Industrial plasma fractionation, a complex and highly regulated technology, remains largely inaccessible to many low- and middle-income countries (LMICs). This, combined with the limited availability and high cost of plasma-derived medicinal products (PDMPs), creates deficiency of access to adequate treatment for patients in resource-limited countries, and leads to their suffering. Meanwhile, an increasing number of LMICs produce surplus plasma, as a by-product of red blood cell preparation from whole blood, that is discarded because of the lack of suitability for fractionation. This article reviews pragmatic technological options for processing plasma collected from LMICs into therapies and supports a realistic stepwise approach aligned with recent World Health Organization guidance and initiatives launched by the Working Party for Global Blood Safety of the International Society of Blood Transfusion. When industrial options based on contract or toll plasma fractionation programme and, even more, domestic fractionation facilities require larger volumes of quality plasma than is produced, alternative methods should be considered. In-bag minipool or small-scale production procedures implementable in blood establishments or national service centres are the only realistic options available to gradually reduce plasma wastage, provide safer treatments for patients currently treated with non-pathogen-reduced blood products and concurrently improve Good Manufacturing Practice (GMP) levels with minimum capital investment. As a next step, when the available volume of quality-assured plasma reaches the necessary thresholds, LMICs could consider engaging with an established fractionator in a fractionation agreement or a contract in support of a domestic fractionation facility to improve the domestic PDMP supply and patients' treatment.

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Plasma-derived medicinal products (PDMPs) are recognized internationally as essential medicines required to treat various acute and chronic conditions including congenital deficiencies of plasma proteins in haemophilia and primary immune deficiency. Global provision of these medicines is dominated by a small number of commercial companies, influencing the price and availability of the products. Achieving a level of strategic independence from this dominance is now seen as a public health priority in many countries. During the Regional Congress of the International Society for Blood Transfusion (ISBT) in Cape Town, South Africa, in November 2023, around 50 delegates from 24 countries participated in a workshop (WS) organized jointly by the International Plasma and Fractionation Association (IPFA) and the ISBT Working Party on Global Blood Safety on pathways towards provision of PDMPs from domestic plasma independent of commercial purchase in the open market. The WS was structured around three themes, each addressed by a separate group: Quality/safety requirements for plasma for fractionation (PfF) Stepwise access for safe plasma proteins Approaching contract fractionation A synthesis of conclusions from these groups included the following: The need to acquire support from government authorities for a national plasma policy, recognizing the difficulties posed by unstable political and bureaucratic environments. The value of embedding plasma and PDMPs within a patient blood management (PBM) paradigm to promote optimal clinical use of PDMPs. Training of blood/plasma collection personnel in the relevant principles of Good Manufacturing Practice (GMP), coupled with regulatory oversight of plasma product production in the engaged jurisdictions. Appreciation that limited access to contract fractionation may necessitate a stepwise approach, which may include small-scale preparation of versions of essential plasma proteins as an intermediate phase towards the manufacture of industrial-scale PDMPs from domestic plasma.

BACKGROUND AND OBJECTIVES:Actions are needed to improve access to safe plasma-derived medicinal products (PDMPs) in low- and middle-income countries (LMICs). MATERIALS AND METHODS:The International Society of Blood Transfusion (ISBT) Working Party for Global Blood Safety organized an on-line workshop during 21-23 September 2021 to advance access to safe plasma proteins in resource-constrained countries, consistent with recent World Health Organization (WHO) guidance documents. RESULTS:The meeting drew attention to the considerable unmet needs for access to essential PDMPs in LMICs, in particular coagulation factors and immunoglobulins, and stepwise actions to address these deficits. First, improved access to safe plasma protein therapies requires blood component separation with prevention of wastage of recovered plasma. Quality and safety of collected blood and plasma must be assured so that plasma in excess of transfusion needs can be processed into safe plasma proteins. Second, local production of safe plasma proteins can be implemented using available technologies to locally obtain pathogen-reduced plasma and prepare pathogen-reduced cryoprecipitate and immunoglobulins from small plasma pools. Third, when a sufficient, stable volume of quality-assured plasma is available (approximately 50,000 L/year), contract or toll fractionation by a foreign plasma fractionator can expand the supply of PDMPs. Fourth, when the national infrastructure supports high-technology industrial production and stable volumes of quality plasma reach at least 200,000 L/year, technology transfer for domestic fractionation can be considered. CONCLUSION:Action is needed including commitments of the organizations that made the workshop possible (WHO, ISBT, World Federation of Haemophilia [WFH], Plasma Protein Therapeutics Association [PPTA], International Plasma Fractionation Association [IPFA], International Patient Organization of Primary Immunodeficiencies [IPOPI] and International Federation of Blood Donor Organizations [FIODS]).

