Blood transfusion risk: protecting against the unknown

In relation to viruses—which, classically, have posed the greatest potential risk to transfusion recipients—British blood is among the safest in the world. For HIV, the risk per unit of transfusion is about 1 in 2.5 million.¹ But British blood services are now faced with the challenge of managing a potential risk from the transmissible spongiform encephalopathies, notably variant Creutzfeldt-Jakob disease. This challenge is particularly difficult given the lack of firm data on either the likely scale of variant Creutzfeldt-Jakob disease infection in Britain or the likelihood that the causative agent is present in and transmissible by donated blood. The announcement by the Department of Health, following advice from the Committee on Safety of Medicines, on 26 February of “further precautionary measures” in relation to the use of British plasma in blood products brings the challenge sharply into focus.

In March 1997 the World Health Organisation concluded that there is no proved or even probable instance of transmission of Creutzfeldt-Jakob disease by blood, blood components, or plasma derivatives, though it did identify a requirement to assess further the potential risk posed to transfusion by variant Creutzfeldt-Jakob disease.² Lack of evidence of risk is not evidence of absence of risk.³ The report that PrP deposition can be identified in tonsillar biopsy specimens from patients with variant Creutzfeldt-Jakob disease suggests greater lymphoreticular involvement than that seen in classical forms of the disease.⁴ In response to these and other data the Department of Health, following the advice of the Spongiform Encephalopathy Advisory Committee, commissioned an independent risk assessment of the possibility that leucodepletion of blood components might reduce any risk of transmission of variant Creutzfeldt-Jakob disease by transfusion. The outcome of this is still awaited. This, taken in conjunction with the Committee on Safety of Medicines’ recommendations, is likely to result in fundamental changes to the provision of transfusion services and products in Britain.

The Committee on Safety of Medicines has identified several measures which together aim at both ensuring the continued availability of safe and effective plasma products and minimising the risk of exposure to variant Creutzfeldt-Jakob disease through these products. Measures include a requirement to recall products manufactured from plasma pools that include donations from individuals strongly suspected of suffering from variant Creutzfeldt-Jakob disease, thus extending previous recommendations that covered only confirmed cases. To minimise the impact of any future recalls albumin made from British plasma will no longer be used as an excipient in medicinal products, including vaccines. Recombinant factor VIII (presumably incorporating a “safe” source of human albumin stabiliser) will be made available for all new patients with haemophilia and for those aged under 16.

All medicinal products manufactured from British donor plasma will be reviewed to determine which products should in future be produced from plasma sourced from countries which do not have clusters of cases of variant Creutzfeldt-Jakob disease. The plasma fractionation centres in England and Scotland will be allowed to import plasma for onward manufacture. The Medicines Control Agency will inspect the suppliers of this plasma to determine that their source donors, even if paid, are as safe as British donors in respect of viral transmission. British transfusion specialists have long promoted voluntary unpaid donation as a mechanism for assuring the safety of blood components and products. In attempting to reduce the theoretical risk of transmitting variant Creutzfeldt-Jakob disease we need to ensure that other infectious risks are not forgotten.

The safety of fractionated products has improved greatly in recent years and is assured by a number of approaches. Meticulous donor selection procedures, careful inventory management, and testing with the polymerase chain reaction may enable plasma pools to be created from paid donors with viral loads similar to those present in pools derived from unpaid volunteers (J Reilly, data presented at conference on blood safety, Washington, 1998). When combined with specific steps in the manufacturing process to inactivate and remove viruses, such approaches will assure the safety of products in relation to viral transmission. This may not be possible for all products, and the Committee on Safety of Medicines may conclude that in some instances British plasma remains the preferred source. Anti-D immunoglobulin may fall into this category. In such cases clinical indications will need to be re-evaluated—including, for anti-D, the recent recommendations on antenatal prophylaxis.⁵

With access to alternative supplies of plasma the British fractionation centres will be able to continue production, ensuring that their facilities, expertise, and trained staff are not lost. Investment in research in this area will be needed to aid understanding of the distribution of variant Creutzfeldt-Jakob disease in blood and possible methods to remove or inactivate the agent. Hopefully in time it will be possible to resume processing of British plasma.

How will this be judged? New cases of variant Creutzfeldt-Jakob disease in the population are meticulously monitored, and epidemiologists will refine models to predict the likely size of any epidemic and when it may peak following the removal of infected beef from the food chain. Understandably, huge interest has been generated by the report of a monoclonal antibody that can discriminate between normal and abnormal prion protein.⁶ It is hoped that this may lead to a test to detect infected individuals and to possibilities for affinity purification of plasma products to remove any abnormal prion protein.

This comprehensive package of precautionary measures has obvious resource implications. Just as these precautions should be seen in the light of the bovine spongiform encephalopathy epidemic, so, we hope, will the identification of resources. With reorganised blood services striving to improve consistency and good practice while finding efficiency savings, new policies should not detract from other areas of blood safety. We have a difficult message to convey to blood recipients and to blood donors: British blood is safe, but we are always seeking ways of making it safer. One of our first challenges following these announcements is to persuade donors that they are still urgently needed and that, as always when we have needed them, they should continue coming forward to give their blood.

News p 726