REVIEW URRENT C OPINION
Emerging microbial threats to the United States blood supply Louis M. Katz
Purpose of review In this short review, several emerging agents are described to demonstrate potential responses of the blood community to emerging and potentially emerging infections. Recent findings Critical questions are raised as we consider appropriate approaches to these agents. Can we identify risk thresholds below which interventions are not required, that is, are there tolerable infectious risks of transfusion? Who are the stakeholders responsible for that determination? What is the role of health economic analysis for informing those decisions? If we decide that cost–utility thresholds for transfusion medicine are appropriately several fold higher than for the rest of clinical medicine, who has responsibility for being certain whether those priorities are funded? Summary Four agents will be discussed to highlight the evolving considerations in response to these considerations. Keywords risk management, risk tolerance, transfusion-transmitted infections
INTRODUCTION The classic transfusion transmissible infections (TTIs), hepatitis B virus, hepatitis C virus, and HIV fell to historic lows [1] as the blood community learned to recruit low-risk donors, deployed sensitive, specific screening tests and applied current good manufacturing practices to the operations at blood centers. New threats, of lesser absolute magnitude, are emerging and warrant considering interventions to improve transfusion safety. These TTIs require the presence of an agent in the blood of asymptomatic donors that survives processing and storage. They must be infectious after parenteral inoculation, and cause clinically significant and recognizable illness in recipients [2]. To the end of being prepared for new threats, more than 70 agents have been assessed for these characteristics and fact sheets published. New agents have been added and the originals reassessed as needed [3 ]. What follows are short discussions of four agents that fulfill our criteria for concern about which decisions about transfusion safety will be required in the near future for the United States blood supply. &
BABESIA MICROTI Human babesiosis is an Ixodes tick-borne, malarialike protozoan parasite infection caused primarily
by Babesia microti in the United States, with hyperendemic foci in the Northeast and moderate prevalence in the upper Midwest [4]. It is the most frequent TTI in the United States [5]. A 2011 review identified 162 cases of transfusion-transmitted Babesia (TTB) from 1979 to 2009, 159 from B. microti [6], 83 of which (52.2%) were recognized from 2005 to 2009. The increase reflects greater recognition of the association with transfusion, the broadening geographic range, and increasing incidence of infection. With passive TTB surveillance, it is certain that these represent a fraction of the transmissions, but national reportability since 2011 should improve case finding. Because donors and donations ‘travel’, a fraction of TTB resulted from transfusion outside the endemic states, demanding a high index of suspicion for recognition. Morbid outcomes from TTB are most common at the extremes of age and among the asplenic and immunocompromised patients. TTB is diagnosed during all 12 months,
America’s Blood Centers, Washington, DC, USA Correspondence to Louis M. Katz, MD, America’s Blood Centers, Washington, DC 20005, USA. Tel: +1 202 654 2995; e-mail: lkatz@ americasblood.org Curr Opin Hematol 2014, 21:509–514 DOI:10.1097/MOH.0000000000000089
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KEY POINTS Emerging infections continue to be recognized as potential threats to transfusion safety. Identification and exclusion of donors at risk for TTIs and donation testing continue to be the primary methods for mitigation, as they have been for traditional TTI agents. The role of health economic analyses in decisionmaking about TTIs is unclear, but their use, in the context of a comprehensive risk-informed decisionmaking process, is being proposed to address questions about the balance between our historically precautionary approaches and appropriate use of scarce healthcare resources.
reflecting persisting subclinical parasitemia for months to years in donors after vector-borne infection [7 ]. In 2010, the Food and Drug Administration’s (FDA) Blood Products Advisory Committee supported the need for regional testing of blood donors for babesiosis [8]. In the absence of FDA-licensed donor screens, serology and molecular testing (PCR) are under evaluation, alone and in combination. Antibody assays can detect acute infections after a short seronegative window period, but miss infections in the window before seroconversion. PCR can detect donors early, before serology. Seropositive donors may remain positive for extended periods after spontaneous or medical cure, and PCR can be insensitive to low parasite burdens in infected, healthy donors. Indirect immunofluorescent antibody (IFA) testing and PCR were implemented to select low-risk red blood cell units for high-risk neonatal and hemoglobinopathy patients at a blood center in a hyperendemic area [9]. The approach was operationally feasible, and no TTB was seen after use of 787 units in the target population, compared with seven cases after 6500 prior unscreened units. This study was underpowered to detect a statistically significant difference from the pretesting era. Among 2113 screened units, there were 26 positive IFA results and no positive PCR. In another study, 1002 highrisk donors were tested with a research IFA and realtime PCR, finding 25 seropositive donations and three PCR positives, of which one was seronegative in the window period [10]. During testing of 17 422 donations from a high-risk donor population using IFA, with PCR testing of seropositive samples, 208 seroreactive donors were found and 29 out of 139 tested with PCR were positive [11]. Lookback to recipients of 656 prior cellular components from &
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the seropositive donors yielded 63 recipients to be tested for B. microti. A total of 33.3% (5/15) from lookback during 1999–2000 were B. microti reactive, compared with 6.3% (3/48) after implementation of indefinite deferral of seropositive donors, demonstrating the potential impact of removing testpositive donors from the donor base. In a prospective evaluation of a research arrayed IFA and PCR on 30 435 donors in a high-endemic area, 133 donors were seropositive and PCR negative, 14 were seropositive and PCR positive, and five were seronegative and PCR positive (window infections) [12]. No TTB occurred from screened donations, compared with six cases from contemporary unscreened units (no denominator supplied). Data on test performance and the incidence of TTB are inadequate to quantitate with precision the residual risk of TTB or the relative health economic impacts of proposed screening strategies across the geographic spectrum of United States blood collectors. A cost-effectiveness analysis examined the impacts of alternative approaches in endemic areas in Connecticut, Massachusetts, Minnesota, New Jersey, New York, Rhode Island, and Wisconsin [13 ]. Incremental cost-effectiveness ratios (ICER) were compared with other blood safety initiatives. Serology, compared with the current donor query about a history of babesiosis, had an ICER of $760 000/quality-adjusted life year (QALY), ‘which compares favorably to currently adopted practices for preventing’ other TTIs. Serology and PCR had an ICER of $8.8 million/QALY compared with serology. In a second cost-effectiveness analysis comparing screening in four, seven, or 20 states with decreasing incidences and national screening [14 ], combination of ELISA and PCR screening costs an estimated $5.2 and $6.6 million/QALY in the four and seven state programs, respectively, and more for wider screening. The least expensive approach, ELISA alone in four states, costs $2.6 million/QALY (95% credible intervals from $290 000 to $10.5 million). No PCR strategy is cost effective at $1 million/QALY, approximating the cost utility of a number of currently accepted interventions. Accepting the assumptions in the models, they argue for skepticism about the utility of any screening outside hyperendemic states and a critical approach inside them, especially if one takes issue with using ‘accepted’ donor-screening thresholds as the comparator. Health economic data can help us understand whether screening rises to a priority demanding its use, and will inform decisions about if and where testing is performed – only on donors in endemic areas, there and among travelers to those areas or more broadly, with a single assay or both serologic and molecular tests. Are there testing strategies that provide manufacturers with sufficient &
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return on investment to proceed to commercialization of affordable assays?
