arabia. b The case from Japan had resided in the UK for 24 days in the period 1980–96.
5 deaths in 2011 and only 1 death since (Figure 3). Fears of a large epidemic have receded, but there remains the possibility of further outbreaks of cases related to BSE infection in individuals with a heterozygous or valine homozygous genotype at codon 129 of PRNP and it is possible that such cases may occur with an extended incubation period and perhaps with a different clinical and pathological phenotype. It is also likely, by analogy with other human prion diseases such as kuru, that there will be an extended tail to the epidemic with a low annual number of deaths for years or even decades. Cases of vCJD have been found in a number of other countries, mainly, but not exclusively, in Europe (Table 1). To date, 27 cases have been identified in France with a peak in annual deaths some 5 years later than in the UK, consistent with a mathematical model which attributes the French cases to exposure to exports of BSE-infected materials from the UK rather than to indigenous BSE. Cases of vCJD are attributed by country according to the country of normal residence at the time of the onset of clinical symptoms. This does not necessarily correlate with the country in which exposure to BSE took place and it is of note that 2/4 US cases, 2/4 Irish cases, and 1/2 Canadian cases and the single case in Taiwan all had a history of extended residence in the UK during 1900–96 and were probably exposed to BSE in the UK rather than the country of attribution. The third US case had lived for most of his life in the country of origin, Saudi Arabia, and a further case has been identified from this country, which is not known to have BSE. One possibility is that human BSE exposure was related to exports from the UK, a matter of concern as exports from the UK and other European countries were distributed worldwide. The single case of vCJD in Japan could be related to this factor, although the individual had also spent a short period of time in the UK. Although measures to minimize human exposure to high-
6
Bovine Spongiform Encephalopathy
titer bovine tissues were introduced in continental Europe more than 10 years after the UK, it is likely that the total number of vCJD cases in other countries will be significantly less than in the UK. Concerns about the public health implications of BSE and vCJD have increased with the identification of transfusion transmission of vCJD. Four recipients of non-leucodepleted red cells, donated by individuals who later developed vCJD, have either developed vCJD (n ¼ 3) or have become sub- or preclinically infected (n ¼ 1). In the latter case, an individual who died of an intercurrent illness was found to have immunostaining for PrPSc in spleen and one lymph node. The three clinical cases were methionine homozygotes and the preclinical case a heterozygote at codon 129 of PRNP, thus indicating that methionione homozygotes are not the only ones susceptible to secondary infection. In all four instances of transmission of infection by blood transfusion, the donation had been given months to years prior to clinical onset in the donor, indicating that infection is present in blood during the incubation period. The three clinical cases developed symptoms between 6 and 9 years after transfusion, and it is of note that the four infections developed out of a total cohort of 26 individuals who survived at least 5 years after transfusion, indicating that this route is an efficient mechanism of transmitting vCJD infection from person to person. Although transfusion transmission of vCJD has only been identified in the UK, individuals with vCJD who had previously donated blood have been found in France, Spain, Ireland, and Saudi Arabia. There is no firm evidence, to date, of secondary transmission of vCJD through plasma-derived products, contaminated surgical instruments, or vertically from mother to child and, although risk assessments suggest that the risks by some of these routes are limited, the period of observation is currently too short to exclude the possibility of alternative routes of transmission in the future, taking account of the potentially extended incubation periods in these diseases. A range of measures have been introduced in many countries to limit the risks of secondary transmission of vCJD, including, for example, deferral of blood donors with a history of extended residence in the UK.
