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Infectious Disorders - Drug Targets 2011, 11, 45-56
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Approaches to Minimize Infection Risk in Blood Banking and Transfusion
Practice
Paul F. Lindholm*, Kyle Annen and Glenn Ramsey
Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA
Abstract: The use of blood donor history and state-of-the-art FDA-licensed serological and nucleic acid testing (NAT)
assays have greatly reduced the “infectious window” for several transfusion-transmitted pathogens. Currently transmission of human immunodeficiency virus (HIV), Human T-cell Lymphotropic Virus (HTLV), hepatitis viruses and West
Nile Virus are rare events. The seroprevalence of cytomegalovirus in the donor population is high and cytomegalovirus
infection can cause significant complications for immunocompromised recipients of blood transfusion. Careful use of
CMV seronegative blood resources and leukoreduction of blood products are able to prevent most CMV infections in
these patients. Currently, bacterial contamination of platelet concentrates is the greatest remaining infectious disease risk
in blood transfusion. Specialized donor collection procedures reduce the risk of bacterial contamination of blood products;
blood culture and surrogate testing procedures are used to detect potential bacterially contaminated platelet products prior
to transfusion. A rapid quantitative immunoassay is now available to test for the presence of lipotechoic acid and
lipopolysaccharide bacterial products prior to platelet transfusion. Attention has now turned to emerging infectious diseases including variant Creutzfeldt-Jakob disease, dengue, babesiosis, Chagas’ disease and malaria. Challenges are presented to identify and prevent transmission of these agents. Several methods are being used or in development to reduce
infectivity of blood products, including solvent-detergent processing of plasma and nucleic acid cross-linking via photochemical reactions with methylene blue, riboflavin, psoralen and alkylating agents. Several opportunities exist to further
improve blood safety through advances in infectious disease screening and pathogen inactivation methods.
Keywords: Transfusion, infection risk, bacterial contamination, sepsis, screening, emerging infectious agents, pathogen inactivation, leukocytes.
INTRODUCTION
A quarter-century ago in 1985, blood banks began to
emerge from the crisis of human immunodeficiency virus
(HIV), not only with the first donor test for anti-HIV but also
with a new commitment to vigilance. After many more layers of research, screening tests and regulatory requirements,
blood transfusions are safer than ever, and the 1980’s transfusion anxiety in patients and health-care professionals has
greatly subsided. But behind the scenes, blood banks continue to respond to infection risks old and new. Our goal in
this review is to provide a succinct answer for the clinician
seeking information on the current status and future direction
of transfusion-transmitted disease prevention.
First, we summarize the current preventive measures and
residual risks from recognized bloodborne viral agents such
as hepatitis, HIV, human T-cell lymphotropic virus (HTLV),
cytomegalovirus (CMV), and West Nile virus (WNV). Secondly, we discuss the less well-known risk of bacterial sepsis
from transfusions, and the safety initiatives blood banks are
adopting against this threat. Thirdly, we anticipate the
emerging infectious agents of most concern to blood banking
experts. Finally, we present an update on technologies under
development for the inactivation of pathogens, known and
unknown, in tomorrow’s blood components.
*Address correspondence to this author at the Department of Pathology,
Northwestern University, Feinberg School of Medicine, 303 East Chicago
Avenue, Chicago, IL 60611; Tel: (312) 926-8483; Fax: (312) 503-8249;
E-mail: [email protected]
1871-5265/11 $58.00+.00
VIRAL PATHOGENS TRANSMITTED BY BLOOD
TRANSFUSION
The long asymptomatic periods of persons infected with
viral pathogens and their proven effectiveness at being
transmitted through blood products has made the need for
state-of-the art testing and effective donor-screening methods a necessity. The sensitivity of available screening methods is limited by the “window-period”, in which a donor has
become infected but the viral load is too low to be detected.
This remains the primary risk for possible transmission [1].
The predicted infection risk is calculated based on correlations between test sensitivities, length of window periods
and prevalence within the local population; this is referred to
as mathematical modeling [2].
Nucleic acid testing (NAT) licensed by the U.S. Food
and Drug Administration (FDA) for blood donor screening is
utilized to detect ribonucleic acid (RNA) of hepatitis C virus
(HCV), HIV, and WNV. Further the donor samples must be
nonreactive for hepatitis B virus (HBV) surface antigen
(HBsAg) and antibodies to HBV core antigen (anti-HBc),
HIV-1 and -2, HTLV types I and II, and HCV [3].
HIV-1 and -2: Estimated Risk of Transmission is
1:2,300,000 [4]
The HIV/AIDS epidemic and its transmissibility through
blood transfusion raised concern for the safety of the United
States blood supply in the early 1980’s. Serologic screening
was implemented in 1985, leading to a precipitous decline in
© 2011 Bentham Science Publishers Ltd.
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Lindholm et al.
transfusion-transmitted infection [5]. Combining serologic
testing with stringent donor screening for high-risk behavior
and residence or travel in endemic areas has made our blood
supply one of the safest in the world.
HIV-1 is found worldwide, and is the most common
strain in the United States. There is a varying distribution of
subtypes: HIV-2 is found predominantly in West Africa,
with some incidence in Europe. The window period for HIV1 NAT testing is 7-10 days. Emerging strains which may
pose a future threat include the African O and N types as
well as type M Asian recombinant mosaics [1]. In response
to these threats, NAT testing for new strains is under development, and donor screening criteria is adjusted to exclude
donors from high-risk areas, such as Cameroon and its
neighbors. An EIA test was approved for HIV group O testing in August of 2003. Donor centers which utilize this test
method may elect to accept donors from Group O endemic
regions [6].
Hepatitis B: Estimated Risk of Transmission is 1:280,000
to 1:352,000 [4]
Transfusion associated hepatitis (TAH) was first reported
in 1943 [7]. Since then, Hepatitis B and C have been discovered, and implementation of an all-volunteer blood donation
system in the US combined with sensitive screening tests
have reduced the risk of transmission to a level which can
only be estimated by a mathematical model [8, 9].
