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In the 1950s, Australia played a pivotal role in describing kuru in Papua New Guinea.¹ This devastating illness was caused by transmission of infectivity from human-to-human through cannibalistic mourning rituals involving infected brain tissue. At the peak of the kuru epidemic, more than 5% of the population practising these rituals died each year. The more recent agricultural practice of supplementing ruminant feeds with protein derived from bovine meat and bone meal (a practice differing in no substantial way from cannibalism) has resulted in the bovine-to-bovine cycle of transmission of BSE, a particularly virulent strain of this infectious protein. It is now clear that BSE has crossed the bovine-human species barrier, and that the result is the variant form of CJD (vCJD) in humans.²

The next year or so may be crucial in estimating the likely extent of the epidemic of vCJD in Europe. Last year, the number of new cases in the United Kingdom grew at the disturbing rate of 30%³ (yielding a total of more than 90 cases since the epidemic commenced in 1995), and there were approximately 20 deaths from vCJD. The source of this human pathogen has been convincingly linked to the preceding outbreak of BSE, with transmission occurring orally. Unlike the classical forms of sporadic CJD, the vCJD strain has a propensity for replication in peripheral lymphoreticular tissue.

Although the UK outbreak of BSE is now almost under control, the same can not be said for the rest of Europe, where recent evidence suggests that increasing numbers (albeit from a low base) of affected cattle are to be expected in France, Germany, Switzerland, Portugal and the Republic of Ireland (Box).⁴ As more sensitive biochemical assays become available for the detection of the disease-associated forms of the prion protein (PrP^Sc), it is likely that subclinical forms of BSE will be detected. Australia's monitoring program includes examination of diseased cattle, but there is as yet no random sampling. Ruminant protein is prohibited from entering the feed of ruminants.

In the United Kingdom, the regulatory authorities have taken unprecedented steps to reduce the risks of transmission of BSE from cattle. These include severe restrictions on all feeding of mammalian proteins to ruminants, severe restrictions on specified bovine and ovine offals entering the human food chain, and a ban on cattle over 30 months of age entering the human food chain. Further measures will be introduced to minimise the risks of establishing a reservoir of self-sustaining human-to-human infectivity, including:

• universal leukodepletion of all blood donations;

• cessation of use of UK-sourced plasma for the preparation of licensed blood products (eg, coagulation factors, albumin);

• increased levels of decontamination of surgical instruments, especially those used for neurosurgery and ophthalmic surgery;

• increased use of disposable surgical instruments, initially for tonsillectomies, but possibly extending to other equipment which comes into direct contact with tissues of known high infectivity (central nervous system, ophthalmic tissues, lymphoreticular system).

The Australian responses to this new threat have been cumulative and consistent with measures that have been progressively introduced in other countries that remain BSE-free. Surveillance mechanisms are in place to monitor the occurrence of classical forms of CJD, and to rapidly identify any cases of vCJD which might occur in people in Australia who were exposed to the disease in Europe. This is being achieved through the National CJD Case Registry (based at the Department of Pathology, University of Melbourne, and funded by the Commonwealth Department of Health and Aged Care). The CJD Case Registry also provides a diagnostic service for interpretation of brain tissue samples and a western blot test of the 14-3-3 phosphoprotein, which is present in all nerve cells and released into the extracellular space when the cells degenerate. It is measured in cerebral spinal fluid and has proven utility in the clinical diagnosis of classical forms of CJD.⁵ The CJD Case Registry is also able to examine tonsil and other lymphoid tissues, which may be biopsied for the diagnosis of vCJD, and to provide genetic tests for mutations and susceptibility for the PrP^Sc-related gene.

Of paramount importance is safety of the Australian blood supply. Concern about the risk of transmitting vCJD through blood and blood products has been rising steadily, culminating with the disclosure of infectivity in the blood of a sheep, which occurred halfway through the incubation period after it had been experimentally infected with BSE.⁶ Although no case of either classical or variant CJD has yet been linked to contamination of blood or blood product,⁷ the propensity for PrP^Sc to accumulate in the lymphoreticular system, coupled with the experimental demonstration of infectivity in blood,⁸ was sufficient to convince the Australian regulatory authorities to introduce a deferral of donations of blood from people who have lived in the United Kingdom for more than six months between 1980 and 1996. Six months was chosen by US authorities as an arbitrary interval calculated to balance reduction in risk and preserving sufficient blood donors so as not to jeopardise the blood supply. Currently, questions have been raised about extending the donor deferral to residents of other European countries with an emerging BSE problem.

