Abstract

Since the 1970s, introduction of serological assays targeting virus-specific antibodies and antigens has been effective in identifying blood donations infected with the classic transfusion-transmitted infectious agents (TTIs; hepatitis B virus [HBV], HIV, human T-cell lymphotropic virus types I and II, hepatitis C virus [HCV]). Subsequently, progressive implementation of nucleic acid–amplification technology (NAT) screening for HIV, HCV, and HBV has reduced the residual risk of infectious-window-period donations, such that per unit risks are <1 in 1 000 000 in the United States, other high-income countries, and in high-incidence regions performing NAT. NAT screening has emerged as the preferred option for detection of newer TTIs including West Nile virus, Zika virus (ZIKV), and Babesia microti. Although there is continual need to monitor current risks due to established TTI, ongoing challenges in blood safety relate primarily to surveillance for emerging agents coupled with development of rapid response mechanisms when such agents are identified. Recent progress in development and implementation of pathogen-reduction technologies (PRTs) provide the opportunity for proactive rather than reactive response to blood-safety threats. Risk-based decision-making tools and cost-effectiveness models have proved useful to quantify infectious risks and place new interventions in context. However, as evidenced by the 2015 to 2017 ZIKV pandemic, a level of tolerable risk has yet to be defined in such a way that conflicting factors (eg, theoretical recipient risk, blood availability, cost, and commercial interests) can be reconciled. A unified approach to TTIs is needed, whereby novel tests and PRTs replace, rather than add to, existing interventions, thereby ameliorating cost and logistical burden to blood centers and hospitals.

Introduction

Blood-transfusion therapy is integral to management of diverse hematological and other diseases. Prevention of transfusion-transmitted (TT) infectious agents (TTIs) remains a key element of blood-transfusion safety. Attributes of TTIs that pose greatest risk to blood safety include an asymptomatic infectious phase in the donor and the ability to persist despite processing and storage1-3 ; furthermore, TTIs must be associated with clinically significant adverse outcomes to warrant intervention. The responses to potential TTIs (eg, donor deferral, testing, and pathogen-reduction technologies [PRTs]) have advanced remarkably in terms of speed of assessment and implementation and efficacy of interventions, yet continue to be constrained by the need to strike a balance between blood availability, cost, and safety.

Blood-donor screening began in the 1940s with testing for syphilis, followed in the early 1970s by testing for hepatitis B surface antigen (HBsAg). Data from initial HBsAg screening demonstrating higher rates of infection in paid donors led to conversion to an all-volunteer blood supply in the United States and many other countries in the mid-1970s.4,5  The recognition of transfusion-associated AIDS in 1982 and 1983 (subsequently linked in 1984 to HIV) as a worldwide blood-safety threat resulted in a paradigm shift toward more rapid implementation of blood-safety interventions, not only for HIV but also for other known and potential TTIs, and for increased surveillance for new agents. This also led to transformation of blood-banking organizations, practices, and regulatory oversight in the United States and many other countries.4,5 

Over the ensuing decades, donor deferral criteria have been implemented to exclude donors with infectious disease risk factors, testing for major TTIs has been enhanced,4,5  and systematic approaches for surveillance and responses to potential emerging infectious diseases (EIDs) have been developed.1-3,6,7  Also, it has been recognized that in addition to “classic” TTIs that cause chronic asymptomatic infections in donors, other agents that cause acute infections may be transmitted at significant rates if there are focal epidemics or ongoing vector-mediated or recurrent seasonal transmission. Salient examples where interventions were implemented in the United States include nationwide testing for interdiction of donations from donors with Trypanosoma cruzi, West Nile virus (WNV), and Zika virus (ZIKV) infections, as well as selective testing for Babesia microti infection in endemic regions. Furthermore, testing for bacterial contamination of platelet components after collection/manufacture was instituted to prevent septic transfusion reactions. Donor deferrals were implemented to reduce the risk of variant Creutzfeldt-Jakob disease (vCJD) and several other agents during outbreaks. Research studies have also excluded several infectious agents as significant blood-safety threats, whereas development and implementation of PRTs enables a proactive rather than a reactive response to new infectious threats.

Overview of current risks and laboratory screening to reduce these risks in the United States

Laboratory screening of blood donors for the classic TTIs (HIV, hepatitis B virus [HBV], hepatitis C virus [HCV]) has evolved from performance of progressively more sensitive serological assays in the 1970s to 1990s to adoption of nucleic acid–amplification technologies (NATs) to detect acute window period (WP; when donor-screening markers are not yet detectable but a transfusion is still infectious) and occult infections. NAT screening has also been implemented for other acute infections transmitted by blood components (eg, WNV8,9  and ZIKV in the United States,10,11  and hepatitis E virus [HEV] in Japan and some European countries12,13 ). Table 1 includes interventions and estimates for risk of TTIs from single-unit transfusions; risk will be higher (ie, multiplied by the number of units) for patients who receive multiple units.14,15 

Table 1.

