http://www.bloodjournal.org/cgi/content/full/105/6/2266
Silliman CC, Ambruso DR, Boshkov LK.
Bonfils Blood Center, 717 Yosemite St, Denver, CO 80230.
christopher.silliman@uchsc.edu.
Transfusion-related acute lung injury (TRALI) is a life-threatening adverse effect of transfusion that is occurring at increasing incidence in the United States and that, in the past 2 reporting years, has been the leading cause of transfusion-related death. TRALI and acute lung injury (ALI) share a common clinical definition except that TRALI is temporally and mechanistically related to the transfusion of blood/blood components. In prospective studies, 2 patient groups, 1 requiring cardiac surgery and 1 with hematologic malignancies and undergoing induction chemotherapy, were predisposed. Two different etiologies have been proposed. The first is a single antibody-mediated event involving the transfusion of anti-HLA class I and class II or antigranulocyte antibodies into patients whose leukocytes express the cognate antigens. The second is a 2-event model: the first event is the clinical condition of the patient resulting in pulmonary endothelial activation and neutrophil sequestration, and the second event is the transfusion of a biologic response modifier (including lipids or antibodies) that activates these adherent polymorphonuclear leukocytes (PMNs), resulting in endothelial damage, capillary leak, and TRALI. These hypotheses are discussed, as are the animal models and human studies that provide the experimental and clinical relevance. Prevention, treatment, and a proposed definition of TRALI, especially in the context of ALI, are also examined.
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Full Text Version:
Historical background
Transfusion-related acute lung injury (TRALI) was first reported
in 1951
1 and 1957,
2 and findings from the initial case series
were published in 1966.
3 In 1970
4 and 1971,
5 it was postulated
that leukoagglutinins to HLA and non-HLA antigens were etiologic
in TRALI reactions; however, it was not until 1985, with the
report of a series of 36 patients,
6 that TRALI was recognized
as a distinct clinical entity. With more aggressive transfusion
support and increased recognition of this syndrome, TRALI has
become a common clinical complication of transfusion. In the
past 2 reporting years, it has been named the leading cause
of transfusion-related death in the United States.
7
Clinical presentation and treatment
Although TRALI develops within 6 hours of transfusion,
6,8-10 most occurrences take place during transfusion or within the
first 1 or 2 hours after it.
8,9,11-14 Clinical findings of TRALI
consist of the rapid onset of tachypnea, cyanosis, dyspnea,
and fever (1°C or higher.).
6,9 Although hypotension was
reported in most patients in the early clinical studies of TRALI,
it is not a consistent finding.
6,11,12 Auscultation of the lungs
reveals diffuse crackles and decreased breath sounds, especially
in dependent areas.
6,9 Physiologic findings include acute hypoxemia,
with PaO
2/FiO
2 less than 300 mm Hg, and decreased pulmonary
compliance despite normal cardiac function.
6,9,12,15 Radiographic
examination reveals diffuse, fluffy infiltrates consistent with
pulmonary edema (
Figure 1).
6,9 In short, the clinical diagnosis
of TRALI is identical to that of acute lung injury (ALI), as
described by Bernard et al
16 (
Table 1). Treatment consists of
aggressive respiratory support, including supplemental oxygen
and mechanical ventilation.
6,9,12 Milder forms of TRALI have
been described that require prompt delivery of supplemental
oxygen alone.
11,12,17,18 As with ALI and the acute respiratory
distress syndrome (ARDS), there is no role for treatment with
corticosteroids or diuretics.
9,12,18-20 One infant was successfully
treated with extracorporeal membrane oxygenation (ECMO) for
a particularly severe clinical presentation.
