FDA workshop on emerging infectious diseases: evaluating emerging infectious diseases (EIDs) for transfusion safety

C O N F E R E N C E R E P O R T

FDA workshop on emerging infectious diseases: evaluatingemerging infectious diseases (EIDs) for transfusion safety_3084 1..17

Chintamani Atreya, Hira Nakhasi, Paul Mied, Jay Epstein, James Hughes,* Marta Gwinn,*

Steven Kleinman,* Roger Dodd,* Susan Stramer,* Mark Walderhaug,* Peter Ganz,*

Raymond Goodrich,* Clark Tibbetts,* and David Asher*

On May 11, 2010, experts in the field of emerginginfectious diseases (EIDs) and other partici-pants from blood centers, academia, govern-ment agencies, and the industry gathered

at the Hilton Hotel in Gaithersburg, Maryland, fora 2-day public workshop entitled “FDA Workshop onEmerging Infectious Diseases: Evaluating Emerging Infec-tious Diseases (EIDs) for Transfusion and TransplantationSafety.” The first day of the workshop focused on transfu-sion safety was opened with a few welcome remarks fromDr Carolyn Wilson, Associate Director for Research, CBER,FDA, followed by introductory remarks from Dr JayEpstein, Director, Office of Blood Research and Review,CBER, FDA. Subsequently 10 speakers presented theirviews on the workshop topic ranging from the lessonslearned from our past experiences with infectious agents tothe current cutting edge technologies to detect as well as toreduce the infectious agent burden in transfusion settings.

A brief commentary on each presentation followedby the presentation as submitted by the speakers and a

summary of the panel discussion are reported here.A transcript of the entire public workshop is availableonline at http://www.fda.gov/cber/minutes/workshop-min.htm.

PLENARY TALK

Emerging infections: lessons learned and implica-tions for the transfusion and transplantation commu-nities. James Hughes, MD, Emory University, Atlanta,GA

Brief commentaryMany diverse factors contribute to the emergence andspread of infectious diseases such as physical and envi-ronmental, genetic and biologic, and social, political,and economic. Among these are human demographics,behavior, and sanitation; closer human contact with wild-life and its habitat; failure of control measures; interna-tional travel and commerce (which results in populationmovements and transport of agents, reservoirs, andvectors); microbial adaptation and change; human sus-ceptibility to infection, climate, and weather; and evenlack of political will and complacency. Surveillance is theongoing systematic collection, analysis, and interpreta-tion of outcome-specific data that need to be closely inte-grated with the timely dissemination of those data tothose responsible for taking public health action. Approxi-mately 70% of recognized 68 or so EIDs (42) have beenzoonotic (able to transmit from animals to humans, withwildlife being an increasingly important source as reser-voirs or vectors for disease) and new threats will emerge,many of which will be zoonotic. The key will be to unitehuman and veterinary medicine, to anticipate potentialthreats to blood safety, and to be vigilant with early detec-tion, improving our predictive capability and improvingcoordination and communication. Recent outbreaksremind us of the need for strong national and inter-national partnerships, including multidisciplinary and

ABBREVIATIONS: ARC = American Red Cross; CFS = chronic

fatigue syndrome; EID(s) = emerging infectious disease(s);

PrP = prion protein; PRT(s) = pathogen reduction

technology(-ies); RPM(s) = resequencing pathogen

microarray(s); SARS = severe acute respiratory syndrome;

TSE(s) = transmissible spongiform encephalopathy(-ies);

vCJD = variant Creutzfeldt-Jakob disease; WNV = West Nile

virus; XMRV = xenotropic murine leukemia virus–related virus.

From the US Food and Drug Administration, Rockville, MD.

Address reprint requests to: Chintamani Atreya, PhD, US

Food and Drug Administration, 1401 Rockville Pike, Suite 400N,

HFM-300, Rockville, MD 20852; e-mail: chintamani.atreya@

fda.hhs.gov.

*Speakers at the workshop and their affiliations are

embedded in the text as appropriate.

Received for publication December 13, 2010; revision

received January 3, 2011, and accepted January 3, 2011.

doi: 10.1111/j.1537-2995.2011.03084.x

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transdisciplinary collaborations that include the humanand animal public health sectors.

Speaker’s summary of the presentationThe fact that infectious disease mortality decreasedduring the first half of the 20th century1 led many peopleto think that infectious diseases had been largely con-trolled in the United States. However, during the past 30to 40 years, a number of new infectious diseases havebeen identified, and many other previously recognizedinfectious diseases have increased in incidence.

In 1992, the Institute of Medicine issued an importantreport on the concept of emerging infections.2 The com-mittee, cochaired by Nobel laureate Dr Joshua Lederbergand Dr Robert Shope, defined new, reemerging, or drug-resistant infections as those whose incidence in humanshas increased within the past two decades or whoseincidence threatens to increase in the near future. Thecommittee identified six factors contributing to diseaseemergence and reemergence: changes in human demo-graphics and behavior, advances in technology and indus-try, economic development and changes in land usepatterns, international travel and commerce, microbialadaptation and change, and breakdown of public healthmeasures as a result of the complacency. In 2003, the Insti-tute of Medicine revisited this topic with Dr Lederbergcochairing the committee with Dr Margaret Hamburg,now Commissioner of the FDA.3 This committee validatedthe original six factors in disease emergence and addedseven more: human susceptibility to infection, climateand weather, changes in ecosystems, poverty andsocial inequality, war and famine, lack of political will, andbioterrorism.

Alert frontline health care workers are criticallyimportant in detection of emerging diseases; examplesinclude clinicians, laboratorians, pathologists, veterinar-ians, research scientists, and public health officials. WestNile virus (WNV) infection was discovered in 1999 inQueens, New York, after alerts from a veterinarian and aclinician.4 The strain was genetically identical to a viruscirculating in Israel; its means of importation was and isstill unknown. The vast majority of people infected withWNV are asymptomatic. To compound the problem forthe transfusion and transplantation communities, peakviremia in infected individuals who become ill occursbefore onset of symptoms. In 2002, five novel modes ofWNV transmission were identified, including transfusedblood and blood products5 and transplanted organs.6

Public health agencies and the transfusion and transplan-tation communities took rapid action, implementingeffective public health interventions.

Transmission of rabies virus from an organ donor tofour recipients occurred in 2004.7 An episode of lympho-cytic choriomeningitis virus transmission by organ trans-

plants occurred in 2005.8 More recently, a new arenaviruswas identified in a cluster of fatal transplant-associateddiseases.9 Another recent event involved transplant-transmitted tuberculosis and another involved Bala-muthia mandrillaris, an organism that was initiallydiscovered in 1986 and causes a severe infection of thecentral nervous system.10 A recent transplant-associatedtransmission event occurred, and a pathologist made thediagnosis.

