Pediatr Clin N Am 49 (2002) 1211 – 1238

Transfusion medicine for the pediatrician

Keith C. Quirolo, MDa,b,*
a
Department of Clinical Laboratory Medicine, University of California, San Francisco,
Moffitt-Long Hospital, 505 Parnassus Avenue, San Francisco, CA 94143-0100, USA
b
Department of Hematology, Children’s Hospital and Research Center at Oakland, 747 52nd Street,
Oakland, CA 94609, USA

Over the past few years, major changes in transfusion medicine have improved
the safety of the supply of blood, particularly in the areas of infectious disease
testing (Fig. 1) and processing. Since about 1990, blood banking has been
regulated as a manufacturing process similar to the manufacture of pharmaceu-
ticals [1]. This has led to more uniform blood products with more predictable
outcomes. Recommendations have been made for universal leukoreduction [2],
more uniform collection of blood products [3], pathogen inactivation of blood
products [4], and a quest for a ‘‘zero risk’’ blood product. These new practices
and regulations have made blood banking more complex, resulting in the
acquisition of many local blood banks by the two major blood suppliers: Blood
Systems Inc. and the American Red Cross.

Screening for infectious disease

Currently, all blood donations are screened for HIVantigen, antibodies to HIV-1
and HIV-2, human T lymphotrophic virus (HTLV I-II), hepatitis B surface antigen
(HBsAg), hepatitis B core antigen (HBC), hepatitis C (HCV), and syphilis. Nucleic
acid testing (NAT) [5], used under an investigative new drug license from the US
Food and Drug Administration (FDA), uses a transcription-mediated amplification
[6] to test for HIVand hepatitis C but not hepatitis B. There are algorithms to define
positive screening tests. In addition to laboratory testing, a donor questionnaire is
used to decrease the likelihood of transmission of malaria, HIV, and sexually
transmitted viral infections, as well as to identify other conditions or travel history
that would indicate that a donor’s blood is high-risk for disease transmission. The
list of potential blood-borne pathogens is long (Box 1). Not all blood-borne viruses

* Department of Clinical Laboratory Medicine, University of California, San Francisco, Moffitt-

Long Hospital, 505 Parnassus Avenue, San Francisco, CA 94143-0100, USA.
E-mail address: kquirolo@mail.cho.org

0031-3955/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved.
PII: S 0 0 3 1 - 3 9 5 5 ( 0 2 ) 0 0 0 9 0 - 1
1212 K.C. Quirolo / Pediatr Clin N Am 49 (2002) 1211–1238

Fig. 1. Declining risk of viral infection in blood products. (From Busch MP. Closing the windows on
viral transmission by blood transfusion. In: Stramer SL, editor. Blood safety in the new millennium.
Bethesda (MD): American Association of Blood Banks; 2001. p. 33 – 54; with permission.)

are pathogenic, though: hepatitis G and the TTV and SEN viruses have been found
not to cause disease [7].

Viral pathogens/NAT testing

Once an individual has become infected with a viral pathogen, there is a
window of time (Fig. 2) during which the viral load is too low, or is intermittently
too low, to be detected by pooled sample NAT. Recipients of donated blood
products are at highest risk for infection during this window phase. Because NAT
testing is so sensitive and there are so few instances of virally infected products,
only mathematical models based on research data can predict the risk of infection
from a single transfusion. The problem of detecting risk during the window phase
has recently been reviewed [8]. Another concern is the risk that an individual unit
may be improperly tested or has a variant strain of pathogen that the highly
sensitive and specific NAT will not detect.
Currently, NAT testing is performed in minipools (MP) of 16 or 24 units. If an
MP test is positive, the individual donations in that pool can be further tested to
detect the infected unit or source of a false positive. During the window phase
before the ramp-up of viral replication, sample dilution may cause MP testing to
be inaccurate. A low level of virus that would be missed with MP testing could be
detected with individual unit testing (ID); however, ID is prohibitively expensive,
time-consuming, and identifies few additional positive units.

HIV
NAT testing has increased detection of HIV-infected units and significantly
shortened the window phase. Mathematical modeling of HIV-infected products
predicts that ID NAT rather than MP testing would result in an increased
 K.C. Quirolo / Pediatr Clin N Am 49 (2002) 1211–1238 1213

Box 1. Transmissible pathogens

Viruses
Enveloped Retroviral agents: HIV-1, HIV-2, HTLV I-II
Herpes Virus: CMV, HHV-6, HHV-8, EBV
Hepatitis Virus: HBV, HBC
Non-enveloped Hepatitis Virus: HAV
Other Virus: Parvovirus B-19
Bacteria
Gram Positive Staphylococcus Streptococcus viridans
epidermidis Enterococcus ssp.
Staphylococcus aureus Bacillus cereus
Coagulase negative
Staphylococcus
Gram Negative Yersinia enterocolitica Pseudomonas
Salmonella enteritidis fluorescence
Serratia marcescens Citrobacter freundii
Escherichia coli Enterobacter cloacae
Flavobacterium spp. Coliforms
Klebsiella pneumoniae
Protozoa
Plasmodium spp. Trypanosoma cruzi
Babesia microti Toxoplasma gondii
Leishmania donovani Ehrlichia chaffeensis
Spirochete
Borrelia burgdorferi Treponema pallidum
Rickettsia Rickettsia rickettsii
Prions vCJD
Not all of these pathogens have been proven to be transfusion
transmitted and some are not pathogenic.

detection of 3 viral positive units per 10 million units tested (6 units with MP
versus 9 units with ID). During the first year of MP NAT testing, four cases of
HIV would have been missed with antigen testing, a detection rate of 5.2 per
10 million units. From a cost-effectiveness perspective, the current cost per case
detected with HIV p24 antigen testing is $40 million per case [9]; with MP NAT
testing the cost per case of HIV is $1.7 million, and with ID testing the cost would
be $2.7 million per case. HIV p24 testing will probably be discontinued when
NAT testing becomes the FDA standard, because any antigen-positive product
should be detectible by NAT.
Current studies are in the process of defining the infective dose of virus; in the
case of HIV, this could be less than 100 genome equivalents per ml (gEq/ml).
Currently with MP NAT, the risk of contracting HIV from a single unit
1214 K.C. Quirolo / Pediatr Clin N Am 49 (2002) 1211–1238

Fig. 2. Illustration of the window phase and the ramp-up phase of viral replication. The window phase
is the period after initial infection before virus can be consistently detected to the beginning of the
ramp-up phase. The ramp-up phase is the period from detection to the peak of viral load. (From Busch
MP. Closing the windows on viral transmission by blood transfusion. In: Stramer SL, editor. Blood
safety in the new millennium. Bethesda (MD): American Association of Blood Banks; 2001. p. 33 –
54; with permission.)

transfusion is between 1:1,930,000 [10] and 1:3,500,925 [11]. In 1996, the risk
was 1:676,000 [12] with HIV p24 antigen testing as the standard.

