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BSE crisis – transmission through blood transfusions?
2
Research Update
TRENDS in Molecular Medicine Vol.7 No.1 January 2001
Research News
BSE crisis – transmission through blood transfusions? Janet Fricker Three separate recent publications are raising concerns about the dangers of the Blood Transfusion Service becoming infected with variant Creutzfeldt–Jakob disease (vCJD). The first study, by researchers from the Institute for Animal Health (Compton, Newbury, UK) reported the transmission of bovine spongiform encephalopathy (BSE) to a sheep by transfusion with whole blood taken from another sheep1. Researchers consider sheep to provide a good model of vCJD. Like humans there is extensive peripheral pathogenesis in sheep, with infectivity being found throughout the organs of the nervous system. In cattle no one has found infectivity outside the nervous system of BSE infected animals. ‘In addition, sheep are large animals, about the size of humans and take blood transfusions that equate in volume,’ says Professor Chris Bostock, director of the Institute of Animal Health, and a spokesman for the study. The team fed UK Cheviot sheep with cattle brains known to be infected with BSE, and then before they displayed any symptoms transfused their blood into healthy Cheviot sheep from a scrapie-free flock of New Zealand-derived animals. Controls were sheep transfused with blood from uninfected UK Cheviot sheep. Of the 19 sheep injected, one showed transmissible spongiform encephalopathy (TSE) signs after 610 days. Symptoms included weight loss, moderate pruitus, trembling and licking of the lips, hindlimb ataxia and proprioceptive abnormalities. The donor sheep had eaten BSE material for 318 days before the transfusion, but did not display signs of the condition for a further 311 days, indicating that the blood would have been infective half way through the incubation period. The team believed that their finding was so significant that they took the unusual step of publishing a research letter immediately, as opposed to waiting several more years until the experiments were completed. In response to the publication the Department of Health said that there
remains no evidence that CJD or vCJD has ever been transmitted to humans through blood transfusion or blood products. ‘The research also points out that whole blood is not used for human blood transfusions in the UK. White cells are now removed from blood for transfusion (leucodepletion), and all blood products used in the UK are made from plasma imported from countries where there is no evidence of vCJD,’ said a spokesman. ‘Leucodepletion is a compromise. It will get rid of most of the infectivity, but it won’t get rid of it all. Leucocytes have a short shelf life and undoubtedly release infectivity into the blood,’ says Richard Lacey, professor of medical micro biology at Leeds University (Leeds, UK). A study from The Neuropathogenesis Unit, at the Institute for Animal Health (Edinburgh, UK) suggests that there is indeed cause for concern2. Researchers led by Richard Somerville found that the plasma of mice challenged with the 301 V strain of mouse-passaged strain of BSE agent contained low levels of infectivity. Blood from 55 mice infected with the 301V mouse-passaged strain of BSE agent was collected when they developed clinical neurological disease and pooled. The plasma was drawn off after sedimentation and injected into 48 mice, four of whom were subsequently found to be infected with 301 V. ‘These studies were not originally designed to investigate the effectiveness of leucodepletion, but it was nevertheless an observation that we thought important to report,’ says Bostock. ‘The blood was taken from mice at the clinical end point of the disease, and the Blood Transfusion Service would never use blood from a clinically infected human patient,’ says Bostock, who is cautious to read too much into the results. The Neuropathogenesis Unit is now undertaking further studies in the 301V mouse model to look at the partitioning of infectivity in different blood fractions when they spike the plasma with preparations of infected material. Andrew Hill and his colleagues at the time from the Medical Research Council