DENGUE VIRUSES These flaviviruses are the most important vectorborne disease on the planet, with 50–100 million symptomatic infections annually. Billions of people live in areas where transmission occurs [15]. The virus is endemic in tropical and subtropical areas of Asia and the Americas, and although present in Africa, its epidemiology there is poorly characterized. Dengue is the most frequently confirmed cause of fever in United States travelers returning from affected areas. The prevalence of dengue antibody reaches 40% on the United States side of Texas– Mexico border. Dengue is endemic in the United States commonwealth of Puerto Rico, where partial screening of the blood supply with investigational nucleic acid-based test (NAT) has been done in recent years demonstrating rates of apparent viremia similar to those for West Nile virus in the United States before NAT screening [16]. Viremia is present 2–4 days before symptoms, persisting 4–5 days during illness, but half of infections are asymptomatic. Competent Aedes mosquito vectors are present in the United States, and recent mosquitoborne spread (especially, Florida in Key West during 2009–2010 and Martin and St. Lucie counties in 2013) has heightened concern that autochthonous dengue may threaten transfusion safety. Collections were briefly suspended in the counties affected during the 2013 Florida outbreak, but this was feasible because of the limited contribution of those areas on collections in the region (G LeParc, personal communication). A handful of transfusion transmissions have been documented and reported: one from nonendemic Hong Kong [17], three in a Singapore cluster [18], and one in Puerto Rico [19]. The latter was found by tracing a unit positive for dengue RNA in a research study from the donor to the recipient. Why, in the face of millions of mosquito-borne infections, are these the only transmissions that have been recognized? Donor studies in epidemic areas of Brazil, Puerto Rico, and Honduras demonstrate dengue RNA in 0.06, 0.07–0.2, and 0.40% of donors, respectively, with virus culturable from some. In a linked donor-recipient study in Rio de Janiero and Recife, Brazil during their 2012 epidemic, 51 RNA-positive (of 7871 tested) units were transfused to 42 recipients. Final evaluation of 23 recipients was possible using their immunoglobulin M and RNA results, of whom five were not susceptible. There were five probable and one
possible transmission to 18 susceptible recipients, a transfusion transmission rate of 33% [20 ]. Posttransfusion clinical profiling of these recipients identified no statistically significant differences between recipients of RNA positive or negative units ([21 ] and M Busch, personal communication). In the epidemic setting, many recipients may be protected by prior immunity, and/or RNA-positive units may not contain an infectious dose because of low titer viremia, and/or the presence of neutralizing antibody. Few data exist to inform mitigation strategies in nonendemic areas, such as the United States. Certainly, the recipient of an infectious unit will more likely be susceptible, but the number of such units will be far smaller. Available mitigation strategies include recall of donated components when the donor reports a postdonation illness diagnosed or compatible with dengue after travel, temporary deferral of donors after travel to endemic areas, and screening of some or all donations with NATs. The latter two are likely to be most effective. Travel deferrals long enough to avoid asymptomatic, viremic donors must be assessed for their impact on the adequacy of the blood supply, but have been applied ex-United States successfully. For dengue and other acute viral infections, these are likely to be 2–4 weeks after return from epidemic foci. RNA testing needs justification in an appropriate risk–benefit analysis. Testing becomes a more viable option if sustained vector-borne transmission is established in the mainland United States, where suspension of local collections would most likely compromise the adequacy of the blood supply. &
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CHIKUNGUNYA VIRUS This mosquito-borne alphavirus has caused hundreds of thousands of infections in Africa, the islands of the Indian Ocean, south Asia, and some Pacific islands during the past decade. It is clinically similar to dengue, but with prominent, often prolonged, arthralgia. Mortality is unusual [22]. Aedes aegypti is an effective urban vector, and Aedes albopictus is an alternate. A viral mutation is associated with very high viral loads in A. albopictus, contributing to the recent explosive outbreaks in the Indian Ocean and parts of south Asia. Transfusion transmission is theoretically possible because virus is present in blood for several days and 20% of infections are asymptomatic [23 ]. Modeling the epidemic on Reunion Island from 2005 to 2007, with its 40% attack rate, estimated a peak prevalence of 1500 out of 100 000 infected donations [24]. Modeling in Thailand, during a less intense epidemic,
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suggested 38–52 viremic donations out of 100 000 should have been expected [25 ]. Despite these estimates, no cases of transfusion transmission have yet been recognized worldwide. Chikungunya is receiving attention in the United States because autochthonous mosquito transmission was recognized in the Caribbean during December 2013. Cases have increased rapidly and more than 400 000 infections were reported by August 2014. With the high volume of travel from the United States to the Caribbean, introduction of the virus to the United States mainland, where vectors are widespread, is probable. A. aegypti is present in the southernmost United States, extending as far west as California, and A. albopictus has spread to approximately one out of three of the continental United States from the Gulf and southeast to as far north as New York and as far west as California [26]. The Caribbean virus does not have the E1 mutation, so its explosive spread by A. albopictus is unlikely. No donor question is used to reduce the risk of Chikungunya transmission from asymptomatic donors. Current deferral criteria for travel to malarious areas include many regions affected by recent Chikungunya outbreaks, but most of the Caribbean is malaria-free. Some national blood authorities in the European Union and elsewhere use temporary deferral periods after travel to the tropics, including areas that are not malaria endemic. These mitigate risk from dengue, Chikungunya virus and other acute viral pathogens by preventing donation until the resolution of asymptomatic viremia. They would be associated with an operational burden and significant donor loss in the United States, so assessment of their impact on the blood supply must precede any such deferrals. Donor education and active contact of donors after phlebotomy to increase reporting of postdonation symptoms to blood centers might facilitate quarantine and withdrawal of potentially infectious components from ill donors with exposure in epidemic settings [27]. Donor screening with sensitive NAT to identify viremic donors is not available. Mass investigational screening of the blood supply for West Nile virus was implemented less than 1 year after the recognition of transfusion-associated infections in 2002 [28]. Manufacturers are considering developing Chikungunya NAT prototypes for similar deployment at need but valid financial concerns may impact their decisions to develop donor screening assays. An interesting discussion is at what point a precautionary intervention, that is, one that might work and will not cause unreasonable ‘harm’, ought to be implemented. Transmission by blood has never been recognized despite very high attack rates in &&
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local epidemics and the wide magnitude of the virus’ spread. This discussion unfolds among interested stakeholders in the blood community, at the FDA, in the public health community, the test builders and in the provider community that, as end user of blood, must be asked about their willingness to bear the benefits and costs of mitigation efforts.
