Trcmsfirsion Medicine. 1996. 6, 2 13-2 I5

EDITORIAL

Prion disease and blood transfusion

This edition of Transfusion Medicine contains an article by S . Dealler outlining his personal assessment of the potential risk of bovine spongiform encephalo- pathy (BSE) to humans posed by blood transfusion in the UK (Dealler, 1996). This is particularly timely given the recent report from the CJD Surveillance Unit in Edinburgh of 10 cases of a new variant form of Creutzfeldt-Jakob disease (CJD) and a possible aetiological linkage with BSE (Will et al., 1996).

CJD is a rare disease with an incidence of approxi- mately one per million population (Collinge & Rosser, 1996). The majority of cases occur sporadically, some are inherited - so called familial CJD - and others have been attributed to the transfer of infectious material (Brown et al., 1992). These latter cases are largely related to the administration of pituitary- derived hormones. Pituitary-derived growth hormone and pituitary-derived gonadotrophins used in the management of infertility have both been associated with subsequent development of CJD. The disease has also been transmitted from implantation of dura mater and following corneal transplants. Acquired, or iatrogenic, CJD is of particular relevance to Trans- fusion Services since it demonstrates that the disease can be transmitted by therapeutic agents, and that transmission can occur via peripheral routes as well as by direct intracerebral inoculation. Inevitably this raises the question of the possibility that CJD and other forms of prion disease might be transmitted by transfusion of blood or blood products.

The biology of these diseases has recently been reviewed (Prusiner, 1995). Scientific opinion favours the ‘prion hypothesis’ whereby the disease is caused by the presence of an abnormal form of a naturally occurring protein. The existence of ‘proteinacious infectious particles’ (prion proteins) as a causative agent of spongiform encephalopathies was first postulated by Prusiner and subsequent work has demonstrated that these infections can be transmitted in the absence of nucleic acid, thus differentiating them from viruses. Prion proteins are remarkably resistant to normal virus inactivation procedures. In prion disease the natural protein (PrP protein) is converted into an abnormal form (termed PrP scrapie, the prion protein). The prion protein appears to be capable of converting normal PrP protein which has a

0 1996 Blackwell Science Ltd

multiple helical structure into the abnormal variant where much of the back bone structure straightens out, thus setting up a cascade and build up of the abnormal form. The abnormal PrP may arise by random change in a normal individual, as occurs in sporadic CJD. In familial CJD a point mutation in the DNA coding for the protein leads to an increased susceptibility to formation of the abnormal protein form. These observations are of relevance to transfu- sion. If the pion protein is present in the blood of asymptomatic individuals harbouring the disease then the protein could be transmitted by transfusion and this could occur in sporadic and familial forms as well as in iatrogenic disease. Thus in theoretical terms the underlying aetiology may be less relevant in the context of the ability to transmit the disease by transfusion. This will be important when considering possible mechanisms for minimizing the risk of trans- mission of CJD by this route.

Transmission of prion disease between different animal species can occur. This appears to be limited by a ‘species barrier’. Different forms of prion protein presumably differ in their capacity to transform normal human PrP into the abnormal prion protein. This issue is discussed by Dealler in his article when considering whether BSE poses a risk to humans. The possibility that the newly described variant of CJD might represent a human form of BSE raises two issues for transfusion. Firstly, once BSE has been able to produce disease in man the species barrier would not be of relevance in the context of onward transmission by transfusion. Secondly, the transmission characteristics of variant CJD may differ significantly from those of the classical form of the disease. In this particular setting the absence of documented trans- mission of CJD by transfusion cannot be taken as evidence that the new disease cannot be transmitted by this route.

Two main sources of evidence exist which may enable us to determine the likelihood that prion disease might be transmitted by blood. This involves data arising from studies in the experimental mouse model and secondly information from epidemiological studies.

Experimental data has demonstrated that the prion agent is present in buffy coat cells of infected animals

213

214 Editorial

(Manuelidis et al., 1985). This involved direct intra- cerebral inoculation of infected cells. Peripheral inoculation, i.e. into the blood stream, has not been associated with development of disease in animal studies (Brown, 1995). No data on the risk of transfusion of plasma appear to be available. These data should be viewed with caution and the results may not necessarily pertain to the potential risk of transmission of CJD, or indeed BSE, by transfusion in man.

A number of published studies have reviewed the epidemiological characteristics of reported cases to determine whether transfusion may be a possible source of prion disease in man. Esmonde et al. (1993) reviewed 202 cases of CJD reported to the CJD surveillance unit in Edinburgh. There was no excess of cases with a history of blood transfusion or indeed donation of blood. It was concluded that blood transfusion is not a significant risk factor for CJD. Klein & Dumble (1993) reported four cases of CJD that had occurred in Australian recipients of blood transfusion and highlighted the need to establish effective surveillance of this particular disease to enable an accurate assessment of risk to be under- taken. Heye et al. (1994) reported a lookback study of recipients of an individual donor who subsequently developed CJD. Recipients of 35 out of 55 donations could be identified, of whom nine were alive at the time of study. No evidence of transmission of CJD was found. There has been no reported case of CJD in multiply exposed haemophiliacs despite many years of treatment with fractionated coagulation concentrates. Operalski 8c Mosley (1995) cite such evidence as indicating that such products do not pose a risk for prion transmission. Creange et al. (1996) however, describe a case of CJD arising in a recipient of a liver transplant who received human albumin solution; one of the donors contributing to the pool was subsequently diagnosed as having probable CJD.

