nvCJD or vCJD TSE PrP, and Blood, updated information
PA03-L03
Safety profile of plasma for fractionation donated in the United Kingdom, with respect to variant Creutzfeldt-Jakob disease
S Thomas1, B Roberts2, D Domanovic3, K Kramer4, D Klochkov5, S Sivasubramaniyam6, D Miloslavich7, J Plancon8, F Rossi9, D Misztela10, L Kirkpatrick11, G Miflin12, J Birchall13, L McLintock14, R Knight15
1Joint UK Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee, 2Department of Health and Social Care, London, United Kingdom, 3European Blood Alliance, Brussels, Belgium, 4Wageningen University, Wageningen, Netherlands, 5CSL Behring, Bern, Switzerland, 6CSL Behring, Haywards Heath, United Kingdom, 7Marketing Research Bureau, Greenacres, United States, 8EPODIN, Baule, France, 9International Plasma and Fractionation Association, Amsterdam, Netherlands, 10Plasma Protein Therapeutics Association, Annapolis, United States, 1111 Northern Ireland Blood Transfusion Service, Belfast, 12NHS Blood and Transplant, London, 13Welsh Blood Service, Cardiff, 14Scottish National Blood Transfusion Service, 15UK National CJD Research & Surveillance Unit, University of Edinburgh, Edinburgh, United Kingdom
Background: Plasma-derived medicinal products (PDMPs) are life-saving and life-improving therapies, but demand is rising and the starting material is in short supply: Europe depends on importation of PDMPs manufactured with plasma from countries including the United States of America (US). Plasma from United Kingdom (UK) resident donors has not been fractionated since 1999 when this precautionary measure was introduced in response to the outbreak of variant Creutzfeldt-Jakob Disease (vCJD).
Aims: We gathered the latest evidence on the safety of UK plasma for fractionation and present it for review.
Methods: The epidemiology of vCJD over the last 23 years was reviewed, as were PDMP manufacturing processes. We reviewed recent risk assessments and regulatory policy changes in the UK and other jurisdictions, and performed a risk analysis using mathematical modelling. Blood service, industry and patient viewpoints were included, and ethical issues were considered.
Results: The vCJD outbreak was much smaller than had been feared and there have been no transfusion transmissions since 1999, when leucodepletion was introduced (allowing for an assumed eight-year incubation period more than 40M components were transfused up to 2015).
There are numerous and effective vCJD risk-reduction steps in the plasma donation and manufacturing process of PMDPs, and effective sanitisation processes in place in fractionation facilities. In February 2021, after a review by the UK Medicines and Healthcare products Regulatory Agency, the UK Government authorised the use of UK plasma to manufacture immunoglobulin for UK patients, and extended this to albumin in February 2023. Following separate reviews concluding no significant difference in the risk posed, the US, Australia, Ireland, Hong Kong and Israel also lifted their deferrals of blood donors with a history of living in the UK.
Mathematical modelling showed that the risk from each unit of donated plasma that is fractionated, using a process with a 4-log prion reduction factor (the industry minimum requirement), is over 7000 times less likely to lead to a vCJD transmission than if that unit was used for transfusion. This suggests that there would be less than one death from vCJD for every 36.4 billion units of UK plasma that are fractionated—this approximates to one possible death from vCJD transmission every 33,000 years. There is considerable uncertainty in the precision of this modelling and these numbers should be viewed with some caution but it is clear that the probability of vCJD transmission through the use of UK plasma for fractionation is extremely low.
Industry and patient groups support the review of guidelines that may enable the use of UK plasma and would bring significant immediate benefits to patients and to the resilience of the European supply chain. It is ethical to do so give the opportunity to provide significant benefits to patients currently in need of treatment.
Summary/Conclusions: UK Plasma is safe for fractionation and blood regulators and operators are strongly encouraged to review their guidelines in the context of current safety evidence and the rising demand for PDMPs in Europe.
