TRALI Transfusion-related acute lung injury

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TRALITransfusion-related acute lung injury

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• ?????
• ??? ??

2
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???? ???? ??
?????? 1 /12,000-30,000 ?????? / ???????
???? 1 / 100 ??
???? 1 / 100 ??
????? ?? ??
?????(TRALI) ?? ??
??????? 1 / 1,500-8,000 ???????/????
B????? ?1 / 300,000 ???????????
??????? ?1 / 1,200,000 ?????????????
3
Donor Screening of Blood-borne Diseases in Taiwan
?(??) 86 87 88 89 90 91 92 93 94 95 96
HBsAg () 2.97 2.49 2.03 1.83 1.56 1.49 1.09 0.85 0.61 0.57 0.48
HCV Ab () 0.67 0.24 0.48 0.35 0.37 0.33 0.28 0.23 0.18 0.18 0.13
HIV 1/2 Ab () 0.03 0.45 0.13 0.08 0.14 0.14 0.06 0.08 0.09 0.08 0.10
HTLV ?/? AB() 0.10 0.06 0.04 0.04 0.04 0.05 0.05 0.04 0.02 0.03 0.02
4
Accumulated Transfusion Transmitted HIV in Taiwan
1. ?????97?7? 2. ?????96??????,97???????
5
2007?7???? ?????250c.c.??,????????????3??????3?,??
??????? ,?????????200??????
96.12.27 ????
?????????????????(EIA)??22??????????,?????????(N
AT)?????11? ? ????????????????NAT??????????
6
Source FDA report on blood safety
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TRALI

• 1980s the term TRALI was first used and the
  idea that leukocyte antibodies cause TRALI
  becomes widely accepted
• 1983 (Popovsky, Able, and Moore)
• TRALI defined A series of 5 cases of pulmonary
  transfusions reactions
• 19 implicated donors
• One donor for each case had an HLA antibody
• 1985 (Popovsky and Moore)
• 36 cases
• Leukocyte antibodies in 89
• HLA antibodies in 65

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Transfusion Related Acute Lung Injury (TRALI)

• Severe shortness of breath within 4 to 6 hours of
  a transfusion
• No signs of fluid overload
• Pulmonary infiltrates on chest x-ray
• Hypotension or hypertension (15 respective)

9
Am J Respir Crit Care Med. 1994149818-824.
Transfusion. 2004441774-1789.
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TRALI NHLBI Working Group Definition

• TRALI
• New ALI
• Onset of symptoms or signs is within 6 hours
  after the transfusion of plasma containing blood
  components
• ALI (Acute Lung Injury)
• Acute onset
• Chest x-ray Bilateral infiltrates
• Pulmonary artery occlusion pressure 18 mm Hg or
  lack of clinical evidence of left atrial
  hypertension
• Hypoxemia Ratio of PaO2/FiO2 300mm Hg or O2
  saturation of less 90 on room air
• Clinical Diagnosis

Crit Care Med 200533721-726
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TRALI

• Most often associated with transfusion of ?plasma
  containing products
• Whole blood ,Packed red blood cells, Fresh frozen
  plasma (FFP), Platelets, IVIG (rare)
• Majority of deaths associated with
• ? FFPgt apheresis plateletsgt RBCs
• The most common cause of transfusion related
  fatalities reported to the FDA (16-25)
• Frequency 1/5,000-1/50,000

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Diagnosis

• TRALI is a clinical syndrome, rather than a
  disease with a single etiology.
• The diagnosis is a clinical and radiographic
  diagnosis.
• The diagnosis of TRALI is NOT made on the basis
  of reference laboratory test results, including
  those for white cell (HLA, neutrophil) antigen
  and/or antibody testing.

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TRALI Clinical Course

• Symptoms generally resolve in 24 to 48 hours
• Symptoms may resolve before diagnosis is made
• Mortality 10 to 50
• Moore SB. Critical Care Medicine 2006 34
  S114-117
• Rana R et al. Transfusion 2006461478-1483

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Clinical outcome (morbidity)
No.
Required oxygen support 36 100
Required mechanical ventilation 26 72
Pulmonary infiltrates
Rapid resolution (lt96hrs) 29 81
Slow resolution (gt7 days) 6 17
Mortality 2 6
Long-term sequelae 0 0
Popovsky et al. Transfusion 1985. Popovsky and
Haley 2000 ?13 died
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TRALI Treatment