Hepatitis B remains the greatest risk of the “classical”
transfusion-transmitted viruses. The majority of infections
are asymptomatic, although roughly 20% develop fulminant
hepatitis. Approximately 5% of infected adults will become
chronic carriers, with the incidence much higher in children.
The prolonged window period of the virus, with reports of
up to 150 days, accounts for the higher risk of transmission
with transfusion [10]. The American Red Cross estimates the
average window period at 38 days. Implementation of NAT
for HBV has decreased the window period by 5-8 days, resulting in a new calculated risk of 1:352,000. Because current practices of pooled testing varies between blood centers,
and HBV NAT is not required by the FDA, the window period for HBV averages 38-43 days [11]. As routine HBV
vaccination of children in the US increases our herd immunity, and we develop increasingly effective testing, eradicating the risk of transfusion-transmitted HBV may be a possibility.
Hepatitis C: Estimated
1:1,800,000 [4]
Risk
of
Transmission
is
HCV is a parenterally transmitted virus, with 80% of
infected individuals developing a chronic carrier state. The
majority of infections are asymptomatic, with elevated liver
enzymes and nonspecific symptoms presenting in 20-30% of
cases. Lifelong carrier infections can lead to the late presentation of cirrhosis and an increased risk of hepatic malignancy [4]. The window period for NAT testing is 7-10 days,
similar to that of HIV-1, and far shorter than that of HBV,
thus accounting for the lower transmission risk.
Hepatitis D: Risk Unknown: Presumed to be Rare
Hepatitis D (HDV), or delta virus, is a defective RNA
virus which requires the presence of HBsAg for its surface
coat. The main risk in relation to transfusion is the theoretical transmission of occult HDV to a HBV-positive patient.
Since the virus cannot be transmitted without co-infection by
HBV, this event should be prevented by the routine screening for HbsAg and anti-HBc [9].
Hepatitis A and E: Risk Unknown: Presumed to be Rare
Hepatitis A (HAV) and E (HEV) are primarily transmitted via fecal-oral route, with an incubation of 28 days, and
peak viral load two weeks prior to the onset of symptoms.
While parenteral transmission is well-documented, the actual
risk is unknown. Reported cases have usually been traced
back to a recently infected individual. Transmission of HEV
is extremely rare and limited to several recent case reports
[4].
HTLV-I and –II: Estimated Risk of Transmission is
1:2,993,000 [4]
HTLV is not well understood. HTLV-I infection is asymptomatic: however, it confers the increased risk of T-cell
leukemia/lymphoma, neurologic and immunologic disease.
HTLV-II infection is only known to be associated with an
increase in common illnesses, which suggests an immunosuppressive effect. The transmission of HTLV-I disease with
an infected product has been reported to be 10-30%, although there have been no reports of transmission through
acellular products [4]. HTLV is cell-associated, making the
use of leukocyte-reduced products, in addition to viral
screening, a method of risk reduction.
HHV-8: No Reported Cases in the US
Human Herpes Virus 8 (HHV-8) infection is associated
with Kaposi’s sarcoma and Castleman’s disease in immunosuppressed hosts, particularly those co-infected with HIV. A
gamma-herpes virus, it has tropism to monocyte-macrophages and lymphocytes. Cases of transmission via transfusion have not been reported in the United States; it is therefore considered extremely low risk, although transmission
via kidney transplant has been reported. In Sub-Saharan Africa, where seroprevalence is estimated at 40%, and transfusion of non-leukocyte reduced, fresh whole blood is common
practice, transfusion-transmitted infections have been reported [12].
Cytomegalovirus: Common
CMV is a transfusion-transmissible pathogen which can
cause significant complications in immunocompromised
recipients. CMV infection in the immunocompetent host
results in a chronic carrier state, with latent virus residing in
the donor’s leukocytes. This infection is common in the US
with seroprevalence in the donor population of 50-80%. Because of this high prevalence, the deferral of all CMVpositive donors would severely limit the available blood
supply [4]. There are currently two methods which can be
Approaches to Minimize Infection Risk in Blood Banking and Transfusion Practice
utilized to decrease the risk of transmission to those at risk
for significant disease: leukoreduction and CMV-seronegative donors. The indicated populations for use of either of
these methods include premature infants, the fetus of pregnant women, transplant recipients, HIV infected individuals
and oncology patients who may be undergoing immunosuppressive therapy [1].
The preference among Transfusion Medicine specialists
has varied over the years. First, by using blood donors who
tested seronegative for CMV, then washing packed red blood
cells (PRBC) to reduce the number of leukocytes present,
and finally to utilizing leukocyte-reduction filters, which
have now become effective enough to reduce the leukocytes
in each dose to less than 5x106. The effectiveness of both
seronegative donors and leukoreduction has been observed
closely, and are currently considered to be equivalent for the
prevention of CMV transmission. It would make intuitive
sense that the application of both of these methods would
provide the highest level of protection, but studies have
failed to demonstrate benefit [13]. It is important to note that
only the use of leukoreduction filters during the initial preparation of the product, and not bedside filters, has been shown
to be consistently effective.
To complicate the issue, Ziemann et al. found that donors
who were CMV seropositive for 1 year or longer were unlikely to have measurable plasma CMV DNA, while 44% of
donors who had recently seroconverted, and 3% of donors in
the seronegative window period had measurable plasma
DNA. These findings suggest that seropositive donors who
converted more than one year prior may have the lowest risk
for transmission of CMV [14]. The results of this study are
not yet being utilized in current practice.
Some transfusionists prefer to take a “belt and suspenders” approach by giving both CMV-seronegative and leukoreduced blood to those at the highest risk: premature infants,
fetuses requiring intrauterine transfusion and pregnant
women. The benefit of this approach has not been proven
[6].
West Nile Virus: Uncommon, Risk Varies by Season and
Location
WNV causes a self-limiting febrile illness in 20% of immunocompetent hosts. While only 0.7% of these individuals
will develop a meningoencephalitis, immunocompromised
individuals develop this complication in 40% of infections.