HCV
NAT testing has had a huge impact on the transmission of HCV via blood
products. HCV has a very long window phase (Fig. 3) with a very high viral titer
before antibody can be detected in the serum. The average period of infectivity
before antibody detection is between 41 and 61 days. Alanine aminotransferase
has been used as a marker for HCV in the past because it is elevated weeks before
the antibody can be detected The doubling time for HCV is only 17 hours (HIV
doubling time is 21.5 hours); therefore, the ramp-up after the window phase is
rapid. The viral load is very high when detection becomes possible. This high
viral titer ramp-up also makes the difference between MP and ID detection less
dramatic because the slope from the window phase to the plateau is so steep. A
troublesome feature of HCV is that there are periods during the window phase
when the viral RNA increases to levels intermittently detectable by NAT. It is not
known what risk these intermittent increases pose to recipients.
Determining the infectivity during the window phase of HCV and other
infective agents is an active and important area of study in blood safety. During
the first year of NAT testing there were 42 positive units detected that would have
 K.C. Quirolo / Pediatr Clin N Am 49 (2002) 1211–1238 1215

Fig. 3. Window phase dynamics for HIV, HVC, and HBV primary infection. 0, initial infection; dt,
doubling time. (From Busch MP. Closing the windows on viral transmission by blood transfusion. In:
Stramer SL, editor. Blood safety in the new millennium. Bethesda (MD): American Association of
Blood Banks; 2001. p. 33 – 54; with permission.)
1216 K.C. Quirolo / Pediatr Clin N Am 49 (2002) 1211–1238

been missed with antibody screening, a detection rate of 40.3 per 10 million units.
Currently, the risk of HCV from a single transfusion is 1:260,000 to1:543,000
[10], compared with a risk of 1:103,000 in 1996 [12].

HBV
NAT testing is less sensitive for HBV because HBV has a long doubling time
(2.8 days), a slow increase in viremia, and a high rate of infectivity (10 HBV
DNA gEq in chimpanzees causes infection) [8]. The level of HBV DNA during
this long window phase is low and not consistently identified by NAT testing.
HBV may be infective 40 days before the detection of HBsAg. For these reasons,
the effectiveness of NAT testing for HBV is less dramatic than for HCV and HIV.
The risk of infection from a single transfusion in 1999 was 1:138,700; the risk in
1996 was 1:63,000.
There are two new developments in HBV testing. The first is a more sensitive
HBsAg assay that is claimed to be equivalent to NAT. The second development
concerns recent studies that have shown infectivity in donors who are HbsAg-
negative and anti-HBc –positive. These studies are from Japan, where HBV is
endemic and point to a source of infectivity not previously appreciated. The new
HBsAg testing may place HBV NAT in question; the actual risk of infection by
HbsAg-negative and anti-HBc – positive has to be evaluated in this country [13].

HTLV I/HTLV II
HTLV screening began in the United States in 1988. Because of the high degree
of cross-reactivity between these two viruses, it was soon discovered that donors
thought to be infected with HTLV I were actually infected with HTLV II. HTLV I
is a retrovirus associated with adult T cell leukemia [14], tropical spastic
paraparesis/HTLV I– associated myelopathy [15], and uveitis [16]. In addition,
there is increased incidence of infections and immune-mediated disease in persons
harboring this virus, indicating a mild to moderate immune-deficient state.
Testing is effective in detecting infected donors [12]. The combined donor
prevalence in 1991 was 0.05% [17]. In a recent review of the Retrovirus
Epidemiology Donors Study, 1,817,502 donors were evaluated; 201 donors
tested positive for HTLV I, while 513 tested positive for HTLV II [18]. The
incidence of seroconversion to HTLV I or HTLV II in blood recipients is low.
There are more data on donors who have tested positive for these viruses [19]
than recipients. Very few donors had clinical evidence of infection.

Bacterial contamination of blood products

Bacterial sepsis from contaminated blood products is the second leading cause
of transfusion-related death (Fig. 4) in the United States today, behind transfusion
errors. Between 1990 and 1998, there were 277 reported transfusion-related
deaths, 17% of which were due to bacterial contamination. The fact that patients
 K.C. Quirolo / Pediatr Clin N Am 49 (2002) 1211–1238 1217

Fig. 4. Risk of bacterial contamination relative to the risk of other, more familiar pathogens. Bacterial
contamination estimates for red blood cells and platelets are based on the BaCon study (unpublished
data). (Adapted from Busch MP. Closing the windows on viral transmission by blood transfusion. In:
Stramer SL, editor. Blood safety in the new millennium. Bethesda (MD): American Association of
Blood Banks; 2001. p. 33 – 54; with permission.)

receiving blood transfusions are likely to have complex medical conditions and
are frequently immune suppressed contributes to the morbidity of transfusion-
related sepsis. The culture positive rate for red blood cells is as high as 0.2%. The
reported incidence of platelet contamination for single-donor apheresis platelet
products is much lower, on the order of 0.006% to 0.02%, and 0.02% to 0.5% of
individual units in platelet concentrates. The incidence of platelet contamination
has varied among studies (Table 1).
There are three major studies of bacterial contamination in blood products: the
French BACTHEM study [20], the United Kingdom SHOT study [21,22], and
the United States BaCon study (unpublished data). There has been a recent
review of the detection of bacterial contamination in cellular blood products [23];
however, there are currently no standards for detection of bacterial contamination
of products other than visual inspection.
Bacteria can contaminate blood products in several ways. The most common is
inadequate decontamination of the skin before venous puncture. McDonald et al

Table 1
Comparison of numbers of bacterially contaminated platelet products by study
Study % Contaminated (n) Products
Single donor platelets Ness et al [29] 0.006% (2) 30,197
French BACTHEM [34] 0.003% (9) 282,848
Yomitovian et al [39] 0% 2476
Platelet concentrate (% per unit) Liu et al [33] 0.053% (14) 26,210
Chiu et al [31] 0.046% (10) 21,503
Platelet concentrates are more frequently contaminated but are diluted before administration. Single
donor platelets have a greater volume with higher numbers of bacteria per unit administered and are
more frequently implicated in sepsis.
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[24] reported on several skin preparations and found that the standard American
Association of Blood Banks was only 83.2% effective in removing bacteria from
the venipuncture site on donors. Because of the large bore needles used to collect
blood products, skin plugs are sometimes found in collection bags [25]. Skin
bacteria are the most common contaminants, but as can be seen from the studies
cited below, they do not carry the highest morbidity. Transient bacteremia [26]
caused by dental procedures, endoscopy, and even chewing gum is short-lived but
is nevertheless a potential source of blood product contamination.