HEPATITIS E VIRUS This hepevirus was identified as causing a large 1978 Kashmiri epidemic. It was distinguished from hepatitis A by serologic methods and implicated in outbreaks as early as the mid-1950s. It causes asymptomatic to fulminant infections, and in the immunosuppressed can cause chronic infection and cirrhosis. Mortality is low, although maternal mortality during the last trimester of 10–20% has been reported [29]. The four genotypes cause more than 3 million cases and 700 000 deaths annually. Genotypes 1 and 2 cause large epidemics in the developing world associated primarily with fecal contamination of potable water. Genotypes 3 and 4 are zoonotic (in pigs and other species, in addition to human infection) and associated with food-borne transmission after consumption raw or insufficiently cooked meat or viscera, or with close environmental contact to an infected source. These infections are most often documented in Japan and Europe (from bivalve mollusks, boudin noir, figatelli sausage, dinuguan) [30,31]. Genotype 3 is endemic in the United States (swine). The third National Health and Nutrition Examination Survey (1988–1994) [32] found a United States seroprevalence of 21%, but it is rarely clinically recognized in the United States. From 2005 to 2012, Centers for Disease Control and Prevention documented 26 cases from a total of 154 obscure clinical hepatitis cases evaluated (11/26 attributed to infection in other countries) [33]. Viral RNA is found in asymptomatic blood donors, persisting for 4–6 weeks (as long as 112 days). Chronic infection can occur in immune-deficient patients and progress to cirrhosis. At the case report level, transfusion transmissions are well documented, especially in Europe and Japan (reviewed in [34]), but the risk in the United States appears low [35 ]. Background presentations and discussion of the appropriate response to hepatitis E virus (HEV) by the United States blood community were held at the FDA Blood Products Advisory Committee in 2012 [36]. The committee accepted an FDA framework for a sequential approach to estimating the United States transfusion risk and formulating an appropriate response. It included characterization of &
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candidate NAT using WHO standards for HEV RNA and a panel of virologically confirmed clinical samples would be conducted. Then, performance of large-scale studies of blood donors with validated molecular assays to determine the prevalence of viremic (NAT-positive) blood donors and characterization of serologic assays with virologically confirmed clinical samples would be conducted. Studies on linked donor–recipient repositories with these validated tests to assess transfusion transmission of HEV would follow. Implicit in acting on donorrecipient studies is a judgment about acceptable risk. Whether an explicit risk-informed approach can displace a historically highly precautionary approach to blood safety decision-making in the United States, where cost-effectiveness thresholds of $1 million/QALY are not unusual, remains an open question [37 ]. With regard to health economic analyses of testing for B. microti and other emerging infections, it is germane to note that the United States FDA concerns itself with the safety, purity, and potency of the blood supply and has chosen to require testing with very high costs per QALY and other metrics, for example, nucleic-acid testing for HIV, hepatitis C virus, and hepatitis B virus, and serological testing for infection with Trypanosoma cruzi, the agent of Chagas disease. In the United States, other agencies within the Department of Health and Human Services, especially the Center for Medicare and Medicaid Services, are responsible for reimbursement decisions, but are not frequently consulted when decisions are made at the FDA, resulting in no or delayed coverage for the FDA’s decisions – in a sense unfunded mandates. One ought to look carefully for an example for the United States of the incorporation of health economic analysis in decision-making at the recent decision in the United Kingdom, largely on these grounds, not to recommend the implementation of pathogen reduction for platelets, despite its ability to mitigate known and potentially emerging TTIs [38]. &
CONCLUSION Multiple potential pathogens are of current interest with regard to their potential impacts on transfusion safety. Each requires an individualized, risk-based, decision-making process when considering the need for and substance of mitigation strategies. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Busch MP. Cooley Award Lecture: transfusion-transmitted viral infections: building bridges to transfusion medicine to reduce risks and understand epidemiology and pathogenesis. Transfusion 2006; 46:1624– 1640. 2. Stramer SL, Hollinger FB, Katz LM, et al. Emerging infectious disease agents and their potential threat to transfusion safety. Transfusion 2009; 43 (Suppl 2):1–29. 3. AABB EID working group. Fact sheets created or updated post publication & of the TRANSFUSION August 2009 supplement. http://www.aabb.org/ resources/bct/eid/Pages/eidpostpub.aspx. [Accessed 24 May 2014] These fact sheets provide a structured assessment of our current understanding of these pathogens for transfusion safety. 4. CDC. Babesiosis: epidemiology and risk factors. http://www.cdc.gov/parasites/babesiosis/epi.html. [Accessed 23 May 2014] 5. Vannier E, Krause PJ. Current concepts: human babesiosis. N Engl J Med 2012; 366:2397–2407. 6. Herwaldt BL, Linden JV, Bosserman E, et al. Transfusion-associated babesiosis in the United States: a description of cases. Ann Intern Med 2011; 155:509–519. 7. Leiby DA, Johnson ST, Won KY, et al. A longitudinal study of Babesia & microti infection in seropositive blood donors. Transfusion 2014; 54:2217– 2225. Demonstration of persistent B. microti infection in donors. 8. Food and Drug Administration. Meeting of the Blood Products Advisory Committee. Risk of Babesia infection by blood transfusion and potential strategies for donor testing; 26 July 2010. www.fda.gov/AdvisoryCom mittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/ BloodProductsAdvisoryCommittee/ucm205013.htm. [Accessed 28 May 2014] 9. Young C, Chawla A, Berardi V, et al. Preventing transfusion-transmitted babesiosis: preliminary experience of the first laboratory-based blood donor screening program. Transfusion 2012; 52:1523–1529. 10. Johnson ST, Van Tassell ER, Tonnetti L, et al. Babesia microti real time-PCR testing of Connecticut blood donors: potential implications for screening algorithms. Transfusion 2013; 53:2644–2649. 11. Johnson ST, Cable RG, Leiby DA. Lookback investigations of Babesia microtiseropositive blood donors: seven-year experience in a Babesia-endemic area. Transfusion 2012; 52:1509–1510. 12. Moritz E, Johnson ST, Winton C, et al. Prospective investigational blood donation screening for Babesia microti (Bm). Transfusion 2013; 53:13A; Abstract P1. 13. Simon MS, Leff JA, Pandya A, et al. Cost-effectiveness of blood donor & screening for Babesia microti in endemic regions of the United States. Transfusion 2014; 54 (3 Pt 2):889–899. A cost-effectiveness analysis of screening strategies for B. microti in endemic states. 