WNV emerged in the US in 1999, with the first human infection described in New York City. It has now spread across
the US and into Canada, Mexico and both Central and South
America. WNV reached its peak in the US in 2002-2003,
with 23 transfusion-transmitted cases reported [15]. The virus replicates in mosquito and avian species. While 18
mammalian species have been documented as contracting the
illness, they represent a dead-end host. The only known human-to-human transmission of WNV has been through transfusion and organ transplant. Blood donor screening was initiated in 2003, with mini-pool nucleic acid testing. During
times of high WNV activity, typically from late spring to
early fall, conversion from NAT mini-pool to individual unit
screening is performed so as to reduce the false negative rate
from low viral load donors.
Infectious Disorders - Drug Targets 2011, Vol. 11, No. 1
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Epstein-Barr Virus: Rare, Limited to Case Reports
Epstein-Barr Virus (EBV) is rarely transmitted via transfusion. Also known as Human Herpes Virus-4, it is the
causative agent of infectious mononucleosis and has been
associated with Burkitt’s lymphoma, in addition to other
lymphoproliferative disorders. The seroprevalence in the US
is >90%. Infectious mononucleosis has been reported in association with solid-organ transplant recipients, while aggressive lymphoproliferative disorders have only been identified in cord-blood stem-cell recipients with weakened immune systems [4]. EBV is transmitted via B-lymphocytes;
leukoreduction could presumably decrease the incidence of
transmission, however this has not yet been proven in clinical trials.
BACTERIAL INFECTION AND SEPSIS RESULTING
FROM BLOOD TRANSFUSION
Bacterial Contamination of RBC Units and Septic Transfusions
Sepsis associated with transfusion of a bacterially contaminated RBC unit is a very rare event; however, when it
has occurred, it is most often associated with proliferation of
Gram-negative bacilli. The bacteria are likely present within
the bloodstream of an asymptomatic donor at the time of
collection. The prevalence of clinically significant sepsis
outcomes is estimated to be approximately 1 per million
RBC units by the Centers for Disease Control and Prevention (CDC) [16]. Yersina enterocolitica and Serratia
marcescans contaminants have been most often associated
with symptomatic transfusion-associated sepsis.
In New Zealand, the symptomatic Yersina contamination
rate was reported as 1 in 65,000 with a 1 in 104,000 fatality
rate [17]. When cultures of RBC units and recipients with
febrile transfusion reactions were performed at the Dana
Farber Cancer Institute, the contamination rate was 1 in
38,465 units transfused [18, 19]. The incidence of transfusion associated sepsis varies between reports which may be
due to differences in recognition, reporting and regional
variation [20]. Sepsis associated with transfusion of a contaminated RBC unit is associated with high fever, rigors and
hypotension beginning during or shortly after the transfusion. If bacterial contamination is suspected, the transfusion
should be halted immediately and Gram’s stain and blood
culture obtained from both the blood bag and the recipient.
Autologous RBC units are considered to be a safe blood
component with respect to infectious disease risk. There are
six reported cases of bacterial sepsis associated with use of
autologous RBC units including 5 cases with Yersina enterocolitica and one from Serratia liquifaciens [21-24], though
all but one was published over 15 years ago. Retrospectively,
the patients infected by Yersinia had gastrointestinal symptoms near the time of donation. In one case, a patient’s infected toe ulcer may have been the source of Serratia contamination of a RBC unit [25]. These autologous donors who
developed transfusion-associated sepsis fortunately survived.
The rate of fatal transfusion-transmitted bacteremia has
been estimated to be 0.13 per million units transfused in the
US [16]. Twenty-five transfusion-associated fatalities from
whole blood or RBC thought to be due to bacterial contami-
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nation were reported to the FDA from 1995 to 2004 [26].
Gram negative bacteria accounted for 80% of these cases
with Staphylococcus aureus and S. epidermidis for 20% of
the cases. The most common microorganisms reported were
Klebsiella, spp., Serratia spp., Escherichia coli, Pseudomonas spp. and Yersinia enterocolitica [26]. Septic transfusions associated with infusion of bacterial endotoxin may
lead to shock, oliguria, consumptive coagulopathy and high
host cytokine levels [27, 28]. The mortality rate associated
with transfusion of a contaminated RBC unit is greater than
60 percent; death occurs rapidly with a median of 25 hours
from the time of transfusion [29].
The refrigerated storage of RBC units plays an important
role in limiting bacterial proliferation. Prospective studies
have shown a very high incidence of bacterial contamination
with the Staphylococcus and Propionibacterium organisms
in 2 to 4 per 1000 RBC units [20]. These microorganisms
generally proliferate poorly at 1 to 6 degrees Celsius. However, psychrophilic, Gram-negative organisms such as
Yersinia enterocolitica, especially strain O:3, remain viable
and replicate in iron-rich RBC storage conditions [30]. Other
bacteria reported to contaminate RBC include Serratia spp.,
Pseudomonas spp., Enterobacter spp., Campylobacter spp.,
and Escherichia coli any of which can cause endotoxic
shock [30]. Yersinia enterocolitica may be acquired by donor ingestion of contaminated foods and infection may cause
abdominal pain and diarrhea or may be asymptomatic [29,
31]. The organisms are presumably introduced into the donated RBC unit collected during transient donor bacteremia
during a recent infection. A donor history of recent gastrointestinal illness, dental or genitourinary procedures may be
associated with bacteremia and may lead to a decision of
donor deferral. Unfortunately, the donor history is not a very
sensitive or specific indicator of bacteremia or product contamination.
Many reported RBC-associated Yersinia sepsis events
have occurred when the donor units were stored greater than
3 weeks [32]. Experimental spiking studies indicate that
Yersinia grows in the contaminated RBC unit after a lag
phase of approximately 2 weeks, and may grow exponentially to reach very high concentrations [32]. The Blood
Products Advisory Committee of the FDA considered reducing the storage time to reduce the risk of transfusing Yersinia
contaminated RBC units [20]. However, concern over compromise of the nation’s blood supply and logistical problems
of replacing shorter outdate RBC units caused this recommendation to be rejected.