Prion Unit and Department of Neurogenetics, Imperial College School of Medicine (London, UK) demonstrated that a strain of hamster prions, which were thought to be nonpathogenic for conventional mice, leads to high levels of prion replication in these mice without causing clinical disease3. ‘The significance of our work is that we observed animals that harboured significantly levels of infection, and yet otherwise appeared healthy,’ says Hill. Dr Steve Dealler, a medical microbiologist from Burnley General Hospital (Burnley, UK) has shown that by simple calculation the Blood Transfusion Service faces a terrible problem; if the transfusion of a unit of blood from someone incubating vCJD led to the disease in a recipient after 20 years of incubation, then one in ten cases of vCJD will be derived from blood transfusions. ‘We warn patients about the risk of drugs – they also could be told that there is a risk of TSE being transferred in blood but we all realize that the worry induced by this could be of less value than the information. However, the medical population should certainly be made to realize the risk and avoid transfusion when it is not necessary. The large amounts of plasma and platelets that we infuse from UK donors in leucodepleted blood must be remembered, and this does not seem to have reached the profession’. Dealler believes that one solution for the blood transfusion service would be to offer the drug pentosan polysulphate (PPS) to patients as a prophylactic agent at the time of transfusion. PPS, which has been used as an oral treatment for interstitial cystitis since 1989 in the US, adheres to heparan binding sites of PrPsc – the form of prion protein considered to be infectious – and has been shown to prevent prion infection in animals, and to inhibit prion production in test tube infected cell cultures. ‘PPS does not penetrate the central nervous system but prion infections develop outside the CNS initially permitting its use prophylactically in the early incubation period,’ says Dealler, who
http://tmm.trends.com 1471-4914/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S1471-4914(00)01871-2
Research Update
believes that urgent consideration needs to be given to the ethical and practical design of clinical trials to test the value of PPS in preventing iatrogenic vCJD. ‘The problem is that the drug lost its patent many years ago and so drug companies are not interested in pushing it through all the loops that the Medicines Control Agency would demand,’ says Dr
TRENDS in Molecular Medicine Vol.7 No.1 January 2001
Dealler, who has prescribed the drug on a named patient basis for laboratory workers inadvertently injected with prions4. References 1 Houston, F. et al. (2000) Transmission of BSE by blood transfusion in sheep. Lancet 356, 999–1000 2 Taylor, D.M. et al. (2000) Infectivity in the blood of mice with a BSE-derived agent. The Journal of Hospital Infection 46, 78–79
3
3 Hill, A.F. et al. (2000) Species-barrierindependent prion replication in apparently resistant species. Proc. Natl. Acad. Sci. U. S. A. 97, 10248–10253 4 Dealler, S.F. The use of pentosan polysulphate as a prophylactic in prion infection. www.airtime.co.uk/bse/pentrev.htm
Janet Fricker [email protected]
Cord blood: from waste product to valuable resource Kathryn Senior In September 2000, the Foundation for the Accreditation of Hematopoietic Cell Therapy (FAHCT) in the US, in collaboration with NETCORD, an international organisation of the oldest and largest umbilical cord blood banks, set up the most rigorous voluntary accreditation of cord blood banking yet seen (see Box 1). Accreditation is expected to cover cord blood banks in the US, Canada, Europe, Australia, Israel and Japan; other blood banks around the world may eventually all subscribe to a similar system. Until a few years ago, the idea of using cord blood was hardly even considered; the most likely destination for a healthy placenta was the waste incinerator. ‘Now, cord blood is already becoming a main source for stem marrow cell transplants,’ says Michel Revel, Chairman of Bioethic Committee of the Israel Academy of Science and Professor of Molecular Genetics (Weizmann Institute of Science, Rehovot, Israel). Each placenta and cord contains enough stem cells to successfully treat a child with leukaemia, avoiding the need for a bone marrow donor and over 1500 cord blood transplants have now taken place worldwide. Preliminary clinical experience suggests that cord blood stem cells produce a less severe graft versus host disease (GVHD) when compared with bone marrow cells from adult donors. This could mean that cord blood donors and recipients do not need to be HLA-matched with the same rigour as currently practised for bone marrow transplants. However, Shara Cohen (Chairman of The UK Cord Blood Immunology Group, Barnet, Hertfordshire, UK) warns that ‘although reduced GVHD has been observed, we do not yet know why.’ Research in Cohen’s group is investigating the molecular events that make cord blood cells produce a lower GVHD (Refs 1,2).