Further Reading Bradley R (1998) An overview of the BSE epidemic in the UK. Developments in Biological Standard 93: 65–72. Brown P, McShane LM, Zanusso G, and Detwiler L (2007) On the question of sporadic or atypical bovine spongiform encephalopathy and Creutzfeldt–Jakob disease. Emerging Infectious Diseases 12(12): 1816–1821. Collee JG and Bradley R (1997a) BSE: A decade on – Part 1. Lancet 349: 636–641. Collee JG and Bradley R (1997b) BSE: A decade on – Part 2. Lancet 349: 715–721. Cousens S, Everington D, Ward HJT, Huillard J, Will RG, and Smith PG (2003) The geographical distribution of variant Creutzfeldt–Jakob disease in the UK: What can we learn from it? Statistical Methods in Medical Research 12: 235–246. Hewitt PE, Llewelyn CA, Mackenzie J, and Will RG (2006) Creutzfeldt–Jakob disease and blood transfusion: Results of the UK Transfusion Medicine Epidemiology Review study. Vox Sanguins 91: 221–230. Hilton DA, Ghani AC, Conyers L, et al. (2004) Prevalence of lymphoreticular prion protein accumulation in UK tissue samples. Journal of Pathology 203: 733–739. Kimberlin RH (1996) Speculations on the origin of BSE and the epidemiology of CJD. In: Gibbs CJ Jr. (ed.) Bovine spongiform encephalopathy: The BSE dilemma, pp. 155–175. New York: Springer. Valleron A-J, Boelle P-Y, Will R, and Cesbron J-Y (2001) Estimation of epidemic size and incubation time based on age characteristics of vCJD in the United Kingdom. Science 294: 1726–1728. Ward HJT, Everington D, Cousens SN, et al. (2006) Risk factors for variant Creutzfeldt–Jakob disease: A case-control study. Annals of Neurology 59: 111–120. Wells GAH, Scott AC, Johnson CT, et al. (1987) A novel progressive spongiform encephalopathy in cattle. Veterinary Record 121: 419–420. Wilesmith JW, Ryan JBN, and Atkinson MJ (1991) Bovine spongiform encephalopathy: Epidemiological studies of the origin. Veterinary Record 128: 199–203. Wilesmith JW, Wells GAH, Cranwell MP, and Ryan JB (1988) Bovine spongiform encephalopathy: Epidemiological studies. Veterinary Record 123: 638–644. Will RG, Ironside JW, Zeidler M, et al. (1996) A new variant of Creutzfeldt–Jakob disease in the UK. Lancet 347: 921–925. World Health Organisation, Food and Agricultural Organisation, Office International des Epizooties, Technical Consultation on BSE: Public health, animal health, and trade. (2002).
Relevant Website oie.int http://www.oie.int – OIE website.
Introduction BSE Clinical and Subclinical Infection The Origin of BSE Epidemiology Variant CJD Clinical and Subclinical Infection The Origin of vCJD Epidemiology
1 1 1 2 2 4 4 4 4
Introduction Bovine spongiform encephalopathy (BSE) is a prion disease of cattle, which was first identified in 1986, and has subsequently become a source of widespread concern for policymakers and public health. To date, more than 184 000 cases have been identified in the UK and more than 5000 cases in other countries, primarily, but not exclusively, in Europe. The origin of BSE is unknown, but may have been related to scrapie contamination of cattle feed, with amplification of the epidemic through within-species recycling of infection. Legislative measures, including restrictions on the feeding of ruminant protein to ruminants, has led to a marked decline in annual numbers of identified cases in all countries, and it is likely that the introduction and implementation of appropriate control measures will lead to the eradication of BSE. In 1996, a new form of human prion disease, variant Creutzfeldt–Jakob disease (vCJD), was identified in the UK, and epidemiological and laboratory data indicate that this disease is a zoonosis caused by infection with BSE, probably through past dietary exposure to infection. The human population in the UK and many European countries were exposed to significant titers of BSE infectivity over a period of years from about 1980, but the possibility of an extensive epidemic of vCJD has not materialized. There has been a relatively limited and declining annual mortality rate in the UK and, with the exception of France, only isolated cases in other, mainly European, countries. However, future outbreaks of vCJD, perhaps related to polymorphisms in the human prion protein gene (PRNP), cannot be excluded and concern for public health has continued with the demonstration of transmission of vCJD through blood transfusion. Accurate predictions of future numbers of cases are hampered by many uncertainties including the mean incubation period of human BSE infection and the prevalence of sub- or preclinical infection in exposed populations.
