Transcript TRALI: It’s Not Just For Blood Bankers Anymore

TRALI: It’s Not Just For Blood
Bankers Anymore
Norman D. Means, MD, FCAP
Blood Bank of Alaska
TRALI
What is it?
Transfusion-Related Acute Lung Injury
• First described by Popovsky , Abel and Moore
in 1983 Am Rev Resp Dis 1983;128:185-9
– Acute Pulmonary Edema
– Respiratory Distress
– Hypoxemia
– Hypotension
– Fever
– In the setting of a recent transfusion
History
• Case reports as long ago as 1951
– “Noncardiogenic edema”
– “Allergic pulmonary edema”
– “Hypersensitivity reaction”
– “Leukoagglutinin transfusion reaction”
History
• TRALI is a difficult diagnosis to make, since
there are often confounding underlying
medical conditions that tend to obscure the
diagnosis
• TRALI is one subset of Acute Lung Injury
– Spectrum of disorders
Acute Lung Injury
• Spectrum of injury
• Acute Respiratory Distress Syndrome (ARDS) is
most severe form
• Many potential causes, including many causes
which are treated by transfusion
– Up to 40% of acutely ill, actively bleeding patients
will develop ALI
• Pulmonary edema may develop
simultaneously
ALI/ARDS
Other possible causes of ALI/ARDS
• Sepsis
• Trauma
• Aspiration
• Shock
• others
Acute Lung Injury
• ARDS Mortality 30 – 40%
• TRALI Mortality
6 – 12%
Consensus conferences
• North American-European Consensus
Conference on ARDS (1994)
• NHLBI Working Group (2002)
• Canadian Consensus Conference (2004)
North American European CC
Acute Lung Injury definition:
• Acute hypoxemia
– PaO2/FiO2 <300 mm Hg
• Pulmonary edema on frontal CXR
• Pulmonary artery occlusion pressure <18 mm
HG or no evidence of left atrial hypertension
NHLBI WG /Canadian CC
Defined TRALI
• Adopted NAECC definition of ALI
• TRALI if 6 hours since transfusion
• Risk factors for ALI
– Canadian: “possible TRALI”
– NHLBI: interpret time course
Why is TRALI suddenly so important?
Transfusion-associated fatalities
reported to the FDA 1990-1998
Cases
%
HTR
161
50
Bacterial Contamination
46
14
TRALI
29
9
Non-bacterial infections
23
7
Transfusion-associated GVHD
18
6
Source: Lee, JH Workshop on Bacterial Contamination of Platelets, 9/24/99; adapted from Menitove, JE Complications of
Transfusion (p 1617), in Clinical Laboratory Medicine, 2nd Ed. (2001) , McClatchey, KD, ed.
Transfusion-associated fatalities
reported to the FDA 2005-2006
Cases
%
64
51
25
20
15
12
HTR(ABO)
9
7
TACO
9
7
TRALI
HTR (non-ABO)
Microbial infection
• Cases
• 6
Source: Fatalities reported to the FDA following blood collection and transfusion (2005-2006); from
http://www.fda.gov/cber/blood/fatal0506.htm
Differential Diagnosis of TRALI
TACO
Transfusion-Associated Circulatory Overload
TACO
• The most common transfusion reaction
• 1-8% of post surgical patients requiring
transfusion
• Age > 60 may develop with only a single unit
of pRBC
• Dyspnea, orthopnea, elevated BP, pedal
edema, crackles, tachycardia, infiltrates
• Elevated BNP
Anaphylactic Reactions
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Bronchospasm
Wheezing
Laryngeal edema
Urticaria/Erythema
Hypotension
Rapid onset after start of transfusion
IgA deficiency
Transfusion-Associated Sepsis
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Fever
Hypotension
Shock
Rapid onset
Bacteria present
Platelets most at risk
Pathophysiology of TRALI
• Traditional model (antibody transfer)
• Transfer of biologic response modifiers
Traditional Model
• Passive transfer of antibody via transfusion
• HLA Class II, HNA, HLA Class I antibodies
• Sensitized donors
– Multiparous women
– Organ and tissue transplant recipients
– Previously transfused blood donors
Traditional Model
• Bray, et al (2004)
– 308 randomly selected units of plts, pRBC, FFP,
cryoprecipitate
– Overall 22% of units had HLA antibodies
• FFP 29%
• Cryo 24%
Hum Immunol 2004;65:240-4
Traditional Model
• Why don’t we see more TRALI?