14. Goodell A, Bloch E, Krause P, Custer B. Costs, consequences, and cost&& effectiveness of strategies for Babesia microti donor screening of the US blood supply. Transfusion 2014; 54:2245–2257. A detailed cost-effectiveness analysis of screening strategies for B. microti in endemic states. 15. WHO. Dengue and severe dengue. http://www.who.int/mediacentre/factsheets/fs117/en/. [Accessed 23 May 2014] 16. Mohammed H, Linnen JM, Munoz-Jordan JL, et al. Dengue virus in blood donations, Puerto Rico 2005. Transfusion 2008; 48:1348–1354. 17. Chuang WW, Wong TY, Leung YH, et al. Review of dengue fever cases in Hong Kong during 1998–2005. Hong Kong Med J 2008; 14:170– 177. 18. Transfusion-Transmitted Dengue Infection Study Group. Tambyah PA, Koay ES, Poon MLM, et al. Dengue hemorrhagic fever transmitted by blood transfusion. N Engl J Med 2008; 359:1526–1527. 19. Stramer SL, Linnen JM, Carrick JM, et al. Dengue viremia in blood donors identified by RNA and detection of dengue transfusion transmission during the 2007 dengue outbreak in Puerto Rico. Transfusion 2012; 52:1657– 1666. 20. Custer B, Loureiro P, Lopes M, et al. Dengue transfusion transmission rate & during large epidemics of denv-4 in Rio de Janeiro and Recife, Brazil. Vox Sanguinis 2014; 107 (S1):160. This is an estimate of the transmissibility of dengue virus by transfusion. 21. Custer B, Sabino EC, McClure C, et al. Prevalence of symptomatic dengue && virus infection in transfused patients. Vox Sanguinis 2013; 105 (S2):41. Transfusion-transmitted dengue patients in this small study were not clinically distinguishable from controls. 22. Centers for Disease Control and Prevention. Chikungunya fever. http:// www.cdc.gov/chikungunya/fact/index.html. [Accessed 21 May 2014]
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Transfusion medicine and immunohematology 23. Appassakij H, Khuntikij P, Kemapunamanus M, et al. Viremic profiles in asymptomatic and symptomatic Chikungunya fever: a blood transfusion threat? Transfusion 2013; 53:2567–2574. These are studies in Thai donors infected with Chikungunya, profiling viremia, and establishing the very rate of symptomatic infection. 24. Brouard C, Bernillon P, Quatresous I, et al. Estimated risk of Chikungunya viremic blood donation during an epidemic on Reunion Island in the Indian Ocean. Transfusion 2008; 48:1333–1341. 25. Appassakij H, Promwong C, Rujirojindakul P, et al. The risk of blood trans&& fusion-associated Chikungunya fever during the 2009 epidemic in Songkhla Province, Thailand. Transfusion 2014; 54:1945–1952. Chikungunya infection is evaluating using models applicable to West Nile virus and the rate of asymptomatic viremia estimated under the conditions of the Thai epidemic. 26. CDC. Chikungunya information for vector control programs. www.cdc.gov/ chikungunya/pdfs/CHIKV_VectorControl.pdf. [Accessed 20 May 2014] 27. EID Working Group. Chikungunya virus. http://www.aabb.org/resources/bct/ eid/Pages/eidpostpub.aspx. [Accessed 21 May 2014] 28. NHLBI Emerging Infectious Disease Task Force convened November 7. Glynn SA, Busch MP, Dodd RY, et al. Emerging infectious agents and the nation’s blood supply: responding to potential threats in the 21st century. Transfusion 2013; 53:438–454. 29. Emerson SU, Purcell RH. Hepatitis E virus. In: Knipe DM, Howley PM, editors. Fields virology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2013. pp. 2242–2258. 30. Hoofnagle JH, Nelson KE, Purcell RH. Hepatitis E. N Engl J Med 2012; 367:1237–1244. 31. AABB EID Working Group. Hepatitis E virus. http://www.aabb.org/ resources/bct/eid/Pages/eidpostpub.aspx. [Accessed 24 May 2014] &
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32. Kuniholm MH, Purcell RH, McQuillan GM, et al. Epidemiology of hepatitis E virus in the United States: results from the third National Health and Nutrition Examination Survey, 1988–1994. J Infect Dis 2009; 200:48–56. 33. Drobeniuc J, Greene-Montfort T, Le NT, et al. Laboratory-based surveillance for hepatitis E virus infection, United States, 2005–2012. Emerg Infect Dis 2013; 19:218–222. 34. Nelson KE. Transmission of hepatitis E virus by transfusion: what is the risk? Transfusion 2014; 54:8–10. 35. Xu C, Wang R, Schecherly C, et al. An assessment of hepatitis E virus in US & blood donors and recipients: no detectable HEV RNA in 1939 donors tested and no evidence of HEV transmission to 362 prospectively followed recipients. Transfusion 2013; 53:2505–2511. No HEV RNA was found in this small United States donor coohort. 36. Food and Drug Administration. Meeting of the Blood Products Advisory Committee. Hepatitis E virus (HEV) and blood transfusion safety. 20 September 2012. http://www.fda.gov/AdvisoryCommittees/Committees MeetingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisory Committee/ucm298652.htm. [Accessed 29 May 2014] 37. Menitove JE, Leach-Bennett J, Tomasulo P, Katz LM. How safe is safe enough, & who decides and how? From a zero-risk paradigm to risk-based decision making. Transfusion 2014; 54:753–757. The authors describe an evolving framework for risk-informed decisionmaking and the key roles of stateholder engagement and health economics analysis. 38. SaBTO: Advisory Committee on the Safety of Blood Tissues and Organs. Pathogen inactivation of platelets: report of the SaBTO Working Group. https://www.gov.uk/government/uploads/system/uploads/attachment_data/ file/324354/SaBTO_platelets_report.pdf. [Accessed 14 July 2014]
Volume 21 Number 6 November 2014
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Emerging microbial threats to the United States blood supply Louis M. Katz
Purpose of review In this short review, several emerging agents are described to demonstrate potential responses of the blood community to emerging and potentially emerging infections. Recent findings Critical questions are raised as we consider appropriate approaches to these agents. Can we identify risk thresholds below which interventions are not required, that is, are there tolerable infectious risks of transfusion? Who are the stakeholders responsible for that determination? What is the role of health economic analysis for informing those decisions? If we decide that cost–utility thresholds for transfusion medicine are appropriately several fold higher than for the rest of clinical medicine, who has responsibility for being certain whether those priorities are funded? Summary Four agents will be discussed to highlight the evolving considerations in response to these considerations. Keywords risk management, risk tolerance, transfusion-transmitted infections
INTRODUCTION The classic transfusion transmissible infections (TTIs), hepatitis B virus, hepatitis C virus, and HIV fell to historic lows [1] as the blood community learned to recruit low-risk donors, deployed sensitive, specific screening tests and applied current good manufacturing practices to the operations at blood centers. New threats, of lesser absolute magnitude, are emerging and warrant considering interventions to improve transfusion safety. These TTIs require the presence of an agent in the blood of asymptomatic donors that survives processing and storage. They must be infectious after parenteral inoculation, and cause clinically significant and recognizable illness in recipients [2]. To the end of being prepared for new threats, more than 70 agents have been assessed for these characteristics and fact sheets published. New agents have been added and the originals reassessed as needed [3 ]. What follows are short discussions of four agents that fulfill our criteria for concern about which decisions about transfusion safety will be required in the near future for the United States blood supply. &