Red cell products

After processing, which can include leukoreduction, red blood cells are kept at
4° C for the 42 days of their storage life; this temperature slows the multiplication
of bacteria. Leukoreduction can reduce intracellular bacteria [27] in the product,
including Yersinia enterocolitica [28] a potential cause of sepsis. The only
bacterial screening test performed on red blood cell products is for Treponema
palladium and is a screen for sexual behavior, not infection risk. T palladium is
viable for 92 hours in stored red blood cell products.
Published reports from the BACTHEM and SHOT studies document the
bacterial contamination of red blood cells. The BACTHEM study covered the
years 1996 to 1998. During that time, 158 suspected cases of transfusion-
transmitted infection were reported, but only 41 met the criteria to be included
as events in the study. All of the patients who became septic had severe
underlying disease. The majority of the episodes occurred in older adults, but
there was one death in a pediatric patient. Sepsis correlated with the bacterial
contaminant rather than the type of blood product received. All deaths were
associated with gram-negative sepsis. Although Y enterocolitica is frequently
believed to be associated with red blood cell sepsis, it was less common
than Acinetobacter, Klebsiella, and Escherichia coli as a cause of sepsis in
this study.
The SHOT study reviewed all cases of morbidity from transfusion from 1996
to 1998. Only 3% of the morbidity was infectious; the types of bacteria
implicated in sepsis were similar to the BACTHEM study. The single death
from bacterial contamination of red blood cells was due to Y enterocolitica.
Y enterocolitica is a more common contaminant of red blood cells in the United
States than in the United Kingdom or France. The Centers for Disease Control
reported 21 cases of Y enterocolitica sepsis in 1997; there were 11 cases between
1985 and 1991 and 10 cases between 1991 and 1996. It was not noted whether
these cases were from leukocyte-reduced units; however, it is believed that
leukocytes continue to ingest bacteria following collection and that early
leukodepletion may decrease this protective effect. The optimum time for
leukoreduction has not been determined.
Red cells can be visually screened before administration for color changes and
clotting. If present, cultures of the unit should be obtained and the unit should be
discarded or quarantined. All febrile transfusion reactions, including fevers
 K.C. Quirolo / Pediatr Clin N Am 49 (2002) 1211–1238 1219

within 24 hours of a transfusion, should be considered as possible septic events

and treated as such. Most symptoms of infection will occur within 6 hours.
Hospital blood banks should hold blood bags for 24 hours after a transfusion for
culture in the event of fever in the recipient.

Platelet products
There have been numerous reports of infectious complications from platelet
transfusions. Ness et al [29] reported the incidence of platelet contamination to be
1:4300 units. In the BACTHEM study, the risk of infection from a blood product
was 3 times higher for platelet products, 5.5 times higher for apheresis platelet
products, and 12 times higher for pooled platelet products. In addition, mortality
for apheresis platelet products was 7 times higher than with red blood cell
products. Over the past several years, there has been a dramatic increase in the
use of platelet obtained by apheresis in transfusions. Some studies have
demonstrated a decrease in the incidence of infectious complications with the
use of apheresis [29], while others have not [20,30].
The bacteria found in contaminated platelet products are predominantly skin
flora; more severe episodes of sepsis are usually caused by gram-negative
organisms. In the Ness study, there were four deaths, three from skin flora and
one from E coli. This is similar to other studies [31].
Platelet products have a storage life of 5 days. This figure would be even
shorter if 24 to 48 hours were used to culture all products and follow up positive
cultures. Platelets, like red blood cells, can be visually examined before
transfusion for signs of contamination such as discoloration, aggregation, and
swirling (cloudiness) [32]. As with red blood cell transfusions, all fevers that
develop within 24 hours should be treated as a potential septic event. Platelet
bags should be retained by the blood bank for 24 hours in the event of fever.

New methods to detect bacterial contamination

Several studies have evaluated the use of culture and gram stain to identify
bacterially contaminated platelet products [33]. These studies have been cumber-
some and time-consuming, although some have been successful in decreasing
contaminated products. Few studies have evaluated red blood cell products.
Currently, there are no methods in common practice to detect bacterial contam-
ination of blood products.

Red blood cells

Red cells have a storage life of 42 days; in the future, this period may extend
to 63 or 70 days [34,35]. This allows ample time for bacterial surveillance by
culture. There have been two recent reports of surveillance by culture using
special bags attached to the collection system currently used for red blood cell
collection. Bruneau et al [36] focused on the contamination resulting from skin
flora introduced in the first 15 ml and second 15 ml of blood collected and found
1220 K.C. Quirolo / Pediatr Clin N Am 49 (2002) 1211–1238

that 2.2% of samples collected were positive for skin flora (first 30 ml of
donation). Diversion of only the first aliquot would reduce the risk of contam-
inating the unit to 0.06%. No plasma tested positive, and no unit testing positive
in the second aliquot was a true positive. A study by de Korte et al [37] examined
a system for collecting an aliquot from the entire donation for bacterial culture; it
was reported that 0.34% of the units tested had a bacterial contaminant.

Platelets
Platelets are much more likely than red blood cells to cause bacterial sepsis,
because they are stored at 20° to 24° C and potentially have a higher bacterial
load. There have been many studies of methods for determining bacterial
contamination of platelets, including antibiotic-labeled probes [38], visual
inspection , pH and glucose testing [32], and the use of gram stain and culture
[39]. Most of these tests are laborious and time-intensive, possibly taking longer
than the 5-day storage life of the product. A system similar to the red blood cell
culture methods that will use a specially designed collection system and use
oxygen consumption as a marker for bacterial growth will be marketed soon. One
abstract reported using bacterial cultures on the second day of storage to extend
the storage life of platelets safely to 7 days [40].

