ORIGINAL ARTICLE

Emerging infectious disease agents and their potential threat to transfusion safety

Susan L. Stramer, F.Blaine Hollinger, Louis M. Katz, Steven Kleinman, Peyton S. Metzel, Kay R. Gregory, and Roger Y. Dodd

INTRODUCTION BACKGROUND: Emerging infections have been identi- fied as a continuing threat to human health. Many such The concept of emerging infectious disease (EID) has infections are known to be transmissible by blood trans- developed over the last 2 decades, as it became apparent fusion, while others have properties indicating this that full control of infectious disease had not been potential. There has been no comprehensive review of achieved. From 1997 data, the World Health Organization such infectious agents and their threat to transfusion (WHO) estimated that infectious diseases were respon- recipient safety to date. sible for about 33% of all deaths worldwide primarily in STUDY DESIGN AND METHODS: The members of the developing world, and these diseases remain one of AABB’s Transfusion Transmitted Diseases Committee the principal challenges to human survival (WHO The reviewed a large number of information sources in World Health Report 1998: Life in the 21st Century. A order to identify infectious agents with actual or poten- vision for all. World Health Organization, Geneva, 1998; tial risk of transfusion transmission now or in the future http://www.who.int/whr/1998/en/index.html). Emerging in the US or Canada; with few exceptions, these agents infections are defined as those whose incidence in do not have available interventions to reduce the risk of humans has increased within the past 2 decades or threat- 1 such transmission. Using a group discussion and ens to increase in the near future. Emergence may be due writing process, key characteristics of each agent were to evolution of an existing organism, to the spread of a identified, researched, recorded and documented new agent, to the recognition of an infection that has been in standardized format. A group process was used to present in the population but has gone undetected, or to prioritize each agent on the basis of scientific/ the realization that an established disease has an infec- epidemiologic data and a subjective assessment of tious origin. Emergence also may be used to describe the public perception and/or concern expressed by regula- reappearance of a known infection after a decline in inci- 1 tory agencies. dence. The first emerging infection to have a major effect RESULTS: Sixty-eight infectious agents were identified on blood safety was human immunodeficiency virus and are described in detail in a single Supplement to (HIV), the agent responsible for acquired immunodefi- TRANSFUSION. Key information will also be provided ciency syndrome (AIDS), and the lessons learned from in web-based form and updated as necessary. The highest priorities were assigned to Babesia species, Dengue virus, and vCJD. CONCLUSION: The information is expected to support From the Scientific Support Office, American Red Cross, the needs of clinicians and transfusion medicine experts Gaithersburg, Maryland; Eugene B. Casey Hepatitis Research in the recognition and management of emerging infec- Center, Baylor College of Medicine, Houston, Texas; Mississippi tions among blood donors and blood recipients. Valley Regional Blood Center, Davenport, Iowa; UBC School of Medicine, Victoria, BC, Canada; AABB, Bethesda, Maryland; Fenwal, Inc., Lake Zurich, Illinois; Regulatory Affairs, AABB, Bethesda, Maryland; and American Red Cross Holland Labora- tory, Rockville, Maryland. Address correspondence to: Susan L. Stramer, PhD, Scien- tific Support Office, American Red Cross, 9315 Gaither Road, Gaithersburg, MD 20877; e-mail: [email protected]. doi: 10.1111/j.1537-2995.2009.02279.x TRANSFUSION 2009;49:1S-29S.

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that epidemic have sensitized us to the need to be alert to respiratory syndrome (SARS), a disease caused by an those emerging infections that can impact blood safety in animal coronavirus previously unrecognized in humans the future. and again probably transmitted from exotic mammals Any infection with an asymptomatic blood-borne used as a food source.5 Another cause for emergence is the phase has the potential for transmission by transfusion, expansion of existing infections into a larger geographic whether the infectious phase is prolonged, as is the case region and/or a greater proportion of a susceptible popu- for hepatitis B virus (HBV) or HIV,or short, as in the case of lation, often brought about by ecological and/or behav- West Nile virus (WNV) or dengue virus (DENV). Other ioral changes or by population movement. A striking characteristics that are necessary for transmission by example of this has been the emergence of WNV in the transfusion are the survival/persistence of the infectious Americas.6,7 It is unclear how the virus, which is primarily agent in collected blood or components, and its ability to a bird-mosquito pathogen for which humans become an cause infection by the intravenous route. Transfusion unintentional host, initially entered the United States transmission will be of little relevance unless the agent (US), but its subsequent spread across the continent and also causes identifiable disease in the recipient. The fre- into the Caribbean and Latin America has been extraordi- quency with which an infection is transmitted to blood narily rapid and complete. Other examples of potentially recipients depends directly upon the length of the asymp- transfusion-transmissible agents that are expanding tomatic blood-borne period, how often blood is donated geographically include DENV and chikungunya viruses during this period, and the immune status of the recipient (CHIKV), Plasmodium species (malaria), Babesia species, population. A number of factors relating both to the infec- and Trypanosoma cruzi (the agent of Chagas disease).8-12 tious agent and to the genetic and immunologic makeup Another source of apparent emergence is the new recog- of the recipient also will determine the frequency and nition of existing human agents, often as a result of severity of the disease resulting from the infection. pathogen discovery techniques. Examples of this include Concern about transfusion-transmitted infections human herpesvirus-8 (HHV-8), the nonpathogenic GB seems to be driven by two sets of factors. First is the public viruses (GBV-C, initially termed hepatitis G virus or health impact of the infection, characterized by its fre- HGV),13 and Torque teno viruses (TTV/SEN-V).14 Some quency and the severity of the outcomes, and by the risk of infections emerge (or re-emerge) as a result of the break- secondary transmissions that can be determined in more down of public health measures for previously controlled or less quantitative terms. Second is the public reaction infections including the failure of initially effective vac- to the disease, which appears to be driven, in some cines, antibiotics, or vector control programs; examples examples, more by emotional aspects and is not readily are the re-emergence of malaria in areas of prior control quantitated. The public response may be disproportion- and the geographical spread of DENV and CHIKV. Finally, ate to the severity of the infection. However, both aspects otherwise benign infections may become serious patho- must be considered when responding to the threat of gens in the face of modern medical treatments, par- transfusion-transmitted infections. Priority setting in ticularly those involving immunosuppression. This group response to potential and emerging transfusion- includes agents like cytomegalovirus (CMV) and other transmitted infections must evaluate both the public herpesviruses, human parvovirus B19 (B19V), and Babesia health aspects, driven by scientific data, and the public species. response to, or perception of, the agents and their risk. Several factors that can contribute to the emergence Many mechanisms lead to the emergence of infec- of an infection frequently work together. Environmental tious diseases.2 Most dramatic is the appearance of a com- change (often as a result of human interventions) is a pletely new human infection. This most often reflects a major source, but changes in living conditions also may circumstance in which a zoonotic infection crosses over have a significant impact. Urbanization, particularly in the into the human population. A classic example is HIV/ developing world, can lead to very crowded conditions AIDS, which is thought to have occurred as a result of with limited hygiene. Social disruption and conflict also cross-species transmission of simian immunodeficiency have been associated with numerous outbreaks. Of par- viruses from monkeys to great apes and then to humans in ticular relevance to transfusion medicine is travel, which Africa.3 The original transmission perhaps occurred as a has been a major factor in the spread of emerging infec- result of preparation of bushmeat derived from apes for tion (consider, for example, HIV, Plasmodium species, T. human consumption. Such species crossings may be cruzi, DENV, and CHIKV).3 Sometimes the spread of an accompanied, or facilitated, by genetic changes in the emerging agent is a result of the importation of an animal infectious agent.2,4 In the case of HIV, the subsequent host (for example, the introduction of monkeypox into the transmission of the virus resulted from a variety US), a vector such as a mosquito, or even a food. Mobile of human behaviors involving sexual and injection drug reservoirs (e.g., birds) can transport pathogens from one use networks, travel, and blood-borne transmissions. A region to another over long distances (for example, WNV second example of such a species jump was severe acute or the highly pathogenic H5N1 influenza A virus). In the

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context of transfusion, while donor travel may not initiate Ideally, there should be systems in place to deal with or expand an epidemic, it can result in the transmission of emerging infections, not only generally, but also specifi- an exotic, foreign agent to a recipient. cally in the context of transfusion safety. Primarily, this is There have been a number of articles and reviews on the responsibility of agencies that are charged with the the subject of emerging infections and their impact, or maintenance of public health, the management of the potential impact, on transfusion-associated illnesses,9,10,15 blood supply, and its regulation. As it is unlikely that but there does not appear to be any systematic review the first occurrence of an emerging infection will be seen identifying a wide range of such agents and their key pro- in a transfused recipient, it is important that there be a perties. Neither is there any comprehensive guidance to system of assessing the threat and risk of emerging transfusion service and clinical staff on how best to recog- infections for their potential impact on blood safety and nize and manage emerging transfusion-transmitted infec- availability. This requires a process for evaluating each tions. In this context, it is important to note that while emerging infection for its transmissibility by this route decisions and recommendations about the overall man- and for estimating the severity and potential extent of the agement of blood safety are likely to be made at the insti- threat. The risk assessment should help to define the need tutional level (i.e., regulatory agency, blood system, or for, and urgency of, development and implementation of professional organization), individual practitioners also interventions to reduce the risk of transmission of the have specific responsibilities. A blood center or transfusion agent. Such interventions, if implemented, must then be service physician may need to decide whether to accept or evaluated for efficacy and modified as appropriate. defer and how to counsel a donor with a history of disease, There is no simple formula for recognizing that a infection, or exposure, while a caregiver may be faced with transfusion-transmitted infection has occurred, particu- the challenge of diagnosing, recognizing the link to blood, larly in the case of a rare or unusual disease agent. Nev- and reporting a suspected posttransfusion infection. ertheless, many such events have been recognized by The intent of this Supplement is to provide a set of astute clinicians. Knowledge of the potential for trans- tools identifying, describing, and prioritizing those EID mission of an emerging infection can be valuable and agents that have an actual or potential risk of transmis- very likely contributed to the relatively early recognition sion by transfusion and for which there is no currently of transfusion transmission of WNV.16,17 Unusual post- implemented intervention. Of necessity, this list of transfusion events with a suspected infectious origin emerging agents is not, and can never be, exhaustive due should be brought to the attention of experts in infec- to the nature of EID agents, but it does reflect the con- tious diseases and public health agencies for assistance sensus opinion of a group of experts. The major part of in identification and follow-up. Investigation of illness the Supplement consists of a set of 68 Fact Sheets, each occurring a few days or more after transfusion can diag- of which provides referenced, systematic information nose infections using serologic or molecular evidence of about a single agent. (See Appendix 2.) Included is stan- infectious agents in posttransfusion samples. However, dard background information about each agent, along such detection is by no means definitive. A pretransfu- with an assessment of those characteristics specifically sion patient sample is extremely helpful if available, as related to transfusion transmission. Although it is not this will reveal whether an infection predated the trans- intended that the Fact Sheets should provide specific fusion. Clinicians may not realize that type and cross- recommendations about donor or patient management, match samples and diagnostic blood specimens may be consensus opinions about prudent approaches to a available for up to 2 weeks following collection before number of issues (such as donor deferral periods) are they are discarded by the laboratory. Finally, recall and included wherever possible based on facts that are cur- further testing of associated donors can tell us whether rently inferred or known. Additionally, an attempt has one or more of them was the likely source of the infec- been made to rank the agents according to the consen- tion. Ideally, if the responsible agent can be isolated from sus opinion about their anticipated impact upon blood both donor and recipient, molecular analyses, such as safety. Such a ranking should not be regarded as defini- nucleic acid sequencing, can assist in identifying or tive, and another group of experts may come to different excluding the same agent from the two sources. When a conclusions. However, it may serve to focus attention on connection is made, testing of co-component recipients agents that merit more immediate attention in the devel- can further confirm transmission from a single donor via opment of plans for future interventions and might serve multiple blood components. to focus the attention of the clinician on possible starting There are significant problems in recognizing that points for the diagnosis of an unfamiliar infection poten- infections with very long incubation periods may have tially associated with transfusion. It is critical to re- been transmitted by transfusion; this was illustrated by member, however, that the very essence of emerging HIV/AIDS, which did not result in well-defined illness infections is that their evolution and manifestations are until long after the infection occurred. This delayed early inherently unpredictable. recognition of transfusion-transmitted HIV and concealed

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the magnitude of the infectious donor and infected reci- ity of this approach have proven adequate historically as a pient populations. Proactive approaches to transfusion standalone strategy, with the exception of the dramatic transmission of EIDs, especially those with lengthy incu- reduction in HIV transfusion transmission in the early bation periods, include the serologic or molecular evalu- 1980s in San Francisco following targeted questioning25) ation of appropriate donor-recipient sample repositories, and upon the use of laboratory tests, or a combination of or engaging in active surveillance such as that used in the these approaches. The availability of a specific donor United Kingdom (UK) to identify the transmission of screening test, however, should make it possible to elimi- variant Creutzfeldt-Jakob disease (vCJD) by transfu- nate or at least refine donor questions.26 Finally, there is sion.18,19 However, donor-recipient repositories require a hope that pathogen-reduction methods will provide a large investment to create and maintain and have other generalized, proactive intervention to eliminate or reduce limitations such as adequacy of sample size to detect rare the risk of transmission of emerging infections by events, the timing of collection of the retained samples transfusion; however, such methods are not yet available (which may predate the agent’s emergence), and the for all blood components and their success and safety geography of collected samples which may be outside of have not undergone extensive validation in the real the affected area.20 Hemovigilance programs, while world. valuable for other reasons, are unlikely to contribute sub- Usually interventions are not implemented until it stantially to the identification of newly emerging post- is clear that transfusion transmission has occurred, transfusion infections since they are generally designed to although in some cases the potential outcome of trans- identify well-defined acute outcomes. mission is considered to be so severe that regulators An important component of preparedness is the require action even in the absence of documented trans- establishment of close relationships between blood estab- mission as was the case for vCJD (a decision that was lishments, regulatory authorities, public health agencies, based on, and cited in retrospect to justify, a rather strin- the medical community, and industry. This was exempli- gent form of the precautionary principle27,28). Regulators fied by the rapid and effective response in the US to the have considered, and some have even implemented, pre- emergence of WNV and the subsequent recognition of its cautions to reduce the risk of transmission of the non- transfusion transmissibility. Appropriate donor screening pathogenic simian foamy virus (SFV) out of fear that tests were rapidly developed and deployed within less infection occurring in a human might be accompanied by than a year of the confirmation of the threat to blood a mutation conferring disease-causing capability to the safety.7,21,22 virus.29 Although it is reasonable to consider plans for the The precautionary principle is often cited when management of an emerging transfusion-transmitted decisions about interventions to reduce the risk of infection, it is not clear when, whether, or how a response transfusion-transmitted infections are discussed. It is sug- to a potential threat should be triggered. Ideally, given the gested that in the absence of any specific information availability of suitable resources, studies to assess the about the efficacy of an intervention, implementation is actual extent and nature of the risk conveyed by high- appropriate as long as it does no harm. Commentary on priority agents would be undertaken. Assessment of the the precautionary principle suggests that it should not prevalence and incidence of the infection in the donor be invoked without some evaluation to assure that the population and of the nature and dynamics of emergence measure is not extreme and does not exceed other mea- would provide valuable information, as would investiga- sures taken in similar circumstances.30 The hope is that tion of the infectivity of the agent and of potential inter- information in this Supplement will contribute to ventions. These activities may be time-consuming and informed decision making and to appropriate and well- inappropriate in the face of an explosive outbreak, reasoned application of “precautionism.” although they may offer a foundation for decision making in the face of a less dramatic emergence, as was done FRAMEWORK FOR ASSESSMENT for T. cruzi antibody blood donation screening in the US.23,24 The Supplement is a project undertaken by the AABB The question of when to take specific actions to Transfusion-Transmitted Diseases (TTD) Committee. prevent or mitigate transfusion transmission of an EID The TTD provides consultation on all facets of transfu- agent is beyond the scope of this Supplement. However, sion and transplantation-related diseases and associated the information provided should contribute materially to donor management and laboratory testing. It consists the factual background necessary to make such decisions of volunteer members with expertise in various areas of and help establish some guiding principles for decision infectious disease and blood center operations, and making. Interventions may be based upon questioning includes liaisons from the Food and Drug Administration prospective donors about their medical risk or exposure (FDA), Centers for Disease Control and Prevention histories (although neither the sensitivity nor the specific- (CDC), the US Department of Defense (DOD), the