BSE Clinical and Subclinical Infection All prion diseases are degenerative conditions of the central nervous system and present with progressive and fatal neurological disorders. The clinical features of BSE include weight loss, reduced milk yield, ataxia and hyperesthesia, progressing to recumbency and death. Although there is a wide age range of affected cattle, the majority of cases are aged 4–6 years. Identification of clinically affected animals is critical to analysis of the epidemiology of BSE and for protection of public health, but depends on recognition of the clinical phenotype or active testing in abattoirs. As in other prion diseases, BSE has a protracted incubation period, in BSE a mean of about 5 years prior to the onset of clinical signs, and infectivity may be present in some tissues, particularly in the pre-terminal stages. However, the tissue distribution of infectivity in BSE is relatively restricted in comparison to other prion diseases such as sheep scrapie. Effective protection of public health depends on accurate case identification in the field or testing for the presence of disease in the abattoir to prevent clinically unrecognized cases entering the human food chain. Passive surveillance for BSE has proved to be a relatively inefficient strategy for case identification and varies by country according to available skills and resources and the size of the cattle population. Active testing for BSE in abattoirs by examination of the obex region of the brain stem for disease-associated prion protein (PrPSc) has proved to be a reliable method of identifying infected animals. This has allowed more precise information on the course of the BSE epidemic, although the costs of systematic testing of cattle populations are significant and the testing regimes in many countries are becoming less stringent with the decline in the number of identified cases. ☆
Change History: July 2014. RG Will updated Figures 1, 2, 3 and Table 1. Text updated in a number of places to provide up to date data.
Reference Module in Biomedical Research
http://dx.doi.org/10.1016/B978-0-12-801238-3.02540-X
1
2
Bovine Spongiform Encephalopathy
Infectivity in prion diseases is not restricted to the central nervous system and may involve peripheral tissues, particularly in the lymphoreticular system, in which the agent replicates during the incubation period prior to neuroinvasion and clinical disease. In order to minimize human exposure to infection from preclinical or unrecognized clinical cases, many countries have introduced a ban on certain bovine tissues from entering the human food chain from apparently healthy cattle. A ‘specified bovine offal’ ban was introduced in the UK in 1989 and an extended list of tissues, the ‘specified risk materials’ in other European countries in 2000. Implementation and enforcement of these measures is essential to protect public health in countries with a significant risk of human exposure to BSE. The original list of proscribed tissues was based on information from previous studies in sheep scrapie, but experimental pathogenesis studies have subsequently provided information on the tissue distribution of infectivity in BSE during the incubation period and in the clinical phase. Infectivity in BSE can be identified in tonsil at 10 months after challenge, in terminal ileum after 6–18 months, in the dorsal root ganglia at 32 months, with clinical onset and involvement of brain at 35 months. Many tested tissues have been negative by bioassay in mice and a restricted range of tissue by similar studies in cattle, indicating that the anatomical distribution of BSE is relatively restricted in comparison to other prion diseases such as sheep scrapie. A more extensive tissue involvement in BSE, including involvement of sciatic nerve, has been suggested by the development of more sensitive techniques for the identification of either PrPSc or infectivity.
The Origin of BSE BSE was first identified in the UK in 1986 and epidemiological investigation indicated that the disease was a common source epidemic caused by infection in cattle feed in the form of meat and bone meal. This hypothesis has been strongly supported by the decline in the BSE epidemic in the UK about 5 years after a ban on feeding ruminant protein to cattle and the effectiveness of similar measures in other countries. The original hypothesis was that the initial source of infection was sheep scrapie, which had been inadvertently included in cattle feed, and that sufficient levels of infection had been present to cross the ‘species barrier’ between sheep and cattle. Circumstantial evidence of a change in the production methods for meat and bone meal in the 1970s provided an explanation for the timing of the initial cases and the subsequent extensive epidemic was attributed to subsequent recycling of infected cattle tissues to cattle. An alternative hypothesis for the origin of BSE is that this was due to the development of spontaneous disease in a single animal, which was used in the production of meat and bone meal and recycling of infection within the cattle population resulted in an epidemic. The true origin of BSE is unknown and will probably never be established with certainty. However, any hypothesis must be consistent with the origin of BSE in the UK rather than any other country. The UK had a large sheep population, a high incidence of scrapie, and a practice of feeding meat and bone meal to calves. If spontaneous BSE actually occurs, by analogy with sporadic CJD, the probability of a spontaneous case will be proportionate to the size of the cattle population and that in the UK was smaller than some other countries such as the USA, Australia, and New Zealand, and the latter two countries are believed to be free of classical scrapie and BSE.