This document provides a commentary and further elaboration on the conclusions reached during a recent international workshop on plasma protein therapies organized by the Working Party for Global Safety of the International Society of Blood Transfusion (ISBT). The workshop addressed the profound deficiency in access to safe plasma protein therapies that persists in low- and middle-income countries (LMICs). We provide additional factual economic and technological information that highlights why local production of small-scale virus-inactivated concentrates of clotting factors and immune globulins from domestic recovered plasma through stepwise introduction of available validated technologies is a pragmatic approach to gradually improve the care of patients with bleeding disorders and immune deficiencies in LMIC while supporting progress toward fractionation of plasma. This strategy is in line with a recent WHO guidance. We stress that the active involvement of international blood donor and blood transfusion organizations, patient organizations, governments and industry will be essential in supporting stepwise and sustainable improvements in access to safe, effective, and quality assured plasma protein therapies.

This document prepared and endorsed by the Working Party on Global Blood Safety of the International Society of Blood Transfusion presents elements, as of April 2020, to take into consideration in the preparation and transfusion of COVID-19 convalescent plasma as a possible treatment approach of COVID-19. The document covers the following important factors to have in mind when considering this treatment: (a) eligibility criteria of convalescent COVID-19 patients to donate whole blood or plasma, (b) pre-screening and pre-donation testing of convalescent COVID-19 donors; (c) criteria for collection of COVID-19 plasma; (d) post-donation treatment of plasma; and (e) it offers recommendations for plasma transfusion.

Ethical principles should prevail in the collection, testing and use of COVID-19 convalescent plasma (CCP) for human research in low- and middle- income countries. To appropriately guarantee safety, only blood establishments that comply with recognized quality standards should collect CCP.

The limited clinical data available suggest that convalescent plasma (CP) may have a therapeutic benefit in COVID-19 [1]. Absent any known effective therapy and considering the potential for local production, COVID-19 CP is becoming a global priority for investigational use. High-income countries with established national infrastructures and effective regulatory oversight can produce quality and safe plasma for transfusion that complies with international standards [2] and have initiated controlled clinical studies of COVID-19 CP [3, 4]. Unfortunately, in low- and middle-income countries (LMIC) safe blood collection and transfusion are the challenges in the absence of a well-organized and nationally regulated blood collection system and limitations of critical resources and manpower. Nevertheless, provision of COVID-19 CP in LMIC needs to comply with the same principles of product safety and ethics regarding collection and use as in HIC, and guidance is needed [5, 6]. The preparation of COVID-19 CP in LMIC should be organized as national initiatives supervised by the Ministries of Health and coordinated by the National Blood Services (or in its absence, cooperating blood establishments demonstrably meeting quality standards) to assure that legal and ethical guidelines for human research are applied to COVID-19. COVID-19 CP should be obtained only from volunteer, non-remunerated donors with reliable clinical, virologic or serologic evidence of prior infection with SARS-CoV-2. CP can be collected without additional testing for SARS-CoV-2 at >14 days after full recovery from symptoms. However, as an additional precaution against contagion in the donor room, prior demonstration of resolution of infection by a non-reactive Nucleic Acid Test (NAT) for SARS-CoV-2 performed on a nasopharyngeal swab sample can be considered for collections of CP between 14 and 28 days after full recovery from symptoms [7]. Collecting blood or plasma only from male donors or from female donors who have never been pregnant (including miscarriages and abortions) is advised for prevention of Transfusion Related Acute Lung Injury (TRALI). Selection criteria for blood donation and blood testing procedures should meet the established local requirements and standards. Where plasmapheresis is unavailable, CP should be prepared through component separation from whole blood (WB) while selecting donors carefully to avoid causing undue red cell loss and a low haemoglobin level. Transfusing convalescent WB should be considered only if WB transfusion is clinically indicated. ABO and RhD testing are needed to ensure blood group compatibility of CP and red blood cells. The COVID-19 epidemic is one additional wake-up call that capacity building of a sustainable national blood system integrated within the public health system is crucial to ensure adequate, accessible and safe life-saving blood products in all countries, including in emergency situations [8]. All authors have contributed to the drafting and approved the final version of the manuscript. The authors are members of the Organizing Committee of the Working Party on Global Blood Safety of the International Society of Blood Transfusion. Jay Epstein's contributions to this article reflect his own views and should not be construed to represent FDA's views or policies.

