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- Materials and methods
Background and Objectives This paper reports the results to 1 March 2006 of an ongoing UK study, the Transfusion Medicine Epidemiological Review (TMER), by the National CJD Surveillance Unit (NCJDSU) and the UK Blood Services (UKBS) to determine whether there is any evidence that Creutzfeldt–Jakob disease (CJD), including sporadic CJD (sCJD), familial CJD (fCJD), and variant CJD (vCJD) is transmissible via blood transfusion.
Materials and Methods Sporadic CJD and fCJD cases with a history of blood donation or transfusion are notified to UKBS. All vCJD cases aged > 17 years are notified to UKBS on diagnosis. A search for donation records is instigated and the fate of all donations is identified by lookback. For cases with a history of blood transfusion, hospital and UKBS records are searched to identify blood donors. Details of identified recipients and donors are checked against the NCJDSU register to establish if there are any matches.
Results CJD cases with donation history: 18/31 vCJD, 3/93 sCJD, and 3/5 fCJD cases reported as blood donors were confirmed to have donated labile components transfused to 66, 20, and 11 recipients respectively. Two vCJD recipients have appeared on the NCJDSU register as confirmed and probable vCJD cases. The latter developed symptoms of vCJD 6.5 years and 7.8 years respectively after receiving non-leucodepleted red blood cells (RBCs) from two different donors who developed clinical symptoms approximately 40 and 21 months after donating. A third recipient, given RBC donated by a further vCJD case approximately 18 months before onset of clinical symptoms, had abnormal prion protein in lymphoid tissue at post-mortem (5-years post-transfusion) but had no clinical symptoms of vCJD. CJD cases with history of transfusion: Hospital records for 7/11 vCJD and 7/52 sCJD cases included a history of transfusion of labile blood components donated by 125 and 24 donors respectively. Two recipients who developed vCJD were linked to donors who had already appeared on the NCJDSU register as vCJD cases (see above). No further links were established.
Conclusion This study has identified three instances of probable transfusion transmission of vCJD infection, including two confirmed clinical cases and one pre- or sub-clinical infection. This study has not provided evidence, to date, of transmission of sCJD or fCJD by blood transfusion, but data on these forms of diseases are limited.
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- Materials and methods
This study has identified three instances in which a recipient of a transfusion derived from a ‘vCJD’ donor has developed infection with vCJD, including two clinical cases and one pre- or subclinical infection [7–9]. These are three different donor/recipient pairs. In view of the small size of the total at-risk recipient population (n = 66) and the background mortality rate for vCJD in the general UK population (0·24/million/annum), these observations provide strong evidence that vCJD can be transmitted from person to person through blood transfusion. This finding has had important implications for public health policy nationally and internationally.
The risk of developing vCJD infection in the surviving recipient population is significant but cannot be precisely estimated because of variables including the timing of blood donation in relation to clinical onset in the donor, the influence of the codon 129 genotype of donor and recipient and the effect of the introduction of leucodepletion in 1999. Furthermore, the currently observed number of infections in the recipient population may be an underestimate as some surviving recipients may yet develop vCJD and there is limited available information on the outcome in the cohort of deceased recipients; a significant proportion of these individuals may not have survived long enough to express clinical disease even if infected. The minimum incubation period in CJD transmitted from person to person by a peripheral route is 4·5 years in kuru and growth-hormone-related CJD [10,11] and only nine deceased recipients survived for longer than this period. An investigation of the hospital records of the deceased recipients is underway, and to date, none had clinical features of vCJD pre-mortem. However, the identification of the individual with ‘preclinical’ vCJD infection was dependent on post-mortem examination of peripheral lymphoreticular tissues, and, to date, no equivalent tissues have been available in the deceased transfusion recipients. Extrapolating from the three observed infections in the total recipient population is likely to lead to an underestimate of the overall risk of transfusion transmission of vCJD, although the introduction of leucodepletion in 1999 may have reduced the risk to recipients transfused after this date.