Epidemiology The first cases of BSE in the UK probably occurred in the early 1980s and the subsequent epidemic peaked in 1992 and then declined as a result of the ban on feeding ruminant protein to ruminants, introduced in the UK in 1988 (Figure 1). At its peak, more
Figure 1 Annual number of cases of BSE identified in the UK. Data from OIE Website.
Bovine Spongiform Encephalopathy
3
than 30 000 clinical cases were identified annually by passive surveillance, although it is likely that there was under-ascertainment of cases, particularly in the early years of the epidemic and before the introduction of an active abattoir testing program. In addition, mathematical models suggest that at least 1 000 000 preclinically infected cattle may have entered the human food chain in the 1980s prior to the introduction of measures to minimize human exposure to BSE. To date, more than 40 000 affected cattle born after the introduction of the ruminant feed ban have been identified, indicating that this measure was not fully enforced. There is no good evidence of alternative vertical or lateral routes of transmission in BSE. A likely explanation for these cases is that meat and bone meal was still being fed to other species such as pigs and poultry and that cross contamination in feed mills resulted in continuing cattle exposures. A reinforced feed ban, prohibiting the feeding of meat and bone meal to any farmed species, was introduced in 1996 and only 178 cases of BSE born after this date have been identified, possibly linked to importation of animal feed. An experimental challenge study in BSE has shown that as little as 1 mg of infected brain is sufficient to cause infection by the oral route. It is of note, however, that the BSE epidemic continues to decline and in 2013 there were only 3 cases in the UK. Live cattle and bovine products, including cattle feed, were exported from the UK in the 1980s and early 1990s and from other European countries in later years. It is likely that the risk of cattle exposure to BSE has a widespread geographical distribution. BSE was identified in Ireland in 1989, in Portugal and Switzerland in 1990, in France in 1991, and has subsequently been identified in all original member states of the European Union (EU). A ban on feeding ruminant protein to ruminants was introduced in the EU in 1994 and an SRM ban in 2000, although some countries introduced these measures earlier. In contrast to the UK, the passive surveillance system appears to have been relatively inefficient in identifying cases of BSE in most countries (with the exception of Switzerland), and it was with the introduction of a mandatory abattoir testing program in 2000–01 that some countries first identified indigenous BSE (e.g., Denmark, Germany, Italy, and Spain), with resulting extensive public concern. It is likely that cases of BSE may not have been identified in preceding years and the true size of BSE outbreaks in some counties, although limited in relation to the size of the UK epidemic, is unknown. In recent years, there has been a decline in the number of cases in all European countries (Figure 2), underlining the importance of introducing and enforcing measures to prevent the recycling of infection within cattle populations. Cases of BSE have been found in small numbers in non-European countries, including Canada (19), Israel (1), Japan (36), and the USA (3, including 1 that originated in Canada). Despite the limited numbers of these cases, their identification has had important implications for trade. The possibility that risk of BSE may have been widely disseminated has resulted in a recommendation that all countries carry out a risk assessment, taking into account the possibility of importation of relevant risk materials and the possibility of recycling infection within cattle populations. Active abattoir testing for BSE can be an efficient means of identifying cases of BSE, but the precise populations to be tested, that is, normal slaughter, fallen stock, casualty animals, etc., and the numbers of required tests in specific populations are controversial. In the EU in 2005 over 10 000 000 cattle were tested at a cost of 45 euros per test, with 561 positives. New and atypical forms of BSE have been identified through the active testing programs, Cases of a novel form of BSE defined by a differential neuropathology and biochemical prion protein characteristics, H and L type bovine spongiform encephalopathy, were first recognized in Italy, and subsequently a small number of cattle with brain prion protein characteristics different from both the Italian cases and BSE itself have been found, mainly in Europe. The total number of atypical BSE cases identified is currently
Figure 2 Annual number of cases of BSE identified in some European countries. Data from OIE Website.