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American Society of Hematology, and the Association of • With good documentation, the agent must be trans- Public Health Laboratories. missible by transfusion or by organ/tissue transplan- The TTD committee undertook this project to collate, tation or such transmission must be biologically in a series of Fact Sheets, information concerning EID plausible (i.e., the agent is present in plasma or asso- agents posing demonstrated or potential risk to the safety ciated with blood cells or donor tissue during a time of transfusion or transplant recipients (Appendix 2). Spe- when the donor is asymptomatic or has a biological cifically, the task was to review and prioritize the status of basis to suggest the possibility to replicate in blood, current and EID agents that could be transfusion trans- tissue, or organs). mitted with potential adverse outcomes for recipients. • The agent must have the possibility of being intro- Creation of such a thorough review document was judged duced into the blood supply during an epidemic, fol- to be useful for overall policy development and strategic lowing an act of bioterrorism, or inadvertently during planning. In this document, most of the emphasis is its emergence. placed on transfusion-transmitted disease agents; • The agent must lack a current intervention strategy however, it should be noted that many issues relevant to that is widespread and known to be effective. agents transmitted by transfusion will overlap with agents that are transplant transmitted. Due to the potential for Many of these agents are considered pandemic blood-borne transmission of agents that are transplant threats or to have epidemic potential outside the US and transmitted, several agents for which organ transmission Canada, but the primary focus for this Supplement was has been documented, even in the absence of transfusion the presence, or threat, of the agent emerging in the US transmission, have been included (e.g., rabies virus and and Canada. lymphocytic choriomeningitis virus).31,32 Development of the Fact Sheets was an iterative The AABB TTD committee was aware of previous process. First a list of potential agents that met the pro- efforts to develop tools for communicating the threat of posed definitions for inclusion was developed and the EID agents entering the blood supply and was able to format for presenting the information was devised. Both obtain current versions of Héma-Québec internal EID naturally occurring agents and agents that could be charts (G. Delage, vice president, Medical Affairs) and considered bioterrorism threats were included. The information from the US DOD; materials being developed preliminary draft of each Fact Sheet was prepared by an by the US Public Health Service were requested but not individual TTD member. Each Fact Sheet was then sub- made available. Findings of meetings such as the CDC jected to broad discussion and underwent several addi- conference on tick-borne diseases33 and FDA conferences tional review cycles by various groups within the TTD. on parvovirus B19, malaria, and donor behavioral risks Articles in conventional and esoteric publications were were scrutinized: scrutinized to document blood-borne capability. This review included intensive fact checks and standardization • www.fda.gov/downloads/BiologicsBloodVaccines of format, culminating in a final review by the entire TTD NewsEvents/WorkshopsMeetingsConferences/ committee. TranscriptsMinutes/UCM055339.pdf Each Fact Sheet contains data published primarily in • www.fda.gov/downloads/BiologicsBloodVaccines peer-reviewed journals or texts that are relevant to the NewsEvents/WorkshopsMeetingsConferences/ agent and its potential to be transfusion transmitted, and TranscriptsMinutes/UCM054429.pdf when available also includes data relevant to transplant- • www.fda.gov/downloads/BiologicsBloodVaccines transmitted agents. They include general background and NewsEvents/WorkshopsMeetingsConferences/ epidemiologic information, as well as information specific TranscriptsMinutes/UCM054430.pdf to blood donation. In lieu of a comprehensive bibliogra- phy, a suggested reading list is provided for each agent Although the original intent was to prepare a series of that includes the most relevant citations on the agent’s consolidated matrices, it was apparent that the amount of capacity for transfusion transmission, and the source information collected exceeded the format of a simple articles documenting transfusion-transmission events. matrix and instead the document evolved into multipage The list of suggested reading includes one or more recent Fact Sheets for each specific agent. review articles or book chapters that will familiarize the In determining which specific EID agents should be reader with the agent’s general biologic and epidemio- included in this review, the following factors were consid- logic characteristics. ered (agents for which the FDA requires donor testing Pertinent consensus categories that were selected by have been excluded from this publication): the TTD core leadership for the Fact Sheets were designed to provide the necessary background for each agent as • The agent must infect or pose a potential risk to well as other data that were deemed relevant for a discus- humans. sion of their threat to recipient safety. These include:

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Disease Agent: Many sources were used to judge the plausibility of Disease Agent Characteristics: blood transmission. Obviously, peer-reviewed publica- Disease Name: tions and textbooks are of great importance and have Priority Level: been cited in the suggested reading, but for several of the • Scientific/Epidemiologic evidence regarding judgments, the necessary data have not appeared in those blood safety: venues. Other reputable and easily accessible public data • Public perception and/or regulatory concern sources such as the ProMed electronic mailing list server regarding blood safety: and websites like those of the US CDC and the WHO were • Public concern regarding disease agent: used as appropriate: Background: • http://www.promedmail.org/pls/otn/f?p=2400:1000 Common Human Exposure Routes: • http://www.cdc.gov/ Likelihood of Secondary Transmission: • http://www.who.int/en At-Risk Populations: Vector and Reservoir Involved: An estimate of the level of concern about the health Blood Phase: threat from each agent was undertaken to suggest thresh- Survival/Persistence in Blood Products: olds for intervention(s) to reduce or prevent transmission Transmission by Blood Transfusion: by transfusion.This was an unavoidably subjective process Cases/Frequency in Population: that included a review of the biology and epidemiology of Incubation Period: the agents, an estimate of public and regulatory concerns Likelihood of Clinical Disease: about the agents and an assessment of the availability of Primary Disease Symptoms: sensitive and specific donor screening approaches. The Severity of Clinical Disease: priority assessment also was driven by questions such as Mortality: an agent’s geographic location/presence, projections of Chronic Carriage: changes in geographic distribution (where it was going), Treatment Available/Efficacious: and where and how frequently prospective donors would Agent-Specific Screening Question(s): be at potential risk of exposure. In addition, the existence of Laboratory Test(s) Available: surveillance adequate to allow recognition and reporting Currently Recommended Donor Deferral Period: of putative transfusion transmissions, whether from phy- Impact on Blood Availability: sicians treating patients or reports to state or local health • Agent-specific screening question(s): departments, federal or national public health agencies or • Laboratory test(s) available: blood collection facilities was considered.The deliberation Impact on Blood Safety: also took into account the incubation period for each agent • Agent-specific screening question(s): and a rough estimation of the period of time that would • Laboratory test(s) available: be required to realize that there is a potential public Leukoreduction Efficacy: health threat. In so doing, the TTD committee applied the Pathogen Reduction Efficacy for Plasma Derivatives: experience and interventions used for prior emergent Other Prevention Measures: transfusion-transmitted agents to evaluate the selected Suggested Reading: EID agents. These included the potential impact of behav- ioral and testing interventions in addition to pathogen Documentation of transfusion transmission and its reduction strategies. Pathogen reduction strategies that clinical outcomes was a key component of this project. were analyzed included the impact of leukoreduction, When documentation was lacking, agents were evaluated physicochemical methods used in the manufacture of for their potential for transfusion transmission. For the clotting factors, and methods used outside the US or in former, the task was relatively straightforward. For the development in the US for cellular components and trans- latter, it was much more difficult because of a paucity of fusable plasma. Possible interventions were evaluated data and difficulties in proving the negative proposition relative to their potential to be effective and their estimated that transfusion is not implicated in transmission. The impact on the donor base. occurrence of an asymptomatic blood phase and its dura- If there is a shortcoming to what is known about the tion (whether a long-term chronic carrier state or shorter- many agents for which blood is a plausible vector, it is our term acute infection) were the critical elements used to passive surveillance system for transfusion transmission. estimate this “risk” of transmission. Available evidence For example, how often do clinicians seeing DENV in about the persistence or survival of an infectious agent endemic areas and during epidemics obtain the critical during blood component manufacture and storage was history related to transfusion? Are significant rates of examined where possible. Treatment availability and its transfusion-transmitted DENV obscured during an epi- effectiveness were reviewed. demic of vector-borne infection? The judgments made in

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these Fact Sheets should lead to discussions of where and ation included proof of transfusion transmission; preva- how to enhance surveillance by clinicians, the transfusion lence of the agent in an asymptomatic population that medicine community, and public health agencies if we might donate blood, blood components, or in some cases think the threat from an agent rises to the level of gather- organs and tissues; the possibility of an outbreak resulting ing more evidence. in increased incidence over a specific time frame; the A primary use of the Fact Sheets is to present methods attack rate and severity of disease caused by the agent; to decrease the risk of a given agent in the event of a and the availability of effective prevention strategies or transfusion-transmitted threat. However, each Fact Sheet treatment. If there was no published or other credible can also serve as a medical and technical resource to documentation that an agent had been transmitted by blood providers including medical directors or other cli- transfusion to humans, it could be assigned a risk of theo- nicians and blood center or transfusion service staff in the retical or absent. Theoretical was used if transmission event that donors or transfused patients present with a was biologically plausible because the agent had a blood history of or evidence for infection with one of these phase during asymptomatic infection. Absent was used if agents. Importantly, readers must understand that these this possibility was judged to be remote or if the agent was Fact Sheets do not represent regulatory guidance, but not associated with any known human disease. instead serve as an indicator of what is known, and as such Classification of the public perception and/or regula- can be used as a starting point to develop policy. tory concern for each agent’s risk was an inherently more The agents included in this Supplement have been subjective process. Regulatory concern was judged prima- chosen based on what we know now and the current judg- rily on whether such agents had been discussed in public ment of the members of the TTD committee. During the forums such as the FDA’s Blood Products Advisory Com- time it has taken to complete this work, additional Fact mittee (BPAC) or as part of other regulatory deliberations Sheets already have been incorporated into the document (e.g., simian foamy virus, monkeypox, and variants of HIV, and multiple revisions have been made to the original Fact HBV or HTLV). The category of public concern about an Sheets. As new information is accumulated, the TTD will agent was assessed by reviewing whether the agent had edit the Fact Sheets. Thus, additions and deletions to the been discussed in the popular press in relationship to Supplement are to be expected and encouraged; a 3-year transfusion and whether queries to the AABB or major cycle is planned. Readers are encouraged to challenge the blood providers had occurred. assessments, provide data, and suggest edits. Much of the Each category received an assessment of risk of value of the Supplement will be realized in the future if its high, moderate, low, very low, or absent. As previously audience sees it as a living document. Mechanisms to discussed, the scientific/epidemiologic risk category also receive public review/comments will be communicated included a classification of theoretical. When risk could through AABB publication channels; those comments not be precisely classified, an agent was assigned an inter- may result in revisions of Fact Sheets prior to regularly mediate categorization or a range (e.g., from low to very scheduled revisions, depending on the nature of the low) depending on where in the US/Canada, or outside comment. The Fact Sheets published in this Supplement the US/Canada, concern exists. will be posted on the AABB website. Modification of the The overall prioritization of risk was a synthesis of Fact Sheets or new additions to the Supplement will be the ratings in each category based on consensus of the posted on the AABB website. group with greater emphasis given to ratings in the first two categories: scientific/epidemiologic risk and public PRIORITIZATION OF SPECIFIC AGENTS and/or regulatory concern regarding blood safety. Categories of agents deemed to be of high or moderate The prioritization effort is intended to suggest where intel- priority are indicated by color: red, orange, and yellow lect and resources should be spent in planning for the as indicated below. The agents that have not been given future. This is an especially important message for devel- a priority status at this time were placed in a white opers of blood donation screening tests or pathogen category for the purpose of the Tables in this Supple- reduction methods since the lead time for research and ment; most of these agents remain on the watch list of development and clinical trials to bring products to the potential threats, while some have been assessed to have market place is generally many years. very little possibility of causing disease in transfusion Each agent was assigned a priority risk level under recipients. three different categories: scientific/epidemiologic evi- Red. Agents with low to high scientific/epidemiologic dence regarding blood safety, public perception and/or evidence of risk regarding blood safety with the potential regulatory concern regarding blood safety, and public for severe clinical outcomes. This priority also may be concern regarding the disease agent. influenced by the committee’s estimate of the risk of Scientific/epidemiologic risk assessment was based emergence of these agents in the US and Canada as well as on a review of available data. Factors taken into consider- public and/or regulatory concern.

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Orange. Agents with sufficient scientific/epide- the general US population and 2) the possibility of an even miologic evidence of risk in regard to blood safety that lower carrier rate in the US blood donor population due to might support their elevation to a higher priority in the travel deferrals based on time spent in the UK and Europe. future. These resulted in a priority rating of low for the scientific/ Yellow. Agents with absent to low scientific/ epidemiologic risk category. However, based on high epidemiologic evidence of risk regarding blood safety for public concern about this agent in the UK and other areas which there is public and/or regulatory concern. of the world that has influenced public perception in the White. Agents that were evaluated but no higher US about “mad cow disease,” considerable FDA attention priority appears warranted at this time. This category to the issue of vCJD transfusion transmission, and the very represents a watch list, subject to modification as circum- difficult donor counseling issues and potential for large stances change. numbers of donor deferrals attendant on implementation Appendix 1, Table A1 provides a complete listing of all of a test for vCJD, this agent was assigned a high rating agents by group (i.e., prions, viruses, rickettsiae, bacteria, with regard to public concern about blood safety. With all protozoa, and nematodes); Tables A2 through A11 provide factors taken into account, this led to the assignment of the priority scores for each agent by group. A complete the red priority category for vCJD. assignment of the prioritized agents is provided in Tables A12 through A14. Those agents associated with Dengue viruses (DENV) documented cases of transfusion transmissions are listed The assignment of the risk of transfusion transmission of in Table A15. Agents that are vector-borne are listed in DENV in the US is based on scientific/epidemiologic Table A16. The Fact Sheets are included as Appendix 2. evidence of transfusion transmissibility,35,36 and was Agents classified in the red, orange, and yellow cat- influenced by several opposing factors. In favor of a egories are as follows: higher risk were: 1) the common occurrence of asymp- tomatic infections and occurrence of viremia during the • Red category agents (highest priority): human variant asymptomatic period; 2) the demonstration of relatively Creutzfeldt-Jakob disease, dengue viruses, and high rates of virus-specific RNA detection in studies of Babesia species (Table A12). blood donors from endemic areas;37,38 3) the occurrence • Orange category agents: Chikungunya virus, St Louis of epidemics that affect a relatively high percentage of encephalitis virus, Leishmania species, Plasmodium the population at any one time; 4) the presence of com- species, and T. cruzi (Table A13). petent mosquito vectors in large parts of the US; 5) the • Yellow category agents: chronic wasting disease demonstration of high seroprevalence rates in US popu- prions, human herpesvirus 8, HIV variants, human lations on the Texas-Mexico border;39 and 6) the occur- parvovirus B19, influenza A virus subtype H5N1, rence of localized epidemics in Hawaii and Texas and simian foamy virus, Borrelia burgdorferi, and hepati- in Puerto Rico from where collected blood may be tis A virus (Table A14). imported into the continental US. In favor of a lower risk were: 1) the low incidence of autochthonous transmis- sion in the US and 2) travel deferral for visits to malarial Red category agents endemic locations that extensively overlap with DENV- Human variant Creutzfeldt-Jakob disease (vCJD) endemic areas that should defer returning donors with The assignment of the risk of transfusion transmission of asymptomatic DENV infection. A consideration of all of vCJD in the US is based on scientific/epidemiologic evi- these factors led the committee to assign a value of low dence of transfusion transmissibility and was influenced for scientific/epidemiologic risk in regard to blood safety. by several opposing factors. In favor of a higher risk were: However, in non-US DENV-endemic areas, this assign- 1) data from the UK indicating that if a donor is incubating ment would be moderate to high based on the preva- vCJD, there appears to be a risk of transfusion transmis- lence of the agent. Public concern for blood safety was sion18 and potentially a risk to hemophiliacs who received judged to be very low to absent in the US but moderate UK-derived plasma products prior to the implementation to high in some dengue-endemic areas. Overall, these of interventions to decrease BSE that were put into effect considerations led to the classification of DENV as red in 1996 (vCJD abnormal prion protein found in a patient priority category agents. with hemophilia at postmortem, Health Protection Agency, CJD Section, London, UK, http://www.hpa. Babesia species org.uk/webw/HPAweb&HPAwebStandard/HPAweb_C/ Based on the large number of transfusion-transmitted 1195733818681?p=1225960597236) and 2) the rapid mor- cases reported and the perception there is gross under- tality associated with clinical disease and the lack of reporting,40,41 Babesia was assigned a risk rating of effective treatment.34 In favor of a lower risk were: 1) the moderate to high on scientific/epidemiologic grounds presumed very low to absent rate of carriers of the agent in regarding blood safety. Pertaining to public concern, the

