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Blood, 1
October 2008, Vol. 112, No. 7, pp. 2617-2626.The hazards of blood transfusion in historical perspective
Harvey J. Alter1,*,
and Harvey G. Klein1,*
ASH 50TH ANNIVERSARY REVIEW
1 Department of Transfusion Medicine, National
Institutes of Health, Bethesda, MD Abstract
The beginning of the modern era of
blood transfusion coincided with World War II and the
resultant need for massive blood replacement. Soon
thereafter, the hazards of transfusion, particularly hepatitis
and hemolytic transfusion reactions, became increasingly
evident. The past half century has seen the near
eradication of transfusion-associated hepatitis as well
as the emergence of multiple new pathogens, most notably
HIV. Specific donor screening assays and other
interventions have minimized, but not eliminated, infectious
disease transmission. Other transfusion hazards persist,
including human error resulting in the inadvertent
transfusion of incompatible blood, acute and delayed
transfusion reactions, transfusion-related acute lung
injury (TRALI), transfusion-associated graft-versus-host
disease (TA-GVHD), and transfusion-induced immunomodulation.
These infectious and noninfectious hazards are reviewed
briefly in the context of their historical evolution.
"Blood transfusion is like marriage: it should not be entered
upon lightly, unadvisedly or wantonly or more often than is
absolutely necessary." This tongue-in-cheek simile from Robert
Beal has an inherent truth that serves as the foundation for
this historical review. Although blood transfusion is
increasingly safe, it remains hazardous in many respects,
and its history is replete with severe, sometimes fatal,
complications that are both infectious and noninfectious
in origin. Only the highlights can be chronicled in this
brief overview.
Transfusion-associated hepatitis
The American Society of Hematology (ASH) was just a gleam in
William Dameshek's eye when serum hepatitis emerged as a major
hazard of blood transfusion among surviving battlefield
casualties of World War II. Whereas ASH was rapidly
organized in the aftermath of the war, it took nearly 3
decades before the hepatitis B virus, then termed the
serum hepatitis virus, was identified and a blood
screening test developed. This arduous path from
observation to discovery culminated in the serendipitous finding
of the Australia antigen in 1963.1
In the early 1960s, Baruch Blumberg, a geneticist then at
the National Institutes of Health (NIH), discovered
polymorphisms in human β-lipoproteins using the technique
of Ouchterlony immuodiffusion.2 Harvey
Alter, then a clinical fellow in transfusion medicine at
NIH, was using the same technique to investigate whether
antibodies to human protein variants might cause
transfusion reactions. The similarity of approaches,
albeit to different ends, led to a collaboration that
screened the serum of multiply transfused patients against
the serum of diverse global populations for evidence of
antibodies to polymorphic proteins. A characteristic of
lipoprotein immunoprecipitates was that they stained blue
when a lipid stain was applied. In 1963, a precipitin was
observed that stained only weakly for lipid, but
intensely red when counterstained for protein. It was
this "thin red line," the result of the interaction between
the serum of a multiply transfused hemophiliac patient from
Brooklyn and the serum of an Australian aborigine, that
ultimately became the breakthrough finding in the then
semidormant field of hepatitis research (Figure
1). Initially called the "red antigen," it was
subsequently termed the Australia antigen (Au) and,
later, the hepatitis B surface antigen (HBsAg).
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Figure 1.
Au antigen discovery. An Australian aborigine
(top) and the precipitin line formed between the
aboriginal serum and that of a multiply transfused
patient with hemophilia (bottom). The precipitin
failed to stain for lipid, but stained red with the
azocarmine counterstain for protein. Reprinted with
permission of Nature Publishing Group from Alter HJ
and Houghton M, Hepatitis C virus and eliminating
posttransfusion hepatitis (Nat Med.
2000;6:1082-1086).
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Early investigations of Au sought prevalence and disease
associations. Interestingly, the antigen was found in
0.1% of the normal donor population but in 10% of
patients with leukemia. Thus, when the first paper to
describe Au was published in 1965,1 it
made note of the association with leukemia and even
speculated that this antigen might be part of the then
postulated leukemia virus. At the time of discovery,
there was no sense that this cryptic red antigen would
unravel a hepatitis mystery that dates to early
descriptions by Hippocrates.
In 1964, Blumberg moved to the Institute for Cancer Research
in Philadelphia, where he continued to unravel the Au
conundrum. He believed at the time that Au was a
genetically determined human protein that possibly
enhanced susceptibility to leukemia, and thus elected to
study patients with Down syndrome, who had an inherited
predisposition to leukemia. Although initiated on a
faulty premise, study findings were definitive and highly
relevant: Down patients who resided in large institutions had
an Au prevalence of 30%, whereas those in smaller institutions
had a prevalence of 10%, and those living at home only 3%; the
antigen was absent in newborn Down cases.3
This observation suggested that Au was not inherited, but
rather a manifestation of crowded living conditions and
thus possibly related to an unidentified infectious
agent. This background was prelude to a serendipitous
event. A technologist in the Blumberg lab who had long
served as an Au-negative control retested her blood at
the time she was feeling ill and turning icteric. Her previously
Au-negative blood tested strongly positive, coincident with
the onset of classic acute hepatitis. This initial link to a
hepatitis virus was confirmed in expanded studies4
and subsequently shown to be specific for the hepatitis B
virus.5 In retrospect, these
findings nicely explained the association with institutionalized
patients and the high prevalence in patients with leukemia,
who were both highly exposed by transfusion and
immunosuppressed with a proclivity to the HBV carrier
state.