BACKGROUND:Risk-based decision making is increasingly recognized as key to support national blood policy makers and blood operators concerning the implementation of safety interventions, especially to address emerging infectious threats and new technology opportunities. There is an urgent need for practical decision support tools, especially for low- and middle-income countries that may not have the financial or technical capability to develop risk models. WHO supported the development of such a tool for blood safety. The tool enables users to perform both a quantitative Multi-Criteria Decision Assessment and a novel step-by-step qualitative assessment. STUDY DESIGN AND METHODS:This paper summarizes the content, functionalities, and added value of the new WHO tool. A fictitious case study of a safety intervention to reduce the risk of HIV transmission by transfusion was used to demonstrate the use and usefulness of the tool. RESULTS:Application of the tool highlighted strengths and weaknesses of both the quantitative and qualitative approaches. The quantitative approach facilitates assessment of the robustness of the decision but lacks nuances and interpretability especially when multiple constraints are taken into consideration. Conversely, while unable to provide an assessment of robustness, the step-by-step qualitative approach helps structuring the thought process and argumentation for a preferred intervention in a systematic manner. CONCLUSION:The relative strengths and weaknesses of the quantitative and step-by-step qualitative approach to risk-based decision making are complementary and mutually enhancing. A combination of the two approaches is therefore advisable to support the selection of appropriate blood safety interventions for a particular setting.

Vox SanguinisVolume 114, Issue 6 p. 635-636 Letter to the Editor Improving haemophilia therapy in developing countries: virus-safe cryoprecipitate Jean-Claude Faber, Jean-Claude Faber Association Luxembourgeoise des Hémophiles, Luxembourg, LuxembourgSearch for more papers by this authorJay Epstein, Jay Epstein US Food and Drug Administration, Silver Spring, MD, USASearch for more papers by this authorThierry Burnouf, Corresponding Author Thierry Burnouf thburnouf@gmail.com orcid.org/0000-0002-0507-9243 College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan T. Burnouf, Graduate Institute of Biomedical Materials and Tissue Engineering & International PhD Program in Biomedical Engineering, College of Biomedical Engineering,Taipei Medical University, Wuxing Street, Xinyi District, Taipei, Taiwan 110. E-mail: thburnouf@gmail.comSearch for more papers by this author Jean-Claude Faber, Jean-Claude Faber Association Luxembourgeoise des Hémophiles, Luxembourg, LuxembourgSearch for more papers by this authorJay Epstein, Jay Epstein US Food and Drug Administration, Silver Spring, MD, USASearch for more papers by this authorThierry Burnouf, Corresponding Author Thierry Burnouf thburnouf@gmail.com orcid.org/0000-0002-0507-9243 College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan T. Burnouf, Graduate Institute of Biomedical Materials and Tissue Engineering & International PhD Program in Biomedical Engineering, College of Biomedical Engineering,Taipei Medical University, Wuxing Street, Xinyi District, Taipei, Taiwan 110. E-mail: thburnouf@gmail.comSearch for more papers by this author First published: 10 June 2019 https://doi.org/10.1111/vox.12794Citations: 3Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume114, Issue6August 2019Pages 635-636 RelatedInformation