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agent was assigned a very low rating nationally but the US or Canada and 2) potentially effective prevention a moderate rating in areas known to be endemic for methods (specific geographical deferral for time spent in the agent (i.e., states in the Northeast and upper Iraq or travel to other areas where leishmaniasis and Midwest). Regulatory concern is evidenced by sponsor- malaria are both endemic, and the widespread use of leu- ship of a workshop on transfusion-associated babesiosis koreduction in North America). Public concern regarding in September 2008 by the FDA (http://www.fda. blood safety was judged to be low based on discussions at gov/downloads/BiologicsBloodVaccines/NewsEvents BPAC meetings. Because these agents have been demon- WorkshopsConferences/TranscriptsMinutes/ strated to be transmissible by transfusion and because UCM051501.pdf). Overall, the increasing recognition of they can potentially be introduced into the US by return- transfusion-transmitted cases, the severe outcomes that ing military personnel (as well as by other travelers), it was can occur in immunocompromised and asplenic trans- judged that Leishmania species could be of increasing sig- fusion recipients, and the lack of effective interventions nificance to blood safety in the future. to prevent transfusion transmission led to the classifica- tion of this agent in the red priority category. Plasmodium species Malaria is a major infectious disease associated with transfusion in many emerging and developing countries. Orange category agents In contrast, this risk is much lower in developed countries due to lack of endemicity of the agent. The Plasmodium Chikungunya virus (CHIKV) species were assigned a scientific/epidemiologic risk Due to the lack of any proven transfusion-transmitted rating of low in the US and in most nonendemic countries cases, CHIKV was assigned a scientific/epidemiologic risk in regard to blood safety due to their low prevalence rating of theoretical in regard to blood safety. However, coupled with the effective use of donor deferrals due to several scientific and epidemiologic factors were judged to travel, residence, or having had malaria. However, the risk contribute to the potential for an increased risk from this may be moderate to high in some nonendemic countries agent in the future. These include the rapid re-emergence based on the demographics and travel patterns of their of the infection in the Indian Ocean and parts of Africa donor population. Similarly, public concern regarding and Asia since 2005,42 the geographical spread of the virus both blood safety and transmissibility by other routes is by travelers returning from endemic areas to nonendemic likely to vary between endemic and nonendemic regions. regions, the presence of appropriate mosquito vectors In the US, the level of public concern was judged to be in various geographic locations including the US, the moderate. Several factors contribute to the possibility that increased vector efficiency of newly emerged strains, malaria may increase as a transfusion risk. These include and the presence of asymptomatic viremia in infected the re-emergence of the disease in nonendemic geo- individuals.43,44 graphic regions due to immigration and travel, an increase in sporadic cases of “airport malaria,” the occurrence of St Louis encephalitis virus (SLEV) autochthonous transmission in nonendemic countries Due to the lack of any proven transfusion-transmitted when plasmodia are introduced by immigrants (or rarely cases, SLEV was assigned a scientific/epidemiologic risk travelers), the possibility that global climate change could rating of theoretical regarding blood safety. However, due result in an expanded range of vectors, and the lack of a to its close phylogenetic relationship and similar epide- screening assay to interdict donors for whom risk is not miology to WNV, and the possibility for large outbreaks of recognized. St Louis encephalitis in the US, this agent was judged to have the potential to be a blood safety concern in the Trypanosoma cruzi future. T. cruzi is included even though an FDA-licensed test for blood donor screening has been available since Decem- Leishmania species ber 2006. The assignment of a blood safety scientific/ These agents were assigned a scientific/epidemiologic epidemiologic risk rating for this agent was influenced by risk rating of low in regard to blood safety. This risk rating the implementation of blood donor screening in 2007 by was influenced by several opposing factors. In favor of a the majority of US blood centers. Based on evidence of higher risk were: 1) transfusion transmission documented transfusion transmission in Central and South America, in at least three cases (and perhaps as many as 10) in documentation of transfusion-transmitted cases in North which the transfused recipients were either infants or America prior to donor screening, and the risk mitigation immunocompromised patients;45 2) the propensity for achieved by donor screening, this agent was assigned a chronic carriage of the agent; and 3) the presence of scientific/epidemiologic risk rating of low regarding asymptomatic parasitemia. In favor of a lower risk were: blood safety. When assessing public concern for blood 1) lack of any documented transfusion transmission in safety, T. cruzi was assigned a rating of moderate based

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on public and regulatory attention given to the introduc- This agent was assigned an overall priority rating of yellow tion of blood donor screening. Although the risk of trans- based on FDA concerns regarding potential transfusion mission of this agent should be decreasing in the US, transmission. These concerns would increase if donor uncertainties persist regarding autochthonous transmis- deferral criteria were to be modified for males who have sion and the sensitivity of the donor screening assay. sex with males, due to the relatively high prevalence of After 2 years of universal donor screening by most blood infection in this population. collection facilities in the US, testing strategies will likely be modified to a selective strategy, based upon at least HIV variants one-time testing of every donor. The committee felt Due to the lack of any proven transfusion-transmitted that this agent should be assigned an overall priority of cases, these agents were assigned a scientific/ orange, at least for the interval required for data relating epidemiologic risk rating of theoretical regarding blood to the efficacy of donor screening and the number of pre- safety. Although the wild-type agent (HIV-1, Group M) is vious transfusion transmissions (as assessed by lookback transfusion transmitted, transmission of HIV variants has investigations) to be collected and analyzed. not been documented. Assuming HIV variants are trans- missible by transfusion, the risk should be minimal in the US due to low local prevalence, cross-reactivity of HIV Yellow category agents screening tests, and use of questions for malaria exposure Chronic wasting disease (CWD) that would temporarily exclude donors who traveled to This prion agent has never been detected in humans and areas in Africa where HIV variation occurs at a high rate. no transfusion transmission has occurred, leading to a Since HIV variants may result in AIDS, the public concern blood safety scientific/epidemiologic risk rating of theo- in regard to blood safety was judged to be low to moderate. retical. However, because of public awareness of another In addition, the FDA has, appropriately, continued to be prion agent, vCJD, which is associated with mad cow concerned about the ability of blood screening tests to disease and lethal human infection, it was judged that detect all HIV variants and the ability of donor history there was low to moderate public concern about the pos- questions to screen out all potentially at-risk donors. For sibility that the CWD prion agent also might cross the these reasons, HIV variants have been assigned a priority species barrier.46-48 Public concern specific to blood rating of yellow. safety, however, was judged to be very low. Because of new scientific and public focus on this agent and its Human parvovirus B19 (B19V) associated disease in deer and elk in the US and Canada, Transfusion transmission of B19V from blood compo- the limited amount of research that has been done to nents has been proven, with at least four cases docu- date, the potential for this prion agent to behave in a mented in the literature. However, the frequency of manner similar to vCJD, and the extensive opportunities transmission has not been determined or estimated for donor exposure attendant to the popularity of through established mathematical models. These factors hunting, public health agencies (i.e., CDC) and regula- resulted in the assignment of a scientific/epidemiologic tory agencies responsible for blood safety have expressed risk rating of very low to low regarding blood safety. some concern even in the absence of any substantiating Public concern regarding blood safety risk was judged to data. As a result, this agent was assigned an overall pri- be very low in the US with the exception of some ority rating of yellow. concern among specific patient groups (i.e., patients with hemophilia, those with chronic anemia such as Human herpesvirus 8 (HHV-8) sickle cell disease or thalassemia, bone marrow trans- Although HHV-8 transfusion transmission has been plant recipients, and other immunocompromised indi- proven in Africa,49 a material risk of such transmission in viduals). Based on historical transmissions of B19V to the US has not been convincingly established.50 The US recipients of Factor VIII, there has been ongoing scien- risk should be considerably lower than that in Africa based tific and regulatory concern about the safety of plasma on several factors: the frequency of HHV-8 in the blood derivatives, leading many manufacturers and regulatory donor population is lower in the US, the storage age of authorities to require B19V DNA qualification testing of blood components is longer, and leukoreduction is incoming plasma and release testing of manufactured commonly, though not universally, employed. Despite lots. When such B19V DNA testing is applied to recovered transfusion transmission, clinical disease has not been plasma, the issue of how to manage associated remain- documented to have resulted from such transmission. ing in-date components from B19V DNA-positive Taken together, these factors resulted in a scientific/ donors has been a subject of much debate. For these epidemiologic risk rating of low in regard to blood safety. reasons, this agent has been assigned a priority rating of Public concern for blood safety also was judged to be low. yellow.

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Influenza A virus, subtype H5N1 apprehension of Lyme disease in areas of the country with Due to the lack of any proven transfusion-transmitted a higher prevalence of this disease, the agent has been cases, this highly pathogenic avian influenza agent was assigned a priority rating of yellow. assigned a blood safety scientific/epidemiologic risk rating of theoretical. Furthermore, based on the biology of Hepatitis A virus (HAV) known influenza viruses and of H5N1, it was concluded HAV transmission through blood is uncommon, but well 51 that transfusion transmission was unlikely to occur. documented, and can lead to secondary cases especially However, because H5N1 has been discussed as an agent when transmission occurs among infants in neonatal that could lead to a worldwide influenza pandemic, public intensive care units. Viremia often precedes the develop- concern about community transmission of this agent was ment of symptoms by 7-14 days. The presumed rarity of judged to be high, whereas concern related specifically to transfusion-associated cases is due to several factors that blood safety was judged to be very low. The high profile of include a short viremic phase, low concentration of virus this agent in the public health sector, especially with in the blood, absence of a carrier state, neutralization of regard to pandemic planning, led to assigning a priority the virus by specific antibody in other components con- rating of yellow. currently administered, routine immunization in popula- tions with high HAV incidence, and increasing prevalence Simian foamy virus (SFV) of immunity in recipients with age. HAV remains in the Although SFV transfusion transmission has been docu- yellow category based on the fact that the scientific/ mented in experiments in nonhuman primates, trans- epidemiologic evidence regarding blood safety is low but mission by transfusion has not been demonstrated in public concern is low to moderate, especially during a humans. In addition, this agent has not been shown to community outbreak of the disease. In the US, risk of cause any human disease. For these reasons, this agent transmission during a common source epidemic is miti- was assigned a scientific/epidemiologic risk rating of gated by the addition of a specific question to the donor theoretical with regard to blood safety. Public concern questionnaire regarding exposure that leads to a 120-day about this agent was judged to be absent. In contrast, deferral postexposure. some level of concern has been demonstrated by regula- tory agencies. This concern relates to the theoretical possibility that clinical disease does occur but has not Selected specific white category agents yet been recognized and/or that mutated strains of this In addition to the previously categorized agents, several agent may eventually show increased pathogenicity in agents on the watch list (i.e., white category agents) merit humans.2,4 In the US, SFV has been discussed at meetings further discussion, either because of recently changing of the BPAC without concern expressed by stakeholder information (e.g., hepatitis E virus [HEV] and Anaplasma groups or other members of the public (http://www. phagocytophilum) or because of concerns about the fda.gov/ohrms/dockets/ac/04/transcripts/2004-4074t1. potential use of the agent in a bioterrorist attack. Some of htm). In contrast, Health Canada, the Regulatory agency these latter agents are discussed in more detail in the in Canada (http://www.hc-sc.gc.ca/dhp-mps/brgtherap/ section on bioterrorism. activit/fs-fi/fact_simian_foamy_virus_spumeux_simien_ feuillet-eng.php), requires a permanent deferral for Hepatitis E virus (HEV) potential blood donors whose employment involves A small number of cases of HEV transmission by blood contact with monkeys or their body fluids.29 For these transfusion has been documented52 both in areas classi- reasons, this agent has been assigned a priority rating of cally viewed as endemic for human infection as well as in yellow. developed, industrialized countries.53 The sporadic (nontransfusion) cases in humans observed in the US Borrelia burgdorferi have been mostly imported from endemic areas.53 Due to the lack of any proven transfusion-transmitted This has led to assignment of a scientific/epidemiologic cases, this agent was assigned a scientific/epidemiologic risk rating of very low for this agent. The impact of risk rating of theoretical regarding blood safety. If this disease currently remains very low in the US and transfusion-transmission does occur, it is likely to be rare. public concern is absent for blood safety and clinical Conversely, given that this agent has been recognized and disease. Nevertheless, the potential for human infection in studied for many years, public concern about the general the US remains a possibility given that an HEV reservoir transmissibility of this agent and its resulting disease exists in pigs. The existence of this reservoir, combined manifestations (i.e., Lyme disease) was judged to be mod- with several cases of transfusion transmission in other erate, whereas public concern regarding blood safety was developed countries, indicates that HEV may increase in judged to be very low. Based primarily on the public priority.

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Anaplasma phagocytophilum synthesis, opinion, and public perception).56 The lesson There have been two published case reports of that we have learned since HIV emerged as a transfusion-transmitted infection in the US (one as an transfusion-transmitted agent is that what we do to abstract54 and one by the CDC in Morbidity and Mortality protect the safety of the blood supply is dependent on Weekly Report55). Due to this low number of both science and the expectations of the communities reported transfusion-transmitted cases, the scientific/ that we serve. epidemiologic risk assigned was very low. However, it is likely that more cases have occurred and have not been recognized or reported. Given the high seroprevalence CATEGORY A AGENTS OF BIOTERRORISM: rates in donors in some geographic locations, the demon- BLOOD SAFETY IMPLICATIONS AND strated survival of the organism in refrigerated red cells, ACTIONS IN THE EVENT OF AN ATTACK documented transfusion transmission in animal models, and an unknown period of asymptomatic bacteremia, it Blood establishments need to be appropriately prepared is possible that an increasing number of transfusion- in the event of a bioterrorist event. Key concerns are the transmitted cases will be recognized if surveillance is management of the existing and future blood supply once adequate. an attack has been identified. This requires knowledge of the potential impact of agents of bioterrorism on blood CATEGORIZATION INTERSECTION: safety and availability. Different actions may need to be SCIENCE VERSUS THE PUBLIC’S taken depending upon the magnitude of the attack and PERCEPTION the agent(s) involved. The CDC has classified several agents that might be As noted, categorization of agents on the scientific/ used for bioterrorism. Those considered to be of the epidemiologic scale was based on data that appeared in gravest concern are classified as Category A (http:// the scientific literature. In contrast, the public perception www.bt.cdc.gov/agent/agentlist-category.asp#a), and categorizations were developed by a more subjective include the agents of anthrax, botulism, plague, small- process. Agents may have low scientific priorities but pox, tularemia, and viral hemorrhagic fevers. These may be high on the public’s “radar” screen if the agents agents, exclusive of botulism, are listed in Appendix 1, are perceived as being those that might lead to signifi- Table A17. The characteristics and potential actions rela- cant human disease. As a means of showing the various tive to these agents are summarized in Appendix 1, conflicts or agreements in priorities, agents having red, orange, or yellow priority levels were plotted by factor- Range reflects subjectivity/uncertainty analytic representation56 (Fig. 1) where high geographic variability the x-axis is the scientific/ Plasmodia epidemiologic scale that ranges from a vCJD theoretical transfusion-transmission moderate risk to higher levels of proof of trans- mission and/or disease severity and T. cruzi SLE virus

incidence. In contrast, the y-axis is Leishmania HIV variants public concern (i.e., perception of risk) low CWD ranging from absent to high that occurs Babesia Influenza virus subtype H5N1 B. burgdorferi Dengue viruses B19 virus HAV Chikungunya virus Chikungunya

when there is the perceived potential HHV-8 Public Perception for dread, catastrophic or fatal conse- very low quences often accompanied by social stigma (e.g., HIV/AIDS) with lack of control over the outcome. Risk com- SFV munication and risk management absent science have shown that the higher the perceived risk, the more people want to theoretical very low low moderate high see the risk reduced, and the more they Science/Epidemiology want to see strict regulation employed to achieve the desired reduction in risk. Fig. 1. EID agent priority matrix, where the y-axis represents the priority based on Risk management efforts are destined public perception ranging from absent to high and the x-axis represents the to fail unless they are structured using priority based on science and epidemiology ranging from theoretical to high such a two-way process (expert data (see text).

