Controlling New Prion Diseases

Controlling New Prion Diseases

May 19, 2001 New 
England Journal of Medicine by Raymond P. Roos, M.D.
Like the murrain -- the fifth plague in the biblical story of Exodus, which targeted cattle -- a new prion disease called Bovine Spongiform Encephalopathy (BSE) has had a devastating impact. Millions of cattle have been destroyed and billions of dollars spent throughout the world. The socioeconomic, political, and public health toll has been staggering.

In this issue of the Journal, Prusiner (1) describes prions, the infectious proteins that are responsible for this group of diseases. He also proposes that abnormally processed proteins such as prions cause other neurodegenerative diseases. Prions have remarkable properties for a pathogen: transmissibility with a very long incubation period (e.g., an average of five years for BSE in cows and possibly more than a decade for new variant Creutzfeldt-Jakob disease, a form of BSE transmitted to humans), absence of immunogenicity, and resistance to inactivation and to protease digestion. The unusual properties of prions have posed challenges for surveillance and control.

BSE originated in the United Kingdom in the 1980s, probably from cattle feed that was initially contaminated with tissue from sheep infected with scrapie, a prion disease in sheep and goats. (2,3) Remnants of slaughtered cattle that had fed on the infected material were then used as a source for feed, resulting in the continual recycling of material from BSE-infected cattle back into feed. These conditions allowed the prion to adapt to cattle.

Changes in rendering procedures (in which the carcass is processed after the removal of readily consumable parts) may have allowed the maintenance of sufficiently high prion levels for efficient transmission. Although the number of cases of BSE in cattle has decreased substantially over time in the United Kingdom (from a high of over 37,000 cases in 1992 to 1537 in 2000), cases have recently been identified in other countries, in part through the use of immunologic screening tests. These countries include Germany, Ireland, and France (with 7 cases, 145 cases, and 161 cases, respectively, in 2000). (4)

Initially, there was a false sense of security with respect to the risk of the transmission of BSE to humans. Epidemiologic studies had found no link between scrapie and the sporadic form of Creutzfeldt-Jakob disease (the most common prion disease in humans), which appears to occur spontaneously throughout the world. It is now apparent that the properties of the BSE agent are distinct from those of other prions. Approximately 100 cases of new variant Creutzfeldt-Jakob disease, a new disease that causes dementia and has distinctive neuropathological features, have been reported since 1996. (3,5) All these cases have been in the United Kingdom, except for two confirmed and one probable case in France and one confirmed case in Ireland.

There is compelling evidence of the transmission of new variant Creutzfeldt-Jakob disease to humans, probably through the consumption of meat contaminated with BSE-infected central nervous system tissue.

To date, there is no evidence of BSE or new variant Creutzfeldt-Jakob disease in the United States. To limit the spread of BSE, in 1989 the U.S. Department of Agriculture banned the importation of live ruminants (cud-chewing animals, including cows and sheep) and most ruminant products from countries with known cases of BSE. In 1997, the ban was extended to apply to countries deemed to have inadequate animal-import restrictions or surveillance, which included all the European countries. The live-ruminant ban has been successful; the relatively small number of sheep and cattle imported before the ban have virtually all been accounted for.

Some biomedical products that contain or have been exposed to ruminant-derived materials from countries on this BSE list are still in use in the United States, including some vaccines that contain products such as fetal-calf serum. However, the risk of transmission of prions from vaccines seems remote for several reasons. The oral and parenteral routes of vaccination are relatively inefficient for transmission. The bovine-derived material is present in extremely small amounts, is unlikely to have been derived from an infected cow, and comes from tissues that are unlikely to be very infectious with respect to BSE (e.g., blood). Finally, epidemiologic data suggest that new variant Creutzfeldt-Jakob disease is not transmitted through vaccination.

Despite the presumed safety of vaccines, the Food and Drug Administration (FDA) has requested that manufacturers use bovine-derived products only from countries that are not on the BSE list. To avoid the perception of a risk of prion disease from vaccination, these measures must be enforced. An additional concern (6) involves the relative lack of regulation of dietary supplements with tissue or gland extracts (e.g., from the pituitary) containing bovine central nervous system tissue that may come from countries on the BSE list. New laws are needed to control the importation of these products.

The Department of Agriculture has had a screening program for BSE since 1990. Neuropathological examinations have been performed on more than 12,000 U.S. cattle that exhibited neurologic signs before slaughter, such as difficulty walking ("downer" cattle). All the results were negative. Screening should be extended to include a much larger proportion of the more than 150,000 downer cattle in the United States each year, including cattle that die before they are slaughtered. Some asymptomatic animals older than four years of age should also be tested, since prions accumulate over time in the infected host and are therefore easier to detect in older animals.