However, whereas scientific and quality control issues surrounding cord blood transplantation are being tackled with vigour, finding the right approach to solving some of the ethical problems is more difficult. Jeffrey Kahn (Director of the Center for Bioethics, University of Minnesota, Minneapolis, MN, USA) says that the most important long-standing issue is the distinction between private blood banks and public community banks. ‘Private banks, which are more common in the US than in Europe, arrange collection of cord blood from individual births and store it for the future use of that child and that child only,’ he explains. ‘The banks call this “the ultimate insurance policy” but private blood banking is a case of “me-first” thinking that is potentially problematic,’ says Kahn. For example, once a private bank has stored cord blood
it is unavailable for use by anyone else but the donor’s child. ‘The probability that a child will actually need its cord blood in the first few years of life is very low, and so each privately stored unit of cord blood is effectively locked up, useless in the vast majority of cases.’ Cohen adds that there are also medical reasons that argue against private storage. ‘If a child develops a bone-marrow deficiency in the first few years of life, there is no guarantee that the problem will not also be present in stem cells in the cord blood,’ she explains. EUROCORD, the European consortium on cord blood banking, is opposed to private banking. Countries in Europe, including the UK, favour community blood banks that collect and store individual cord blood units anonymously and make them available to treat any child that needs a haematopoietic cell transplant. Public banking offers many
Box 1. Raising standards for cord blood In order to ensure that cord blood available for transplantation is the highest possible quality, FAHCT accreditation will require the following: • A genetic and medical history, including the mother’s infectious disease risk • Tests for blood borne pathogens including HIV-1, HIV-2, HIV-1-Ag and HTLV I/II, Hbs Ag, HBc, HCV, CMV and a serological test for syphilis • Collected cord blood units must be tested to determine the total nucleated cell count, including red blood cells, the total number of CD34 + cells and haematopoietic colony-forming units For the first time, the guidelines direct banks to track the clinical outcome of cord blood recipients. ‘Data obtained should include survival rates for related or
unrelated allogenic and/or autologous cord blood units,’ explains FAHCT President and NETCORD member Elizabeth Shpall. Cord blood banks should also report their clinical outcomes data to cord blood transplant registries, such as EUROCORD. ‘To optimise the quality of the Cord Bank inspections, a further Inspector Training session (a mock inspection) was arranged in early November, where 20 of the most experienced FAHCT Cord Bank inspectors jointly inspected one bank. Actual Cord Bank inspections are due to begin early this year, and we anticipate a minimum of 30 banks to be inspected soon thereafter, many of whom have already applied and are waiting for the inspection date to be scheduled,’ says Shpall.
http://tmm.trends.com 1471-49140/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S1471-4914(00)01879-7
Research Update
TRENDS in Molecular Medicine Vol.7 No.1 January 2001
Research News
BSE crisis – transmission through blood transfusions? Janet Fricker Three separate recent publications are raising concerns about the dangers of the Blood Transfusion Service becoming infected with variant Creutzfeldt–Jakob disease (vCJD). The first study, by researchers from the Institute for Animal Health (Compton, Newbury, UK) reported the transmission of bovine spongiform encephalopathy (BSE) to a sheep by transfusion with whole blood taken from another sheep1. Researchers consider sheep to provide a good model of vCJD. Like humans there is extensive peripheral pathogenesis in sheep, with infectivity being found throughout the organs of the nervous system. In cattle no one has found infectivity outside the nervous system of BSE infected animals. ‘In addition, sheep are large animals, about the size of humans and take blood transfusions that equate in volume,’ says Professor Chris Bostock, director of the Institute of Animal Health, and a spokesman for the study. The team fed UK Cheviot sheep with cattle brains known to be infected with BSE, and then before they displayed any symptoms transfused their blood into healthy Cheviot sheep from a scrapie-free flock of New Zealand-derived animals. Controls were sheep transfused with blood from uninfected UK Cheviot sheep. Of the 19 sheep injected, one showed transmissible spongiform encephalopathy (TSE) signs after 610 days. Symptoms included weight loss, moderate pruitus, trembling and licking of the lips, hindlimb ataxia and proprioceptive abnormalities. The donor sheep had eaten BSE material for 318 days before the transfusion, but did not display signs of the condition for a further 311 days, indicating that the blood would have been infective half way through the incubation period. The team believed that their finding was so significant that they took the unusual step of publishing a research letter immediately, as opposed to waiting several more years until the experiments were completed. In response to the publication the Department of Health said that there