BABESIA MICROTI Human babesiosis is an Ixodes tick-borne, malarialike protozoan parasite infection caused primarily
by Babesia microti in the United States, with hyperendemic foci in the Northeast and moderate prevalence in the upper Midwest [4]. It is the most frequent TTI in the United States [5]. A 2011 review identified 162 cases of transfusion-transmitted Babesia (TTB) from 1979 to 2009, 159 from B. microti [6], 83 of which (52.2%) were recognized from 2005 to 2009. The increase reflects greater recognition of the association with transfusion, the broadening geographic range, and increasing incidence of infection. With passive TTB surveillance, it is certain that these represent a fraction of the transmissions, but national reportability since 2011 should improve case finding. Because donors and donations ‘travel’, a fraction of TTB resulted from transfusion outside the endemic states, demanding a high index of suspicion for recognition. Morbid outcomes from TTB are most common at the extremes of age and among the asplenic and immunocompromised patients. TTB is diagnosed during all 12 months,
America’s Blood Centers, Washington, DC, USA Correspondence to Louis M. Katz, MD, America’s Blood Centers, Washington, DC 20005, USA. Tel: +1 202 654 2995; e-mail: lkatz@ americasblood.org Curr Opin Hematol 2014, 21:509–514 DOI:10.1097/MOH.0000000000000089
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KEY POINTS Emerging infections continue to be recognized as potential threats to transfusion safety. Identification and exclusion of donors at risk for TTIs and donation testing continue to be the primary methods for mitigation, as they have been for traditional TTI agents. The role of health economic analyses in decisionmaking about TTIs is unclear, but their use, in the context of a comprehensive risk-informed decisionmaking process, is being proposed to address questions about the balance between our historically precautionary approaches and appropriate use of scarce healthcare resources.
reflecting persisting subclinical parasitemia for months to years in donors after vector-borne infection [7 ]. In 2010, the Food and Drug Administration’s (FDA) Blood Products Advisory Committee supported the need for regional testing of blood donors for babesiosis [8]. In the absence of FDA-licensed donor screens, serology and molecular testing (PCR) are under evaluation, alone and in combination. Antibody assays can detect acute infections after a short seronegative window period, but miss infections in the window before seroconversion. PCR can detect donors early, before serology. Seropositive donors may remain positive for extended periods after spontaneous or medical cure, and PCR can be insensitive to low parasite burdens in infected, healthy donors. Indirect immunofluorescent antibody (IFA) testing and PCR were implemented to select low-risk red blood cell units for high-risk neonatal and hemoglobinopathy patients at a blood center in a hyperendemic area [9]. The approach was operationally feasible, and no TTB was seen after use of 787 units in the target population, compared with seven cases after 6500 prior unscreened units. This study was underpowered to detect a statistically significant difference from the pretesting era. Among 2113 screened units, there were 26 positive IFA results and no positive PCR. In another study, 1002 highrisk donors were tested with a research IFA and realtime PCR, finding 25 seropositive donations and three PCR positives, of which one was seronegative in the window period [10]. During testing of 17 422 donations from a high-risk donor population using IFA, with PCR testing of seropositive samples, 208 seroreactive donors were found and 29 out of 139 tested with PCR were positive [11]. Lookback to recipients of 656 prior cellular components from &
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the seropositive donors yielded 63 recipients to be tested for B. microti. A total of 33.3% (5/15) from lookback during 1999–2000 were B. microti reactive, compared with 6.3% (3/48) after implementation of indefinite deferral of seropositive donors, demonstrating the potential impact of removing testpositive donors from the donor base. In a prospective evaluation of a research arrayed IFA and PCR on 30 435 donors in a high-endemic area, 133 donors were seropositive and PCR negative, 14 were seropositive and PCR positive, and five were seronegative and PCR positive (window infections) [12]. No TTB occurred from screened donations, compared with six cases from contemporary unscreened units (no denominator supplied). Data on test performance and the incidence of TTB are inadequate to quantitate with precision the residual risk of TTB or the relative health economic impacts of proposed screening strategies across the geographic spectrum of United States blood collectors. A cost-effectiveness analysis examined the impacts of alternative approaches in endemic areas in Connecticut, Massachusetts, Minnesota, New Jersey, New York, Rhode Island, and Wisconsin [13 ]. Incremental cost-effectiveness ratios (ICER) were compared with other blood safety initiatives. Serology, compared with the current donor query about a history of babesiosis, had an ICER of $760 000/quality-adjusted life year (QALY), ‘which compares favorably to currently adopted practices for preventing’ other TTIs. Serology and PCR had an ICER of $8.8 million/QALY compared with serology. In a second cost-effectiveness analysis comparing screening in four, seven, or 20 states with decreasing incidences and national screening [14 ], combination of ELISA and PCR screening costs an estimated $5.2 and $6.6 million/QALY in the four and seven state programs, respectively, and more for wider screening. The least expensive approach, ELISA alone in four states, costs $2.6 million/QALY (95% credible intervals from $290 000 to $10.5 million). No PCR strategy is cost effective at $1 million/QALY, approximating the cost utility of a number of currently accepted interventions. Accepting the assumptions in the models, they argue for skepticism about the utility of any screening outside hyperendemic states and a critical approach inside them, especially if one takes issue with using ‘accepted’ donor-screening thresholds as the comparator. Health economic data can help us understand whether screening rises to a priority demanding its use, and will inform decisions about if and where testing is performed – only on donors in endemic areas, there and among travelers to those areas or more broadly, with a single assay or both serologic and molecular tests. Are there testing strategies that provide manufacturers with sufficient &
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return on investment to proceed to commercialization of affordable assays?