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Table A18. These high-priority agents include organisms also become apparent that individuals may be colonized that pose a risk to national security because they: but exhibit no symptoms. Inhalation and gastrointestinal anthrax have incubation periods of 1-7 days, and if • Can be easily disseminated. untreated, fatality rates of 97% and 25-60%, respectively. • Can be transmitted from person to person. Cutaneous anthrax has an incubation period of 1-12 days • Result in high morbidity or mortality rates and have and an untreated fatality rate of 20%. Anthrax is not the potential for major public health impact. transmitted from person to person. While B. anthracis is • Might cause public panic and social disruption. frequently present in the blood of ill patients, the FDA • Require special action for public health preparedness. reports that bacteremia is thought to be extremely unlikely in asymptomatic individuals. Consequently, The items that require specific consideration for anthrax transmission by blood transfusion is not believed blood organizations in relation to a bioterrorist attack are: to occur provided blood is collected only from healthy • The risk of infectivity of blood components if an donors with normal temperatures. exposed individual gives blood prior to the appear- A bioterrorism attack would most likely occur ance of symptoms. through distribution of anthrax spores by the aerosol • The risk of contamination of collected blood as a route and/or distribution of the spores in powdered form. result of direct or indirect deposition of the agent on Spores are resistant to sterilization by chemicals or heat blood containers (also putting staff at risk). and restoring a contaminated area to a safe condition is • The impact of a bioterrorist attack on the availability difficult and time-consuming. In the event of known con- of donors and facility personnel. tamination of a blood establishment, it would be neces- • The impact of the attack upon the need for blood sary to evacuate staff and donors and to close the components. establishment pending remediation. • The impact of regulatory actions taken in response to In 2001, following the anthrax attacks, the FDA an attack. issued Guidance for Industry entitled: “Recommen- dations for assessment of donor suitability and blood A major attack may compromise the safety of the and blood product safety in cases of possible ex- blood supply to such an extent that blood collection posure to anthrax” (http://www.fda.gov/BiologicsBlood operations would have to be shut down in the area Vaccines/GuidanceComplianceRegulatoryInformation/ impacted by the attack. In addition, it may be necessary Guidances/Blood/ucm076711.htm). In this document, to quarantine in-date products, at least until the nature, the FDA did not recommend any changes to standard extent, and likely date of the attack is known. However, donor screening and blood collection practices to iden- an attack of lesser magnitude (for example, the anthrax tify or otherwise query donors who may have been attacks in 2001) will probably require management of exposed to anthrax. (Note that the document was pre- each donor and product according to individual pared after a rather limited exposure and that regulatory circumstances. advice might change in the face of a massive attack.) The The CDC bioterrorism page (http://www.bt.cdc.gov/ FDA did recommend deferral for donors with diagnosed agent/agentlist.asp) is a useful resource providing descrip- anthrax, suspected skin lesions, or known colonization tive information on all agents and ways to manage until they have completed a full course of antibiotic suspected attacks or exposures. There are also links to treatment and have been shown to be free of the bacte- other sites covering issues including reporting and clean- ria. Donors with skin lesions suspected to be anthrax up. A series of articles in the Journal of American Medical should be deferred until the lesion is later shown not to Association provides very useful information and the be anthrax or until the lesion is shown to be anthrax and specific reference is noted in each subtitle below. The the individual completes a full course of treatment and key characteristics of the agents listed in Table A18 are the infection is considered to be resolved. outlined. In the event that a donor reports postdonation infor- mation of anthrax, in-date blood components from prior donations should be quarantined and retrieved promptly; 57 Anthrax this should date back to the time of exposure or 60 days Anthrax is caused by the gram-positive, spore-forming prior to onset of illness, whichever is shortest. The FDA bacterium, Bacillus anthracis. Three forms of disease are also recommends recipient notification and that medical recognized: inhalation anthrax resulting from respiratory directors should determine an appropriate course of exposure (most likely to occur in the event of a deliberate action in the event of postdonation illness among donors attack); gastrointestinal anthrax resulting from the con- suspected of having been exposed. Should direct contami- sumption of contaminated food; and cutaneous anthrax nation of components with anthrax spores occur, blood manifesting as skin lesions, most often on the hand. It has products would have to be destroyed.

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Botulism58 donors with respiratory symptoms should be referred for Botulism results from exposure to a toxin produced by the medical evaluation and treatment. In the event of a major bacterium Clostridium botulinum. The toxin is extraordi- regional outbreak, it may be necessary to suspend blood narily potent and a lethal human dose is thought to be collection in that region until the outbreak is terminated. 0.09-0.15 mg intravenously, 0.70-0.90 mg by inhalation and Significant residual contamination of facilities is unlikely, 70 mg orally. Natural forms of botulism are foodborne, as the bacterium is very sensitive to environmental wound, and intestinal, but all have similar clinical out- inactivation. comes, namely an acute, afebrile descending flaccid paralysis that may lead to death from paralysis of the 60 muscles of respiration. The incubation period depends on Smallpox the quantity of preformed toxin to which an individual is Smallpox is caused by a large DNA virus known as the exposed and, in the case of foodborne exposure, may variola virus. Unlike other potential bioweapons, smallpox be from 2 hours to 10 days, but is usually 18-36 hours. has been eradicated in nature. The disease spreads rapidly A bioterrorist attack is likely to occur as a result of from person to person by droplet and aerosol routes and distribution of the toxin by the aerosol route or perhaps by by direct contact: contaminated surfaces such as bedding deliberate contamination of food. An attack via the water and clothing also may spread the infection. Individuals are supply is technically not feasible. most infectious from the time that the rash appears until There is no possibility of person-to-person transmis- 7-10 days thereafter. The usual incubation period is 12-14 sion of C. botulinum. It would seem very unlikely, if not days (with a 7-17 day range), and there is asymptomatic impossible, that a lethal dose could be transmitted by viremia starting about 3-4 days after exposure. The mor- blood transfusion, as such transmission would require tality is up to 30% and there is no known effective treat- that the donor would have to have a lethal dose of pre- ment. A biological attack would likely involve aerosol formed toxin in the blood. Thus, no Fact Sheet was devel- release that would be recognized as a cluster of cases. Each oped for C. botulinum. Donor deferral and quarantine and case may infect 10-20 others and isolation of cases would retrieval of components will not be needed unless an be required. Although there is no reported case of trans- attack targeted a blood establishment for contamination mission of smallpox by transfusion, this remains a possi- of products. bility. Therefore, robust interventions would be required for blood establishments, including deferral of cases and case-contacts and quarantine and recovery of blood com- 59 Plague ponents collected up to 21 days prior to the first case. Plague is caused by the gram-negative bacterium, Yersinia Second wave cases would complicate the situation. There pestis. There are two major forms of disease: bubonic, also would be obvious concern about staff exposure and it usually acquired by the bites of fleas that have fed on may be necessary to cease all operations until the extent of bacteremic rodents; and pneumonic, resulting from the outbreak is determined. Environmental contamina- aerosol (respiratory) exposure. Primary or secondary sep- tion from the attack itself will not be a serious issue as the ticemic plague also may occur. Pneumonic plague is the virus is not expected to persist in the environment for form most likely to occur as a result of a bioterrorist attack, more than 2 days. It is likely that an attack would result in although intentional transmission using infected fleas has the implementation of widespread vaccination programs. occurred. The overall mortality of bubonic plague is about The FDA has provided guidance on donor management 15%, but 50-60% of cases may die in the absence of treat- in the context of a smallpox vaccine program (http:// ment. Untreated pneumonic disease is usually fatal. Pneu- www.fda.gov/BiologicsBloodVaccines/GuidanceComplia monic disease may be transmitted from person to person nceRegulatoryInformation/Guidances/Blood/ucm07511 through respiratory droplets. The incubation period is 1-7 5.htm). It should be noted that this guidance requires days or 1-4 days for primary pneumonic plague. A bioter- donor deferral and such a deferral may have a significant rorist attack would manifest itself as an outbreak of impact upon product availability (particularly for plate- rapidly fatal respiratory illness 1-6 days after the attack; lets). An attack with smallpox is likely to be extremely chal- secondary cases would occur. Affected individuals may lenging to the blood system. have been bacteremic briefly at some time prior to the appearance of illness; therefore, their donated blood must 61 be presumed to be infectious. Quarantine and retrieval of Tularemia blood collected up to 10 days prior to the recognition of Tularemia is caused by a small, gram-negative bacterium, the outbreak would probably be prudent in the event of a Francisella tularensis. This organism infects a number of large outbreak. Presenting donors exposed to known cases wild animals naturally and may be found as an environ- should be deferred (probably for 2 weeks or until com- mental contaminant. Humans may be infected via the pletion of a prophylactic course of antibiotics). Staff or aerosol or droplet route, accidental inoculation, the bite of

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fleas or other arthropods, or even via food or water. The direct contact with symptomatic cases; consequently, it agent is highly infectious, with as few as 10 organisms may be necessary to defer such individuals from donation. causing disease. However, person-to-person transmission The viruses are not expected to survive very long in the does not occur. It is likely that a bioterrorism attack would environment, so there should be no significant facility be accomplished via an aerosol release. This would result clean-up issues for blood establishments. Finally, it in an outbreak of acute, febrile illness with respiratory should be noted that the clinical effects of these agents symptoms. The incubation period is 3-5 days, with a range may result in a need for blood components, and especially of 1-14 days. Although subjects may be incapacitated in a platelets, to correct the bleeding. matter of days, the untreated disease may be prolonged and can last weeks to months. Untreated inhalation tula- PATHOGEN REDUCTION AS A SAFETY remia may have a mortality rate of 30-60%. Bacteremia STRATEGY FOR EID does occur and deferral of cases and individuals thought to be at risk of primary exposure would be necessary, pending Introduction successful completion of therapy or of antibiotic prophy- This Supplement presents detailed information on laxis. Additionally, quarantine and recovery of products selected EID agents, including their biology, potential collected from the time of the presumed attack until its threat to recipient safety, and existing interventions. His- recognition would be advisable. Although the organism is torically, the transfusion medicine community’s response relatively hardy, simple surface decontamination with 10% to EID agents has been to add new donor deferral criteria bleach would be adequate and residual contamination and/or new screening tests. EIDs will continue to appear, from the attack is not anticipated to be a problem. and continuous addition of deferrals and screening tests may not be sustainable. Furthermore, this approach involves waiting for disease emergence, identification of 62 Viral hemorrhagic fevers the agent, understanding of epidemiological risk factors of This is a complex area as about eight different viruses infection to craft donor deferrals, and then development belonging to four different groups are thought to be and implementation of an assay. During this interval potential threats for a bioterrorist attack. However, there before introduction of the assay, morbidity and mortality are some general shared characteristics. All are enveloped may accumulate. This reactive strategy of donor qualifica- RNA viruses and all tend to cause a similar illness. Person- tion via questions and tests will continue unless more to-person spread by direct contact with infected blood broad-reaching interventions are developed and imple- and body fluids is a primary route of transmission, espe- mented. Pathogen reduction (PR) offers a proactive cially among those providing direct care for infected strategy to address these threats; if a PR technology offers persons. Viruses that might be used in this context include a broad spectrum of inactivation, there is a high likelihood Ebola, Marburg, Lassa, NewWorld arenaviruses, RiftValley that it will inactivate the new agent, thereby preventing fever, yellow fever, Omsk hemorrhagic fever, Crimean- infections and perhaps obviating the need for the intro- Congo hemorrhagic fever, and Kyasanur Forest disease duction of new donor deferral criteria and new screening viruses. A deliberate attack would most likely involve an tests. PR should also be of benefit in those situations aerosol release of virus. The result would be an outbreak of where an assay fails to detect an infectious agent due to a undifferentiated febrile illness 2-21 days later. Clinical low level of antigen/antibody/nucleic acid in the test manifestations could include rash, hemorrhagic manifes- sample during the “window period” when the analyte has tations, and shock. Case fatality rates would depend upon not reached its detection threshold. Finally, PR may the agent used, but vary from a low of 0.5% (Omsk hem- interdict agents with very long incubation periods or orrhagic fever) to a high of 90% (Ebola). Diagnosis would unrecognized pathogenicity for which the association not be easy and it might take time before the cause of the with transfusion may be obscure. outbreak was established. Depending on the agent used, The intent of the following section is to provide an considerable caution may have to be used in patient care. overview of what is known regarding PR systems that Some, but not all, of the viruses are somewhat responsive have progressed to clinical trials or have been imple- to selected antiviral drugs. These viruses are present in the mented in other countries. It provides a brief review of blood, but little is known about viremia in the presymp- each PR method by blood component including: the tomatic phases. Quarantine and recovery of products company name and the name of the technology, the from infected, and possibly exposed, donors collected company’s website (as a source of additional unpub- during the incubation period would have to be under- lished data), a description of how the process would be taken. If the involved virus were not identified, the pre- used, the agent’s mechanism of action, a composite table sumed maximum incubation period would have to be of published inactivation results, and a brief summary of used; this could be 4 weeks or more. Secondary cases the clinical performance and regulatory status. There is would be most likely to occur among caregivers with also brief commentary on limitations of PR, including

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the long and complex regulatory cycle (especially in the platelet with low plasma content can be collected and US and Canada), reductions in product efficacy or toxi- photochemically treated; after treatment, platelet additive cology associated with PR technologies, and lastly, agents solution (PAS) is then added to yield a platelet stored in that might be resistant either inherently or due to high 65% PAS and 35% plasma (Fig. 3B) (Raymond Goodrich, concentrations of the agent in the product. This review pers. comm., 2009). does not address costs associated with the use of these technologies. MacoPharma Theraflex UV for platelets Platelets suspended in approximately 65% Storage Solu- PLATELET PATHOGEN REDUCTION tion for Platelets (SSP, including magnesium and potas- SYSTEMS sium, MacoPharma, Tourcoing, France) and 35% plasma There are three technologies for PR in platelets, none of are loosely placed on a quartz plate in bags to produce a which is licensed for clinical use in the US or Canada: thin platelet layer (approximately 4-5 mm), then treated

• Cerus Corporation INTERCEPT Blood System™ (http://www.cerus.com) Concord, CA, USA; • CaridianBCT Biotechnologies Mirasol® PRT (http:// www.caridianbct.com/) Lakewood, CO, USA; and • MacoPharma’s Theraflex© UV. (http://www. macopharma.com/) Tourcoing, France.

