Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal
neurodegenerative diseases that affect both humans and animals. The diseases include:
scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle (commonly called mad cow disease) and Creutzfeldt-Jakob disease (CJD) and its variant form (vCJD) in humans. The hallmark of prion diseases is the accumulation of abnormal prions in the central nervous system. The disease is characterized by neuropathology by the presence of numerous deposits or plaques known as amyloid proteins or “florid plaques” and vacuoles or holes in areas of the brain such as the cerebellum and cerebrum.[1,2] The pathogen responsible for the transmission of vCJD and all TSEs is believed to be abnormal prion.[3]

1 Prusiner SB et al. Proc Natl Acad Sci 90:10608-10612
2 Center for Disease Control and Prevention, USA, Update 2002: Bovine Spongiform Encephalopathy and Variant Creutzfeldt-Jakob Disease
3 Prusiner SB. Science 1982;216:136-144

The risk is difficult to determine due to a long incubation period from exposure to illness, the number of cases yet to develop in the UK from the high exposure rate, the sensitivity of surveillance in various countries, and the compliance with public health measures in all countries. In the UK, the current risk of vCJD from consumption of beef appears to be in the range of one case per 10 billion servings of beef.^[2]

2 Center for Disease Control and Prevention, USA, Update 2002:
   Bovine Spongiform Encephalopathy and Variant Creutzfeldt-Jakob Disease

Prions stand for proteinaceous infectious particles which are not inactivated or destroyed by
procedures that modify nucleic acids.[3] The normal cellular form, which is found in different
tissues and organs in the body, is designated PrPc and contains mainly alpha helix (about 42%)
with little beta sheet protein structure (about 3%). The normal forms are soluble in detergent,
mainly monomeric and do not exist as aggregates and can be digested by an enzyme called
proteinase K. In contrast, the abnormal prion, designated PrPSc, is rich in beta sheet (43%), is
partially resistant to digestion by proteinase K, insoluble in detergent and tends to form
aggregates or polymeric structures.[3]. Unlike viruses, bacteria, fungi and parasites, prions do not
contain deoxyribonucleic acid (DNA) or ribonucleic acid (RNA). In contrast to viruses, prions are
nonimmunogenic. They do not elicit an immune response because the host has been rendered
tolerant to PrPSc by PrPc.[4] Prions reproduce by recruiting the normal cellular isoform and
stimulating its conversion into the disease-causing isoform, PrPSc.[4,5]

3 Prusiner SB. Science 1982;216:136-144
4 Prusiner SB. Scic Am, 2004; 86-93.
5 Prusiner SB. Proc Natl Acad Sci, USA 1998;95:13363-13383

Many countries have reported cases of cattle afflicted with BSE. There have been 182 deaths in humans from vCJD, although the number of asymptomatic carriers is unknown.^[4] For information on the incidences of BSE, please see http://www.defra.gov.uk/animalh/bse/statistics/incidence.html

These figures show the number of suspect cases referred to the CJD surveillance unit in Edinburgh, and the number of deaths of definite and probable cases in the UK, up to 6th January 2006.

COUNTRY	vCJD DEATHS
Canada	1
France	13
Ireland	3
Italy	1
Japan	1
Netherlands	1
Portugal	1
Spain	1
U.S.	1
U.S. (Recent Case)	1
UK	158
Worldwide	182

4 Prusiner SB. Scic Am, 2004; 86-93. CJD Statistics: CJD Surveillance unit, Edinburgh. Update, October 1, 2004.  http:www.cjd.ed.ac.uk/figures.htm

The variant form of CJD (vCJD) is the human equivalent of BSE and is believed to be caused by the consumption of meat products contaminated with BSE. vCJD is different from the classical form of CJD. For example, the median age at death of patients with classic CJD is 68 years, and very few cases occur in persons under 30 years of age. In contrast, the median age at death of patients with vCJD in the United Kingdom is 28 years. vCJD predominantly affects younger people and has atypical clinical features, with prominent psychiatric (such as anxiety, insomnia or withdrawal) or sensory symptoms at the time of clinical manifestation of the disease.^[4,6,7,8]  In vCJD, PrPSc builds up not just in the brain but also in the lymphoid system, such as tonsils and appendix, suggesting that PrPSc enters the blood stream at some point. To date over 154 cases of vCJD deaths in people have been confirmed worldwide with most of the cases (144) occurring in the United Kingdom.^[4,9]

4 Prusiner SB. Scic Am, 2004; 86-93.
6 Hill AF et al. Lancet 1997;349:99-100.
7 Hill AF et al. Lancet 1999;353:183-189
8 Ironside et al. Lancet 200;355:1693-1694
9 CJD Statistics: CJD Surveillance unit, Edinburgh. Update, October 1, 2004.  http:www.cjd.ed.ac.uk/figures.htm

