MINIREVIEW

crossm

Transfusion-Transmitted Infections: an Update on Product

Screening, Diagnostic Techniques, and the Path Ahead
Christina L. Dean,a Jenna Wade,a John D. Robacka

a
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia,

Downloaded from http://jcm.asm.org/ on June 21, 2020 by guest

USA

ABSTRACT The mandated testing of blood components for infectious diseases,

to prevent transfusion-transmitted infections (TTIs), began in the 1950s. Since
then, changes in predonation questionnaires and advances in testing techniques
have afforded more sensitive and specific tests for pathogens, in addition to allow-
ing earlier detection. Given that these approaches have very low but detectable fail-
ure rates, the recent development and implementation of proactive pathogen reduc-
tion approaches is the new forefront of TTI prevention strategies. With globalization
and the ability of pathogens to evolve rapidly, continuous redefining of testing stan-
dards and laboratory techniques is paramount for maintaining a safe blood supply.
KEYWORDS infectious disease

D onor blood product safety and effectiveness are primary concerns of transfusion
medicine specialists and blood collection centers worldwide. In the United States,
prospective blood donors are first screened with a mandatory predonation question-
naire that was developed collaboratively by the blood collection industry and the Food
and Drug Administration (FDA). Blood samples from donors who pass this step are then
tested, using a growing list of highly sensitive infectious disease screening assays. Over
the past several decades, advances in these laboratory testing techniques have allowed
earlier detection of certain infectious diseases, resulting in a safer blood supply avail-
able to patients. However, emerging infectious diseases continue to pose a risk to the
blood supply because of the considerable time that may be required to develop, to
validate, and to gain regulatory approval for new testing methods to detect these
agents. Thus, great efforts are being made to develop technologies to protect patients
from new and emerging infectious agents for which we do not currently test. In this
minireview, we describe the origins of blood supply infectious disease testing, advance-
ments made to prevent transfusion-transmitted infections (TTIs), and future directions
to improve the safety of donated blood components, with a primary focus on U.S.
practices.

HISTORICAL OVERVIEW OF TESTING OF U.S. BLOOD PRODUCTS FOR

Accepted manuscript posted online 18
INFECTIOUS DISEASES April 2018
The FDA is the regulatory body that oversees the infectious disease testing require- Citation Dean CL, Wade J, Roback JD. 2018.
ments for all blood components intended for transfusion. The FDA describes approved Transfusion-transmitted infections: an update
on product screening, diagnostic techniques,
testing and defines TTIs in title 21, parts 610 and 630, of the Code of Federal
and the path ahead. J Clin Microbiol
Regulations, which has changed over the years as new infectious diseases emerge in 56:e00352-18. https://doi.org/10.1128/JCM
the United States. In general, the FDA defines a TTI as a pathogen that is known to be .00352-18.
fatal, to be life-threatening, or to cause severe impairment and that is potentially Editor Colleen Suzanne Kraft, Emory University
transmissible through the blood supply (1). Assessing donated blood products for Copyright © 2018 American Society for
Microbiology. All Rights Reserved.
antibodies to Treponema pallidum was the first TTI test to be required by the FDA, in the
Address correspondence to Christina L. Dean,
1950s, following documented cases of syphilis infection associated with blood trans- cdean6@emory.edu.
fusion. Since that time, additional testing requirements have evolved following the

July 2018 Volume 56 Issue 7 e00352-18 Journal of Clinical Microbiology jcm.asm.org 1

Minireview Journal of Clinical Microbiology

identification of several additional infectious diseases found in highly transfused per-

sons. In the 1960s, posttransfusion hepatitis (PTH) was found to have a strong associ-
ation with the transfusion of blood products from paid donors (2). This revelation led
not only to the development of the first assay for detecting the hepatitis B surface
antigen (HBsAg) but also to the evolution of a volunteer-only blood donation system,
both of which greatly reduced PTH rates. The finding that hepatitis B virus (HBV) could
be transmitted by transfusion laid the groundwork for the subsequent discovery of
non-A, non-B hepatitis, as neither hepatitis A virus nor HBV could account for all cases
of PTH (3). Unfortunately, it would be two decades before hepatitis C virus (HCV) was
cloned and identified as the causative agent; shortly thereafter, HCV antibody testing
was implemented. Prior to the development of specific tests for HCV, surrogate markers
associated with non-A, non-B PTH, such as alanine aminotransferase and anti-hepatitis
B core antibody (HBcAb), were used to exclude donated blood products that carried a

