Intensive Care Med (2007) 33[Suppl 1]:S12–S16
DOI 10.1007/s00134-007-2874-2
Jonathan P. Wallis Transfusion-related acute lung injury (TRALI):
presentation, epidemiology and treatment
J. P. Wallis
Consultant Haematologist and Honorary Senior Lecturer
Department of Haematology
Freeman Hospital
Newcastle upon Tyne NE7 7DN
UK
e-mail: jonathan.wallis@nuth.nhs.uk
History
Transfusion-related acute lung injury (TRALI) was
clearly described in a paper by Brittingham [1] in 1957.
Numerous case reports have been published since, but
the condition drew wider attention in 1985 following a
prospective observational study at the Mayo clinic
where Popovsky and Moore documented an incidence of
acute respiratory distress of 1 per 5000 units of blood
components transfused [2]. Despite this, knowledge of
TRALI remained poor in many medical specialities. The
advent of systematic haemovigilance reporting systems
has led to better education and to greater recognition of
TRALI.
Clinical presentation
The typical patient presents with sudden deterioration in
lung function within 2 h of receiving a plasma-rich blood
component, most often fresh frozen plasma (FFP). There
are clinical signs of pulmonary oedema, and chest X-ray
shows a nodular infiltration or bats’ wing pattern of
oedema as also seen in acute respiratory distress syn-
drome (ARDS) from other causes. The patient is usually
hypotensive and has a cough, perhaps with frothy spu-
tum. Fever and chills may or may not be present. On tra-
cheal intubation the presence of large volumes of frothy
white or pink tracheal aspirate are characteristic. Hypox-
ia may be severe.
The prime diagnostic consideration is to exclude car-
diogenic pulmonary oedema. Clinical signs, electrocardio-
graph, echocardiograph, pulmonary artery wedge pressure
or oesophageal Doppler measurement of left atrial pres-
sure may all be of value. Unlike cardiogenic pulmonary
oedema, the patient with TRALI is typically hypo-
volaemic due to substantial loss of circulating plasma
through leaky capillaries. The tracheal aspirate, as in
ARDS due to capillary leak, has a high albumin content
close to that of the serum, which is also not the case for
cardiac pulmonary oedema. In patients who have an endo-
tracheal tube it is quite simple to collect a sample of fluid
and estimate albumin content at the same time as measur-
ing serum albumin. An albumin level of 70% or more of
the serum albumin level strongly suggests a non-cardiac
cause. The measurement of brain or B-type naturetic pep-
tide has also been suggested as a possible discriminator
though this may not be available urgently in many centres
[3]. Because the diagnosis of ARDS due to capillary leak
requires different treatment from cardiac pulmonary oede-
ma, any test used to help the acute management of TRALI
must be available rapidly to be of value.
The secondary diagnostic consideration is to look for
or exclude other causes of ARDS, though finding such a
cause does not exclude TRALI, as two insults are more
likely than one to produce clinical symptoms and signs.
The classical diagnostic triad of acute severe TRALI
may be considered to be hypoxia, hypotension and high
albumin content of the frothy tracheal exudate, all occur-
ring within 2 h of a plasma-containing blood transfusion.
Aetiology
There are three strands of evidence that support the sup-
position that anti-leucocyte antibodies are the common
cause of TRALI.

1. Circumstantial evidence. The condition has repeated-
ly been observed following the transfusion of parous
female plasma, but rarely after transfusion of male
donor plasma. In most reported cases the donor anti-
body specificity matches that of the recipient leuco-
cytes when both have been determined [4,5].
2. Experiments in humans. There have been three report-
ed cases of severe TRALI resulting from medical
studies in which plasma containing strong leucocyte
antibodies was deliberately transfused to a healthy in-
dividual [6-8].
3. Experiments in animals. Animal models show the oc-
currence of a capillary leak in lungs that is dependent
on the presence of both donor antibody and antigen-
positive recipient leucocytes [9-11].
There is an alternative suggestion that bioactive lipids
may accumulate in aged cellular components and cause
lung injury [12]. This theory is also backed up by experi-
mental evidence but would seem to be less common as a
cause than the antibody mechanism, as evidenced by re-
ports and investigations of lung injury in haemovigilance
schemes in which plasma components as opposed to cel-
lular components are the commonest cause [13].
Neutrophil-specific antibodies have been reported to
cause TRALI but in the majority of cases antibodies to
HLA, both class I and II, seem to be the cause. HLA an-
tibodies are common in the plasma of parous women
[14, 15].