PA03-L04
Risk of variant Creutzfeldt-Jakob disease for the Canadian blood supply
A Pozzo di Borgo1,2, M Germain3, S O'Brien4, G Delage2, C Renaud2, A Lewin2,5
1Public Health, Université de Montréal, 2Medical Affairs and Innovation, Héma-Québec, Montreal, 3Medical Affairs and Innovation, Héma-Québec, Quebec, 4Epidemiology and Surveillance, Canadian Blood Services, Ottawa, 5Medicine and Health Science, Université de Sherbrooke, Sherbrooke, Canada
Background: Despite the >20-year absence of new transfusion-associated cases of variant Creutzfeldt-Jakob disease (vCJD), transfusion-transmission remains theoretically possible due to asymptomatic carriers. Blood services have introduced donor deferrals to mitigate this risk, but this measure limits the donor base.
Aims: To estimate the risk of a donation being contaminated with vCJD (“risk of vCJD”) in Canada should current vCJD deferral criteria be lifted.
Methods: The model used Bayesian networks and a Markov chain Monte Carlo method to simulate a cohort of 10 million blood donors observed between 2023 and 2120. The model accounted for several variables that may influence the risk of vCJD, including the number of “at-risk” donors (i.e., those with an extended travel/immigration history in Western Europe), PRNP genotype at codon 129, demographics, and the type of labile blood product donated. Donors were no longer considered at risk past the incubation period, as they should be deferred by pre-donation screening. Moreover, donors were assumed to be infectious only in the late phase of the incubation period. Separate models were developed for the two blood services in Canada, that is, Héma-Québec (HQ, which operates in Québec) and Canadian Blood Services (CBS, which operates in other provinces). Two estimates of vCJD prevalence were considered: a high estimate of 1 case in 2028 individuals derived from the Appendix-II study, and a low estimate of 1 case in 588,235 individuals derived from Garske to Ghani's stochastic model. Three scenario analyses were conducted to test the sensitivity of model outputs to assumptions on vCJD prevalence (i.e., high vs. low estimate); the presence or absence of a second wave; and the proportion of deferred at-risk donors, which was reduced by 20% relative to the base case in the optimistic scenario (Table 1).
PA03-L04 - Table 1. Model scenario
| Scenario | vCJD prevalence in the UK | Second wave | % of at-risk donors |
|---|---|---|---|
| Base case | Low (1 in 588,235) | Yes | HQ = 1.90% CBS = 3.00% |
| Optimistic | Low (1 in 588,235) | Yes | HQ = 1.52%a CBS = 2.40%a |
| Pessimistic i | High (1 in 2028) | No | HQ = 1.90% CBS = 3.00% |
| Pessimistic ii | High (1 in 2028) | Yes | HQ = 1.90% CBS = 3.00% |
Results: In the base case, the simulated HQ cohort comprised 188,825 (1.9%) at-risk donors, and the CBS cohort comprised 324,313 (3.2%) such donors. Over 98 years of observation, no donors were predicted to be infectious at either blood service, and no donations would be contaminated. At HQ, the risk of vCJD was estimated at 0.0, or ≤1 in 294 million based on the upper bound of the 95% confidence interval (CI). At CBS, this risk was also estimated at 0.0, or ≤1 in 312 million based on the upper bound of the 95% CI. Similar results were obtained in the optimistic scenario, but not in pessimistic scenarios i (only for CBS) and ii. In pessimistic scenario i, at HQ, the risk of having a contaminated donation was estimated at 0.0, or ≤1 in 294 million based on the upper bound of the 95% CI. At CBS, this risk was ≤1 in 50 million based on the upper bound of the 95% CI. In pessimistic scenario ii, under the same assumption, at HQ, the risk of having a contaminated donation was estimated at ≤1 in 77 million based on the upper bound of the 95% CI. At CBS, this risk was ≤1 in 16 million based on the upper bound of the 95% CI.
Summary/Conclusions: Given that there are roughly 230,000 whole blood donations each year at Héma-Québec and 800,000 at CBS, the risk of having a vCJD-contaminated donation appears minimal in Canada (i.e., based on the 95% CI upper bound of the pessimistic scenario ii, 1 in 335 years and 1 in 20 years, respectively). These results thus support lifting current vCJD deferral criteria.