Downloaded from http://jcm.asm.org/ on June 21, 2020 by guest

risk of transmitting PTH (4, 5). Testing for HBV and HCV now includes nucleic acid
testing (NAT) for DNA and RNA, respectively, which further reduces the window period
for detection of these viruses.
The AIDS epidemic was undoubtedly the greatest threat to the blood supply in the
20th century and was a major factor in how donated blood products are screened
today. It has been estimated that approximately 12,000 people were infected with
human immunodeficiency virus (HIV) via blood transfusions before 1985 (6). The
hemophilia population suffered greatly from transfusion-transmitted HIV, with many
patients becoming infected before the first case of AIDS was even documented (7).
Fortunately, the discovery of HIV as the causative agent of AIDS and the relatively rapid
implementation of antibody testing in 1985 led to a dramatic decrease in the number
of transfusion-transmitted HIV cases. In addition, the FDA recommended changes to
donor screening questionnaires to defer potentially HIV-infected persons from donat-
ing in the first place, by identifying behaviors associated with HIV/AIDS. Improvements
in HIV-1 antibody tests and subsequent implementation of testing for anti-HIV-2, HIV-1
p24 antigen, and HIV RNA further reduced the number of cases of HIV transfusion
transmission, by reducing the window period for detecting HIV infection in blood
donors.
Human T-cell lymphotropic virus I (HTLV-I) and HTLV-II are retroviruses that were
discovered before HIV (which was first designated HTLV-III). HTLV-I, which is endemic in
Japan and the Caribbean region, is the etiological agent known to cause adult T-cell
leukemia and HTLV-associated myelopathy/tropical spastic paresis (8). HTLV-II, which is
endemic in the American Indian population, is closely related to HTLV-I, although its
pathogenicity is less well understood (9). Despite the inherently lower prevalence of
HTLV-I/HTLV-II infections in the United States, compared to areas in which the viruses
are endemic, the FDA first recommended testing of all allogeneic blood donations for
anti-HTLV-I/HTLV-II antibodies in 1988, after high rates of seroconversion were found
following blood transfusion in areas in which the viruses are endemic (8, 10). Antibody
testing specific for HTLV-II was introduced in the late 1990s, and the blood supply
continues to be screened for both viruses today.
Insect-vector-transmitted infections are a constant threat to the global blood supply,
and determining which pathogens to screen for in the United States can be challeng-
ing. Some carriers may be asymptomatic and unaware of being infected, adding to the
difficulty of protecting the blood supply. Currently, the FDA recommends specific
testing of donated blood products for Trypanosoma cruzi, West Nile virus (WNV), and
Zika virus (ZIKV) (1). T. cruzi, the parasite responsible for Chagas disease, can cause
chronic asymptomatic infection for decades before producing serious sequelae, such as
cardiac and gastrointestinal complications. The number of cases of Chagas disease in
the United States is estimated to be over 200,000; cases are largely seen among Latin
American immigrants exposed to T. cruzi while living in areas in which the parasite is
endemic (11). Rare reports of autochthonous cases have been documented, although
the mechanism of disease acquisition is not fully understood (12). Since seroconversion
in the United States is rare, the FDA recommends that all blood donors be tested only

July 2018 Volume 56 Issue 7 e00352-18 jcm.asm.org 2

Minireview Journal of Clinical Microbiology

once for T. cruzi antibodies (13). The Flavivirus WNV first emerged in the United States
in 1999 and was found to be transmissible through the blood supply via viremic donors,
who might or might not have detectable WNV antibodies (14). The majority of
individuals acutely infected with WNV are asymptomatic; however, serious neurological
diseases can occur. Because anti-WNV antibody testing was determined to be insuffi-
ciently sensitive, a NAT method was developed and implemented in 2003 to screen all
allogeneic blood donations (15). Another Flavivirus, ZIKV is endemic in areas of Africa
and Asia and recently prompted global concern as spread of the virus reached Brazil by
2015 and the continental United States by 2016 (16). Similar to WNV, individuals
infected with ZIKV are usually asymptomatic or present with nonspecific complaints,
but serious neurological diseases, such as Guillain-Barré syndrome, have been associ-
ated with ZIKV infection (17, 18). The population at greatest risk for serious complica-
tions from ZIKV infection appears to be pregnant women. This concern came following

Downloaded from http://jcm.asm.org/ on June 21, 2020 by guest

the Brazilian outbreak and the association of ZIKV with devastating neurological effects,
such as microcephaly, in fetuses and infants during acute maternal infection (19).
Studies conducted at that time found that asymptomatic viremia could last from
several weeks to several months after exposure and ZIKV RNA was prevalent in 1% of
blood donors in Puerto Rico (20, 21). Therefore, in 2016 the FDA designated ZIKV a
relevant TTI and recommended that all blood products intended for transfusion in the
United States be tested for ZIKV RNA via NAT (22).

METHODS OF DONOR SCREENING AND TESTING

Screening of blood donors for infectious diseases consists of predonation question-
naires and postdonation testing of blood products. The donor history questionnaire
assumes that donors understand the questions asked and that their answers regarding
certain behaviors are truthful. Donor history questionnaires allow the collection center
to assess the current general health of the donor, as well as certain behaviors associated
with TTIs, prior to blood collection. Some medications and exposures elucidated
through the questionnaire can result in the collection center deferring the donor either
permanently or for a specified time period. The questionnaire can be helpful when
laboratory testing is not available or feasible to detect certain infectious diseases that
are identified as TTIs by the FDA (1). In the United States, the FDA requires blood
collection centers to use predonation questions to assess donors for potential exposure
to prion disease (classic Creutzfeldt-Jakob disease [CJD] and variant CJD [vCJD]),
Plasmodium species, and Babesia species, due to the lack of FDA-approved screening
tests (23–25). Donors are assessed for risks of classic CJD and vCJD and are excluded if
they have a family history of CJD or potential exposure to CJD (e.g., dura mater graft
or xenotransplantation) or vCJD (e.g., travel to Europe during an outbreak) (24). While
cases of transfusion-transmitted CJD have never been documented in the United
States, epidemiological studies indicate that vCJD has been transmitted via blood
transfusions in the United Kingdom (26). There are currently no screening tests for CJD
or vCJD that have been approved by the FDA, leading to the strict guidelines for
deferring individuals with potential exposures.
Temporary deferrals exist for donors with recent travel to an area in which malaria
is endemic, as well as for those who have emigrated from areas in which malaria is
endemic (23). Transfusion-transmitted malaria in the United States is rare, and case
numbers have declined in the past few decades with improvements in the donor
history questionnaire. Reported cases are more commonly associated with immigrants
from areas in which malaria is endemic, compared with travelers born in the United
States, and Plasmodium falciparum is the most common species identified in such cases
(27). The deferral periods for malaria, based only on the donor history questionnaire,
have raised concerns for many years. Proposals have been made to implement testing
of donors for Plasmodium species, so as not to lose potential noninfected donors during
the deferral period and yet to exclude individuals who remain infectious beyond the
deferral period (27). Unfortunately, a sufficiently sensitive malarial screening test for
blood products has yet to be approved by the FDA.

