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TRALI: It’s Not Just For Blood Bankers Anymore
Norman D. Means, MD, FCAPBlood 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
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.
Cases %
HTR 161 50
Bacterial Contamination 46 14
TRALI 29 9
Non-bacterial infections 23 7
Transfusion-associated GVHD 18 6
Transfusion-associated fatalities reported to the FDA 2005-2006
• Cases • 6
Source: Fatalities reported to the FDA following blood collection and transfusion (2005-2006); from http://www.fda.gov/cber/blood/fatal0506.htm
Cases %
TRALI 64 51
HTR (non-ABO) 25 20
Microbial infection 15 12
HTR(ABO) 9 7
TACO 9 7
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
• Bronchospasm• Wheezing• Laryngeal edema• Urticaria/Erythema• Hypotension• Rapid onset after start of transfusion• IgA deficiency
Transfusion-Associated Sepsis
• 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• 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• 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 alveoliRespiratory 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# of cases of severe TRALI
%
HLA Class I 4 10HLA Class II 17 47HLA Class I and II 3 8HNA(HNA-3a)
12(10/12)
33
Total 36
Reil A, et al. Vox Sanguinis 2008;95(4):313-317
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
• 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
• CE Chapman and LM Williamson Transfus Med Hemother 2008;35:93-96
TRALI cases reported to SHOT (1996-2002)
Incidence
High plasma
FFP/ cryo-poor plasma
31/2.3 million 1:74,000
Platelets 17/1.5 million 1:88,000
Low Plasma
Cryoprecipitate 1/0.5 million 1:500,000
pRBC 28/15.6 million 1:577,000
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