Thus, through observation, serendipity, and perseverance, a
unique antigen was found that proved to be an integral part
of the hepatitis B virus envelope protein and then served as
the foundation for (1) the first donor screening and
diagnostic assay for human hepatitis; (2) a highly
effective hepatitis B vaccine that not only prevents
hepatitis B, but also prevents HBV-associated
hepatocellular carcinoma; and (3) the recognition of
non-A, non-B (NANB) hepatitis by serologic exclusion and
hence, ultimately set the stage for the discovery of the hepatitis
C virus. This is a heady outcome for a single precipitin line
that stained the wrong way.
In 1967, prospective studies of posttransfusion hepatitis were
initiated at NIH by Bob Purcell, Paul Holland, Paul Schmidt,
and John Walsh and then continued over the course of almost
3 decades by this author (H.J.A.). The earliest study in this
seriesshowed that the incidence of TAH in multiply transfused
cardiac surgery patients astonishingly exceeded 30% and that
much of that risk was due to the use of paid donor blood.6
In 1970, the NIH Blood Bank simultaneously adopted an
all-volunteer donor system and introduced a
first-generation agar gel assay to screen for HBsAg. The
outcome of this dual intervention was dramatichepatitis
rates fell by 70% to a new baseline level of
approximately 10%7 (Figure
2). Retrospective testing showed that only 25% of TAH
was hepatitis Brelated, leaving 75% of cases tentatively
classified as non-B hepatitis. By 1973, the development
of more sensitive enzyme-linked immunosorbent assay
(ELISA) screening assays for the detection of HBsAg led
to the near eradication of hepatitis B cases within our study
population (Figure 2). In 1975, Feinstone,
Kapikian, and Purcell8 at NIH
discovered the hepatitis A virus (HAV), and we immediately
tested stored sera from our non-B hepatitis cases.
Surprisingly, not a single case was due to HAV, the only
other known hepatitis virus at that time. Hence, the
origin of the designation "non-A, non-B hepatitis,"9
a descriptive term that we thought would be short-lived,
but the agent defied serologic definition for almost 15
years. However, in the interim, the infectious nature of
the NANB agent was proved in a series of chimpanzee transmission
studies,10,11
and its physical characteristics were partially defined
by testing the effects of in vitro manipulations on
subsequent infectivity in the chimp. In this way it was shown
that the NANB agent was lipid-encapsidated12
and 30 nm to 60 nm in diameter.13
These experiments narrowed the taxonomic range of viral
agents to be considered and raised the possibility that
the NANB agent might be a flavivirus, as first suggested
by Bradley14 and as eventually proved
true. Of most significance, prospective follow-up showed
that NANB hepatitis was generally a persistent infection
and that it evolved to cirrhosis in approximately 20% of
cases,15 an incidence that is still
valid today.
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Figure 2.
The decreasing incidence of
transfusion-associated hepatitis in blood recipients
monitored prospectively. Incidence, traced from
1969 to 1998, demonstrates a decrease in risk from
33% to nearly zero. Arrows indicate main
interventions in donor screening and selection that
effected this change. Reprinted with permission of
Nature Publishing Group from Alter HJ and Houghton
M, Hepatitis C virus and eliminating
post-transfusion hepatitis (Nat Med.
2000;6:1082-1086).
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In the 1980s, we attempted various surrogate interventions to
prevent TAH, particularly alanine amino-transferase (ALT) and
anti-hepatitis B core (anti-HBc) testing of donor blood. Both
these interventions were predicted to have 30% to 40% efficacy
in retrospective analyses of stored donor and recipient
samples.16,17
However, their impact in prospective follow-up was marginal.
Nonetheless, as the cumulative result of surrogate testing,
anti-HIV testing, and the more judicious use of blood in the
wake of the AIDS epidemic, hepatitis incidence had fallen to
4% by 1989 (Figure 2). At that time,
Houghton and associates at Chiron Corporation cloned the
NANB agent and called it hepatitis C virus (HCV).18
To validate their discovery, Chiron requested a coded
NANB panel that we had constructed from pedigreed sera
proven to transmit NANB infection to humans or chimpanzees.
Although multiple other claims of NANB discovery had failed
this panel, Chiron broke the code flawlessly. We then selected
15 characteristic NANB hepatitis cases from the NIH
prospective study and showed that each patient developed
anti-HCV antibody in temporal relation to their acute
TAH, and that a positive donor could be identified in 80%
to 88% of cases.19 Hence, NANB
metamorphosed seamlessly into HCV. Houghton and coworkers'
unique application of the then emerging field of
molecular biology was a monumental effort extending over
6 years that culminated in the first donor screening test
for antibody to HCV in 1990. Hepatitis incidence then
fell from 4% to 1.5% and a second-generation anti-HCV
assay introduced in 1992 achieved virtual zero incidence
(Figure 2). At present, TAH incidence is so low
that it has to be mathematically modeled, and the risk of
hepatitis C is calculated to be 1 case in every 1.5
million to 2 million exposures, a remarkable incidence
compared with the 30% rate that prevailed in 1970 and the
10% rate in 1980.