• Hypoxemia
• Supplemental oxygen
• Intubation and mechanical ventilation
• Hypotension
• Intravenous fluids
• Agents to increase blood pressure
• Corticosteroids
• Diuretics is rather contraindicative

Moore SB. Critical Care Medicine 2006 34
S114-117
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TRALI-EtiologyPart I the role of WBC antibodies

• Antibodies to white blood cells, including
  antibodies to
• granulocyte antigens
• HLA class?antigens
• HLA class?antigens

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Implicated antibody in TRALI
HLA antibody Granulocytea antibody total
Donor 28 41 50
Recipient 7 4 11
61
Popovsky and Haley, 2000
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?????TRALI??? ??????
????????????TRALI??,FDA?????? ??JAMA
20022871968-71
19
54 years male patient Received FFP for reversal
of Coumadin effect Developed respiratory rest
and died 45 min after transfusion
JAMA 20022871968-71
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Trali donor history look back

• Donor 54 y/o female donor
• 290 donations (plasma donations)
• 3 pregnancies
• Lab detection of anti-granulocyte specific 5b
  antigen(HNA-3a) (In Whites, 90 5b)

JAMA 20022871968-71
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Clinical scenarios of 15 TRALI among 13 patients
Retrospective chart review of 50 patients who
received her plasma , 40 developed Trali-like
symptoms.
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TRALI donor history look back

• ???? 54 y/o ????
• 290 ???(???????)
• 3 ???
• Lab ??????? HNA-3a (5b antigen) (???, 90
  HNA-3a positive). Pts typing unavailable.
• ??50??????????,????40?????
• ??TRALI???,??????,???????,?
• ????????????????????

(JAMA 20022871968-71)
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Transfusion 200747545-550

• A donor, implicated in two febrile reactions, was
  found to have anti-HNA-2a (but no HLA class I
  antibodies)
• total 27 donations (apheresis plasma), resulted
  in 39 transfusions
• Chart review found 12 transfusion reactions (9
  patients), ranging from dyspnea, chills, rigors,
  and fever.
• 9 with lung symptoms
• 9 (9/12, 75) with leukopenia
• None of them had documented TRALI

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The transfusion of neutrophil-specific antibodies
No. Symptoms WBC pre WBC post
1 Dyspnea immediately 1.93 0.544
2 Chills, dyspnea, BP?, immediately 4.8 0.901
3 Chills, agitation, BP?, cyanosis 2.5hr after 14.8 15.7
4a Dyspnea immediately 1.11 0.438
4b Chills, rigors, immediately 3.82 0.510
4c Chills, rigors, wheezing, BP?, immediately 1.77 0.44
4d Chills, rigors, immediately 0.452 0.473
5 Chills, rigors, cyanosis, 1 hr, BT up 1 degree 1.390 1.670
6 Dyspnea, hyperventilation, rigor, 20 min after 0.403 0.186
7 Dyspnea, chest pain, rigors, chills, fever, and tachycardia 20 min 0.444 0.059
8 Chills, rigors, dyspnea, 2 hr 1.76 0.456
9 Chills, headache, 15 min 1.670 0.425
Transfusion 200747545-550
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??????????TRALI ????? ????????????????????
Transfusion 200747545-550
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Mechanisms Leading to TRALI

• 2 proposed pathophysiologic mechanisms
• The antibody hypothesis
• The neutrophil priming hypothesis
• Both
• Supported by clinical and experimental
  observations.
• Lead to a final common pathway of increased
  pulmonary capillary permeability, resulting in
  pulmonary edema.

Due to wide spectra of reactions after receiving
anti-WBC antibodies, a two hit theory was
proposed.
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The neutrophil priming mechanism(two-event
hypothesis)

• 1st event causes neutrophils to be primed, but
  not activated (first hit)
• may be caused by underlying condition (e.g.
  infection, surgery, inflammation)
• 2nd event causes activation of primed
  neutrophils (second hit)
• a consequence of transfusion
• may be antibodies (via antigen-antibody
  reactions) or other biologically active
  substances (e.g., biologically active lipids,
  CD40L)

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Patient Factors

• TRALI is more common in
• Surgery patients
• Patients with hematological malignancies and
  cardiac disease

Moore. Crit Care Med 2006 34 S114-S117 Silliman
et al. Blood 2003 101454-462
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Popovskys old model
Two hit model
Lung (2006) 184177185
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TRALI-surveillance (2003-2005)from American Red
Cross

• 550 reported cases involving 72 fatalities
• -gtretrospective review of fatalities revealed 38
  cases of probable TRALI
• 63 (24/38) belonging to plasma transfusion
• 71 (27/38) female donor with WBC antibody
• Female antibody-positive donors are more likely
  to be associated with TRALI (OD 9.5, 95 CI
  2.9-31.1)

Transfusion 200747599-607)
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Leukocyte antibodies in blood donors

• Female donors
• around 7.7-17 with HLA antibodies
• 0.1 or less with neutrophil antibodies (HNA
  antibodies)
• In female with previous pregnancy 15-31
• Male donors with HLA or HNA antibodies are
  extremely rare.