Epidemiology
The reported incidence of clinically evident TRALI
varies from 1 in 5000 transfused units as reported by
Popovsky and Moore, to 1 in 100-300 000 reported by
some haemovigilance schemes[16, 17]. We observed an
incidence of 1 in 7900 units of FFP transfused. Palfi et
al. in a prospective trial reported that 1 in 50 units of
FFP caused some degree of cardiorespiratory impairment
[18].
On the assumption that the commonest mechanism is
donor antibody-related, then donor, donation, recipient
and transfusion variables can be expected to affect the
observed incidence. To develop clinical TRALI requires
antibody concordant with a recipient antigen to be trans-
fused at a rate sufficient to activate the effector cells.
whether they are neutrophils, monocytes or lung macro-
phages [19].
The chief variable amongst the donor population is
the proportion of parous female donors, and, for them,
the time from last pregnancy to donation [20]. A minor
variable is the heterogeneity of the donor and recipient
HLA and other leucocyte antigens. In both a completely
homogeneous population or a very heterogeneous popu-
lation with regard to HLA antigen types, the chance of
S13
Table 1 Factors influencing the reported incidence of TRALI
Donor population variables
Number of female donors
History of pregnancies
HLA antigen heterogeneity
Donation variables
Plasma content
Antibody titre
Antibody specificities
Transfusion variables
Rate of transfusion
Recipient variables
Other pulmonary insults
Inherited immunological/inflammatory predisposition
Acquired immunological/inflammatory predisposition
Physician variables
Knowledge of the condition
Recognition of the condition
Reporting to blood centre or other authority
receiving an antibody against an HLA antigen specificity
will be small. However, most populations present suffi-
cient variability in antigen types for antigen-antibody
concordance to be quite common.
Donation variables include the amount of single-do-
nor plasma in any component and the titre and perhaps
the class of antibody present.
The main transfusion variable is likely to be the rate
of plasma, and thus antibody, infusion. Although there is
no direct experimental evidence with regard to this, rapid
transfusion of an antibody is more likely to produce lung
damage than slow transfusion of the same total amount
of antibody. Most antibodies are IgG and these have a
wide extravascular distribution. Higher peak plasma con-
centrations will be seen following rapid infusion. The
majority of red cell units are plasma-reduced or in opti-
mal additive solution, and are given electively over a
minimum of 90 min. For a unit of optimal additive solu-
tion red cells this will equate to a plasma infusion rate of
0.2ml/min, and to about 0.8 ml per min for plasma-re-
duced red cells. FFP containing 250 ml of plasma is
mostly transfused in cases of massive haemorrhage and
is often given over 15 min. This equates to a plasma in-
fusion rate of 16.6 ml per min, some 20-80 times the rate
for elective red cell transfusion. It is perhaps not surpris-
ing that TRALI is mainly reported following rapid trans-
fusion of plasma-rich components.
Clinically evident TRALI can be expected to be very
dependent on the type of transfusion practice in an insti-
tution, being higher in units using more FFP and trans-
fusing in emergencies.
Recipient variables are undetermined but may include
other pulmonary insults such as recent cardiac bypass
and underlying genetic heterogeneity that may make
S14
some individuals more prone to develop a capillary leak
syndrome, parallel to the heterogeneity that makes some
individuals more prone to develop disseminated intravas-
cular coagulation when challenged with a septic shock. It
is also possible that premedication with corticosteroids
or other agents could protect the lungs from damage by
downregulating cellular and immune responses.
It can be expected that actual rates of TRALI will
vary considerably according to these factors (Table 1). It
has, however, become clear that a larger variable in the
reported incidence of TRALI is the recognition of the re-
action by clinicians. In this regard the seminal report is
by Kopko et al. [21], who diagnosed a case of TRALI
due to an antibody to human neutrophil antigen 3a (pre-
viously known as 5b). The donor was a regular plasma
donor. HNA 3a is a common antigen that will be found
on the cells of 90% of Caucasian population. Retrospec-
tive followup of previous recipients of this single-donor
plasma revealed 15 cases of respiratory distress out of 36
recipient episodes. None of these cases prior to the index
case had been reported to the local blood centre though
some may have been recognized by clinicians. Diagnosis
depends on some familiarity with and knowledge of the
condition. Knowledge of the condition among clinicians
has been shown to be poor [22]. In the UK, increased ed-
ucation has resulted in a steady rise in reports of TRALI
to the serious hazards of transfusion scheme (SHOT),
from 8 in 1996-7 to 40 in 2002-3.