4
Bovine Spongiform Encephalopathy
over 60 and the majority are in the older age groups (>10 years) and most had no clinical signs. The origin of these cases is unknown and the implications for human health, if any, are uncertain.
Variant CJD Clinical and Subclinical Infection vCJD presents clinically with psychiatric symptoms, including depression and withdrawal, followed after a mean of 6 months by progressive ataxia and cognitive impairment, associated with involuntary limb movements. The mean survival is 14 months. vCJD affects younger age groups than in sporadic Creutzfeldt–Jakob disease (sCJD) with a mean age at death of 29 years (range 16–74 years), and it has been proposed that this may be related to either age-related susceptibility or variation in dietary exposure by age. All tested definite and probable clinical cases have been methionine homozygotes at codon 129 of the human prion protein gene (PRNP). The pathogenesis of vCJD is distinct from other human prion diseases as there is evidence of significant involvement of peripheral tissues and in particular the lymphoreticular system, including lymph nodes, spleen, appendix, and tonsil, in addition to the central nervous system. Infectivity is also present in peripheral nerves and large intestine and PrPSc in enteric plexus, adrenal, ileum, and skeletal muscle. Infectivity may be present in some peripheral tissues during the incubation period and act as a source of potential secondary iatrogenic infection, for example, through blood transfusion. The prevalence of sub- or preclinical infection has not been established with certainty in any population, but anonymized screening of appendectomy specimens in the UK has led to estimates that there may be a minimum prevalence of infection of 493 per million, translating to about 30 000 individuals in the age group 10–30 years who are currently infected, taking account of the age distribution of those from whom specimens were sourced. Positive appendix specimens were found in all codon 129 genotype, suggesting that individuals of all genetic backgrounds may be susceptible to infection with BSE.
The Origin of vCJD The hypothesis of a causal link between BSE and vCJD is supported by a range of evidence. The clinical and pathological phenotypes are remarkably consistent and distinct from previous experience. The characteristic neuropathological findings, including widespread deposition of florid plaques of PrPSc, have not been recognized previously in human prion disease, and review of archive tissues in a number of countries has failed to identify any case with the typical pathological phenotype prior to the identification of vCJD in the UK. Retrospective review of deaths certified under a range of rubrics and review of neuropathology in a limited number of these cases have failed to identify past cases of unrecognized vCJD. This evidence strongly suggests that vCJD is a new disease. Laboratory studies have demonstrated that the infectious agent in vCJD is almost identical to the BSE agent in terms of incubation period and brain lesion distribution in experiments carried out on wild-type and transgenic mice. The biochemical characteristics of the PrPSc deposited in the brain in vCJD are similar to BSE and distinct from other human prion diseases. Macaque monkeys inoculated experimentally with BSE develop florid plaques similar to those in vCJD. These studies indicate that the BSE agent is the cause of vCJD. It has been proposed that BSE-infected humans through past dietary exposure, probably to high-titer bovine tissues and, in particular, spinal cord, dorsal root ganglia, and products containing mechanically recovered meat. Direct evidence of this hypothesis is lacking, not least because of the difficulties in investigating exposures that may have taken place years or even decades in the past. Furthermore, details of dietary history are necessarily obtained from surrogate witnesses because of the cognitive impairment that develops in vCJD. A case–control study comparing dietary exposures in cases of vCJD and age-matched population controls is consistent with increased risk through past oral intake of food products likely to have contained high levels of BSE infectivity, but the potential biases in this study compromise any firm conclusions. It is however of note that the mortality rate of vCJD is approximately double in the north when compared to the south of the UK, and this may reflect regional differences in past dietary exposures. Neither descriptive analyses nor case–control studies have provided evidence of any plausible alternative route of BSE exposure in vCJD cases, including past occupation or previous surgery. The occurrence of a novel form of human prion disease, vCJD, in a country with a potentially new risk factor, BSE, first raised the possibility that these conditions were linked. Importantly, data from a harmonized system for surveillance of CJD in Europe indicated, in 1996, at the time vCJD was first found in the UK, that similar cases had not been identified in other countries. Improved efficiency of surveillance in the UK was therefore unlikely to explain the identification of this new disease. Subsequently, cases of vCJD have been found in other countries, but the fact that some of the cases occurred in countries with a very limited risk of exposure to indigenous BSE and had a history of residence in the UK during the time of maximal human exposure to BSE supports the concept that BSE is indeed the cause of vCJD.