Yes, animal studies have shown that infectious prions can be transmitted to healthy animals
through transfusions from infected animals.[10,11,12] More recently, two cases of human
transmission of vCJD through transfusion of blood components from an asymptomatic donor
who subsequently developed the disease were reported.[13,14] These recent cases of vCJD
transmission through blood in human have thus dispelled any lingering doubts about blood
infectivity in humans with vCJD.[15]

10 Houston et al. Lancet 2000; 356: 999-1000
11 Hunter et al. J Gen Virol 2002; 83: 2897-2905
12 Bons et al. Transfusion 2002; 42:513-516
13 Llewelyn et al. Lancet 2004;363:417-421
14 Peden et al. Lancet 2004;364:527-529.
15 Brown P and Cervenakova L. Curr Opin Hematol 2004;11:351-356

Experimental transmission of BSE and vCJD in mice showed similarities to human vCJD.^[16,17]  Clinical illness due to vCJD was not seen before 1994 and to date no cases of vCJD have been reported in countries that are BSE-free. In addition, Western blot analysis of infectious prions from vCJD patients and BSE infected animals had similar molecular characteristics.^[18] The interval between the initial exposure (1984-86) and the onset of vCJD (1994-1996) is consistent with the known incubation period of the disease.

16 Scott MR et al. Proc Natl Acad Sci 1999; 96:15137-15142
17 Bruce et al. Nature 1997; 389:498-501
18 Collinge et al. Nature 1996; 383:685-690

vCJD, like classic CJD, has an unusually long incubation period measured in years. Generally, there are no clinical signs or symptoms of the disease present during this incubation period. A feature of the human epidemic has been the young age of most patients. A study published by Peter Bacchetti of the University of California in San Francisco concluded that the median age of victims suggest that “biologic factors peaking in the third decade of life may hasten disease.”^[19]  

19 Bacchetti P. Age and variant Creutzfeldt-Jakob disease. Emerg Infect Dis 2003;12:1611-1612

A majority of all patients tested to date have had methionine homozygosity (methionine/methionine) at the polymorphic codon 129 of the prion protein gene (PRNP). This initially suggested that people who do not carry this genotype may have increased resistance to vCJD.^[20] However, a recent report of a preclinical case of vCJD in a patient heterozygous (methionine/valine) at codon 129 of the PRNP suggests that the susceptibility to vCJD infection is not confined to the methionine homozygous PRNP genotype.  This latter observation has major implications for future estimates and surveillance of vCJD because about 50% of the UK population falls into this new group.^{[14, 21]} Together, these two genotypes comprise approximately 90% of the population.

14 Peden et al. Lancet 2004;364:527-529.
20 Center for Disease Control and Prevention, USA, Update January 20, 2004
21 Bhattacharya S. New Sci 2004;August 4-13,2459:1-4

BSE (commonly called mad cow disease) affects the brain of cattle. The BSE outbreak started in 1984-86 and may have resulted from the feeding of scrapie-containing sheep meat and bone meal (a dietary supplement prepared from parts of sheep, cattle, pigs and chickens that are processed, or rendered, for industrial use) to cattle. As infected cattle became food for other cattle, BSE began appearing throughout the UK cattle population, reaching a high of 37,000 identified cases in 1992. There is evidence that the outbreak of BSE was amplified by feeding rendered bovine meat-and-bone meal to young calves.^[22,23,24]

22 Wilesmith JW et al. Vet Rec 1991;128:199-203
23 Wilesmith JW. Semin Virol 1991;2:239-245
24 Nathanson N et al. Am J Epidemiol 1997;145:959-969

So far only cattle have been diagnosed with BSE. However, sheep are also known to be susceptible to the BSE agent by the oral route. In countries where sheep and goats had been fed contaminated feed, there may have been transmission from generation to generation.  Experimental transmissions of BSE to other animal species, except chickens and hamsters, have been reported.  However, it is important to note that no natural occurrence of BSE has been reported in other animal species beside cattle.^[23,24,26]

23 Wilesmith JW. Semin Virol 1991;2:239-245
24 Nathanson N et al. Am J Epidemiol 1997;145:959-969
26 Bradley R. Prions: A challenge for Science. Rabenau HF, Cinatl J, Doerr HW (eds):  Publisher, Karger 2001;7: pp105-144

There are currently no sensitive methods for the detection of infectious prions in potential blood donors that may be incubating the infectious agent for vCJD.^[27]

27 Brown P et al. Transfusion 1999; 39:1169-1178

To prevent the spread of BSE, severe restrictions have been placed on the importation of live ruminants such as cattle, sheep and goats, and certain ruminant products from countries where BSE is known to exist. In many European countries, public health control measures including elimination of sick animals, bans on specified risk materials and increased BSE surveillance are aimed at preventing contamination of the human food chains. vCJD transmission risk via blood transfusion is being minimized by a number of measures including a ban on blood donation from people that lived for 3 months or more in the UK between 1980 and 1996. Universal leukocyte reduction was introduced in the UK as a preventative measure to reduce the risk of transmission of vCJD through blood transfusion.^[29,30]  However, recent reports from animal studies suggest that leukocyte reduction is only about 42% effective in reducing the risk of transmission of infectious prion, since not all prions found in the blood are cell-associated.^[31] New technology that removes both leukocytes and prions are in development and have been shown to prevent the transmission of prion disease in an animal model.^[32]