Recent literature reviews have concluded thatbetween two-thirds and three-quarters of importantexamples of disease emergence or reemergence representzoonotic disease events.11 The One Health Initiativereflects the convergence of human health, animal health,and ecosystem health and places emphasis on early detec-tion before transspecies transmission occurs.12

A number of lessons have been learned from recentoutbreaks: the importance of strong national and interna-tional partnerships, increased multidisciplinary collabo-rations, health system strengthening, transparency andpolitical will in fighting complacency, global commitmentto addressing inequities, strategic and preparedness plan-ning, developing research agendas, addressing trainingand education priorities, and facilitating proactivecommunication.

What does the future hold? Some examples includeanother influenza pandemic, more antimicrobial resis-tance, more national and international food-bornedisease outbreaks, the possibility of yellow fever beingreintroduced in Latin America or introduced for the firsttime into Asia, additional associations between microbesand chronic diseases, and unexpected events.

In conclusion, the trends that impact disease emer-gence and reemergence favor the microbes. New threatswill emerge; many will likely be zoonotic. Anticipation andearly identification of the potential threats to blood supplyand risks associated with organ and tissue transplantationis very important. Vigilance, sustained political will, betterpredictive capability, improved coordination and commu-nication, and multidisciplinary partnerships are criticallyimportant.

IDENTIFICATION, SURVEILLANCE, ANDPRIORITIZATION OF EIDS

1. Horizon scanning: examples from genomics andEIDs. Marta Gwinn, MD, Centers for Disease Control andPrevention, Atlanta, GA

Brief commentaryVarious current effective methods of horizon scanning,that is, the systematic examination of potential threats,opportunities, and likely developments, and the ability todetect novel and unexpected issues, persistent problems,

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or trends have been briefly discussed. Horizon scanningcomplements evidence synthesis, and this was illustratedby using several examples as it relates to the EIDs.

Speaker’s summary of the presentationMany government functions, including public health,require a capacity for systematically examining potentialthreats, opportunities, and consequences. Such “horizonscanning” is expected to discover new and unexpectedproblems, as well as to monitor ongoing trends. Horizonscanning thus complements evidence-based practice,which is built on systematic reviews of past experience.Comprehensive reviews of ongoing and potential futurechallenges posed by infectious diseases have been con-ducted in both the United States and the United King-dom.13,14 In a rapidly evolving environment, horizonscanning for emerging infectious threats will require acontinuous, wide-ranging, and adaptable approach.Advances in communications technology, especially theInternet, provide infrastructure that may be useful for sur-veillance and early warning of public health hazards.15

The Centers for Disease Control and Prevention’sOffice of Public Health Genomics (OPHG, http://www.cdc.gov/genomics) has used the Internet to monitordevelopments in human genome research and technologywith potential application to public health and to commu-nicate relevant information to professionals and thepublic. For example, the HuGE Navigator (http://www.hugenavigator.net) provides access to a continuouslyupdated knowledge base in human genome epidemiol-ogy. Data are uploaded weekly from PubMed followinga curation process that employs both human andartificial intelligence.16 OPHG also uses Google Alerts(http://www.google.com/alerts) to identify genomics-related news and events of interest; an update is publishedonline every week (http://www.cdc.gov/genomics/update/current.htm) and more than 30,000 subscribersare notified by e-mail.

OPHG currently uses a customized combination ofGoogle Alerts to scan the horizon for new tests based ongenome technology. Experience with this approach sinceOctober 2009 has found industry sources to be among themost useful; in part, this is because test developers andproviders have an incentive to advertise and promotethe use of new tests. Public health interest in thesetests focuses on both premature translation (marketingtests without established validity or utility) and “lost intranslation” (failure to recognize tests that could improvedisease prevention or treatment). The curated horizonscanning results are made available in an online databaseof new genetic tests, the GAPP Finder (http://www.hugenavigator.net/GAPPKB/topicStartPage.do).

The value of particular data sources and techniqueswill vary according to horizon scanning objectives.

Several approaches that have been used or proposed formonitoring EIDs can be considered for use in antici-pating infectious threats to blood safety. These includePubMed case reports, Google Alerts, and websites thatsummarize electronic surveillance and reporting data.For example, we used the “Limits” feature in PubMedto perform a focused search for case reports oftransfusion-associated infection, such as that by Weldand colleagues.17 We also conducted a 1-month pilotstudy (February 15-March 14, 2010) that used a GoogleAlert to identify the top 10 news stories each week on“infected blood.” Of the 240 items found, only 39 (16%)were directly related to transfusion safety and most ofthese referred to legal and policy issues.

ProMED-mail is an Internet-based reporting systemmaintained by the International Society for InfectiousDiseases to report and monitor outbreaks of infectiousdiseases worldwide.18 Querying the online database for“transfusion” identified nine reports from January to mid-April 2010, of which four were updates on prion disease.An April 18, 2010, update on an ongoing Q-fever outbreakin the Netherlands reported that blood donations in theaffected area had been screened for Coxiella burnetiisince March 15.

Several published examples describe the use ofsearch engine or website query data to monitor orpredict outbreaks of infectious diseases.19 Recent reviewsdiscuss some potential applications and challenges ofthese methods.15,20 HealthMap (http://healthmap.org/en/) is a new online system that combines active surveil-lance of the Internet with global, community-levelreporting capacity.21 As the overlapping worlds of publichealth, medicine, and research continue to evolve on theInternet, new approaches to detecting emerging infec-tious threats to blood safety may become possible.

2. Repositories pertinent to transfusion safety. StevenKleinman, MD, University of British Columbia, Victoria,British Columbia, Canada

Brief commentaryThe characteristics of the current repositories of speci-mens that have been established through the years andthe specific purpose for which each was established—especially the large-scale TTVS, RADAR, and TRIPSlinked donor-recipient repositories—was discussed. Inthe past the contributions of each repository have beenvaluable in allowing for the evaluation of transfusiontransmission of known agents; therefore, these reposito-ries may be a very useful source for identifying new andfuture EID agents. In addition, maintenance of theserepositories, including information on how and when toaccess these resources and what criteria are needed foraccess, were discussed.

FDA EID WORKSHOP PROCEEDINGS


Speaker’s summary of the presentationThere are a variety of useful repositories of frozen plasmaand blood specimens from blood donors and recipientsthat have been collected over the past 30 years.22-24 Testingthese repositories provides a means to evaluate transfu-sion transmission of known and future agents. Reposito-ries are of several types: donor only, recipient only, andlinked donor-recipient. Repositories containing recipientsamples are logistically difficult and expensive to collectwhile linked donor-recipient repositories are even morelogistically complex and expensive.

There are three large-scale donor-recipient reposito-ries in the United States.22 These are the Transfusion-Transmitted Virus Study (TTVS, collected from 1974-79),the Retrovirus Epidemiology Donor Study (REDS) Alloge-neic Donor and Recipient repository (RADAR, collectedfrom 1999-2003), and the Transfusion Related InfectionsProspectively Studied (TRIPS, collected from 2001through the present).22-24 There are also recipient-onlyrepositories (Frequency of Agents Communicable byTransfusion [FACTS], collected from 1985-1991) anddonor-only repositories (Transfusion Safety Study [TSS],collected from 1984 to 1985, and REDS general reposito-ries, collected from 1991 to 1995).22,25-27

Repositories have been used for many importantstudies in the field of transfusion-transmitted infectionand have been accessed years and decades after they wereinitially stored. These studies have included evaluation ofagents (e.g., human immunodeficiency virus [HIV], hepa-titis C virus [HCV], human herpesvirus-8, B19V, hepatitisG virus, TT virus) that were not known or deemed impor-tant at the time the repository was established.22-30 Donorrepositories can be used to determine agent prevalenceover time and recipient-only repositories provide useful(but not definitive) data on transfusion transmission.Linked donor-recipient repositories serve both purposes.