– Antigen-antibody pairing
– Threshold concentration of antibodies
– Preexisting endothelial “priming” may potentiate
response
Bioactive Response Modifier Model
• Accumulation of IL-6, IL-8, PAF, IFN-γ, TNF-α,
NO, bioactive lipids
• Transfusion leads to activation of
inflammatory cascade (NO→vasoconstriction)
• Damage to alveolar capillaries or increased
hydrostatic pressure
– Pulmonary Edema
Bioactive Response Modifier Model
• These bioactive agents have been shown to
accumulate in stored blood products over
time.
• Levels may rise high enough to “prime”
neutrophils or endothelial cells
• Some evidence that these may rarely trigger
TRALI directly.
Pathophysiology of TRALI
• Probably all of these models have some role
to play in the causation of TRALI
• Other causes may emerge
Pathophysiology of TRALI
• End result is damage to the pulmonary
capillary endothelium
• Neutrophil-induced damage
– Activated neutrophils
• express HLA Class II and HNA antigens
– Activated pulmonary endothelium
• express HLA Class II antigens
Pathophysiology of TRALI
• Activated neutrophils
– Response to various priming agents
• PAF, TNF-α, IL-8, GM-CSF, IFN-γ, LPS, infectious agents
– Anatomic and physiologic changes
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Stiffening (actin polymerization)
Adhesivity (β2 integrins, selectins)
Clustering of surface receptors (FcγRIIa, β2 integrins)
Release of toxic granule enzymes
Formation of NADPH oxidase → Reactive oxygen
species
Pathophysiology of TRALI
• Activated neutrophils
– Activation may be triggered by a number of events
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Infection
Cardiovascular disease
Leukemia
Recent surgery
Others (trauma?, hemorrhage?)
– Mechanical sequestration and aggregation in
pulmonary microvasculature
Pathophysiology of TRALI
• Activated endothelium
– Increased adhesivity (selectins, ICAM-1)
– Promotes priming of “captured” neutrophils
– Interaction of activated endothelium and
neutrophils leads to endothelial damage/TRALI
• Platelet activation
• Increased neutrophil aggregation
• Complement activation
– Role unclear
Pathophysiology of TRALI
• Neutrophil specific antibodies
• HNA, HLA Class II, and HLA Class I
– Some are strong enough to trigger TRALI alone
• Presence of leukoagglutinins is especially worrisome
• Leukoagglutinins may stimulate active neutrophil
aggregation
Pathophysiology of TRALI
• Activated neutrophils are sequestered in the
microvasculature of the lungs
– Production of bioactive products
• ROS
• Enzymes
• Endothelial damage
• Exudation of fluid and neutrophils into alveoli
Respiratory compromise
Pathophysiology of TRALI
• Exudative (high protein) fluid in alveoli
– TACO has transudative (low protein) protein in alveoli
– Damage to the pulmonary capillary endothelium leads
to leakage into alveoli
– Due to activated neutrophils damaging endothelium
Pathophysiology of TRALI
• Presence of HLA-antibodies and HNA
antibodies in a blood product does not
necessarily mean that these antibodies will
cause TRALI
• Cognate antigens in recipient may be
necessary
HLA and HNA antibodies
• HLA antibodies identified in 70-75% of all
TRALI cases
– 85-90% antibody in transfused product
– 10% in recipient
– Rare inter-donor cases
• antibody in transfused product directed against antigen
in other transfused product
• HNA antibodies 10-15%
• 10-15% ? ?