21
| Figure 1. Chest x-rays and microscopic pathology examination of a patient with fatal TRALI. (A) Chest x-ray of the patient before surgery demonstrating low lung volumes with subsegmental bibasilar atelectasis, no evidence of pleural effusion, focal consolidation, or pneumothorax, and normal cardiomediastinal silhouette. (B) Chest radiograph at the time TRALI was recognized, which demonstrates extensive bilateral areas of consolidation in the mid and upper lobes of the lung consistent with aspiration or edema with a normal cardiac silhouette, new since the previous examination earlier on the same day. The endotracheal tube tip is 6 cm above the carina, the nasogastric tube is coiled within the hypopharynx before extending to the proximal trachea, and the right internal jugular introducer sheath tip overlies the proximal superior vena cava. These extensive areas of consolidation in mid and upper lobes are most concerning for noncardiogenic pulmonary edema. (C) Plastic-embedded histologic sections of the lungs at autopsy were stained with hematoxylin and eosin, toluidine blue, or Jones stains, and were examined by light microscopy under an OptiPhot-2 microscope equipped with a 20 x/0.4 objective lens (Nikon, Melville, NY). Images were photographed with a Nikon CoolPix 4500 camera and acquired with Apple Mac OS x 10.3.5 (Apple, Cupertino, CA) running Portfolio 7 software (Extensis, Portland, OR). There is significant extravasation of PMNs into the alveoli and air spaces with interstitial and intra-alveolar edema (blue arrows). Toluidine blue and Jones stains demonstrate dilated capillaries and a prominence of inflammatory neutrophils in the capillaries and air spaces (yellow arrows). Histologic findings are consistent with early acute respiratory distress syndrome.
|
Table 1. Clinical criteria for the diagnosis of ALI and TRALI16
|
| Insidious, acute onset of pulmonary insufficiency |
| Profound hypoxemia, PaO2/FiO2 less than 300 mm Hg* |
| Bilateral fluffy infiltrates consistent with pulmonary edema |
Pulmonary artery wedge pressure less than or equal to 18 mm Hg |
No clinical evidence of left atrial hypertension
|
* If arterial blood gas values are unavailable, pulse oximetry less than 90% meets the criterion for hypoxemia
Irrespective of the pulmonary end-expiratory pressure (PEEP)
The mortality rate from TRALI ranges from 5% to 25%; rates in
the lower end of the range are more common.
9,11,14,20 Most patients
recover within 72 hours; however, the data regarding TRALI are
limited, and the attendant morbidity and mortality may be underappreciated
because of lack of recognition and underreporting.
9,11,14,20 Autopsy specimens have demonstrated pulmonary findings consistent
with ARDS, including widespread leukocyte infiltration with
interstitial and intra-alveolar pulmonary edema, hyaline membrane
formation, and destruction of the normal lung parenchyma (
Figure 1).
11,22-26 In addition, in epidemiologic studies of ARDS, blood
transfusion was implicated as the most common risk factor for
the genesis of ARDS, and a number of these patients may represent
severe cases of TRALI.
22
Differential diagnosis
The differential diagnosis of patients who have pulmonary insufficiency
after transfusion must include circulatory overload, anaphylactic
transfusion reactions, and transfusion of blood products contaminated
with bacteria.
9,14,20 Transfusion-associated circulatory overload
(TACO) develops within minutes to hours of transfusion as respiratory
distress with tachypnea, tachycardia, hypertension, and cyanosis.
27,28 All blood components have been implicated in TACO, and it rapidly
responds to aggressive diuresis and ventilatory support.
28 Anaphylactic
transfusion reactions involve respiratory distress related to
bronchospasm manifested by tachypnea, wheezing, cyanosis, and
severe hypotension.
29 Facial and truncal erythema and edema
are common with urticaria, characteristically involving the
head, neck, and trunk.
29 The respiratory distress from anaphylactic
transfusion reactions is related to laryngeal and bronchial
edema rather than to pulmonary edema, as in TRALI.
29 These reactions
occur rapidly during the transfusion of any type of protein-containing
blood component and may occur after the transfusion of small
volumes of blood.
29 Transfusion-related bacterial sepsis after
transfusion of contaminated peripheral red blood cells (PRBCs)
or platelet concentrates manifests as fever, hypotension, and
vascular collapse, which may include respiratory distress, and
must be considered in patients with pulmonary insufficiency
who have undergone transfusion.
30 Last, although some symptoms
and signs of immediate hemolytic transfusion reaction may overlap
with TRALI, they are easily distinguished by the presence of
hemolysis.
9,13
Incidence and patient predisposition
In North America, the reported incidence of TRALI is 1 in 5000
to 1 in 1323 transfusions,
6,11,12 with newer data from Quebec
reporting an incidence of 1 in 100 000 to 1 in 10 000 (depending
on the transfused product).