There are several limitations of what can be learnedfrom testing of repository samples. They can only provide atime-specific snapshot of the existence of an agent in theblood supply and therefore are not useful for studyingagents that emerged subsequent to establishing the reposi-tory. The repositories can also be limited by their geo-graphic catchment area, which may be different from theregion(s) where a new agent emerges. Also, althoughrepository testing can determine an agent’s transmissionrate and can provide confidence intervals around thisestimate, it is more difficult to demonstrate lack oftransmission with statistical confidence.Thus despite theirusefulness, testing of repository samples will not always beable to answer questions about newly discovered agentsand the possibility of their transfusion transmission.22

Currently NHLBI has custodianship for many of theserepositories through the NHLBI Biologic Specimen Reposi-tory and a program known as BioLINCC (Biologic Speci-

men and Data Repository Information CoordinatingCenter).31 The mission of the program is to acquire, store,and distribute quality biospecimens to the scientific com-munity using standardized processes and procedures.Further information on how to request access to repositorysamples can be obtained at http://biolincc.nhlbi.nih.gov/.

3. Babesia versus xenotropic murine leukemia virus–related virus: which way? Roger Y. Dodd, PhD, AmericanRed Cross, Rockville, MD

Brief commentaryThe critical information about a particular EID comesfrom answering the following questions: Is the agentblood-borne? Is there an asymptomatic blood-bornephase? Have transfusion transmissions been observed?Does the agent survive component manufacture andstorage? Does the agent cause disease? What is the diseaseattack rate? What are the severity, mortality, and treatabil-ity of the disease? What is the donor prevalence and inci-dence? Is it significant? Is there professional, regulatory,and public concern? Are interventions available? Whatwould be the impact of those interventions on resources?To explore these questions further, the workshop focusedon a case study with two EID agents that are at differentstages of the decision process in the public health sector.

Speaker’s summary of the presentationA number of objective and subjective criteria must beevaluated to prioritize efforts to control the transmissionof emerging infections by transfusion. While ideally, deci-sions should be made on the basis of the public healthimpact of any given infection, there is also a need to con-sider public perception, which is not necessarily congru-ent.32 Two agents of current concern are discussed in thiscontext.

Criteria for establishing prioritiesThese criteria were discussed elsewhere in the workshop,but in brief, the public health issues relate to the likeli-hood of transmission of a given agent by transfusion, theseverity and treatability of resultant disease, the numberof preventable cases, and current epidemiologic pattern ofinfection. The criteria relating to public perception are lesstangible and are more difficult to quantitate, but relate tofear of the disease and its nature, the extent to which thereis a sense that the risk is imposed, and to public and mediaportrayal of the situation. To some extent, such percep-tions are still impacted by the HIV/AIDS crisis.

BabesiaThe transfusion transmissibility of Babesia spp. has beenrecognized for many years now, with at least 70 docu-mented cases in the United States, the majority of which

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are caused by Babesia microti.33 The agent is an intraeryth-rocytic parasite that is transmitted by ticks and which,although geographically restricted, is clearly demonstrat-ing a steady increase in incidence and range. Prevalencerates among blood donors in endemic areas may be inexcess of 1% and some studies imply local transmissionrisk as high as one per thousand donations. Patientsinfected by transfusion may manifest a wide range ofoutcomes from asymptomatic infection to death, whichoccurs in an appreciable proportion of reported cases.Interestingly, apart from specific professional and regula-tory attention, there seems to be relatively little in the wayof public concern about transfusion-transmitted Babesia.

Xenotropic murine leukemia virus-related virusXenotropic murine leukemia virus–related virus (XMRV)is a recently described retrovirus, potentially originatingfrom mice. It was originally recognized among some (butby no means all) patients with advanced prostate cancer.34

More recently, a high-profile paper reported this virus in67% of a population of patients with chronic fatigue syn-drome (CFS) and also among 3.7% of normal controls; itwas noted that such a virus had the potential for transfu-sion transmission.35 A number of other studies have so farfailed to reproduce this finding and the issue must beregarded as controversial. However, at the current time,there is no definitive evidence of transfusion transmissionof the virus, there is no definitive causal relationshipbetween the virus and any disease, and there are no cleardata to define the prevalence or incidence of the virus inthe donor population. The virus has received a great dealof public attention, particularly from CFS patients andtheir advocates. This has prompted calls for deferral ofCFS patients from blood donation, including such actionfrom an HHS advisory committee (http://www.hhs.gov/advcomcfs/recommendations/05102010.html).

Considerations relating to prioritiesFrom the perspective of public health, it is not difficult tocharacterize the situation with respect to Babesia. In theabsence of an intervention (none is available at this time),it seems likely that transfusion-transmitted cases of thedisease will continue to occur, probably with graduallyincreasing frequency. There is no basis for assuming thatthere will be any significant change in the nature ofthe disease or the pathogenicity of the organism. It shouldnot be difficult to quantitate costs and benefits ofinterventions.

In contrast, at the current time, it is not possibleto establish any reasonable predictions with respect toXMRV. None of the key variables has been established andthere is really no basis for any realistic assumption (AABBXMRV Fact sheet: http://www.aabb.org/resources/bct/eid/Pages/default.aspx). The possibilities range fromcompletely benign to a serious situation in which the virus

(or a mutant form of the virus) is transfusion transmissible,occurs at high frequency in the donor population, andcauses a dread disease with a lengthy incubation period.

From the perspective of public concern, despite theobvious problems associated with Babesia, there doesnot appear to be any significant public pressure to act,although professionals and regulators have recognized thesituation and have called for action. In the case of XMRV,there seems to be considerable interest and specificconcern about what is clearly an unknown threat.However, there is again no available, logical intervention.The transmission of both infections by transfusion wouldbe anticipated to be preventable by application of a suit-able donor test or by pathogen reduction.

ConclusionsIt does not appear possible to make a direct comparison ofBabesia and XMRV at present, since to do so would requirereconciliation of a ranking made on the basis of data withone based on hypothesis and emotion. However, it wouldbe reasonable to suggest that the focus for Babesia shouldbe to make a decision about the development and intro-duction of testing based on objective data. In contrast,urgent attention should be paid to developing the neces-sary data to understand the actual threat offered by XMRVand, if necessary, the most effective interventions.