Epidemiology Up to June 2014, 177 cases of vCJD have been identified in the UK, all but three of which are presumed to be related to past dietary exposure to BSE. The annual number of deaths from vCJD in the UK peaked in 2000 with 28 cases and has subsequently declined to
Bovine Spongiform Encephalopathy
5
Figure 3 Number of vCJD deaths per annum (UK).
Table 1
Country UK France Rep. of Ireland Italy USA Canada Saudi Arabia Japan Netherlands Portugal Spain Taiwan
Number of vCJD cases per country (June 2014) Total number of primary cases (number alive)
Total number of secondary cases: blood transfusion (number alive)
Residence in UK >6 months during period 1980–96
174(0) 27(0) 4(0)
3(0)
177 1 2
2(0) 4a(0) 2(0) 1(0)
0 2 1 0
1b(0) 3(0) 2(0) 5(0) 1(0)
0 0 0 0 1
a
The third US patient with vCJD was born and raised in Saudi Arabia and has lived permanently in the United States since late 2005. According to the US case report, the patient was most likely infected as a child when living in Saudi Arabia. b The case from Japan had resided in the UK for 24 days in the period 1980–96.
5 deaths in 2011 and only 1 death since (Figure 3). Fears of a large epidemic have receded, but there remains the possibility of further outbreaks of cases related to BSE infection in individuals with a heterozygous or valine homozygous genotype at codon 129 of PRNP and it is possible that such cases may occur with an extended incubation period and perhaps with a different clinical and pathological phenotype. It is also likely, by analogy with other human prion diseases such as kuru, that there will be an extended tail to the epidemic with a low annual number of deaths for years or even decades. Cases of vCJD have been found in a number of other countries, mainly, but not exclusively, in Europe (Table 1). To date, 27 cases have been identified in France with a peak in annual deaths some 5 years later than in the UK, consistent with a mathematical model which attributes the French cases to exposure to exports of BSE-infected materials from the UK rather than to indigenous BSE. Cases of vCJD are attributed by country according to the country of normal residence at the time of the onset of clinical symptoms. This does not necessarily correlate with the country in which exposure to BSE took place and it is of note that 2/4 US cases, 2/4 Irish cases, and 1/2 Canadian cases and the single case in Taiwan all had a history of extended residence in the UK during 1900–96 and were probably exposed to BSE in the UK rather than the country of attribution. The third US case had lived for most of his life in the country of origin, Saudi Arabia, and a further case has been identified from this country, which is not known to have BSE. One possibility is that human BSE exposure was related to exports from the UK, a matter of concern as exports from the UK and other European countries were distributed worldwide. The single case of vCJD in Japan could be related to this factor, although the individual had also spent a short period of time in the UK. Although measures to minimize human exposure to high-
6
Bovine Spongiform Encephalopathy
titer bovine tissues were introduced in continental Europe more than 10 years after the UK, it is likely that the total number of vCJD cases in other countries will be significantly less than in the UK. Concerns about the public health implications of BSE and vCJD have increased with the identification of transfusion transmission of vCJD. Four recipients of non-leucodepleted red cells, donated by individuals who later developed vCJD, have either developed vCJD (n ¼ 3) or have become sub- or preclinically infected (n ¼ 1). In the latter case, an individual who died of an intercurrent illness was found to have immunostaining for PrPSc in spleen and one lymph node. The three clinical cases were methionine homozygotes and the preclinical case a heterozygote at codon 129 of PRNP, thus indicating