31 In Europe, TRALI is rarer, with
reported incidences of 1.3 in 1 000 000 to 1 in 7900.
32-35 Although
the true incidence of TRALI remains unknown, it is unlikely
to be calculated until a consensus definition can be reached.
Although no specific patient groups are predisposed to TRALI,
Van Buren et al
36 first postulated that the clinical status
of the patient played a significant role in the pathogenesis.
In a retrospective series of 10 TRALI patients compared with
10 patients with uncomplicated febrile or urticarial transfusion
reactions, investigators hypothesized that TRALI was the result
of 2 independent insults, similar to animal models of ALI.
11,37,38 All patients in the TRALI group (10 of 10) had an antecedent
"first event" including recent (within 72 hours) major surgery,
active infection (bacterial or viral), massive transfusion (replacement
of total blood volume daily for 4 days), or cytokine administration
(granulocyte–colony-stimulating factor [G-CSF] or granulocyte-monocyte
stimulating factor) compared with the control group, in which
only 2 of 10 patients had a possible predisposing condition
(recent surgery and G-CSF administration) (
P < .05).
11 The
authors postulated that these first events might have predisposed
patients to TRALI through activation of the pulmonary endothelium,
resulting in polymorphonuclear leukocyte (PMN) sequestration
in the lungs.
11 Transfusion was the second event that activated
these sequestered PMNs, which were adherent to the pulmonary
vasculature, resulting in endothelial damage, capillary leak,
and TRALI.
11 Three of the 4 proposed predisposing conditions
appeared to have clinical relevance with respect to TRALI because
other groups have postulated that these same clinical conditions
may increase patient susceptibility to TRALI. They are (1) massive
transfusion has been implicated as a risk factor for TRALI in
patients receiving solid organ transplants
39; (2) follow-up
information from the Mayo Clinic, in its series of 36 TRALI
patients, revealed that all these patients had undergone recent
(within 48 hours) surgery
20; and (3) cytokine administration
was proposed as the predisposing event in a report of a patient
with antibody-negative TRALI.
40 In addition, active infection
is the most common predisposing clinical condition for the development
of ALI and may also be associated with TRALI.
16 A nested case-control study compared 46 consecutive patients
with TRALI to 225 hospital patients who received transfusions
during the same time interval and did not experience any adverse
effects.
12 Compared with controls who underwent transfusion,
2 patient groups were at particular risk for TRALI: those in
the induction phase of treatment for hematologic malignancies
(
P < .0004) and those with cardiovascular disease who required
bypass surgery (
P < .0006).
12 In addition, other patient
groups, including those receiving fresh frozen plasma (FFP)
for coumadin reversal and those with thrombotic thrombocytopenic
purpura and widespread endothelial activation, appear to be
at risk for TRALI.
6,17,20,39,41,42 TRALI has also been reported
in patients requiring transplantation of bone marrow and solid
organ; ALI in these patients should be considered an untoward
reaction related to the graft or to supportive care.
43-50 Further
prospective analyses of patients who have undergone transfusion
are required to properly identify patients who are at risk for
TRALI.
Implicated blood components
In published series of TRALI, plasma-containing blood components
are most commonly implicated with whole blood–derived
platelet concentrates (WB-PLTs),
20 which have caused the largest
number of these reactions, followed by FFP,
6,9,20 PRBCs,
6,9,20 whole blood,
6,9,20 apheresis platelet concentrates (A-PLTs),
9,40,47,51 granulocytes,
52-54 cryoprecipitate,
9,43 and intravenous immunoglobulin
(IVIG).
55 IVIG has the capacity to cause TRALI if it contains
a significant amount of antileukocyte antibodies directed against
antigens on host leukocytes, but given that there is only a
single case report of IVIG-related TRALI, this may be a rare
event.
55 Although the plasma fraction of blood or blood components
rather than the cellular constituents appears to be etiologic
in TRALI, two of the most frequently implicated products (PRBCs
and WB-PLTs) do not contain large amounts of plasma.
13 However,
although WB-PLT pools may contain significant amounts of plasma,
the relative amount of plasma from each donor, the source of
the antileukocyte antibody or biologic response modifier that
may cause TRALI, remains small.