In summary, the experimental evidence, although limited, identifies a theoretical risk that prion disease might be transmitted by transfusion. There is, how- ever, no clear evidence that this has occurred. The paucity of data is of concern and it is important that steps are now taken to establish effective surveillance of reported cases of CJD, particularly so in the light of the reported possible linkage of BSE to the newly described variant of CJD within the UK. The absence of information in this area restricts our ability to provide definitive reassurance to potential recipients of transfusion. The absence of evidence of transmission does not equate to an absence of risk, particularly so in a low-incidence disease such as CJD.

Transfusion Services have a responsibility to take

reasonable steps to prevent inadvertent transmission of infections. In the absence of diagnostic assays suitable for use in the transfusion setting the only effective mechanism currently available to minimize the risk is by the exclusion of individuals considered to be at higher risk of acquiring the disease. Transfusion Services in the US and Europe exclude potential donors who have received treatment with human- derived pituitary hormones. Within the UK, human growth hormone recipients have been excluded since 1989 and recipients of pituitary-derived gonadotrophin since 1993. Exclusion of recipients of dura mater and corneal transplants is undertaken in some countries as is exclusion of donors. with a family history of CJD. The potential impact of this latter exclusion should not be underestimated. In contrast to recipients of pituitary-derived hormones, such individuals will not have received counselling in relation to any increased risk and this particular exclusion will need to be very sensitively handled to avoid unnecessary concern being caused. Inevitably the introduction of donor exclusion criteria in this area will result in established donors being identified who are deemed to be ' at risk'. This will result in notifications to plasma fractionators. Different views on the requirement for action have been taken by regulatory authorities in Europe and the United States. Interim guidance from the FDA in the United States requires plasma pools which contain donations from implicated donors to be quarantined, and fractionated product must only be issued for therapeutic use if withholding them would result in an inability to meet clinical needs (FDA, 1995). Within Europe there is currently no requirement to take such action. These different approaches are perhaps symptomatic of the paucity of reliable scientific data relating to transfusion and prion disease. The inconsistent approaches will present problems to manufacturers of fractionated plasma products and will need to be addressed. Most importantly, we must take urgent steps to over- come this lack of information to enable future decisions to be evidence based. In particular, we require evidence that CJD, especially the putative bovine- passaged variant, does not transmit to experimental animals by the intravenous route, regardless of dose. Naturally, these types of investigations would be greatly helped if a convenient test for the rapid diagnosis of CJD could be developed.

REFERENCES

Brown, P. (1995) Can Creutzfeldt-Jakob disease be trans- mitted by transfusion. Current Opinion in Haematology, 2,

0 1996 Blackwell Science Ltd. Transfusion Medicine, 6, 2 13-2 15

412-411.

Editorial 2 1 5

Brown, P., Preece, M.A. & Will, R.G. (1992) Friendly fire in medicine: hormones, homografts, and Creutzfeldt-Jakob disease. Lancet, 340, 24-27.

Collinge, J. & Rossor, M. (1996) A new variant of Prion disease. Lancet, 347, 1996- 1997.

Creange, A., Gray, F., Cesaro, P. & Degos, J. (1996) Pooled plasma derivatives and Creutzfeldt-Jakob disease. Lancet, 347,482.

Dealler, S . (1996) A matter for debate: the risk of bovine spongioform encephalopathy to humans posed by blood transfusion in UK. Transfusion Medicine, 6, 217-222.

Esmonde, T.F.G., Will, R.G., Slattery, J.M., Knight, R., Harries-Jones, R., De Silva, R. & Matthews, W.B. (1993) Creutzfeldt-Jakob disease and blood transfusion. Lancet,

FDA (1995) Food and Drug Administration's special Advisory Committee on Creutzfeldt-Jakob disease. June 22, Bethesda, Maryland, USA.

Heye, N., Hensen, S. & Muller, N. (1994) Creutzfeldt- Jakob disease and blood transfusion. Lancet, 343,298-289.

Klein, R. & Dumble, L.J. (1993) Transmission of Creutz-

341,205-207.

feldt-Jakob disease by blood transfusion. Lancet, 341, 768.

Manuelidis, E.E., Kim, J.H., Mericangas, J.R. & Manuel- idis, L. (1985) Transmission to animals of Creutzfeldt- Jakob disease from human blood. Lancet, 2, 896-897.

Operalski, E.A. & Mosley, J.W. (1995) Pooled plasma deri- vatives and Creutzfeldt-Jakob disease. Lancet, 346, 1224.

Prusiner, S.B. (1995) The prion diseases. Scientific Amer- ican, 30-37.

Will, R.G., Ironside, J.W.,' Zeidler, M., Cousens, S.N., Estibeiro, K., Alperovitch, A., Poser, S., Pocchiari, M., Hofman, A. & Smith, P.G. (1996) A new variant of Creutzfeldt-Jakob disease in the UK. Lancet, 347,921-925.

PETER FLANAGAN. AND JOHN A.J. BARBARAT *Leeds Blood Centre,

Bridle Path,

and f North London Blood Centre, Colindale Avenue,

London NW9 SBG, UK.

Lee& LS1S 7TW

0 1996 Blackwell Science Ltd, TransJrsion Medicine, 6, 213-215