Transfusion Related Acute Lung Injury

TRALI

Raul H. Morales-Borges , MD Medical Director

American Red Cross Blood ServicesPuerto Rico Region

What’s all this I hear about fatal

Trolleys? Never mind!

That’s TRALI !

First TRALI Reported

• 1992• Reported to the Center for Biologics

Evaluation and research (CBER)• Popovski MA, Chaplin HC, Moore SB:

Transfusion-related lung injury: a neglected serious complication of hemotherapy. Transfusion 1992; 32:589-592.

Statistics: Reports of TRALI• 15% of Transfusion-related fatalities on 1976-1985 &

1986-1995.• As of FY2000 this represented 13% of all transfusion

fatalities.• According to the FDA, it’s responsible of 24 fatalities

annually from 2003 to 2005. • Is the 3rd cause of transfusion-related death.• Actual Death Rate: 6 per year; Mortality rate: 6-10%.• Actual Prevalence: 200 patients per year.

More statistics…

• 1/5000 transfusions

• 1/300 transfusions of PRBC’s

TRALI fatalities reported to the FDA (1999-2009).

Benjamin R J Blood 2011;117:4163-4164

©2011 by American Society of Hematology

TRALI in ICU• In Patients with GI Bleeding (Benson AB

et al: Intensive Care Med 2010):– Is common in patients with End-stage liver

disease (29% vs. 1%,p<0.01).– FFP 86% than other products.

• TACO in ICU (Li G et al: Transfusion 2010):– Common in left ventricular dysfunction &

FFP’s.

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• Hypoxemia due to non- cardiogenic pulm. edema– CXR: bilateral diffuse pulm. infiltrates (nl. ♥ & vessels)– PaO2/FiO2 < 300 mmHg– Normal JVP; PCWP ≤ 18 mmHg; Nl./unΔ’d BNP

• Hypotension; occasionally begins with hypertension• Fever (1-2oC elevation)• Onset within 6 hrs. of transfusion, usually within

the first 1-2 hrs.• Occ. recognized transient neutropenia (80-90%

reductions in some patients)

What Is TRALI?“Transfusion-Related Acute Lung Injury”

8

Diagnostic Features by Dr. Eder

• Onset within 1 – 6 hours of transfusion

• Acute respiratory distress

• Acute bilateral pulmonary edema (non-cardiogenic)

• Severe hypoxemia

• Hypotension

• Fever

• Mild to severe clinical spectrum

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Prevalence & Pathogenesis

• Passive hemovigilance data (subject to under-recognition & -reporting)– All components: 1:55,556 (Sweden) to 1:260,000

(Germany)

– Plasma: 1:11,363 (Finland) to 1:66,667 (Denmark)

– 49% Plasma, 29% RBCs, 13% Plts., 7% mixed, 2% WB

• Active surveillance– 1:1,323 (Canada) to 1:5,000 components (Mayo)

Healthy Sick

Neutrophil Priming

Strength of transfused mediators

Threshold

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Prevalence & Pathogenesis

• 28% of blood PMN pool is in the lung– ~50 capillaries per transit, ½ <PMN diameter

• Priming stimuli decrease PMN deformability and ↑ capacity for tissue entry & toxin release; endothelial activation can also tether and prime PMNs– Priming w/ surgery, infection, cancer, cardiac disease, cytokine

administration (e.g., G-CSF), massive transfusion

• Infused leukocyte Abs (HNA > HLA Class II > HLA Class I) & bioactive substances [lyso-PCs, CD40L] capable of directly or indirectly (HLA Class II) activating PMNs to varying degrees to reach threshold for:– PMN toxin release & extravasation alveolar exudate

• Possible to have recipient antibody against donor PMNs, but LR makes this unlikely

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ARC High Prob. Fatalities, 2003 – 2005

ARC Hemovigilance Program

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Strategies to Reduce TRALI

• Appropriate use of blood products• Deferral of donors implicated in TRALI• Reduce exposure to individual donor plasma

– Platelet additive solutions – Whole blood-derived platelets instead of apheresis platelets

• Reduce exposure to alloreactive plasma– Selective use of male plasma, apheresis platelets & WB– Selective use of products from donors lacking a history of allo-

exposure (transfusion/pregnancy)– Use of products from donors tested and found negative for HLA

and/or HNA antibodies• Reduce exposure to bioactive substances in “aged”

cellular blood products in proven susceptible individuals– Wash or plasma-reduce “aged” products– Preferentially use fresher products

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The Plasma Problem – Nearly Solved

• Plasma was responsible for the majority of TRALI fatalities reported to ARC (~63%)– Female neutrophil antibody-positive donors were

implicated in the majority of deaths (71%) • Only ~27% of recovered plasma is transfused

to patients– Male plasma units can be diverted from fractionation

back to transfusable plasma to replace female units no longer useable for transfusion

