Is Sporadic Creutzfeldt-Jakob Disease Transfusion-Transmissible?
Transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of extremely rare and fatal neurodegenerative diseases. TSEs are caused by the buildup of prions (PrPTSE), proteins that cause normal proteins(PrPC) in the brain to fold improperly.1 Creutzfeldt-Jakob disease (CJD) is the most common prion disease in humans and can be subclassified as sporadic (sCJD), familial (fCJD) which is an inherited form, or iatrogenic (iCJD) which is due to medical treatment. There is also a variant form of CJD (vCJD), linked to consuming beef contaminated causing TSE bovine spongiform encephalopathy (commonly known as Mad Cow’s Disease).2,3
The normal PrPC is expressed in all mammalian tissues, including humans. In blood, PrPC is mostly found in plasma, but is also present in white blood cells and platelets4,5. Based on the widespread expression of PrPC and infectivity of PrPTSE in non-neuronal tissues, especially in patients with vCJD6,7, investigators raised concerns about the potential transfusion transmissibility of prion diseases. While CJD is not known to be transfusion-transmitted, the same cannot be said of vCJD. To date of the 177 UK vCJD cases, only 18 individuals had donated blood components that were subsequently used and traced to identified recipients. Four recipients of components from three donors died of TT-vCJD 8,9 and a probable fifth case in a hemophilia patient10 has been reported in the United Kingdom (UK).
While experimental evidence indicates that blood from some sCJD patients harbors infectivity, data from several case-control11,12 and lookback studies show no evidence of transfusion-transmission of sCJD. The Red Cross, in collaboration with and funding from the US Centers for Disease Control and Prevention (CDC), is conducting a lookback study on the transmission risk of the non-variant forms of CJD through blood transfusion. The study has been active since 1995, and in 2017 the most recent results were published in Transfusion.13
Currently, through a study funded through a five year contract, the Red Cross study has enrolled 79 CJD diagnosed blood donors who gave 1,954 donations (median 18 donations per donor). From those donations, 1,056 traceable transfused recipients have been identified for the study. According to the most recent National Death Index search, 814 recipients are deceased and 242 are alive, with no reported CJD transfusion transmission. These results are comparable to those of UK’s Transfusion Medicine Epidemiology Review (TMER) and Denmark/Sweden’s SCANDAT2 study.14, 15 Collectively these three studies contributed 147 donors and more than 13,900 person-years of follow-up. The results of these studies strongly indicate that the transfusion-transmissibility of sCJD remains theoretical. If sCJD is transmissible via blood, it is undoubtedly less infectious than vCJD.
Because of these findings, in April 2020, the US Food and Drug Administration (FDA) released “Recommendations to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Components Guidance for Industry”.16 This document recommended the removal of deferral status to what was previously considered CJD exposure risks, including the consumption of UK-sourced beef on US military bases; clinical treatment with human-derived growth hormone; and self-identified donors who have a blood relative with CJD.
Altogether, the data summarized above, highlight the relevance of lookback studies to inform policy changes and the importance of continuing surveillance of human prion diseases to ensure the safety of the blood supply.
Link to abstract:
Paula Saá PhD & Whitney Steele, PhD, MPH
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6. Ramasamy I, Law M, et al. Organ distribution of prion proteins in variant Creutzfeldt-Jakob disease. Lancet Infect Dis 2003; 3: 214-22.
7. Wadsworth JD, Joiner S, et al. Tissue distribution of protease resistant prion protein in variant Creutzfeldt-Jakob disease using a highly sensitive immunoblotting assay. Lancet 2001;358: 171-80.
8. Hewitt PE, Llewelyn CA, et al. Three reported cases of variant Creutzfeldt-Jakob disease transmission following transfusion of labile blood components. Vox Sang 2006;91: 348.
9. Peden AH, Head MW, et al. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 2004;364: 527-9.
10. Peden A, McCardle L, et al. Variant CJD infection in the spleen of a neurologically asymptomatic UK adult patient with haemophilia. Haemophilia 2010;16: 296-304.
11. Collins S, Law MG, et al. Surgical treatment and risk of sporadic Creutzfeldt-Jakob disease: a case-control study. Lancet 1999;353: 693-7.
12. Zerr I, Brandel JP, et al. European surveillance on Creutzfeldt-Jakob disease: a case-control study for medical risk factors. J Clin Epidemiol 2000;53: 747-54.
13. Crowder LA, Schonberger LB, et al. Creutzfeldt-Jakob disease lookback study: 21 years of surveillance for transfusion transmission risk. Transfusion 2017;57: 1875-8.
14. Urwin PJ, Mackenzie JM, et al. Creutzfeldt-Jakob disease and blood transfusion: updated results of the UK Transfusion Medicine Epidemiology Review Study. Vox Sang 2016;110: 310-6.
15. Holmqvist J, Wikman A, et al. No evidence of transfusion transmitted sporadic Creutzfeldt-Jakob disease: results from a bi-national cohort study. Transfusion 2020;60: 694-7.
16. Food and Drug Administration USDHHS. Recommendations to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Components [monograph on the internet]. 2020. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/recommendations-reduce-possible-risk-transmission-creutzfeldt-jakob-disease-and-variant-creutzfeldt
Links to Additional Resources/Information
a. ARC, current donor eligibility: https://www.redcross.org/about-us/news-and-events/press-release/2020/red-cross-to-implement-fda-eligibility-changes.html
b. CDC, general information: https://www.cdc.gov/prions/cjd/index.html
c. FDA, recommendation to reduce transfusion transmission: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/recommendations-reduce-possible-risk-transmission-creutzfeldt-jakob-disease-and-variant-creutzfeldt
National Death Index: https://www.cdc.gov/nchs/ndi/index.htm