AJCP / COMMENTARY
NISHOT
On Target, but There’s No Magic Bullet
Paul D. Mintz, MD
A patient receiving a transfusion of RBCs in the United
States (or anywhere else in the developed world) has a far
greater chance of receiving an ABO-incompatible transfusion
than of acquiring transfusion-transmitted HIV infection.1 In
fact, the mistransfusion of ABO-incompatible blood is the
most common cause of serious morbidity and mortality as a
result of RBC transfusion.2 The risks of transfusion have
received considerable scrutiny ever since Jean Denis
performed the first human transfusions in 1667 in Paris.
Denis transfused calf and lamb blood into humans and
incurred the enmity of his colleagues, who preferred blood-
letting. A decree was issued proscribing the performance of
blood transfusion unless sanctioned by the Faculty of Medi-
cine of Paris.3 Thus, regulatory oversight and auditing of
transfusion practices are not new activities.
In contrast with many of the noninfectious serious
hazards of transfusion (NISHOT), the risks of transfusion-
transmitted virus infection and efforts to prevent such an
occurrence have received considerable attention and
resources since the first publication reporting the transmis-
sion of HIV by a blood transfusion.4 The risk of acquiring
HIV infection from transfusion has been reduced approxi-
mately 10,000-fold in the United States since this report.5 In
San Francisco, CA, the risk of transmitting HIV by blood
transfusion was as high as 1.2 per hundred blood units trans-
fused early in the epidemic.6 The current risk in the United
States has been calculated to be approximately 1 in 1.93
million. 5 Of the more than 9,000 transfusion recipients
reported with AIDS, only 43 received blood components that
had tested negative after the implementation of HIV anti-
body testing.7 Since this test was implemented in 1985, tens
of millions of patients in the United States have received
802 Am J Clin Pathol 2001;116:802-805
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blood transfusions. However, a recent report by Kopko et al8
serves as an important reminder that the risk of acquiring
HIV is not zero. Is this remarkable record of improved safety
sufficient? Clearly, public policy has said it is not. Hence,
single donor nucleic acid testing for HIV is likely to be
required as soon as feasible.
With respect to the transmission of viruses, transfusion
safety depends on a series of processes that serve to reduce
infectious risks. These start with efforts to educate potential
blood donors about eligibility criteria for donation. The fact
that the prevalence of seropositivity for transfusion-trans-
mitted viruses is substantially lower in the blood donor popu-
lation than in the general population suggests these donor
education efforts are at least partially successful.5 Other safe-
guards include careful donor screening, selection, and
deferral; infectious disease testing; opportunities for donors
to contact collection agencies after donation; and donor
tracing and notification following instances of transmission
of infection. However, these processes are imperfect. At
times, potential donors misunderstand questions or are delib-
erately dishonest. Kopko et al8 concluded that the donor who
tested positive for HIV p-24 antigen in their report had not
revealed sexual exposure to individuals at high risk for HIV
infection. Williams et al9 found that 1.9% of donors who had
donated within the previous 2 months and who responded to
an anonymous survey reported a deferrable risk present at the
time of their most recent donation. Conry-Cantilena et al10
noted that 42% of donors testing positive for antibodies to
hepatitis C virus had a history of intravenous drug use, even
though they had previously undergone questioning in which
such drug use had been denied. Donors should be informed
that laboratory screening tests have limitations and that not
© American Society of Clinical Pathologists

providing accurate information during the donor history
process can result in the transmission of viral infection.
Thus, despite the implementation of donor testing to detect
11 different infectious disease markers and a donor question-
naire that has 32 separate questions addressing infectious
risks (some of which have multiple parts), vigilance in the
donor qualification process is essential.