that methionione homozygotes are not the only ones susceptible to secondary infection. In all four instances of transmission of infection by blood transfusion, the donation had been given months to years prior to clinical onset in the donor, indicating that infection is present in blood during the incubation period. The three clinical cases developed symptoms between 6 and 9 years after transfusion, and it is of note that the four infections developed out of a total cohort of 26 individuals who survived at least 5 years after transfusion, indicating that this route is an efficient mechanism of transmitting vCJD infection from person to person. Although transfusion transmission of vCJD has only been identified in the UK, individuals with vCJD who had previously donated blood have been found in France, Spain, Ireland, and Saudi Arabia. There is no firm evidence, to date, of secondary transmission of vCJD through plasma-derived products, contaminated surgical instruments, or vertically from mother to child and, although risk assessments suggest that the risks by some of these routes are limited, the period of observation is currently too short to exclude the possibility of alternative routes of transmission in the future, taking account of the potentially extended incubation periods in these diseases. A range of measures have been introduced in many countries to limit the risks of secondary transmission of vCJD, including, for example, deferral of blood donors with a history of extended residence in the UK.
Further Reading Bradley R (1998) An overview of the BSE epidemic in the UK. Developments in Biological Standard 93: 65–72. Brown P, McShane LM, Zanusso G, and Detwiler L (2007) On the question of sporadic or atypical bovine spongiform encephalopathy and Creutzfeldt–Jakob disease. Emerging Infectious Diseases 12(12): 1816–1821. Collee JG and Bradley R (1997a) BSE: A decade on – Part 1. Lancet 349: 636–641. Collee JG and Bradley R (1997b) BSE: A decade on – Part 2. Lancet 349: 715–721. Cousens S, Everington D, Ward HJT, Huillard J, Will RG, and Smith PG (2003) The geographical distribution of variant Creutzfeldt–Jakob disease in the UK: What can we learn from it? Statistical Methods in Medical Research 12: 235–246. Hewitt PE, Llewelyn CA, Mackenzie J, and Will RG (2006) Creutzfeldt–Jakob disease and blood transfusion: Results of the UK Transfusion Medicine Epidemiology Review study. Vox Sanguins 91: 221–230. Hilton DA, Ghani AC, Conyers L, et al. (2004) Prevalence of lymphoreticular prion protein accumulation in UK tissue samples. Journal of Pathology 203: 733–739. Kimberlin RH (1996) Speculations on the origin of BSE and the epidemiology of CJD. In: Gibbs CJ Jr. (ed.) Bovine spongiform encephalopathy: The BSE dilemma, pp. 155–175. New York: Springer. Valleron A-J, Boelle P-Y, Will R, and Cesbron J-Y (2001) Estimation of epidemic size and incubation time based on age characteristics of vCJD in the United Kingdom. Science 294: 1726–1728. Ward HJT, Everington D, Cousens SN, et al. (2006) Risk factors for variant Creutzfeldt–Jakob disease: A case-control study. Annals of Neurology 59: 111–120. Wells GAH, Scott AC, Johnson CT, et al. (1987) A novel progressive spongiform encephalopathy in cattle. Veterinary Record 121: 419–420. Wilesmith JW, Ryan JBN, and Atkinson MJ (1991) Bovine spongiform encephalopathy: Epidemiological studies of the origin. Veterinary Record 128: 199–203. Wilesmith JW, Wells GAH, Cranwell MP, and Ryan JB (1988) Bovine spongiform encephalopathy: Epidemiological studies. Veterinary Record 123: 638–644. Will RG, Ironside JW, Zeidler M, et al. (1996) A new variant of Creutzfeldt–Jakob disease in the UK. Lancet 347: 921–925. World Health Organisation, Food and Agricultural Organisation, Office International des Epizooties, Technical Consultation on BSE: Public health, animal health, and trade. (2002).
Relevant Website oie.int http://www.oie.int – OIE website.