Screening should be performed with immunologic tests similar to those used in Europe (e.g., an enzyme-linked immunosorbent assay or Western blot assay for the detection of protease-resistant prion protein). (7) The use of such tests would lower the cost of screening and permit rapid, large-scale analyses. Such tests, however, had not been approved for use in the United States as of April 2001.

The Department of Agriculture should establish and enforce guidelines for the slaughter of cattle in order to decrease the chance of contamination of meat with infected central nervous system tissue. These guidelines should address methods of killing, early removal of the spinal cord from the carcass, and waste disposal (e.g., the use of chemicals to inactivate prions as well as to decrease the huge volume of potentially infected waste).

To limit widespread transmission of BSE from contaminated feed, as occurred in the United Kingdom, the FDA in 1997 banned most mammalian proteins from ruminant feed. This ban is not sufficiently comprehensive: blood, gelatin, and "plate waste" (i.e., leftover food from restaurants) should not be exempted, as they currently are. The FDA inspects facilities such as feed mills and rendering plants to confirm compliance with the ban and to ensure that cattle feed is not commingled with rendered material from cattle (which is still used as feed for nonruminants, such as chickens and pigs). Approximately 25 percent of these facilities initially failed inspection, although later inspections showed much better compliance. To provide greater safety and eliminate the need for inspections, all rendered material from cows should be banned from use in any feed.

The emergence of new variant Creutzfeldt-Jakob disease in the United Kingdom led to enhanced surveillance for human prion diseases by the Centers for Disease Control and Prevention (CDC). (8) A registry of human prion disease has been established with the use of data on causes of death, such as information from death certificates. In collaboration with Case Western Reserve University, in Cleveland, the CDC established a national surveillance center, which performs neuropathological examinations and immunologic tests for prion protein in brain tissue.

In addition, a cerebrospinal fluid assay is performed for 14-3-3 protein, a member of a large family of regulatory and binding proteins that is a proposed marker for Creutzfeldt-Jakob disease (but distinct from the prion protein). A better test than the assay for 14-3-3 protein needs to be developed, since levels of this protein are frequently normal in persons with new variant Creutzfeldt-Jakob disease and may be increased in both sporadic cases of Creutzfeldt-Jakob disease and nonprion diseases. (9)

Although no patient with new variant Creutzfeldt-Jakob disease has been identified among those thought to have a prion disease, ascertainment of cases has been incomplete. Autopsies are performed infrequently in patients with prion diseases, at least in part because of concern about safety on the part of pathologists. To improve surveillance, physicians should be aware of current monitoring efforts. Autopsies should be performed in all cases of prion disease in order to identify "florid plaques" (1) and on that basis diagnose new variant Creutzfeldt-Jakob disease definitively. This effort should be facilitated by the subsidy of the associated costs and the establishment of regional pathology centers to assist with or conduct autopsies.

The safety of the blood supply has received special attention, since studies suggest that prions are present in blood and bone marrow in BSE and in lymphoid tissues in new variant Creutzfeldt-Jakob disease. (10) If blood products such as intravenous immune globulin were contaminated, they could lead to widespread infection, since they are prepared from huge pools of donors and are administered to many recipients. On the other hand, the absence of cases of new variant Creutzfeldt-Jakob disease among patients with hemophilia is reassuring. (11) At present, potential blood donors in the United States who have clinical features resembling those of new variant Creutzfeldt-Jakob disease are excluded from the pool of donors, and any blood or blood product from a donor in whom new variant Creutzfeldt-Jakob disease subsequently develops is destroyed.

In order to address the risk of blood donation from normal persons who have been exposed to BSE but also to avoid life-threatening blood shortages, potential donors who have lived in the United Kingdom for six or more cumulative months between 1980 and 1996 are excluded. Extending this policy to people who have lived in other European countries is prudent, given the increase in the numbers of cases of BSE. Such exclusions should also be considered for donors of other tissues, especially dura mater and corneas collected after death. These tissues are easily contaminated with central nervous system tissue, which could cause iatrogenic Creutzfeldt-Jakob disease if the donor had unrecognized disease. (12)

The long incubation period for prion diseases still makes it uncertain how extensive the outbreak of new variantCreutzfeldt-Jakob disease will be. It is clear, however, that we need strong safeguards. Federal regulatory agencies must intensify programs of surveillance and control. These efforts will require additional funding, and a high priority should be given to the development of diagnostic tests for case surveillance and screening of donors. In addition, an advisory committee on prion disease needs to be established as an independent umbrella group, with representatives from the federal regulatory agencies, academia, industry, and the public. Such a committee could address issues that overlap or fall between the jurisdictions of the individual agencies and provide overall guidance.

Raymond P. Roos, M.D. , University of Chicago,Pritzker School of Medicine, Chicago, IL 60637

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