July 2018 Volume 56 Issue 7 e00352-18 jcm.asm.org 3

Minireview Journal of Clinical Microbiology

Another parasite of concern for the United States blood supply is Babesia. Over 160
cases of transfusion-transmitted Babesia (mostly Babesia microti) have been docu-
mented since the 1970s, making it the most common transfusion-transmitted parasite
in the United States (25, 28). The donor history questionnaire indefinitely defers donors
who report a history of babesiosis, due to the severe and sometimes fatal disease that
can occur following infection. Because asymptomatic carriers unaware of infection pose
a threat to the blood supply, the AABB (formerly known as the American Association of
Blood Banks) recommended that the FDA expedite approval of a Babesia blood donor
screening test and that, when such a test is made available, it be applied to all red
blood cell products, especially in areas with high levels of infection, such as the
Northeast and upper Midwest (29). Indeed, in March 2018, the FDA licensed an
antibody assay as well as a NAT to detect B. microti in whole blood; official FDA
recommendations for screening of the blood supply are expected by the end of 2018.

Downloaded from http://jcm.asm.org/ on June 21, 2020 by guest

By design, the donor history questionnaire has allowed collection centers to select out
donors with low risks of carrying infectious diseases. However, the questionnaire does
not capture all infectious donors and, due to the seriousness of diseases caused by TTIs,
testing methods must be highly sensitive and specific.
As an additional safeguard beyond the donor questionnaire, postdonation testing is
utilized to detect some TTIs for which FDA-approved tests are available (e.g., HIV, HBV,
HCV, HTLV-I/HTLV-II, ZIKV, WNV, T. cruzi, and syphilis). Testing methodologies for
screening donated blood products for possible TTIs have vastly improved over the
years. Blood collection centers must use highly sensitive, FDA-approved testing meth-
ods to screen for TTIs in donated blood products before making the blood products
available for transfusion. Serological methods to detect antibodies have been the
mainstay of TTI screening tests since syphilis testing was first implemented nearly 70
years ago. FDA-approved serology tests are currently utilized to detect HBV, HCV,
HIV-1/HIV-2, HTLV-I/HTLV-II, syphilis, and T. cruzi. In general, if a donated blood product
is found to be positive for a TTI, then that product is discarded and the donor is notified
and deferred for a specified time period, depending on the TTI identified. Because
false-positive results can occur with all highly sensitive screening tests, the FDA has
established algorithms for confirmatory testing and reentry of individuals into the
donor pool, again depending on the TTI in question.
The last documented case of transfusion-transmitted syphilis was over 50 years ago.
This success is attributable to implementation of routine testing, improvements in the
donor history questionnaire to defer donors with potential exposure, poor spirochete
survival during blood product storage, and an overall decrease in the number of cases
in the U.S. population (30). Potential blood donors are screened for syphilis with both
the donor history questionnaire and serological testing of all blood donations. Individ-
uals are deferred from donating if they report, on the questionnaire, a history of syphilis
in the previous 12 months. Several FDA-approved treponemal and nontreponemal tests
are available for screening donated blood products and confirming reactive results.
Nontreponemal assays, such as the rapid plasma reagin (RPR) and the Venereal Disease
Research Laboratory (VDRL) tests, are laborious and have the potential to defer non-
infected donors due to a lack of specificity. In such cases, follow-up testing with a
treponemal assay can rule out a false-positive result or confirm the initial positive result,
with the latter resulting in a 12-month deferral (30). Treponemal tests, including
enzyme immunoassays, agglutination assays, and fluorescent antibody assays, have
better specificity and are favored by collection centers for their ability to be automated.
An initial positive result from a treponemal screening assay can be confirmed with an
alternative treponemal assay, with a second positive test result leading to deferral of
the donor for 12 months (30).
Serological testing for HTLV-I/HTLV-II has evolved since screening was first imple-
mented in the late 1980s. The first licensed serological assays were aimed at detecting
HTLV-I but incidentally detected cross-reactive anti-HTLV-II antibodies, although with
less sensitivity (31). Since those assays were unable to differentiate between the
homologous HTLV-I and HTLV-II viruses, molecular testing was necessary to distinguish

July 2018 Volume 56 Issue 7 e00352-18 jcm.asm.org 4

Minireview Journal of Clinical Microbiology

between the two for appropriate donor counseling, as the disease sequelae differ
between these viruses (8). Unfortunately, such methods were neither widely available
nor FDA approved for blood product screening. Therefore, improvements in the
detection and differentiation of HTLV-II and HTLV-I were sought. In 1997, the FDA
licensed an HTLV test with acceptable detection capabilities for both anti-HTLV-I and
anti-HTLV-II antibodies and henceforth required all blood products intended for trans-
fusion to be tested with this assay, permanently deferring donors found to be positive
for HTLV-I or HTLV-II (31).
The first FDA-licensed T. cruzi serological screening assay for blood donors became
available in 2007, followed by the 2010 FDA recommendation to screen all blood
donors once for the parasite (13). A blood product found to be positive for T. cruzi in
a screening test is removed from the blood supply, and the donor is notified and
permanently deferred from donating blood. Supplemental licensed tests are available