P195
Primary immunodeficiency patients exposed to UK-sourced immunoglobulin: Surveillance for asymptomatic carriage of abnormal prion protein
L Kanguru1, K Karekwaivanane1, S Lowrie1, K Ladhani2, J Cooper2, C Smith1, R Knight1
1National CJD Research & Surveillance Unit, UOE, Edinburgh, 2National Institute for Biological Standards & Control, South Mimms, United Kingdom
Background: Variant Creutzfeldt - Jakob disease (vCJD) is a very rare disease, associated with an abnormal form of prion protein. Most cases have been attributed to eating bovine spongiform encephalopathy (BSE) contaminated meat products. However, secondary transmission has occurred through blood transfusion and has been attributed, on one occasion, to treatment with a plasma product. Between 1996 and 2000, two intravenous immunoglobulin (Ig) products used to treat primary immunodeficiency diseases (PID) patients were manufactured from UK donor plasma-nine of these donors subsequently developed vCJD.
Aims: This study concerns the follow-up of patients exposed to these treatments to identify any case of vCJD, and, if found, to assess the likelihood of infection through this specific exposure.
Methods: Consenting patients had annual telephone and biennial face-to-face follow-up. Medical records were reviewed to identify any tissue and autopsy samples suitable for analysis. Blood samples were taken, anonymised and sent to the National Institute for Biological Standards and Control for storage pending possible future prion testing. PRNP-Codon 129 genotyping, histopathology, immunohistochemistry and PET blot analysis were undertaken. All cases are followed up to death or withdrawal.
Results: Of 79 cases included, none have yet shown symptoms or pathological evidence of vCJD. 58% were male, 70% born between 1960 and 1979, and 60% are still alive. The majority had a PID diagnosis of Common Variable Immunodeficiency (71%), and MM genotype (46%). The median time from first potential exposure to censor date was 20 years (range 8.9-28.2 years). Eight were known to have been treated with implicated batches (ones that included donations from pre-clinical vCJD donors), collectively contributing 155.1 person years of observation following first potential exposure. 46 cases donated 237 tissue specimens. Of these, 48 specimens from 22 cases were considered of sufficient quality (including from post-mortem). The average time from first exposure to specimen collection was 13.3 years (range 0-22.3 years). 7of the 21cases who have died underwent autopsy examination, with various causes of death, but not including vCJD: Aspiration pneumonia with disseminated carcinomatosis (1); Liver diseases (3); Alzheimer's disease/ cerebral amyloid angiopathy/progressive multifocal leucoencephalopthy (2); gastrointestinal haemorrhage of unknown cause (1).
Summary/Conclusions: We present the results of a follow-up study of patients with a potential exposure to vCJD infection via intravenous immunoglobulin products prepared from UK donor plasma, with some batches including donations from preclinical vCJD individuals. We found no evidence of transmission of vCJD, however, the incubation period from a potentially low dose exposure may be long. Uncertainties remain concerning the number of asymptomatic vCJD infections in the UK population, the risk of infection via blood components or plasma products derived from such individuals. The small number of vCJD cases, confirmed blood transmissions, and the absence of any vCJD transmission in this study is reassuring, and is evidence to support U.K. plasma being used in plasma product production. However continued surveillance for vCJD, and follow-up of these PID cases is important for public health confidence.
P282
Transmission of variant Creutzfeldt-Jakob disease through blood transfusion and plasma-derived products: a narrative review of observed and modelized risks
A Pozzo Di Borgo1, A Gaussen2, S Rochette3, S O'Brien4, M Germain2, C Renaud3, A Lewin3,5
1Public Health, Unieversité de Montréal, Montreal, 2Medical Affairs and Innovation, Héma-Québec, Québec, 3Medical Affairs and Innovation, Héma-Québec, Montreal, 4Epidemiology and surveillance, Canadian Blood Services, Ottawa, 5Medicine and health science, Université de sherbrooke, Sherbrooke, Canada
Background: Secondary transmission of variant Creutzfeldt-Jakob disease (vCJD) can occur through blood transfusion or receipt of plasma-derived products. However, published reviews on this topic are outdated, focused on a single country or product type, or did not comprehensively review how vCJD may impact the safety of the blood supply.