Vox SanguinisVolume 115, Issue 2 p. 213-214 Letter to the Editor Recovered plasma for fractionation: call for quality standards to end wastage Thierry Burnouf, Corresponding Author Thierry Burnouf thburnouf@gmail.com orcid.org/0000-0002-0507-9243 Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan Thierry Burnouf, Graduate Institute of Biomedical Materials and Tissue Engineering & International PhD Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, 250 Wuxing Street, Xinyi District, Taipei city, Taiwan E-mail: thburnouf@gmail.comSearch for more papers by this authorJay Epstein, Jay Epstein FDA, Silver Spring, MD, USASearch for more papers by this authorJean-Claude Faber, Jean-Claude Faber Association Luxembourgeoise des Hémophiles, Luxembourg City, LuxembourgSearch for more papers by this author Thierry Burnouf, Corresponding Author Thierry Burnouf thburnouf@gmail.com orcid.org/0000-0002-0507-9243 Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan Thierry Burnouf, Graduate Institute of Biomedical Materials and Tissue Engineering & International PhD Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, 250 Wuxing Street, Xinyi District, Taipei city, Taiwan E-mail: thburnouf@gmail.comSearch for more papers by this authorJay Epstein, Jay Epstein FDA, Silver Spring, MD, USASearch for more papers by this authorJean-Claude Faber, Jean-Claude Faber Association Luxembourgeoise des Hémophiles, Luxembourg City, LuxembourgSearch for more papers by this author First published: 24 November 2019 https://doi.org/10.1111/vox.12871Citations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume115, Issue2February 2020Pages 213-214 RelatedInformation

3,110,308 ll/963 Bellamy, Jr. ........................ 128/24 3,140,716 7/1964 Harrison et al. .................... 128/399 4,321,919 3/1982 Edelson .......... 28/214 R 4,398,906 8/1983 Edelson ................................... 604/6 4,424,201 1/1984 Valinsky et al. ........................ 424/3 4,428,744 1/1984 Edelson ................................... 604/6 4,464,166 8/1984 Edelson ................................... 604/6 4,568,328 2/1986 King........................................ 604/6 4,573,960 3/1986 GoSS ........................................ 604/6 4,573,961 3/1986 King........... 604/6 4,573,962 3/1986 Troutner ... 604/6 4,578,056 3/1986 King et al. .............................. 604/6 4,596,547 6/1986 Troutiner ................................. 604/4 4,623,328 11/1986 Hartranft ................................ 604/4 4,651,739 3/1987 Oseroff et al. ...................... 28/395 4,727,027 2/1988 Wiesehahn et al. ................ 435/173 4,748, 120 5/1988 Wiesehahn ......... 435/173 4,846,788 7/1989 Heitz et al. ............................ 604/20

Coming shortly after outbreaks of dengue and chikungunya virus in related locations, the recent outbreak of Zika virus in the southern part of the western hemisphere is yet another reminder that infectious pathogens continue to emerge rapidly and can adversely affect public health, including the safety of the blood supply. In response to Zika virus, public health measures that rely largely on donor deferral and sourcing of blood from non-outbreak areas until a blood donor screening test becomes available have been implemented to address the safety of the blood supply in the United States. However, a more universal approach to ensuring blood safety in the setting of rapidly emerging infectious diseases is needed.