Cerus Corporation INTERCEPT Blood System for platelets Platelets suspended in approximately 65% additive solu- tion (InterSol, Fenwal, Inc., Lake Zurich, IL) and 35% plasma are treated by adding amotosalen, a psoralen com- pound, to the platelets and delivering 3 Joules (J)/cm2 ultraviolet A light (320-400 nm) in approximately 5 minutes. This results in irreversible cross-linking of nucleic acids. Unreacted amotosalen and photoproducts Fig. 2. Cerus Corporation INTERCEPT Blood System for are adsorbed during incubation of illuminated platelets in platelets. a separate container containing the Compound Adsorption Device (CAD) for at least 4 hours and up to 16 hours; the platelets are transferred to a final container for storage and transfusion.63 The process is shown in Fig. 2.

CaridianBCT Biotechnologies Mirasol for platelets Platelets suspended in 100% plasma are treated by adding riboflavin (the normal nutrient, vitamin B2) to the platelets, then delivering 6.2 J/cm2 ultraviolet (UV) light (265-370 nm) in approxi- mately 10 minutes. This results in irre- versible photo-oxidative damage to nucleic acid. After illumination, the product is ready for transfusion without further processing.64,66 The process is shown in Fig. 3A. Alternatively, Caridi- anBCT Biotechnologies is developing a Fig. 3. CaridianBCT Biotechnologies Mirasol for platelets. (A) Platelets stored in process in which a hyperconcentrated 100% plasma. (B) Platelets stored in PAS.

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by exposure to 0.3 J/cm2 monochro- matic wavelength UV light (254 nm) with intense agitation (approximately 100 cycles/min) for about 1 minute.65 No photoactive compound is required; nucleic acid damage presumably occurs due to cyclobutyl ring formation. After illumination, the platelets are trans- ferred into a storage container and are ready for transfusion with no further processing. The process is shown in Fig. 4.

Fig. 4. MacoPharma Theraflex UV for platelets. Pathogen reduction in platelets Data that have been published in peer- TABLE 1. Log10 reduction of known transfusion-transmitted viruses reviewed journals are provided in in platelets Tables 1 through 4. Data from abstracts Virus INTERCEPT63 Mirasol64,66 or unpublished data available from Enveloped studies conducted by the manufacturers HIV-1 • Cell-free >6.2 5.9 (includes cell-associated) are included as personal communica- • Cell-associated >6.1 See above tions from the companies’ represen- • Proviral To limit of detection 4.5 > tatives. Cerus (INTERCEPT) has HBV 5.5 CID50* > > HCV 4.5 CID50 demonstrated 6.4 log activity for HTLV-I, cell-associated 4.7 CHIKV in platelets (Lily Lin, pers. HTLV-II, cell-associated 5.1 comm., 2009). CaridianBCT Biotech- CMV, cell-associated >5.9 WNV >6.067 5.2 nologies (Mirasol) has demonstrated Nonenveloped inactivation of the following agents: B19V 4-5.568 Viruses: Sindbis virus (3.2 logs); influ- HAV 0† enza A virus (>5.3 logs); infectious * Chimp Infectious Dose where 50% of the animals become infected. † No reduction was observed (Lily Lin, pers comm., 2009). bovine rhinotracheitis virus (2.1 logs); HAV (2 logs); HBV (>4 logs by PCR); bovine enterovirus (3.0 logs); pseudora- bies virus (2.5 logs); encepha- TABLE 2. Log10 reduction of model viruses in platelets lomyocarditis virus (3.2 logs); CHIKV Virus Model for INTERCEPT63 Mirasol64,66 (2-3 logs); Bacteria/Yeast: Acinetobacter Enveloped baumannii (1.8 logs); Klebsiella oxytoca Vesicular stomatitis Enveloped viruses >5.8 >6.3 Ն 69 (1 log); K. pneumoniae (2.8 logs); Strep- Influenza A (H5N1) Influenza viruses 5.9 Duck HBV HBV >6.2 ID50* tococcus mitis (3.7 logs); S. pyogenes (2.3 Bovine viral diarrhea HCV >6.0 logs); Yersinia enterocolitica (3.3 logs); SARS >6.270 > Candida albicans (1.8 logs); and Vaccinia 5.2 Nonenveloped Protozoa: Plasmodium falciparum Bluetongue Nonenveloped viruses 6.1-6.4 (>3.0 logs); and Babesia microti Calicivirus Nonenveloped viruses 1.7-2.4 (>5.0 logs) (Raymond Goodrich, pers. Simian adenovirus 15 Nonenveloped viruses 0.7-2.3 Human adenovirus 5 Nonenveloped viruses >5.7 comm., 2009). MacoPharma Theraflex Porcine parvovirus Nonenveloped viruses 0† Ն5.0 UV process for platelets using only UVC * Infectious dose where 50% of the ducks are infected. and agitation has been presented at † No reduction was observed. meetings held by the AABB, ISBT, and German Society for Transfusion Medi- cine and Immunohaematology and has shown inactiva- > PLASMA PATHOGEN REDUCTION tion against the following viruses: WNV ( 5 logs); Sindbis SYSTEMS virus (5.6 logs); encephalomyocarditis virus and porcine parvovirus (5-6 logs); vesicular stomatitis virus (VSV) (>6 The same three companies have processes for PR in logs); Suid herpesvirus 1 (3.7 logs); HIV-1 (1.4 logs) (Frank plasma. Cerus and CaridianBCT Biotechnologies use the Tolksdorf and Stefan Reichenberg, pers. comm., 2009). same photoactive substance and process as employed in

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their respective platelet PR system TABLE 3. Log10 reduction of bacteria and spirochetes in platelets outlined above with some minor mo- Theraflex difications. MacoPharma (Theraflex© INTERCEPT71 Mirasol66 UV65 MB-plasma) has developed a photo- Gram Negative Escherichia coli >6.4 >4.4 Ն4.0 chemical process that incorporates Serratia marcescens >6.7 4.0 Ն5.0 methylene blue (MB) and visible light. Klebsiella pneumoniae >5.6 4.8 None is approved for clinical use in the Pseudomonas aeruginosa 4.5 >4.5, >4.7* Ն4.9 Salmonella choleraesuis >6.2 US or Canada. These processes are Yersinia enterocolitica >5.9 shown in Figs. 5 through 7, respectively. Enterobacter cloacae 5.9 Ն4.3 Octapharma (Lachen, Switzerland; Gram Positive Staphylococcus epidermidis >6.6 4.2 4.8 http://www.octapharma.com) devel- S. aureus 6.6 3.6 Ն4.8 oped a PR process for pooled plasma S. aureus MRSA Strain 4.8 units intended for large-scale manufac- Streptococcus pyogenes >6.8 Listeria monocytogenes >6.3 turing of what is commonly known as Corynebacterium minutissimum >6.3 solvent/detergent (S/D) plasma (Octa- Bacillus cereus (includes spores) 3.6 plas).79,80 A slightly different S/D plasma B. cereus (vegetative) >5.5 1.9† 4.3 B. cereus (isolated from donated blood) 2.7 product manufactured by Vitex was Bifidobacterium adolescentis >6.0 licensed in the US but is no longer Propionibacterium acnes >6.2 4.5 marketed.79,81,82 Lactobacillus species >6.4 Clostridium perfringens (vegetative form) >6.5 Ն4.7 Spirochetes Treponema pallidum Ն6.8 to Յ7.0 Cerus Corporation INTERCEPT Borrelia burgdorferi >6.8 Blood System for plasma * ATCC 43088 and ATCC 27853, respectively. † ATCC 7064. The INTERCEPT system for plasma is similar to their platelet system. After addition of amotosalen to the plasma and illumination, the plasma flows through a Compound Adsorption Device (CAD) to remove TABLE 4. Log10 reduction of protozoa/rickettsia in platelets unreacted amotosalen and photoproducts. The process is INTERCEPT Mirasol shown in Fig. 5. Plasmodium falciparum Ն6.072 Trypanosoma cruzi >5.373,74 6.075 Leishmania mexicana >5.076 CaridianBCT Biotechnologies Mirasol plasma Leishmania major, strain Jish >4.376 >5.077 system > 72 Babesia microti 5.3 CaridianBCT Biotechnologies plasma system requires a Orientia tsutsugamushi >5.078 transfer of the plasma into a final freezing/storage con- tainer after illumination. This process is shown in Fig. 6.

MacoPharma Theraflex MB-plasma system MacoPharma’s Theraflex MB requires 1 mM MB and 180 J/cm2 illumination dose using low-pressure sodium lights with a peak wavelength of 590 nm for inactivation. Since MB cannot permeate leukocytes, the Theraflex MB disposable is offered in two formats: if the plasma has already been membrane filtered, the set does not include a leukoreduction filter. Alternatively, if the plasma has not been leukoreduced, the disposable incorporates a leukoreduction filter. Both configurations include a filter for removal of MB and photoproducts.84 This process is shown in Fig. 7.

Octapharma octaplas® plasma system Fig. 5. Cerus Corporation INTERCEPT Blood System for S/D treatment of plasma is performed by adding 1% (w/w) plasma.83 tri(n-butyl) phosphate (TNBP) and 1% (w/w) octoxynol-9

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resistant to the S/D inactivation process or if neutralizing antibody is not present at a sufficient titer to neutralize the chal- lenging agent.

Pathogen reduction in plasma Published results for pathogen reduc- tion in plasma are provided in Tables 5 through 8. Data from abstracts or Fig. 6. CaridianBCT Biotechnologies Mirasol plasma system. unpublished data available from studies conducted by the manufacturers are included as personal communications from the companies’ representatives. Cerus (INTERCEPT) has demonstrated inactivation of >5.5 logs of O. tsutsuga- mushi in an animal model. CaridianBCT Biotechnologies (Mirasol) has evaluated inactivation of a variety of transfusion- transmitted and model viruses (envel- oped and nonenveloped) and parasites. The inactivation spectrum in plasma is the same as Mirasol platelets, since the platelets are suspended in 100% plasma Fig. 7. MacoPharma Theraflex MB-plasma system. and plasma actually constitutes the bulk of the media in which the inactivation process is being performed (Raymond TABLE 5. Log10 pathogen reduction for known or potential transfusion-transmitted viruses in plasma Goodrich, pers. comm., 2009). Octap- Virus INTERCEPT83 Theraflex MB85,86 Octaplas81,82 harma has conducted additional recent Enveloped viral inactivation studies that have HIV-1 shown: HIV-1 (>6.3 logs); VSV (Ն7.5 > Ն Ն • Cell-free 6.8 5.45 7.2 > • Cell-associated >6.4 logs); Sindbis ( 5.4 logs); pseudorabies

HBV >4.5 CID50* Ն6.0 CID50 virus (>6.3 logs); and Herpes simplex > Ն HCV 4.5 CID50 5.0 CID50 virus-2 (>6.1 logs). Since the product is HTLV-I, cell-associated Ն4.5 HTLV-II, cell-associated >5.7 cell free, risk from cell-associated CMV Ն4.08 viruses is also reduced. Further stu- WNV Ն6.8 Ն5.78 dies have demonstrated a substantial CHIKV Ն7.6 Nonenveloped immune neutralization capacity in B19V 1.8 plasma pools for the following viruses: HAV 0† B19V (10.8 logs); HAV (Ն10.0 logs); HEV * Chimp Infectious Dose where 50% of the animals become infected. (Ն9.4 logs); Coxsackievirus B6 (Ն8.6 † No reduction was observed. logs); HSV-1 (>11.1 logs) and poliovirus type 1 (Ն10.9 logs). (Tor-Einar Svae and Marc Maltas, pers. comm., 2009); (Triton X-100) to plasma and incubating for 4 hours at Immune neutralization occurs when an antibody specific 30°C. The plasma is then subjected to oil extraction and for an infectious agent binds to that agent and renders it phase separation to remove the TNBP; solid phase extrac- noninfectious, but such neutralization cannot always be tion to remove the Triton X-100; sterile filtration and relied on because of the unknown prevalence of specific aseptic filling into plastic containers; and fast freezing at antibodies in the donor population. Յ-60°C, followed by storage at Յ-30°C.80 It should be noted that S/D treatment of plasma is not intended as a PR RED BLOOD CELL PATHOGEN REDUCTION method for nonenveloped viruses. S/D plasma is manu- SYSTEMS factured by pooling approximately 600-1500 source or recovered plasma donations, respectively; it is possible CaridianBCT Biotechnologies is using a photochemical that transmission of an agent may occur if that agent is process for treating whole blood which incorporates

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TABLE 6. Log10 reduction of model viruses in plasma Virus Model for INTERCEPT83 Theraflex MB85,86 Octaplas81,82 Enveloped Vesicular stomatitis Enveloped viruses >4.9 Ն8 Influenza A (H5N1) Influenza A viruses >5.7 Ն4.4

Duck HBV HBV 4.4-4.5 Ն6 Ն7.3 ID50 Bovine viral diarrhea HCV Ն6.0 Ն5.44 Ն6.1 Sindbis HCV Ն6.9 Pseudorabies virus CMV, HSV Ն5.48 Ն7 Infectious bronchitis virus Coronaviruses 4.9 Herpes simplex virus-2 Enveloped viruses >6.1 SARS Ն5.5 Nonenveloped Bluetongue Nonenveloped viruses 5.1 Calicivirus Nonenveloped viruses Ն3.9 Human adenovirus 5 Nonenveloped viruses Ն6.8 Ն5.33

requiring platelet transfusion support. In the US, Cerus TABLE 7. Log10 reduction of bacteria and also conducted radiolabel recovery and survival studies in spirochetes in plasma healthy volunteers, including a study in which treated INTERCEPT83 platelets were also gamma irradiated.88 Results from these Gram Negative Klebsiella pneumoniae Ն7.4 studies showed a 15-20% decrease in radiolabel recovery Yersinia enterocolitica >7.3 and survival studies in INTERCEPT platelets compared to Anaplasma phagocytophilum (HGA) agent >4.2 control platelets. One of the patient trials was a bleeding Gram Positive Staphylococcus epidermidis >7.3 time study. The bleeding time correction and time to next Spirochetes transfusion were not statistically different between the Treponema pallidum >5.9 groups, despite a lower corrected count increment (CCI) Borrelia burgdorferi >10.6 in the INTERCEPT group.89 INTERCEPT platelets were evaluated in thrombocy- topenic patients in a two-arm, double-blind clinical Phase TABLE 8. Log10 reduction of protozoa in plasma III-like trial in Europe using buffy coat platelets (euro- INTERCEPT83 Theraflex MB SPRITE).90 One hundred three (103) subjects were enrolled Plasmodium falciparum Ն6.9 in this trial, 52 patients received 311 test transfusions, and Trypanosoma cruzi >5.0 >4.9 to >5.887 Babesia microti >5.3 51 patients received 256 control transfusions. Patients who received test platelets showed no statistically signifi- cant differences in their CCI compared to controls at 1 hour; however, the CCIs at 24 hours did become signifi- riboflavin and UV light that is similar to their Mirasol cantly different. There was an insignificant decrease in process for platelets and plasma. This product is currently time between transfusions (3.0 vs. 3.4 days, test vs. control, being tested in clinical trials in the US under an FDA- respectively). Clinical hemostasis, hemorrhagic, and approved investigational device exemption (IDE) aggregate adverse events were similar between groups. (Raymond Goodrich, pers. comm., 2009). Cerus also conducted a smaller pilot study in Europe that Cerus Corporation is designing a process for RBCs showed that 7-day INTERCEPT platelets were well toler- that uses a chemical cross-linker, specific for nucleic acid. ated and prevented bleeding. Noninferiority in terms of Cerus’ product entered a Phase III trial several years ago in 1-hour CCI could not be demonstrated with a prespecified the US, but issues with neoantigen formation brought that noninferiority margin of 2200.91 trial to a halt. A redesign of the process has eliminated In the US, Cerus conducted a large (n = 645) Phase immunogenicity in laboratory and animal studies. A III double-blind, two-arm trial (INTERCEPT vs. untreated Phase I trial in healthy volunteers is underway (Lily Lin, platelets) in thrombocytopenic patients using apheresis pers. comm., 2009). platelets (SPRINT). Clinical efficacy as measured by inci- dence of WHO bleeding Grade 2, 3, and 4 was not CLINICAL TRIALS/CLINICAL EXPERIENCE different between the two groups. However, 1-hour CCI, days to the next platelet transfusion, and number of Platelet clinical trials platelet transfusions were statistically different, all favor- Cerus Corporation INTERCEPT platelets have undergone ing the control group.92 This finding reflected a difference examination in at least 4 clinical trials in patients in the mean platelet dose per transfusion in the two