Blood-safety interventions over time and current estimates of the rate of potentially infectious units entering the US blood supply despite safety interventions

PathogenClinical syndromesBlood-safety interventions (approximate year of implementation in US)Current per unit risk estimate
HIV • Acute seroconversion illness • HIV-Ab (1985) 1 in 2 million 
• AIDS • MP-NAT (1999) 
HCV • Acute hepatitis • HCV-Ab (1990) 1 in 2 million 
• Chronic hepatitis • MP-NAT (1999) 
• Cirrhosis  
HBV • Acute hepatitis • HBsAg (1971) 1 in 2 million 
• Chronic hepatitis • HBcAb (1986) 
• Cirrhosis • MP-NAT (2009) 
• Hepatocellular carcinoma  
HTLV-I/II • Adult T-cell leukemia/lymphoma • HTLVI/II-Ab (1988) 1 in 3 million 
• HTLV-associated myelopathy/tropical spastic paraparesis  
CMV • Retinitis • Selective CMV-Ab (1980s) <1 in 3 million 
• Enteritis • Leukoreduction (∼2000) 
• Disseminated infection  
WNV • Neuroinvasive disease • MP-NAT/seasonal ID-NAT (2003) <1 in 3 million 
ZIKV • Congenital Zika syndrome (including microcephaly) • ID-NAT (2016) <1 in 3 million* 
• Guillain Barré • MP-NAT (2018) 
T pallidum • Syphilis T pallidum Ab (1948) None but theoretical risk from RT-stored platelets 
Bacteria • Sepsis • Arm disinfection (early) STR from platelet: 1 in 100 000 
 • Inlet diversion pouches (early 2000s) 
 • Bacterial culture platelets (mid 2000s) 
 • Pathogen reduction (∼2016) 
 • Point-of-care testing (∼2016) 
Plasmodium spp. • Malaria • Risk factor based donor deferral (1970s or before) <1 in 3 million 
Babesia spp. (B microti• Babesiosis • Selective testing (not mandated) in high-endemicity areas (∼2014) Not known§,|| 
T cruzi • Chagas disease T cruzi Ab (2007) <1 in 3 million 
vCJD • Transmissible spongiform encephalopathy • Risk factor–based donor deferral (2000) None, but theoretical risk 
PathogenClinical syndromesBlood-safety interventions (approximate year of implementation in US)Current per unit risk estimate
HIV • Acute seroconversion illness • HIV-Ab (1985) 1 in 2 million 
• AIDS • MP-NAT (1999) 
HCV • Acute hepatitis • HCV-Ab (1990) 1 in 2 million 
• Chronic hepatitis • MP-NAT (1999) 
• Cirrhosis  
HBV • Acute hepatitis • HBsAg (1971) 1 in 2 million 
• Chronic hepatitis • HBcAb (1986) 
• Cirrhosis • MP-NAT (2009) 
• Hepatocellular carcinoma  
HTLV-I/II • Adult T-cell leukemia/lymphoma • HTLVI/II-Ab (1988) 1 in 3 million 
• HTLV-associated myelopathy/tropical spastic paraparesis  
CMV • Retinitis • Selective CMV-Ab (1980s) <1 in 3 million 
• Enteritis • Leukoreduction (∼2000) 
• Disseminated infection  
WNV • Neuroinvasive disease • MP-NAT/seasonal ID-NAT (2003) <1 in 3 million 
ZIKV • Congenital Zika syndrome (including microcephaly) • ID-NAT (2016) <1 in 3 million* 
• Guillain Barré • MP-NAT (2018) 
T pallidum • Syphilis T pallidum Ab (1948) None but theoretical risk from RT-stored platelets 
Bacteria • Sepsis • Arm disinfection (early) STR from platelet: 1 in 100 000 
 • Inlet diversion pouches (early 2000s) 
 • Bacterial culture platelets (mid 2000s) 
 • Pathogen reduction (∼2016) 
 • Point-of-care testing (∼2016) 
Plasmodium spp. • Malaria • Risk factor based donor deferral (1970s or before) <1 in 3 million 
Babesia spp. (B microti• Babesiosis • Selective testing (not mandated) in high-endemicity areas (∼2014) Not known§,|| 
T cruzi • Chagas disease T cruzi Ab (2007) <1 in 3 million 
vCJD • Transmissible spongiform encephalopathy • Risk factor–based donor deferral (2000) None, but theoretical risk 

As a worst-case scenario, it can be assumed that any unit containing a pathogen will transmit that infection to a recipient. The estimates for risk of TTIs are for single-unit transfusions; risk will be higher (ie, multiplied by the number of units) for patients who receive multiple units either in single exposures or over a treatment course. See Kleinman and Stassinopoulos14  and Kleinman et al15  for extrapolated risks for large transfusion exposure clinical events (platelets and RBCs) and various chronically transfused recipient populations.14,15 

Ab, antibody testing; Ag, antigen testing; ID, individual donation; MP, minipool; RT, room temperature; STR, septic transfusion reaction.