Emerging pathogens
With the advent of comprehensive donor screening, NAT testing, and
perhaps universal leukoreduction, blood transfusion is safer than it was only
a decade ago. Pathogens like HIV, HCV, and HBV are a persistent but vanishing
risk of transfusion. Infections once considered low risk have become more
significant (Table 2). For these low-risk pathogens there are no approved
screening tests. The blood supply is protected by accurate history taking and
deferral at the time of donation and in some cases by the apparent low virulence
of the organism.

Human herpes virus

There are eight human herpes virus (HHV) species, four of which are of
importance in transfusion medicine. Cytomegalovirus (CMV) is the most
common. Two of the HHVs have been implicated in oncogenesis: Epstein-Barr
virus (EBV), which has been documented to be transmitted via blood transfusion,
and human herpes virus-8 (HHV-8), which has not. Two other HHVs that infect
mononuclear cells are HHV-6 and HHV-7. HHV-6 infects leukocytes, natural
killer cells, and monocytes, and is the causative agent for roseola. HHV-7 infects
the same cell lines as human herpes virus-6 and has been associated with viral
rashes. All of these viruses are lymphotrophic, and their transmission could be
reduced by leukocyte filtration.
 K.C. Quirolo / Pediatr Clin N Am 49 (2002) 1211–1238 1221

Table 2
Emerging pathogens and their relationship to leukocytes and transmission
Pathogen Vector Leukocyte associated Documented transmission
Viral
CMV Human Yes Yes
EBV Human Yes Yes
HHV-8 Human Yes Yes
HHV-6/HHV-7 Human Yes No
Protozoa
Trypanosoma Insect Yes Yes
Plasmodium Mosquito No Yes
Tick-borne
Babesiosis Deer tick No Yes
Ehrlichioses Deer tick Yes No
Borrelia Deer tick Yes No
Rickettsia Wood tick Yes One case
Prion
vCJD Bovine/Human Yes No
Emerging pathogens may become more important sources of blood product contamination as
screening eliminates other risks. With the exception of CMV, blood products are not routinely tested
for these potential pathogens.
Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV, human herpes virus; vCJD,
variant Creutzfeldt-Jakob disease.

CMV
CMV is a common virus that infects approximately 40% of blood donors,
though there is a geographic variation. In the immunocompentent person the viral
infection is not severe, but the virus remains latent in mononuclear cells for an
indefinite period. Immunocompentent individuals are infected with CMV but do
not develop CMV disease. CMV disease is characterized by retinitis, gastro-
enteritis, and interstitial pneumonitis, which can be fatal in the seronegative
immunocompromised host. Seronegative immodeficient individuals at risk of
developing CMV disease as a result of a CMV-positive transfusion include: the
fetus, premature infants less than 1200 g, recipients of allogeneic stem cell
transplants, solid organ recipients, and individuals with HIV.
In the mid-1980s, bedside leukofiltration was used in an attempt to reduce the
incidence of CMV disease in at-risk patients. There have been numerous studies
and reviews regarding the safety and equivalence of leukoreduced blood products
to seronegative products. As prestorage leukofiltration and apheresis platelet
collection became more common, research showed that a three-log reduction in
leukocytes could render products statistically as safe as CMV-negative products
[41]. CMV studies were complicated by the seasonal variation in the detection of
CMV DNA in seropositive individuals. In addition, detection of CMV DNA may
or may not equate with infective virus, and seronegative individuals can have
detectible levels of CMV DNA.
There is a long history of use of leukoreduced blood products being
considered ‘‘CMV safe.’’ The Institute for Clinical Evaluative Sciences in
1222 K.C. Quirolo / Pediatr Clin N Am 49 (2002) 1211–1238

Ontario recently published a consensus statement [42] on the use of

leukoreduced products as CMV safe. A second reviewer (Box 2) [43] did
not recommend use of leukoreduced products as equivalent to CMV-negative
blood products under all circumstances. It would seem prudent to transfuse
CMV-negative, leukoreduced blood products to seronegative patients in par-
ticularly high-risk situations such as in utero surgery, expectant mothers, very
low birth weight infants, recipients of T cell – depleted stem cells during
transplant, and autologous transplant recipients. Studies comparing leukore-
duced with leukoreduced CMV-negative blood products will make clinical
decision-making easier.

EBV
It has been demonstrated that EBV is transmitted by transfusion [44] to
immunocompromised patients. This virus is the etiologic factor in posttransplant
lymphoproliferative disorder, Burkitt’s lymphoma, Hodgkin’s disease, and naso-
pharyngeal carcinoma. Currently, there is no screening test for the presence of
EBV in blood products. Theoretically, leukoreduction could decrease the risk of
transmission, but transmission during active viremia would not be prevented.
Defining the at-risk recipients, the infective dose of virus, and the effectiveness of
leukoreduction are active areas of research.

HHV-8
HHV-8 was discovered in 1994 as the etiologic agent of Kaposi sarcoma in
HIV-infected individuals. It has also been implicated as an agent in multicentric
Castelman’s disease and primary effusion lymphoma. Research has shown that
HHV-8 is transmitted by renal transplantation to seronegative recipients [45]. A
recent report from France [46] reveals that HHV-8 is primarily transmitted by
sexual contact.

Protozoan
Protozoal infection transmitted by blood transfusion is rarely documented
[47]. There is some evidence that leukoreduction reduces the numbers of some
protozoan organisms in blood products [48].

Plasmodium spp (malaria)

Infection by this protozoal pathogen is the most common and important in
transfusion medicine. There are four species of Plasmodium that infect humans:
P falciparum, P vivax, P malariae, and P ovle. There have been approximately
3000 transfusion-transmitted cases reported worldwide since 1911 [49]. In a
recent review of cases [50] in the United States, there were 93 cases of malaria
transmitted by transfusion over a period of 30 years. In the United States 54% of
the cases were caused by P falciparum and P vivax. Of the remaining, 2% were
 K.C. Quirolo / Pediatr Clin N Am 49 (2002) 1211–1238 1223

Box 2. Indications for the use of CMV-‘‘safe’’ cellular blood products

Category A: populations in whom the use of CMV-‘‘safe’’

cellular blood products has been proven to reduce the incidence
and morbidity of CMV infection using controlled trials

 Low birth weight infants born to seronegative mothers

 Seronegative recipients of seronegative donor bone marrow
(allogeneic)
 Seronegative recipients of autologous bone
marrow transplants