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groups; the INTERCEPT group patients received a higher transfusion-associated graft-versus-host disease (TA- proportion of doses <3.0 ¥ 1011. There was a statistically GVHD) were reported. Furthermore, the use of 65% addi- significant reduction in transfusion reactions in those tive solution to replace plasma in this platelet PR system patients receiving the INTERCEPT platelets compared to may have contributed to a lower rate of acute transfusion the control (3 vs. 4.1%). However, there was an increase reactions.97,98 In a study completed in 2006 at the Blood in three specific pulmonary events in the INTERCEPT Transfusion Center, Mont Godinne, Belgium, blood com- group: acute respiratory distress syndrome (ARDS), ponent usage was evaluated in two 3-year blocks, one pneumonitis not otherwise specified, and pleuritic chest before implementation of INTERCEPT and one after, in pain. Reanalysis of this apparent increase of pulmonary 688 and 795 patients, respectively. Primary diagnoses adverse reactions with INTERCEPT transfusions by both were similar in the two study groups: hematology the study investigators and independent experts blinded (approximately 40%), oncology (approximately 6%), car- to patient treatment did not confirm this difference. The diovascular surgery (approximately 30%), and other original observations were attributed to inconsistent surgery and general medical services (approximately reporting of ARDS from SPRINT study sites and charac- 20%). Red cell and platelet usage was statisti- teristics of the classification system used.93,94 cally unchanged before and after implementation of CaridianBCT Biotechnologies Mirasol Platelets have INTERCEPT.99 been tested in three clinical trials. The company studied In a separate study, the routine use experience from in vivo recovery and survival of platelets in normal vol- two periods in EFS-Alsace, France was compared, one unteers and found an approximate 25% decrease in before implementation of platelet additive solution and recovery and survival in the Mirasol group.95 Results of a INTERCEPT and one after, in 2050 and 2069 patients, Phase III-like clinical trial at six blood establishments respectively. In both periods, patients were transfused and six hospitals in France were reported at the 2008 according to conventional medical indications. The AABB Annual Meeting.96 In this study, efficacy data were results show that transfusion of INTERCEPT platelets to a analyzed on 80 subjects who received Mirasol-treated broad patient population for a spectrum of indications (test) or control apheresis platelets. Patients who was well tolerated. The incidence of adverse events was received test platelets showed a statistically significant less than untreated platelet components suspended in (p < 0.002) lower 1-hour CCI compared to control plate- plasma. No increase in the total platelet dose and RBCs lets. However, the CCIs were not statistically different at transfused to patients was observed.100 24 hours. There was also a statistically shorter time Two additional clinical studies were conducted per between transfusions during the period of the first eight country specific requirements: one in Luebeck, Ger- transfusions in the test group compared to the control; many101 and the other in Basel, Switzerland.102 Physicians this difference was not observed beyond the eighth ordered INTERCEPT platelets according to standard clini- transfusion. The number of platelet transfusions per cal practice. However, INTERCEPT platelets were used in patient, total platelet dose, platelet transfusion per day of place of gamma irradiation for prevention of TA-GVHD. support, percent refractory patients, the number of red In the Luebeck study, 560 INTERCEPT transfusions were cells per patient, the number of WHO Grade 2, 3 and 4 administered to 52 patients with hematological malig- bleeding events, and serious adverse events were not sta- nancies. In the Basel study, 551 INTERCEPT platelet com- tistically different between the groups (p > 0.05). No ponents were administered to 46 patients of whom 38 neoantigenicity was observed. were hematology-oncology patients. The results of these MacoPharma has completed preclinical studies of its studies show low rates of overall acute platelet transfu- Theraflex UV process; it is currently under evaluation in sion reactions. No bleeding complications were attri- Phase I studies. butable to the INTERCEPT platelets. Results of an investigator study involving 500 INTERCEPT platelet transfusions in 83 pediatric hematology-oncology Platelet clinical experience patients in a routine clinical setting were reported.103 This To date, over 200,000 Cerus INTERCEPT platelet doses study showed that transfusion of pediatric patients with have been transfused in routine clinical use. An ongoing INTERCEPT platelets was well tolerated and provided postmarketing observational hemovigilance program has therapeutic count increments. been established to monitor the safety profile of INTER- As part of CaridianBCT Biotechnologies Mirasol CEPT platelets. Two reports representing over 12,500 Evaluation Program, several hundred Mirasol-treated transfusions of INTERCEPT platelets to 2051 patients in platelet products have been transfused in routine use. No 11 European centers in five countries from October 2003 Mirasol-related adverse reactions have been reported at to January 2007 demonstrated good clinical tolerance any of the participating blood centers or hospital sites. and a safety profile similar to untreated platelets. No This program has been expanded considerably in 2009 episodes of transfusion-related acute lung injury or and is targeting several thousand transfusions which will

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be monitored for adverse event reporting (Raymond Goo- Octapharma octaplas has been evaluated in several drich, pers. comm., 2009). uncontrolled, observational trials in liver transplant, cardiac surgery, and TTP patients, with no differences noted between S/D plasma and FFP. There have been a Plasma clinical trials few randomized, controlled clinical trials in patients with INTERCEPT plasma has been evaluated in clinical studies severe coagulopathy or undergoing cardiopulmonary in the US. In their first human clinical study, subjects bypass surgery, with no clinical differences noted. donated plasma with half of the plasma treated with the Whether these studies were sufficiently powered to see INTERCEPT system and half prepared as standard fresh any differences is debatable. frozen plasma (FFP). Subjects then received warfarin over 4 days to lower the Factor VII levels. On day 4, subjects received either their own standard FFP or INTERCEPT- Plasma clinical experience FFP.After 2 weeks, subjects underwent an identical proto- Over 6 million units of Octapharma octaplas have col and received the other type of FFP. Factor VII kinetics been transfused, and it has been accepted as thera- were the same in subjects after either INTERCEPT FFP or peutically equivalent to standard FFP. No postmarketing 104 standard FFP. The efficacy and safety of INTERCEPT hemovigilance trials have been published. plasma in patients with congenital coagulation factor MacoPharma Theraflex MB has been registered or is deficiencies was evaluated in a single-arm open-label in routine use in 20 countries, including Germany, clinical trial. The results of this 34-patient trial with defi- Switzerland, Spain, Greece, Italy, France, Belgium, and ciencies of coagulation factors I (fibrinogen), II, V, VII, X, the UK. In spite of laboratory observations demonstrat- XI, and XIII demonstrated that INTERCEPT plasma pro- ing some loss of coagulation factors, clinical reports have vided coagulation factor recovery and pharmacokinetics been generally satisfactory. Postmarketing hemovigilance comparable to conventional plasma, with prothrombin studies from Greece and Spain evaluating 8500 units and time (PT) and activated partial thromboplastin time 88,000 units, respectively, have been reported, with no 105 (aPTT) responses sufficient for adequate hemostasis. adverse events associated with MB-FFP and satisfactory Furthermore, in a randomized, double-blind clinical trial clinical outcomes.109,110 Castrillo et al.111 also reported a in 121 patents with acquired coagulopathy, Mintz et al. 5-year experience with MB plasma with no adverse reac- demonstrated that INTERCEPT-FFP supported hemosta- tions observed. MB-FFP in TTP patients has been evalu- sis similar to conventional FFP, with no differences in the ated in several small studies, comparing MB-FFP to 106 use of blood components, clinical hemostasis, or safety. untreated FFP and its effectiveness is a subject of debate. In a Phase III trial, Cerus evaluated the safety and effec- Two studies in Spain, one retrospective and one prospec- tiveness of INTERCEPT-FFP compared to standard FFP in tive, demonstrated that there was a lower remission rate a small group of patients with thrombotic thrombocy- and higher volume of FFP required for treating TTP when topenic purpura (TTP). Remission was achieved in 14 of using MB-FFP compared to control (untreated) FFP.112,113 17 (82%) patients receiving INTERCEPT-FFP, and 16 of 18 It has been hypothesized that this is due to decreased (89%) patients receiving standard FFP.Time to remission, levels of ADAMTS13, the enzyme generally thought relapse rates, time to relapse, total volume, and number of to be deficient or inhibited in these patients; FFP units exchanged were not significantly different however, MB treatment does not affect the activity of between both groups. No antibodies to amotosalen were ADAMS13.114,115 detected.107 A hemovigilance program similar to that established for INTERCEPT platelets is ongoing to docu- ment and monitor the safety of INTERCEPT plasma transfusion.108 Limitations of pathogen reduction Methylene blue processes similar to MacoPharma Agents with intrinsic resistance to PR processes include Theraflex MB have been used in Europe for over 10 years, prions, some nonenveloped viruses such as HAV, and bac- with over 4 million units transfused in various clinical set- terial spores. Furthermore, extraordinarily high-titer tings. However, there have been no large controlled, ran- viruses like B19V or HBV may not be inactivated below an domized clinical trials comparing MB-FFP to standard infectious dose. Therefore, surveillance for the emergence FFP. Most patient studies have been small and/or used of new agents will remain critical even after the introduc- laboratory rather than clinical endpoints. tion of PR. CaridianBCT Biotechnologies has evaluated their Since blood components currently carry very low Mirasol-treated plasma in several in vitro studies and it risks of infectious agent transmission, any manipulation has been demonstrated to meet the 14th Edition, Council to further mitigate known risks will be difficult to justify of Europe Guidelines for protein content for standard if it introduces any material new risk to transfusion FFP (Raymond Goodrich, pers. comm., 2009). recipients. Critical questions have been raised about

22S TRANSFUSION Volume 49, August 2009 Supplement EID AND TRANSFUSION SAFETY short- and long-term safety of PR systems to transfusion PATHOGEN REDUCTION AND ITS recipients, to blood center and hospital staff who may POTENTIAL FOR EID AGENTS be exposed to them, and to the environment in which The potential utility of PR can be appreciated by review- they are manufactured, used, and in which they are ing the list of 16 agents assigned red, orange, or yellow disposed. priority in this exercise. The data cited, either for specific Potential toxicologic effects of the candidate PR agents or relevant models, suggest that only the vCJD systems have been examined in many dimensions. These prion of the red agents, and the CWD prion, human par- include acute, subacute, and chronic toxicity, blood com- vovirus B19, and HAV among the others, will likely ponent incompatibility, genotoxicity, carcinogenicity, and escape inactivation from clinically relevant titers in impact on reproduction and development. platelets and plasma with application of the systems In general, the residual levels of active PR ingredients being brought forward. The data available for RBCs are in fully processed blood components are below the limit not adequate to instill great confidence at this point, but of detection in available direct toxicity assays due to early data certainly support concentrated research robust removal steps included in the processes. Also, efforts. While some see the absence of a single process water-soluble molecules are rapidly excreted with no applicable to all components as a barrier to the use of accumulation in fat. There are, however, diverse reaction PR, just the prospect of controlling bacterial contamina- products derived from the active agents and establishing tion of platelets, the most common serious infection large safety margins for these products is difficult due to associated with contemporary blood transfusion in the dose per volume constraints (John Chapman, pers. developed world, is an example of its potential power. comm., 2009). Pathogen reduction would be a useful intervention to Compatibility with cellular elements and plasma pro- reduce transfusion transmission of the agents respon- teins is critical. Neoantigenicity with sensitization to sible for babesiosis, Chagas disease, and malaria. Babe- treated components is one aspect. Another is the impact siosis from RBC transfusion is widely understood to be on the recovery, survival, and function of blood elements. more prevalent than published reports have suggested, It is important to understand whether or not PR will and antibody to T. cruzi testing has been adopted nearly increase transfusion requirements related to loss of thera- universally in the US while emerging evidence demon- peutic product, or if processing disturbs the delicate strates that T. cruzi transmission may be less common balance in physiologic pathways like coagulation. than had been anticipated when decisions were made to All PR methods in development for cellular blood pursue donor testing. Deferral for minimal risk of products rely on interactions with microbial nucleic transfusion-transmitted malaria remains a source of acids, raising the specter of carcinogenicity and mutage- serious donor loss. A rational approach to testing for nicity, and of adverse impacts on reproduction and these three parasites may be selective screening strate- development. The study of these potential effects is very gies, but less than universal screening is a strong disin- difficult, expensive, and time-consuming. While in vitro centive for test builders to bring a donor screening assay and animal studies can be completed with reasonable through the rigorous and costly regulatory approval speed and economy and are reassuring when negative, process; thus, market forces may prevent or delay test the clinical events of interest are expected to be quite development. Potentially, PR bypasses this “one agent- rare and may have very long latent periods until recog- one test” approach while protecting both recipients and nition. This raises barriers on the path toward regulatory the donor supply. Similarly, if the next agent to emerge as approvals. Special, more vulnerable populations may a serious threat is an enveloped virus like HBV, HIV, HCV, need additional focus in clinical studies. These include and WNV, it is probable that the approaches in develop- pregnant and fertile women, the fetus, newborns, and ment will be robust, prospectively obviating the need for growing children, those requiring massive acute transfu- deferrals and testing. It is also anticipated that a thor- sions, and patients who receive chronic transfusion ough review of the currently used donor screening ques- support. There needs to be a level of comfort that those tions and tests will be required to assess their continued with impaired kidney and liver function are not at need once robust pathogen reduction methods are avail- elevated risk of adverse events. able. Similarly, well-controlled postmarketing studies will Although the companies have been authorized to be needed to determine if adverse outcomes occur as a market their products in many countries (Table 9), adop- result of widespread use of PR and the impact of PR on tion and routine use of these technologies has been transfusion-transmitted disease. relatively limited. Blood centers, hospitals, and transfu- sion services will continually evaluate the cost versus CONFLICT OF INTEREST benefit of each of these technologies; at the present time, the most efficient and effective process(es) is Peyton S. Metzel is an employee of Fenwal, Inc. Fenwal, unknown. Inc. manufactures InterSol platelet additive solution and