Aims: We reviewed existing data on observed and modelized risks of transfusion-transmission of vCJD.
Methods: We conducted a non-systematic, narrative review of relevant articles in MEDLINE. The literature was searched by three independent authors using keywords related to prion disease transmission by blood transfusion, epidemiological studies, and risk models, without restrictions on publication date. The results were supplemented with references cited by relevant articles. The references identified by each author were pooled, duplicates were removed, and the final set was selected based on consensus.
Results: To date, five patients are suspected to have acquired clinical vCJD or a vCJD infection after receiving a blood- or plasma-derived product from a donor who later developed clinical vCJD. All were transfused with non-leukodepleted red blood cells in the United Kingdom (UK) between 1996 and 1999, before the adoption of universal leukodepletion; three were methionine homozygous (MM) at codon 129 of PRNP; and two were methionine-valine heterozygotes (MV). Two UK-based, descriptive cohort studies evaluated the risk of vCJD among recipients of vCJD-implicated factor VIII concentrate (N = 787) and recipients of UK-sourced immunoglobulin (N = 75). These studies found no case of clinical vCJD over ~13 years of follow-up. Ten modeling studies were identified, including seven that reported on the risk of having a vCJD-contaminated donation, six on the risk of infection, and 6 on the risk of clinical vCJD. The risk of having a contaminated donation was generally <23 per million donations, that of infection was generally <10 per million transfusions or doses, and that of clinical vCJD was generally <2 per million transfusions or doses. Several countries have reassessed or are reassessing the need for vCJD deferral policies. Animal studies support that vCJD has preferential tropism for leukocytes and that leukoreduction is effective in reducing (but not eliminating) the risk of transmission. Prion reduction filters have been developed but are not used anywhere, possibly because of conflicting results in animal studies and the substantial costs of implementing this technology amid a waning vCJD epidemic. Despite initial concerns of a second vCJD wave driven by non-MM individuals, there has been only one autopsy-confirmed case of clinical vCJD in an MV individual. Further, the high prevalence of PrPsc-positive appendices observed in the UK (1 in 2028 individuals in the Appendix-II study) may reflect dietary exposure to the bovine spongiform encephalopathy agent rather an ongoing, active infection. According to expert consensus, should a second wave occur, no more than a few cases may arise.
Summary/Conclusions: No cases of transfusion-associated vCJD have been reported since the adoption of universal leukodepletion in the UK in 1999. Furthermore, descriptive cohort studies and modeling studies suggest the risk of having a contaminated donation is minimal. Initial concerns of a second, more significant wave have yet to materialize despite the high prevalence of PrPsc-positive appendices in the UK. Therefore, the ongoing trend to reassess or (in some countries) fully withdraw vCJD deferral criteria seems justified and may significantly expand the donor base.
P089
Removal of UK-residence deferral for variant Creutzfeldt-Jakob disease: Impact on donor sufficiency in Australia
C Seed1, V Hoad1, H McManus2, P Kiely1, C Styles1, M Law2, J Kaldor2, I Gosbell1,3
1Donor and Product Safety Unit, Australian Red Cross Lifeblood, Melbourne, 2Kirby Institute, University of New South Wales, Sydney, 3School of Medicine, Western Sydney University, Penrith, Australia
Background: Until recently, Australian Red Cross Lifeblood indefinitely deferred people with prior residency in, or extended travel to, the UK during the risk period 1980–1996 (‘UK donors’) to mitigate the potential vCJD risk to blood safety. Regulatory approval to remove the deferral was underpinned by published (McManus, Vox Sanguinis 2022) mathematical modelling that concluded its removal would not increase the risk of vCJD transfusion-transmission beyond levels considered tolerable for blood safety. The modelling predicted a substantial sufficiency benefit, estimated at approximately 17,000 donors and 58,000 donations annually. The deferral was removed on 25 July 2022.
