Kopko PM, Marshall CS, MacKenzie MR, Holland PV, Popovsky MA. Transfusion-Related Acute Lung InjuryReport of a Clinical Look-Back Investigation. JAMA. 2002;287(15):1968-1971. doi:10.1001/jama.287.15.1968
Author Affiliations: Sacramento Blood Centers, Sacramento, Calif (Drs Kopko, MacKenzie, and Holland); Department of Pathology, University of California at Davis Medical Center, Sacramento (Dr Marshall); and Haemonetics Corp, Braintree, Mass (Dr Popovsky).
Context Transfusion-related acute lung injury (TRALI) is a syndrome that includes
dyspnea, hypotension, bilateral pulmonary edema, and fever. TRALI is the third
leading cause of transfusion-related mortality, but it is probably underdiagnosed
Objective To determine if blood products from a frequent plasma donor, whose blood
product was implicated in a fatal case of TRALI, caused symptoms of TRALI
in other recipients of her plasma.
Design, Setting, and Participants Retrospective chart review (conducted from November 2000 through April
2001) of 50 patients who received blood components within 2 years (October
1998 through October 2000) from a donor linked to a transfusion-related fatality.
Main Outcome Measure Occurrence of mild/moderate (dyspnea with fever, chills, hypotension,
and/or hypoxemia) or severe (acute pulmonary edema or need for mechanical
ventilation) reaction associated with transfusion.
Results Superimposed illness prevented assessment of TRALI in 14 patients. Of
the 36 patient charts that could be reviewed, 7 mild/moderate reactions were
reported in 6 patients (16.7%) and 8 severe reactions were reported in 8 patients
(22.2%). Of 5 patients who received multiple transfusions from the same donor,
2 experienced 2 reactions: one had 2 mild/moderate reactions and the other
had both a mild/moderate and a severe reaction. While 5 of the 7 mild/moderate
reactions were reported to the hospital transfusion service, only 2 of the
8 severe reactions were reported. Only 2 reactions (1 mild/moderate and 1
severe) were reported to the regional blood collection facility.
Conclusions TRALI was frequently underdiagnosed and underreported in recipients
of blood products from a donor whose blood products may have caused TRALI
in several transfusion recipients. Clinical education and awareness of this
often-overlooked diagnosis are imperative for appropriate prevention and treatment.
Transfusion-related acute lung injury (TRALI) is a clinical syndrome
associated with transfusion that typically includes dyspnea, hypoxemia, hypotension,
bilateral pulmonary edema, and fever.1 Symptoms
may occur during the period between the beginning of transfusion and 4 hours
afterward. The severity of symptoms can range from mild to severe. However,
in a large series of TRALI cases, 100% required oxygen support, and 72% also
required mechanical ventilation.2 In this same
series, symptoms resolved within 96 hours in 80% of patients. The other 20%
of patients required longer support, which was associated with persistence
of pulmonary infiltrates on chest radiograph.
TRALI has been associated with the presence of granulocyte antibodies,
HLA class I antibodies,2 HLA class II antibodies,3 and biologically active lipids4
in donor plasma. All plasma-containing blood components, including red blood
cells, platelets, fresh frozen plasma (FFP), and cryoprecipitate, have been
implicated in TRALI.1 Infusion of even small
volumes of plasma can trigger the reaction.5
Intravenous immunoglobulin prepared from a large pool of plasma has also been
reported to cause TRALI,6 but pooled solvent
detergent–treated plasma has not.
Severity of TRALI does not appear to be related to the volume of plasma
infused, but may be correlated with the degree of hypoxemia.2
Infusion of white blood cell antibodies alone is probably not sufficient to
induce TRALI.7 Approximately 20% of women who
have had 2 pregnancies have antibodies to leukocytes.8
Therefore, if infusion of antibodies alone were sufficient to cause TRALI,
the reaction would be relatively common. Although it seems natural to assume
that the transfusion recipient must possess the corresponding leukocyte antigen
for an antibody to cause TRALI, such an association has not been demonstrated.