DENGUE VIRUSES These flaviviruses are the most important vectorborne disease on the planet, with 50–100 million symptomatic infections annually. Billions of people live in areas where transmission occurs [15]. The virus is endemic in tropical and subtropical areas of Asia and the Americas, and although present in Africa, its epidemiology there is poorly characterized. Dengue is the most frequently confirmed cause of fever in United States travelers returning from affected areas. The prevalence of dengue antibody reaches 40% on the United States side of Texas– Mexico border. Dengue is endemic in the United States commonwealth of Puerto Rico, where partial screening of the blood supply with investigational nucleic acid-based test (NAT) has been done in recent years demonstrating rates of apparent viremia similar to those for West Nile virus in the United States before NAT screening [16]. Viremia is present 2–4 days before symptoms, persisting 4–5 days during illness, but half of infections are asymptomatic. Competent Aedes mosquito vectors are present in the United States, and recent mosquitoborne spread (especially, Florida in Key West during 2009–2010 and Martin and St. Lucie counties in 2013) has heightened concern that autochthonous dengue may threaten transfusion safety. Collections were briefly suspended in the counties affected during the 2013 Florida outbreak, but this was feasible because of the limited contribution of those areas on collections in the region (G LeParc, personal communication). A handful of transfusion transmissions have been documented and reported: one from nonendemic Hong Kong [17], three in a Singapore cluster [18], and one in Puerto Rico [19]. The latter was found by tracing a unit positive for dengue RNA in a research study from the donor to the recipient. Why, in the face of millions of mosquito-borne infections, are these the only transmissions that have been recognized? Donor studies in epidemic areas of Brazil, Puerto Rico, and Honduras demonstrate dengue RNA in 0.06, 0.07–0.2, and 0.40% of donors, respectively, with virus culturable from some. In a linked donor-recipient study in Rio de Janiero and Recife, Brazil during their 2012 epidemic, 51 RNA-positive (of 7871 tested) units were transfused to 42 recipients. Final evaluation of 23 recipients was possible using their immunoglobulin M and RNA results, of whom five were not susceptible. There were five probable and one
possible transmission to 18 susceptible recipients, a transfusion transmission rate of 33% [20 ]. Posttransfusion clinical profiling of these recipients identified no statistically significant differences between recipients of RNA positive or negative units ([21 ] and M Busch, personal communication). In the epidemic setting, many recipients may be protected by prior immunity, and/or RNA-positive units may not contain an infectious dose because of low titer viremia, and/or the presence of neutralizing antibody. Few data exist to inform mitigation strategies in nonendemic areas, such as the United States. Certainly, the recipient of an infectious unit will more likely be susceptible, but the number of such units will be far smaller. Available mitigation strategies include recall of donated components when the donor reports a postdonation illness diagnosed or compatible with dengue after travel, temporary deferral of donors after travel to endemic areas, and screening of some or all donations with NATs. The latter two are likely to be most effective. Travel deferrals long enough to avoid asymptomatic, viremic donors must be assessed for their impact on the adequacy of the blood supply, but have been applied ex-United States successfully. For dengue and other acute viral infections, these are likely to be 2–4 weeks after return from epidemic foci. RNA testing needs justification in an appropriate risk–benefit analysis. Testing becomes a more viable option if sustained vector-borne transmission is established in the mainland United States, where suspension of local collections would most likely compromise the adequacy of the blood supply. &
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CHIKUNGUNYA VIRUS This mosquito-borne alphavirus has caused hundreds of thousands of infections in Africa, the islands of the Indian Ocean, south Asia, and some Pacific islands during the past decade. It is clinically similar to dengue, but with prominent, often prolonged, arthralgia. Mortality is unusual [22]. Aedes aegypti is an effective urban vector, and Aedes albopictus is an alternate. A viral mutation is associated with very high viral loads in A. albopictus, contributing to the recent explosive outbreaks in the Indian Ocean and parts of south Asia. Transfusion transmission is theoretically possible because virus is present in blood for several days and 20% of infections are asymptomatic [23 ]. Modeling the epidemic on Reunion Island from 2005 to 2007, with its 40% attack rate, estimated a peak prevalence of 1500 out of 100 000 infected donations [24]. Modeling in Thailand, during a less intense epidemic,
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suggested 38–52 viremic donations out of 100 000 should have been expected [25 ]. Despite these estimates, no cases of transfusion transmission have yet been recognized worldwide. Chikungunya is receiving attention in the United States because autochthonous mosquito transmission was recognized in the Caribbean during December 2013. Cases have increased rapidly and more than 400 000 infections were reported by August 2014. With the high volume of travel from the United States to the Caribbean, introduction of the virus to the United States mainland, where vectors are widespread, is probable. A. aegypti is present in the southernmost United States, extending as far west as California, and A. albopictus has spread to approximately one out of three of the continental United States from the Gulf and southeast to as far north as New York and as far west as California [26]. The Caribbean virus does not have the E1 mutation, so its explosive spread by A. albopictus is unlikely. No donor question is used to reduce the risk of Chikungunya transmission from asymptomatic donors. Current deferral criteria for travel to malarious areas include many regions affected by recent Chikungunya outbreaks, but most of the Caribbean is malaria-free. Some national blood authorities in the European Union and elsewhere use temporary deferral periods after travel to the tropics, including areas that are not malaria endemic. These mitigate risk from dengue, Chikungunya virus and other acute viral pathogens by preventing donation until the resolution of asymptomatic viremia. They would be associated with an operational burden and significant donor loss in the United States, so assessment of their impact on the blood supply must precede any such deferrals. Donor education and active contact of donors after phlebotomy to increase reporting of postdonation symptoms to blood centers might facilitate quarantine and withdrawal of potentially infectious components from ill donors with exposure in epidemic settings [27]. Donor screening with sensitive NAT to identify viremic donors is not available. Mass investigational screening of the blood supply for West Nile virus was implemented less than 1 year after the recognition of transfusion-associated infections in 2002 [28]. Manufacturers are considering developing Chikungunya NAT prototypes for similar deployment at need but valid financial concerns may impact their decisions to develop donor screening assays. An interesting discussion is at what point a precautionary intervention, that is, one that might work and will not cause unreasonable ‘harm’, ought to be implemented. Transmission by blood has never been recognized despite very high attack rates in &&
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local epidemics and the wide magnitude of the virus’ spread. This discussion unfolds among interested stakeholders in the blood community, at the FDA, in the public health community, the test builders and in the provider community that, as end user of blood, must be asked about their willingness to bear the benefits and costs of mitigation efforts.