Category B: populations at high risk of significant morbidity as

the result of transfusion-acquired CMV infection, but the incidence
of transfusion-acquired CMV infection in these populations has not
been clearly documented or the benefit of using CMV-‘‘safe’’
cellular blood products has not been proven

 Seronegative pregnant women requiring antepartum transfu-

sion or intrauterine blood transfusions and seropositive women
requiring intrauterine blood transfusions in the second semester
 Low birth weight infants born to seronegative or seropositive
mothers or other seronegative immunosuppressed patients
requiring granulocyte transfusions
 Seronegative recipients of seronegative donor lungs and livers
and possibly other organs excluding heart and kidney recipients
 Seronegative HIV-infected and AIDS patients and children
born to HIV-infected mothers

Category C: populations who may be at higher risk of trans-

fusion-acquired CMV infection or morbidity, but in whom the
incidence or morbidity of transfusion-acquired CMV infection is
low or poorly documented

 Low birth weight infants born to seropositive mothers

 Infants with birth weights >1500 grams born to seronegative
mothers
 Neonates receiving ECMO (extracorporeal membrane oxygen-
ation) and other neonates requiring extensive transfusion
support (i.e. exchange transfusion, cardiovascular surgery)
 Seronegative recipients of seronegative donor kidneys and
hearts
 Seronegative patients with malignant disease receiving chemo-
therapy
1224 K.C. Quirolo / Pediatr Clin N Am 49 (2002) 1211–1238

 Seronegative patients with hematologic or genetic disorders

requiring repetitive transferors in who bone marrow trans-
plantation may be a future therapeutic option
 Seronegative patients experiencing major trauma or splenec-
tomy

Category D: populations in which the incidence and morbidity

associated with transfusion-acquired CMV is low, and the use of
CMV-‘‘safe’’ cellular blood products is not indicated

 Infants with birth weights >1,500 grams born to seropositive

mothers
 Other seronegative immunocompentent patients
 Seropositive transfusion recipients (excluding neonates)

Although leukoreduced red blood cell products are statistically as

safe as CMV-negative products, some patients would benefit from
CMV-negative products when available. (Adapted from Preciosi-
ties JK. The cytomegalovirus-‘‘safe’’ blood product: is leukoreduc-
tion equivalent to antibody screening? Transfus Med Rev
2000;14:126; with permission.)

unidentified and 3% were mixed; the rest were caused by P malariae and P ovale.
Of the donors identified, 75% were infective at the time of donation, and 60%
were foreign born; of the cases since 1994, 62% would have been deferred by the
existing donation criteria. There were three cases between 1996 and 1998; two of
these cases were fatal.

Trypanososma cruzi (Chagas’ disease)

Trypanososma cruzi is endemic in Mexico, Central America, and South
America, where it is transmitted by a diatomite insect during a blood meal. In
the United States, the infection is a current threat to the blood supply of
California, Arizona, New Mexico, Texas, and other states with a large
immigrant population. In Los Angeles, the seroprevalence in donors has been
estimated to be between 1 in 500 and 1 in 7500. In some areas of Texas, the
seroprevalence is 1 in 7700. In Miami, the prevalence is 1 in 9500 [51]. Other
areas of the country report transfusion-transmitted T cruzi, as well; there have
been only five reported cases of T cruzi transmission by blood transfusion in
North America, compared with a 13% to 49% transmission rate in Brazil.
Transfusion to an immune deficient host (four of the reported North American
cases) causes fulminant disease. The diagnosis can be made by serology, PCR,
and microscopy.
 K.C. Quirolo / Pediatr Clin N Am 49 (2002) 1211–1238 1225

Tick-borne infections
Transfusion-transmitted tick-borne infections are at least as rare as protozoal
infections. These infections tend to be seasonal and have geographic distribu-
tions. History of transfusion should be kept in mind when there seems to be no
other risk factor for a tick-transmitted disease.

Babesiosis microti (Human babesiosis)

Babesiosis microti was first recognized as a human pathogen in 1969. This
intracellular parasite is endemic in the northeastern and midwestern United States
with cases also reported in California and Washington. The parasite is transmitted
to humans and deer by the tick Ixodes scapularis. The reservoir for this pathogen
is a species of white footed mouse. Because of transmission by a tick vector,
blood-borne infection is seasonal. There have been approximately 25 cases
reported in the past 20 years. The parasite can survive in refrigerated red blood
cells for as long as 21 days.

Ehrlichioses spp. (Ehrlichiosis)

There are five species of Ehrlichioses. E chaffeensis causes human monocytic
ehrlichiosis (HME). E ewingii and another unidentified species resembling the
two animal species (E equi and E phagocytophila) cause human granulocytic
ehrlichiosis (HEG). HME was first described in 1986 and HGE in 1994. HME
occurs in the south central United States; HGE occurs in the northeastern and
midwestern states. The HGE parasite is transmitted by Ixodes scapularis and
I pacificus. E chaffeensis is transmitted by Ambylomma americanum. These
parasites infect humans and are found in the cellular elements of blood. There is
the potential of transmission by transfusion, though there are no reported cases.

Borrelia burgdorferi (Lyme disease)

Lyme disease was first described in 1977 and is the most common tick-borne
disease in the continental United States. Ninety percent of the cases are reported
in 10 states in the mid-Atlantic, northeastern, and upper midwestern regions of
the United States. The signs and symptoms of this disease are well known by
pediatricians. Even with widespread and frequent diagnosis, this spirochete has
never been implicated in a transfusion-related infection.

Rickettsia rickettsii (Rocky Mountain spotted fever)

Rickettsia rickettsii has been known for over a century and is endemic in most
of the continental United States. Rocky Mountain spotted fever is transmitted by
the American dog tick (Dermacentor variabilis) and the Rocky Mountain wood
tick (Dermacentor andersoni). There has been one case of transfusion-transmit-
ted Rocky Mountain spotted fever [52].
1226 K.C. Quirolo / Pediatr Clin N Am 49 (2002) 1211–1238

Table 3
Comparison between variant and classical Creutzfeldt-Jakob disease
Clinical presentation vCJD CJD
Age of onset Early Late
Mean age at death 30 years 67 years
Psychiatric and Frequent early in the Appear later in the course
sensory symptoms course of the disease of the disease
EEG changes Absence of EEG changes Diagnostic EEG changes
Duration of illness 14 months 4 months
Neuropathologic features Florid prion protein plaques Florid plaques uncommon
surrounded by spongiform changes
Immunohistochemistry Abnormal prion protein detectable Abnormal prion protein not
in lymphoid tissue detected in lymphoid tissue
Abbreviations: CJD, Creutzfeldt-Jakob disease; EEG, electroencephalogram; vCJD, variant
Creutzfeldt-Jakob disease.

