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• W2757204566 abstract "Bacterial contamination of platelets remains the foremost infectious risk to the US blood supply. Breeches in aseptic technique, coupled with platelet storage at high temperature (20-24°C) in gas-permeable bags, favors bacterial growth, particularly with skin flora (e.g., coagulase-negative Staphylococcus and S. aureus) introduced at the time of platelet collection.1 Despite extant safeguards (i.e., donor arm disinfection,2 diversion pouches,3 and primary bacterial culture4), bacterial contamination and associated septic transfusion reactions continue to exact a significant toll. Contemporary estimates suggest that there is laboratory evidence of bacterial growth in 0.94 to 0.96 per 10,000 transfused platelet products, with a concomitant risk of nonfatal and fatal septic transfusion reactions in 1 per 100,000 and 1 per 500,000 transfused platelet products, respectively.5 Indeed, 10% of all transfusion-associated fatalities that were reported to the US Food and Drug Administration (FDA) between 2011 and 2015 were ascribed to bacterial contamination of blood products, for which platelets were overwhelmingly responsible.6 The residual risk of bacterial contamination of platelets is of sufficient clinical importance that the FDA is investigating additional blood-safety measures, which were communicated in a draft guidance in March 2016.7 The guidance outlines two broad approaches to contend with the residual risk of bacterial contamination of platelets: pathogen reduction and/or additional bacterial testing (i.e., either rapid testing before issuing or secondary culture of platelets). In this issue of TRANSFUSION, Li and colleagues argue in favor of rapid bacterial testing using an economic or cost-based argument.8 The authors offer a comprehensive analysis, comparing the costs of platelets that have been subjected to pathogen inactivation (PI), in this case using INTERCEPT (Cerus Corporation), with that of secondary testing of platelets using the Platelet PGD Test (Verax Biomedical). The authors conclude that hospitals will assume a 30% greater cost with PI-treated platelets than if testing with PGD were to be applied. Although the cost is difficult to overlook, the debate is more nuanced, with both strengths and limitations of the different approaches. PI and other pathogen-reduction systems offer a comprehensive approach to infectious risk that is not confined to bacterial contamination. Although various pathogen-reduction approaches are in use, INTERCEPT (Cerus Corporation) has gained the most traction—at least in the US market—having already obtained FDA licensure for use in platelets and plasma. INTERCEPT employs photochemical inactivation (the combination of a proprietary psoralen and ultraviolet light) to render pathogens and white blood cells unable to replicate. INTERCEPT has demonstrated effectiveness against different classes of pathogens, including the conventional bacteria commonly implicated in septic transfusion reactions (e.g., S. aureus), the major transfusion-transmissible viruses (e.g., human immunodeficiency virus [HIV], hepatitis B virus [HBV], hepatitis C virus [HCV], West Nile virus, etc.), and protozoa (e.g., Trypanosoma cruzi, Babesia microti, and Plasmodium falciparum). Collectively, pathogen reduction affords benefit against emerging, re-emerging, and potentially novel pathogens. It also offers a host of secondary benefits that include effective prevention of transfusion-associated graft-versus-host disease.9, 10 The latter bypasses the need for irradiation, which continues to pose logistical and security challenges to transfusion services. Importantly, pathogen reduction–treated platelets have demonstrated safety and efficacy comparable to those of untreated platelets.11 Nonetheless, Li and coworkers describe the current limitations of pathogen reduction.8 Foremost is cost. The authors cite a hospital purchase price of $100 per PI-treated platelet product. Despite a host of factors that could influence the direct cost, this seems a fair, contemporary estimate. There are also additional factors that further compound the cost, such as a lower platelet recovery and survival after the transfusion of PI-treated platelets, thus necessitating a higher number of transfusions than standard (i.e., untreated) platelets. A 20 to 30% increase in cost to contend with a single infectious risk is not trivial, particularly in a financially strained industry that has been the subject of significant downsizing over the past 5 years.12 In short, hospitals are likely to resist such an increase. That leaves a second approach of rapid testing before platelet issue. Two platforms have been licensed for this purpose, the Platelet PGD Test (Verax Biomedical), which is the focus of Li and colleagues’ analysis,8 and the BacTx assay (Immunetics, Inc.). The Platelet PGD Test (Verax Biomedical) employs a proprietary technology to detect conserved antigens lipoteichoic acid and lipopolysaccharide found in Gram-positive and Gram-negative bacteria, respectively.13 Similarly, the BacTx assay (Immunetics, Inc.) is a rapid colorimetric assay that detects bacterial peptidoglycan, a component of bacterial cell walls, thus enabling the detection of both Gram-positive and Gram-negative bacteria.14 Inherent to rapid testing is an expectation of low technical complexity and ease of use. A key advantage is that it is undertaken near the time of issue (i.e., within 24 hours of transfusion for the Platelet PGD Test). In so doing, the infectious status of the product can be gauged—accurately—before transfusion. Thus, the Platelet PGD Test offers the means to extend the platelet shelf life to 7 days, relieving pressure on transfusion inventories and reducing the risk of platelet outdating. However, the major advantage of rapid bacterial testing is also the proverbial “dual-edged sword,” introducing formidable logistical challenges to transfusion management. Turnaround times of 30 minutes and 60 minutes are required for the BacTx and Platelet PGD assays, respectively, before they can be called negative. Although tests can be set up in parallel, and a test may be called positive before completion of the test time, the inherent delay may prove intolerable for high-volume transfusion settings, notably in the context of trauma and/or massive transfusion. Such an approach may lend itself better to use in clinical settings, where demand is low and transfusions are predominantly prophylactic in nature (e.g., outpatient oncology). Although it is comparatively less expensive than pathogen reduction, rapid testing is also by no means a “cheap” option, requiring both purchase of the test kits and the technologist time to run the tests. Finally, although testing can be completed 24 hours ahead of release, this proves difficult to operationalize, given uncertainty about how many transfusions will occur in any given day. Non-transfused platelets will need to undergo repeat testing, compounding the institutional cost and logistical burden. A third option is that of a second bacterial culture system at the transfusing facility. This revisits the assumed deficiency in primary culture systems. Specifically, there is risk that the initial inoculum shortly after collection (i.e., that sampled for primary culture) is too small for detection. False-negative test results with primary bacterial culture (i.e., undertaken 24 hours after blood collection) are well described, with an incidence ranging from 0.215, 16 to 0.06%17 and with surprisingly little difference observed between buffy coat and apheresis platelets.5 In contrast, a second bacterial culture system is based on sampling of the platelet product at time of receipt (approximately 3 days after collection) at the transfusing facility (e.g., hospital); this optimizes detection, given the interval growth, if there is contamination. In itself, this lends an additional safeguard against bacterial contamination. It also can be implemented at large institutions, where the volume of transfusion is high and time-sensitive. From recent experience at our institution, secondary bacterial culture could be effectively implemented and has already shown benefit (detection of breakthrough cases of bacterial contamination) at comparable or lower cost than the presented alternatives. Importantly, it has not been disruptive to routine workflow. Nonetheless, a second bacterial culture is inherently a redundant system; the cost is not insignificant, requiring additional technologist time to sample blood products, load the cultures, and manage positive results. There is also a risk of false-positive results, both because of the system itself as well as introduction at the time of sampling. Acknowledging personal biases, I would say that cost analysis imparts a selectively skewed argument. First, the testing-versus-pathogen reduction debate is focused on the prevention of a single pathogen or, in this case, a class of pathogens (i.e., bacteria), thus neglecting the collateral benefit that actually makes pathogen reduction compelling. Pathogen reduction offers a broad-based strategy against multiple classes of pathogens, including those agents both known (e.g., the major transfusion-transmitted infections, such as HIV, HBV, and HCV) and emerging. The latter extend to agents that are currently in the process of being addressed (e.g., Babesia, Zika) as well as those as yet unknown, which undoubtedly will emerge and need to be addressed. Second, the health-economic debate portrays pathogen reduction as an incremental cost, in which it complements rather than replaces extant testing (e.g., Treponema pallidum, T. cruzi, Zika, etc.) and culture (i.e., bacteria). Although it may be naive to assume that some level of testing for the major transfusion-transmitted infections (i.e., HIV, HBV, and HCV) would be abandoned with the use of pathogen reduction, testing could be rationalized, particularly for those agents in which screening remains low yield, at least in the United States (e.g., Zika, T. cruzi, and human T-lymphotropic virus). As just one example, the current strategy of individual-donor nucleic acid testing for Zika is projected to incur $137 million annually in testing costs18; photochemical inactivation has already been shown to be effective against Zika.19 From a global health perspective, bacterial contamination of platelets and other blood products in low-income to middle-income countries remains grossly neglected,20, 21 for which pathogen reduction offers an innovative step forward. To preempt the critics, the cost and technical considerations of pathogen reduction are amplified in resource-poor settings, detracting from a short-term solution to bacterial contamination. Furthermore, if broadening the debate beyond platelets, a red blood cell or whole-blood pathogen-reduction technology has yet to be licensed in the United States. Given that red blood cells are the major transfused blood product, this renders much of the above argument about rationalizing testing a moot point, at least given a short-term outlook. Bacterial contamination remains a significant challenge to blood safety, the full extent of which is likely not visible given under-reporting.22 Yet, we are left with the dissatisfying absence of a perfect solution. Primary bacterial culture after early (24-hr) sampling still fails to address bacterial contamination completely. The residual risk of breakthrough infection is ascribed to false-negative test results, whereby sampling is undertaken early when bacteria may still be in lag phase and thus quantitatively insufficient for detection. Rapid testing and secondary bacterial culture are logistically complex and/or costly, necessitating additional staff to maintain workflow effectively. Pathogen reduction is relatively simple from the perspective of the transfusing institution; but it remains a high-cost technology. Alternative approaches, such as nucleic acid testing and flow cytometry,23, 24 have also been investigated yet do not seem to have been widely implemented. One size does not necessarily fit all: instead, there is a range of options that should be tailored specifically to a given institution's needs, tempered by what the regulation allows. Residual risk of bacterial contamination is actively being addressed: new, mandatory countermeasures are likely to be forthcoming, and the available options will both improve and expand with time, whereby wider adoption and technical innovation will reduce cost and continue to bolster blood transfusion safety. EMB is a co-investigator on a Terumo-BCT–sponsored trial to evaluate pathogen reduction of platelets in the United States. Evan M. Bloch, MBChB, MD, MS e-mail: ebloch2@jhmi.edu Department of Pathology Johns Hopkins University, School of Medicine Baltimore, MD" @default.
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• W2757204566 title "Residual risk of bacterial contamination: what are the options?" @default.
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