4. EIDs and risks for transfusion safety; past, presentand future. Susan Stramer, PhD, American Red Cross,Gaithersburg, MD

Brief commentaryHow should we prioritize EID agents? This can beaddressed by developing an EID agent priority matrixusing public or regulatory concern on one axis and scien-tific evidence of blood safety risk on another axis. Forexample, such priority matrix, developed by one groupof experts, led to the suggestion that dengue viruses,Babesia, and variant Creutzfeldt-Jakob disease (vCJD) arethe EID agents that should be prioritized for an effectiveintervention. These “prioritized agents” have commondenominators: they are transfusion transmitted, they areincreasing in worldwide frequency, they cause disease inrecipients, and they lack specific and effective interven-tions. The question evolves to, “What’s the appropriateaction now?” Implementing blood donor testing forBabesia is an option that could be considered, but forXMRV additional research is needed with perhaps imple-menting an interim blood safety intervention until themain questions about XMRV as an EID that could threatenblood safety are answered. To address some of theissues in EID identification and prioritization, the AABBtransfusion-transmitted disease EID completed a 4-yearproject that consisted of: 1) describing known and



potential EID agents for which transfusion transmission isdocumented or its potential exists and no effective inter-vention exists, 2) creating fact sheets for the agents, and 3)prioritizing agents as to their blood safety threat. The chal-lenging questions to the community are: Should the targetbe zero risk or evidence based? How do we stimulate inter-est and participation from the manufacturers in the faceof small market and margins? And where will the fundingcome from as threats emerge or current technologybecomes antiquated?

Speaker’s summary of the presentationOver the past 10 years, HIV, HCV, and hepatitis B virus(HBV) have been the focus of blood safety with respect todecreases in infectious disease risks. In addition, screen-ing for WNV RNA and Trypanosoma cruzi antibodies havebeen introduced in response to risks posed by differentexposures in our donor population. HIV, HCV, and HBV forthe most part share similar transmission routes (i.e.,parenteral and known risk behaviors) and questioning ofdonors along with increasingly sensitive blood donorscreening tests have been responsible for the vast majorityof observed reductions in residual risk. For example, sincethe implementation of HIV-1/HCV nucleic acid testing(NAT) in the US, the American Red Cross (ARC) hasdetected 244 (1:270,000) HCV-infected donors and 32 (1:2million) HIV-infected donors over the past 10 years oftesting of greater than 66 million donations. Current, per-donation residual risks are estimated at 1 in 1,467,000 forHIV and 1 in 1,149,000 for HCV.36 Although higher, beforethe widespread implementation of HBV NAT, the HBV per-donation residual risk from the same ARC donor popula-tion is estimated at 1 per 280,000 to 1 per 357,000.37 Thesefigures were derived by taking the product of estimateddonor incidence of 3 to 5 per 100,000 person-years andremaining window periods that range from 9.1 to 7.4 daysfor HIV and HCV and 30 to 38 days for HBV. Similarmethods for estimates of yield and residual risk have beenused worldwide.

However, the world is changing, with increaseddemands to look at different mitigation strategies toaddress risks from newly identified or EID agents. Themost recent introductions, WNV and T. cruzi, may be thelast for which the existing paradigm of screening interven-tions that have relied on testing each donation are used.38

For WNV, which was introduced after an unprecedentedmosquito-borne epidemic in the United States, and therecognition of transfusion and transplant transmissions,seasonal approaches may be more effective with the use ofoptimal “triggering” strategies.39 Since the implementa-tion of screening, 11 WNV transfusion transmissions haveoccurred in the background of more than 12,000 neuroin-vasive disease cases and identification of more than 2400viremic donors of which 25 to 30% required the more sen-

sitive individual-donation NAT for detection. In contrast,with the availability of a licensed donor screening test atthe end of 2006, developed in response to changes in USdonor demographics and the documentation of transfu-sion or transplant transmission, most of the United Statesintroduced universal screening for T. cruzi antibody.40

Although more than 500 donors have been identified asantibody confirmed positive by the ARC (1:28,000 preva-lence), lookback data have documented a questionableclinical need for testing in that only two infected recipi-ents from one infected donor have been identified frommore than 100 recipients tested. Thus, the industry haslooked carefully at changes in screening strategies withmost of the United States now only performing a one-timedonor qualification method for testing.

The remaining risks from EID agents are unpre-dictable but a committee of experts from the AABBTransfusion-Transmitted Diseases committee assembledand published a supplement to TRANSFUSION (August2009) summarizing what is currently known regarding 68agents for which such emergence is possible.32 Agentswere selected based on the existence of a blood-bornephase (with or without document transfusion trans-mission), clinically relevant disease, and no currentwidespread and effective intervention. Emergence orreemergence is based on changing global environmentalpatterns and human activities that favor the spread ofsuch agents. Thus the majority of agents are vector borneand zoonotic in origin and a worldwide approach to con-trolling these agents has had variable success. Agentsstudied included prions, viruses, rickettsia, bacteria, para-sites, and even one nematode with each agent havinga fact sheet devoted to the agents’ characteristics andresulting diseases, prioritization ranking, transmissionroutes, treatment, existing methods of detection, andpotential existence and efficacy of interventions. Agentprioritization, using both scientific or epidemiologicfactors and concerns from the public at large, includingthe regulators,32 indicated that three agents ranked asthose of greatest concern in the United States: Babesiaspecies,33,41 dengue virus,42,43 and the prion responsible forvCJD.44 Pathogen reduction or removal was also addressedas a proactive approach to reducing or eliminating these68 agents before a recognized epidemic and potentialtransfusion transmission versus the usual reactive screen-ing approach. Since the publication of the EID supple-ment, the fact sheets and prioritization tables havebeen posted on the AABB website (http://www.aabb.org/resources/bct/eid/Pages/eidsupp.aspx). The websiteposting also includes an additional fact sheet on XMRV, agammaretrovirus, with controversial links to CFS andprostate cancer.34,35 Since pathogen emergence andrelated information is constantly changing, new factsheets will be posted or updated as needed. However,more importantly, changes in approaches for continued

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maintenance of blood product safety, including the iden-tification of new agents of concern, should be expected.

5. Risk assessment and EIDs in blood. Mark Walder-haug, PhD, US Food and Drug Administration, Rockville,MD

Brief commentaryThe risk assessment aspect of the EIDs, which has com-ponents such as hazard identification (which is easy forsome EIDs but not others), a dose-response assessmentfor the infectious agent, an exposure assessment in whichvariables are represented as distributions and not as pointestimates, and risk characterization is an important partin developing response to threat from EIDs to blood safety.Risk characterization is a synthesis of all of that informa-tion that estimates the health effect of exposure, withuncertainties, in a form that risk managers and stakehold-ers can understand and use. Risk management considersrisks and benefits and compares potential mitigation“what-ifs?” such as how does the risk change by testing allor some or by changing the questionnaire, and so forth,and the number of cases prevented for each mitigation forthe emerging blood-borne threat.

Speaker’s summary of the presentationRisk assessment is a framework for integrating dataand knowledge about risks to support decision making.This framework was established in 1983 by the NationalAcademy of Sciences in a publication entitled “RiskAssessment in the Federal Government: Managing theProcess.”45 The intent of the document was to explore therelationship between science and policy with the goal ofbringing more transparency to controversial regulatorydecisions. Transparent and scientifically sound decision-making for EIDs in blood is critical as stakeholders—bothconsumers and the regulated industry—desire greater andbetter communication. Structuring what is known aboutEIDs in blood in a risk assessment framework can helpregulators better communicate the critical issues associ-ated with their decision making.