Volume 49, August 2009 Supplement TRANSFUSION 23S 4 TRANSFUSION 24S TABLE 9. Development/regulatory status AL. ET STRAMER Platelets FFP Regulating agency or development status INTERCEPT Mirasol Theraflex UV INTERCEPT Mirasol Theraflex MB Octaplas Development Status, US Phase III Completed Phase I Completed Phase III Completed Phase III Completed Development Status, Europe Completed Completed Phase I Completed Completed Completed Completed US FDA Canadian MOH ✓ CE Mark or MAA* CE CE CE CE CE CE MAA For sale In: oue4,Ags 09Supplement 2009 August 49, Volume • Argentina ✓✓ • Australia ✓ • Austria ✓ • Belgium ✓✓ ✓✓✓✓ • Brazil ✓✓ • Canada ✓ • Croatia ✓ • Czech Republic ✓✓✓ • Finland ✓✓ ✓✓ ✓ • France ✓✓✓✓† • Germany ✓ ✓✓ • Greece ✓✓✓ • Gulf Central Committee ✓ • Hungary ✓✓✓ • Iceland ✓✓ ✓ ✓ • Ireland ✓ ✓ • Italy ✓✓ ✓✓✓✓ • Kazakhstan ✓✓✓ • Kuwait ✓✓ ✓ ✓ • Luxembourg ✓✓✓ • Malaysia ✓✓✓ • Mexico ✓ • Netherlands ✓ • New Zealand ✓ • Norway ✓✓ ✓✓ ✓ • Oman ✓ • Poland ✓✓ ✓✓✓ • Portugal ✓✓ ✓✓ ✓ • Romania ✓ • Russia ✓✓✓ • Saudi Arabia ✓✓✓ • Singapore ✓ ✓ • Slovakia ✓✓ ✓✓ ✓ • Slovenia ✓✓✓ • Spain ✓✓ ✓✓✓ • Sweden ✓✓ ✓✓ ✓ • Switzerland ✓ • Thailand ✓✓✓ • Turkey ✓ • UAE ✓ ✓ •UK ✓✓ • Vietnam ✓ • Yemen ✓ * Council of Europe approval or Marketing Authorization Approval. A CE Mark alone is not adequate regulatory authority to market a device in many countries in Europe including the UK, France, and Germany. † SD-plasma available, similar to Octaplas. EID AND TRANSFUSION SAFETY

is the contract disposables manufacturer for Cerus Corpo- 19. Lefrère JJ, Hewitt P. From mad cows to sensible blood ration INTERCEPT platelets and plasma. No other con- transfusion: the risk of prion transmission by labile blood flicts of interest were declared. components in the United Kingdom and in France. Trans- fusion 2008;49:797-812. 20. Reesink HW, Engelfriet CP, Hyland CA, Coghlan P, Tait B, REFERENCES Wsolak M, Keller AJ, Henn G, Mayr WR, Thomas I, Osse- laer JC, Lambermont M, Beaten M, Wendel S, Qiu Y, 1. Emerging Infections. Microbial threats to health in the Georgsen J, Krusius T, Mäki T, Andreu G, Morel P, Lefrère United States. Washington, DC: Institute of Medicine; J-J, Rebulla P, Giovanelli S, Butti B, Busch MP et al. 1992. Biobanks of blood from donors and recipients of blood 2. Wolfe ND, Dunavan CP, Diamond J. Origins of major products. Vox Sang 2008;94:242-60. human infectious diseases. Nature 2007;447:279-83. 21. Busch MP, Caglioti S, Robertson EF, McAuley JD, Tobler 3. Morens DM, Folkers GK, Fauci AS. Emerging infections: a LH, Kamel H, Linnen JM, Shyamala V, Tomasulo P, Klein- perpetual challenge. Lancet Infect Dis 2008;8:710-19. man SH. Screening the blood supply for West Nile virus 4. Parrish CR, Holmes EC, Morens DM, Park EC, Burke DS, RNA by nucleic acid amplification testing. N Engl J Med Calisher CH, Laughlin CA, Saif LJ, Daszak P. Cross-species 2005;353:460-7. virus transmission and the emergence of new epidemic 22. Stramer SL, Fang CT, Foster GA, Wagner AG, Brodsky JP, diseases. Microbiol Mol Biol Rev 2008;72:457-70. Dodd RY. West Nile virus among blood donors in the 5. Peiris JSM, Guan Y, Yuen KY. Severe acute respiratory syn- United States, 2003 and 2004. N Engl J Med 2005;353: drome. Nat Med 2004;10(12 Suppl):S88-S97. 451-9. 6. Petersen LR, Hayes EB. Westward ho?—the spread of West 23. Leiby DA, Herron RM Jr, Read EJ, Lenes BA, Stumpf RJ. Nile virus. N Engl J Med 2004;351:2257-9. Trypanosoma cruzi in Los Angeles and Miami blood 7. Dodd RY. Emerging infections, transfusion safety, and donors: impact of evolving donor demographics on sero- epidemiology. N Engl J Med 2003;349:1205-6. prevalence and implications for transfusion transmission. 8. Dodd RY. Current risk for transfusion transmitted infec- Transfusion 2002;42:549-55. tions. Curr Opin Hematol 2007;14:671-6. 24. Leiby DA, Herron RM, Garratty G, Herwaldt BL. Trypano- 9. Dodd RY, Leiby DA. Emerging infectious threats to the soma cruzi parasitemia in US blood donors with serologic blood supply. Annu Rev Med 2004;55:191-207. evidence of infection. J Infect Dis 2008;198:609-13. 10. Alter HJ, Stramer SL, Dodd RY. Emerging infectious dis- 25. Busch MP, Young MJ, Samson SM, Mosley JW, Ward JW, eases that threaten the blood supply. Semin Hematol Perkins HA. Risk of human immunodeficiency virus (HIV) 2007;44:32-41. transmission by blood transfusions before the implemen- 11. Leiby DA. Threats to blood safety posed by emerging tation of HIV-1 antibody screening. The Transfusion protozoan pathogens. Vox Sang 2004;87(Suppl 2): Safety Study Group. Transfusion 1991;31:4-11. S120-2. 26. Orton SL, Stramer SL, Dodd RY. Self-reported symptoms 12. Leiby DA. Emerging infectious agents. Dev Biol (Basel) associated with West Nile virus infection in RNA-positive 2005;120:11-5. blood donors. Transfusion 2006;46:272-7. 13. Kleinman S. Hepatitis G virus biology, epidemiology, and 27. Wilson K, Ricketts MN. The success of precaution? Man- clinical manifestations: implications for blood safety. aging the risk of transfusion transmission of variant Transfus Med Rev 2001;15:201-12. Creutzfeldt-Jakob disease. Transfusion 2004;44:1475-8. 14. Hino S, Miyata H. Torque teno virus (TTV): current status. 28. Wilson K, Wilson M, Hébert PC, Graham I. The applica- Rev Med Virol 2007;17:45-57. tion of the precautionary principle to the blood system: 15. Alter HJ, Klein HG. The hazards of blood transfusion in the Canadian blood system’s vCJD donor deferral policy. historical perspective. Blood 2008;112:2617-26. Transfus Med Rev 2003;17:89-94. 16. Biggerstaff BJ, Petersen LR. Estimated risk of transmission 29. Heneine W, Kuehnert MJ. Preserving blood safety against of the West Nile virus through blood transfusion in the emerging retroviruses. Transfusion 2006;46:1276-8. US, 2002. Transfusion 2003;43:1007-17. 30. Foster KR, Vecchia P, Repacholi MH. Risk management. 17. Pealer LN, Marfin AA, Petersen LR, Lanciotti RS, Page PL, Science and the precautionary principle. Science 2000; Stramer SL, Stobierski MG, Signs K, Newman B, Kapoor 288:979-81. H, Goodman JL, Chamberland ME. Transmission of West 31. Srinivasan A, Burton EC, Kuehnert MJ, Rupprecht C, Nile virus through blood transfusion in the United States Sutker WL, Ksiazek TG, Paddock CD, Guarner J, Shieh WJ, in 2002. N Engl J Med 2003;349:1236-45. Goldsmith C, Hanlon CA, Zoretic J, Fischbach B, Niezgoda 18. Hewitt PE, Llewelyn CA, Mackenzie J, Will RG. M, El-Feky WH, Orciari L, Sanchez EQ, Likos A, Klint- Creutzfeldt-Jakob disease and blood transfusion: results malm GB, Cardo D, LeDuc J, Chamberland ME, Jernigan of the UK Transfusion Medicine Epidemiological Review DB, Zaki SR; Rabies in Transplant Recipients Investigation study. Vox Sang 2006;91:221-30. Team. Transmission of rabies virus from an organ donor

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to four transplant recipients. N Engl J Med 2005;352:1103- blood donation during an epidemic on Reunion Island in 11. the Indian Ocean, 2005 to 2007. Transfusion 2008;48: 32. Fischer SA, Graham MB, Kuehnert MJ, Kotton CN, Srini- 1333-41. vasan A, Marty FM, Comer JA, Guarner J, Paddock CD, 45. Cardo LJ. Leishmania: risk to the blood supply. Transfu- DeMeo DL, Shieh WJ, Erickson BR, Bandy U, DeMaria A sion 2006;46:1641-5. Jr, Davis JP, Delmonico FL, Pavlin B, Likos A, Vincent MJ, 46. Belay ED, Schonberger LB. The public health impact of Sealy TK, Goldsmith CS, Jernigan DB, Rollin PE, Packard prion diseases. Annu Rev Public Health 2005;26:191-212. MM, Zaki SR, et al.; LCMV in Transplant Recipients Inves- 47. Belay ED, Maddox RA, Williams ES, Miller MW, Gambetti tigation Team. Transmission of lymphocytic choriomenin- P, Schonberger LB. Chronic wasting disease and potential gitis virus by organ transplantation. N Engl J Med 2006; transmission to humans. Emerg Infect Dis 2004;10:977-84. 354:2235-49. 48. Safar JG, Lessard P, Tamgüney G, Freyman Y, Deering C, 33. McQuiston JH, Childs JE, Chamberland ME, Tabor E; Letessier F, DeArmond SJ, Prusiner SB. Transmission and Working Group on Transfusion Transmission of Tick- detection of prions in feces. J Infect Dis 2008;198:81-9. borne Diseases. Transmission of tick-borne agents of 49. Hladik W, Dollard SC, Mermin J, Fowlkes AL, Downing R, disease by blood transfusion: a review of known and Amin MM, Banage F, Nzaro E, Kataaha P, Dondero TJ, potential risks in the United States. Transfusion 2000;40: Pellett PE, Lackritz EM. Transmission of human herpesvi- 274-84. rus 8 by blood transfusion. N Engl J Med 2006;355: 34. Will RG, Ward HJT. Clinical features of variant 1331-8. Creutzfeldt-Jakob disease. Curr Top Microbiol Immunol 50. Dollard SC, Nelson KE, Ness PM, Stambolis V, Kuehnert 2004;284:121-32. MJ, Pellett PE, Cannon MJ. Possible transmission of 35. Tambyah PA, Koay ESC, Poon MLM, Lin RVTP, Ong BKC, human herpesvirus-8 by blood transfusion in a historical Transfusion-Transmitted Dengue Infection Study Group. United States cohort. Transfusion 2005;45:500-3. Dengue hemorrhagic fever transmitted by blood transfu- 51. Zou S. Potential impact of pandemic influenza on blood sion. N Engl J Med 2008;359:1526-7. safety and availability. Transfus Med Rev 2006;20:181-9. 36. Chuang VWM, Wong TY, Leung YH, Ma ESK, Law YL, 52. Matsubayashi K, Kang JH, Sakata H, Takahashi K, Shindo Tsang OTY, Chan KM, Tsang IHL, Que TL, Yung RWH, Liu M, Kato M, Sato S, Kato T, Nishimori H, Tsuji K, Maguchi SH. Review of dengue fever cases in Hong Kong during H, Yoshida JI, Maekubo H, Mishiro S, Ikeda H. A case of 1998 to 2005. Hong Kong Med J 2008;14:170-7. transfusion-transmitted hepatitis E caused by blood from 37. Mohammed H, Linnen JM, Muñoz-Jordán JL, Tomashek a donor infected with hepatitis E virus via zoonotic food- K, Foster G, Broulik AS, Petersen L, Stramer SL. Dengue borne route. Transfusion 2008;48:1368-75. virus in blood donations, Puerto Rico, 2005. Transfusion 53. Boxall E, Herborn A, Kochethu G, Pratt G, Adams D, Ijaz 2008;48:1348-54. S, Teo C-G. Transfusion-transmitted hepatitis E in a “non- 38. Linnen JM, Vinelli E, Sabino EC, Tobler LH, Hyland C, Lee hyperendemic” country. Transfus Med 2006;16:79-83. TH, Kolk DP, Broulik AS, Collins CS, Lanciotti RS, Busch 54. Eastlund T, Persing D, Mathiesen D, Kim D, Bleging J, MP. Dengue viremia in blood donors from Honduras, McCann P, Heiler G, Raynovic S. Human granulocytic Brazil, and Australia. Transfusion 2008;48:1355-62. ehrlichiosis after red cell transfusion. (Abstract). Transfu- 39. Centers for Disease Control and Prevention (CDC). sion 1999;39(Suppl):117S. Dengue hemorrhagic fever—U.S.-Mexico border, 2005. 55. Centers for Disease Control and Prevention (CDC). Ana- MMWR Morb Mortal Wkly Rep 2007;56(31):785-9. plasma phagocytophilum transmitted through blood 40. Gubernot DM, Lucey CT, Lee KC, Conley GB, Holness LG, transfusion—Minnesota, 2007. MMWR Morb Mortal Wkly Wise RP. Babesia infection through blood transfusions: Rep 2008;57(42):1145-8. reports received by the US Food and Drug Administra- 56. Slovic P. Perception of risk. Science 1987;236:280-5. tion, 1997-2007. Clin Infect Dis 2009;48:25-30. 57. Inglesby TV, Henderson DA, Bartlett JG, Ascher MS, 41. Leiby DA. Babesiosis and blood transfusion: flying under Eitzen E, Friedlander AM, Hauer J, McDade J, Osterholm the radar. Vox Sang 2006;90:157-65. MT, O’Toole T, Parker G, Perl TM, Russell PK, Tonat K; 42. Charrel RM, de Lamballerie X, Raoult D. Chikungunya Working Group on Civilian Biodefense. Anthrax as a bio- outbreaks—the globalization of vectorborne diseases. N logical weapon: medical and public health management. Engl J Med 2007;356:769-71. JAMA 1999;281:1735-45. 43. Bianco C. Dengue and Chikungunya viruses in blood 58. Arnon SS, Schechter R, Inglesby TV, Henderson DA, donations: risks to the blood supply? Transfusion 2008;48: Bartlett JG, Ascher MS, Eitzen E, Fine AD, Hauer J, Layton 1279-81. M, Lillibridge S, Osterholm MT, O’Toole T, Parker G, Perl 44. Brouard C, Bernillon P, Quatresous I, Pillonel J, Assal A, TM, Russell PK, Swerdlow DL, Tonat K; Working Group on De Valk H, Desenclos JC. Workgroup “Quantitative esti- Civilian Biodefense. Botulinum toxin as a biological mation of the risk of blood donation contamination by weapon: medical and public health management. JAMA infectious agents.” Estimated risk of Chikungunya viremic 2001;285:1059-70.