Downloaded from http://jcm.asm.org/ on June 21, 2020 by guest

to rule out false-positive results. If individuals are found to be negative with a supple-
mental test, then they may be eligible for reentry into the donor pool after a 6-month
period with negative results with two different screening tests, as well as a negative
result with the supplemental test (13). In addition, the donor history questionnaire asks
potential donors to report a history of Chagas disease, and those who respond yes are
permanently deferred from donating blood. In the recently revised guidance, however,
the FDA no longer recommends that this question be included, as current serological
testing is sufficient for identifying T. cruzi among blood donors (32).
Serological screening tests have proved to be useful and cost-effective tools in
helping to keep the blood supply safe. However, antibody development can take
several weeks after pathogen exposure, resulting in a so-called window period between
the time of infection and the point at which infectious donors can first be detected by
testing. Indeed, much of the residual transfusion-related transmission of HIV, HCV, and
HBV is from seronegative donors within this window period. During the 1990s, intense
focus was placed on developing assays to identify these seronegative donors and to
reduce the transmission rates of these pathogens further. NAT to detect viral DNA or
RNA showed promising results, compared to antibody testing, by reducing the window
period for HCV by 50 to 60 days and that for HIV by 11 to 15 days (33, 34). U.S. blood
collection centers introduced HIV and HCV NAT screening for all donated blood
products in 1999, with subsequent FDA approval of these testing methods in 2002. The
NAT method detects both HIV-1 and HCV RNA and has similar sensitivities when used
with individual donor samples or pools of 16 to 24 donor samples, which reduces
overall test costs (34, 35). If a pooled sample tests positive, then subsequent testing is
performed to determine the individual source of positivity. Once an individual donor tests
positive for HCV or HIV via NAT, the blood product is excluded from the blood supply and
the donor is notified and permanently deferred from donating blood products. In addition,
the collection center performs a “look back” to identify any blood donations from that
donor in the previous 12 months, removing those products from the blood supply or, if the
unit has already been transfused, notifying the recipient of possible exposure. Because
false-positive results can occur, there are specific scenarios in which donors with positive
HCV or HIV NAT results are allowed to reenter the donor pool after a designated period (8
weeks for HIV and 6 months for HCV), if repeat testing shows negative antibody results and
NAT results (34). Implementation of NAT has had a substantial effect in reducing the
transfusion transmission of HCV and HIV to estimated residual risks of 1:1.2 million and 1:1.5
million, respectively (33, 35).
Detection of HBsAg and HBcAb were the first serological tests implemented for
detection of HBV and are still used as part of the testing algorithm today. HBV NAT was
added to the HCV/HIV testing platform in 2007, and the FDA formally recommended
testing all blood products with HBV NAT in addition to HBsAg and HBcAb tests in 2012
(36, 37). Recent estimates predict a reduction in the window period for detecting HBV,
compared to antibody testing, of 8 to 20 days (38). Individuals found to be positive for
HBV are permanently deferred from donating blood. Similar to HIV and HCV NAT
algorithms, individuals with suspected false-positive HBV NAT results may be eligible

July 2018 Volume 56 Issue 7 e00352-18 jcm.asm.org 5

Minireview Journal of Clinical Microbiology

for reentry into the donor pool after a 6-month deferral period and subsequent
negative HBcAb, HBsAg, and NAT results (36). HBV NAT has reduced the transfusion
transmission to an estimated residual risk of approximately 1:1 million (38).
NAT is also used for the detection of WNV and ZIKV, as a measure to prevent
transmission during the infectious acute viremic phase. As mentioned earlier, NAT for
WNV began in 2003 and was initially performed on either individual samples or pools
of 6 to 16 donor samples. However, concerns were raised after some studies found that
testing of pooled samples was less sensitive than testing of individual samples, due to
low-level viremia in donors, leading to breakthrough cases of transfusion transmission
of WNV (15). Therefore, the FDA now recommends that blood products intended for
transfusion must undergo individual NAT during times of high WNV infectivity (39).
Blood products found to be positive for WNV are discarded, and the donor is notified
and deferred for 120 days. Additionally, a look back is performed and any products from

Downloaded from http://jcm.asm.org/ on June 21, 2020 by guest

that individual donated in the previous 120 days that are still in inventory are also
discarded (39). The FDA determined ZIKV to be a relevant TTI in 2016 and recom-
mended that all blood products intended for transfusion be screened individually with
an investigational ZIKV NAT (22). Deferral and look-back procedures for ZIKV are similar
to those for WNV, as described above. The recommendations regarding testing of
blood products for ZIKV are likely to change, as more information regarding disease
pathogenesis and new models based on pooled NAT and seasonal testing results
become available.
Another measure used to reduce transmission of infectious agents is leukoreduc-
tion, which removes leukocytes from donated cellular products (i.e., red blood cells and
platelets) via a filter or through the blood collection process (i.e., in-process leukore-
duction during apheresis collections). This procedure can reduce human leukocyte
antigen (HLA) alloimmunization, febrile nonhemolytic transfusion reactions, and trans-
fusion transmission of cytomegalovirus (CMV). The latter effect is important for pro-
tecting certain CMV-seronegative immunocompromised patients who could suffer
significant morbidity and death during CMV infection. Deferring blood donors based on
CMV status is not feasible, due to the high prevalence of CMV seropositivity in the
general population. Leukoreduced blood products are considered by most to be CMV
safe; however, large studies are lacking, making it difficult to develop formal guidelines
regarding the use of products from CMV-seronegative donors versus CMV-untested,
leukoreduced products for certain patient populations (40).
Bacterial contamination of blood products is less publicized than some of the TTIs
discussed previously, but it accounts for far more complications of blood transfusion.
The AABB and FDA have specific guidelines for preventing, detecting, and monitoring
bacterial contamination in blood products, especially platelet products. Two types of
platelet products are available in the United States, namely, whole-blood-derived
platelets and apheresis-derived platelets. Whole-blood-derived platelets can be stored
as single units or as pools of single units from 4 to 6 donors. Regardless of the platelet
type, units are all stored for up to 5 days after collection at 20°C to 24°C, an ideal
temperature for bacterial growth. In 2003, the AABB recommended multiple interven-
tions to combat bacterial contamination, including proper skin cleansing, phlebotomy
diversion kits, and implementation of bacterial culture techniques for all platelet
components collected (41). Since the implementation of routine bacterial screening, it
is estimated that 1 of 5,000 platelet units is contaminated with bacteria and septic
transfusion reactions are associated with approximately 1 of 75,000 platelet transfu-
sions (42). Although bacterial contamination is still a significant complication of blood
transfusion, advancements in testing methods and pathogen reduction therapies are
striving to improve the safety of the blood supply.