– Reduces available transfusable FFP; replaced by PF24

– ~99% O & A plasma is male; >95% B is male, but AB plasma still ~1/3rd female

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The Intervention – and Its Results

Eder AF, et al. Transfusion 2010;50:1732-42; ARC Hemovigilance Program

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US FDA TRALI Fatalities

http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ReportaProblem/TransfusionDonationFatalities/ucm204763.htm

ARC & others implement

male-predominant

plasma transfusion

strategy

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Apheresis Platelets – Looking for a Solution

• Aim is to reduce TRALI risk without compromising the availability of blood components

• SurveyMonkey responses (late 2009) from 43% of AABB-member blood centers (producing 1.57M units; in 2006 1.86 units produced nationwide) and 24% of hospitals

Kleinman S, et al. Transfusion 2010;50:1312-21.

Implemented

Future Plans

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HLA Alloantibody Testing

In-house HLA Lab

In-house Other Lab

Send out

Who’s Being Tested?

(n=20 blood centers)

On Which Platform?

(n=19 blood centers)

(Only 2 very small centers were testing transfused &

transplanted donors)

Kleinman S, et al. Transfusion 2010;50:1312-21.

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Antibody Testing

• 17 of 20 do / will not use results as release criterion

• 19 of 20 planned to retest (14 after alloexposure, 4 at specified time intervals, 1 undecided)

• 19 of 19 notify donors of positive test results • 19 of 20 redirect Ab-positive donors to WBD

(10 allow cryo production, but none allow transfusable recovered plasma)

• None perform HNA Ab testing

Kleinman S, et al. Transfusion 2010;50:1312-21.

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ARC’s Automated HLA Ab Detection Study

• 2432 apheresis donors from 5 regions tested in 2007 for HLA Class I or II Ab on approved GTi automated ELISA platform (176 samples per shift; $6 list price per test; manufacturer-fixed cutoff) and prototype automated Luminex One Lambda LabScreen Mixed assay (700 samples per shift; $15 per test; cutoff determined by user – 3SD from mean of nonalloexposed males just as in REDS II LAP study)

• 764 samples reactive by ELISA or “ultrasensitive” Luminex cutoffs (NBGRs of 2.5; used for transplant patients) tested by Luminex single-antigen beads to identify specificity of the reactivity

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Donor Demographics

Median Age = 51

Parity

66.9% of women were allo-exposed(65.5% pregnancy, 1.4% tfxn. / txp. only

[overall 6.0% tfxn. / 1.0% txp. / 0.2% both])

4.6% of men were allo-exposed by transfusion or transplantation

(3.7% tfxn. / 0.8% txp. / 0.1% both)

93.0% Caucasian2.3% Asian / P.I.

1.6% African-American3.2% Other

New England, PJ, GC&P, Lewis & Clark, & So. Cal. Regions

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HLA Class I / II Ab Reactivity

EF = alloexposed [pregnancy, transfusion, transplant] females, EM = alloexposed males, UEF = unexposed females, UEM = unexposed males

No statistically-significant difference between

subgroups

37.6%

(1.4 – 5.4%)

21.0%

52.0%

31.1% - 33.5%

~6.5%

Results in loss of 4.8%

of donor base

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Effect of Additional Pregnancies

8.2%

20.0%

32.3%

18.4%

3.3%

30.4%

21.5%

17.8%

10.6%

2.5%

0%

10%

20%

30%

40%

0 Preg 1 Preg 2 Preg 3 Preg 4+ Preg

Alloexposure Status

% R

eact

ive

Ser

a(C

lass

I, II

or

Bo

th) ELISA

Luminex 22.9 /16

( n=275) (n=85) (n=163) (n=135) (n=161)

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HLA Ab Characteristics

ELISA Class I

High PRA

Med PRA

Low PRA

High MFI

81.3% 58.8% 40.0%

Mod MFI

61.5% 41.2% 14.3%

Low MFI

30.4% 12.5% 8.7%

Of the 186 Class I and 177 Class II definable-antibody specificities identified by selective single-antigen testing, ELISA & “tuned” Luminex assays more often define higher titer (MFI) & breadth (PRA) samples as reactive; for example, Class I ELISA:

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Study Conclusions

• Anti-HLA detection in transplant patients requires exquisite sensitivity to identify low levels of Ab which may increase after transplant & threaten the graft

• At lower NBG ratios, Luminex identifies more donors with Ab specificity (progressively lower titer / breadth), but false-positive reactivity increases as well and more donors are deferred – High sensitivity in TRALI mitigation which identifies fixed low-titer

/ narrower specificity Ab may not improve safety, but will erode the donor base which results in platelet shortages

• Alloexposed females had the highest rates of reactivity and in this group, ELISA performed similarly to Luminex at cutoff 3SD from mean nonalloexposed males’ NBGR– ELISA vs. Luminex platform benefits & challenges

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Study Conclusions (cont’d)