Threats to blood safety from infectious agents, and subsequent public health action, are hardly novel. Transfusion transmission of Treponema pallidum, the etiologic agent of syphilis, was recognized in the early 20th century soon after the first successful transfusions, and in response, donor tests for syphilis-related antibodies were introduced.1 Later in the 1960s, hepatitis B virus was found to cause posttransfusion jaundice, and sensitive donor screening tests for hepatitis B surface antigen (HBsAg) were added to donor testing in the early 1970s. The AIDS epidemic in the 1980s presented an entirely new kind of challenge to blood safety, with the need to respond urgently to a newly emerging blood-borne and sexually transmitted infection with catastrophic implications. A massive scientific and public health response to AIDS resulted in discovery of human immunodeficiency virus (HIV) as the etiologic agent and then licensure of blood donor screening tests a year later. Since the emergence of HIV, numerous recognized and emerging blood safety concerns (e.g., human T-lymphotropic virus, hepatitis C virus [HCV], cytomegalovirus, malaria, variant Creutzfeldt-Jakob disease, Chagas disease, and bacterial contamination) have been addressed by a multitiered approach comprising donor deferrals through education and risk factor–based screening with questionnaires; a limited physical examination; use of deferral registries to prevent future unsuitable collections; laboratory testing for markers of infection including nucleic acid tests (NATs) for some agents; and use of pathogen reduction technologies (PRTs) for certain blood components, all within a system highly regulated by the US Food and Drug Administration (FDA). Nevertheless, more recently emerging threats, including arboviruses and parasites, have presented novel challenges related to unpredictable local vector-borne spread and have exposed continued vulnerabilities to blood safety that call for urgent action. Arboviruses, transmitted by arthropods (primarily mosquitoes), are relatively new emerging threats to blood safety and present a particular challenge due to rapid and large-scale epidemics affecting the United States and its territories. While more than 100 pathogenic arboviruses are known to exist and some, particularly yellow fever and dengue, have been associated with outbreaks historically in the continental United States, none has caused recent outbreaks before the emergence of West Nile virus (WNV) in 2002. Unlike typical blood-borne viruses such as hepatitis viruses and HIV, which establish chronic infections, arboviruses cause predominantly acute infections, thus presenting a threat to blood safety only while a donor is transiently viremic, either during the disease incubation period or with an asymptomatic or a mild, undetected symptomatic infection. The challenge arises from rapid epidemic spread of an arbovirus in new geographic areas, resulting in immediate safety risks to the blood supply and an urgent need for intervention. Additionally, direct viral detection in donated blood, a generally costly measure, is needed since testing for antibodies, which take time to develop after infection and persist, would fail to interdict most infectious donations and result in deferral of large numbers of acceptable donors with previously resolved infections. The US WNV epidemic was the first example of a large-scale arboviral threat to the US blood supply, requiring an urgent response across government and nongovernment agencies. Beginning with reports in August 2002 of a WNV infection acquired by organ transplantation, ultimately being traced to a WNV-infected blood transfusion received by the organ donor, awareness of a rapidly spreading vector-borne, transfusion-transmitted agent associated with morbidity (e.g., neurologic disease) and mortality led to calls for blood donor screening tests for WNV.2 Collaborations among federal agencies, state public health laboratories, blood collection organizations, and test kit manufacturers led to the availability of investigational donor screening tests within 7 months of a November 2002 workshop in which consensus had been reached on the urgency and path forward. Fortunately, WNV isolates had been sequenced and were available for sharing, and technology platforms for NAT of blood donations for HIV and HCV could be readily adapted to WNV by the manufacturers. WNV has since become endemic in the United States, necessitating an indefinite program of donation testing. A decade later, there have been regional outbreaks of other arboviral diseases, namely chikungunya, that has spread rapidly in the Caribbean and Latin America since 2013, and dengue, with focal transmission in Hawaii, Florida, and Texas, as well as large seasonal epidemics of both arboviruses in Puerto Rico and the US Virgin Islands. During periods of local vector-borne transmission of dengue virus, blood centers in affected areas of Florida and Hawaii have voluntarily suspended blood collections, necessitating outsourcing. In Puerto Rico, a strategy to quarantine collected blood until donors can be contacted about any postdonation arboviral-related symptoms has been implemented. Overall, however, progress in addressing transfusion risks from dengue and chikungunya viruses has been slow, reflecting a general sense of limited health impact in the continental United States without a strong market incentive for test kit development. In contrast, the dramatic spread of Zika virus in the Americas since 2015 has generated a sense of public health urgency akin to AIDS or pandemic influenza, along with immediate concern over blood safety. Zika virus is different from dengue and chikungunya viruses in terms of the perceived threat to public health based on the neurologic complications and severe congenital disease associated with the infection.3 Like dengue virus, most infections with Zika virus are asymptomatic. With both viruses, however, and especially dengue, symptomatic cases can be severe and sometimes fatal. The neurologic complications of Zika virus infection can be a significant feature, including Guillain-Barré syndrome and microcephaly and other severe fetal brain defects in infants exposed in utero. The reports of these conditions may only be the beginning of recognition of complications, particularly with virus exposure during fetal development and autoimmune complications in adults.4 Also, unlike dengue and chikungunya, the risk of sexual transmission of Zika virus adds a dimension of public health risk to both vector-borne and potential transfusion transmission.5 In this issue of TRANSFUSION, the first probable case of transfusion transmission of Zika virus is reported from Brazil.6 Barjas-Castro and colleagues document a case of “lookback” to a liver transplant patient in which a donor reported illness 3 days postdonation that led to laboratory tests, which were found to be positive for Zika virus RNA by real-time polymerase chain reaction (RT-PCR), and Zika virus recovery in frozen plasma from the original donation, as well as positive RT-PCR and Zika virus recovery in blood samples from the recipient. Although transfusion of platelets (PLTs) as a source of recipient infection could not be shown unequivocally, the temporal correlation of events strongly support this finding. First, viremia in the recipient was documented at 4 days posttransfusion, consistent with known incubation periods for Zika virus. The patient was thought unlikely otherwise to be exposed based on origin from a nonepidemic area and hospitalization in a mosquito-free area for 5 days before documentation of a positive RT-PCR test for Zika virus. Additionally, the donor and recipient viruses were 99.8% homologous based on aligned fragments from the donor isolate in comparison with the whole virus sequence from the (although the epidemic strain is highly clonal). Other iatrogenic sources of Zika virus infection were not ruled out, including the transplanted liver, other donors of