International press reports from Europe have highlighted growing concerns about the spread of bovine spongiform encephalopathy (BSE) or mad cow disease. BSE is a fatal brain disease affecting cattle, and the disease appears to be transmitted to humans by eating infected beef products. The human form of BSE is called variant Creutzfeldt-Jakob disease (vCJD).
The recent outbreaks of BSE in Europe are causing concern among the bleeding disorders community for several reasons:
- Published studies suggest that animal forms of vCJD may be transmissible by blood to animals (although as yet no human transmission by blood of either vCJD or classical CJD has been identified in spite of vigorous searches for cases).
- Cases of BSE are no longer limited to the United Kingdom. In recent months the number of cases of BSE has been increasing in France and elsewhere in Europe. According to the World Organization for Animal Health, internal (non-imported) BSE has been identified in 11 European countries.
- In a few countries reporting BSE in cattle herds, patients with vCJD have now been identified. These include the U.K., France, and Republic of Ireland.
- It is possible that an increase in the number of people in Europe infected with vCJD could mean an increased risk that a blood donation contaminated with vCJD may get into a plasma pool and be used in the manufacture of plasma products in countries where BSE exists.
The WFH is taking these concerns very seriously. It has recently organized a Task Force on TSEs to monitor developments and provide balanced, realistic, and timely information on vCJD and other transmissible spongiform encephalopathies (TSEs).
Agencies that regulate blood products are also taking the concerns seriously. One response by regulators is to increase bans on blood donations from people who lived or have spent time in countries where BSE has been identified. For example, many countries banned donations from people who lived or spent time in the U.K. between 1980 and 1996, and some countries, such as Canada, have extended the ban to people who have spent time in France. Similarly, in January, an Advisory Committee of the U.S. Food and Drug Administration (FDA) met to discuss whether the FDA should reconsider its policies on the suitability of blood donors who lived or traveled in countries where BSE has been identified, and to discuss the risks of CJD and vCJD transmission by human cells, tissues, and cellular and tissue-based products. The Advisory Committee recommended tightening restrictions on blood donors and donations from France, Portugal, and Ireland. The Committee decided that the number of BSE cases elsewhere in Europe was too small to justify adding those countries to the blood donation ban.
It is being recognized that restricting donations may create blood shortages, so it is very important to balance all the relevant risks and benefits to patients. As mentioned earlier, there have been no reports of vCJD transmission by blood or blood products, and no case of vCJD or classical CJD has been found in a person with hemophilia. Because the risk of transmission by blood transfusion is still theoretical, it is difficult if not impossible to estimate the level of risk of blood products.
Until a case is identified – and vigorous searches for cases continue – one of the major questions facing the global hemophilia community is: "which is the greater threat to people with hemophilia, the risk of vCJD being transmitted through blood products, or the risk of a possible shortage of concentrates?" This is a question the WFH is continuing to address as information develops. The Task Force on TSEs has just released a report on vCJD and plasma-derived products, by Dr. Albert Farrugia from the Australian National Regulatory Authority, which is summarized here.
Summary of WFH Task Force on TSEs Report
Variant CJD first appeared among persons in the U.K. in 1995. Symptoms were similar to those of the classical form of CJD, which is an extremely rare and rapidly progressive fatal disease of the brain. All patients diagnosed with vCJD had eaten meat before 1991, and it was suggested that the disease was the result of cross-species transmission of BSE caused by eating contaminated beef products. Evidence to support this hypothesis continues to accumulate.
Assessing the Risk of vCJD and Plasma-derived Products
Two primary factors affect the potential of transmitting vCJD via blood products used to treat hemophilia and von Willebrand disease:
- How much infectious agent is present in the starting plasma raw material. This will depend on the frequency of vCJD in the blood donor population and the extent to which the infectious agent in blood remains in the plasma after the blood has been separated.
- The extent to which an infectious agent in starting plasma is destroyed during the manufacturing process used to produce concentrates.
Two other factors make an accurate assessment difficult for health officials. First, it is hard to determine the level of vCJD agent in the donor population, because the extent to which BSE and vCJD have established themselves outside the U.K. is unknown. Second, the behaviour of the BSE/vCJD agent in plasma fractionation schemes is also unknown, and current assumptions are based upon experiments on animal models with usual strains of CJD. The following paragraphs summarize the current level of knowledge on these factors.
1. Potential Infectivity in European Donor Plasma
Presently, it is reasonable to base an assessment of risk on the assumption that the potential level of vCJD agent (or infectivity) in European plasma is related to the number of new cases (or incidence) of vCJD in the donor population, and that the number of cases of vCJD is related to the number of cases of BSE in the country.
Based on this assumption, four countries with confirmed cases of BSE that export plasma-derived products available for the treatment of hemophilia A, hemophilia B, and von Willebrand disease were identified: Belgium, France, Germany, and Italy. While cases of BSE have also been confirmed in Ireland and Portugal, these countries were not included because they do not export products.