Risk assessment is structured into four parts: hazardidentification, hazard characterization (also called dose-response assessment), exposure assessment, and riskcharacterization. Hazard identification is the determina-tion of whether or not a hazard is linked to a specifichealth effect. For most EIDs, this identification is notdifficult—some arthropod-borne viruses cause an asymp-tomatic viremia in blood donors, and blood from thesedonors can spread the infection to blood recipients. Thisidentification helps establish the scope of the risk assess-ment. For other potential pathogens, the identification ismore difficult. For example, is XMRV the cause of CFS andcan it be spread through blood transfusion?46 As of this

writing, the answers to these two questions are unknown.Hazard characterization (dose-response assessment)

is the determination of how much exposure to a hazardcauses a specific health outcome. In the case of EIDs inblood, how many virus particles in a unit of blood does ittake to cause a sustained infection? For some EIDs it couldbe as little as one virus, one bacterium, or one protozoan.For other EIDs it could take thousands or more. In somesituations, the storage and processing of a blood productmay have a significant impact on the hazard characteriza-tion because of mortality of the pathogen during storage.47

Exposure assessment is the determination of howmuch exposure to the hazard is taking place in an indi-vidual or in a population. For EIDs in blood, the determi-nation of donor exposure is usually in terms of how manyunits of EID-infected blood a recipient receives. In othermodels, a risk assessment may want to consider the like-lihood of exposure of a blood donor to a specific EID, likedengue, and the subsequent exposure to a recipient. Thenumber of hours a donor spends outside exposed to mos-quitoes might be an important component of an exposureassessment.48

Risk characterization is a description of risk includingthe amount of uncertainty associated with that risk. In thecase of EIDs in blood, the integration of the amount ofexposure of a specific hazard (for example, the number ofasymptomatic carriers of Babesia) with the infectivity of aunit of blood collected from an asymptomatic carriercould yield a prediction of the number of cases oftransfusion-transmitted EIDs (in this example, cases ofbabesiosis). This estimate would not be a single point esti-mate, but should be a statistical distribution reflecting theuncertainty of both the exposure assessment and thehazard characterization combined. Risk characterizationsprovide the risk manager with a comprehensible descrip-tion of the risk along with the limitations of the data andthe assumptions of the risk model.

Risk assessment is intended to support risk manage-ment, which takes the objective results of risk assessmentand integrates it with policy alternatives, social, and politi-cal concerns. Risk managers must consider many aspectsof their decision making in addition to the risk data andmodels. Risk assessment is intended to assure that thescientific component of the decision is as sound as thedata and our knowledge will allow.

6. Strategies for managing EID threats to blood safety: aHealth Canada perspective. Peter R. Ganz, PhD, HealthCanada, Ottawa, Ontario, Canada

Brief commentaryHealth Canada has a framework for managing risks suchas EIDs where interrelated steps are grouped into threephases: 1) issue identification (identify a possible risk to



blood safety), 2) risk assessment (such as donor risk ofexposure) by surveillance and hemovigilance and benefitassessment, and 3) risk management (in which optionssuch as testing are identified and analyzed, a strategy isselected and implemented, and then the results are moni-tored and evaluated, implementing surveillance measuresto assess residual risks to the system). This follows two keyquestions: 1) Should there be greater international col-laboration in managing EID risks? Risk management ismultifaceted, and a global enterprise, and as the wayforward, it needs global partners in managing strategies toaddress EIDs. A suggestion was made for stronger linkswith other governments, regulatory authorities, andpublic health to manage EID risks including interven-tions, increase networking of researchers to form betterlinkages with governments for global coordination of EIDblood safety responses, and develop a process to describehow decisions were made; and 2) what is the appropriatevehicle or process to put this into action?

Speaker’s summary of the presentationThe emergence of infectious diseases such as severe acuterespiratory syndrome (SARS), swine and avian flu, andothers has drawn wide interest and attention not only inpublic health but also in political arenas. Of pathogenscausing EIDs, approximately 75% are zoonotic (able totransmit from animals to humans), with wildlife being anincreasingly important source as reservoirs or vectors fordisease.49-52

A key element of EIDs is closer human contact withwildlife and its habitat as has been documented for originsof a number of EIDs such as SARS and pandemic flu. Theincrease in international trade and travel is also impor-tant. The emergence of WNV in North America, and AIDSand SARS globally, for example, arose from such travel andtrade. This globalization of people and products is difficultto control and is largely related to readily accessible airtravel (expected to grow by 5% per year for at least the next20 years). Therefore, the problem of EIDs will continue togrow. However, in the context of managing overall risksto blood safety, EID risks need to be considered as oneof several broader but also important risks includingcurrent good manufacturing practice or quality riskissues, patient-specific risks to transfusion (transfusion-associated circulatory overload, transfusion-associatedacute lung injury, ABO incapabilities, and other immuno-logic risks), as well as the availability of blood and bloodcomponents (supply issues).

Strategies for risk management of EIDs in CanadaGood health policy and effective risk management forEIDs depends on good scientific evidence. To satisfy thisrequirement, data need to be accessible and available in atimely manner. A complication that often arises is con-founding evidence that may negatively impact managing

risk in a desired time frame. Health Canada has an existingframework for managing risks such as EIDs, which is con-tained within a broader decision-making framework. At itscore is a process for identifying and managing a broadvariety of risks to health such as those from diseases, haz-ardous substances, food, medical devices, drugs, tobacco,and consumer products. These risks fall within thebroader purview of Health Canada’s regulatory man-date.52 The framework consists of a series of intercon-nected and interrelated steps. Six steps are involved thatmay be grouped into three phases: issue identification(identify the issue and put it into context), risk assessment(assess risks and benefits), and risk management (identifyand analyze options, select a strategy, implement thestrategy, and monitor and evaluate the results). Integral tothe framework are risk-benefit considerations, which areconsidered to as key to the management of EIDs.

In addition to Health Canada and the Public HealthAgency of Canada, Canada’s two blood system operators,Canadian Blood Services and Hema Quebec, as well asblood banks and clinical staff in hospitals, also playcentral and essential roles in managing risk mitigationstrategies for EIDs.

General formula for managing infectious agents risk toblood safetyWhen managing risk, Health Canada considers severalinputs drawn from published literature, surveillance andrisk modeling data, and global experience (if any). Occa-sionally, there are other considerations such as political orpopulation-centered concerns that are addressed in anoverarching fashion by governments. As to the specificprocesses used for managing EID risks to blood safety,they begin with the initial identification of a possible riskto blood safety gathered through surveillance data eitherthrough existing local public health avenues domesticallyor through global surveillance networks. Likely this wouldinform the characterization of donor risk of exposure. Thisaspect may be difficult to characterize because exposure iscommon in endemic areas that are changing with climateand ecology. There is also the complication of the mobilityof donors (and, necessarily, blood). Further assessment ofdonor risk perhaps through seroprevalence surveys maybe followed by donor or donation screening. Finally, thereis an onus to develop sensitive, specific laboratory donorscreening assays, which is often complicated by having toassess whether selective versus universal donor screening,routine versus periodic or seasonal screening, and/orserologic versus NAT are appropriate.