Transfusion-transmitted HIV
As the hepatitis story was evolving slowly through the 1970s
and early 1980s, a new disease exploded into recognition and
struck terror into both blood recipients and those responsible
for the blood supply. In 1981, unusual opportunistic
infections and cancers, particularly Pneumocystis
carinii and Kaposi sarcoma (KS), were reported for
the first time among men who have sex with men (MSMs).20
Originally localized to New York and California, this
acquired immunodeficiency disease spread rapidly; by May
1982, 1 year after the first case report, 355 cases had been
recognized in the United States,21
primarily in MSMs, injection drug users (IDU), and
persons immigrating from Haiti. Concern for transmission
by transfusion was aroused in late 1982 when 3 cases were
observed in patients with hemophilia A in whom clotting
factor concentrates were the only probable source.22
Further evidence for transfusion transmission came in 1983,
when a multiply transfused infant developed immunodeficiency
and opportunistic infections posttransfusion, and 1 platelet
donor to this infant was found to have developed AIDS 10
months after the index donation.23
In the absence of an identified agent and an appropriate
screening test, transfusion-associated AIDS cases
continued to accrue at alarming rates. By 1992 there were
9261 cases of AIDS attributed to blood transfusion administered
before the introduction of anti-HIV screening assays in 1985.
The total number of transfusion-related HIV infections has
been estimated at 12 000.24
Of the 37 019 AIDS cases identified by 1987, 741 (2%)
were in transfused adults, 61 (0.2%) in transfused
children, and 364 (1%) in recipients of clotting factor
concentrates.25 Among all AIDS cases
in children, transfusion accounted for 12%. Tragically,
based on surveys in 1982-1984, 74% of persons with factor
VIII deficiency and 39% of those with factor IX
deficiency were antiHIV-positive.26
Approximately 90% of severe hemophiliacs were
HIV-infected before the first case of AIDS was recognized
in 1981.
A dramatic and remarkable decrease in the incidence of
transfusion-transmitted AIDS followed the groundbreaking
discovery of HIV in late 1983 and 1984 by investigative
groups led by Luc Montaigne27 and
Robert Gallo.28 Within a year of
these discoveries, an assay for anti-HIV was licensed and
used to test all transfused products; HIV prevalence in
volunteer donors at that time was 0.04%. Since the
implementation of donor screening, only 49 transfusion-associated
cases have been identified, primarily from window period
donations before the introduction of nucleic acid
screening tests for HIV RNA in 2000. No cases have been
attributed to clotting factor concentrates after the
introduction of virocidal treatments in the early 1980s.
The current risk of transfusion-transmitted HIV is
estimated to be 1 case per 2 million transfusions.
The blood bank community has been chastised for its perceived
failure to act during the early years of the AIDS epidemic,
and many lawsuits were brought based on the failure to
introduce antihepatitis B core testing as a surrogate
marker for HIV and for being late to introduce
inactivation measures for clotting factor concentrates.
In retrospect, both of these measures would have been
highly effective, but the decisions were not easy when
viewed in real time. It is hard to convey the pressures
existing in 1982 to 1984 in the face of an exploding epidemic
of a fatal disease whose etiology was unknown, whose link to
transfusion was initially tenuous, whose prevention by direct
blood screening was impossible, whose prevention by indirect
means would significantly diminish the blood supply, and whose
primary risk groups brought pressure not to be excluded as
blood donors by virtue of lifestyle. We write this not as
apologists for early inaction, but to portray the
immense, seemingly insurmountable dilemmas that existed
at the time.
One positive outcome of the AIDS tragedy was adoption of a new
paradigm in blood transfusion, the precautionary principle,
which states that "for situations of scientific uncertainty,
the possibility of risk should be taken into account in the
absence of proof to the contrary" and that "measures need to
be taken to face potential serious risks."29
This paradigm for action has served well to protect
against emerging infections that followed in the wake of
HIV. Nonetheless, in the absence of preemptive pathogen
inactivation, the blood supply remains vulnerable to an
emerging, potentially lethal agent that, like HIV, has a
long asymptomatic viremic phase before disease recognition.
Zoonotic infections that threaten the blood supply
The most recent threats to the blood supply have been agents
that primarily affect animals but, through efficient mosquito
or tick vectors or the food supply, have adapted to humans as
secondary hosts and have spread by transfusion because of an
ensuing circulatory phase. These vector-borne agents include
Plasmodium spp (malaria), dengue fever virus, West Nile
virus (WNV), Trypanosoma cruzi (Chagas disease),
Babesia spp (babesiosis), human herpesvirus-8 (KS
virus), and others. These are not newly emergent viruses,
as was HIV, but rather have emerged as new threats due to
changing population dynamics or altered migration
patterns of intermediate hosts and vectors.
WNV is a case in point. Previously confined to Africa, India,
and the Middle East, in 1999 it suddenly appeared in the New
York City borough of Queens, perhaps transported by a single
infected bird or a mosquito hitching a ride on a 747.
Fifty-nine clinical cases of WNV infection were
identified in the 1999 New York outbreak.30
By 2002 to 2003, nearly 14 000 symptomatic cases of WNV
fever or meningoencephalitis had been identified across
the entire continent, including Canada and Mexico; it is
estimated that several hundred thousand individuals were
infected. From this reservoir, 4 transplant-associated cases31
and 23 transfusion-transmitted symptomatic cases32
were identified by 2002, and it is estimated that at
least 100 times that number of asymptomatic infections
also occurred. A nucleic acid test for WNV was developed
very rapidly and implemented in time for the mosquito
season of 2003. Testing has identified and interdicted
more than 2000 potentially infectious blood components during
the test's first 3 years of use.33
Residual transfusion cases are now exceedingly rare.