HLA and HNA antibodies
HLA Class I
HLA Class II
HLA Class I and II
HNA
(HNA-3a)
Total
# of cases of
severe TRALI
4
17
3
12
(10/12)
36
Reil A, et al. Vox Sanguinis 2008;95(4):313-317
%
10
47
8
33
HLA and HNA antibodies
• HNA-3a antibodies in 6 of 10 fatal cases in this
study
• Remainder were HLA Class II and HNA-2a
HLA testing
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All test rely on the AHG test
Plasma or serum is reacted to test antigens
Wash unbound antibody away
Incubate with anti-IgG
Wash unbound anti-IgG away
Detection
HLA testing
• Complement Dependent Cytotoxicity
– Live cells
– Mix with complement
– Count living cells (dye exclusion)
– Very labor intensive
– Least sensitive
– Cellular test
• Not specific for HLA antibodies
HLA testing
• ELISA
– Full range of antigens bound to test wells
– Usually one well for Class I and one well for Class II
– Less sensitive
– Manual testing currently
• automation under development
– Acellular (specific for HLA antibodies)
– No indeterminant tests: cutoff value
HLA testing
• Flow Cytometry
– Latex microparticle beads with antigen
– Complex test that is labor intensive
• Indeterminate results possible
– Acellular
– Can distinguish between class I and class II due to
differences in luminescence markers
• Single run tests for both
HLA testing
• Luminex
– Similar to Flow cytometry
• Antigen coated microbeads
• Fluorescent-tagged antibodies
– Simpler chemiluminescence test
• Instrument is smaller
• Less expertise to operate
• Both class I and class II can be simultaneously tested
– Manual test, but automation looks easiest
– No indeterminate tests…cutoff value
HNA testing
• Expensive ($200-300) , few labs doing this at
the moment
• Generally tests are labor-intensive and require
high level of expertise to perform
HNA testing
• Granulocyte agglutination testing
– Serum incubated for 4-6 hours with fresh
neutrophils
– Presence of antibodies cause clumping of
neutrophils
– Least sensitive of tests
HNA testing
• Granulocyte immunofluorescence (GIF)
– Similar to AHG test
– Pretreatment with 1% paraformaldehyde to
prevent antibody binding to Fc portion of
neutrophil receptor
– Microscopy: Can have high background
fluorescence making it difficult to read weak
results
– Flow cytometer is most often used now
I got a TRALI case! What do I do now?
Tenth Law of the House of God
IF YOU DON’T TAKE A TEMPERATURE,
YOU CAN’T FIND A FEVER.
-- Samuel Shem (1978)
Investigation of Suspected TRALI
• Increased numbers of reported TRALI fatalities
in past few years is due in large part to
increased awareness on part of the folks at
the bedside
• Education of clinical personnel about TRALI
recognition is critical.
– CCC criteria
– NHLBI WG criteria
Investigation of Suspected TRALI
• Clinician notifies transfusion service of
possible TRALI case
• Initial prompt investigation of possible TRALI is
performed by the transfusion service.
Investigation of Suspected TRALI
• Acute hypoxemia
– PaO2/FiO2 <300 mm Hg
• NEW bilateral pulmonary infiltrates on frontal
CXR
• Pulmonary artery occlusion pressure <18 mm HG
or no evidence of left atrial hypertension
• Occurring within 6 hours of transfusion of blood
products
• No evidence of pre-existing ALI prior to
transfusion
Investigation of Suspected TRALI
• Easiest way to exclude TRALI ??
• Onset of symptoms > 6 hours post transfusion
Investigation of Suspected TRALI
• The results of the initial investigation should be
reviewed with the transfusion service medical
director.
• Medical director of the Blood Bank of Alaska is
available for telephone consultation with the
transfusion service medical director, if needed.
– (907) 222-5600 BBAK
– (907) 947-2690 (after hours, urgent calls only)
• Close cooperation between transfusion service
and donor center is essential.
Investigation of Suspected TRALI
• If TRALI is suspected after initial investigation is
completed, then transfusion service should begin
laboratory testing.