13
Pathogenesis
Two basic mechanisms have been proposed for the pathogenesis
of TRALI for immunocompetent hosts, and another mechanism has
been hypothesized for neutropenic patients.
6,11,17,51 For patients
with normal absolute neutrophil counts, adherence and activation
of neutrophils leads to endothelial damage, capillary leak,
and ALI (
Figure 2A-B). The first hypothesis is that TRALI is
secondary to a single antibody-mediated event (
Figure 2A). In
this model, TRALI is caused by the passive infusion of donor
antibodies directed against recipient antigens on the surfaces
of their leukocytes or the infusion of donor leukocytes into
a recipient with antibodies directed against these donor leukocytes.
6,9,17 The second hypothesis postulates that TRALI is caused by at
least 2 independent events (
Figure 2B).
11,12,20,26 The first
event relates to the underlying clinical condition of the patient
such that the patient has pulmonary endothelial activation resulting
in pulmonary sequestration of neutrophils.
11,12,20,26 Transfusion
is the second event; it involves the infusion of specific antibodies
directed against adherent PMNs in the lung or against other
biologic response modifiers, including lipophilic compounds,
that cause activation of the microbicidal arsenal of these primed,
adherent PMNs, resulting in endothelial damage, capillary leak,
and TRALI.
11,12,20,26 In addition, albeit rarely, TRALI has
been reported in neutropenic patients.
51 In these patients it
is thought that TRALI is caused by the infusion of vascular
endothelial growth factor (VEGF), an effective permeability
factor,
56-59 or by the infusion of antibodies against HLA class
II antigens that reside on pulmonary vascular endothelium and
cause endothelial shape change and fenestration (
Figure 2C).
60-62 Each of these mechanisms in neutropenic patients might elicit
mild pulmonary leak.
| Figure 2. Pathogenesis of TRALI. (A) TRALI may be precipitated by a single clinical event, the infusion of donor antibodies directed against host leukocytes, which causes complement activation, pulmonary leukostasis, PMN activation, endothelial damage, capillary leak, and ALI. (B) TRALI may be the result of 2 clinical events: the first consists of the clinical condition of the host, which causes pulmonary endothelial activation and adherence of PMNs, resulting in pulmonary sequestration. The second event, consisting of the transfusion of biologic response modifiers (biologically active lipids, antibodies directed against specific HLA class I or II or granulocyte antigens) in the blood component then activates these adherent PMNs and precipitates TRALI in predisposed patients. ROS indicates reactive oxygen species. (C) In neutropenic patients, TRALI may be precipitated by agents that directly cause endothelial fenestration, including high levels of VEGF or high levels of HLA class II antibodies directed against antigens on the pulmonary endothelium. |
|
Antibody-mediated TRALI caused by HLA class I and antigranulocyte antibodies
In 1985, Popovsky and Moore
6 proposed the infusion of donor
antibodies to explain TRALI. This study documented donor antibodies
to granulocytes in 89% of these cases and antibodies to HLA
antigens in 72% of cases examined.
6 Most of the granulocyte
antibodies did not exhibit specificity, but 59% of the HLA class
I antibodies did.
6 These findings have been confirmed by a number
of other groups, and approximately 50% of donor antileukocyte
antibodies display specific reactivity to recipient antigens.
9,36,63,64 This pathogenesis has also been postulated for the transfusion
of antigranulocyte antibodies.
9,36,63,64 This infusion of leukoagglutinins
is thought to cause complement activation, resulting in PMN
influx into the lung, followed by activation of these PMNs and
release of cytotoxic agents, in turn resulting in endothelial
damage, capillary leak, and pulmonary damage.
6,9,64 Thus, these
antibodies are likely to be cytotoxic antibodies to confer such
biologic activity when recognition of a leukocyte antigen occurs.
6,12,27,65-67 In addition, TRALI can be caused by the binding of recipient
antibodies to discrete antigens on transfused donor granulocytes;
however, the number of viable PMNs is an issue, and such a mechanism
represents only 10% of TRALI cases.
9,68 This mechanistic sequence
has particular relevance to patients receiving granulocyte transfusions
and in whom alloantibodies, episodes of pulmonary leukostasis,
and ALI develop.
68
One particularly good example of antibody-mediated TRALI was
reported by Dykes et al
45 in a woman who underwent lung transplantation.