Vox Sanguinis 200792247-249 Transfusion
199939103-106 Platelet 19945234-235
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2007, 2, 23 ???
??????????
TRALI
?? 2005??, ??2007?????? ????
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TRALI cases in UK
2007 SHOT online report
UK Male plasma donor only since 2005.
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UK plasma sources

• Male plasma donor only in UK since 2005
• Since 2004, as a vCJD risk reduction measure, the
  UK Departments of Health have recommended the use
  of FFP sourced from countries with a low bovine
  spongioform encephalopathy prevalence for
  children born after 1 January 1996. In 2005 this
  was extended to all children under 16 years.
• Imported FFP is derived exclusively from male
  donors as a risk reduction measure for
  transfusion-related acute lung injury (TRALI).
• SD (solvent detergent) plasma is thought not do
  casue TRALI ?Octaplasma

BCSH Transfusion Task Force on 2007
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Human neutrophil alloantigens (HNA)
Antigens group Carrier glycoproteins CD Antigens Former names alleles
HNA-1 FCg receptor III CD16b HNA-1a HNA1b HNA1c NA1 NA2 SH FCGR3B02 FCGR3B02 FCGR3B03
HNA-2 NB1 glycoprotein CD177 HNA-2 NB1 -a
HNA-3 Unknown (GP70-95) HNA-3a 5b Unknown
HNA-4 MAC-1 CR3 aMb2-integrin CD11b HNA-4a MART ITGM01 (230G)
HNA-5 LFA-1aLb2-integrin CD11a HNA-5a OND ITGAl01 (2372G)
A Since HNA-2 is defined by isoantibodies formed
by individuals whose neutrophils lack the
glycoprotein, it is not possible to give a
certain allele.
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Human neutrophil alloantigen frequencies ()
Amerindians Asians Africans Whites
HNA-1a 83-91 88-91 46-66 57-62
HNA-1b 36-80 51-54 78-84 88-89
HNA-1c 0-1 lt1 23-31 5
HNA-1 null lt1 lt1 4 0.15
HNA-2 Nt 89-99 98 87-97
HNA-3a Nt Nt Nt 89-96
HNA-4a gt99 Nt Nt 99
HNA-5a 79-97 81 88 86-92
North and south American Indians
Vox Sanguinis 200894277-285
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Clinical condition caused by granulocyte
antibodies
Alloimmune diseases ???????? Autoimmune diesease ????????
Neonatal immune neutropenia Primary autoimmune neutropenia
Transfusion-related acute lung injury (TRALI) Secondary autoimmune neutropenia
Refractoriness to granulocyte transfusion Drug-induced immune neutropenia
Alloimmune neutropenia after BMT Autoimmune neutropenia after BMT
Febrile transfusion reaction
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HLA Class I and II Antibody Testing

• Antigen
• Immune affinity chromatography
• Recombinant technology
• Solid phase assays
• ELISA
• Microbeads-flow cytometry
• Microbeads-modified flow cytometry
• Other
• High throughput testing is possible
• Most HLA antibodies containing products do not
  cause TRALI

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HNA Antibody Testing

• Antigen
• Newly isolated neutrophils
• Assays
• Agglutination
• Immunoflourescence-flow cytometry
• Monoclonal antibody capture
• Mixed passive hemagglutination
• Problems with solid phase
• HNA-3a has not been characterized at a molecular
  level
• No monoclonal antibody to HNA-3a

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Interpreting Antibody Test Results
4 Units RBC (2-4 donors)
TRALI
4 unit FFP (2-4 donors)
12 units platelets (1-12 donors)

• Incidence of leukocyte antibodies in blood donors
• HLA Antibodies
• 4 to 7 of all donors
• Up to 21 of females with 3 for more pregnancies
• Neutrophil Antibodies
• Less than 0.1 of donors

Facts
How to establish the causative relation? A
working consensus is needed.
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Future perspectives

• Improve TRALI report and recall system
• Lab detection
• Donor policy/ donor deterrence policy