Bacterial Contamination of Platelets
The most common transfusion-transmitted disease results
from transfusion of bacterially contaminated platelets [33,
34]. The majority of bacteria isolated from platelet concentrates in platelet-associated bacteremia are constituents of
normal skin flora [18, 19, 33, 35]. The most common isolates
include Staphylococcus epidermidis and Bacillus cereus [36,
37]. Potential sources of these organisms in the collected
blood include incomplete donor skin disinfection; dislocation
of the skin core and donor unit inoculation; donor bacteremia
or contamination of the collection bag, anticoagulant or tubing [20]. Platelet concentrates which are stored at 20 to 24
Lindholm et al.
degrees Celsius are a favorable culture medium for many
bacteria. Currently, platelets have a 5 day shelf-life intended
to limit storage time and reduce the risk of bacterial contamination.
The bacterial contamination rate was found to be 1 in
1000 to 1 in 3000 platelet units in several surveillance studies [33, 34, 38]. The reported sepsis rates associated with
platelet transfusions range between 1 in 13,000 and 1 in
100,000 [16, 39, 40]. In prospective studies, a majority of
recipients of contaminated platelets had either no symptoms
or developed fever and chills with no clinical sequelae [20,
38]. Some episodes associated with transfusion of contaminated platelets may resemble febrile non hemolytic transfusion reactions. Nevertheless, there is evidence that bacterial
sepsis from transfusion of contaminated platelet concentrates
is frequently unrecognized and underreported [30].
The fatality rate associated with transfusion of contaminated platelets varies between studies and countries and may
depend on the product type, method of surveillance and the
use of active reporting methods. A study from Johns Hopkins University reported a 1 in 17,000 fatality rate with
transfusion of pooled platelets and 1 in 61,000 for apheresis
platelets [40]. A fatality rate of 1 in 48,000 platelet units was
reported from the University Hospitals of Cleveland [41].
The FDA has collected data on transfusion-associated sepsis
and fatality for platelet transfusions [26]. The majority of
reported fatal cases associated with platelet transfusion have
involved Gram-negative bacteria with the most common
being Klebsiella pneumoniae, Escherichia coli, Serratia
marcescans, Enterobacter spp. and Psedomonas aeruginosa.
The most common gram positive bacteria reported in fatal
sepsis-associated transfusions include Staphylococcus epidermidis, S. aureus and group G Streptococcus. Approximately 12 percent of fatalities reported from United Kingdom, France and the US were contaminated with Grampositive normal skin flora [42].
Several measures are available to reduce the risk of initial
inoculation of the platelet concentrate. Careful skin decontamination with iodine solutions (tincture of iodine or povidone-iodine) is generally the most effective method for reducing bacterial contamination of the skin [43, 44]. For donors allergic to iodine, chlorhexidine may be used for skin
disinfection. In spite of careful skin disinfection procedures,
bacteria may be carried into the blood bag by the skin core
that enters through the collection needle. It has been found
that diversion of the first several milliliters of blood from the
primary blood container significantly reduces the amount of
bacteria that enter from the skin [45]. This diversion method
is now widely practiced by blood collection centers. Diversion is most effective at reducing contamination from skin
flora, but does not reduce bacterial contamination from
blood-borne Gram-negative microorganisms.
The use of apheresis collected platelets has limited donor
exposure and led to a 3-fold decrease in septic transfusion
risk [40]. In addition, apheresis platelets are currently tested
by bacterial culture which likely further reduces the contamination rate for this product. The optimal time for platelet
storage is currently 5 days. Using second generation plastics
with increased gas transport properties, platelet storage was
extended to 7 days in the early 1980s [46]. However, due to
Approaches to Minimize Infection Risk in Blood Banking and Transfusion Practice
concern for an increased rate of contamination, the shelf-life
was returned to 5 days [20, 47]. A study to extend the platelet outdate to 7 days with aerobic and anaerobic cultures was
approved by the FDA in 2005, but the study was later suspended due to a higher rate of contamination in the older
platelet products [48, 49].
Several methods have been tested to improve bacterial
detection in blood products, including microscopic examination, surrogate markers, endotoxin assay, bacterial
DNA/RNA detection, rapid immunoassay and bacterial cultures. Since 2004, the College of American Pathologists
(CAP) and the AABB (formerly the American Association
of Blood Banks) have required systems and methods to detect the presence of bacteria in platelet concentrates, and
surrogate methods including pH, glucose, pO2 and pCO 2
measurements have been allowed [50, 51]. These methods
can be validated and are rapid, but have low sensitivity.
Measurements of product pH and glucose levels are commonly used for random donor platelets issued by the blood
bank. Microscopic examination with Gram’s stain or
Acridine Orange has been found to have high sensitivity and
specificity in 4 to 5-day old platelets, but may be complicated with false positive determinations [18, 52]. True positives have been found in units with very high bacterial concentrations of >106 CFU/ml. Endotoxin assays are limited to
detection of Gram-negative organisms [32].
Recently, a rapid qualitative immunoassay has been approved and cleared for marketing by the FDA [53]. The test
was originally approved for detection of aerobic and anaerobic Gram positive and Gram negative bacteria as an adjunct
to FDA approved culture methods on leukocyte reduced
apheresis platelet units. The test uses a hand-held device that
can detect lipotechoic acid (LTA) and lipopolysaccharide
(LPS) present on the surface of a wide spectrum of common
human pathogenic bacteria that have caused septic transfusion events [16, 54]. The test can be performed in 30 minutes
by the hospital transfusion service 72 hours after collection
and prior to the time of issue. The test is now approved to
test platelet pools from whole blood collections. Initial studies indicate that the test can detect bacteria in the platelet
concentrate at a level of less than 105 CFU/ml. By report,
clinical studies indicate that the test has improved the sensitivity of detecting bacteria by 100 to 1000-fold over existing
methods [53].
