Key clinical message
Transfusion-Related Acute Lung Injury (TRALI) has been associated with
neutrophil reacting antibodies in transfused blood products. We report a
case of life threatening TRALI in an obstetric patient triggered by
transfusion from a non-transfused male blood donor. A residual risk of
TRALI exist, even in a male-only plasma setting.
Introduction
Transfusion-related acute lung injury (TRALI) is a clinical diagnosis
defined by the Canadian Consensus Panel1. The
diagnostic criteria include acute onset hypoxemia during or within 6 h
of transfusion, bilateral infiltrates on the chest radiograph and
exclusion of other risk factors for acute lung injury
(ALI)2. Life-threatening cases of TRALI can be
provoked by the presence of neutrophil reacting antibodies in the
transfused blood product3. These antibodies are often
related to multiparous women; thus, most countries use male plasma only
for transfusions. This practice has substantially reduced the risk of
TRALI. However, a residual risk persists; therefore, transfusion therapy
must be goal-directed to diminish the risk of over-transfusion and
adverse effects4. An estimate from recent
hemovigilance data have reported a frequency of TRALI of approximately
1/65.000 transfusions5.
Case report
A 34-year-old nullipara woman with no past medical history was admitted
to the hospital at 41 + 5 weeks of gestation. Acute caesarean delivery
was performed, due to failure to progress, and a live male infant was
delivered. Eight hours postpartum, the patient’s condition deteriorated
with severe abdominal pain, a fall in haemoglobin (12.9 to 7.4 g/dl),
and ultrasonic signs of intraperitoneal fluid. An acute laparotomy
showed a small leak from the right corner of the uterus and 2150 ml of
blood was removed from the abdominal cavity. One hour before surgery,
the patient received a transfusion of one unit of leukocyte-reduced red
blood cell concentrate (RBC), and intra-operatively she received three
units of RBCs and four fresh frozen plasma (FFP) units. Near surgery
completion, during transfusion of the fourth FFP unit, the patient
became hypoxic. Arterial oxygen tension dropped from 100 to 82%, clear
frothy sputum emerged from the endotracheal tube, and systemic blood
pressure decreased from 140/100 to 90/40 mmHg. The patient received
intravenous furosemide (40 + 60 mg), however there was no response to
treatment. Echocardiography within one hour after onset of symptoms
revealed normal left ventricular function. TRALI diagnosis was
strengthened with a chest radiograph, which showed extensive bilateral
lung infiltrates (Figure 1). Computed tomography scan of the chest
indicated acute respiratory distress syndrome. Two hours before the
first transfusion, the neutrophil count was 12.0 x
109/L (normal range 1.5-7.5 x
109/L), and it dropped to 0.38 x
109/L at 4 h after onset of symptoms (Figure 2).
Simultaneously, the platelet count dropped from 164 x
109/L to 59 x 109/L, and the
monocyte count dropped from 0.84 x 109/L to 0.00 x
109/L. The patient was sedated on ventilator support.
She received 125 mg methylprednisolonsuccinate intravenously (IV) and
following 50 mg of IV hydrocortisone every 6 hours. She had normal body
temperature (35.6-36.9°C) and infection was ruled out, with negative
cultures of blood, urine, and endotracheal secretion. The patient’s
condition improved gradually; after 41 h, she was extubated, but
required oxygen support for an additional 60 h. Five weeks later, a
chest radiograph showed complete regression of infiltrates and no signs
of sustained lung injury.
Serological analysis
The patient received blood products originating from eight different
blood donors All donors were tested for; anti-HLA class I and anti-HLA
class II antibodies, for granulocyte- and lymphocyte-reacting antibodies
with a combination of direct and indirect flow cytometric
granulocyte/lymphocyte immunofluorescence tests (Flow-D-GIFT, Flow-GIFT,
Flow-LIFT), granulocyte antibodies with a granulocyte agglutination test
(GAT) and the LABScreen Multi assay. Antibody specificity was confirmed
with monoclonal antibody specific immobilization of granulocyte antigens
(MAIGA). Human neutrophil antigen (HNA) typing was performed with a
TaqMan real time polymerase chain reaction method (Q-PCR), as previously
described6. We confirmed the findings after 3 months
and 6 months. All assays were performed in an International Society of
Blood Transfusion (ISBT) granulocyte serology reference laboratory.