*

No cases reported in the United States and only 4 possible TT cases reported globally, all in Brazil during the large 2015 to 2016 outbreak.

These interventions have been adopted only by some blood centers or hospitals.

This is the risk for a clinically septic event from a platelet transfusion. The actual rate of transfusing a bacterial contaminated platelet may be much higher (estimate of 1 in ∼2000 U). The risk of an STR from a RBC transfusion is much lower (<1 in 1 million).

§

These are RBC parasites and risk is from transfusion of packed RBCs.

||

Because Babesia testing is performed extensively but not universally in highly endemic areas of the United States, it is unclear how much residual risk still remains.

Viruses

The development of the incidence-WP risk-estimation model in the 1990s highlighted that the largest contributor to residual risk posed by established TT viruses is the infectious WP that precedes development of host-response serological markers.16,17  Extensive research to understand the dynamics and infectivity of acute and chronic viremia,18-22  coupled with advances in molecular diagnostic technologies such as polymerase chain reaction (PCR) and transcription-mediated amplification (TMA), led to development and implementation of NAT assays for blood-donor screening in the late 1990s in the United States and globally.23,24  Single-virus NAT assays targeting HCV and then HIV-1, which were performed on manual or semiautomated testing systems in the early 1990s, evolved into multiplexed NAT screening systems (HIV, HBV, and HCV in the same assay) capable of detecting diverse variants on highly automated, high-throughput platforms. Initial implementation that required testing of relatively large “minipools” (MPs; composed of 16-96 donor plasma samples) evolved to testing of smaller MPs (4-16 samples) and even individual donations (IDs).24-26  These advances have reduced risk to <1 in 1 000 000 per unit (Figure 1). However, policy debates continue over the cost-effectiveness (CE) of NAT-testing strategies in different settings, particularly in resource-constrained countries.27,28 

Figure 1.

Risks of major TT viruses, progressive blood safety interventions and consequent costs, and EIDs that have been investigated for impact on blood safety over the past 4 decades. (A) Per unit infectious risk for HBV, HCV, and HIV from 1980 to 2018. (B) Temporal relationship of progressive interventions to reduce risks of TTIs to median service fee for acquisition of RBC components from blood-collection organizations in the United States (provided by Louis Katz, America’s Blood Centers [these service fee costs do not reflect increases in the Consumer Price Index for medical care services, which increased fivefold to sevenfold from 1980 to 2018]). (C) Potential TT-emerging infection agents that were investigated over the past 25 years. Red indicates agents proven to be blood-safety threats for which interventions were implemented; blue, agents established to be legitimate infectious agents but not TT or associated with diseases; and green, alleged threats determined to not cause human infections or those due to artifacts. *No interventions in the United States, but interventions implemented in some countries where HEV incidence is higher. HGV, hepatitis G virus; ICL, idiopathic CD4+ T-lymphocytopenia; MERS-Cov, Middle Eastern respiratory syndrome coronovirus; PARV-4, parvovirus type 4; PTLV, primate T-cell lymphotrophic viruses; SARS, severe acute respiratory syndrome; SFTSV, severe fever with thrombocytopenia virus; SFV, simian foamy virus. Modified from Perkins and Busch4  with permission.

Figure 1.

Risks of major TT viruses, progressive blood safety interventions and consequent costs, and EIDs that have been investigated for impact on blood safety over the past 4 decades. (A) Per unit infectious risk for HBV, HCV, and HIV from 1980 to 2018. (B) Temporal relationship of progressive interventions to reduce risks of TTIs to median service fee for acquisition of RBC components from blood-collection organizations in the United States (provided by Louis Katz, America’s Blood Centers [these service fee costs do not reflect increases in the Consumer Price Index for medical care services, which increased fivefold to sevenfold from 1980 to 2018]). (C) Potential TT-emerging infection agents that were investigated over the past 25 years. Red indicates agents proven to be blood-safety threats for which interventions were implemented; blue, agents established to be legitimate infectious agents but not TT or associated with diseases; and green, alleged threats determined to not cause human infections or those due to artifacts. *No interventions in the United States, but interventions implemented in some countries where HEV incidence is higher. HGV, hepatitis G virus; ICL, idiopathic CD4+ T-lymphocytopenia; MERS-Cov, Middle Eastern respiratory syndrome coronovirus; PARV-4, parvovirus type 4; PTLV, primate T-cell lymphotrophic viruses; SARS, severe acute respiratory syndrome; SFTSV, severe fever with thrombocytopenia virus; SFV, simian foamy virus. Modified from Perkins and Busch4  with permission.