Nucleic acid testing for bacterial DNA/RNA detection
has sensitivity and specificity close to 100 percent when
compared to culture, but due to more complex technology
has not been widely available [55, 56]. Two FDA approved
culture systems are currently available. The BacT/Alert system measures CO2 to detect as low as 10 CFU/ml bacteria in
12 to 26 hours [57]. The system must be inoculated by a
needle and is not completely closed. False positives may
occur due to sample contamination and instrument signal
errors [20]. True positives have been found to occur in approximately 1 in 5000 units tested [58]. The Pall enhanced
bacterial detection system measures O2 consumption, but
does not detect obligate anaerobes. In one study, a confirmed
positive rate of 1 in 5133 units was found and the isolates
were Staphylococcus spp. and Streptococcus spp [59].
Infectious Disorders - Drug Targets 2011, Vol. 11, No. 1
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Bacterial Sepsis with Transfusion of Contaminated
Plasma Products
Plasma and cryoprecipitate are stored frozen below -18
degrees Celsius and are very rarely significantly contaminated with bacteria. Burkholderia cepacia and Pseudomonas
aeruginosa have been isolated from plasma and cryoprecipitate thawed in a contaminated water bath [60]. These environmental organisms normally grow optimally at 30 degrees
Celsius and may contaminate the ports of the bag and spread
when the units are spiked for transfusion. This form of contamination is best prevented by maintaining a clean water
bath and using a barrier to avoid contact of the unit with the
water during the thawing process.
A report of contamination of human serum albumin with
Enterobacter cloacae may have resulted from manufacturing
problems [61]. Infusion of contaminated albumin products
has caused febrile reactions, transient bacteremia and septic
shock. Clinical recognition led to detection of a multi-state
outbreak leading to a worldwide recall of albumin. Occasionally, albumin has become contaminated with Pseudomonas species [62]. Human serum albumin is pasteurized at
60 degrees Celsius for 10 hours, which inactivates several
viruses, but may not ensure bacterial sterility.
Spirochetes and Rickettsias
The infectious agent of syphilis is Treponema pallidum,
an anaerobic bacterium that cannot be seen with Gram’s
stain and does not grow by in vitro culture. Only three cases
of transfusion transmitted syphilis have been reported in the
literature since 1969 [63-65]. The very rare occurrence of
syphilis infection from blood transfusion may be attributed
to several factors including improved donor questioning and
selection; improved serologic screening; exclusion of at risk
donors by viral testing; refrigerator storage of blood and high
oxygen tension in platelet concentrates non-permissive to
Treponema growth and antibiotic use common in blood recipients [20].
The infectious phase of syphilis is brief and the Treponema organisms survive only a few days during refrigerated storage of blood. The serologic tests for syphilis (STS)
become positive during the seroconversion phase following
the spirochetemia. These tests may play a limited role in
preventing syphilis transmission by transfusion [66]. Most
positive STS may be biological false positives and unrelated
to syphilis infections. Nevertheless, an argument has been
made for the role of STS testing as a surrogate marker for
individuals at risk for other sexually transmitted diseases.
Serologic tests for syphilis are still required for blood donation.
The etiologic agent of Lyme disease, Borrelia burgdorferi could possibly be transmitted by transfusion; however,
there are no known human transfusion transmitted cases
[67]. Blood donations have occurred with subsequent diagnosis of donor Lyme disease; however, no recipient spirochete infections were detected.
The obligate intracellular rickettsia etiologic agents of
Rocky Mountain spotted fever, ehrlichiosis and scrub typhus
could possibly be transmitted by transfusion [68-70]. A single case of Rocky Mountain spotted fever (Rickettsia rick-
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ettsii) transmitted by transfusion has been documented [70].
Ehrlichiosis chaffeensis can remain viable in stored RBC
units suggesting that transfusion-acquired infection is possible [69]. Rocky Mountain spotted fever and/or human
monocytic ehrlichiosis developed in National Guard trainees
in 1997 at Fort Chaffee, Arizona. Ten units from the infected
trainees were transfused before recall; however, none of the
recipients the blood developed clinical infections [68].
EMERGING INFECTIOUS DISEASES
The AABB Transfusion-Transmitted Diseases Committee recently reviewed emerging infectious agents and rated
variant Creutzfeldt-Jakob disease (vCJD), babesiosis, and
dengue as their highest concerns [71]. Chagas’ disease and
malaria were in the next-highest priority group.
Variant Creutzfeldt-Jakob Disease
vCJD was first recognized in 1995 as the human form of
bovine spongiform encephalopathy (BSE), which became
epidemic in British cattle in the 1980’s [72]. BSE and vCJD
are among the transmissible spongiform encephalopathies
(TSE), a family of animal and human neurological diseases
thought to be mediated by prions. Prions are cell-membrane
proteins of unknown function. In the brain, the presence of
an abnormally folded ß-sheet version of the prion protein
(PrPTSE) induces similar folding and aggregation of the normal -helical form (PrPC). After years of incubation, vCJD
manifests as a uniformly fatal neurodegenerative disease.
TSEs are usually transmitted by foods containing pathogenic
prions, and humans presumably acquired vCJD from infected beef. In contrast, the incidence of sporadic traditional
CJD has been stable, with no evidence of dietary or bloodborne transmission.
Epidemiological studies of the 170 vCJD cases in Britain
revealed that three of them had received non-leukoreduced
RBC 6 to 8 years previously from donors who developed
vCJD 1.5-3.5 years after donating [73]. These three cases
confirm animal experiments showing transfusion transmission of pathogenic prions. vCJD prions were also found in
two autopsies of blood-product recipients who died of other
causes; one was a RBC recipient and the other was a hemophiliac treated with factor VIII concentrates [73, 74]. These
deaths were investigated because they had donors who later
developed vCJD. The hemophilia patient raised concern that
blood derivatives also can be infectious, because he received
factor concentrates derived from plasma donations from an
eventual vCJD victim.
The RBC recipient with autopsy prions was also of interest because it was the first recognized case of infection in a
patient with a prion genotype outside the previously identified risk group. All patients with vCJD disease have been
homozygous for methionine (M/M) at the prion gene PRNP
codon 129, and it had been hoped that only the 40% of the
British population with this genotype was susceptible. However, the RBC recipient was among the 50% of persons with
the methionine/valine (M/V) heterozygosity, and since then,
two more asymptomatic infections have been identified in
persons with the V/V genotype, in a surveillance study of
tonsillectomy and appendectomy specimens. The British
epidemic has waned after food safety measures were insti-
Lindholm et al.
tuted, but there is concern that perhaps the incubation period
is simply longer in the M/V and V/V genotypes, which will
lead to a new wave of cases [72].