Variant Creutzfeld-Jakob disease (vCJD) exemplifies a truly
emergent disease passed through the food chain to humans and
from them to other humans through blood transfusion. vCJD is
not strictly an infectious disease, but it behaves as such
because of transmissible, abnormally folded prions that
cause the human equivalent of bovine spongiform
encephalopathy (BSE, or "mad cow disease"). Cows were
infected by feed (offal) contaminated by
prion-contaminated neurologic tissue from sheep with scrapie.
The BSE epidemic spread rapidly in the United Kingdom until
controlled by cattle slaughter and bans on offal production.
Approximately 8 years after the beginning of the BSE epidemic,
unusual cases of a neurologic disease, primarily in young
adults, began to appear in the United Kingdom and were
shown to be due to a BSE-like variant that was designated
vCJD. This added to the growing list of transmissible
spongiform encephalopathies (TSEs). Approximately 160
cases of human vCJD disease have been recognized in the
United Kingdom and 30 elsewhere in the world34
and have been attributed to ground beef products that
contained neurologic tissue from BSE-infected cattle.
Four transfusion-transmitted cases have been traced to 3
donors who became symptomatic with vCJD 3 or more years
after the index donation.35,36
Thus, there is a long asymptomatic carrier state for vCJD
that currently defies detection. Furthermore, these
abnormally folded prions are highly resistant to
inactivation procedures. The primary intervention at
present is to indefinitely defer donors who have a
history of visiting BSE-affected European countries,
particularly Great Britain, during the years of likely exposure.
This policy has had substantial impact on blood availability.
Considerable efforts are in place to develop assays to detect
abnormal prions or filters that would remove them from blood
products. Fortunately, as the result of comprehensive public
health measures, both BSE and vCJD are on the wane, though
neither has been eradicated.
Bacterial contamination
The earliest efforts to interdict a transfusion-transmitted
infection involved syphilis. Kilduffe and DeBakey identified
more than 100 cases that had been published after 1915, all
from direct transfusion.37 Some
138 cases had been reported by 1941. Screening began in
1938 and all blood collections are still tested for the
presence of T pallidum. However, spirochetes do
not survive well in citrated blood stored for more than 72
hours, so few transmissions have been documented in the
developed world since the 1940s. The last case published
in the United States was reported from the Clinical
Center at the National Institutes of Health in 1969.38
Bacterial contamination of stored blood components originally
collected in reusable glass bottles was among the earliest
recognized risks of transfusion.39
The introduction of sterile interconnected plastic
container systems and controlled refrigeration of blood
components seemed to eliminate this risk by the 1960s; however,
this proved not to be the case. The risk for RBC transfusion
remains very low, estimated at 0.21 infections per million
units.40 However, platelet components
remain particularly vulnerable to bacterial contamination
because their storage temperature (20°-24°C) facilitates
microbial growth. For more than 25 years the risk of
contamination by bacteria and bacterial pyrogens was
largely ignored. Few components were cultured for
bacteria and even fewer reports were published. Contamination
of platelets is now recognized to have occurred in 1 of every
2000 to 5000 collections before the recent implementation of
bacterial testing, and bacterial sepsis from apheresis
platelets had been measured at 1 in 15 000 infusions.41,42
Introduction of routine culture within the last 5 years
has reduced the risk by approximately 50%. The residual
risk of a septic transfusion reaction from a
culture-negative single-donor unit has been calculated at
1 in 50 200.43 Approximately half the
contaminations come from skin flora, and probably derive
from cored skin at the venipuncture site, whereas the
remainder probably represent organisms that circulate
transiently in the asymptomatic blood donor. Strategies
such as improving the venipuncture site skin preparation,
diverting and discarding the initial few milliliters of
collected blood, and introducing point-of-issue rapid bacterial
screening will likely reduce the risk; however the most
effective strategy would be introduction of preemptive
pathogen reduction that would inactivate bacteria as well
as viruses.44
Hemolytic transfusion reactions
The first clinical transfusions, almost 200 years ago and almost
a century before the discovery of blood groups, were
associated with a 50% mortality.45
Because the deaths occurred during or shortly after
transfusion and because the blood was freshly collected,
it is unlikely that infectious agents played any role in
these deaths (Figure 3). How many of these deaths
were attributable to blood group incompatibility and how
many to the severity of the underlying illness remain
unknown. Landsteiner's discovery of the major blood
groups, although not intended to improve transfusion
safety, permitted the first pretransfusion compatibility
testing and prevented at least some of the deaths related
to ABO incompatibility.46 During the
ensuing 50 years, evolving serologic techniques including
the direct antiglobulin (Coombs) test led to the
discovery of numerous new red-cell antigens and
antibodies. Nevertheless, mortality related to acute
hemolytic transfusion reactions remained disturbingly
frequent well into the 20th century with rates approaching 1
in every 1000 transfusions.37,47
Improved compatibility testing and technology that
identifies and links donated blood with laboratory test
results and the intended recipient have dramatically
reduced the risk, but hardly eliminated it. Acute hemolytic
transfusion reactions and related mortality are now estimated
at approximately 1 in 76 000 and 1 in 1.8 million units
transfused, respectively.48
In the most recent analysis of transfusion-related deaths
reported by the Food and Drug Administration (FDA), 7%
were attributed to ABO-associated hemolytic reactions and an
additional 20% to non-ABO antibodies.49
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Figure 3.