Aims: To analyse the sufficiency impact (additional donors and donations) of removing the deferral by tracking the donation metrics of the cohort of newly eligible UK donors, in the first 6-months after the policy change.
Methods: Lifeblood's donor questionnaire retained the UK deferral screening question until a version update effective from February 12, 2023. This permitted the identification of the cohort of newly eligible donors. Their donations were tracked for the period between 25 July 2022 and 24 January 2023 (6-month study period) and compared with baseline Lifeblood donation metrics and the modelled sufficiency predictions.
Results: A total of 38,462 UK donors attended to donate 78,762 times. Of these, 32,358 donors (females = 19,456, males = 12,902) successfully donated 67,916 times during the study period, representing 8.4% of the 804,830 total Lifeblood collections, at an average collection success rate of 86.2%. Of the 67,914 total donations excluding discards and autologous (n = 276), 40,108 were fresh blood and 27,530 were plasma donations for further manufacture. The trend of weekly donations by newly eligible UK donors showed an initial peak in the first 2 weeks (4020 and 3064 for weeks 1 and 2, respectively) with a subsequent stabilisation, maintaining high donations rates with a weekly average of 2866 in the last 2 weeks of the study period.
Summary/Conclusions: Cessation of the UK residence deferral for Australian donors has resulted in sufficiency gains well exceeding modelled predictions in the continuing absence of vCJD in Australia. In the first 6-months after the deferral was removed, the 67,914 additional fresh blood and plasma donations is more than double the predicted number, and if the trend at the end of the study period continues, will result in excess of 100,000 additional donations in the first year. The model assumed that UK donors would donate at rates proportional to that of the current donor base. However, the higher than modelled number of additional donations was expected because UK donors have factors associated with a higher rate of blood donation, such as higher education status. The additional donations occurred at a time when blood supplies were low due to ongoing COVID-19 pandemic impacts, and they helped avoid a potentially more significant blood shortage. If these newly eligible donors had not donated, donations would have been 88% of the inventory target; the additional collections allowed 96% of the inventory target to be achieved. The cohort of new and returned donors appear to be highly committed and have already made a substantial contribution to supporting both plasma for fractionation inventory, as well as local red blood cell and platelet inventories.
P193
Use of fresh frozen plasma, fibrinogen concentrate and cryoprecipitate in Ireland
A Farrelly1, B Doyle1, H Moloney1, T Hervig1
1Irish Blood Transfusion Service, Dublin, Ireland
Background: Based on the risk of transfusion transmitted vCJD, Irish plasma was removed as a therapeutic component over two decades ago. Following a review process in 2018, this decision was reversed. Considering the global shortage of Plasma Derived Medicinal Products (PDMPs), Ireland is now in a position to evaluate its contribution to the European supply of plasma, and move towards the use of Fresh Frozen Plasma (FFP) sourced from the Irish donor population.
The Irish Blood Transfusion Service (IBTS) has the sole responsibility for the distribution of fibrinogen concentrate and FFP in Ireland. The IBTS imports FFP (LG Octaplas™) and fibrinogen concentrate 1g (Riastap™) to supply Irish hospitals, which cater for a population of just over 5 million. Cryoprecipitate is prepared using Irish plasma and is used for paediatric surgery only. Ireland is currently collecting approximately 38,000L of whole blood derived recovered plasma, most of which is used for in vitro diagnostics.
Aims: This study is a retrospective, ten year review of the use of FFP, fibrinogen concentrate and cryoprecipitate in Ireland. This data can provide information on product usage in a country impacted by vCJD where alternative products were sourced to meet patients’ needs.
Methods: IBTS figures for total units distributed to hospitals were collated from 2012 to 2022, for Uniplas™, Octaplas™, LG-Octaplas™, Riastap™ and Cryoprecipitate.
Results: Comparing 2012 and 2022, the FFP usage decreased from 21,122 units to 17,340 units, a 17.9% reduction. Fibrinogen concentrate (1g) usage increased from 4683 to 8955 units, a 91.2% increase. Cryoprecipitate usage decreased from 161 to 83 units, a 48.4% decrease.