HEPATITIS E VIRUS This hepevirus was identified as causing a large 1978 Kashmiri epidemic. It was distinguished from hepatitis A by serologic methods and implicated in outbreaks as early as the mid-1950s. It causes asymptomatic to fulminant infections, and in the immunosuppressed can cause chronic infection and cirrhosis. Mortality is low, although maternal mortality during the last trimester of 10–20% has been reported [29]. The four genotypes cause more than 3 million cases and 700 000 deaths annually. Genotypes 1 and 2 cause large epidemics in the developing world associated primarily with fecal contamination of potable water. Genotypes 3 and 4 are zoonotic (in pigs and other species, in addition to human infection) and associated with food-borne transmission after consumption raw or insufficiently cooked meat or viscera, or with close environmental contact to an infected source. These infections are most often documented in Japan and Europe (from bivalve mollusks, boudin noir, figatelli sausage, dinuguan) [30,31]. Genotype 3 is endemic in the United States (swine). The third National Health and Nutrition Examination Survey (1988–1994) [32] found a United States seroprevalence of 21%, but it is rarely clinically recognized in the United States. From 2005 to 2012, Centers for Disease Control and Prevention documented 26 cases from a total of 154 obscure clinical hepatitis cases evaluated (11/26 attributed to infection in other countries) [33]. Viral RNA is found in asymptomatic blood donors, persisting for 4–6 weeks (as long as 112 days). Chronic infection can occur in immune-deficient patients and progress to cirrhosis. At the case report level, transfusion transmissions are well documented, especially in Europe and Japan (reviewed in [34]), but the risk in the United States appears low [35 ]. Background presentations and discussion of the appropriate response to hepatitis E virus (HEV) by the United States blood community were held at the FDA Blood Products Advisory Committee in 2012 [36]. The committee accepted an FDA framework for a sequential approach to estimating the United States transfusion risk and formulating an appropriate response. It included characterization of &
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candidate NAT using WHO standards for HEV RNA and a panel of virologically confirmed clinical samples would be conducted. Then, performance of large-scale studies of blood donors with validated molecular assays to determine the prevalence of viremic (NAT-positive) blood donors and characterization of serologic assays with virologically confirmed clinical samples would be conducted. Studies on linked donor–recipient repositories with these validated tests to assess transfusion transmission of HEV would follow. Implicit in acting on donorrecipient studies is a judgment about acceptable risk. Whether an explicit risk-informed approach can displace a historically highly precautionary approach to blood safety decision-making in the United States, where cost-effectiveness thresholds of $1 million/QALY are not unusual, remains an open question [37 ]. With regard to health economic analyses of testing for B. microti and other emerging infections, it is germane to note that the United States FDA concerns itself with the safety, purity, and potency of the blood supply and has chosen to require testing with very high costs per QALY and other metrics, for example, nucleic-acid testing for HIV, hepatitis C virus, and hepatitis B virus, and serological testing for infection with Trypanosoma cruzi, the agent of Chagas disease. In the United States, other agencies within the Department of Health and Human Services, especially the Center for Medicare and Medicaid Services, are responsible for reimbursement decisions, but are not frequently consulted when decisions are made at the FDA, resulting in no or delayed coverage for the FDA’s decisions – in a sense unfunded mandates. One ought to look carefully for an example for the United States of the incorporation of health economic analysis in decision-making at the recent decision in the United Kingdom, largely on these grounds, not to recommend the implementation of pathogen reduction for platelets, despite its ability to mitigate known and potentially emerging TTIs [38]. &
CONCLUSION Multiple potential pathogens are of current interest with regard to their potential impacts on transfusion safety. Each requires an individualized, risk-based, decision-making process when considering the need for and substance of mitigation strategies. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Busch MP. Cooley Award Lecture: transfusion-transmitted viral infections: building bridges to transfusion medicine to reduce risks and understand epidemiology and pathogenesis. Transfusion 2006; 46:1624– 1640. 2. Stramer SL, Hollinger FB, Katz LM, et al. Emerging infectious disease agents and their potential threat to transfusion safety. Transfusion 2009; 43 (Suppl 2):1–29. 3. AABB EID working group. Fact sheets created or updated post publication & of the TRANSFUSION August 2009 supplement. http://www.aabb.org/ resources/bct/eid/Pages/eidpostpub.aspx. [Accessed 24 May 2014] These fact sheets provide a structured assessment of our current understanding of these pathogens for transfusion safety. 4. CDC. Babesiosis: epidemiology and risk factors. http://www.cdc.gov/parasites/babesiosis/epi.html. [Accessed 23 May 2014] 5. Vannier E, Krause PJ. Current concepts: human babesiosis. N Engl J Med 2012; 366:2397–2407. 6. Herwaldt BL, Linden JV, Bosserman E, et al. Transfusion-associated babesiosis in the United States: a description of cases. Ann Intern Med 2011; 155:509–519. 7. Leiby DA, Johnson ST, Won KY, et al. A longitudinal study of Babesia & microti infection in seropositive blood donors. Transfusion 2014; 54:2217– 2225. Demonstration of persistent B. microti infection in donors. 8. Food and Drug Administration. Meeting of the Blood Products Advisory Committee. Risk of Babesia infection by blood transfusion and potential strategies for donor testing; 26 July 2010. www.fda.gov/AdvisoryCom mittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/ BloodProductsAdvisoryCommittee/ucm205013.htm. [Accessed 28 May 2014] 9. Young C, Chawla A, Berardi V, et al. Preventing transfusion-transmitted babesiosis: preliminary experience of the first laboratory-based blood donor screening program. Transfusion 2012; 52:1523–1529. 