After the transfusion of 2 U PRBCs, she became dyspneic and
had marked hypoxia, and chest x-ray revealed a unilateral "white-out"
of the transplanted lung. Antibodies to HLA-B44 were present
in the donor of the second PRBC unit, and the antigen was expressed
on the transplanted lung but not on the uninvolved lung. The
patient did recover after intensive support, and this case provides
an elegant example of antibody-mediated TRALI.
45
Animal models of antibody-mediated TRALI. The relevance of these
observations was reported in an ex vivo rabbit model of TRALI
that demonstrated ALI characterized by severe pulmonary edema
resulted from the infusion of a mixture of human PMNs {HNA-3a
(5b) positive}, human HNA-3a antibodies, and rabbit plasma as
a complement source.
67 In this ex vivo model pulmonary edema
occurred 3 to 6 hours after the infusion of the admixture; however,
if any of the 3 components was deleted (HNA-3a antibodies, HNA-3a-positive
PMNs, or complement), lung pulmonary edema would not occur.
67 Furthermore, if immunoglobulins with indeterminate antigen specificity
were infused with complement and human PMNs, ALI was not observed.
67 Recently, Bux et al
69 have updated this model and have demonstrated
that using antigranulocyte antibodies and PMNs that have the
cognate antigens may cause pulmonary edema without the addition
of a complement source.
Modeling constraints. Although antibodies to HLA class I or
granulocyte antigens explain many TRALI cases, a number of problems
with this antibody-mediated mechanism remain. In the original
description, only 59% of the immunoglobulins identified demonstrated
antigen specificity, and in published series of TRALI, only
approximately 50% of the implicated antibodies demonstrated
specificity for recipient antigens.
6,9 Because such nonspecific
antibodies did not cause TRALI in the ex vivo animal model,
the significance of these immunoglobulins, especially in the
context of TRALI, is undefined.
67 The precise mechanism for
antibody-mediated TRALI is unknown
6,9; moreover, in a number
of cases of TRALI, an antibody is not present either in the
donor or in the recipient,
7,9-12,40,65 and recently a case of
autologous TRALI has been reported.
15 Even when antibodies are
transfused into patients with the cognate antigens on the surfaces
of their leukocytes, most patients do not acquire TRALI.
18,36,70 Last, the ex vivo animal model of TRALI by Seeger et al
67 introduced
PMNs into the lung perfusate. This model used sterile plastic
tubing, which is known to effectively prime PMNs in clinical
situations including cardiac bypass and dialysis.
71-73 Thus,
if one considers the effects of the tubing on the circulating
PMNs, this may be seen as a 2-event model: the first is the
"inflammatory effect" of the tubing on the HNA-3a+ PMNs, and
the second is the introduction of the HNA-3a antibodies with
rabbit plasma, a complement source.
67,71-73
TRALI secondary to the infusion of class II HLA antibodies
Kopko et al
17 have postulated that TRALI is caused by the infusion
of HLA class II antibodies with specificity for class II antigens
in the recipient, and these findings have been confirmed by
other groups.
74,75 Furthermore, they demonstrated in vitro that
HLA class II antibodies implicated in TRALI could activate circulating
monocytes that expressed these antigens, causing synthesis of
significant amounts of TNF-
, IL-1
, and tissue factor over a
4-hour time period compared with monocytes incubated with control
sera.
76 These cytokines have the capacity to activate PMNs,
leading to endothelial damage capillary leak and TRALI.
10,76 In addition, because HLA class II antigens may be expressed
on endothelial cells (ECs), especially after inflammatory stimuli,
61,62 these investigators questioned whether the infusion of HLA class
II antibodies into a recipient with cognate antigen expression
on the pulmonary endothelium may manifest TRALI because of endothelial
activation, changes in cellular shape, fenestration, and capillary
leak.
76 Such a hypothesis is attractive, especially in the neutropenic
patient who develops TRALI, but further work is required to
test this hypothesis.
Modeling constraints. The infusion of HLA class II antibodies
into patients who express the cognate antigens represents an
attractive model for TRALI but raises a number of questions.
First, though the synthesis of cytokines by circulating monocytes
has the potential to cause TRALI, there is a significant time
delay (4 hours) for the production of these inflammatory mediators;
moreover, in these studies, the cytokines were intracellular
and were not released extracellularly.