Sketch of Blundell's gravitator. Blood from
the donor dripped into a cup fixed several feet
above the arm of the recipient and was directed
through tubing into the recipient's vein. Adapted
from Blundell J, Observations on transfusion
(Lancet. 1828;2:321) with permission from Elsevier.
Illustration by Marie Dauenheimer.
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Most deaths from acute hemolysis are still caused by mistakes
in identifying blood samples, blood components, and blood
recipients. In a recent 10-year period, 1 in every 38 000
red cell units (RBC) transfused in New York state
resulted in an error-related ABO-incompatible
transfusion.48 Half of these errors
occurred outside of the blood bank. A large international
survey of 62 hospitals reported, based on 690,000
samples, that 1 in every 165 blood specimens is
mislabeled or miscollected.50 In
contrast, the use of national patient identification
systems in Sweden and Finland has reduced the rates of
miscollected samples to levels too low to measure
directly. In the United States, the rate of mislabeled
samples and miscollected samples is 1000- to 10 000-fold
greater than the risk of clinically significant
transfusion-transmitted viral infection. We have room for
improvement.
In the era of whole blood transfusion, acute hemolysis followed
infusion of plasma containing antibodies to red-cell antigens
(passively acquired antibody). Today, acute hemolysis
resulting from passive antibody is uncommon, because RBCs
contain only small amounts of plasma, fresh frozen plasma
infusions are restricted to ABO-compatible donors, and
acute hemolysis caused by transfused antibodies other
than those in the ABO system is unusual. However, severe
reactions still occur when mismatched plasma is infused
with apheresis platelets.51 A report
in Blood underscores the risk of infusing anti-D
to treat immune thrombocytopenia.52 In
the latter case, the incidence of acute hemolysis is estimated
at 1 in 1115 patients treated, and the mechanism of
intravascular hemolysis remains unexplained.
Delayed hemolytic transfusion reactions (DHTR) are more common
but usually less severe than acute hemolysis. Delayed
reactions occur when a patient previously sensitized by
pregnancy or transfusion receives "incompatible red
cells," because the low titer of circulating alloantibody
escapes detection by pretransfusion testing. Over the
years, DHTR have led to the identification of previously
undescribed red-cell antigens. Studies from our
institution more than 40 years ago determined that red cell
alloimmunization occurs at a frequency of approximately 1% per
unit transfused, and in up to 36% of transfused patients with
sickle cell disease.53,54
We know now that the rate of sensitization is affected by
both genetic factors and the patient's immune status.
DHTR commonly go unrecognized because they occur several
days after transfusion, which today means often after hospital
discharge, The low-grade fever, a decline in hemoglobin
concentration, fatigue, and mild jaundice commonly go
unrecognized.55 However, we
and others have noted that DHTR can be severe, even fatal,
particularly in patients with sickle cell disease.56
The incidence of DHTR is now estimated at approximately 1
in 6000 units transfused, it but may be decreasing as a
result of more effective pretransfusion screening.57
To further reduce the risk of alloimmunization and DHTR,
extended red-cell phenotyping using a combination of
serology and newly introduced molecular techniques can provide
matched red cells to chronically transfused patients,
particularly those who are "immune responders" and those
with sickle cell disease.58
Reactions associated with leukocytes and leukocyte
antibodies
The possibility that leukocyte antibodies might cause transfusion
reactions arose from the discovery more than 50 years ago of
potent leukoagglutinins in the serum of patients who developed
fever repeatedly after transfusions. Transfusion of the
leukocyte-rich fraction of blood produced a severe
febrile reaction, whereas transfusion from the same unit
with less than 10% of the buffy coat caused none.59
In a confirmatory study, the minimal number of leukocytes
required to produce a reaction varied from 0.25
x 109 to more than 25
x 109, and the degree
of temperature elevation corresponded to the number of
incompatible leukocytes transfused and the rate of
transfusion.60 These early studies
suggested that leukocyte-poor blood prepared for patients
who have febrile reactions due to leukoagglutinins should
contain fewer than 0.5 x
109 leukocytes, or approximately 10% of the number in
a unit of fresh blood. Such levels were difficult to achieve
consistently and economically with early centrifugal component
preparation methods. After the development of efficient
leukoreduction filters, most blood components in the
developed world are now processed to achieve leukocyte
levels that are lower by several orders of magnitude.
Transfusion reactions related to leukocyte antibodies are now
recognized to include a range of signs and symptoms in
addition to fever, including dyspnea, hypotension,
hypertension, and rigors. As the pathophysiology of these
reactions has become better understood, some puzzling
aspects have been explained. Antibodies bind to the
transfused leukocytes and the resulting complexes
activate monocytes, which release cytokines with pyrogenic
properties.61 We have come to
appreciate that the frequency of febrile reactions
depends on the type of blood component, its storage
conditions, and a variety of factors specific to the
recipient. For RBC transfusion, reported frequency ranges
from less than 1% to more than 16%.62,63
In contrast to RBC, fever occurs in as many as 30% of
platelet transfusions, a striking disparity that may
reflect platelet-specific factors as well as the effects
of inflammatory cytokines, chemokines, and bacterial
pyrogens that accumulate in platelet concentrates during several
days of storage at room temperature. A series of seminal
studies indicated that pyrogens in these concentrates
reside in the plasma and increase over time.64
In a large randomized study,65 only
2.2% of platelet transfusions resulted in a moderate or
severe reaction, and prestorage removal of white cells by filtration
significantly decreased the reaction rate. For immunized
patients, HLA-matched platelets also result in lower
reaction rates.