Little is known regarding the effect of antibody titer, antibody avidity,
or leukocyte-antigen density on the severity or frequency of TRALI reactions.1
Other recipient factors, however, may play a role in TRALI. A 2-event
hypothesis of TRALI has been advanced as a possible way of explaining why
some recipients experience the reaction while others do not.1,4
It has been theorized that a transfusion recipient must first have a predisposing
condition and then receive plasma that contains leukocyte antibody or biologically
active lipid.4 Conditions thought to predispose
transfusion recipients to develop TRALI include infection, cytokine administration,
recent surgery, and/or transfusion of large volumes of blood products.4
Leukocytes coated with antibodies localize to the pulmonary microvasculature.9 The release of cytokines by these antibody-coated
leukocytes in the vascular space is thought to lead to an increase in vascular
permeability and exudation of fluid and protein into the alveolar spaces.1,10 The degree of fluid exudation likely
determines the severity of the pulmonary reaction and whether oxygen administration
or mechanical ventilation is required.
TRALI is fatal in 5% to 10% of cases,2,11
and is the third leading cause of transfusion-related mortality.12
Unfortunately, the signs and symptoms associated with TRALI can easily be
attributed to other causes, including fluid overload, pneumonia, and acute
respiratory distress syndrome (ARDS).1,13
Pulmonary edema, with bilateral "white out" on chest radiograph (Figure 1), similar to that seen in ARDS,
is generally present along with fever and hypotension. The key to distinguishing
TRALI from other forms of pulmonary edema is recognition that the pulmonary
edema is noncardiogenic and that affected patients do not have volume overload.1 This distinction is important because treating patients
with TRALI with aggressive diuresis can result in further hypotension, shock,
and death.14,15 Treatment should
consist of maintenance of hemodynamic status and ventilatory assistance. An
extensive review of TRALI, including diagnostic criteria, has recently been
Although TRALI is often discussed in the transfusion literature, it
has received little attention among clinicians. Therefore, it is likely to
be underrecognized as a clinical entity. We report a fatal case of TRALI following
an FFP transfusion from a frequent plasma donor. Prior transfusions from this
frequent plasma donor had not been reported to the regional blood center as
causing any transfusion reactions.
A 54-year-old man was given FFP for reversal of coumadin effect prior
to elective knee surgery. Approximately 45 minutes after initiation of the
FFP transfusion, the patient experienced respiratory arrest. He died 6 hours
later despite aggressive attempts at cardiopulmonary resuscitation.
The blood donor, whose blood component was implicated in this reaction,
was a 54-year-old woman who had made 290 previous donations. She had had 3
pregnancies, resulting in 2 births and 1 abortion. The donor's plasma was
found to be strongly positive for granulocyte 5b antibody. Although the granulocyte-specific
5b antigen is present in more than 90% of whites,16
this was the first time this donor was implicated in a case of TRALI, despite
more than 15 years of frequent donation. The donor was permanently deferred
from future donations. During the transfusion-related fatality investigation,
the Food and Drug Administration (FDA) investigator requested that we perform
a look-back study to determine if previous recipients of this donor's blood
components had experienced TRALI or other transfusion reactions.
All donations made by the implicated donor in the 2 years prior to the
fatality were investigated. Transfusion service medical directors at the facilities
that transfused the donor's FFP units were asked to perform chart reviews,
including review of both physicians' and nurses' notes, to determine if any
other recipients had an adverse reaction to this donor's blood components.
They were asked to determine and report if the recipients experienced fever,
chills, hypotension, dyspnea, pulmonary edema, ARDS, or any other untoward
event within 6 hours of transfusion.
Reactions were classified as either mild/moderate or severe. Mild/moderate
reactions consisted of dyspnea with fever, chills, hypotension and/or oxygen
desaturation, but without documented evidence of acute pulmonary edema or
need for mechanical ventilation. Severe reactions were defined as any reaction
with clinical or radiographic evidence of acute pulmonary edema and/or need
for mechanical ventilation within 6 hours of transfusion. Recipients were
excluded from the analysis if their underlying clinical condition prevented
the reviewer's ability to determine if a symptomatic reaction was related
to the transfusion. These preexisting conditions included pulmonary edema,
ARDS, or rapidly deteriorating clinical status resulting in efforts of cardiopulmonary
resuscitation prior to transfusion of the blood component.
The donor made 73 donations (72 plasmaphereses and 1 whole blood) in
the 2 years prior to her deferral. A total of 54 patients received 63 blood
products from this donor. The remaining components were either quarantined
when the donor was deferred or not transfused for other reasons. Underlying
illness prevented evaluation for evidence of TRALI following transfusion in
14 patients. Charts were unavailable for review in 4 patients.