BSE remains very rare in American cattle, and the US
has had only three recognized vCJD cases, all in non-natives
who presumably were infected elsewhere [75]. The FDA
recommends deferral of US blood donors with past extended
European residence [76]. However, further measures to reduce prion transmission are being examined for blood components.
Carrier detection by blood testing presents several difficult challenges [72]. The test must be sensitive for extremely
low infectious levels of prions (<1 pg/ml) which are abnormal only in their conformation. Unlike currently approved
animal tissue tests, donor testing must be performed in large
scale with rapid turnaround. Since there are no readily available sources of infected human blood, especially pre-illness,
test validation would be problematic. Sensitivity of another
sort would apply to the implications of a positive test for
donor counseling. However, numerous parties have tests
under development which are based on monoclonal antibodies or other ligands which differentially bind to the PrPTSE
protein or its aggregates. Some tests would also amplify the
PrPTSE protein by using it to aggregate normal PrPC. The
British National Health Service Blood and Transplant
(NHSBT) authority estimated that universal donor prion
screening could cost 15-25 ($23-38) per unit (1 = $1.52,
April 2010) [77].
The other strategy for risk reduction is prion filtration
[72]. In whole blood, prion infectivity is about equally divided between plasma and leukocytes, so prion filtration
includes high-efficiency leukocyte removal. Prions are adsorbed with affinity resins or other ligands which can remove over 3 logs of infectivity in studies of experimentally
spiked blood. For blood components, filter manufacturers
have initially focused on RBC. The NHSBT is evaluating the
P-Capt RBC filter from MacoPharma (Tourcoing, France),
and is considering its routine use for patients born after 1995
(after British dietary exposure ended) or with hemoglobinopathies [77]. (The American Red Cross participated in a
joint venture which developed the underlying technology for
this filter.) About 13% of the RBC hemoglobin content is
lost in the filtration process, so multiply-transfused patients
may require more units [78]. Pall (Port Washington, NY) has
a RBC filtration system which received the Council of
Europe mark, and Asahi Kasei (Tokyo, Japan) is developing
a RBC filter. The NHSBT projected the potential cost of
universal filtration in Britain to be 41 per unit ($62) [77].
(For comparison, their baseline RBC price is 124 ($188),
comparable to the US average of $214 in 2006 ([7]).
Chronic wasting disease is a TSE of deer and elk in the
Great Plains, Wisconsin, Illinois, and other US regions. This
syndrome has no human infectivity known to date, but the
CDC has precautionary recommendations for hunters and
butchers [79].
Babesiosis
Babesiosis is a seasonal tickborne intraerythrocytic parasitic disease caused by several Babesia species endemic to
Approaches to Minimize Infection Risk in Blood Banking and Transfusion Practice
southern New England, the upper Midwest, and the West
Coast. Immunosuppressed or asplenic patients are particularly affected. Transfusion transmission by RBCs has been
recognized for years, but nine fatal transfusion-transmitted
cases in 2005-08 stimulated fresh concern at the FDA [80].
Blood donors in Connecticut had a seroprevalence of 1.1%
in antibody testing [81]. Screening questions about tick exposure do not correlate well with donor infections. At a recent FDA workshop on transfusion babesiosis, experts discussed the relative merits of donor testing for antibody or for
nucleic acid. (Single-donor NAT, not pooled-donor NAT as
is currently routine, would be needed for sufficient sensitivity.) Various algorithms were considered for testing universally, regionally, seasonally, or for selected transfusion recipients at highest risk [82]. A task force was formed to advise the FDA on future directions.
Dengue
Like WNV, dengue is an arbovirus (arthropod-borne)
infection which has periodic large outbreaks in endemic areas. Dengue is characterized by fever, rash, and bone pain;
some patients develop thrombocytopenia, hemorrhagic fever
and shock. Also like WNV, antibodies appear only after
viremia begins, so NAT is more useful for detection of recent donor infection. Two cases of transfusion transmission
by RBC and plasma have been recognized in southeast Asia
[83]. Dengue occurs in warm-weather areas which often
overlap with malarial donor deferral regions. However, outbreaks have occurred in Hawaii and southern Texas, and
dengue is endemic in Puerto Rico. A pilot study in Puerto
Rican blood donors found a NAT-positive rate of more than
1 in 1400, suggesting the possibility that several dozen viremic blood components are collected annually in residents
and travelers from Puerto Rico [84]. There is no approved
donor test.
Chagas’ Disease
Trypanosoma cruzi, the parasite causing Chagas’ disease,
has long been recognized in Latin America as a transfusiontransmitted infection. In 1999 the Pan American Health Organization estimated that 20% of transfusions from infected
donors transmitted T. cruzi to the recipient [85]. Several
transfusion-related cases from immigrant donors were recognized in the US and Canada, generally via platelet transfusions, and concern grew for the need to interdict this agent in
the US blood supply [86]. An antibody test for blood donors
was approved by the FDA in 2006, and US blood collection
facilities have applied it either to all donors or to those donors with a history of residence in areas at risk. However,
lookback studies of 241 previous transfusions from newly
identified T. cruzi-positive donors revealed only 2 possible
transmissions from one platelet donor (2 of 32 total platelets
traced), and these were still under investigation when presented to the FDA [87]. Blood donors in the US with evidence of past T. cruzi appear to be far less infectious than
donors in endemic areas.