Still, the record with respect to the transmission of
known viruses speaks to the considerable increase in safety
that has been achieved. In 1968 in the United States, the per-
patient risk of acquiring posttransfusion hepatitis was
approximately 30%.11 The subsequent elimination of paid
and imprisoned donors and the implementation of serologic
tests for hepatitis B and hepatitis C have resulted in a present
per-unit risk of the transmission of hepatitis C virus of less
than 1 in 543,000 (including the impact of pooled nucleic
acid testing) and a risk of approximately 1 in 338,000 per
unit for hepatitis B, for which nucleic acid testing presently
is not performed in the United States.5
The remarkable progress in diminishing serious viral
infectious hazards of transfusion has not been matched by a
similar reduction in noninfectious risks or the risk of bacte-
rial contamination.1,2,12 As a result, blood transfusion recip-
ients today experience adverse effects from NISHOT at a
rate that exceeds viral infectious hazards by 100- to 1,000-
fold.2 The most common noninfectious hazards include the
mistransfusion of an ABO-incompatible unit of blood,
circulatory overload, transfusion-related acute lung injury
(TRALI), transfusion-induced graft-vs-host disease, and
metabolic derangements. Hemovigilance programs in
Europe and Canada have documented that continuing trans-
fusion-related morbidity is substantially related to these
noninfectious hazards. 13-15 In fact, NISHOT may be
substantially underestimated since reporting has been
inconsistent in the past. In addition, near-miss events,
which would have resulted potentially in a serious reaction,
typically are not reported. For example, when a pretransfu-
sion sample is determined in a hospital blood bank labora-
tory to have an ABO group result that does not agree with
the historic records, this potentially fatal error goes unre-
ported. Under the new biologic product deviations
reporting regulations issued by the US Food and Drug
Administration (FDA), many such occurrences that poten-
tially put patients at risk will still not be reported.16 The
most common clerical error resulting in mistransfusion
repeatedly has been shown to be misidentification of the
patient at the bedside at the time of transfusion.1 This error
is not required to be reported by the new regulations,
although an existing FDA regulation requires reporting of
fatal reactions [21CFR 606.170(b)]. In fact, fatal ABO-
incompatible transfusions have been repeatedly reported
for more than 20 patients each year in the United States.17
© American Society of Clinical Pathologists
AJCP/ COMMENTARY
Importantly, the incidence of these fatal reactions has not
decreased substantially during the last several decades.18-20
At present in the United States, the risk of receiving an
ABO-incompatible transfusion exceeds the aggregate risk
of known transfusion-transmitted viral infections.1
The American Association of Blood Banks (AABB) has
affirmed its commitment to working with health care
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providers and policy-makers to reduce the risks of NISHOT.2
The AABB recommends the implementation of a nonpuni-
tive, national, transfusion-related error reporting system. The
system already established between the airline industry and
the Federal Aviation Administration may serve as a model in
this regard.21 The AABB also will emphasize in its assess-
ment and accreditation process the enforcement of existing
standards to ensure safe blood administration practices.
AABB standards require that all errors in the process of
sample collection, patient identification, and other aspects of
blood administration be identified and corrected.22 In addi-
tion, the AABB has stated that it will formally request the
Joint Commission on the Accreditation of Healthcare Orga-
nizations to bring renewed focus in its accreditation process
to the effectiveness of hospital programs in reducing transfu-
sion errors.2 Hospitals should welcome the AABB’s initia-
tive as an opportunity to review and strengthen practices that
help ensure blood transfusion safety. Transfusing institutions
should consider appointing an individual or a group of indi-
viduals that have as part of their responsibilities monitoring
and addressing transfusion-related errors.23 Hospital infec-
tion-control programs can serve as a model for such a
system. In addition, the development and implementation of
enhanced technologies to reduce errors in patient, patient
sample, and blood component identification are important
elements in improving transfusion practices. The AABB also
has called for enhanced federal support for research directed
at noninfectious risks of transfusion. Increased attention to
nonviral hazards need not decrease our vigilance regarding
infectious risks.
The FDA has issued a letter to physicians regarding
TRALI.24 In this letter, the FDA suggests that cases be
reported voluntarily as a serious adverse reaction through its
MedWatch program.25 This action may signal the FDA’s
increasing attention to NISHOT.