THE FUTURE OF BLOOD DONOR SCREENING AND EMERGING BLOOD SAFETY

CONCERNS
Improvements in the donor history questionnaire and testing methodologies to
screen blood donors have proved to be successful. Unfortunately, residual transmission

July 2018 Volume 56 Issue 7 e00352-18 jcm.asm.org 6

Minireview Journal of Clinical Microbiology

of infectious agents still occurs, and current strategies do not protect the blood supply
from new emerging pathogens. Therefore, a great deal of effort has been focused on
developing an effective proactive approach that can be applied to all blood products,
in hopes of reducing TTIs while minimizing the technical and financial burdens of
screening individual blood donors. These methods, known as pathogen inactivation (PI)
(43), have been used to reduce the transmission of pathogens in manufactured plasma
derivatives (e.g., albumin and immunoglobulins) since the 1980s. Myriad techniques,
including pasteurization, solvent-detergent treatments, low-pH incubation, and nano-
filtration, have been used successfully to inactivate pathogens in plasma derivatives
(44). These and other PI methods are widely used in Europe to treat platelet and plasma
products intended for transfusion (45). However, the use of such methods to treat
blood products in the United States has lagged in gaining FDA approval, pending large
studies demonstrating an acceptable safety profile. Indeed, only recently were two PI

Downloaded from http://jcm.asm.org/ on June 21, 2020 by guest

methods approved for such use in the United States. In 2013, the FDA approved a
solvent-detergent method, which inactivates enveloped viruses by disrupting the lipid
membrane but is ineffective against nonenveloped viruses, for use on plasma products
intended for transfusion. Newer PI methods include using chemical compounds to
cross-link DNA or RNA, preventing replication of infectious agents. In 2014, a psoralen/
UV-irradiation-based method was licensed by the FDA for treatment of plasma and
apheresis platelet products intended for transfusion (46). PI methods using other
compounds are currently being investigated for effectiveness and safety for the treat-
ment of plasma, platelets, and red blood cells. Implementing such treatments may
reduce the rates of residual TTIs and can potentially protect the blood supply from new
emerging infections.
The HIV/AIDS epidemic of the 1980s first demonstrated the vulnerability of the
blood supply to emerging pathogens. Since then, the AABB Transfusion Transmitted
Diseases Committee continuously monitors and assesses the dangers of emerging
unknown pathogens, as well as the geographical expansion of known pathogens. The
combined efforts of this committee and the research community have allowed expe-
ditious identification of emerging infectious diseases and implementation of screening
methods to detect such pathogens. The response to the ZIKV outbreak of 2016
exemplifies the concerted efforts of these groups and their exceptional effects in
protecting the blood supply. Since its inception, the AABB committee has published
over 60 fact sheets on emerging infectious disease agents; it currently considers vCJD,
dengue viruses, chikungunya virus, hepatitis E virus (HEV), and Babesia species as high
priorities for increased monitoring in the U.S. blood supply (47, 48). With a multitude of
infectious diseases and the increasing ease of human travel, concentrated efforts and
a streamlined approach to detect and to eliminate pathogens from the U.S. blood
supply are paramount.

SUMMARY
In this minireview, we have described the history of blood supply testing for
infectious diseases, changes in predonation and postdonation testing aimed at reduc-
ing TTIs, and current investigations and developments to improve the identification
and removal of infected donated blood components. PI shows great potential in
reducing the transmission of pathogens in donated blood components; it would allow
effective removal of infectious agents missed by current means of detection, as well as
emerging infectious disease agents that are not currently tested for directly. This
technology, along with AABB recommendations, is guiding the search for superior
standards and methods to further reduce TTIs, thereby improving the safety of donated
blood components and, in turn, patient care.

ACKNOWLEDGMENT
We have no conflicts of interest to disclose.