Graft-versus-host disease
Transfusion-associated graft-versus-host disease (TA-GVHD) occurs
when immunocompetent allogeneic lymphocytes in transfused
blood engraft in the recipient, proliferate, and mount an
attack against the host tissues. The earliest reports of
what was once considered a rare and invariably fatal
disease involved fetuses receiving intrauterine exchange
transfusion and children with impaired immunity such as
the Wiskott-Aldridge syndrome and thymic aplasia.66,67
The clinical picture of fever, rash, diarrhea, hepatitis,
lymphadenopathy, and pancytopenia drew comparison with
the runt syndrome developed by newborn mice that were
challenged with adult splenocyte infusion.68
Over the years, recipient risk factors have been found to
include a wide range of immune defects, lymphoid
malignancies, and certain solid tumors, immunosuppressive
medications (most recently purine analogues such as
fludarabine), and even advanced age in patients
undergoing cardiac surgery.6972
However, no cases of TA-GVHD have been reported in
patients with AIDS, despite other evidence of profound
immunodeficiency.73
TA-GVHD occurs between 4 and 30 days after transfusion of any
cellular blood component. Whereas cases have been seen when
fresh plasma was transfused, no well-documented cases have
been associated with fresh-frozen plasma or
cryoprecipitate. Fresh blood may predispose to lymphocyte
engraftment, although "freshness" may be no more than a
surrogate marker for the number of immunocompetent
lymphocytes. For many years, the diagnosis was based strictly
on clinical findings. Molecular diagnosis is now widely
available. The histologic features, although not
pathognomonic, are sufficiently typical that once the
diagnosis is considered, skin biopsy proves an easy,
sensitive, and relatively benign diagnostic procedure.
Diagnosis can be predicted reliably by finding circulating donor
lymphocytes in an afflicted patient and confirmed by detecting
donor DNA in the biopsy specimen.74
TA-GVHD appears to be increasing as a result of increases in
the surgical procedures, immunosuppressive therapies and
transfusion strategies (blood from matched or related
donors) that predispose to allogeneic cell engraftment.
The risk of TA-GVHD may be reduced by leukoreduction, but
this is not standard of care to prevent the disease.
TA-GVHD can be eliminated only by irradiating blood
components with at least 25 Gy or by chemophototherapy to inactivate
donor T lymphocytes.75,76
Treatment of TA-GVHD still ranges from difficult to
futile. When the full-blown syndrome occurs, mortality
approaches 90%.77 Should evolving
pathogen reduction technologies that disrupt nucleic acid
be applied to most cellular blood components in the
future, TA-GVHD may become little more than a historical
footnote.
Transfusion-related acute lung injury
One severe transfusion reaction, originally termed noncardiogenic
pulmonary edema, has been associated with leukocyte antibodies
in donor plasma. The earliest clinical description may well
have been published in Blood by National Cancer
Institute investigators, although the reaction they
detailed after a rapid infusion of malignant mononuclear
cells does not meet the current strict definition of
transfusion-related acute lung injury (TRALI).78,79
In 1957, Brittingham first reported the classic syndrome and
the ability to provoke it by injecting blood containing
leukoagglutinins into a research subject.80
During the next 25 years, occasional reports appeared in
the general medical literature. The entity TRALI with its
characteristic clinical and radiographic findings was
defined in the 1980s.81 TRALI is now
the most frequent cause transfusion-related mortality
reported to the FDA.49
TRALI has been estimated to occur after approximately 1 in every
5000 blood component transfusions.82
Mortality has been reported as high as 15%. A record
review of recipients of blood from an implicated donor
indicates that TRALI remains underdiagnosed, especially
in the intensive care setting. Of 36 recipients of plasma
from 1 donor whose plasma contained a neutrophil antibody
that caused a fatal pulmonary reaction, 7 sustained mild to
moderate and 8 sustained severe pulmonary reactions.83
Only 2 of the 8 severe reactions were reported to the
hospital transfusion service, and only 2 of the 15
reactions were reported to the blood collector. We have
had a similar experience.84
TRALI has been observed after transfusion of most
plasma-containing blood components. The single exception
appears to be pooled solvent detergent-treated plasma, in
which the manufacturing process may dilute even
high-titer antibodies present in any single unit. As few
as 2 mL of plasma seems to be sufficient to cause
respiratory distress. In most cases the responsible
antibodies are found in the donor. Antibodies directed against
numerous leukocyte antigens have been implicated in TRALI,
including HLA antibodies, granulocyte-specific
antibodies, and even monocyte-specific IgG.85
In 20% to 30% of TRALI cases, no leukocyte antibody is
detected, and leukocyte antibodies may not precipitate TRALI
even when the recipient expresses the cognate antigen. These
puzzling findings may mean that (1) the syndrome has an
alternative cause, (2) the culprit is an antibody not
detected by current methods, or (3) "2 hits" are
required, as has been reported in Blood.86
Several strategies have been proposed to prevent TRALI. For
many years, the sole intervention was to deter blood donors
associated with a case of TRALI from further donation. In the
Netherlands, plasma that tests positive for HLA antibodies is
discarded; few cases of TRALI have been reported since this
policy was begun. Most centers in the United Kingdom and the
United States now avoid transfusing plasma from female donors
to reduce the chances of exposing a patient to HLA and other
leukocyte antibodies that may have been elicited through
pregnancy.