A further important variable in estimating individual risk is the time from blood donation to clinical onset in the donor and, although evidence from animal studies in relation to this issue is conflicting [12–14], it is likely that an extended gap between blood donation and clinical onset in the donor will reduce the risk of transfusion transmission. All tested clinical cases of vCJD have been methionine homozygotes at codon 129 of PRNP, but the individual with ‘pre-clinical’ transfusion transmitted infection was heterozygous at this locus , indicating that individuals with this genotype are susceptible to secondary infection with vCJD. Except for the three cases infected through blood transfusion, the codon 129 genotypes of the recipient population are not known. Although the relative risk of secondary infection in relation to the codon 129 genotype is uncertain, a recent study in a transgenic mouse model suggests that individuals with all human codon 129 genotypes may be susceptible to secondary infection with vCJD, with a hierarchy of risk from methionine homozygotes to heterozygotes to valine homozygotes . Risk may vary according to genetic background, but it cannot be assumed that some recipients will possess an absolute genetic barrier to infection.
The analysis of vCJD cases with a history of blood transfusion has identified over 100 donors to these cases, although the great majority were linked to one vCJD case who had undergone an organ transplant. A risk assessment has suggested that these donors are themselves at significant risk of developing vCJD and these individuals have been informed of this risk and have been advized not to act as blood or organ donors. To date, none of these individuals have developed vCJD, with the exception of the two donors linked to the two clinical cases of vCJD described above.
Plasma derived from vCJD cases has been used in the production of plasma derived products, including clotting factors and immunoglobulin. To date, there is no evidence that vCJD has developed in a recipient of these products. However, the potential incubation period from a presumed low dose exposure by a peripheral route may be prolonged and current observational data cannot exclude the possibility of transmission of vCJD through plasma products. A risk assessment carried out in the UK suggested that, on worst case assumptions, some plasma products could be associated with an additional risk of developing vCJD in relation to the background population risk through exposure to BSE and since 1999 plasma for the production of plasma products has been imported to the UK from other countries. In contrast to labile blood components, plasma products are manufactured using a production process, some steps of which may reduce TSE infectivity . Together with the estimated relatively low levels of initial infectivity in plasma used in fractionation, the risks from plasma products are probably much lower than the risks from transfusion of labile blood components.
An important question raised by the evidence of transfusion transmission of vCJD is whether other human TSEs may be transmissible through this mechanism. Cumulative evidence in sCJD over many years does not suggest that sCJD is transfusion transmitted . Case-control studies have not demonstrated an increased risk of sCJD through a past history of blood transfusion [18–20] and lookback studies have not linked blood transfusions derived from sCJD blood donors to sCJD cases [21,22]. However, the case-control methodology may be compromised by control selection (some studies of CJD used hospital based controls) and this type of research cannot exclude rare transfusion transmission events. The lookback study of sCJD (and fCJD) from the TMER study provides only limited evidence, not least because of the difficulties in tracing blood donations made years or decades in the past, and there is only one study of sCJD equivalent to the TMER study of vCJD . This has not provided evidence of transfusion transmission of sCJD, despite prolonged periods of follow-up in a proportion of cases. There is however a need to continue the study of blood transfusion and sCJD, and this will become of particular importance should highly sensitive tests for infectivity in blood be developed . There is recent evidence of prion protein deposition in peripheral tissues in sCJD, including muscle . However, the increased lymphoreticular involvement in vCJD in comparison to sCJD may be associated with an increased risk of transfusion transmission of vCJD.
The TMER study has provided compelling evidence that vCJD is transmissible through blood transfusion, representing the first evidence of transmission of human TSEs through this route and via material sourced from a peripheral tissue rather than the high level infectivity tissues of the central nervous system. The manifest implications for public health of transmission transfusion of vCJD have led to measures to minimize the risk from blood transfusion  and plasma products derived from cases incubating vCJD and many of these actions were taken years in advance of the evidence for transfusion transmission, both in the UK and many other countries. Although there is uncertainty about the potential for transfusion transmission of vCJD to lead to a self-sustaining epidemic, the introduction of a policy of deferring transfusion recipients as blood donors in the UK has minimized this possibility. Other actions to reduce the risk, such as the introduction of filtration devices, are under consideration in the UK, but the identification of vCJD cases with a history of blood donation in France, Ireland, Spain and Saudi Arabia indicates that this issue has an international dimension. One determinant of the risk is the population prevalence of vCJD infection, which is almost certainly highest in the UK, but the identification of secondary transmission of vCJD underlines the importance of international surveillance systems both for human and animal prion diseases.