Two other classes of TT viral agents that establish chronic but latent infections in donors are human lymphotropic virus types I and II (HTLV-I/II) and cytomegalovirus (CMV), Epstein-Barr virus (EBV), and other human herpes viruses (HHVs; varicella zoster virus [VZV], HHV-6, HHV-7, HHV-8). Prevention of TT of HTLV-I/II was addressed by implementation of antibody assays in the United States in the late 1980s.29-31  The TT risk of CMV32,33  was first addressed by selective provision of CMV-seronegative components to immunosuppressed at-risk recipient populations (eg, transplant recipients, neonates). Although studies have identified viral nucleic acids in donor blood, the TT risk of other herpes viruses is controversial; these highly prevalent viruses have either not been demonstrated to be TT or to cause disease in recipients, many of whom already harbor latent HHV infections under immune control. Consequently, screening is not performed for EBV or other HHVs.34-37  The cell-associated nature of these infections coupled with the adoption of universal leukocyte reduction (LR) in most developed countries has led to reconsideration of the need for serological screening for CMV, with LR considered equivalent to CMV antibody-negative blood products by some authorities.38,39 

Arthropod-borne viruses (arboviruses), transmitted by a variety of mosquito and tick species, cause a wide spectrum of disease in humans spanning from asymptomatic infections and mild flu-like illness to severe and potentially fatal hemorrhagic and neurological syndromes.40  Concern with regard to blood safety relates to infected individuals developing acute high-level viremia without symptoms for several weeks following infection. The epidemiology of arboviruses is highly variable and unpredictable, ranging from localized, isolated events, to recurrent seasonal outbreaks, to massive epidemics. Agents of recent TT concern include WNV, Dengue viruses (DENV), Chikungunya virus (CHIKV) and ZIKV.40 

WNV entered the United States in the late 1990s. In 2002 and 2003, 23 TT cases were identified, with recipients developing severe and even fatal neuroinvasive disease.41  Within 9 months of recognition, newly developed WNV NAT assays were implemented in MP format using existing NAT platforms.8,9  Although over 1000 infected blood donations were interdicted in 2003, small numbers of TT cases continued to occur, resulting from donations with WNV RNA below detection levels of MP testing.8,9  This led to a new testing strategy, termed targeted ID-NAT, in which detection of MP-NAT+ donor(s) in a specific geographic area triggered a switch to ID-NAT testing. Progressive enhancement of the ID-NAT trigger (to the current trigger of a single MP-NAT yield case in a surveillance zone) has virtually eliminated WNV TT. Testing has proven highly effective in the United States, where there have been annual WNV outbreaks for the past 15 years with 300 to 1000 WNV RNA+ donations interdicted each year.42,43 

Although DENV and CHIKV are not prevalent in the continental United States, outbreaks in Asia-Pacific countries, south and Central America, and Caribbean islands prompted concern for TT in those locales and in returning US travelers. Rates of DENV and CHIKV RNA+ donations in Puerto Rico and several Latin American countries were shown to exceed 1% during active mosquito-transmission seasons.42,44-47  A study in Brazil during large DENV-4 outbreaks established the dynamics of donor viremia46  and documented an ∼33% rate of TT from DENV RNA+ transfusions.45  However, DENV-related symptom incidence in hospitalized patients infected by transfusion or other routes was similar to that in control noninfected patients,45  which led to discontinuation of prospective DENV NAT screening in Puerto Rico and several other countries.

In 2015, the outbreak of ZIKV in Brazil showed associations with Guillain-Barré syndrome and fetal brain abnormalities including microcephaly in the offspring of infected pregnant women.48  These severe clinical outcomes, the documentation of several probable TT cases in Brazil, and ZIKV’s spread to Puerto Rico led to the US Food and Drug Administration (FDA) requirement to screen blood collections in Puerto Rico using ID-NAT assays (developed and implemented within 3-6 months) beginning in April 2016.49  ZIKV RNA was immediately detected and 339 infected donations were interdicted through 31 December 2016, likely preventing several hundred TT cases.50  As mandated by the FDA,51  ZIKV testing by ID-NAT was phased-in throughout the continental United States between June and December 2016. This resulted in detection of ∼100 RNA+ donations, most from recent travelers to ZIKV outbreak countries who were in the tail end of infection with very low RNA levels and high titers of neutralizing antibodies, and hence at very low risk for TT.10,11,52  The epidemics in the Americas have since waned and very few cases of clinical disease or RNA+ donations were detected in 2017 and 2018. This led to revision of the FDA guidance to allow for conversion to targeted ID-NAT, similar to the WNV-testing strategy.51  There has been criticism over the FDA-mandated rapid implementation of ZIKV ID-NAT due to the observed low yield and low risk of TT to pregnant women, as well as very poor CE.53-56  However, the public expectation of maintaining trust in the safety of the blood supply was deemed paramount in the face of uncertainty.

