Transfusion safety in the 21st century: how tightly should the blood community close the window(s)?

HIV was present in 1.1% of transfused blood during the early 1980s in some communities [1]. Perceived shortcomings in the response of the blood community, regulators, and public health authorities led to an exceptionally precautionary approach to transfusion-transmitted infections [2]. In return for unprecedented protection of transfusion recipients, blood donors have since been subjected to behavioral interrogation and testing, which uses 9 assays for 6 transfusion-transmissible infections, with great success. Behavioral deferrals (blood donor deferrals for high-risk behaviors) are surrogates, usually developed in the absence of acceptable laboratory tests, and they are blunt instruments. Still, for HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV), donor recruitment and interviewing reduce the prevalence of infection in donations from first time blood donors by 80% [3], compared with the US population. Behavioral deferrals are retained after test deployment as a layer of protection against false-negative test results, test errors, and erroneous component distribution. Residual transmission still occurs, and the lack of positive and negative predictive value for donor history causes donor loss and confusion, which are potent stimuli for test development. Food and Drug Administration (FDA)–approved donor tests are among the most sensitive and specific serological tests available in any venue. By 1993, the estimated risks of missing a potentially infectious donation during the seronegative window, with tests for HBV surface antigen (HBsAg) with anti-HB core antigen, anti-HCV antigen, and/or anti-HIV antigen, fell to one in 63,000, one in 103,000, and one in 493,000, respectively [4]. Tests for human T lymphotropic virus types I and II and syphilis are also required; tests for West Nile virus (WNV) and Trypanosoma cruzi have been voluntarily adopted. In 1996, despite clinical trials involving 500,000 donors that failed to demonstrate yield of additional infected blood donors compared with antibody assays [5, 6], HIV p24 antigen testing was required for all US blood donations [7, 8], a policy exemplary of the risk aversion dominating transfusion medicine with respect to infectious diseases. Direct viral detection was being used because of its promise to close the seronegative window between HIV infection, infectivity, and the evolution of a detectable antibody response. Nucleic acid amplification tests (NATs) were developed at the same time, after studies of multiple closely spaced samples in seroconversion panels from paid plasma donors showed NAT to be more sensitive during acute infection than antibody (and antigen) detection [9, 10]. The Commissioner of Food and Drugs urged their development in 1994, and their use was subsequently required by European manufacturers of plasma derivatives (e.g., clotting factors and intravenous immunoglobulins), to whom US blood centers provide recovered plasma. In 1999, with sufficient automation to support the throughput needed for donor screening, unlicensed polymerase chain reaction and transcriptionmediated amplification assays for HIV and HCV were implemented under Investigational New Drug (IND) exemptions from the FDA [11–13]. Testing minipools (MP-NAT) of aliquots from 16 –24 donations allowed the processing of millions of donations annually and the discontinuation of p24 testing, while providing adequate sensitivity for the high viremia characteristic of HIV and HCV infections prior to seroconversion. Serologic analysis continued for the detection of chronic infections. The modeled risks from these 2 viruses are now around 1 in 2 million donations [14]. HBV NAT is not widely used because contemporary HBsAg assays approach the sensitivity of MPNAT [15], anti-HB core antigen testing Received 24 June 2008; accepted 25 June 2008; electronically published 4 September 2008. Potential conflicts of interest: none reported. Financial support: Abbott Diagnostics Division; Roche Molecular Systems. Reprints or correspondence: Louis M. Katz, MD, 5500 Lakeview Pkwy., Davenport, Iowa 52807 ([email protected]). The Journal of Infectious Diseases 2008; 198: 1258 – 61 © 2008 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2008/19809-0002$15.00 DOI: 10.1086/592278 E D I T O R I A L C O M M E N T A R Y