|
|
Summation and glimpse toward the future
|
Although blood transfusion will never be absolutely safe, tremendous
progress has been made and promising new approaches are on the
horizon. For infectious diseases, there are limits to
increasing test sensitivity and resistance to adding new
screening assays for every emerging agent. The optimal
approach is preemptive pathogen reduction (PR). Current
technologies require the addition of either psoralens or
riboflavin to blood, followed by exposure to UV light.44
These methods are being applied to platelets in Europe
and will compete with methylene blue and solvent detergent
for treatment of plasma. They are not currently licensed in
the United States. Both methods disrupt nucleic acid and fully
inactivate or significantly reduce replication of all known
viral, bacterial, and protozoal pathogens. The main impediment
to universal usage of this technology is the ineffectiveness
of light to sufficiently penetrate red blood cells.
Alternatives that work independent of light activation
are required and are currently being studied.44
PR techniques will likely be adopted for platelets and
plasma even before a complete inactivation scheme is
fully implemented.
To prevent hemolytic reactions, several advanced identification
systems link donor and recipient with greater precision so as
to thwart human error. In addition, rapid, automated,
economical genetic typing of red cells is being developed
to insure compatibility across a broader range of
antigens. TA-GVHD, currently prevented by selective
irradiation, will be supplanted once universal PR
technology becomes available. The likelihood of TRALI from
plasma or apheresis platelets can be reduced by using a
preponderance of male or nulliparous female donors or by
typing for leukocyte antibodies. Bacterial infections
have been reduced but not eradicated by culturing
apheresis-derived platelets early in storage. PR of
platelets will be highly effective once introduced. In the
interim, a rapid and sensitive point-of-release bacterial
detection system should supplement culture techniques.
Blood transfusion has reached levels of safety that could not
have been imagined a decade ago, and future innovations that
are both plausible and in progress will diminish the residual
risk further. Nonetheless, the relative calm could be
perturbed again by an emerging pathogen with lethal
potential. In addition, concerns about
transfusion-related immunomodulation87
and the safety of blood that ages during prolonged
storage need to be resolved.88
So, Dr Beal, we have a good but not perfect marriage, and
we anticipate that continued counseling will further improve
the relationship.
Contribution: H.J.A. and H.G.K. equally planned, wrote, and
edited the manuscript.
Conflict-of-interest disclosure: The authors declare no competing
financial interests.
Correspondence: Harvey J. Alter, Department of Transfusion
Medicine, Building 10, Room 1C711, NIH, Bethesda, MD
20892; e-mail:
halter@dtm.cc.nih.gov
.
Submitted July 10, 2008; accepted July 10, 2008.
DOI: 10.1182/blood-2008-07-077370
*H.J.A. and H.G.K. are equal
coauthors of this work.
As a Jewish boy growing up in New
York City, it was predetermined that I would become a
doctor. It was a rite of passage: bar mitzvah and then on
to medical school. Although my occupational goal was
established early, I never considered medicine as a path
to research. My goal was always to enter clinical practice,
but events small and large conspired otherwise. As a senior
at Rochester Medical School and an intern at Strong Memorial
Hospital, I attended the now historic Atlantic City ASCI/ACRF
meetings in 1961, and over a 3-inch pastrami sandwich I
decided to keep my academic options open and apply to the
National Institutes of Health. However, before I was
commissioned in the Public Health Service, a crisis in
Berlin prompted a letter to me that began "Greetings" and
contained a subway token to get me to the army base at
Fort Dix, NJ. It took many frantic phone calls and,
particularly, enormous support from Scott Swisher, then
Chief of Hematology at Strong Memorial, to get me to NIH before
my draft report date. Thus, I became a member of the "yellow
berets," a fierce cadre of draft-dodging incipient scientists
who joined forces in the 1960s to protect NIH from imminent
attack by Johns Hopkins. Those first years at NIH affected my
life profoundly; there I met my career and my wife, one of
which had permanency. I also met Richard Aster, who was
just beginning his illustrious career studying platelet
immunology. It was Aster who heard a lecture on protein
polymorphisms by Baruch Blumberg and suggested that I see
Blumberg because of the similarity of our technical
approaches. I did, and we entered into a collaboration
that soon led to the discovery of the Australia antigen. My
first important publication was on this discovery, and my
first first-author publication was the biophysical
characterization of Au. I was excited to have it
published in Blood. My life changed as the result
of that "thin red line," but the change was not immediate
because I was still determined to enter clinical
practice. Thus, I went to the University of Washington to complete
my residency training, then returned to the east coast to
enter a hematology fellowship under Charlie Rath at
Georgetown University. At the end of my fellowship, I
applied to the best group practice in Washington, DC,
which rejected me in favor of a cardiologist. I do not
take rejection well, but Charlie Rath consoled me by
offering a faculty position at Georgetown (and a $12 000 salary).
That was the turning point. After a taste of academia and
hospital-based medicine, I lost my desire for private
practice. Charlie Rath was the consummate physician who
taught me the art of medicine as well as the principles
of hematology, and I will always be indebted to him.