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59. Inglesby TV, Dennis DT, Henderson DA, Bartlett JG, 69. Dupuis K, Sawyer L. Inactivation of influenza virus type A Ascher MS, Eitzen E, Fine AD, Friedlander AM, Hauer J, H5N1 in platelets and plasma by treatment with the Koerner JF, Layton M, McDade J, Osterholm MT, O’Toole INTERCEPT Blood System. Vox Sang 2008;95(Suppl T, Parker G, Perl TM, Russell PK, Schoch-Spana M, Tonat 1):301. K; Working Group on Civilian Biodefense. Plague as a bio- 70. Pinna D, Sampson-Johannes A, Clementi M, Poli G, logical weapon: medical and public health management. Rossini S, Lin L, Vicenzi E. Amotosalen photochemical JAMA 2000;283:2281-90. inactivation of severe acute respiratory syndrome coro- 60. Henderson DA, Inglesby TV, Bartlett JG, Ascher MS, navirus in human platelet concentrates. Transfus Med Eitzen E, Jahrling PB, Hauer J, Layton M, McDade J, Oster- 2005;15:269-76. holm MT, O’Toole T, Parker G, Perl T, Russell PK, Tonat K; 71. Lin L, Dikeman R, Molini B, Lukehart SA, Lane R, Working Group on Civilian Biodefense. Smallpox as a bio- Dupuis K, Metzel P, Corash L. Photochemical treatment logical weapon: medical and public health management. of platelet concentrates with amotosalen and long- JAMA 1999;281:2127-37. wavelength ultraviolet light inactivates a broad 61. Dennis DT, Inglesby TV, Henderson DA, Bartlett JG, spectrum of pathogenic bacteria. Transfusion 2004;44: Ascher MS, Eitzen E, Fine AD, Friedlander AM, Hauer J, 1496-504. Layton M, Lillibridge SR, McDade JE, Osterholm MT, 72. Grellier P, Benach J, Labaied M, Charneau S, Gil H, Mon- O’Toole T, Parker G, Perl TM, Russell PK, Tonat K; salve G, Alfonso R, Sawyer L, Lin L, Steiert M, Dupuis K. Working Group on Civilian Biodefense. Tularemia as a Photochemical inactivation with amotosalen and long- biological weapon: medical and public health manage- wavelength ultraviolet light of Plasmodium and Babesia ment. JAMA 2001;285:2763-73. in platelet and plasma components. Transfusion 2008;48: 62. Borio L, Inglesby T, Peters CJ, Schmaljohn AL, Hughes JM, 1676-84. Jahrling PB, Ksiazek T, Johnson KM, Meyerhoff A, O’Toole 73. Van Voorhis WC, Barrett LK, Eastman RT, Alfonso R, T, Ascher MS, Bartlett J, Breman JG, Eitzen EM Jr, Dupuis K. Trypanosoma cruzi inactivation in human Hamburg M, Hauer J, Henderson DA, Johnson RT, Kwik G, platelet concentrates and plasma by a psoralen (amo- Layton M, Lillibridge S, Nabel GJ, Osterholm MT, Perl TM, tosalen HCI) and long-wavelength UV. Antimicrob Agents Tonat K et al.; Working Group on Civilian Biodefense. Chemother 2003;47:475-9. Hemorrhagic fever viruses as biological weapons: medical 74. Castro E, Gironés N, Bueno JL, Carrión J, Lin L, Fresno M. and public health management. JAMA 2002; 287:2391-405. The efficacy of photochemical treatment with amotosalen 63. Lin L, Hanson CV, Alter HJ, Jauvin V, Bernard KA, Murthy HCI and ultraviolet A (INTERCEPT) for inactivation of KK, Metzel P, Corash L. Inactivation of viruses in platelet Trypanosoma cruzi in pooled buffy-coat platelets. Trans- concentrates by photochemical treatment with amo- fusion 2007;47:434-41. tosalen and long-wavelength ultraviolet light. Transfusion 75. Cardo LJ, Salata J, Mendez J, Reddy H, Goodrich R. Patho- 2005;45:580-90. gen inactivation of Trypanosoma cruzi in plasma and 64. Goodrich RP, Edrich RA, Li J, Seghatchian J. The Mira- platelet concentrates using riboflavin and ultraviolet light. sol™ PRT system for pathogen reduction of platelets and Transfus Apher Sci 2007;37:131-7. plasma: an overview of current status and future trends. 76. Eastman RT, Barrett LK, Dupuis K, Buckner FS, Van Transfus Apher Sci 2006;35:5-17. Voorhis WC. Leishmania inactivation in human pheresis 65. Mohr H, Ute G, Bayer A, Müller TH. Sterilization of plate- platelets by a psoralen (amotosalen HCl) and long- let concentrates at production scale by irradiation with wavelength ultraviolet irradiation. Transfusion 2005;45: short-wave ultraviolet light. Transfusion 2009 doi: 1459-63. 10.1111/j.1537-2995.2009.02228.x 77. Cardo LJ, Rentas FJ, Ketchum L, Salata J, Harman R, 66. Ruane PH, Edrich R, Gampp D, Keil SD, Leonard RL, Melvin W, Weina PJ, Mendez J, Reddy H, Goodrich R. Goodrich RP. Photochemical inactivation of selected Pathogen inactivation of Leishmania donovani infantum viruses and bacteria in platelet concentrates using in plasma and platelet concentrates using riboflavin and riboflavin and light. Transfusion 2004;44:877-85. ultraviolet light. Vox Sang 2006;90:85-91. 67. Gallian P, Vignolo C, Dombey AM, Mayaudon V, Lin L, 78. Rentas F, Harman R, Gomez C, Salata J, Childs J, Silva T, Galichet V, Cantaloube JF, De Micco P. Inactivation of a Lippert L, Montgomery J, Richards A, Chan C, Jiang J, European strain of West Nile virus in single-donor platelet Reddy H, Li J, Goodrich R. Inactivation of Orientia tsut- concentrate using the INTERCEPT Blood System. Vox sugamushi in red blood cells, plasma, and platelets with Sang 2006;91:345-7. riboflavin and light, as demonstrated in an animal model. 68. Sawyer L, Hanson D, Castro G, Luckett W, Dubensky TW Transfusion 2007;47:240-7. Jr, Stassinopoulos A. Inactivation of parvovirus B19 in 79. Salge-Bartels U, Breitner-Ruddock S, Hunfeld A, Seitz R, human platelet concentrates by treatment with amo- Heiden M. Are quality differences responsible for different tosalen and ultraviolet A illumination. Transfusion 2007; adverse reactions reported for SD-plasma from USA and 47:1062-70. Europe? Transfus Med 2006;16:266-75.

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80. Biesert L, Suhartono H. Solvent/detergent treatment of thrombocytopenia: a pilot study. Transfusion 2006;46: human plasma—a very robust method of virus inactiva- 424-33. tion. Validated virus safety of Octaplas®. Vox Sang 92. McCullough J, Vesole DH, Benjamin RJ, Slichter SJ, Pineda 1998;74 Suppl 1:207-12. A, Snyder E, Stadtmauer EA, Lopez-Plaza I, Coutre S, 81. Piet MP, Chin S, Prince AM, Brotman B, Cundell AM, Strauss RG, Goodnough LT, Fridey JL, Raife T, Cable R, Horowitz B. The use of tri(n-butyl) phosphate detergent Murphy S, Howard F IV, Davis K, Lin JS, Metzel P, Corash mixtures to inactivate hepatitis viruses and human L, Koutsoukos A, Lin L, Buchholz DH, Conlan MG. Thera- immunodeficiency virus in plasma and plasma’s subse- peutic efficacy and safety of platelets treated with a pho- quent fractionation. Transfusion 1990;30: 591-8. tochemical process for pathogen inactivation: the SPRINT 82. Horowitz B, Lazo A, Grossberg H, Page G, Lippin A, Trial. Blood 2004;104:1534-41. Swan G. Virus inactivation by Solvent/Detergent treat- 93. Snyder E, McCullough J, Slichter SJ, Strauss RG, Lopez- ment and the manufacture of SD-plasma. Vox Sang Plaza I, Lin JS, Corash L, Conlan MG; SPRINT Study 1998;74 Suppl 1:203-6. Group. Clinical safety of platelets photochemically treated 83. Singh Y, Sawyer LS, Pinkoski LS, Dupuis KW, Hsu JC, Lin with amotosalen HCl and ultraviolet A light for pathogen L, Corash L. Photochemical treatment of plasma with inactivation: the SPRINT trial. Transfusion 2005;45:1864- amotosalen and long-wavelength ultraviolet light inacti- 75. vates pathogens while retaining coagulation function. 94. Corash L, Eiden J, Lin JS. Serious pulmonary adverse Transfusion 2006;46:1168-77. events and acute lung injury following repeat platelet 84. Seghatchian J, Walker WH, Reichenberg S. Updates on transfusions. Transfusion 2008;48(Suppl):28A. pathogen inactivation of plasma using Theraflex methyl- 95. AuBuchon JP, Herschel L, Roger J, Taylor H, Whitley P, Li ene blue system. Transfus Apher Sci 2008;38:271-80. J, Edrich R, Goodrich RP. Efficacy of apheresis platelets 85. Williamson LM, Cardigan R, Prowse CV. Methylene blue- treated with riboflavin and ultraviolet light for pathogen treated fresh-frozen plasma: what is its contribution to reduction. Transfusion 2005;45:1331-41. blood safety? Transfusion 2003;43:1322-9. 96. Goodrich R, Roberts T, Folléa G. Clinical evaluation of 86. Lambrecht B, Mohr H, Knüver-Hopf J, Schmitt H. Photo- Mirasol PRT treated apheresis platelets in thrombocy- inactivation of viruses in human fresh plasma by phe- topenic patients. (Abstract). Transfusion 2008;48(2 Suppl): nothiazine dyes in combination with visible light. Vox 20A. Sang 1991;60:207-13. 97. Osselaer JC, Messe N, Hervig T, Bueno J, Castro E, Espi- 87. Gironés N, Bueno JL, Carrión J, Fresno M, Castro E. The nosa A, Accorsi P, Junge K, Jacquet M, Flament J, Corash efficacy of photochemical treatment with methylene blue L. A prospective observational cohort safety study of 5106 and light for the reduction of Trypanosoma cruzi in platelet transfusions with components prepared with infected plasma. Vox Sang 2006;91:285-91. photochemical pathogen inactivation treatment. Transfu- 88. Snyder E, Raife T, Lin L, Cimino G, Metzel P, Rhein- sion 2008;48:1061-71. schmidt M, Baril L, Davis K, Buchholz DH, Corash L, 98. Osselaer JC, Cazenave JP, Lambermont M, Garraud O, Conlan MG. Recovery and life span of 111indium- Hidajat M, Barbolla L, Tardivel R, Defoin L, Waller C, radiolabeled platelets treated with pathogen inactivation Mendel I, Raidot JP, Kandel G, De Meuter R, Fabrigli P, with amotosalen HCI (S-59) and ultraviolet A light. Trans- Dehenau D, Arroyo JL, Padrón F, Gouezec H, Corral M, fusion 2004;44:1732-40. Jacquet M, Sundin D, Lin L, Corash L. An active haemov- 89. Slichter SJ, Raife TJ, Davis K, Rheinschmidt M, Buchholz igilance programme characterizing the safety profile of DH, Corash L, Conlan MG. Platelets photochemically 7437 platelet transfusions prepared with amotosalen pho- treated with amotosalen HCI and ultraviolet A light tochemical treatment. Vox Sang 2008;94:315-23. correct prolonged bleeding times in patients with throm- 99. Osselaer JC, Doyen C, Defoin L, Debry C, Goffaux M, bocytopenia. Transfusion 2006;46:731-40. Messe N, Van Hooydonk M, Bosly A, Lin JS, Lin L, Corash 90. van Rhenen D, Gulliksson H, Cazenave JP, Pamphilon D, L. Universal adoption of pathogen inactivation of platelet Ljungman P, Klüter H, Vermeij H, Kappers-Klunne M, components: impact on platelet and red blood cell com- de Greef G, Laforet M, Lioure B, Davis K, Marblie S, ponent use. Transfusion 2009;49:1412-22. Mayaudon V, Flament J, Conlan M, Lin L, Metzel P, 100. Cazenave JP, Waller C, Mendel I, Kientz D, Kandel G, Buchholz D, Corash L. Transfusion of pooled buffy coat Raidot JP, Wiesel ML, Laforet M, Isola H. Clinical experi- platelet components prepared with photochemical patho- ence with conventional versus INTERCEPT platelet gen inactivation treatment: the euroSPRITE trial. Blood concentrates transfused to all patients during two one- 2003;101:2426-33. year periods: reduction of adverse events with equivalent 91. Simonsen AC, Johansson PI, Conlan MG, Jacquet M, Lin use of blood products. Vox Sang 2008;95(Suppl 1): JS, Junge K, Lin L, Sørensen H, Borregaard N, Flament J. 305-6. Transfusion of 7-day-old amotosalen photochemically 101. Schlenke P, Hagenah W, Andresen S, Bauhaus M, Sundin treated buffy-coat platelets to patients with D, Lin L, Corash L, Wagner T, Kirchner H. Platelet

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components treated with pathogen inactivation using the 108. Cazenave JP, Osselaer JC, Waller C, Jacquet M, Lin L, INTERCEPT Blood System™: clinical outcomes of the Corash L, Sundin D. An active hemovigilance program first single-centre clinical trial in Germany. Vox Sang utilizing an EDC system to assess safety of 2994 plasma 2007;93(Suppl 1):171. transfusions prepared with the INTERCEPT Blood 102. Infanti L, Job S, Santoro M, Silzle T, Reusch M, Stebler C, System™. Transfusion 2008;48(Suppl 1):29A. Halter J, Sundin D, Propst M, Gratwohl A. Platelet 109. Politis C, Kavallierou L, Hantziara S, Katsea P, Triantaphy- components treated with pathogen inactivation using the lou V, Richardson C, Tsoutsos D, Anagnostopoulos N, INTERCEPT Blood System™: clinical outcomes of the Gorgolidis G, Ziroyannis P. Quality and safety of fresh- first single-centre observational trial in Switzerland. Vox frozen plasma inactivated and leucoreduced with the Sang 2008;95(Suppl 1):289. Theraflex methylene blue system including the 103. Van Haute I, Benoit Y, Bordon V, De Moerloose B, Vande- Blueflex filter: 5 years’ experience. Vox Sang 2007;92: cruys E, Van Lancker S, Van Vooren M, Vandekerckhove B. 319-26. Therapeutic efficacy and safety of transfusion of 110. Larrea L, Calabuig M, Soler MA, Solves P, Mirabet V, Roig pathogen-inactivated platelets to pediatric patients. Vox R. Our nine years experience in plasma inactivation. Vox Sang 2006;91:177. Sang 2007;93(Suppl 1):167. 104. Hambleton J, Wages D, Radu-Radulescu L, Adams M, 111. Castrillo A, Eiras A, Cid J, Castro A, Adelantado M, Abalo Mackenzie M, Shafer S, Lee M, Smyers J, Wiesehahn G, M, Areal C, Flores J, Cabrera J. Quality of methylene blue Corash L. Pharmacokinetic study of FFP photochemically plasma over the last five years. Vox Sang 2006;91:182. treated with amotosalen (S-59) and UV light compared to 112. de la Rubia J, Arriaga F, Linares D, Larrea L, Carpio N, FFP in healthy volunteers anticoagulated with warfarin. Marty ML, Sanz MA. Role of methylene blue-treated or Transfusion 2002;42:1302-7. fresh-frozen plasma in the response to plasma exchange 105. de Alarcon P, Benjamin R, Dugdale M, Kessler C, Shop- in patients with thrombotic thrombocytopenic purpura. nick R, Smith P, Abshire T, Hambleton J, Matthew P, Ortiz Br J Haematol 2001;114:721-23. I, Cohen A, Konkle BA, Streiff M, Lee M, Wages D, Corash 113. Alvarez-Larrán A, Del Río J, Ramírez C, Albo C, Peña F, L. Fresh frozen plasma prepared with amotosalen HC1 Campos A, Cid J, Muncunill J, Sastre J-L, Sanz C, Pereira (S-59) photochemical pathogen inactivation: transfusion A. Methylene blue-photoinactivated plasma vs. fresh- of patients with congenital coagulation deficiencies. frozen plasma as replacement fluid for plasma exchange Transfusion 2005;45:1362-72. in thrombotic thrombocytopenic purpura. Vox Sang 2004; 106. Mintz PD, Bass NM, Petz LD, Steadman R, Streiff M, 86:246-51. McCullough J, Burks S, Wages D, Van Doren S, Corash L. 114. Yarranton H, Lawrie AS, Purdy G, Mackie IJ, Machin SJ. Photochemically treated fresh frozen plasma for transfu- Comparison of von Willebrand factor antigen, von sion of patients with acquired coagulopathy of liver Willebrand factor-cleaving protease and protein S in disease. Blood 2006;107:3753-60. blood components used for the treatment of thrombotic 107. Mintz PD, Neff A, MacKenzie M, Goodnough LT, Hillyer thrombocytopenic purpura. Transfus Med 2004;14: C, Kessler C, McCrae K, Menitove JE, Skikne BS, Damon L, 39-44. Lopez-Plaza I, Rouault C, Crookston KP, Benjamin RJ, 115. del Río-Garma J, Pereira A, Arroyo JL, Mateo J, Alvarez- George J, Lin JS, Corash L, Conlan MG. A randomized, Larrán A, Martínez C, Muncunill J, Barbolla L; Spanish controlled Phase III trial of therapeutic plasma exchange Group of Apheresis (Grupo Español de Aféresis GEA). with fresh-frozen plasma (FFP) prepared with amotosalen ADAMTS-13 activity and von Willebrand factor levels in and ultraviolet A light compared to untreated FFP in methylene blue photo-inactivated plasma and processed thrombotic thrombocytopenic purpura. Transfusion 2006; by either the Springe method or an “in house” system. 46:1693-704. Vox Sang 2008;95:101-5.

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