• The low, statistically-equivalent reactivity rates in alloexposed males and nonalloexposed donors imply that transfusion / transplantation are not important triggers for HLA Ab in healthy apheresis donors– Questioning for transfusion/transplantation history will not help

much in identifying donors with HLA Ab– On average, for every 100 nonalloexposed donors screened,

only two have antibody and another one will be unnecessarily deferred (data not shown)

• The variability of similarly-derived cutoff values between ARC’s study and the REDS II LAP study demonstrates the potential influence of platform, specimen, and reagent lots, emphasizing the importance of local validation of the Luminex to choose reactivity cutoffs

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REDS II LAP Study

• 7920 donors recruited in 2007 from 6 REDS II centers (incl. Southern & New England regions); transfused males intentionally oversampled; One Lambda LabScreen Mixed beads used on manual Luminex platform with cutoff 3SD from mean NBGR of nonalloexposed males; single antigen specificities also determined on samples reactive using “ultrasensitive” cutoffs (NBGR = 2.2)

Triulzi DJ, et al. Transfusion 2009;49:1825-35; Kakaiya RM, et al. Transfusion 2010;50:1328-34; Rios JA, et al. Transfusion 2011;e-pub.

II

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REDS II LAPS Conclusions

• 3SD cutoff yielded reactivity in 24% of prev. pregnant women (30% of those both pregnant & transfused)– Two pregnancy losses (TAb, early SAb) were required to

increase Ab risk– Risk increased with each successive pregnancy (1 – 14.5%

to ≥4 – 32.4%)

• 1.0 – 4.4% of transfused-only women & men and nonalloexposed donors had Ab by Luminex– Transfusion did not increase the risk of HLA Ab

• Deferring all females, all previously pregnant females or only those testing Ab positive would reduce apheresis availability by 37.1%, 22.5% or 5.4%, respectively

Triulzi DJ, et al. Transfusion 2009;49:1825-35; Kakaiya RM, et al. Transfusion 2010;50:1328-34; Rios JA, et al. Transfusion 2011;e-pub.

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HNA Antibody Tests: GIF & GA

Granulocyte Immmunofluorescence

(GIF)

Granulocyte Agglutination

(GA)

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HNA Antibody Tests: MAIGA

*

+ Incubate, wash, lyse

Anti-mouse IgG

Typed WBC

Patient Serum

+

Mouse anti-HNA-x

Anti-human IgG

Monoclonal Antibody Immobilization of Granulocyte Antigens

Immobilize, tag,and read by EIA

+ +*

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HNA Antibody Testing Issues

• REDS II study showed 0.7% prevalence of HNA Ab amongst all donors (0.7% of nonalloexposed males had non-specific Ab only; 0.6% of women with ≥3 pregnancies had specific Ab, only 1/5th of whom did not also have HLA Ab)

• Ab ID is a low volume, time-consuming (GA requires 4-6 hr incubation) test, not yet reliably automated– Ab ID by serology requires fresh neutrophils from typed lab

personnel

• Concurrent presence of HLA Class I antibodies complicates GIF / GA interpretations – MAINA avoids these issues, but technically more challenging

• GIF generally more sensitive except for HNA-3a (the major culprit in severe TRALI), for which GA is better

Gottschall JL, et al. Transfusion 2011;e-pub.

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Automated HNA Ab Testing

• One Lambda is introducing LabScreen Mixed (includes beads for HLA Class I / II and HNA-1a, -1b, -1c, -2a, -4 & -4/5)– In a small French study, 48 of 51 sera suspected of

having alloAb were concordant by Luminex and GIF / MAIGA (kappa coefficient = 0.85)

– ARC’s experience with LabScreen Multi was not as positive, though significant bead & process changes occurred after our trial

– HNA-3a polymorphism recently discovered and not yet available

– Other companies pursuing HNA Ab automation, though no data are as yet available

Fromont P, et al. Transfusion 2010;50:2643-8.

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So… What Are ARC’s Plans?

• Females donating apheresis platelets / plasma asked about prior pregnancies; yes answer (!D32 added with date of last pregnancy / loss) in new donors only → HLA Ab testing from add’l Red Top

• 3d shipping & 10-14d test TAT from 1 of 5 ARC HLA labs using LabScreen Mixed beads on Luminex → DCSC & region notified (15-760 FTD females to be tested per region under R1; ~6700 per year)– !D30 for negative result, !D31 / HLA assertion for

positives (48 hours to retrieve only in-house plasma & apheresis platelets)

– HLA assertion prevents apheresis platelets and transfusable or injectable / frac plasma from shipping

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Treatment & Prognosis of TRALI

• Interruption of the transfusion

• Ventilation & Hemodynamic Support

• No role for the diuretics and corticosteroids.

• 80% resolve within 96 hours.

• Best recommendation…. Prevention.

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Q & A

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Thank You!