Parasites

Three parasitic diseases pose risk to the blood supply: malaria (Plasmodium spp.), Chagas disease (T cruzi), and babesiosis (Babesia spp.).57  Reports of transfusion transmission of other parasitic infections (eg, toxoplasmosis and leishmaniasis) have been extraordinarily rare and often of questionable imputability.57-59 

Babesia, a virulent intraerythrocytic parasite, is the agent of greatest concern in the United States. At least 225 cases of TT babesiosis (TTB) have been reported, almost all from packed red cells.60  Naturally acquired infection via tick bite is frequently mild or even subclinical in immunocompetent hosts but can lead to an asymptomatic carrier state that can persist for years.61 B microti, the predominant cause of human babeisosis62  is widely endemic, particularly in the northeast and upper midwest,63  whereas other Babesia species (eg, Babesia duncani)64  are encountered in other parts of the United States, yet rarely result in TTB. Overrepresentation of high-risk clinical subsets (eg, extremes of age, asplenic, and/or immunocompromised) among transfusion recipients may explain a high fatality rate (∼20%) in TTB. Serological65,66  and molecular (DNA or RNA NAT) donor-screening assays67  have been developed and clinical trials have documented reduced TTB in endemic areas. Although a combined antibody/PCR-based strategy attained FDA licensure in 2018, these assays are not commercially available.68  Currently, donor screening is being performed by investigational NAT selectively in many US endemic regions. These NAT assays amplify highly repeated babesia RNA sequences in lysed donor whole blood, attaining detection of 2 to 3 parasites per milliliter of blood, approximating the infectious dose by blood transfusion,69  and potentially obviating the need for concomitant serological screening.70 

T cruzi, which is transmitted by Triatomine vectors and causes Chagas disease, is widely endemic in Latin America where donor screening with multiple serological assays was successfully implemented decades ago. TT cases in the United States have occurred almost exclusively with platelet components.71  Serological screening of all blood donations was initiated in the United States in 2007.72  Based on subsequent information showing an extremely small risk of US residents contracting T cruzi through insect exposure and absence of incident infections in previously screened repeat blood donors in the United States,73  the screening regimen has been modified to testing of only first-time donors, without the need for testing subsequent donations.74 

There is no routine laboratory screening of donor blood for malarial agents. Questionnaire-based risk assessment and deferral (to detect potential chronic, asymptomatic carriers) is used in the United States. Donors are deferred for 1 to 3 years for either a history of malaria and/or travel in a malaria-endemic country.75  Although this approach has proven effective, rare cases of TT malaria are still reported each year in the United States.76  In some countries, but not the United States, testing for Plasmodium antibodies is used for accelerated reinstatement of deferred donors.

Bacteria

Bacterial contamination of blood products (notably platelets), and associated septic transfusion reactions (STRs) remains a major infectious risk to the US blood supply.77  However, given a nonspecific clinical presentation, high rates of comorbid illness, antibiotic use in transfusion recipients that mask presentation, and lack of uniformity as to how cases are investigated, estimation of STR incidence is challenging.78,79 

Risk-reduction strategies implemented in the 2000s included standardized, enhanced phlebotomy site disinfection, the use of diversion pouches integral to the blood collection set (in order to remove the first aliquot of donor blood, which may have higher concentrations of skin flora), and bacterial culture of platelet components.80  The latter, performed at the blood collection center, typically involves sampling the platelet product ∼24 hours following collection with inoculation into a single aerobic culture bottle. Units of platelets are quarantined for a further 12 to 24 hours prior to release to the transfusing facility. These measures have reduced STR incidence by ∼70% with residual cases primarily due to gram-positive skin/mucosal or environmental flora that are present at low numbers during the initial testing procedure but which later multiply during room temperature (22-24°C) platelet storage.81 