remains no evidence that CJD or vCJD has ever been transmitted to humans through blood transfusion or blood products. ‘The research also points out that whole blood is not used for human blood transfusions in the UK. White cells are now removed from blood for transfusion (leucodepletion), and all blood products used in the UK are made from plasma imported from countries where there is no evidence of vCJD,’ said a spokesman. ‘Leucodepletion is a compromise. It will get rid of most of the infectivity, but it won’t get rid of it all. Leucocytes have a short shelf life and undoubtedly release infectivity into the blood,’ says Richard Lacey, professor of medical micro biology at Leeds University (Leeds, UK). A study from The Neuropathogenesis Unit, at the Institute for Animal Health (Edinburgh, UK) suggests that there is indeed cause for concern2. Researchers led by Richard Somerville found that the plasma of mice challenged with the 301 V strain of mouse-passaged strain of BSE agent contained low levels of infectivity. Blood from 55 mice infected with the 301V mouse-passaged strain of BSE agent was collected when they developed clinical neurological disease and pooled. The plasma was drawn off after sedimentation and injected into 48 mice, four of whom were subsequently found to be infected with 301 V. ‘These studies were not originally designed to investigate the effectiveness of leucodepletion, but it was nevertheless an observation that we thought important to report,’ says Bostock. ‘The blood was taken from mice at the clinical end point of the disease, and the Blood Transfusion Service would never use blood from a clinically infected human patient,’ says Bostock, who is cautious to read too much into the results. The Neuropathogenesis Unit is now undertaking further studies in the 301V mouse model to look at the partitioning of infectivity in different blood fractions when they spike the plasma with preparations of infected material. Andrew Hill and his colleagues at the time from the Medical Research Council
Prion Unit and Department of Neurogenetics, Imperial College School of Medicine (London, UK) demonstrated that a strain of hamster prions, which were thought to be nonpathogenic for conventional mice, leads to high levels of prion replication in these mice without causing clinical disease3. ‘The significance of our work is that we observed animals that harboured significantly levels of infection, and yet otherwise appeared healthy,’ says Hill. Dr Steve Dealler, a medical microbiologist from Burnley General Hospital (Burnley, UK) has shown that by simple calculation the Blood Transfusion Service faces a terrible problem; if the transfusion of a unit of blood from someone incubating vCJD led to the disease in a recipient after 20 years of incubation, then one in ten cases of vCJD will be derived from blood transfusions. ‘We warn patients about the risk of drugs – they also could be told that there is a risk of TSE being transferred in blood but we all realize that the worry induced by this could be of less value than the information. However, the medical population should certainly be made to realize the risk and avoid transfusion when it is not necessary. The large amounts of plasma and platelets that we infuse from UK donors in leucodepleted blood must be remembered, and this does not seem to have reached the profession’. Dealler believes that one solution for the blood transfusion service would be to offer the drug pentosan polysulphate (PPS) to patients as a prophylactic agent at the time of transfusion. PPS, which has been used as an oral treatment for interstitial cystitis since 1989 in the US, adheres to heparan binding sites of PrPsc – the form of prion protein considered to be infectious – and has been shown to prevent prion infection in animals, and to inhibit prion production in test tube infected cell cultures. ‘PPS does not penetrate the central nervous system but prion infections develop outside the CNS initially permitting its use prophylactically in the early incubation period,’ says Dealler, who
http://tmm.trends.com 1471-4914/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S1471-4914(00)01871-2
Research Update
believes that urgent consideration needs to be given to the ethical and practical design of clinical trials to test the value of PPS in preventing iatrogenic vCJD. ‘The problem is that the drug lost its patent many years ago and so drug companies are not interested in pushing it through all the loops that the Medicines Control Agency would demand,’ says Dr
TRENDS in Molecular Medicine Vol.7 No.1 January 2001
Dealler, who has prescribed the drug on a named patient basis for laboratory workers inadvertently injected with prions4. References 1 Houston, F. et al. (2000) Transmission of BSE by blood transfusion in sheep. Lancet 356, 999–1000 2 Taylor, D.M. et al. (2000) Infectivity in the blood of mice with a BSE-derived agent. The Journal of Hospital Infection 46, 78–79
3
3 Hill, A.F. et al. (2000) Species-barrierindependent prion replication in apparently resistant species. Proc. Natl. Acad. Sci. U. S. A. 97, 10248–10253 4 Dealler, S.F. The use of pentosan polysulphate as a prophylactic in prion infection. www.airtime.co.uk/bse/pentrev.htm