76 Second, this model
has relevance only if the infused antibody specifically recognizes
a recipient antigen.
76 Moreover, one interesting phenomenon
is that cytokine-activated PMNs express HLA class II antigens,
whereas resting PMNs express these antigens at very low levels
or not at all.
77-80 Therefore, if PMNs become primed and adherent,
do they then express HLA class II antigens that may be recognized
by HLA class II antibodies infused with the transfusion, and,
if so, would not ligation of these antigens on primed, adherent
PMNs then cause activation of the microbicidal arsenal, endothelial
damage, and TRALI?
81,82 Such a mechanism is plausible but would
require 2 events: the first would cause adherence of PMNs to
the pulmonary microvasculature, and the second would be the
passive infusion of specific HLA class II antibodies directed
against the class II antigens on the cell surfaces of the primed,
sequestered PMNs.
10,81,83 Despite the plausibility of this mechanism,
one must remember that in vitro cytokine exposure of 72 hours
is required for surface expression of HLA class II antigens
on PMNs
77-81 and that there may be significant differences between
the effects of cytokines on leukocytes in vitro and in vivo.
84 Moreover, investigation of a case of HLA class II antibody–mediated
TRALI did not demonstrate the appearance of such HLA class II
antigens on the surfaces of the patient's intravascular leukocytes.
23 Further work is required to elucidate the mechanism in HLA class
II antibody–mediated TRALI.
In addition, in the past few years the technology for leukocyte
antibody detection has demonstrably changed and has increased
the power and the specificity of the assay, especially with
the use of flow cytometry. This improved technology has led
to more precise definition of the antigen/antibody pairs that
have resulted in TRALI. If one examines these implicated conjugates
of the past 3 years, relatively few antibodies appear to be
etiologic in TRALI (Patricia Kopko, presented at the Consensus
Conference on TRALI, Toronto, Canada, April 2004). These antibody/antigen
pairs include anti–HNA-3a and HNA-3a, granulocyte antigen,
anti–HLA-A2 Creg and HLA-A2 Creg HLA, anti–HLA-B12
and HLA-B12, multiple HLA class II antibody/antigen pairs, and
a mixture of HLA class I and class II antibody/antigen pairs.
These results are different from the data presented by Popovsky
and Moore, and other investigators, that demonstrate 83% concordance
of HLA class I and granulocyte antibodies in patients with TRALI.
6 These findings suggest that only specific antigens may be etiologic
in TRALI and that such antigens may be responsible for signal
transduction in leukocytes that leads to the synthesis and release
of cytokines, EC damage, and TRALI.
Two-event model of TRALI. All proposed models of TRALI in immunocompetent
patients implicate the PMN as the effector cell.
6,11,12,17,20,26 Thus, it is important to understand PMN physiology, especially
the interaction of PMNs with pulmonary vascular endothelium
(
Figure 3A)
85-87 and PMN-mediated cell damage leading to ALI
(
Figure 3B). Moreover, the underlying clinical condition of
the patient is important, as demonstrated in 3 "look-back" studies,
including those of Van Buren et al
36 with a donor with HNA-2b
antibodies, Kopko et al
18 with a donor with HNA-3a antibodies,
and Nicolle et al
70 with 2 donors with multiple HLA class II
antibodies, which demonstrated that most transfused patients
did not develop TRALI even though their leukocytes contained
the cognate antigens.