Despite these interventions, the residual risk of bacterial contamination has been measured as 1 in 1500 to 1 in 3000 based on passive surveillance data, whereas nonfatal and fatal STR are estimated to occur in 1 in 100 000 and 1 in 500 000 transfusions, respectively; however, active surveillance studies indicate that the nonfatal STR rate may be 10-fold greater.82  Additional methods are being considered to further reduce residual risk; these include pathogen reduction, larger volume primary cultures including aerobic and anaerobic bottles, secondary bacterial culture83  (ie, ∼72 hours postcollection), delayed high-volume sampling (sample the platelet unit at 36-48 hours so as to allow bacteria to reach higher concentrations), and point-of-release testing using rapid detection assays.84,85  Each has its own strengths and limitations.77 

Since the 1940s, all donations have been routinely screened for Treponemal pallidum (T pallidum), the causative agent of syphilis. In most blood centers, treponemal-specific antibody tests are used as the initial screening assay to minimize false-positive results. These assays detect all seropositive donors including many with cleared remote infection. Supplemental testing is then undertaken using nonspecific assays (eg, rapid plasma reagin) to provide information to donors about current disease activity to guide counseling and treatment.

Prion diseases and other neurologic diseases of unknown etiology

Concern over potential TT of CJD was triggered in the 1990s by cases of iatrogenic CJD resulting from pituitary-derived growth factor concentrates and dura transplants. Subsequently, large prospective studies in the United States and United Kingdom that reviewed records from 1028 recipients of transfusions from 92 donors later diagnosed with CJD have failed to document any cases of TT CJD86,87 ; it seems reasonable to conclude that TT-CJD does not occur.

The UK outbreak of vCJD resulting from “mad cow disease” raised concerns of blood and plasma-derivative safety due to the explosive scale of the epidemic, oral route of acquisition, and systemic lymphoid dissemination of atypical vCJD prions.88,89  Following quantitative risk analysis that attempted to strike a balance between risk reduction and tolerable decreases of the available blood supply, FDA mandated deferral of donors who had lived in the United Kingdom and other countries with vCJD for specified intervals.90  Rigorous investigations of recipients of donors who later developed vCJD led to confirmation of 4 cases of TT-vCJD91,92  in the United Kingdom and sparked efforts to develop prion-reduction filters and screening assays that could detect vCJD prions in blood in the presymptomatic stage.93-95  Currently, the food-borne vCJD outbreak appears to be over with no cases reported in the United Kingdom in the past several years despite theoretical concern about a second-wave epidemic of long-incubation cases in persons who are heterozygous for a vCJD risk polymorphism in the prion protein.96  Deferral policies in the United States have been slightly modified to reflect historical rather than current time spent in the United Kingdom/other at-risk countries, and expensive, marginally effective testing or filtration technologies are no longer under consideration.

Based on a broader understanding of the pathophysiology of prion diseases and documented parenteral transmission of Alzheimer and Parkinson diseases when large doses of infected material (brain homogenate) were infused into humanized donor mice followed by transfusions to recipient mice, concern has been raised over the potential TT of these diseases.97,98  However, in a recent analysis using the large linked donor-recipient Swedish and Danish database (ScanDat) and national disease registries, no association was demonstrated between incidence of Alzheimers, Parkinson’s or other neurological diseases in recipients of blood products from donors who later developed these diseases.99 

Emerging infectious diseases, previous false alarms, and approaches to surveillance and response

The emergence and consequent risk to blood safety of EIDs has proven to be unpredictable.1-3,6,7  The AABB Transfusion Transmitted Diseases committee in August 2009 published a Supplement to Transfusion that provided focused information on 68 EID agents that pose a real or theoretical threat to transfusion safety,1  but for which existing effective interventions were lacking.100  EIDs of concern span all pathogen classes, with well over 60% being from zoonotic sources. Updated individual agent “Fact Sheets”101  provide information on: agent classification; background on the disease agent’s importance; the clinical syndromes/diseases caused; modes of transmission (including vectors/reservoirs); likelihood of TT and information on known transmission cases; the feasibility and predicted success of interventions that could be used for donor qualification (questioning); tests available for diagnostics or that could be adapted for donor screening; and efficacy of PRT.101 

In a similar effort, the European Centre for Disease Prevention and Control (ECDC) and blood-bank experts in Europe developed the European Up-Front Risk Assessment Tool (EUFRAT)102  that estimates risk and prioritizes EID agents based on concerns that climate change is driving an increased threat to the blood supply. The agents considered of greatest concern were WNV, DENV, Leishmania, CHIKV, malaria, and Borrelia burgdorferi, the agent of Lyme disease. Two agents (CHIKV and B burgdorferi) were included even though TT of these agents has never been documented. The Asia Pacific Blood Network has also recently established the Asia Pacific Strategy for Emerging Diseases to proactively detect and address EID threats in this region.103 