Approaches to increased blood safety in Canada(1985-present)

Infectious agents. One of the guiding principles forblood safety in Canada has been and will continue to be

ATREYA ET AL.


the precautionary principle, which stipulates that authori-ties must act even if there is only a theoretical risk of harmand if risk is possible then we must err on the side ofcaution. Agents for which deferrals were introduced as aprecautionary risk mitigation strategy for EIDs are vCJD,Simian foamy virus, and XMRV. Although risks for trans-mission of vCJD were considered theoretical at the time,transfusion transmission for this agent has now beenestablished with reports of a third case in 2006.53 Trans-mission through transfusion has also been demonstratedfor Simian foamy virus in a monkey model.54

Surveillance of risk is integral to managing risks appro-priately and hemovigilance has become an essentialelement of Health Canada’s risk assessment process forblood safety. Surveillance of EIDs is a mandate of thePublic Health Agency of Canada. Robust surveillancesystems for EIDs have been developed55 with the PublicHealth Agency of Canada having set up a national hemov-igilance system consisting of a Transfusion-TransmittedInfection Surveillance System, as well as a TransfusionError Surveillance System. Together, these surveillancesystems are aimed at improving transfusion processes andmaximizing patient safety.

Current versus future strategies for addressing EID risksto blood safetyHealth Canada’s current strategy for addressing EID risksto blood safety fall into three categories. First there is theneed to identify risks or threats using established EID sur-veillance systems including collection of adverse eventdata and analyses of same. Also, it is important to usedonor deferral algorithms to exclude individuals or groupswith high threat to safety ratios. Second, a need exists todevelop tests for infectious agents with known risksthrough transfusion, if possible. Finally, the implementa-tion of surveillance measures to assess residual risks tosystem following above measures. To mitigate some of therisk to EIDs we promote blood conservation technologiesand good clinical practice with respect to use of blood (ornot!), as well as assess the use of blood replacement tech-nologies with the goal of using less blood to reduce the riskof EID transmission. In the future, we would like to steeraway from the current paradigm of identifying infectiousagents, deferring donors, and developing new tests foremerging agents by introducing technologies that pre-emptively treat blood with agents that are benign or haveno deleterious effects on blood components or in recipi-ents because they would inactivate all types of infectiousagents in blood of all types of donors. These pathogenreduction technologies (PRTs) are currently being evalu-ated by regulatory authorities.

The way forwardA common barrier to regulatory and operational change isthe threat of unknown future risk after introduction of new

technology to manage EIDs, which may or may not havebeen predictable. There is the challenge of how to integrateconsideration of the broad risk tolerance of populations orgovernments. In other words, it is important to integratehealth, financial, reputational, organizational, legal, andpolitical risk. Needless to say this is a difficult consider-ation. Perhaps a “no-fault compensation” strategy wouldserve the need to act quickly while prudently to addressEID threats. This has been done for mass vaccinations forpandemic influenza in some regulatory jurisdictions.

As a result of potential worldwide exposure to EIDs,there are high public expectations for managing EIDthreats to the blood supply as well as in other health areas.This includes involvement of public in decision-makingprocesses allowing for transparency of regulatory pro-cesses. Health Canada has involved stakeholders in itsblood advisory committees for blood, cells, tissues, andorgans as well as other committees.

Given that EID threats do not carry passports crossingborders freely, international collaboration in managingEIDs is a key area identified for development. Strongerlinks with other governments or regulatory authorities andpublic health to manage EID risks is crucial. Complement-ing this would be increased networking of researchers andlaboratories working in the area of EIDs to form betterlinkages with governments. Collaboration and communi-cation with our domestic and international stakeholdersand partners is essential to cope with and prepare for newEIDs.

In the area of blood safety, a number of multilateralorganizations exist including the WHO Global Collabora-tion for Blood Safety and the WHO Blood RegulatorsNetwork. Perhaps these are the groups that should beexamined to increase coordination of EIDs globally.

7. A balanced approach to blood safety: a possiblerole for PRT. Raymond P. Goodrich, PhD, CaridianBCTBiotechnologies, Lakewood, CO

Brief commentaryThe contrast between expectations and realities for PRTand for diagnostic tests was put forward in this presenta-tion. The realities include, for example, that developmentcosts for new diagnostic tests can average $30M per testand for PRT methods can average $500M per method. Theadvantages and limitations of donor selection, donationtesting, and pathogen inactivation and removal wereexamined. The perceived costs for implementing PRThave until now been countered with the potential benefitsof lower infection rates and eliminating some currenttests. This approach was questioned. It was suggested thatcombining methods may offer advantages. An orthogonalprocess approach involving two independent methodswas presented that combines NAT and PRT to cover the



window period. Could testing plus inactivation or removalequal reduced deferrals? The suggestion was made to con-sider where and when it makes sense to apply pathogenreduction in combination with or in lieu of testing ordeferrals. The point was made that no decision can ever bewithout risk. One method cannot be perfect or solve all ofthe problems, nor does it need to be.

Speaker’s summary of the presentationEIDs present the transfusion medicine community with adilemma that may require the use of novel approaches.56

Up to this point in time, our reliance on the use of screen-ing or deferral mechanisms has provided a means toreduce the threat of disease spread via transfusion.57

Increasingly, however, this approach is meeting withfailure in addressing emerging threats to blood supplysafety. There are several reasons for this.

First of all, the use of screening and testing methodsremoves donors with infection from the donor pool. Pro-liferation of tests and deferrals reduces a blood supply forwhich demand is increasing. At some point, blood safetyneeds can also compromise blood availability. Secondly,testing and deferral strategies are often not feasible, giventhe limitations of existing test methods, the geographiclocation and diffuse nature of “high-risk zones,” and theability of some agents to escape detection due to thenature of disease progression and reservoirs in blood andtissue, which combine to make them silent to detectionschemes.58 Finally, the increasing demand and need fortesting methods that are specific in identification ofagents, seasonal in application, and limited to geographicregions of concern makes development on the part ofmanufacturers a challenge in the capital-intensive basedsystem in which they operate as businesses. Continuedinvestment in these areas is dictated by value propositionsnot to society alone, but also to the financial investors whosupport industry. Increasingly, investment justification forthese approaches is becoming tenuous.

PRT affords a way to be able to address many of theseissues by providing a single technology platform capableof addressing concerns due to viral, bacterial, parasitic,and white blood cell–associated disease transmissionagents.59,60 Existing disease risk, in the face of testing, maybe further abrogated or possibly even eliminated with theintroduction of this platform technology. Future EIDthreats to the blood supply can be evaluated under a newset of criteria if such systems were in place, allowing timefor more thorough and detailed investigation into diseasetransmission via blood. Hence, both the practical and thetechnical aspects of the technology make it very appeal-ing. Nevertheless, there are downside considerations thatmust also be taken into account.