| Figure 3. Normal and abnormal neutrophil physiology. (A) Normal PMN emigration from the vasculature to the site of infection or inflammation in the tissues. In response to an infection (grouped ovals) in the tissues, inflammatory signals (stage 1, arrows) diffuse through the tissues to the vasculature and activate the vascular endothelium, causing release of chemokines (stage 2, 4-pointed stars), which attract PMNs to the endothelial surface (stages 3-4).20,102-104 Attraction is followed by selectin-mediated PMN rolling (stage 3) and 2-integrin/ICAM-1–mediated firm adhesion of PMNs to ECs (stage 4).20,102-104 These PMNs, which have undergone a change from a nonadhesive to an adhesive phenotype, are now primed (stage 4).20 Priming of PMNs enhances the microbicidal function of PMNs to a subsequent stimulus and changes the activity of PMNs such that stimuli that normally do not cause the activation of quiescent neutrophils are able to activate primed PMNs.20,88 It is important to note that priming is part of the orderly process of PMN transmigration to the tissues. Although there are benefits to enhanced PMN function, including efficient destruction of pathogens, it is clear priming may be detrimental to the host and may lead to PMN-mediated organ injury, especially ARDS.20 The PMNs then pass by diapedesis through the endothelial layer (stage 5), orient by chemotaxis to the site of infection (stage 5), and phagocytize (stage 6) and destroy the bacterial invaders (stage 6).20,102-104 (B) PMN-mediated tissue injury. If the orderly process of PMN transmigration is altered by a stimulus coming from the intravascular space (4-pointed stars, crosses, triangles) rather than the tissues, these intravascular stimuli activate vascular ECs (arrows) and cause attraction (stage 2), selectin-mediated rolling (stage 3), firm adhesion through the ICAM-1/2-integrin interaction (stage 4), and priming of PMNs (stage 4).20 However, because there are no signals to cause diapedesis and PMN chemotaxis into the tissues, the PMNs become sequestered in the microvasculature.20 These primed, hyperreactive leukocytes may be activated by stimuli (stage 5, large triangle with diamonds) that normally have no effect, including antibodies directed against specific leukocyte antigens or the lipids that accumulate during routine storage of cellular blood components.20 Activation of these adherent PMNs causes endothelial damage (stage 5, ECs with lines) with lines, capillary leak (large arrow, stage 6), and organ injury.20
|
|
Accumulation of PMN priming activity in stored blood
During routine storage of cellular components, an effective
PMN priming activity accumulates that is lipophilic, as determined
by its solubility in chloroform.
88,89 Separation and characterization
of this activity in whole blood (WB), PRBCs, and platelet concentrates
demonstrated that this activity consisted of a mixture of lysophosphatidylcholines
(lyso-PCs).
88,89 These compounds effectively prime the PMN oxidative
burst and can activate primed, adherent PMNs in vitro.
88-91 In addition, an in vitro model of TRALI that used human pulmonary
microvascular endothelial cells (HMVECs) as targets demonstrated
that 2 events were required for PMN cytotoxicity.
91 The first
was HMVEC activation, which caused significant PMN adherence
to the HMVEC surface that required chemokines for PMN attraction
and firm adherence through the PMN
2-intergrins and the ICAM-1
on HMVECs.
88 This PMN adherence mimics pulmonary sequestration
of PMNs.
91 The introduction of lyso-PCs from stored blood, the
second event, activated these adherent PMNs, causing HMVEC death;
however, if the PMNs were not adherent to the HMVECs, even with
the addition of lyso-PCs, no PMN cytotoxicity occurred.
91 In
addition, PMN cytotoxicity in this model could be abrogated
by inhibitors of the respiratory burst.
91 These studies provide
in vitro evidence that TRALI may be the result of 2 independent
events and that endothelial activation resulting in firm adhesion
of PMNs to endothelium is required.
91
Two-event animal model of TRALI. The 2-event model of TRALI
has been verified in an animal model.
26,92 In this model, rats
were treated with endotoxin (lipopolysaccharide [LPS]) for 2
hours to approximate active infection, one of the predisposing
clinical conditions associated with TRALI.
26,92 LPS activates
the pulmonary vascular endothelium, which results in pulmonary
sequestration of PMNs, confirmed by the pulmonary histology.
26,92 The lungs were then isolated and perfused with buffer controls
or 5% plasma from day 0 or day 42 PRBCs or day 0 or day 5 plasma
from both WB-PLTs and A-PLTs.
26,92 Vehicle-pretreated animals
did not evidence acute lung injury with any of the perfusates.
26,92 However, lungs from LPS-pretreated animals perfused with 5%
plasma from day 42 PRBC units or day 5 WB-PLT or A-PLTs, but
not plasma from identical PRBCs, WB-PLTs, or A-PLTs from day
0 or buffer controls, caused acute lung injury, as documented
by pulmonary edema, lung histology demonstrating PMN-mediated
ALI, and increases in leukotriene concentrations.