10. Johnson ST, Van Tassell ER, Tonnetti L, et al. Babesia microti real time-PCR testing of Connecticut blood donors: potential implications for screening algorithms. Transfusion 2013; 53:2644–2649. 11. Johnson ST, Cable RG, Leiby DA. Lookback investigations of Babesia microtiseropositive blood donors: seven-year experience in a Babesia-endemic area. Transfusion 2012; 52:1509–1510. 12. Moritz E, Johnson ST, Winton C, et al. Prospective investigational blood donation screening for Babesia microti (Bm). Transfusion 2013; 53:13A; Abstract P1. 13. Simon MS, Leff JA, Pandya A, et al. Cost-effectiveness of blood donor & screening for Babesia microti in endemic regions of the United States. Transfusion 2014; 54 (3 Pt 2):889–899. A cost-effectiveness analysis of screening strategies for B. microti in endemic states. 14. Goodell A, Bloch E, Krause P, Custer B. Costs, consequences, and cost&& effectiveness of strategies for Babesia microti donor screening of the US blood supply. Transfusion 2014; 54:2245–2257. A detailed cost-effectiveness analysis of screening strategies for B. microti in endemic states. 15. WHO. Dengue and severe dengue. http://www.who.int/mediacentre/factsheets/fs117/en/. [Accessed 23 May 2014] 16. Mohammed H, Linnen JM, Munoz-Jordan JL, et al. Dengue virus in blood donations, Puerto Rico 2005. Transfusion 2008; 48:1348–1354. 17. Chuang WW, Wong TY, Leung YH, et al. Review of dengue fever cases in Hong Kong during 1998–2005. Hong Kong Med J 2008; 14:170– 177. 18. Transfusion-Transmitted Dengue Infection Study Group. Tambyah PA, Koay ES, Poon MLM, et al. Dengue hemorrhagic fever transmitted by blood transfusion. N Engl J Med 2008; 359:1526–1527. 19. Stramer SL, Linnen JM, Carrick JM, et al. Dengue viremia in blood donors identified by RNA and detection of dengue transfusion transmission during the 2007 dengue outbreak in Puerto Rico. Transfusion 2012; 52:1657– 1666. 20. Custer B, Loureiro P, Lopes M, et al. Dengue transfusion transmission rate & during large epidemics of denv-4 in Rio de Janeiro and Recife, Brazil. Vox Sanguinis 2014; 107 (S1):160. This is an estimate of the transmissibility of dengue virus by transfusion. 21. Custer B, Sabino EC, McClure C, et al. Prevalence of symptomatic dengue && virus infection in transfused patients. Vox Sanguinis 2013; 105 (S2):41. Transfusion-transmitted dengue patients in this small study were not clinically distinguishable from controls. 22. Centers for Disease Control and Prevention. Chikungunya fever. http:// www.cdc.gov/chikungunya/fact/index.html. [Accessed 21 May 2014]
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Transfusion medicine and immunohematology 23. Appassakij H, Khuntikij P, Kemapunamanus M, et al. Viremic profiles in asymptomatic and symptomatic Chikungunya fever: a blood transfusion threat? Transfusion 2013; 53:2567–2574. These are studies in Thai donors infected with Chikungunya, profiling viremia, and establishing the very rate of symptomatic infection. 24. Brouard C, Bernillon P, Quatresous I, et al. Estimated risk of Chikungunya viremic blood donation during an epidemic on Reunion Island in the Indian Ocean. Transfusion 2008; 48:1333–1341. 25. Appassakij H, Promwong C, Rujirojindakul P, et al. The risk of blood trans&& fusion-associated Chikungunya fever during the 2009 epidemic in Songkhla Province, Thailand. Transfusion 2014; 54:1945–1952. Chikungunya infection is evaluating using models applicable to West Nile virus and the rate of asymptomatic viremia estimated under the conditions of the Thai epidemic. 26. CDC. Chikungunya information for vector control programs. www.cdc.gov/ chikungunya/pdfs/CHIKV_VectorControl.pdf. [Accessed 20 May 2014] 27. EID Working Group. Chikungunya virus. http://www.aabb.org/resources/bct/ eid/Pages/eidpostpub.aspx. [Accessed 21 May 2014] 28. NHLBI Emerging Infectious Disease Task Force convened November 7. Glynn SA, Busch MP, Dodd RY, et al. Emerging infectious agents and the nation’s blood supply: responding to potential threats in the 21st century. Transfusion 2013; 53:438–454. 29. Emerson SU, Purcell RH. Hepatitis E virus. In: Knipe DM, Howley PM, editors. Fields virology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2013. pp. 2242–2258. 30. Hoofnagle JH, Nelson KE, Purcell RH. Hepatitis E. N Engl J Med 2012; 367:1237–1244. 31. AABB EID Working Group. Hepatitis E virus. http://www.aabb.org/ resources/bct/eid/Pages/eidpostpub.aspx. [Accessed 24 May 2014] &
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32. Kuniholm MH, Purcell RH, McQuillan GM, et al. Epidemiology of hepatitis E virus in the United States: results from the third National Health and Nutrition Examination Survey, 1988–1994. J Infect Dis 2009; 200:48–56. 33. Drobeniuc J, Greene-Montfort T, Le NT, et al. Laboratory-based surveillance for hepatitis E virus infection, United States, 2005–2012. Emerg Infect Dis 2013; 19:218–222. 34. Nelson KE. Transmission of hepatitis E virus by transfusion: what is the risk? Transfusion 2014; 54:8–10. 35. Xu C, Wang R, Schecherly C, et al. An assessment of hepatitis E virus in US & blood donors and recipients: no detectable HEV RNA in 1939 donors tested and no evidence of HEV transmission to 362 prospectively followed recipients. Transfusion 2013; 53:2505–2511. No HEV RNA was found in this small United States donor coohort. 36. Food and Drug Administration. Meeting of the Blood Products Advisory Committee. Hepatitis E virus (HEV) and blood transfusion safety. 20 September 2012. http://www.fda.gov/AdvisoryCommittees/Committees MeetingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisory Committee/ucm298652.htm. [Accessed 29 May 2014] 37. Menitove JE, Leach-Bennett J, Tomasulo P, Katz LM. How safe is safe enough, & who decides and how? From a zero-risk paradigm to risk-based decision making. Transfusion 2014; 54:753–757. The authors describe an evolving framework for risk-informed decisionmaking and the key roles of stateholder engagement and health economics analysis. 38. SaBTO: Advisory Committee on the Safety of Blood Tissues and Organs. Pathogen inactivation of platelets: report of the SaBTO Working Group. https://www.gov.uk/government/uploads/system/uploads/attachment_data/ file/324354/SaBTO_platelets_report.pdf. [Accessed 14 July 2014]
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