PRT methods can reduce pathogen load and poten-tially reduce the risk of disease transmission by blood but

are unlikely to achieve absolute safety for these products.61

In cases where existing test methods are already in placewith demonstrated effectiveness, PRT may be viewed as ameans to extend and enhance the safety profile when usedin combination. In cases where no test methods currentlyexist, PRT may provide a means to greatly reduce if notfully eliminate the existing risks, which are presently notaddressed at all. This may include the ability to reexaminedeferral strategies that presently exist and currentlyreduce blood supply availability.

PRT methods must also be considered in light of thepotential adverse effects that they have on blood productfunctionality and toxicity.62,63 The need for extensivetesting of these methods before more general introductionalso raises considerable financial barriers to development.In general, high barriers in this regard make innovationand problem solving in this field less likely to occur in areasonable and timely fashion.

Introduction of PRT as a means to address bloodsafety issues will require an assessment of risk and willalso require willingness on the part of industry, the trans-fusion medicine and blood banking community, and theregulatory agencies involved to take risk. How that canbest be accomplished and our ability to do so will dependas much on how we perceive those risks as to what theanalysis from a purely mathematical standpoint tells usthey are in absolute magnitude.64,65 In the end, decisionsmust be considered in the face of not making an interven-tion, which also carries with it the potential to fail to meetexisting as well as dynamic and ever-changing concernsrelated to blood safety.

8. High multiplicity resequencing pathogen micro-arrays for EIDs. Clark Tibbetts, PhD, TessArae, PotomacFalls, VA

Brief commentaryWhile the public health community is trying to under-stand how EIDs can be prioritized, in parallel, a number ofmolecular tools have been developed that facilitate accu-rate identification of the EID agents and technologies thatreduce the burden of multiple pathogens in a nonspecificway. For example, the high multiplicity resequencingpathogen microarrays (RPMs) were described as one ofthe cutting-edge technology tools that would enable high-sensitivity multiplexed detection and specific identifica-tion of dozens of the highest blood product and tissuesafety priority level pathogens as a single test using asingle specimen with same-day results.

Speaker’s summary of the presentationAssurance of the safety of blood supplied for transfusion ischallenged by diverse and variable risks of transmission of

ATREYA ET AL.


infectious disease agents, particularly to recipients withdiminished capability to mount effective immunologicdefenses, and this certainly is also true for transplantationof donated tissues and organs. Long lists of pathogens thatmay compromise blood supply safety expand as EID risksare identified.32

Today the most common practice to assure bloodsupply safety is implemented as systematic screening ofindividuals participating in donor pools. Few would arguethat this is adequate, particularly with respect to potentialtransmission of pathogens with relatively low prevalenceamong apparently healthy donors.

Unfortunately, the plausible advantages of analyticaltesting of individual or pooled units of blood for trans-fusion have not been fully realized. Assays based onreverse-transcription polymerase chain reaction (RT-PCR)have been applied for screening of blood and bloodproducts.66-70 However, such tests were developed andintended for use as medical diagnostics, and there areserious shortcomings for screening, monitoring, andsurveillance. In general, such tests:

• Only target individual pathogens deemed sufficientlyprevalent to assure commercial returns on invest-ments in research and development and regulatoryreview;

• Provide no basis for epidemiologic or forensic track-ing of particular strains or variants of detected patho-gens through lineages of donors and recipients; and

• Provide no basis for prospective detection and iden-tification of emergent pathogen threats, since designof an RT-PCR test is utterly dependent on a prioriknowledge of specific signature markers of thetargeted pathogen.

The RPM is an alternative pathogen detection andidentification technology that bridges the gaps betweenmedical diagnostics and requirements for screening,monitoring, and surveillance of blood and blood productsupplies.71-82 RPM can simultaneously test a single aliquotfor presence of multiple pathogens, determine sequencesof detected pathogen genes, and report identification(s) asknown or previously unknown strains or variants. This wasrecently demonstrated by application of an RPM applica-tion developed in 2006 to 2007 that was approved for emer-gency use by the FDA for detection of the 2009 novel H1N1influenza virus pandemic outbreak strain.83-86 The highmultiplicity of RPM minimizes costs for inclusion of manycritical but rarely encountered pathogens. The robust,sequencing-based approach of RPM can detect and iden-tify pathogen genes having at least 80% sequence similarityto the RPM sequence detectors. Analytical and clinicalstudies confirm the capabilities of the RPM test to detectany of dozens of target pathogens, alone or copresent intested specimens. Analytical and clinical sensitivity of theRPM matches performance of the most specific of RT-PCR

tests, as both platforms leverage amplification of tracenucleic acids from tested specimens. However, the RPMlogistically separates amplification from detection, miti-gating risk of false-positive detection and enabling identi-fication of particular pathogens. This unique feature ofRPM is particularly important to minimize refusals of criti-cal blood supplies based on false-positive testing results.

Testing of influenza virus vaccines demonstrates thecapability of RPM to detect and uniquely specify strainsfirst described 50 to 75 years ago, as well as strains thatwere first appearing years after the test itself was designedand manufactured.87 The RPM test developed in 2005 to2006 correctly identified the 2009 novel H1N1 influenzavirus outbreak strain in sentinel cases tested before thestrain’s genome sequence was deposited in public data-bases. Traditional RT-PCR tests have only been developedand distributed months to years after initial outbreakagents have been well characterized (e.g., SARS, A/H5N1,2009 H1N1). In another study, specimens containingvarious A/HN subtypes of avian influenza viruses wereblindly tested by RPM, with unequivocal and correct iden-tifications in same-day test results. In the majority of casesthe RPM assay–generated sequences of viral genes fromeach sample enabled correct identification of the specificreference strains. The RPM also correctly identified avianparamyxoviruses (metapneumovirus and Newcastledisease virus) that were submitted blindly with influenzavirus-negative specimens.

Some of the known and emergent viral, bacterial, andeukaryotic pathogens that may threaten the blood supplycould be simultaneously detected and identified in singleRPM assays of single specimens; these include:

• Chikungunya virus; dengue viruses types 1, 2, 3, and4; hepatitis A, B, and C viruses; HIV Types 1 and 2;human T-lymphotropic virus Types 1 and 2; herpesvi-ruses (herpes simplex virus-1 and -2, cytomegalovi-rus, varicella zoster virus, Epstein-Barr virus, Kaposi’ssarcoma virus, human herpesvirus-8); seasonal andpandemic influenza viruses (including A/H5N1 and2009 H1N1); arenavirus lymphocytic choriomeningi-tis virus; parvovirus B19; rabies virus; WNV; eastern,western, Venezuelan, and St Louis encephalitisviruses; and XMRV.

• Clostridium, Francisella, Yersinia, Bacillus, Myco-bacterium, Streptococcus, Staphylococcus, Borrelia,Rickettsia, Erlichia, and others.

• Plasmodium, Babesia, Trypansoma, Leishmania,Balamuthia, Acanthamoeba, and others.