Prions (Creutzfeldt-Jakob disease)

Prions and prion-related disease have recently been reviewed [53] and
discussed [54] in the medical literature. The emergence of variant Creutzfeldt-
Jakob disease (vCJD) has dramatically altered donor recruitment. The differences
between vCJD and classic CJD can be seen in Table 3. Screening tests to
distinguish between the two isoforms [55] are under investigation, but a test for
routine blood donor screening is unlikely to be available for some time. No cases
of vCJD have been associated with transfusion and there is some debate as to
whether transfusion-transmitted infections are possible. There is an animal model
[56] showing transmission by transfusion is possible. Currently, the only method
of reducing the possibility of transmission is by donor history [2]. The disease has
a long latency period, and transmission by transfusion may be rare. In Europe,
one of the goals of universal leukocyte filtration has been to decrease the
transmission of vCJD.

Transfusion-mediated immune modulation

The first well-documented immune effect of transfusion was reported in 1973
by Opeiz et al [57] and showed increased survival of renal allografts in patients
who had received allogeneic blood transfusions before transplantation. Since this
report, there have been numerous studies and reports of the immune effects of
transfusion [58]. Microchimerism has been detected decades following trans-
fusion of whole blood and other products containing viable leukocytes [59].
Transfusion-related graft versus host disease has been reported in immunocom-
petent patients following transfusion for surgery [60]. Thalassemic children who
were transfused at a younger age have a decreased incidence of alloimmunization
throughout their life [61]. There have been studies to evaluate the effect of
transfusion on the recurrence of cancer [62] and the incidence of infection
 K.C. Quirolo / Pediatr Clin N Am 49 (2002) 1211–1238 1227

following surgery [63]. These effects are frequently cited by proponents of

universal leukocyte reduction as reasons for its institution for all cellular blood
products. It should be noted that the immunomodulatory effects of blood products
appear to be inherent in the leukocyte fraction of transfused products, both at the
cellular level and the cytokine level. Most studies and effects are seen only with
nonleukocyte-reduced products.
Controversy concerning the immunomodulatory effects of nonleukoreduced
red blood cells continues. This is most strikingly represented in the report of a
conference held in March 2000 in Washington, DC, in which experts claimed
both immunomodulatory effects of blood transfusion and disclaimed the same
effects. Vamvakas and Blajchman [64] published a review of the studies of
surgical infection and cancer recurrence one year later. They felt that the
immunomodulatory effects of blood transfusion are small and could not be
conclusively documented for infection or cancer recurrence with the studies done
to date. Patients who may benefit from leukoreduction to prevent possible
immunomodulatory effects are candidates for renal transplant, immunosup-
pressed patients requiring intensive platelet support, premature infants, and
chronically transfused patients.

Transfusion-related acute lung injury

In August 2001, a letter circulated by the US Department of Health and
Human Services warned about the possibility of transfusion-related acute lung
injury (TRALI) in transfused patients [65]. There have been 45 reported fatalities
since 1992. TRALI is thought to be responsible for 13% of all transfusion
fatalities, making it the third leading cause of transfusion-related death. Most
deaths have been associated with the administration of fresh frozen plasma, but
TRALI has also been reported with all blood products containing plasma.
First reported in 1951 [66], TRALI was not widely recognized as a common
complication of transfusion until 1985, when Popvsky and Moore [67] published a
report that described 36 patients with TRALI complications. Initially, it was
theorized that donor human leukocyte antigen (HLA) and neutrophil antibodies
alone were responsible for this pulmonary syndrome. This was probably not the
sole etiology, because 1% to 2% of blood donors have HLA antibodies in their
serum, and TRALI is relatively rare. The prevalence in adult transfusions of packed
red blood cells is 1 in 2000; for platelets it is 3 in 1000 units of concentrate [68].
Clinically, TRALI is similar to acute respiratory distress syndrome. The patient
receives a transfusion of a product containing plasma, be it platelets, whole blood,
packed red blood cells, fresh frozen plasma, cryoprecipitate, or intravenous
gamma globulin (IVIG) [69]. Within 6 hours, but usually sooner, the patient
develops a fever ( > 1° C), tachypnea, and dyspnea. Hypotension has also been
reported. A chest radiograph is consistent with pulmonary edema; the findings can
progress from scattered interstitial infiltrates to complete ‘‘white-out.’’ The
mortality can be as high as 10%. If aggressive respiratory support is instituted
1228 K.C. Quirolo / Pediatr Clin N Am 49 (2002) 1211–1238

immediately, the patient usually improves within 72 hours. Occasionally, oxygen

administration is all that is required. Diuretics are not indicated because the
etiology is microvascular injury without pulmonary edema.
The differential diagnosis for this constellation of symptoms is: circulatory
overload, sepsis, anaphylactic transfusion reaction, and immediate hemolytic
transfusion reaction. Circulatory overload is most common in infants in whom
there has been an error in calculation of blood requirement, and usually occurs
within hours; it is usually not accompanied by fever and typically presents signs
of cardiac enlargement on chest radiograph. Anaphylactic transfusion reactions
usually occur within minutes of receiving a small amount of blood product; these
reactions include bronchospasm, laryngeal edema, wheezing, hypotension, and
urticaria. Bacterial sepsis from a blood component can occur rapidly in an
immune compromised patient but may occur many hours later in an immuno-
competent patient. The manifestation of sepsis is protean and includes fever,
hypotension, and respiratory distress. Pulmonary findings are infrequent. Imme-
diate transfusion reactions can begin with fever, respiratory distress, and
hypotension. Renal involvement and a disseminated intravascular coagulopathy
are common; pulmonary infiltrates are uncommon. A workup for a hemolytic
transfusion reaction will show a positive direct antiglobulin test and will usually
reveal a discrepancy in the blood type of the patient and the product.
If TRALI is due to the infusion of the plasma component of the product,
washing could eliminate this risk; however, only red blood cells easily lend
themselves to washing. The use of products with a shorter storage life has been
advocated because older products have increased lipid and cytokine concen-
trations. Lipid receptor antagonists and calcium channel blockers have also been
used, but more trials are needed to prove their efficacy. Fortunately, like acute
respiratory distress syndrome, TRALI is not common in pediatric patients but
needs to be considered when evaluating a child or adolescent with a transfusion
reaction that includes pulmonary symptoms.