Summary/Conclusions: The use of fibrinogen concentrate has widely replaced cryoprecipitate, with the exception of very limited usage in some paediatric surgery. Fibrinogen concentrate usage saw the most significant change with a 91% increase in usage since 2012. Since 2016 demand for FFP has been approximately 17,000 units per year. Demand for FFP and fibrinogen concentrate reduced in 2020 during the first year of the COVID-19 pandemic, however, demand has since increased. Demand for cryoprecipitate has decreased steadily since 2017. This product is used only in particular paediatric surgeries. The IBTS is working towards re-introducing Irish plasma for therapeutic use, both as FFP and as plasma for fractionation to make PDMPs. The figures analysed in this study will help inform the future demand for plasma in the Republic of Ireland.
P195
Primary immunodeficiency patients exposed to UK-sourced immunoglobulin: Surveillance for asymptomatic carriage of abnormal prion protein
L Kanguru1, K Karekwaivanane1, S Lowrie1, K Ladhani2, J Cooper2, C Smith1, R Knight1
1National CJD Research & Surveillance Unit, UOE, Edinburgh, 2National Institute for Biological Standards & Control, South Mimms, United Kingdom
Background: Variant Creutzfeldt - Jakob disease (vCJD) is a very rare disease, associated with an abnormal form of prion protein. Most cases have been attributed to eating bovine spongiform encephalopathy (BSE) contaminated meat products. However, secondary transmission has occurred through blood transfusion and has been attributed, on one occasion, to treatment with a plasma product. Between 1996 and 2000, two intravenous immunoglobulin (Ig) products used to treat primary immunodeficiency diseases (PID) patients were manufactured from UK donor plasma-nine of these donors subsequently developed vCJD.
Aims: This study concerns the follow-up of patients exposed to these treatments to identify any case of vCJD, and, if found, to assess the likelihood of infection through this specific exposure.
Methods: Consenting patients had annual telephone and biennial face-to-face follow-up. Medical records were reviewed to identify any tissue and autopsy samples suitable for analysis. Blood samples were taken, anonymised and sent to the National Institute for Biological Standards and Control for storage pending possible future prion testing. PRNP-Codon 129 genotyping, histopathology, immunohistochemistry and PET blot analysis were undertaken. All cases are followed up to death or withdrawal.
Results: Of 79 cases included, none have yet shown symptoms or pathological evidence of vCJD. 58% were male, 70% born between 1960 and 1979, and 60% are still alive. The majority had a PID diagnosis of Common Variable Immunodeficiency (71%), and MM genotype (46%). The median time from first potential exposure to censor date was 20 years (range 8.9-28.2 years). Eight were known to have been treated with implicated batches (ones that included donations from pre-clinical vCJD donors), collectively contributing 155.1 person years of observation following first potential exposure. 46 cases donated 237 tissue specimens. Of these, 48 specimens from 22 cases were considered of sufficient quality (including from post-mortem). The average time from first exposure to specimen collection was 13.3 years (range 0-22.3 years). 7of the 21cases who have died underwent autopsy examination, with various causes of death, but not including vCJD: Aspiration pneumonia with disseminated carcinomatosis (1); Liver diseases (3); Alzheimer's disease/ cerebral amyloid angiopathy/progressive multifocal leucoencephalopthy (2); gastrointestinal haemorrhage of unknown cause (1).
Summary/Conclusions: We present the results of a follow-up study of patients with a potential exposure to vCJD infection via intravenous immunoglobulin products prepared from UK donor plasma, with some batches including donations from preclinical vCJD individuals. We found no evidence of transmission of vCJD, however, the incubation period from a potentially low dose exposure may be long. Uncertainties remain concerning the number of asymptomatic vCJD infections in the UK population, the risk of infection via blood components or plasma products derived from such individuals. The small number of vCJD cases, confirmed blood transmissions, and the absence of any vCJD transmission in this study is reassuring, and is evidence to support U.K. plasma being used in plasma product production. However continued surveillance for vCJD, and follow-up of these PID cases is important for public health confidence.
https://onlinelibrary.wiley.com/doi/full/10.1111/vox.13433?campaign=woletoc
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