Janet Fricker [email protected]
Cord blood: from waste product to valuable resource Kathryn Senior In September 2000, the Foundation for the Accreditation of Hematopoietic Cell Therapy (FAHCT) in the US, in collaboration with NETCORD, an international organisation of the oldest and largest umbilical cord blood banks, set up the most rigorous voluntary accreditation of cord blood banking yet seen (see Box 1). Accreditation is expected to cover cord blood banks in the US, Canada, Europe, Australia, Israel and Japan; other blood banks around the world may eventually all subscribe to a similar system. Until a few years ago, the idea of using cord blood was hardly even considered; the most likely destination for a healthy placenta was the waste incinerator. ‘Now, cord blood is already becoming a main source for stem marrow cell transplants,’ says Michel Revel, Chairman of Bioethic Committee of the Israel Academy of Science and Professor of Molecular Genetics (Weizmann Institute of Science, Rehovot, Israel). Each placenta and cord contains enough stem cells to successfully treat a child with leukaemia, avoiding the need for a bone marrow donor and over 1500 cord blood transplants have now taken place worldwide. Preliminary clinical experience suggests that cord blood stem cells produce a less severe graft versus host disease (GVHD) when compared with bone marrow cells from adult donors. This could mean that cord blood donors and recipients do not need to be HLA-matched with the same rigour as currently practised for bone marrow transplants. However, Shara Cohen (Chairman of The UK Cord Blood Immunology Group, Barnet, Hertfordshire, UK) warns that ‘although reduced GVHD has been observed, we do not yet know why.’ Research in Cohen’s group is investigating the molecular events that make cord blood cells produce a lower GVHD (Refs 1,2).
However, whereas scientific and quality control issues surrounding cord blood transplantation are being tackled with vigour, finding the right approach to solving some of the ethical problems is more difficult. Jeffrey Kahn (Director of the Center for Bioethics, University of Minnesota, Minneapolis, MN, USA) says that the most important long-standing issue is the distinction between private blood banks and public community banks. ‘Private banks, which are more common in the US than in Europe, arrange collection of cord blood from individual births and store it for the future use of that child and that child only,’ he explains. ‘The banks call this “the ultimate insurance policy” but private blood banking is a case of “me-first” thinking that is potentially problematic,’ says Kahn. For example, once a private bank has stored cord blood
it is unavailable for use by anyone else but the donor’s child. ‘The probability that a child will actually need its cord blood in the first few years of life is very low, and so each privately stored unit of cord blood is effectively locked up, useless in the vast majority of cases.’ Cohen adds that there are also medical reasons that argue against private storage. ‘If a child develops a bone-marrow deficiency in the first few years of life, there is no guarantee that the problem will not also be present in stem cells in the cord blood,’ she explains. EUROCORD, the European consortium on cord blood banking, is opposed to private banking. Countries in Europe, including the UK, favour community blood banks that collect and store individual cord blood units anonymously and make them available to treat any child that needs a haematopoietic cell transplant. Public banking offers many
Box 1. Raising standards for cord blood In order to ensure that cord blood available for transplantation is the highest possible quality, FAHCT accreditation will require the following: • A genetic and medical history, including the mother’s infectious disease risk • Tests for blood borne pathogens including HIV-1, HIV-2, HIV-1-Ag and HTLV I/II, Hbs Ag, HBc, HCV, CMV and a serological test for syphilis • Collected cord blood units must be tested to determine the total nucleated cell count, including red blood cells, the total number of CD34 + cells and haematopoietic colony-forming units For the first time, the guidelines direct banks to track the clinical outcome of cord blood recipients. ‘Data obtained should include survival rates for related or
unrelated allogenic and/or autologous cord blood units,’ explains FAHCT President and NETCORD member Elizabeth Shpall. Cord blood banks should also report their clinical outcomes data to cord blood transplant registries, such as EUROCORD. ‘To optimise the quality of the Cord Bank inspections, a further Inspector Training session (a mock inspection) was arranged in early November, where 20 of the most experienced FAHCT Cord Bank inspectors jointly inspected one bank. Actual Cord Bank inspections are due to begin early this year, and we anticipate a minimum of 30 banks to be inspected soon thereafter, many of whom have already applied and are waiting for the inspection date to be scheduled,’ says Shpall.
http://tmm.trends.com 1471-49140/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S1471-4914(00)01879-7