An unintended consequence of focusing on enhanced surveillance for potential blood-safety threats has been the identification of numerous agents (including many found through viral discovery programs using metagenomics technologies in which a virus is discovered with or without an associated disease) that can theoretically be transmitted by transfusion but which, upon subsequent investigation, prove not to be104  (see Figure 1). The most striking example of this was xenotrophic murine leukemia-related virus (XMRV), which was reported to be associated with prostate cancer and later chronic fatigue syndrome and to be present in the blood of asymptomatic blood donors.105,106  Intensive research consuming a huge amount of time and money subsequently determined that XMRV did not affect humans and was a laboratory contaminant from cell lines that contained this murine virus.107-111 

These experiences led to the US National Heart, Lung, and Blood Institute (NHLBI) and FDA to convene workshops focused on proactive but rational and systematic responses to EIDs.2,3  An AABB EID subgroup embarked on processes to make decision-making more transparent.7  The Alliance of Blood Operators developed a “Risk Based Decision Making” (RBDM) process, which includes formalized methods for quantifying risk and evaluating interventions.112  This process also includes obtaining stakeholder input.

Global blood safety

The high level of transfusion safety in high-income countries (HICs) has not been matched in most low- to middle-income countries (LMICs). Challenges in LMICs span the entire blood-safety chain from donor selection to posttransfusion surveillance.113  LMICs are often situated in areas that are highly endemic for TTIs. Notable examples include HIV and malaria (sub-Saharan Africa), HBV (Asia), HCV (north and west Africa), and HTLV (Caribbean). Donor selection, the initial safeguard against TTIs, is often suboptimal given an unstable donor pool coupled with the high complexity and cost to recruit voluntary donors, which results in reliance on family replacement donors and/or paid donors and use of whole-blood transfusions.114  In contrast to voluntary nonremunerated blood donors, replacement donors who are recruited in times of need (eg, after blood loss due to accidents or child birth) are widely considered to be higher risk for TTIs. In the context of quality control, collection in hot, humid conditions poses risk of bacterial contamination, which has been illustrated in studies in Africa, where rates of contamination up to 17.5% have been reported.115 

TTI testing is also suboptimal. Systemic challenges such as lack of national regulatory oversight, lack of proficiency testing,29,116,117  poor supply chains, high reagent costs, unreliable cold-chain management and electricity, and lack of skilled personnel contribute to reliance on rapid diagnostic tests (RDTs), particularly in remote settings. However, RDTs have not been validated for the blood-donor population and have repeatedly demonstrated low sensitivity and specificity to detect the major TTIs.116-118  Exclusive use of serological assays is common, thus neglecting the contribution of WP infections in those countries where TTI incidence is highest. Finally, posttransfusion surveillance is lacking, such that recipients who acquire TTIs are very unlikely to be recognized as such; rather, these infections will be attributed to acquisition by other modalities.

Enhanced methods to respond and reduce transmission of TTIs

Pathogen-reduced blood components

A mainstay of the safety profile of manufactured plasma derivatives since the 1980s has been the use of physical and chemical processes to inactivate pathogenic organisms in donated plasma. This proactive approach addresses EIDs even before they are known to be a TT risk.

Application of PRT to cellular blood components (eg, red blood cells [RBCs] and platelets) is more challenging given the need to kill pathogens selectively without affecting the therapeutic efficacy of the transfused cells.14,15  Since 2005, pathogen-reduced (PR) platelets using 2 different PRTs have been in use in many European and international settings.119  One of these technologies was licensed by FDA in late 2014 and is currently being used on part of the US apheresis platelet supply. A similar PRT for fresh-frozen plasma is also FDA licensed but has seen very limited introduction into the United States. PR processes have been developed for treating RBC components or whole blood; these technologies are undergoing clinical trials but are not yet commercially available. Assuming that therapeutic efficacy is maintained and cost issues can be addressed, wide adoption of universal PRT might allow for the relaxation of redundant donor laboratory screening and donor questioning/deferrals. A fully PRT blood supply could reshape the response to new EIDs given that there would be less pressure to develop screening assays. Caveats are that not all infectious agents are inactivated by PRT (nonenveloped viruses and prions show variable resistance) and each manufacturer’s process must be independently evaluated.

Decision-making considerations including health economics

Consequent to the TT-HIV and HCV crises in the 1980s and 1990s, blood-safety policies in many countries have been based on a precautionary paradigm. More recently, consideration has been given to defining a risk level deemed to be tolerable, balancing recipient safety, blood availability, cost, logistics, and stakeholder concerns. This has been formalized into RBDM that has been used by several national blood-collection agencies, in partnership with national regulatory authorities and international transfusion medicine organizations.120  In the United States, where the FDA approves/licenses new tests, technologies, and donor eligibility requirements, there is no organization that has the authority to apply the full spectrum of RBDM analyses in a manner that is binding on blood collection centers and hospitals.