Malaria
Four cases of transfusion-transmitted malaria from Plasmodium species occurred in the US in the most recent ten
Infectious Disorders - Drug Targets 2011, Vol. 11, No. 1
51
years of annual reports (1998-2007) from the CDC [88]. Although not a new risk, transfusion malaria continues to receive attention because of its implications for donor deferrals. Travelers to areas designated as endemic by the CDC
are deferred from blood donation for one year, and persons
who lived >5 consecutive years in an endemic area are deferred from donating for three years [89]. Thus, travel to
malaria areas is a leading reason for donor deferral. Many
donors also fail to report travel for which they should have
been deferred. Malaria-risk travel is the leading reason for
licensed US blood centers to issue blood components which
deviate from safety requirements [90], which in turn leads to
thousands of notices to transfusion services each year about
previously transfused blood components from malaria-risk
donors. However, in the absence of a US-approved donor
test, geographical deferral remains the main defense of the
blood supply. The CDC has country-specific information and
interactive maps on their web site at www.cdc.gov/malaria to
assist travelers, healthcare personnel, and blood collection
facilities.
PATHOGEN INACTIVATION
Solvent/detergent treatment is the most extensively used
method of Fresh Frozen Plasma pathogen inactivation. Solvent detergent treatment removes infectivity by disrupting
the membranes of enveloped viruses, bacteria, protozoa and
cells (Table 1) [91]. This method is used for treatment of
plasma and plasma-derived proteins but does not inactivate
non-enveloped viruses such as hepatitis A and parvovirus.
For many purified plasma proteins, a second pathogen inactivation step consisting of nanofiltration or heat treatment
has been used. Solvent/detergent treatment rapidly inactivates viruses to very low levels and has a very high degree of
safety [92]. A second pathogen inactivation step for plasma
is not available and regulatory requirements to ensure the
safety of solvent-detergent plasma includes NAT screening
for hepatitis A virus (HAV) and parvovirus B19 [93, 94].
Further, the presence of immune antibodies in pooled plasma
may confer protection against these non-enveloped viruses[93, 94]. Also, solvent-detergent treated plasma has not
been associated with transfusion-related acute lung injury
(TRALI) and its use is associated with a reduced incidence
of febrile, allergic and anaphylactic reactions [92]. This may
result from dilution, neutralization and cellular component
removal during the pooling process.
Solvent-detergent treatment generally does not adversely
affect plasma protein activity, except for 2-antiplasmin and
reduced Protein S levels [95]. Reduced 2-antiplasmin levels
in solvent-detergent plasma do not appear to be significant
except in patients with hepatic insufficiency or fibrinolysis
[96]. Solvent-detergent plasma use leading to low Protein S
levels may be associated with thromboembolism in liver
transplantation and in patients with thrombotic thrombocytopenic purpura after repeated plasma exchanges with Octaplas SD plasma [97]. Solvent detergent treated plasma was
licensed in the United States in the 1990s, but later withdrawn from the market.
Methylene Blue (MB) is a positively charged phenothiazine dye which has high affinity for negatively charged compounds including nucleic acids, proteins and DNA. The dye
52
Infectious Disorders - Drug Targets 2011, Vol. 11, No. 1
inactivates viruses by intercalating into DNA and when illuminated with visible light produces singlet oxygen-mediated
DNA damage [98]. Methylene Blue does not effectively
permeate cell membranes and intracellular pathogens may
not be inactivated. This limitation has been overcome by
using a freeze-thaw step to remove leukocytes or by using
leukocyte filtration to remove leukocytes, platelets and cellular fragments. Plasma membrane filters effectively remove
all cellular components and inhibit detectable HIV infectivity in combination with Methylene Blue treatment. Methylene blue generally has low toxicity and has not been reported
to cause formation of neoantigens, although its binding to
membrane proteins may cause loss of RBC viability [99,
100].
Methylene Blue has been used as a second most frequent
approach for pathogen inactivation of Fresh Frozen plasma
either in combination with a freeze-thaw step or leukocyte
filtration (Table 1) [101]. A method for preparing Methylene
Blue treated plasma uses a 0.65 μM filter and a MB removal
device is approved for use in European Blood Centers.
Methylene Blue treatment reduces the levels of certain
plasma factors including fibrinogen, Factor V, and factor
VIII [91, 102]. However, MB-plasma provides better replacement of Protein S and 2-antiplasmin than solventdetergent plasma. Although MB-treated plasma has normal
levels of ADAMTS13 von Willebrand cleaving protease, it
appears less effective than FFP for critical factor replacement in TTP [91, 103].
Psoralens are a class of furocoumarins which are isolated
from plants and have photosenstizing properties. Psoralen
compounds bind and intercalate into DNA or RNA and upon
exposure to light cause cross-linking of single and double
stranded structures [104]. Synthetic S-59 psoralen also binds
to lipids and proteins. Psoralen with ultraviolet light UVA
exposure has been used to inactivate enveloped viruses, bacteria, protozoa and leukocytes.
Psoralen based pathogen inactivation products have been
used for plasma and platelet products. Due to the absorption
of UVA light by hemoglobin causing interference, psoralenbased pathogen inactivation is not available for RBC products [104]. A psoralen-based method named INTERCEPT
Blood System uses compound S-59 and UVA for pathogen
inactivation of plasma and platelets. The product has a high
level of safety; however, urticaria is frequently experienced
by patients treated for coagulation deficiencies [105].
Psoralen treatment also reduces fibrinogen, Factor V, Factor
VIII, Factor VII and Factor X [106]. The product is approved
for use in clinical trials in the US by the FDA. A similar INTERCEPT product for inactivation of enveloped and non
enveloped viruses, bacteria and protozoa in platelets is available in Europe and for clinical trials in the US [104]. The
treatment leads to contact of platelets with surfaces and several measures of platelet activation [107]. The clinical significance of platelet activation, apoptotic cell formation and
cytokine release needs to be established. Post-transfusion
corrected count increment with psoralen-treated platelets
may be reduced compared with untreated platelets [108].
However, a potential benefit of this treatment may be to reduce allergic reactions.
Lindholm et al.
Riboflavin (vitamin B2) is used for phototoxic targeting
of pathogen nucleic acids. Riboflavin and its photoproducts
and catabolites are present in normal blood and it is generally considered to be safe. The phototoxic effect of riboflavin
is due to oxygen-dependent and oxygen-independent damage
of guanine and nucleic acids. Riboflavin based pathogen
inactivation may be effective against enveloped viruses, bacteria, protozoa and some non enveloped viruses [109]. Riboflavin treatment of blood components has been developed
under the name Mirasol. The product functions similarly to
INTERCEPT, but removal of reagents after treatment may
not be necessary and is not currently performed.
