Creutzfeldt‐Jakob disease and blood transfusion: safe or not safe?

W hen addressing transfusion safety in relation to Creutzfeldt-Jakob disease (CJD), we tend to think of negligible or even absent risk for sporadic CJD (sCJD), but with variant CJD (vCJD), our uncertainty disappears. This clarity is due to strong evidence that linked three blood donors, healthy at the time of donation, who were later diagnosed with vCJD, to four recipients who contracted infection after receiving non-leukoreduced red blood cells (nl-RBCs) obtained from these donations. Why the difference between these human diseases, which belong to the group of transmissible spongiform encephalopathies (TSEs) or prion diseases? Why are we concerned about vCJD and not sCJD, and what scientific evidence is available to substantiate our concern or composure? In this issue of TRANSFUSION, Crowder and colleagues present an epidemiological lookback investigation that was conducted at the American Red Cross (ARC) over 21 years aimed at assessing the transfusion transmission risk of sCJD from affected donors to recipients. The authors conclude that the study provides no evidence to support a risk from blood transfusion in sCJD. However, they do not fully dismiss the existence of safety concerns and report that the study should continue. This conclusion resonates with a similar conclusion from another publication that recommends continued surveillance efforts in regard to TSEs. Human TSEs are unusual diseases, because they can be sporadic (approximately 90% of all cases), genetic, or infectious. The agent involved in the pathogenesis of these diseases is a prion, an entity almost entirely composed of misfolded prion protein (PrP) with no detectable nucleic acid. sCJD occurs worldwide without known cause and has an annual incidence of 1 to 1.5 cases per million. Genetic forms comprise familial CJD, Gerstmann-Str€ aussler-Scheinker disease, and fatal familial insomnia, which arise in association with mutations in the prion protein gene (PRNP). Infectious forms include iatrogenic CJD (iCJD), vCJD, and kuru. iCJD occurs as a result of accidental human-tohuman transmission through prior medical treatments, most frequently through contaminated, human-derived pituitary hormones or human dura mater transplants, and rarely via contaminated neurosurgical instruments or corneal grafts. vCJD was identified more than 20 years ago in the United Kingdom and also affected some individuals in other, mostly European, countries; but the outbreak is clearly in decline both in the United Kingdom, where only two cases have been identified since 2011, and internationally. Scientific evidence proves that vCJD was caused by infection with bovine spongiform encephalopathy, probably as a result of dietary exposure to bovine products. In 1995, the ARC, with support from the US Centers for Disease Control and Prevention, established a lookback study to evaluate the risk of transfusion transmission of sCJD, and the current report includes 65 blood donors who were subsequently diagnosed with CJD. The majority of cases (n 5 63) were patients with sCJD, but one individual had familial CJD with a glutamic acid to lysine mutation at codon 200 (E200K) of PRNP, and another with iCJD was a recipient of a human dura mater transplant. Only 64.6% of cases (n 5 42) were confirmed by the neuropathological examination of the brain, including the identification of PrP by immunochemical methods. This rate of definite CJD detection is not surprising, considering that TSEs are not reportable diseases in the United States; and, because of ethical, social, and religious issues, not every clinically diagnosed patient has an autopsy with examination of the brain. The ascertainment of cases has significantly improved since the National Prion Disease Pathology Surveillance Center was established in 1997, with 231 sCJD cases diagnosed in 2016 compared with 44 cases reported in 1998. Two main issues are important for understanding the difficulties investigators face in undertaking TSErelated epidemiological studies involving lookback investigations. One is the rarity of the disease in studied populations. The second is that, unlike other infectious diseases, these disorders manifest after long incubation periods after infection, which may extend to decades. In three instances of vCJD in recipients of nl-RBCs obtained from clinically healthy donors who later developed vCJD, the incubation periods were 6.5, 7.8, and 8.3 years after transfusion. For obvious reasons, the incubation period or duration of the preclinical phase cannot be established in sCJD, which occurs for unknown reasons, mainly in the seventh decade of life, and usually has a very short clinical course (median, 3-4 months). The difficulty in carrying out lookback studies doi:10.1111/trf.14239