CE of many TTI risk-mitigation interventions has been calculated. Initial adoption of serological testing for the classic TT viruses was cost-saving, whereas addition of newer and more expensive tests, such as NAT and tests for lower-risk agents, have much lower CE and add significantly to the cost of blood products (Figure 1). The determination of acceptable CE is based on societal willingness to pay, and factors that impact that decision are complex and culturally nuanced. Many blood-safety interventions routinely exceed the widely cited clinical medicine threshold of $50 000 to $100 000 per quality-adjusted life year (QALY)121  by at least 10-fold (eg, the incremental CE of NAT for HIV/HCV/HBV and WNV NAT are ∼$1.3 million per QALY), yet have been deemed acceptable to maintain public trust in blood safety.

The 2015 to 2017 ZIKV pandemic is illustrative of the challenge of balancing a timely and precautionary response to an emerging TTI threat with economic considerations. Test availability was dependent upon the need to enlist industry partners to develop and commercialize assays rapidly, despite uncertainty of actual or sustainable return on investment. FDA-mandated ID-NAT testing was implemented throughout the United States in 2016 (despite uncertain TT risk) at a projected annual cost of $137 million.53  CE modeling subsequent to implementation of donor screening suggests that the cost utility is vanishingly low (∼$300 million per QALY)55  based on risk to transfusion recipients coupled with the lack of ZIKV+ donations in 2017 and 2018 following dissipation of the epidemic. Hence ongoing ZIKV testing represents a theoretical benefit at extraordinary cost.54 

US blood-collection centers are under severe economic pressure due to declining blood utilization and a reimbursement structure that is increasingly removed from the true costs of production.122  Blood is most often transfused in the hospital inpatient setting in which its costs are embedded in a diagnostic related group and poorly reimbursed to the hospital. Thus, hospitals are resistant to price escalation, resulting in relatively static blood component pricing in the current highly competitive and commoditized US blood-provider environment, and a decade of “cost-containment” practices at hospitals. This has raised the question of the sustainability of the blood industry to innovate and contend with EIDs.123 

Once implemented, donor screening tests are rarely abandoned. A new approach is needed whereby novel assays and technologies like PRT that improve on existing strategies, replace rather than add to existing safety measures. In this way, several tests could be discontinued without compromising transfusion-recipient safety (such as happened with HIV-1 p24 antigen testing). Universal PRT could allow donor testing to be significantly revised (eg, by enhancing multiplexing while reducing sensitivity and costs). However, because many blood-safety interventions are executed under FDA mandates, this will require the FDA to reassess its requirements.

Conclusions

This review has highlighted responses to established TTIs and our evolving and increasingly systematic approach to addressing EID threats. In addition to enhancing recipient safety, operational data from blood-donor screening combined with multifaceted research efforts (Figure 2) are of broad public health and scientific value.124-126  US government agency–funded (eg, National Institutes of Health [NIH], FDA, and Centers for Disease Control and Prevention [CDC]), TTI-focused research programs127-130  have served to advance the understanding of etiology, diagnostics, natural history, and pathogenesis of infectious diseases.

Figure 2.

Methodologies to assess transfusion-transmission risk and, through follow-up studies of blood donors and recipients, to provide insights into epidemiology, natural history, and pathogenesis of emerging infectious diseases (eg, ZIKV). Reprinted from Lanteri et al with permission.126 

Figure 2.

Methodologies to assess transfusion-transmission risk and, through follow-up studies of blood donors and recipients, to provide insights into epidemiology, natural history, and pathogenesis of emerging infectious diseases (eg, ZIKV). Reprinted from Lanteri et al with permission.126 

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

Authorship

Contribution: M.P.B., E.M.B., and S.K. worked collaboratively to develop this review, including organizing content; reviewing the literature; drafting and revising the text, table, and figures; and reading and approving the final submission.

Conflict-of-interest disclosure: M.P.B. is an employee of Vitalant (previously Blood Systems), which co-owns Creative Testing Solutions (both not-for-profit corporations), which performs TTI testing on two-thirds of US blood collections; Vitalant Research Institute receives research funding and M.P.B. has received meeting speaker sponsorship and honoraria from Grifols, Roche, Ortho, and Hologic, and is on the scientific advisory board of Quotient Diagnostics. E.M.B. is a co-investigator on the Miplate trial to compare efficacy of Mirasol (pathogen-reduced) platelets with standard-issue platelets. S.K. provides paid consulting services to Cerus Corporation, which produces a technology to manufacture pathogen-reduced blood components.

Correspondence: Michael P. Busch, Vitalant Research Institute, 270 Masonic Ave, San Francisco, CA 94118; e-mail: mbusch@vitalant.org.

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