Results
The serum from one blood donor, a 61-year old male, reacted positive
against the five donor samples in the flow-GIFT panel and against
patient granulocytes in the direct cross-match test (Table 1). The
antibody showed weak agglutination in the GAT. The LABScreen Multi assay
indicated anti-Fc-gamma-receptor-IIIb. The MAIGA identified an
anti-Fc-gamma-receptor-IIIb (FcGRIIIb; CD16b) antibody. HNA specificity
could not be determined further. The Flow-D-GIFT was negative.
Phenotyping revealed normal CD16b expression on donor granulocytes.
Genotyping revealed the donor as FCGR3B*01+,*02+,*03- . Sequencing
the FCGR3B gene showed no variant FCGR3B alleles.
Identical results were found in all assays at 3 and 6 months follow up.
Samples were retested in a collaborating ISBT reference laboaratory,
with identical results.
Discussion
This patient sustained TRALI during intensive haemodynamic,
echocardiographic, and haematological monitoring. We identified an
anti-FcGRIIIb antibody in a non-transfused male donor sample. This
highly probable trigger made this TRALI case unusual. TRALI is a rare
but potentially life threatening condition and its diagnosis is
primarily based on exclusion. No specific treatment exists and
management consist of supportive care. Approximately 80% of patients
with TRALI require mechanical ventilation. Steroids offer no benefit,
but they are often given, as reported in our case7.
Most patients recover without sequelae; however, the syndrome is
associated with considerable morbidity; the estimated mortality is
6-10%. It has been hypothesized that TRALI results from two insults.
The first is related to the patient’s condition; e.g. surgery, sepsis,
haematological malignancies, and mechanical
ventilation8. These conditions can activate the
pulmonary endothelium, prime neutrophils, and cause their subsequent
sequestration in the lungs, which lowers the patient’s threshold for
TRALI. The second insult is the full activation of primed neutrophils by
biological response modifiers in the blood product. Our patient
displayed a precipitous drop in neutrophils within 4 h after onset of
symptoms. This neutropenia was consistent with massive neutrophil
agglutination in the pulmonary microcirculation. No other known
transfusion reactions are associated with acute transient neutropenia.
Our findings support the hypothesis that antibody-mediated TRALI remains
a residual risk associated with transfusions from the non-transfused
male donor population. The donor we identified had no history of
allo-exposure. However, in his occupation as a sailor, he had received
repeated vaccines. Previous donor studies have found that approximately
1-2% of never-transfused males harboured pan-reactive or nonspecific
leukocyte antibodies9. These naturally occurring
antibodies potentially represent autoantibodies, antibodies that
cross-react with bacterial antigens, or antibodies developed after
immunizations. In the setting of massive bleeding, current guidelines
recommend closely monitoring coagulation with whole blood coagulation
methods, like thromboelastography or thromboelastrometry. Implementing
those strategies might reduce the use of blood components, and thereby
reduce the risk of transfusion reactions10.
In summary, this case reports illustrates the occurrence of
neutrophil-reactive antibodies in low-risk donor samples, and the
liberal use of blood transfusions. Testing all donors for neutrophil
antibodies is expensive and logistically challenging; however, TRALI may
represent one of the last major risks in blood transfusion that remains
to be minimized with serological testing.
Informed consent
Informed consent to describe this case of TRALI was obtained from donor
and patient.
Funding
This work received no funding.
Conflict of Interest
The authors declare no conflicts of interests.
Author Contributions
CNA: Conceptualized the case, had contact with patient and blood donor
and wrote the manuscript
TMH: Involved in data analysis and manuscript preparation
ALF: Performed serological analysis and were involved in manuscript
preparation
JB: Were involved in data requisition and manuscript preparation.
RS: Performed genetic analysis and co-wrote manuscript
KRN: Were involved in all steps and wrote the manuscript
All authors approved the final manuscript as submitted.
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Table 1. Blood donor and patient characteristics including
results from serological and genetic
analysis.