Of the 36 patient charts that could be evaluated, 13 (36.1%) indicated
a transfusion reaction. The clinical scenarios of the patients identified
as having had a transfusion reaction are presented in Table 1. All reactions were temporally associated with an infusion
of FFP. Seven mild/moderate reactions were identified in 6 (16.7%) recipients.
Severe reactions were reported in 8 (22.2%) recipients. Of the 5 patients
who received multiple transfusions from this donor, 2 experienced 2 reactions
each: 1 had 2 mild/moderate reactions, and the other had both a mild/moderate
and a severe reaction. Seven (46.7%) of the 15 reactions (5 of 7 mild/moderate,
2 of 8 severe) were reported to the hospital's transfusion service. Only 2
reactions (13.3%) were reported to the blood collection facility: one was
the fatality and the other was a mild/moderate reaction that occurred while
the fatality was under investigation.
Our findings suggest that TRALI is frequently not diagnosed. Lack of
recognition of this syndrome can result in inappropriate treatment, as well
as failure to report the reaction to the transfusion service and the blood
collection facility. Lack of recognition of TRALI and its reporting in this
series of cases led to numerous reactions and, ultimately, a fatality that
might have been prevented.
TRALI should be included in the differential diagnosis of respiratory
distress (with or without pulmonary edema or ARDS) in the setting of blood
and component transfusions. To underscore this point, the FDA recently issued
an advisory to alert physicians to the characteristics and morbidity of TRALI.17 We recommend that respiratory symptoms occurring
within 2 hours of a transfusion, particularly when combined with fever or
hypotension, should be reported to the transfusion service as a possible case
of TRALI. An evaluation may then be undertaken and advice regarding treatment
provided. Additionally, all confirmed cases of TRALI (both fatal and nonfatal)
should be reported to the FDA.17
Our investigation was performed at the request of the FDA and was not
designed as a prospective clinical study. Therefore, we did not assemble a
matched control group for comparison of rates. However, the general rate of
transfusion reactions is approximately 1%.18
The hospital that received the most components involved in our study had transfused
51 792 blood components, which resulted in 229 documented transfusion
reactions (0.44%) during the selected 2-year period. The reaction rate in
our series of FFP transfusions is much higher. We are unable to determine
if plasma transfusions from the implicated donor had a negative impact on
the clinical course of the patients who were excluded from the analysis because
of the complexity of their underlying illness. We may have thus underestimated
the rate of TRALI, since severely ill patients may be especially predisposed
to develop it.4
Although donor antibodies to white blood cells may be found in about
70% of cases of TRALI,2 they are of uncertain
significance when infused to recipients who do not display signs of TRALI.
It is not clear whether a case of TRALI represents an isolated event, or whether
an implicated donor (with white blood cell antibodies) can cause multiple
cases of TRALI. Our study suggests that donors with leukocyte antibodies who
are implicated in a case of TRALI may represent a future transfusion hazard.
These findings also support performing a routine look-back investigation if
a donor's blood components are implicated in a TRALI case. The results of
a look-back investigation can be used to learn more about this disorder and
to determine if reactions are being underdiagnosed and unreported.
TRALI appears to have a spectrum of clinical presentation. Although
more than 90% of recipients would be expected to be capable of reacting to
granulocyte 5b antibody due to presence of the antigen on their leukocytes,
we found only 36% had clinical evidence of a reaction. Prior authors made
the diagnosis of TRALI only if there was evidence of pulmonary edema.2 Our look-back investigation at recipients of blood
components from a donor with a granulocyte antibody suggests that TRALI may
also present with symptoms that are more subtle. Approximately half of the
cases we identified were less severe and involved dyspnea and oxygen desaturation
but no pulmonary edema or ARDS.
TRALI has been estimated to occur about once in 5000 transfusions.2,19 A recent report suggests it may be
higher.20 The only way to obtain the true frequency
of TRALI is to both recognize and report cases to transfusion services and
blood collection facilities. Diagnosis and reporting of this syndrome would
allow for appropriate treatment and prevent additional reactions in other
recipients. Permanent deferral of all future donations may sometimes be warranted.
Look-back investigations may provide insight into why some recipients experience
severe TRALI with pulmonary edema while others have less severe reactions.