July 2018 Volume 56 Issue 7 e00352-18 jcm.asm.org 7

Minireview
REFERENCES
1. Code of Federal Regulations. 2017. Title 21 (Food and Drugs). Parts 610
(General biological products standards) and 630 (Requirements for
blood and blood components intended for transfusion or for further
manufacturing use). U.S. Government Printing Office, Washington,
DC. https://www.ecfr.gov/cgi-bin/text-idx?SID⫽c5d21c85
fde27aa575d5a50814d915e6&mc⫽true&tpl⫽/ecfrbrowse/Title21/
21cfrv7_02.tpl#0.
2. Walsh JH, Purcell RH, Morrow AG, Chanock RM, Schmidt PJ. 1970.
Posttransfusion hepatitis after open-heart operations: incidence after
the administration of blood from commercial and volunteer donor
populations. JAMA 211:261–265. https://doi.org/10.1001/jama.1970
.03170020025005.
3. Alter HJ, Holland PV, Purcell RH, Lander JJ, Feinstone SM, Morrow AG,
Schmidt PJ. 1972. Posttransfusion hepatitis after exclusion of commer-
cial and hepatitis-B antigen-positive donors. Ann Intern Med 77:
691– 699. https://doi.org/10.7326/0003-4819-77-5-691.
4. Koziol DE, Holland PV, Alling DW, Melpolder JC, Solomon RE, Purcell RH,
Hudson LM, Shoup FJ, Krakauer H, Alter HJ. 1986. Antibody to hepatitis
B core antigen as a paradoxical marker for non-A, non-B hepatitis agents
in donated blood. Ann Intern Med 104:488 – 495. https://doi.org/10
.7326/0003-4819-104-4-488.
5. Alter HJ, Purcell RH, Holland PV, Alling DW, Koziol DE. 1981. Donor transam-
inase and recipient hepatitis: impact on blood transfusion services. JAMA
246:630–634. https://doi.org/10.1001/jama.1981.03320060032017.
6. Peterman TA, Lui KJ, Lawrence DN, Allen JR. 1987. Estimating the risks of
transfusion-associated acquired immune deficiency syndrome and hu-
man immunodeficiency virus infection. Transfusion 27:371–374. https://
doi.org/10.1046/j.1537-2995.1987.27587320525.x.
7. Alter HJ, Klein HG. 2008. The hazards of blood transfusion in historical
perspective. Blood 112:2617–2626. https://doi.org/10.1182/blood-2008
-07-077370.
8. Centers for Disease Control and Prevention, U.S.P.H.S. Working Group. 1993.
Guidelines for counseling persons infected with human T-lymphotropic
virus type I (HTLV-I) and type II (HTLV-II). Ann Intern Med 118:448–454.
https://doi.org/10.7326/0003-4819-118-6-199303150-00009.
9. Murphy EL. 1996. The clinical epidemiology of human T-lymphotropic virus
type II (HTLV-II). J Acquir Immune Defic Syndr Hum Retrovirol 13(Suppl
1):S215–S219. https://doi.org/10.1097/00042560-199600001-00032.
10. Sullivan MT, Williams AE, Fang CT, Grandinetti T, Poiesz BJ, Ehrlich GD.
1991. Transmission of human T-lymphotropic virus types I and II by
blood transfusion: a retrospective study of recipients of blood compo-
nents (1983 through 1988). Arch Intern Med 151:2043–2048. https://doi
.org/10.1001/archinte.1991.00400100115019.
11. Manne-Goehler J, Umeh CA, Montgomery SP, Wirtz VJ. 2016. Estimating
the burden of Chagas disease in the United States. PLoS Negl Trop Dis
10:e0005033. https://doi.org/10.1371/journal.pntd.0005033.
12. Cantey PT, Stramer SL, Townsend RL, Kamel H, Ofafa K, Todd CW, Currier
M, Hand S, Varnado W, Dotson E, Hall C, Jett PL, Montgomery SP. 2012.
The United States Trypanosoma cruzi Infection Study: evidence for
vector-borne transmission of the parasite that causes Chagas disease
among United States blood donors. Transfusion 52:1922–1930. https://
doi.org/10.1111/j.1537-2995.2012.03581.x.
13. Food and Drug Administration. 2017. Guidance for industry: use of
serological tests to reduce the risk of transmission of Trypanosoma cruzi
infection in blood and blood components. CBER Office of Communica-
tion, Outreach, and Development, Silver Spring, MD. https://www.fda
.gov/downloads/BiologicsBloodVaccines/GuidanceCompliance
RegulatoryInformation/Guidances/Blood/UCM528600.pdf.
14. Pealer LN, Marfin AA, Petersen LR, Lanciotti RS, Page PL, Stramer SL,
Stobierski MG, Signs K, Newman B, Kapoor H, Goodman JL, Chamberland
ME. 2003. Transmission of West Nile virus through blood transfusion in
the United States in 2002. N Engl J Med 349:1236 –1245. https://doi.org/
10.1056/NEJMoa030969.
15. Dodd RY, Foster GA, Stramer SL. 2015. Keeping blood transfusion safe
from West Nile virus: American Red Cross experience, 2003 to 2012.
Transfus Med Rev 29:153–161. https://doi.org/10.1016/j.tmrv.2015.03
.001.
16. Galel SA, Williamson PC, Busch MP, Stanek D, Bakkour S, Stone M, Lu K,
Jones S, Rossmann SN, Pate LL. 2017. First Zika-positive donations in the
continental United States. Transfusion 57:762–769. https://doi.org/10
.1111/trf.14029.
July 2018 Volume 56 Issue 7 e00352-18
Journal of Clinical Microbiology
17. Cao-Lormeau VM, Blake A, Mons S, Lastere S, Roche C, Vanhomwegen J,
Dub T, Baudouin L, Teissier A, Larre P, Vial AL, Decam C, Choumet V,
Halstead SK, Willison HJ, Musset L, Manuguerra JC, Despres P, Fournier
E, Mallet HP, Musso D, Fontanet A, Neil J, Ghawche F. 2016. Guillain-Barre