Leukoreduction
Leukoreduction was first proposed as a goal for the blood industry in 1995 by
the FDA. In January 2001, Guidance for Industry [70] was released, arguing in
favor of universal leukocyte reduction. In addition, this document set forth industry
standards for quality assurance, quality monitoring, registration, and production
licensure. The FDA argument accepted most of the reasoning in favor of
leukoreduction: transfusion-associated immunomodulation, bacterial overgrowth,
viral reactivation, reperfusion injury, red blood cell and platelet storage lesions, and
a reduction in the risk of vCJD. The FDA was not convinced that leukoreduction
was protective against transfusion-associated graft versus host disease.
It is recommended that all leukocyte reduction occurs at the time of storage
[71]. There are numerous problems with bedside leukoreduction, including rare
episodes of severe hypotension, lack of quality monitoring for the actual log
 K.C. Quirolo / Pediatr Clin N Am 49 (2002) 1211–1238 1229

reduction of leukocytes, and no quality control for the procedure itself. In

addition, leukocytes in stored products undergo necrosis and release cytokines
and other degradation materials that are not well removed by leukoreduction and
can cause febrile nonhemolytic transfusion reactions. Currently, leukocyte
filtration following collection removes 99.9% of all leukocytes (Table 4) to a
final concentration of 5  106 leukocytes per unit for red blood cell products;
85% of the initial product must be retained during this process. In Guidance for
Industry, the FDA noted that in the future it would require leukocyte-reduced
products to have a final concentration of 1  106 leukocytes.
There are strong arguments for and against universal leukoreduction. Univer-
sal is the key word stressed in all arguments. There is little debate that
leukoreduction benefits some patients and that leukoreduced blood products
have a greater safety profile with few side effects. In all likelihood, universal
leukoreduction will eventually be the standard of care in the United States,
because the only downside of leukoreduction is the cost. In January 2001, the US
Department of Health and Human Resources Advisory Committee on Blood
Safety and Availability made recommendations for leukoreduction [72]. These
recommendations and the recommendations of the University Health Consortium
are presented in Boxes 3 and 4.

Pathogen inactivation
Pathogen inactivation has been a goal of blood banking since the 1940s, when
the pasteurization of albumin was used to prevent jaundice following its infusion.
For stable products such as albumin, there have been advances since the 1980s,

Table 4
Relationship between the numbers of leukocytes in blood products relative to the reduction to their
reduction by filtration
Leukocyte count of Whole blood 1  109
blood products Packed red blood cells 1  108
Frozen/washed red blood cells 1  106 – 7
Apheresis platelets 1  106 – 8
Platelet concentrate (from whole blood ) 1  107

Log of leukocyte Percent leukocyte Residual

reduction Log reduction removal leukocyte count
1 log 90% 1  108
2 logs 99% 1  107
3 logs 99.9% 1  106
4 logs 99.99% 1  105
With today’s technology, it may not be possible to achieve the log reductions recommended by the
FDA (apheresis platelets are reduced at time of collection).
From Preciosities JK. The cytomegalovirus-‘‘safe’’ blood product: is leukoreduction equivalent to
antibody screening. Transfusion Medicine Reviews 2000;14:126; with permission.
1230 K.C. Quirolo / Pediatr Clin N Am 49 (2002) 1211–1238

Box 3. Recommendations for leukoreduction of blood products

Technology Assessment Group

Clinical Practice Advancement Center
University HealthSystem Consortium

Indications for Use of Leukoreduced Components

. Decrease alloimmunization during platelet long-term support

. Reduction of risk of cytomegalovirus infection
. Prevention of febrile non-hemolytic transfusion reactions
. Decrease the incidence of HLA alloimmunization in non-
hepatic solid-organ transplantation

Non-indications for Use of Leukoreduced Components

. Prevention of reactivation of endogenous viral infections

. Prevention of immunomodulatory effects of transfusion
. Reduction of length of hospital stay
. Prevention of transfusion-associated GVHD or TRALI
. Prevention of bacterial sepsis
. Prevention of transmission of cell associated known or
unknown infectious agents
. Prevention of vCJD

Administrative

. Prestorage leukoreduction is recommended

. Use of leukoreduction to maintain a single inventory of
products is not justified

Policy

. Universal leukoreduction is not justified

– For benefit-to-risk reasons
– For benefit-to-cost reasons
. Universal Leukoreduction is not justified to align United
States policy with the policy of other nations
. The FDA should not mandate universal leukoreduction on
the basis of current scientific and medical evidence

Adapted from Ratko TA, Cummings HA, Obermann HA. Evi-

dence-based recommendations for the use of WBC-reduced cellular
blood components. Transfusion 2001; with permission.
 K.C. Quirolo / Pediatr Clin N Am 49 (2002) 1211–1238 1231

Box 4. Universal leukoreduction advisory committee on blood safety

and availability January 2001

1. Universal leukoreduction should be implemented as soon

as feasible.
2. With regard to universal leukoreduction, the Advisory Com-
mittee is concerned about the availability of blood and the
resources necessary to implement universal leukoreduction.
For these reasons, the Advisory Committee recommends that
the actions of the Department of Health and Human Resources
should strive to
a. Minimize the impact on supply
b. Ensure adequate funding for this effort
c. Issue a regulation to implement universal leukoreduction
that addresses these concerns, and
d. Report to the Advisory Committee on a regular basis the
progress toward these goals.
3. Given the unresolved scientific issues in the field, the Advisory
Committee supports continuing research on the effectiveness
of leukoreduction.
4. In the above resolutions, the word ‘‘leukoreduction’’ is
intended to mean prestorage leukoreduction, and the reso-
lutions refer to non-leukocyte cellular blood components.

Source for these recommendations can be found at

www.dhhs.gov/bloodsafety.