• If possible, have all implicated blood product
units returned to the blood bank.
– Even an “empty” bag may retain enough volume to be
useful.
• Culture and gram stain of blood product(s)
• Blood cultures and gram stain of patient’s blood
• Obtain and preserve recipient blood specimen for
possible future HLA/HNA antigen testing.
Investigation of Suspected TRALI
• If TRALI is suspected:
• Complete the TRALI/TTD investigation form and fax
immediately to BB of AK for further investigation.
– Include all pertinent clinical information and diagnoses,
including time course of onset of symptoms
– Include radiologic diagnoses of CXR
– Include lab studies (ABG, CBC, GS, cultures, chemistries)
– List attending physician and contact information
– List contact information for transfusion service
– Include complete list of all unit numbers transfused in the
12 hours prior to the reported onset of symptoms.
Investigation of Suspected TRALI
• BB of Alaska will notify Medical Director.
• Quarantine/recall involved units.
• Medical Director may contact transfusion service
or clinician to obtain additional history or other
information.
• Involved donors will be contacted to return for
HLA antibody testing and possible HNA antibody
testing.
– HNA antibody and antigen testing is very expensive
and difficult to obtain, limiting effectiveness
Investigation of Suspected TRALI
• Several weeks may be required to obtain
testing on all donors.
• Involved donors will be reviewed to see if any
donors have been previously “flagged”
– “Flagged” means that the donor has been
involved in previous TRALI case(s)
Investigation of Suspected TRALI
• Medical Director of BB of AK will obtain all
necessary and available information and
testing results and will make a determination:
– TRALI
– Possible TRALI
– Not TRALI
• Written report of findings
• Fatalities will be reported to FDA
Investigation of Suspected TRALI
• Implicated donors will be deferred from future
donations
• Multiply flagged donors will be evaluated for
future eligibility
Donor Management
• TRALI prevention strategies are still a work in
progress.
• Ongoing efforts to identify causes of TRALI
• Screening tests to reduce risk are not
available.
– Not yet cost effective to test for HLA/HNA
antibodies on all donations
Donor Management
AABB: “TRALI mitigation plan required”
Donor Management
• AABB standard 5.4.2.1
– “Donors implicated in a TRALI event or associated
with multiple events of TRALI shall be evaluated
regarding their continuing eligibility to donate.”
– “Implicated”: A donor who is the source of a
blood product transfused into a recipient within 6
hours of symptom onset in a proven TRALI event
that contains HLA and/or HNA antibodies against
antigen(s) expressed by the recipient.
Donor Management
• UK National Blood Service
• 2003: male-only donors for plasma rich
products (FFP, platelets) in 95% of FFP
– Same day requirement
– SHOT (Serious Hazards of Transfusion)
surveillance system in UK
Donor Management
• UK NHS Blood and Transplant Service
TRALI cases
reported to SHOT
(1996-2002)
Incidence
FFP/ cryo-poor
plasma
31/2.3 million
1:74,000
Platelets
17/1.5 million
1:88,000
Cryoprecipitate
1/0.5 million
1:500,000
pRBC
28/15.6 million
1:577,000
High plasma
Low Plasma
•
CE Chapman and LM Williamson Transfus Med Hemother 2008;35:93-96
Donor Management
• Many US Blood centers have adopted similar
policies
• Reduction of TRALI by 75%, and fatal TRALI by
90%
Donor Management
• Alternative is to use solvent-detergent (SD)
plasma
– Very low risk of TRALI, probably due to dilution
effect
– Reduction of infectious disease
– Production of IVIG and albumin
• Very costly ($13.5 million/year in Canadian
estimate)
Donor Management
• BB of AK
– Male-only FFP donors
– HLA antibody testing of established male and
female apheresis platelet donors
– New apheresis platelet donors male-only
What does the future hold?
What does the future hold?
• SD plasma
• Clearer elucidation of the pathophysiologic
mechanism of TRALI
• Specific antibody screening
– Better technology
– automation
Where have I seen this guy before?
Words A Poppin’ 1975