ARDS is a common complication of patients on in-
tensive care units. Most of these cases do not have the
sudden onset characteristic of severe TRALI, but a rela-
tionship between blood transfusion and poor outcome in
patients on ITU has long been suggested. Unfortunately,
it is difficult, if not impossible, to disentangle confound-
ing factors. The TRICC trial reported an incidence of
pulmonary oedema of 10.7% and ARDS of 11.4% in
those in the liberal transfusion arm, (average of 5.6 units
red cells per patient) and of 5.3 and 7.7%, respectively,
for those in the restrictive arm [23]. The definitions of
these two complications are not given and there may be
some overlap between the two groups. Nevertheless it
suggests that pulmonary oedema, whether due to fluid
overload or to capillary leak, is a common adverse effect
of blood transfusion on ITU and raises the possibility
that there may be a milder form of TRALI that interacts
with other factors to produce ARDS/pulmonary oedema
in patients on ITU. Gajic et al. investigated this possibili-
ty on all patients ventilated for 48 h on the ITU at the
Mayo clinic [24, 25]. They found a strong relationship
between the development of ARDS and the transfusion
of FFP. In a second retrospective study, on patients re-
ceiving FFP for coagulopathy, they came to similar con-
clusions [26]. Taken together with the trial of Palfi et al.,
these findings suggest that milder unrecognized forms of
TRALI may be much more common than previously ap-
preciated [27]. It is worth considering whether the fre-
quency of anti-leucocyte antibodies is sufficient to cause
TRALI so commonly.
Several studies have measured the incidence of an-
tileucocyte antibodies in donors and all have found simi-
lar results [28, 29]. The frequency of detectable antibod-
ies correlates directly with the number of previous preg-
nancies and inversely with time after the last pregnancy.
Overall, approximately 15% of female donors have de-
tectable antileucocyte antibodies. Many of these donors
have antibodies to several specificities and the large ma-
jority are against HLA, both class I and II. Based on the
recorded antibody specificities in donors of the UK Na-
tional Blood Service ( S. McLennan, personal communi-
cation), and the known antigen frequencies in the popu-
lation it is possible to estimate that antibody-positive do-
nor plasma will react with recipient antigens in approxi-
mately 50% of transfusion episodes. It is therefore en-
tirely credible that antibody-related TRALI might be
more common than generally appreciated and might of-
ten contribute to the aetiology of ARDS in multitrans-
fused patients.
Treatment
Treatment of TRALI is largely supportive: respiratory
support with oxygen, continuous positive airways pres-
sure (CPAP) by mask or by mechanical ventilation. Hy-
povolaemia may be an important part of the syndrome
and may be more severe than appreciated. Adequate cor-
rection has been reported to improve response to other
measures. Diuretics, for that reason, may be detrimental.
The place of steroids is uncertain. There is no evidence
that they are either beneficial or detrimental. Given that
the condition is probably due to immune activation of
leucocytes, then it is plausible that they could reduce the
inflammatory damage to the lungs. Whether it is too late
by the time the condition is recognized is not known, but
if the IgG persists in the circulation and damage is con-
tinuing, then it is arguable on a theoretical basis that they
would be effective in preventing further damage. Support
with extracorporeal membrane oxygenation has been re-
ported to support patients until adequate ventilation can
be re-established [30]. Plasmapheresis has been reported
in at least one patient, with possible benefit [31].
How common is TRALI compared to other
complications of transfusion?
Figures from haemovigilance schemes show consider-
able variation in the reported incidence of TRALI, which
are more probably due to variation in recognition than
variation in the true incidence [32]. TRALI accounts for
nearly twice as many deaths due to transfusion than any
other specific complication since the inception of the UK
 S15

reporting scheme, and as many as all other complications
put together. It is therefore the most important recog-
nized cause of transfusion related fatality in the UK at
the present time. Figures from the FDA mandatory re-
porting scheme for transfusion-related fatalities in the
US also show it to be the leading cause of mortality [33].
Prevention
Prevention may be by reducing the use of plasma-rich
components, using male donors for plasma-rich compo-
nents, or by using pooled viricidally treated plasma as an
alternative to single-donor plasma. There is good evi-
dence that FFP is often misused and transfusion rates for
FFP vary considerably between countries with similar
health-care standards [34].There is therefore room for
improvement in usage. Use of optimal additive solution
red cells rather than plasma-reduced red cells, and of
platelet additive solution may also reduce the volume of
single-donor plasma infusion. In the UK, FFP is now
preferentially made from male untransfused donors. The
effects of this policy has been marked reduction in the
reported incidence of TRALI. The incidence of TRALI
with pooled plasma appears to be very low or zero as re-
ported elsewhere in this supplement.

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S16
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