As Klein26 noted, blood transfusion is safer than it has
ever been, but “the usual notions of safety do not necessarily
apply where transfusion is concerned.” Allocation of
resources requires regulators and policy-makers to make
difficult decisions. The prospect of the United States
spending approximately $2 million per quality-adjusted life
year gained as the result of introducing single-unit nucleic
acid testing for HIV alone serves as an example of the price
society has accepted to increase further the safety of the
blood supply, while potentially still not eliminating all viral
Am J Clin Pathol 2001;116:802-805 803
Mintz / NONINFECTIOUS SERIOUS HAZARDS OF TRANSFUSION
transmission. Such testing and analogous testing for hepatitis
C virus and hepatitis B virus of course will not eliminate the
threat of emerging infectious agents or even novel strains of
existing microbes that may elude current testing techniques.
Nor do they address the substantial risk posed by bacterially
contaminated blood components.
An additional element of transfusion safety is blood
availability. The risk of not providing an indicated transfu-
sion is certainly greater than the risk of providing it. The
current intense discussions over the proposal to eliminate
donors in the United States who have spent a certain amount
of time in Europe to prevent the theoretical transmission of
the agent of variant Creutzfeldt-Jakob disease serve as an
example of the need to balance inherent risk and availability.
The current proposals to prevent this agent from potentially
being transmitted by blood transfusion are projected to elimi-
nate between 5% and 9% of eligible blood donors in the
United States.27 In this regard, it is heartening that the
proposed FDA guidelines addressing this issue include
strong consideration of blood availability by requiring any
agency that proposes restrictions more stringent than the
FDA’s in this matter to have demonstrated that sufficient
blood supplies will be available.28 In addition, the federal
government has implemented a survey of 29 sentinel hospi-
tals in the United States to acquire up-to-date data on the
availability of blood components.29 This increased attention
to the consideration of blood availability as a safety issue
represents recognition of the costs and risks of restricting
donor eligibility.
There has never been a consensus regarding what consti-
tutes an acceptable balance of risk and availability regarding
blood transfusion. To date, enormous sums of money have
been spent to achieve increasingly reduced returns with
respect to the risks of viral transmission, while few resources
have been devoted in most institutions and on the part of
regulatory and funding agencies to reducing the noninfectious
risks. While the efforts to reduce viral transmission by trans-
fusion have moved forward relentlessly in developed coun-
tries, millions of blood donations in the world today still are
not tested serologically for HIV, hepatitis B virus, and
hepatitis C virus in developing countries. Sadly, it is among
these countries in which the prevalence of infected persons in
the blood donor population is the highest.
The complexities of our current processes can at some
point become counterproductive. As additional tests are
implemented, it is plausible that some individuals will seek
to be blood donors in order to be tested. If tests are imple-
mented that are expected to identify infectious donors only
rarely, reductions in risk may be counterbalanced by the
arrival of new, less-safe donors. In addition, as greater
numbers of donors are no longer eligible to donate, an
increased number of first-time donors is required. It is well
804 Am J Clin Pathol 2001;116:802-805
established that first-time donors have a higher prevalence of
positivity for infectious markers,30 and, given that all tests
will have a rate of false-negative results, these donors repre-
sent a potentially riskier group.
The multiplicity of risks associated with the transfusion
of human blood has challenged patients, clinicians, adminis-
trators, regulators, and policy-makers and has made the
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process of blood donation increasingly trying for volunteer
donors and blood center staff. These hazards have spurred
considerable investment in the development of pathogen-
reduced and pathogen-inactivated biologic therapies and
acellular oxygen-carrying products. These risks also have
resulted in increased attention to the use of autologous blood.
The fact that bacterial contamination and mistransfusion still
can occur with stored autologous components may not
always be appreciated fully. Clearly, there is no one right
way to allocate resources and develop policy. Appreciation
of the astounding successes in reducing the risks of viral
transmission by blood transfusion must be tempered by our
understanding that such transmission still occurs. Further-
more, enhanced dedication to matching this success with
respect to bacterial contamination and noninfectious hazards
is imperative.
From the Departments of Pathology and Internal Medicine,
University of Virginia Health System, Charlottesville.
Address reprint requests to Dr Mintz: PO Box 800286, Univer-
sity of Virginia Health System, Charlottesville, VA 22908-0286.
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