syndrome outbreak associated with Zika virus infection in French
Polynesia: a case-control study. Lancet 387:1531–1539. https://doi.org/
10.1016/S0140-6736(16)00562-6.
18. Lanteri MC, Kleinman SH, Glynn SA, Musso D, Hoots WK, Custer BS,
Sabino EC, Busch MP. 2016. Zika virus: a new threat to the safety of the
blood supply with worldwide impact and implications. Transfusion 56:
1907–1914. https://doi.org/10.1111/trf.13677.
19. Martines RB, Bhatnagar J, de Oliveira Ramos AM, Davi HP, Iglezias SD,
Kanamura CT, Keating MK, Hale G, Silva-Flannery L, Muehlenbachs A,
Ritter J, Gary J, Rollin D, Goldsmith CS, Reagan-Steiner S, Ermias Y, Suzuki
Downloaded from http://jcm.asm.org/ on June 21, 2020 by guest
T, Luz KG, de Oliveira WK, Lanciotti R, Lambert A, Shieh WJ, Zaki SR. 2016.
Pathology of congenital Zika syndrome in Brazil: a case series. Lancet
388:898 –904. https://doi.org/10.1016/S0140-6736(16)30883-2.
20. Kuehnert MJ, Basavaraju SV, Moseley RR, Pate LL, Galel SA, Williamson
PC, Busch MP, Alsina JO, Climent-Peris C, Marks PW, Epstein JS, Nakhasi
HL, Hobson JP, Leiby DA, Akolkar PN, Petersen LR, Rivera-Garcia B. 2016.
Screening of blood donations for Zika virus infection: Puerto Rico, April
3–June 11, 2016. MMWR Morb Mortal Wkly Rep 65:627– 628. https://doi
.org/10.15585/mmwr.mm6524e2.
21. Meaney-Delman D, Oduyebo T, Polen KN, White JL, Bingham AM, Slavin-
ski SA, Heberlein-Larson L, St George K, Rakeman JL, Hills S, Olson CK,
Adamski A, Culver Barlow L, Lee EH, Likos AM, Munoz JL, Petersen EE,
Dufort EM, Dean AB, Cortese MM, Santiago GA, Bhatnagar J, Powers AM,
Zaki S, Petersen LR, Jamieson DJ, Honein MA. 2016. Prolonged detection
of Zika virus RNA in pregnant women. Obstet Gynecol 128:724 –730.
https://doi.org/10.1097/AOG.0000000000001625.
22. Food and Drug Administration. 2016. Guidance for industry: revised
recommendations for reducing the risk of Zika virus transmission by
blood and blood components. CBER Office of Communication, Outreach,
and Development, Silver Spring, MD. https://www.fda.gov/downloads/
BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/
Guidances/Blood/UCM518213.pdf.
23. Food and Drug Administration. 2014. Guidance for industry: recommen-
dations for donor questioning, deferral, reentry and product manage-
ment to reduce the risk of transfusion-transmitted malaria. CBER Office
of Communication, Outreach, and Development, Silver Spring, MD.
https://www.fda.gov/downloads/BiologicsBloodVaccines/Guidance
ComplianceRegulatoryInformation/Guidances/Blood/UCM080784.pdf.
24. Food and Drug Administration. 2017. Draft guidance for industry: amend-
ment to “Revised preventive measures to reduce the possible risk of trans-
mission of Creutzfeldt-Jakob Disease and variant Creutzfeldt-Jakob disease
by blood and blood products; guidance for industry”. CBER Office of Com-
munication, Outreach, and Development, Silver Spring, MD. https://www
.fda.gov/downloads/BiologicsBloodVaccines/GuidanceCompliance
RegulatoryInformation/Guidances/Blood/UCM590051.pdf.
25. Moritz ED, Winton CS, Tonnetti L, Townsend RL, Berardi VP, Hewins ME,
Weeks KE, Dodd RY, Stramer SL. 2016. Screening for Babesia microti in
the U.S. blood supply. N Engl J Med 375:2236 –2245. https://doi.org/10
.1056/NEJMoa1600897.
26. Crowder LA, Schonberger LB, Dodd RY, Steele WR. 2017. Creutzfeldt-
Jakob disease lookback study: 21 years of surveillance for transfusion
transmission risk. Transfusion 57:1875–1878. https://doi.org/10.1111/trf
.14145.
27. Mungai M, Tegtmeier G, Chamberland M, Parise M. 2001. Transfusion-
transmitted malaria in the United States from 1963 through 1999. N Engl
J Med 344:1973–1978. https://doi.org/10.1056/NEJM200106283442603.
28. Tonnetti L, Laughhunn A, Thorp AM, Vasilyeva I, Dupuis K, Stassinopou-
los A, Stramer SL. 2017. Inactivation of Babesia microti in red blood cells
and platelet concentrates. Transfusion 57:2404 –2412. https://doi.org/10
.1111/trf.14280.
29. Carr-Greer MA. 13 May 2015. AABB statement to the Food and Drug
Administration’s Blood Products Advisory Committee: statement be-
fore BPAC on strategies for implementation of testing for Babesia
microti in blood donors. http://www.aabb.org/advocacy/statements/
Pages/statement150513.aspx.
30. Food and Drug Administration. 2014. Guidance for industry: recom-
mendations for screening, testing, and management of blood donors
jcm.asm.org 8
Minireview
and blood and blood components based on screening tests for
syphilis. CBER Office of Communication, Outreach, and Development,
Silver Spring, MD. https://www.fda.gov/downloads/BiologicsBlood
Vaccines/GuidanceComplianceRegulatoryInformation/Guidances/
UCM340993.pdf.
31. Food and Drug Administration. 1997. Guidance for industry: donor
screening for antibodies to HTLV-II. CBER Office of Communication,
Outreach, and Development, Silver Spring, MD. https://www.fda.gov/
downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatory
Information/Guidances/Blood/UCM170916.pdf.
32. Steele WR, Hewitt EH, Kaldun AM, Krysztof DE, Dodd RY, Stramer SL. 2014.
Donors deferred for self-reported Chagas disease history: does it reduce
risk? Transfusion 54:2092–2097. https://doi.org/10.1111/trf.12590.
33. Zou S, Dorsey KA, Notari EP, Foster GA, Krysztof DE, Musavi F, Dodd RY,
Stramer SL. 2010. Prevalence, incidence, and residual risk of human immu-
nodeficiency virus and hepatitis C virus infections among United States
blood donors since the introduction of nucleic acid testing. Transfusion
50:1495–1504. https://doi.org/10.1111/j.1537-2995.2010.02622.x.
34. Food and Drug Administration. 2017. Guidance for industry: nucleic
acid testing (NAT) for human immunodeficiency virus type 1 (HIV-1)
and hepatitis C virus (HCV): testing, product disposition, and donor
deferral and reentry. CBER Office of Communication, Outreach, and
Development, Silver Spring, MD. https://www.fda.gov/downloads/
BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/
Guidances/Blood/UCM210270.pdf.
35. Stramer SL, Glynn SA, Kleinman SH, Strong DM, Caglioti S, Wright DJ,
Dodd RY, Busch MP. 2004. Detection of HIV-1 and HCV infections among
antibody-negative blood donors by nucleic acid-amplification testing. N
Engl J Med 351:760 –768. https://doi.org/10.1056/NEJMoa040085.
36. Food and Drug Administration. 2012. Final guidance for industry: use of
nucleic acid tests on pooled and individual samples from donors of
whole blood and blood components, including source plasma, to reduce
the risk of transmission of hepatitis B virus. CBER Office of Communica-
tion, Outreach, and Development, Silver Spring, MD. https://www.fda
.gov/downloads/BiologicsBloodVaccines/GuidanceCompliance
RegulatoryInformation/Guidances/Blood/UCM327895.pdf.
37. Stramer SL, Wend U, Candotti D, Foster GA, Hollinger FB, Dodd RY, Allain JP,
Gerlich W. 2011. Nucleic acid testing to detect HBV infection in blood
donors. N Engl J Med 364:236–247. https://doi.org/10.1056/NEJMoa1007644.
38. Stramer SL, Notari EP, Krysztof DE, Dodd RY. 2013. Hepatitis B virus
July 2018 Volume 56 Issue 7 e00352-18
Journal of Clinical Microbiology
testing by minipool nucleic acid testing: does it improve blood safety?
Transfusion 53:2449 –2458. https://doi.org/10.1111/trf.12213.
39. Food and Drug Administration. 2009. Guidance for industry: use of nucleic
acid tests to reduce the risk of transmission of West Nile virus from donors
of whole blood and blood components intended for transfusion. CBER
Office of Communication, Outreach, and Development, Silver Spring, MD.
https://www.fda.gov/downloads/BiologicsBloodVaccines/Guidance
ComplianceRegulatoryInformation/Guidances/Blood/UCM189464.pdf.
40. Heddle NM, Boeckh M, Grossman B, Jacobson J, Kleinman S, Tobian
AA, Webert K, Wong EC, Roback JD. 2016. AABB committee report:
reducing transfusion-transmitted cytomegalovirus infections. Trans-
fusion 56:1581–1587. https://doi.org/10.1111/trf.13503.
41. AABB. 2018. Standards 5.1.5 and 5.6.2. In Standards for blood banks and
transfusion services, 31st ed. AABB, Bethesda, MD.
42. Eder AF, Kennedy JM, Dy BA, Notari EP, Weiss JW, Fang CT, Wagner S,
Dodd RY, Benjamin RJ. 2007. Bacterial screening of apheresis platelets
and the residual risk of septic transfusion reactions: the American Red
Downloaded from http://jcm.asm.org/ on June 21, 2020 by guest
Cross experience (2004 –2006). Transfusion 47:1134 –1142. https://doi
.org/10.1111/j.1537-2995.2007.01248.x.
43. Lozano M, Cid J, Prowse C, McCullough J, Klein HG, Aubuchon JP. 2015.
Pathogen inactivation or pathogen reduction: proposal for standardiza-
tion of nomenclature. Transfusion 55:690. https://doi.org/10.1111/trf
.12996.
44. Burnouf T. 2007. Modern plasma fractionation. Transfus Med Rev 21:
101–117. https://doi.org/10.1016/j.tmrv.2006.11.001.
45. Snyder EL, Stramer SL, Benjamin RJ. 2015. The safety of the blood supply:
time to raise the bar. N Engl J Med 373:882. https://doi.org/10.1056/
NEJMc1507761.
46. Food and Drug Administration. 2016. Draft guidance for industry: bacterial
risk control strategies for blood collection establishments and transfusion
services to enhance the safety and availability of platelets for transfusion.
CBER Office of Communication, Outreach, and Development, Silver Spring,
MD. https://www.fda.gov/downloads/BiologicsBloodVaccines/Guidance
ComplianceRegulatoryInformation/Guidances/Blood/UCM425952.pdf.
47. Stramer SL, Hollinger FB, Katz LM, Kleinman S, Metzel PS, Gregory KR,
Dodd RY. 2009. Emerging infectious disease agents and their potential
threat to transfusion safety. Transfusion 49(Suppl 2):1S–29S. https://doi
.org/10.1111/j.1537-2995.2009.02279.x.
48. Stramer SL. 2014. Current perspectives in transfusion-transmitted infec-
tious diseases: emerging and re-emerging infections. ISBT Sci Ser
9:30 –36. https://doi.org/10.1111/voxs.12070.
jcm.asm.org 9