RPM can as easily be applied to multiplex testing ofsamples from individual units or pools of samples fromblood or blood products for transfusion, as well as in lon-gitudinal testing of candidate donors. The major barrierto such implementations is regulatory, not technical.Current regulatory reviews, models, and practices may



be well suited to medical diagnostics devices and tests(presence or absence of presumptive single target) andtreatment planning for individual patients. However, suchregulatory reviews are not intended, nor particularlyeffective for highly multiplexed, gene sequencing–baseddevices that would be used for screening, monitoring, andsurveillance applications. The immediate availability andadvantages of RPM invite revision of the regulatory reviewmodel for analytical testing to assure safety of blood andblood products.

9. Reducing the risk of transmitting spongiformencephalopathies by human blood and blood products.David M. Asher, MD, US Food and Drug Administration,Rockville, MD

Brief commentaryThe measures that have been taken to reduce the riskof transmission of human transmissible spongiformencephalopathies (TSEs), such as sporadic and vCJD, byhuman blood and blood products, and for managingthe risks of contamination in medical products werediscussed. Further, the current FDA approach for viralclearance validation studies of human plasma–derivedproducts that serve as precedent for TSEs and the latesttechnologies for prion protein (PrP) assays and bloodfilters that are under development were also put forwardfor discussion.

Speaker’s summary of the presentationTSEs (prion diseases) are relentlessly progressive invari-ably fatal brain diseases caused by self-replicating agents,the nature of which is not well understood. The mostcommon human TSE is Creutzfeldt-Jakob disease,88 a rareform of which, “variant” CJD (vCJD) resulted from food-borne infection with the agent of bovine spongiformencephalopathy89—itself postulated to have originatedfrom accidental feeding of cattle with rendered animalproteins contaminated with the agent of a sheep TSE calledscrapie or a similar agent.90 All TSEs are associated withaccumulation in the central nervous system, and some-times other tissues, of an abnormally folded form of anormal host protein called PrP.91 Many authorities believethat the infectious TSE agents are composed of abnormalTSE-associated PrP (WHO-recommended designationPrPTSE; World Health Organization, 2006),92 although theall-protein (“prion”) hypothesis remains controversial.93

Since the 1980s, based on finding of infectivity inblood of animals with TSEs, the FDA has recommendedthe deferral of blood and plasma donors at increased riskof various forms of CJD,94 most recently those who spentsignificant time in countries with highest prevalences ofbovine spongiform encephalopathy in cattle and vCJD in

humans. Although other forms of CJD have not beendirectly implicated in transfusion-transmitted TSE,95

four vCJD infections (two overt, two preclinical) have beenattributed to transfusions with red blood cells96 and afifth to treatment with a plasma-derived factor VIIIconcentrate97,98—all in the UK. Those reports leave littledoubt that sufficient vCJD agent circulates in blood ofsome infected donors during at least the last 3 years ofasymptomatic incubation period to infect recipients.

The FDA believes that US deferral policies have beeneffective in reducing the risk of transfusion-transmittedvCJD and that donor deferrals plus clearance of TSEagents from plasma by manufacturing processes greatlyreduce risk associated with plasma derivatives. It wouldbe desirable to consider adding steps to maintain andeven enhance blood safety while reducing the number ofdeferred vCJD-at-risk donors not actually infected—probably a majority of those currently deferred. Twomethods under study to further reduce the risk of trans-mitting spongiform encephalopathies by blood and bloodproducts include: 1) to develop accessible (using blood orother readily available biologic fluid) antemortem tests(that use blood or other readily available biologic fluids)that identify infected donors during the incubation periodand 2) methods that eliminate (inactivate or remove) TSEagents from blood.

To date, all candidate tests attempting to identifydonors during incubation period of vCJD have been basedon detection of small amounts of PrPTSE postulated to be inblood—an objective made especially difficult becausePrPTSE, if present, must be surrounded by large amounts ofmany other plasma proteins, including a 104-fold orgreater excess of antigenically similar normal PrP93,99 Inany case, no assay of PrPTSE in blood or other accessiblematerial has been approved by the FDA to date either toscreen donors or to diagnose preclinical TSE.

Two filter-like devices have been reported to removeboth PrPTSE and infectivity (detected by bioassay inanimals) from blood spiked with tissue extracts contain-ing TSE agent and blood of animals with experimentalTSEs.100,101 An advisory committee in the UK (where preva-lence of preclinical vCJD, while uncertain, must be muchhigher than that in most other countries) recently recom-mended using such devices, coupled with leukoreduction,to reduce the risk of transfusion-transmitted vCJD forcertain recipients.102 Development of endogenously vCJD-infected blood reference materials would greatly facilitatefuture evaluation of both TSE detection assays and TSEagent removal devices.

ROUNDTABLE DISCUSSION

Panel discussion summary. Paul Mied, PhD, US Food andDrug Administration, Bethesda, MD (Panel Members:David Asher, Harvey Alter, Roger Dodd, Peter Ganz,

ATREYA ET AL.


Raymond Goodrich, Marta Gwinn, Jerry Holmberg, JamesHughes, Matthew Kuehnert, Steven Kleinman, SusanStramer, Clark Tibbetts, and Mark Walderhaug)

The panel discussion focused on 1) criteria to priori-tize EIDs that pose a threat to transfusion safety; 2) devel-opment of a response to the threat from EIDs by publichealth agencies and stakeholders, which included mea-sures such as horizon scanning, surveillance and epide-miology, risk evaluation and assessment, and tools todetect or reduce the risk of EIDs; and 3) lessons learnedfrom our previous experiences in response to EID threatsto transfusion safety.

The major outcomes of the discussion were: 1) Theconcept of prioritization of EIDs for blood safety iscomplex because of various issues such as measurementof acceptable risk, mechanism of communication of riskamong the stakeholders, challenges of risk mitigationbased on prevalence, severity and transmissibility (as wasproposed by AABB, publication), public perception, andsocietal concerns. 2) The issue of threshold for response toa threat is not clear because of various factors that playinto its decision-making process such as risk versusbenefit of response and availability of adequate scientificdata to make the decision to respond and to draw abalance between blood safety versus availability. 3) Theavailability of tests to intervene or respond to a threat.Given the small market for such tests, the panel also heardconcerns from both the panel members and the audiencewith regard to lack of clarity on whom and how the cost todevelop such tests should be addressed. Overall this work-shop raised more thought-provoking questions thanprovided answers. However, it was clear from the discus-sion that there is no single formula for prioritization ofEIDs for blood safety and there is a need for continueddiscussions and robust hemovigilance as new EIDsemerge. For a detailed panel discussion, please refer to theworkshop transcripts.103

ACKNOWLEDGMENTS

The authors thank the workshop organizing committee for their

time and effort in putting together the workshop agenda. Special

thanks to Jerry Holmberg, Mathew Kuehnert, and Harvey Alter for

convening the workshop sessions and Ms Jennifer Scharpf,

MPH, and Ms Rhonda Dawson for their help with organizing the

workshop.

CONFLICT OF INTEREST

The authors do not have any conflict of interest.

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