Pathogen inactivation for red blood cell products has
been explored with alkylating agents, photosensitizing compounds, riboflavin treatments and UVC illumination (Table
1). Alkylating agents include frangible anchor linker effector
(FRALE) and Inactine compounds. A FRALE compound is
composed of a nucleic acid binding ligand linked to an alkylating agent. The FRALE compound inactivates DNA/RNA
by forming covalent links between nucleic acids. One prototype compound, S-303, is used by Cereus Corporation in a
Helinx pathogen inactivation system. The compound has an
acridine based anchor and a nitrogen mustard alkylating
agent. The Helinx pathogen inactivation system has been
shown to inactivate viruses, bacteria, protozoa and leukocytes [92, 110]. The S-303 compound selectively binds to
nucleic acids but also binds and alkylates proteins [111]. The
Helinx system has been tested in phase III trials and worked
equivalently to controls in supporting cardiac surgery patients; however, some patients developed antibodies that
were reactive with S-303 treated RBC and the trial was put
on hold [112]. Methods have been developed to add quenching compounds to reduce the immunoreactivity of the S-303
treated RBCs. The Inactine compounds based system has a
cationic tail that binds DNA and an ethylenamine or azindine
effector group to selectively akylate DNA. An ethylenimine
based compound PEN110 has been developed by Vitek. This
compound inactivates viruses, bacteria, protozoa and leukocytes. A phase III trial using this compound was stopped
because subjects developed antibody responses to PEN110
treated RBCs [111].
Ultraviolet light in wavelength range of 200 to 280 nm is
used as a pathogen inactivation agent because it causes the
formation of pyrimidine adducts that block nucleic acid transcript elongation. Procedures are available for treatment of
platelets and RBC units. The procedure is used to eliminate
contamination with removal of oxygen from the product, UV
illumination and later ozone treatment. UVC illumination
can be used to inactivate modest bacterial and virus contamination, although DNA repair mechanisms may allow some
bacteria to proliferate at modest doses of applied UV light.
Bacillus cereus and viruses appear to require larger doses of
UV light for inactivation; the bacteria may be more resistant
due to the presence of spores. A brief exposure time is required for pathogen inactivation. Large scale investigation is
needed to determine the efficiency and reliability of this
method of pathogen inactivation.
Approaches to Minimize Infection Risk in Blood Banking and Transfusion Practice
Table 1.
Infectious Disorders - Drug Targets 2011, Vol. 11, No. 1
53
Pathogen Reduction Methods for Blood Components
Agent
Solvent-detergent
Plasma
Platelets
RBCs
Yes
NA
NA
Potency Issues
Safety Issues
Earlier version, some factors affected
Pooled plasma
Non-enveloped viruses are resistant
Methylene blue
Yes
NA
NA
Plasma must be leukoreduced.
More recurrence of TTP?
Psoralen (amotosalen)
Yes
Yes
NA
Reduced platelet transfusion increments
Pulmonary adverse effects?
Riboflavin
Yes
Yes
UD
Reduced platelet transfusion increments?
No removal step needed
Ultraviolet light
NA
UD
No
No chemical agent
Alkylating agent (S303)
NA
NA
UD
Antibodies to RBC neoantigens
Yes: Approved in various countries outside the US.
NA: Not applicable.
TTP: Thrombotic thrombocytopenic purpura.
UD: Under development.
CONCLUSIONS
The safety of the blood supply depends on selecting donors with low risk of infectious disease based on donor history and laboratory screening of the blood for known transfusion-transmitted infections. State-of-the-art, FDA licensed
methods for infectious disease screening include NAT for
hepatitis C, HIV, West Nile Virus and serology for hepatitis
B, HIV-1 and -2, HTLV-I and II and Hepatitis C Virus.
Transfusion-transmitted infection risk with these viruses is
currently very small and is limited by test sensitivity; the
“window-period” of the available screening methods and the
prevalence of the infection within the population. Bacterial
contamination of blood products is currently the greatest
remaining infectious disease risk of blood transfusion. Bacterial contamination of platelet concentrates is the most common threat due to room temperature storage conditions optimal for this product. The clinical manifestations of transfusing a bacterially contaminated platelet product may range
from mild fever to severe sepsis leading to fatality. The College of American Pathologists and the American Association
of Blood Banks require accredited blood banks to employ
systems and validated methods to test for bacterial contamination of platelet products. Sepsis from transfusion of bacterially contaminated RBC units is considered very rare. However, Gram-negative bacteria may survive and proliferate in
refrigerated RBC units and transfusion with contaminated
units can cause sepsis, endotoxic shock and death.
Important emerging infectious diseases that may be
transmitted by transfusion include variant Creutzfeldt-Jakob
disease (vCJD), babesiosis, dengue, Chagas’ disease and
malaria. The detection of vCJD carriers will require an extremely sensitive method which may be difficult to validate
due to limited access to positive controls. Deferral of US
blood donors with exposure or family history or past extended European residence are the current approaches used
to avoid vCJD transmission. Babesiosis, dengue, Chagas’
disease and malaria occur in characteristic endemic regions
and donor screening and testing strategies are being considered to prevent transmission through the United States blood
supply. For diseases such as malaria for which no test is cur-
rently available, donor deferral for residence or travel to endemic areas is the primary defense. Several methods are being used or are in development to reduce infectivity of blood
products, including solvent-detergent processing of plasma
and nucleic acid cross-linking with photochemical reactions
with methylene blue, riboflavin or psoralen; the use of alkylating agents is being developed for treatment of cellular
blood products. Although our blood supply is safer than ever
before, several opportunities exist to further improve blood
safety through advances in infectious disease screening and
pathogen inactivation methods.
ABBREVIATIONS
CMV
=
Cytomegalovirus
NAT
=
Nucleic acid testing
FDA
=
Food and Drug Administration
CDC
=
Centers for Disease Control
RBC
=
Red blood cell product
CFU
=
Colony forming units
spp
=
Species
UV
=
Ultraviolet light
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