the pooled PLT product, or other blood products (e.g., red blood cells [RBCs]). However, the circumstantial evidence of positive findings in a recipient subsequent to exposure from a contaminated donation meet established Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network criteria for probable transmission, in the absence of conflicting evidence.7 Soon after the first report on December 31, 2015, of locally transmitted Zika virus infection in Puerto Rico, interventions were put in place to protect the US blood supply, first through a bulletin from the AABB and then guidance from the FDA.8, 9 For areas without active transmission, such as currently in the continental United States, FDA recommendations include 4-week donor deferral for persons with known or suspected infection, travel to areas of active transmission, or sexual contact with men who are known to be infected or have traveled to active transmission areas in the past 3 months. In areas of active transmission, FDA guidance recommends that blood be outsourced from unaffected US areas, unless donations can be screened through FDA permitted investigational laboratory testing or unless the blood components are subjected to PRT with an approved method. This guidance was a challenge for Puerto Rico, an active area of transmission, as most blood on the island is locally collected. Furthermore, a screening test was not initially available and PRT was not widely implemented, since it was FDA approved only for whole blood– or apheresis-derived plasma and for apheresis PLTs. Technology to reduce pathogens in whole blood or RBCs is not yet available. With federal funding support, blood was imported from the continental United States for about a month beginning in March 2016, consistent with the FDA's recommendations.10 Local collection of whole blood and preparation of RBCs in Puerto Rico resumed on April 2, 2016, with the introduction of individual donation testing using an investigational Zika virus–specific nucleic acid assay manufactured by Roche Molecular Systems, Inc., again with federal support. Also in this issue of TRANSFUSION, Lanteri and coworkers11 summarize the global spread of Zika virus, including explosive epidemics that have occurred in Pacific islands (Yap Island, 2007; French Polynesia, 2013-2014) and now widely in the Western Hemisphere (Brazil, 2015, and subsequently in more than 40 countries and territories including Mexico, countries in Central and South America, and various Caribbean islands). The article summarizes the clinical findings and diagnostic challenges presented by epidemic spread of Zika virus and the basis for blood safety concerns. A particular public health challenge, noted by the authors, is the likelihood that vector-borne Zika virus infection may spread to multiple regions of the continental United States. Research studies outlined by Lanteri and colleagues should increase our understanding of the threat of Zika to transfusion safety. The studies summarized will help quantify the risk of transfusion transmission, identify sequelae in recipients of Zika virus–infected blood transfusions, and better describe the epidemiology of infection in Brazil and the United States (particularly Puerto Rico). Additionally, these studies will characterize the duration of viremia and virus detection in body fluids before and after seroconversion through longitudinal collection of samples from infected donors detected by Zika virus RNA screening. Increased availability of specimens from these longitudinal follow-up studies of donors will have the potential to optimize diagnostic testing. Animal models will help to describe the dynamics of acute viremia and serologic markers as well as the distribution of virus in blood, organs, and tissues. These studies will in turn allow refinement of donor screening policies. Many pressing questions remain concerning implementation of blood safety strategies in the context of potential autochthonous transmission of Zika virus in other US areas. First, how are areas of active transmission defined? Public health organizations will need to develop guidance for defining an active area of vector-borne transmission for the purpose of blood safety interventions. Factors under consideration include geographical extent of transmission, number of confirmed infections detected over time, and whether temporally clustered cases are epidemiologically related. Mechanisms need to be established to enable rapid access to listings of affected areas that blood centers can utilize easily as a basis for applying donor deferrals. Once an active area is defined and declared, even assuming the availability of investigational donor screening tests, how will blood centers make decisions whether to outsource blood supplies, laboratory test donations, or use PRT for blood components? Can a risk assessment model help to weigh the costs and benefits? Each choice has risk; even with outsourcing, there is a small but finite risk of collecting blood from an infected donor. Some benefits are difficult to fully quantify; blood donation testing has an additional value, as it will potentially be a valuable addition to surveillance of clinical infections, providing data on the epidemiology of asymptomatic infections. It remains to be determined whether the model for WNV of universal donor testing by NATs in minipools, with triggering of individual donation testing when focal outbreaks are detected based on clinical autochthonous case reports or detection of viremic donors by minipool NAT, will be the best course for intervention against Zika virus in the long term. Whatever the local risk, as with other potentially transfusion-transmitted infections, blood centers and health departments need to be prepared to assure both blood safety and availability. Blood is a critical health care resource, and although the focus in the face of an emerging threat is to maximize product safety, availability is just as important a public health consideration. Large areas of active transmission could cause massive disruption of the blood supply, and blood banks must continue their efforts to encourage health care preparedness.10 These efforts are critically needed to address an expanding Zika virus epidemic. More broadly, as increasing numbers of emerging infections threaten blood safety, progressive addition of donor screening tests targeting individual pathogens has become problematic for many reasons, including uncertainty and delay in their implementation as well as increased costs for and impacts on blood center logistics. A new paradigm is needed! Long-term commitments to develop better technologies are needed in areas such as multiplexing of assays including development of microarray platforms that can accommodate rapid inclusion of markers for additional pathogens. At the same time, interventions are needed that are both precautionary and independent of the specific threat, such as next-generation sequencing for laboratory screening and PRT for all blood components. Additionally, better models are needed to quickly gauge emerging risks as well as residual risks that may remain subsequent to these interventions. Innovations to permit rapid and flexible adoption of pathogen-specific donor screening tests will be helpful, but ultimately, robust technologies that can be applied quickly, regardless of the pathogen, are needed to best prepare us for our battle against the next inevitable emerging transfusion-transmitted infectious disease. We thank Robin Moseley, CDC, for her careful review of this editorial. The authors have disclosed no conflicts of interest. Matthew J. Kuehnert,1 MD e-mail: [email protected] Jay S. Epstein,2 MD 1Office of Blood, Organ, and Other Tissue Safety Division of Healthcare Quality Promotion National Center for Zoonotic and Infectious Diseases Centers for Disease Control and Prevention Atlanta, GA 2Office of Blood Research and Review Center for Biologics Evaluation and Research Food and Drug Administration Silver Spring, MD