26,92 In addition,
both the lipid fraction and purified lipids from stored, but
not fresh, PRBCs, WB-PLTs, and A-PLTs were etiologic in producing
TRALI.
26,92 Thus, the plasma and the lipids from stored blood
products caused TRALI in this model.
26,92
Modeling constraints. The 2-event model requires PMNs and requires
that these PMNs be sequestered in the pulmonary vasculature.
Therefore, apparently healthy patients who experience TRALI
seem to be obviated from this pathogenesis. However, patients
who require transfusion are not healthy by definition. Moreover,
a study of the PMNs from 5 "healthy" donors, by history, demonstrated
that their PMNs were grossly primed, as determined by the appearance
and activity of these PMNs. In fact, all these donors acquired
infections, either viral or bacterial, over the next 24 hours.
90,93 Thus, it may be difficult to determine whether patients who
undergo transfusion are indeed healthy.
Relevance of the 2-event model to clinical TRALI
A retrospective clinical study of TRALI patients demonstrated
effective PMN priming activity in the patients' plasma at the
time TRALI was recognized that had not been in the patient's
pretransfusion typing serum; it was postulated that the clinical
condition of the patient was important as a first event.
11 Furthermore,
no PMN priming activity was present in the plasma of patients
with febrile or urticarial reactions, the PMN priming activity
was lipid, and 2 of 3 predisposing conditions—massive
transfusion and recent surgery, present in the TRALI patients
but not in the controls—have since been implicated by
other groups as predisposing conditions.
11,20,39
In a prospective analysis of TRALI, the role of cytotoxic HLA
class I and class II and antigranulocyte antibodies were examined.
12 Of the donors tested, only 1 of 28 exhibited an antibody with
specificity (HLA-A26) similar to that of positive controls.
12 The implicated blood products demonstrated significant plasma
PMN priming activity compared with similar products from the
same facility and identical storage time that did not cause
transfusion reactions.
12 There was PMN priming activity in all
TRALI patients at the time of recognition that consisted of
neutral lipids and lyso-PCs.
12 In addition, the roles of IL-6
and IL-8 were examined; each increased during storage, but only
IL-6 was significantly increased in the TRALI patients compared
with the pretransfusion sample.
12 Thus, in this series, TRALI
was caused by 2 events. The first was the clinical condition
of the patient, and the second was the infusion of bioactive
lipids in the stored blood component.
12
Merging of the mechanisms of TRALI in immunocompetent patients Recent preliminary data have provided evidence that antigranulocyte
antibodies, namely antibodies directed against HNA-3a, were
able to rapidly prime the fMLP-activated respiratory burst,
analogous to lipids that accumulate during routine blood storage.
94 In addition, these antibodies did not prime the PMNs through
non-specific activation of Fc receptors because pretreatment
of HNA-3a
+ PMNs with F(ab')
2 fragments directed against CD16,
CD32, and CD64 had little effect on the priming activity of
the HNA-3a antibodies.
94 Moreover, antibodies to the HNA-3a
locus did not prime HNA-3a
- PMNs.
94 Therefore, antibodies may
have similar effects on recipient PMNs because other biologic
response modifiers, including lipophilic compounds, which have
the capacity to directly prime PMNs in vitro,
87 cause PMN cytotoxicity
in vitro
91 and elicit PMN-mediated ALI in a 2-event animal model
of TRALI.
26,92 Further work is required to corroborate these
findings and to determine whether these antibodies may directly
cause PMN cytotoxicity in vitro.
Prevention
Decreasing blood usage will likely diminish TRALI because a
number of untoward clinical outcomes are related to transfusion
and must be considered to maximize patient outcome, especially
for ill patients who may require transfusions.
95 Moreover, applying
consistent transfusion guidelines may decrease unnecessary transfusions
and the morbidity associated with such needless patient exposures
to blood products.
95-98 In addition, many investigators, transfusion
medicine professionals, and the American Association of Blood
Banks advocate temporary disqualification of donors implicated
in TRALI reactions until leukocyte antibody testing can be completed.
9,13,76,82 If these donors have antibodies to high-frequency leukocyte
antigens, such as HNA-3a, HLA-A
2, and HLA-B
12, they should be
disqualified from plasma or platelet donation; otherwise, if
these findings are negative, they should be returned to the
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