The Advisory Committee to the Food and drug Administration

has recommended Universal Leukoreduction be implemented as
soon as possible for the national blood supply

such as solvent/detergent processing to nanofiltration methods, in the processes

used to create a safer product. This article does not explore the methods used for
the purification of nonlabile blood products, because an excellent review of this
topic has recently been published [73].
Experiments in pathogen inactivation have used porphyrins, phenothiazines
(methylene blue), cyanines, psoralens (Helinx), and other compounds such as ribo-
flavin, ethylene imines (Inactine), and frangible anchor-linked effector compounds
(FRALEs) to inactivate viruses, bacteria, and leukocytes. A recent review explores
all of the recent studies of pathogen inactivation [10]. Currently, the most
promising methods of pathogen inactivation are psoralens, ethylene imines,
and riboflavin.
1232 K.C. Quirolo / Pediatr Clin N Am 49 (2002) 1211–1238

Psoralens
Psoralens are naturally occurring compounds that were used to treat psoriasis
in the 1970s through oral ingestion followed by ultraviolet light exposure. The
chemistry and toxicity of these compounds was investigated at that time.
Psoralens are planar, aromatic compounds that intercalate with bases in nucleic
acids and, when exposed to ultraviolet light (UVA 320– 400 nm), form covalent
additions (called adducts) to the pyrimidine bases. They can form either mono- or
diadducts, and in either case block nucleic acid replication. These compounds can
be used in a dose that will overwhelm the repair mechanisms of bacteria, viruses
[74], or leukocytes [75], and halt replication and therefore infectivity or function.
Neither red blood cells nor platelets require replication to function, nor are they
affected by psoralens.

FRALEs
FRALEs (S-303) are unique compounds that irreversibly cross-link nucleic
acids without the use of light. They are used to inactivate pathogens in red blood
cell products. FRALEs are reported to decompose after pathogen inactivation.
They have been tested against common viral and bacterial pathogens and have
been proven to be very effective.

Ethylene imine
Ethylene imine is a unique, low molecular weight, water-soluble imine that
crosses cell membranes. The active compound is known as PEN110; the process
of pathogen inactivation is known as the INACTINEÔ process. This compound
does not require light for activation and is effective in low concentrations. The
process of inactivation is complex. The blood product is incubated for 24 hours at
23° C, then washed 12 times with an instrument (Hemonetics) designed
specifically for this process. The finished product is a unit of washed, leukore-
duced, pathogen-free product in a standard preservation solution (AS-3).

Riboflavin
Riboflavin (vitamin B2) is a water-soluble coenzyme that participates in
oxidation reduction reactions. This vitamin is ingested in the diet and is rapidly
taken up by cells to participate in metabolic processes. This vitamin/pathogen
inactivator has only been used in platelets. It is activated by visible light and
cross-links nucleic acids. The latest research on this compound has been
performed in the Netherlands.
Pathogen inactivation holds great promise for the future of transfusion
medicine and blood banking. Like all new medical procedures and pharmaceu-
ticals, the actual risks and benefits of these components and procedures will take
years to determine. The cost of these procedures could be significant.
 K.C. Quirolo / Pediatr Clin N Am 49 (2002) 1211–1238 1233

Red blood cell storage, substitutes, stealth cells

Prolonging red blood cell storage

In 1961, Simon et al [76] demonstrated that adenine could be added to red
blood cells to prolong their survival. In 1977, Zuck et al [77] demonstrated that
this was a viable method of preservation, convincing the FDA to approve adenine
for red blood cell storage. With the removal of plasma and the use of additive
solutions (AS-1, AS-3, and CPDA-1, CPDA-2 or CPDA-3), the storage life of
blood is currently 42 days. Even with these additive solutions, there continues to
be a storage lesion shorting the life of preserved red blood cells. The storage
lesion has been recently reviewed [49].
Recent developments will eventually have an impact on the preservation and
storage of red blood cell concentrates. With new apheresis collection devices it
will be possible to collect leukoreduced products in combinations ready for
transfusion with limited, if any, component processing. These devices can collect
two units of red blood cells; a unit of red blood cells, platelets, and plasma; or
combinations of these components. In addition, because they are apheresis
products, the volume, hematocrit, leukocyte count, and platelet count can be
predetermined by the collection machine [78]. Removing leukocytes and creating
a uniform product will have a positive impact on red blood cell storage. Two
recent reports by Hess and colleagues [34,35] show that the 42-day storage limit
may be extended to 63 or 70 days.

Red blood cell substitutes

A substitute for blood has been an elusive goal [79] since the 1970s, when free
hemoglobin was used as a red blood cell substitute. Since that time, hemoglobin-
based substitutes and perfluorocarbon-based red blood cell substitutes have been
investigated. In 1986, a study of a perfluorocarbon emulsion showed that it was
not an effective substitute for blood products [80]. In 1991, the Center for
Biologics Evaluation and Research published strict guidelines [81] for the
production, use, and efficacy of hemoglobin-based blood substitutes. The only
hemoglobin-based red blood cell substitute currently in clinical use is being
applied in veterinary medicine.
All of these substitutes are marketed as ‘‘bridges’’ to be used for stabilization
until red blood cell products are available. In the past, the safety and availability
of donated blood products has been a driving force for the development of these
products. As the availability and safety of blood products improves, there may be
less demand for these potentially expensive synthetic products.

‘‘Stealth’’ red blood cells

In 1996, the attachment of polyethylene glycol (PEG) to red blood cells was
accomplished [82]. Since that time there have been several groups working with
1234 K.C. Quirolo / Pediatr Clin N Am 49 (2002) 1211–1238

PEG in various forms to coat red blood cells, making their antigens unavailable
for immune interaction when transfused.
In early testing, treated cells did not react with commercially available
antibodies against the Rh antigens (D, C, c, E, e), Kell antigen, or Duffy or
Kidd antigens. Some studies have indicated a shortened survival for PEG-treated
red blood cells, and preliminary indications are that PEG itself may be
immunogenic. A recent report of human red blood cells treated with PEG showed
that PEG did not activate complement but actually enhanced interactions with
ABO-mismatched sera leading to complement activation and cell lysis [83].

Summary
In the next decade, many of the methodologies and research reviewed in this
article will become clinical practice, making the transfusion of blood products
safer and more universally available than they are today. NAT will be standard
and will surely be performed on each unit of product, PCR testing for pathogens
will evolve, and the pathophysiology and immunology of transfusion-related
events such as TRALI and immunomodulation will be elucidated. New methods
of preservation and early detection of contamination will extend the life of blood
products. Red blood cell antigens may be attenuated, making safe products
available to more patients. Clinical vigilance at the bedside and in the blood bank
will remain key areas for transfusion safety. As I have told many a resident and
patient, blood is not saline; there are and will remain risks inherent in this
commonly used medical therapy.

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