Teaching and clinical service at Georgetown University
Hospital (GUH) was all-consuming, and I had very little
time for research. However, I completed a study of the
interrelationships between folic acid, aspirin, and rheumatoid
arthritis that was published in Blood in 1971. After 4
years at GUH, I became discouraged by the lack of
dedicated research time. Just then, the relationship of
Au to hepatitis was unfolding and the opportunity to
return to NIH presented itself. I jumped at this chance
and began the prospective studies that are described in
this review. These led to the finding and clinical characterization
of non-A, non-B (NANB) hepatitis and a series of studies that
culminated in the near eradication of posttransfusion
hepatitis. During the early NANB days, I was extremely
fortunate to enter into a lifelong collaboration and
friendship with Robert Purcell, who added a basic science
dimension to my clinical studies. I owe much of my
success to this collaboration. Together with Purcell and
Steve Feinstone, we used the chimpanzee to establish the
infectivity of NANB and to define many of its physical
characteristics. Simultaneously, working with Jay
Hoofnagel and Adrian DiBisceglie of National Institute of
Diabetes and Digestive and Kidney Diseases, we were able
to demonstrate the serious nature of chronic NANB
hepatitis and its progression to cirrhosis in 20% of cases.
However, despite more than a decade of intensive effort, we
were unable to identify the NANB agent or its serologic
markers. The molecular age and its vastly superior
technology came just too late for us, and we were beaten
by the brilliant blind cloning and immunoscreening
approach performed by Michael Houghton and colleagues at
Chiron Corp. I wrote a poem at that time about coming in
second that I titled, "There's No Sense Chiron Over Spilt
Milk." Nonetheless, using our pedigreed samples, I was
privileged to prove that the NANB agent and the Chiron hepatitis
C agent were one and the same. This closed the final door on
posttransfusion hepatitis and brought me some honors that I
never imagined possible. In the final analysis, I am indebted
to the Public Health Service, for offering me a home at NIH
instead of Fort Dix; to an aborigine and a hemophiliac, whose
plasma precipitated in agar; to serendipity; to my primary
mentors, Swisher, Rath, Blumberg, and Purcell; to a long
series of industrious and brilliant Fogarty Fellows; to
NIH itself, for funding long-term observational studies
with uncertain payoffs; and to my 3 NIH bosses, Paul
Schmidt, Paul Holland, and Harvey Klein, each of whom
allowed me great freedom and fought to obtain whatever
was needed to keep these difficult studies going. As people
now clamor for my retirement, I think I may someday accede to
their wishes, but it is hard to give this up. My life just
fell into the right place at the right time and after 40
years it is still rewarding and exciting. And who knows,
maybe there's a non-A, non-B, non-C, non-D, non-E still
lurking out there to occupy my remaining days.
I planned to become a doctor from a
very early age. My earliest role model was Abraham Small,
my great-uncle and family pediatrician. Uncle Abe, whose
promising academic career was interrupted by the Great
Depression, had studied blood cell morphology with
Kenneth D. Blackfan at Boston Children's Hospital and advised
me that whereas medical practice could provide great
satisfactionobserving Koplick spots could predict that a
sick child would develop measlesa career in research
could lead to better treatments and even prevention. My
early education was heavy on the arts and light on the
sciences. At Boston Latin School I studied Latin, French,
and German, but little chemistry and no biology. As a
Harvard undergraduate, I fell under the spell of the noted
classicist John H. Finley, who maintained that modern
physicians (and lawyers, bankers, and politicians)
desperately need grounding in the humanities. In my case
he was right. I attribute my acceptance at the Johns
Hopkins School of Medicine in part to one of Finley's
famous recommendation letters. At Hopkins I discovered the
intellectual attraction of internal medicine, which led
to 3 years of medical residency. I was heavily influenced
by Philip Tumulty, an outstanding diagnostician and
humanitarian, and C. Lockard Conley, a superb clinician
and scientist. I was fortunate to be accepted into
Conley's hematology training program. Whereas Hopkins emphasized
the preeminence of a research career, I almost certainly would
have entered practice were it not for the draft and the war
in Vietnam. I declined my invitation to relocate to Saigon by
enrolling in the Commissioned Corps of the Public Health
Service, the notorious "yellow berets." I was assigned to
the Centers for Disease Control (Venereal Disease
Branch), but became one of the few to benefit from the
Tuskegee Syphilis Study when, in 1972, before my entry
date, the Branch leadership was disbanded. The incoming
leadership, recognizing that a newly minted hematologist
might not be the ideal epidemic intelligence officer, allowed
me to seek employment elsewhere. Conley's recommendation
landed me a position in the recently established Blood
Division of the National Heart and Lung Institute as
special assistant to its new director, Ernst R. Simon.
Ironically, the draft ended a few days before my entry
date, but I determined that 2 years in Bethesda was
scarcely hardship duty and would be fair payment for my
previous military exemption. Ernie Simon, who had performed
some of the seminal studies on red-cell preservation,
suggested that there was both opportunity and need for
research in blood transfusion. In 1975 I moved to the
then Clinical Center Blood Bank. For more than 30 years
at NIH I have been fortunate to participate in some of
the most stimulating clinical research, including the
first trial of cellular gene therapy, transfusion
transmission of HIV, therapeutic apheresis, and the evolution
of component therapy. With the support of several Clinical
Center directors I have been privileged to help develop
the Department of Transfusion Medicine and to work with
numerous outstanding clinical scientists, foremost of
whom is Harvey J. Alter, with whom I coauthored this
review.
 |
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