There continues to be concern about transmission of variant Creutzfeldt Jakob disease (vCJD) by blood transfusion, with a total of 4 reported cases, plus a potential case of transmission of the prion via a UK-derived plasma derivative, known to have contained potentially infectious donations. Some infections (but no disease) have been found among individuals who are not homozygous for MM at the 129 codon of the PRP gene, raising concern about a possible second wave of disease and an expanded group of potential carriers. There has been no published progress in blood donor testing technologies. One method for prion removal from red cell concentrates has been evaluated by authorities in the UK and Ireland.
Information about transfusion transmitted infectivity
There have now been a total of four cases of transmission of the vCJD prion by transfusion of blood collected from three donors who subsequently developed vCJD. Three of the cases resulted in the development of vCJD in the recipient, while one was detected in the spleen and one lymph node of a transfused patient who died of other causes. This individual had no symptoms of vCJD (1, 2). Interestingly, he was found to be (MV) heterozygous at codon 129 of the PrP gene. The potential significance of infection among non MM genotypes is discussed briefly below. More recently, evidence of pathologic vCJD prions was found in a hemophilic recipient of F VIII concentrates known to have included plasma from a donor who subsequently developed vCJD (3). Again, the recipient patient was free of vCJD symptoms. Modeling studies imply that the infection was most likely to have come from the plasma products (4).
In a paper published in Transfusion, American Red Cross authors reported on the absence of evidence of transmission of classic CJD from donors who subsequently developed the disease. The study involved lookback on 436 recipients of donations from a total of 36 donors who developed the disease subsequent to their donation, finding no cases of CJD among the recipients. A subset of recipients with exposure histories comparable to the UK cohort of patients exposed to vCJD was shown to be at lower risk of developing CJD: a statistically significant (p = 0.012) observation. This supports the absence of infectivity of classic CJD via transfusion (5).
Risk modeling for recipients of plasma derivatives in the US
As a result of the finding of the vCJD prion in a hemophilia patient (described above), and the findings of vCJD prions among non MM individuals, the US FDA has revised its model of the vCJD transmission risk for recipients of US-derived plasma derivatives. The new models were presented at a meeting of the Transmissible Spongiform Encephalopathies Advisory Committee in June, 2009. Although the lowest estimated annual per-person risk has risen 5 to 18-fold, it may still be as low as 1 in 12 million and the maximal estimated risk remains unchanged at 1:12,000, the FDA still regards the risk to US patients to be “extremely small”.
Implications of findings of vCJD prions in non MM individuals
There are several variations at codon 129 of the human PrP gene, resulting in 3 main genotypes, MM, MV and VV, where M signifies methionine and V, valine. To date, all symptomatic cases of vCJD who have been evaluated have been MM homozygous at the 129 codon. Approximately 40% of the UK population has this genotype. However, there have been a number of circumstances (some described above) in which the pathologic prion has been found in asymptomatic individuals with the MV or VV genotype. This has raised two questions. The first is whether there will be a “second wave” of vCJD among individuals with a non MM genotype, perhaps resulting from a much extended incubation period. Second is the question of whether non MM individuals can be infectious carriers of the vCJD prion. This latter concern was included in the newer FDA infectivity model for US-derived plasma derivatives. Both questions await resolution.
Status of interventions against transfusion transmission of TSEs
No significant progress has been reported in the development of any pre-mortem test that could be used for blood donors or donations, although one of the tests under development has undergone some preliminary clinical evaluatation.
Currently, one manufacturer has an available, CE-marked affinity filter intended for use with leukoreduced red-cell concentrates. The procedure has been evaluated in the UK and Ireland, but no decision has been made with respect to its implementation. A process has also been developed for use in the manufacture of solvent-detergent treated plasma for transfusion.
1. Hewitt PE, Llewelyn CA, Mackenzie J, Will RG. Creutzfeldt–Jakob disease and blood transfusion: results of the UKTransfusionMedicine Epidemiologic Review study. Vox Sang 2006;91:221-30.
2. Health Protection Agency. CDR weekly, Vol. 16 No 6; 9February 2006. [cited 2009 May]. Available from: http://www.hpa.org.uk/cdr/archives/2006/cdr0606.pdf
3. Health Protection Agency. Asymptomatic vCJD abnormal prion protein found in a haemophilia patient. [cited June 2009]. Available from: http://www.hpa.org.uk/webw/HPAweb&HPAwebStandard/HPAweb_C/1195733818681?p=1225960597236
4. Health Protection Agency. vCJD Risk assessment calculations for a patient with multiple routes of exposure. http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_100357
5 . Dorsey K, Zou S, Schonberger LB, Sullivan M, Kessler D, Notari E 4th, Fang CT, Dodd RY. Lack of evidence of transfusion transmission of Creutzfeldt–Jakob disease in a US surveillance study. Transfusion 2009;49:977-84.
Prepared by TTD Committee, October, 2009.