BACKGROUND AND OBJECTIVES:The safety of the blood supply in a number of countries is achieved by interventions that include behaviour-based time-limited or indefinite deferrals and screening of donated units for transfusion-transmitted infections. The relatively high sensitivity of nucleic acid testing (NAT) used in blood donor screening has raised the question of whether such time-based deferrals can be eliminated in favour of individual risk assessment.MATERIALS AND METHODS:Data on the annual number of incident human immunodeficiency virus (HIV) infections associated with various behaviours and on the performance characteristics of NAT applied to donor screening were used to model the number of potentially infected units that might escape detection in the worst-case scenario in which individual risk assessment was implemented, but was not effective as a screening tool, and donors did not otherwise self-select for lower risk.RESULTS:In the absence of effective individual risk-based screening or donor self-selection, the model predicts that in the United States, an additional 39 (95% CI 35-43) HIV-infected units would escape detection by nucleic acid testing, potentially capable of exposing approximately 68 (95% CI 61-75) individuals to the risk of HIV infection through the administration of prepared blood components.CONCLUSION:Despite some inherent uncertainty, the worst-case scenario of completely ineffective individual risk assessment, absence of donor self-selection and increased reliance on NAT for blood screening is estimated to be associated with an approximately fourfold increase in the risk of HIV exposure through transfusion in the United States.

Transfusion-transmitted infections have been documented for several arboviruses, including West Nile and dengue viruses (1). Zika virus, a flavivirus transmitted primarily by Aedes aegypti mosquitoes that has been identified as a cause of congenital microcephaly and other serious brain defects (2), became recognized as a potential threat to blood safety after reports from a 2013-2014 outbreak in French Polynesia. Blood safety concerns were based on very high infection incidence in the population at large during epidemics, the high percentage of persons with asymptomatic infection, the high proportion of blood donations with evidence of Zika virus nucleic acid upon retrospective testing, and an estimated 7-10-day period of viremia (3). At least one instance of transfusion transmission of Zika virus has been documented in Brazil after the virus emerged there, likely in 2014 (4). Rapid epidemic spread has followed to other areas of the Americas, including Puerto Rico.