The physicochemical inactivation profile of vCJD differs significantly from classical CJD. While in both types of diseases the infectious agent is likely to consist entirely of the PrP^Sc protein, the differing conformations of the protein may be the reason why the vCJD agent is more resistant to heat inactivation. As further tests on this are carried out, it may become necessary to modify current recommendations for decontamination of surgical instruments. Combining heat (134ºC) with some form of chemical inactivation (1 mol/L NaOH) may prove to be the only effective measure to assure complete sterilisation. These measures are likely to be introduced into the United Kingdom for instruments used at critical sites (brain, eyes, lymphoid tissue), together with increased use of disposable instruments. Australian authorities will need to make an independent assessment of this risk, and then implement appropriate measures.

To assist in this process, a National Health and Medical Research Council Expert Committee has been formed, and one of its immediate tasks is an analysis of risk associated with imported European beef products (eg, canned corned beef). Concurrently, the federal Chief Medical Officer has announced that these products have been suspended from importation and are to be removed from the food supply pending an analysis of any BSE-related risk. The risk from non-food items such as cosmetics and pharmaceuticals will be carefully re-evaluated.

Another lesson from the past comes from the largest outbreak of scrapie in sheep in the 1940s, which was caused by contamination of a vaccine (for louping-ill virus -- a tick-borne flavivirus causing encephalomyelitis, principally in sheep).⁹ It would therefore be prudent to monitor carefully the quality of vaccines prepared for both bovine and human use in the event that they might contain trace amounts of the infectious BSE agent. The recent recall in Ireland of a batch of oral poliovirus vaccine, in which human plasma albumin had been sourced from a pool including a donor who subsequently developed vCJD, highlights the sensitivity of this issue.¹⁰ Although the risks must have been incalculably small, it is clear that the UK regulatory authorities were not prepared to declare the risk negligible. This situation epitomises the difficulties in risk management when the absolute levels of risk are unknown, and are likely to remain unknown for the foreseeable future.

A decade or more from now, we will be able to look back with hindsight and determine whether the correct decisions were made. A judicial inquiry into the BSE epidemic in the United Kingdom has now been through this exercise, and delivered a valuable appraisal of how government, its advisory committees, and the scientific research community conducted the process of risk assessment, management and communication.¹¹ To their credit, veterinary researchers rapidly identified the nature and probable causes of the BSE epidemic within a year of its recognition, and the UK government acted swiftly to break the cycle of bovine-to-bovine transmission. However, serious deficits were identified in the way that government managed the process of assessment, management and communication of the risk to human health. In the 10-year interval between the identification of BSE and the realisation of the emergence of vCJD, the repeated warnings of medical scientific advice were not adequately managed or communicated to the general public.¹² The disastrous consequences of these failures (loss of public confidence in the beef industry, heightened suspicion of all matters related to biotechnological manipulation of foods) will resonate for at least the next decade.

The most pressing need for Australia right now is to ensure that all reasonably practical precautions for risk minimisation are implemented and adequately communicated to the public. Research into better methods of diagnosis and therapeutic strategies should be encouraged. Vigilant surveillance for all forms of CJD should be continued in the expectation that epidemiological risk factors will be elucidated. Australia, once again geographically remote from the epicentre of a major infectious calamity, may be in a prime position to answer critical questions such as cumulative dose effects and incubation periods within members of its population who have been exposed to BSE. We can learn a great deal from the hard lessons which have been visited upon our European colleagues.

Colin L Masters
Department of Pathology, University of Melbourne
Melbourne, VIC and the Mental Health Research Institute of Victoria
c.mastersATunimelb.edu.au

1. Farquhar J, Gajdusek DC, editors. Kuru: early letters and field-notes from the collection of D Carleton Gajdusek. New York: Raven Press, 1981: 338 pp.
2. Will RG, Zeidler M, Stewart GE, et al. Diagnosis of new variant Creutzfeldt-Jakob disease. Ann Neurol 2000; 47: 575-582.
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9. Gordon WS. Advances in veterinary research. Louping-ill, tick-borne fever and scrapie. Vet Rec 1946; 58: 516-520.
10. Birchard K. Concern over vCJD donor in polio-vaccine pool in Ireland. Lancet 2000; 356: 2167.
11. Phillips [Lord], Bridgeman J, Ferguson-Smith M. The BSE Inquiry: report, evidence and supporting papers of the Inquiry into the emergence and identification of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob Disease (vCJD) and the action taken in response to it up to 20 March 1996. Vol 1: Findings and conclusions. London: The House of Commons. The Stationery Office, 2000: 308 pp. (HC 887-I.)
12. Aldhous P. Inquiry blames missed warnings for scale of Britain's BSE crisis. Nature 2000; 408: 3-5.

©MJA 2001