29 United Kingdom Spongiform Encephalopathy Advisory Committee (SEAC) Annual Report 1997-1998:pp10.
     Department of Environment, Food and Rural Affairs:3/04 Page Street, London SW1P 4PO, England, UK.
30 Murphy MF. Transfus Med Rev 1999;13:75-83
31 Gregori L et al. Lancet 2004;364:529-531.
32 Sowemimo-Coker SO. et al. Transfusion 2003;43 Suppl:7A-8A

Most of the methods that are used to kill or inactivate pathogens in blood and blood components are not effective against infectious prions. These methods target nucleic acids components of the pathogens such as deoxyribonucleic acid and ribonucleic acid (DNA or RNA). Since prions lack nucleic acids, they are not inactivated by these technologies.

Since 1996, strong evidence has accumulated for a causal relationship between ongoing global outbreaks of bovine spongiform encephalopathy in cattle, and a prion protein related infection in humans, called variant Creutzfeld Jacob Disease or vCJD.

The BSE epidemic reached its peak in January 1993 with 1,000 new cases in cattle reported per week. The outbreak was attributed to feeding scrapie-containing meat and bone meal from sheep to cattle.

The majority of the cases have been reported in the UK, where it was first described. Almost all infected individuals in the UK are likely to have had exposure between 1980 and 1996 during the outbreak of BSE. The disease has spread beyond the UK with cases of the human disease also reported in France, Italy, Spain, Germany, Japan and in other countries.

Both human vCJD and cattle BSE are invariably fatal brain diseases, caused by similar transformed prion proteins.

The presumed route of transmission of BSE to humans is due to ingestion of meat contaminated with the BSE prion agent. The recent identification of a vCJD infected individual, who received a blood transfusion from a donor who later died of vCJD, raises the possibility that the disease can also be transfusion transmitted.

Data published by the UK CJD Health Protection Agency suggests that vCJD is in decline. However, these results should be interpreted cautiously since new evidence suggests a proportion of the UK population may be incubating vCJD and acting as blood donors.

Given the unknown time interval between exposure and symptoms, and considering the new mode of transmission via transfusion, public health authorities are faced with the complexity of estimating the size of the vCJD epidemic.

The existence of sub-clinical prion carriers raises concerns of a human-to-human wave of vCJD transmission, posing a potential threat to the safety of the blood supply. The risk of vCJD is not restricted to the UK and the examination of the history of blood donation may be required in other European countries and elsewhere.

Many countries have implemented donor deferral measures from regions with a high prevalence of BSE to reduce the risk of exposure. As a result, the donor supply has been reduced by an estimated 5% on average worldwide.

As an additional safeguard, leukodepletion of blood units is used worldwide to reduce the potential level of vCJD prions bound to white cells. Evidence to date, as shown in an animal model suggests the reduction of prions—both free and leukocyte bound ---may provide a higher margin of safety.

Pall Medical is addressing the issue of the potential for transfusion transmission of infectious prions with an innovative proprietary technology.

The novel Pall Leukotrap Affinity prion reduction filter in this model reduces leukocytes and infectious prions—both free and cell associated.

The reduction of prion proteins in blood components is a significant advance toward safer transfusions.

Blood Safety Measures that include:

• Appropriate Donor Deferral and selection
• Blood Screening for Known Pathogens
• Combined with leukoreduction and prion reduction
• Represent a New Blood Safety paradigm vital to protecting transfusion recipients from infectious threats.

US

	Centers for Disease Control and Prevention (CDC). BSE and CJD Information and Resources
	CJD Foundation (For families)
	National Institutes of Health (NIH). Creutzfeldt-Jakob Disease. NIH Institute and Center Resources.
	National Prion Disease Pathology Surveillance Center
	US Food and Drug Administration (FDA): Bovine Spongiform Encephalopathy
	US Food and Drug Administration (FDA): Transmissible Spongiform Encephalopathies Advisory Committee: Issue Summary

UK, CANADA, WHO

	Canadian Blood Service
	Department of Environment, Food and Rural Affairs. Bovine Spongiform Encephalopathy
	Department of Health: Letter to General Practitioners on vCJD
	Health Protection Agency
	National Creutzfeldt-Jakob Disease Surveillance Unit, University of Edinburgh
	Transfusion Medicine Epidemiology Review (TMER)
	World Health Organization (WHO). Variant Creutzfeldt-Jakob Disease