The potential size of a BSE epidemic in each of the four identified countries was estimated, based on the progression of the epidemic in the U.K. and Switzerland. If a similar pattern is repeated, a BSE epidemic in Belgium can be expected to peak in 2002, and in Germany in 2005. The situation in France is more complex, and could not be predicted using this pattern. However, based on the significant increase in BSE cases in 1998, it is assumed that the BSE epidemic in France will peak around 2003-04. No prediction could be made for Italy, because non-imported BSE has only recently been detected there and numbers are still too small.
Based on available data, Dr. Farrugia formulated the following working hypotheses on European donor plasma:
- An epidemic of BSE is expected in several countries in Europe that currently contribute plasma for manufacture into hemophilia treatment products, and it is expected to peak over the next four to six years.
- A BSE epidemic may be associated with a small number of cases of vCJD, particularly in France where the consumption of contaminated meat products from the U.K. make its donor population more at risk than in other countries.
- The expected incidence of vCJD may lead to a small amount of infectious agent in plasma pools for fractionation.
- Active surveillance should allow more precise assessment of the BSE risk in Europe over the next year. In the interim, it may be assumed that besides the U.K. the highest risk of plasma donor infectivity for vCJD comes from France. The larger German donor pool, which contributes to a wide range of products, is considered to be much less affected.
2. Elimination of vCJD Agent during Manufacture of Concentrates
Based on studies on animal forms of vCJD, which have shown that the infective agent is present in the blood before the animals have symptoms, it may be assumed that a similar infectivity is present in the blood of donors in the pre-clinical phase of vCJD, that is before symptoms appear. Therefore, it is crucial that any infectious agent is eliminated in the manufacturing process. No experiments have yet been reported on the ability of plasma fractionation processes to eliminate the BSE/vCJD agent, but a growing number of studies have addressed the potential elimination of other TSEs. Current knowledge on the behaviour of TSE agents suggests that manufacturing of factor VIII and IX concentrates should lead to a great reduction or elimination of infectivity of vCJD if this agent behaves like other TSEs.
The following working hypotheses regarding manufacturing procedures of factor VIII, factor IX, and prothrombin complex concentrates (PCCs) were put forward in the WFH report:
- Since research to date indicates that infectivity is extremely low in blood, most current methodologies for the purification of plasma-derived factor VIII or IX concentrates may be expected to significantly reduce or eliminate vCJD infectivity present in a plasma pool.
- The potential safety from vCJD of PCCs may be less than for purified factor IX, as purification might be expected to eliminate a lower amount of vCJD infectivity than other methods.
- The safety of factor IX concentrates may be significantly enhanced by filtering the product through very fine filters (nanofiltration at 15 nm). Biochemical factors make this measure less feasible for factor VIII.
Further Updates
While there currently is no known indication of transmission of vCJD through hemophilia treatment products, a theoretical risk remains and the WFH Task Force will continue to closely monitor developments in Europe and disseminate information to the hemophilia community. The latest developments in vCJD are posted on the WFH web site monthly, and e-mailed to interested parties as information becomes available. If you would like to be included on the e-mail distribution list, please send an e-mail to louise@wfh.org. Quarterly updates on vCJD and BSE will also be distributed to members with Haemophilia World.
The complete document, "Variant Creutzfeldt-Jakob Disease and Hemophilia: A Risk Assessment of Product Use," prepared by Dr. Farrugia on behalf of the WFH Task Force on TSEs, is available from the WFH web site at www.wfh.org, under vCJD, or can be obtained by contacting WFH headquarters.
Glossary of Terms
BSE: Bovine spongiform encephalopathy, commonly known as mad cow disease. A TSE that affects cattle.
Creutzfeldt-Jakob disease (CJD) or classical CJD : A fatal degenerative disease of the brain.
Encephalopathy: Disease of the brain.
Transmissible spongiform encephalopathy (TSE): A generic term for a variety of infectious diseases that affect the brain. In humans they include CJD, kuru, Gertmann-Sträussler-Scheinker syndrome (GSSS), and fatal familial insomnia; in animals, they are BSE, scrapie, transmissible mink encephalopathy, and chronic wasting disease in elk and mule deer.
Variant Creutzfeldt-Jakob disease (vCJD) or new variant CJD (nvCJD) : A strain of CJD believed to have been transmitted by eating beef infected with BSE.
March 2001
Bruce Evatt, MD
Chair, WFH Task Force on TSEs
Source: Haemophilia World, Vol. 8, No. 1, March 2001
This is intended to provide information only. The World Federation of Hemophilia does not engage in the practice of medicine and under no circumstances recommends particular treatment for specific individuals. In the case of vCJD and individual medical inquiries, the WFH suggests that further details should be sought from personal doctors or hemophilia centre staff. |
