Transfusion Medicine Reviews xxx (2017) xxx–xxx

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Transfusion Medicine Reviews

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Analysis of Transfusion-Related Acute Lung Injury and PossibleTransfusion-Related Acute Lung Injury Reported to the FrenchHemovigilance Network From 2007 to 2013

Georges Andreu a,⁎, Karim Boudjedir b, Jean-Yves Muller c, Elodie Pouchol d, Yves Ozier e, Guillaume Fevre f,Chantal Gautreau g, Jean-François Quaranta h, Christian Drouet i, Claire Rieux j, Paul-Michel Mertes k,Benoit Clavier l, Monique Carlier m, Imad Sandid b

a Institut National de la Transfusion Sanguine, Paris, Franceb Agence Nationale de Sécurité du Médicament, Saint-Denis, Francec Société Française de Transfusion Sanguine, Paris, Franced Etablissement Français du Sang, Saint-Denis, Francee CHRU de Brest, Brest, Francef Service d'anesthésie, Groupe hospitalier Paris Saint-Joseph, Paris, Franceg Assistance Publique Hôpitaux de Paris, Laboratoire d'Immunologie et d'histocompatibilité, Hôpital Saint Louis, Paris, Franceh Cellule d'Hémovigilance, CHU de Nice, Hôpital de Cimiez, Nice, Francei Université Grenoble Alpes, POBox35, La Tronche, Francej Unité de bio-hémovigilance, GHU Henri Mondor, Creteil, Francek Service d'anesthésie-réanimation chirurgicale, Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Strasbourg, Francel Centre de Transfusion Sanguine des Armées «Jean Julliard», rue du lieutenant Raoul Batany, Clamart, Francem Service d'anesthésie, centre hospitalier, Chalons-En-Champagne, France

a b s t r a c ta r t i c l e i n f o

⁎ Corresponding author: Georges Andreu, MD, PhD, InsE-mail addresses: georges.andreu01@gmail.com (G. An

(E. Pouchol), yves.ozier@chu-brest.fr (Y. Ozier), gfevre@h(C. Drouet), claire.rieux@aphp.fr (C. Rieux), paul-michel.mImad.SANDID@ansm.sante.fr (I. Sandid).

Please cite this article as: Andreu G, et al, AnReported to the French Hemovi..., Transfus M

http://dx.doi.org/10.1016/j.tmrv.2017.07.0010887-7963/© 2017 Elsevier Inc. All rights reserved.

Available online xxxx

Keywords:Blood components transfusionHemovigilanceTransfusion-related acute lung injuryHLA and HNA alloimmunization

Using the French Hemovigilance Network database from 2007 to 2013, we provide information on demo-graphics, incidence, and risk factors of reported transfusion-related acute lung injury (TRALI) and possibleTRALI, analyze TRALImitigation efforts for fresh frozen plasma and platelet concentrates, and consider the impactof platelet additive solutions on TRALI incidence. We applied the Toronto consensus conference definitions forTRALI and possible TRALI. Two TRALI subgroups were considered: “antibody positive” when a donor hashuman leukocyte antigen (class I or II) and/or humanneutrophil antigen antibodies and the recipient has cognateantigen, and “antibody negative” when immunological investigation is negative or not done. The analysistargeted 378 cases, divided into antibody-positive TRALI (n= 75), antibody-negative TRALI (n= 100), and pos-sible TRALI (n= 203). TRALI patients were younger and receivedmore blood components than the general pop-ulation of transfusedpatients.Moreover,we identified the following clinical conditionswherepatients seemed tobe at higher risk to develop TRALI: postpartum hemorrhage, acute myeloid leukemia, liver transplantation, allo-geneic and autologous hematopoietic stem cells transplantation, polytrauma, and thrombotic microangiopathy.Policy measures intended to reduce antibody-positive TRALI were found effective for apheresis platelet concen-trates and fresh frozen plasma but not for whole blood–derived platelet concentrates. The use of platelet additivesolutions was associated with a significant reduction in the incidence of TRALI following transfusion of buffycoat–derived platelet concentrates but not following transfusion of apheresis platelets. Our data reinforce theconcept that possible TRALI and TRALI, as defined in the Canadian consensus conference, share many character-istics. No specific policy measures are currently directed at mitigation of possible TRALI despite its impact ontransfusion safety. Despite TRALImitigationmeasures, the overall incidence of TRALI cases reported to the FrenchHemovigilance system was not significantly reduced. Therefore, additional research is needed to reduce, if noteradicate, all TRALI categories.

titut National de la Transfusion Sanguine, 6 rue Alexandredreu), Karim.BOUDJEDIR@ansm.sante.fr (K. Boudjedir), jy

psj.fr (G. Fevre), chantal.gautreau@sls.aphp.fr (C. Gautreauertes@chru-strasbourg.fr (P.-M. Mertes), clavier@ctsa-arm

alysis of Transfusion-Related Acute Lung Injuryed Rev (2017), http://dx.doi.org/10.1016/j.tm

© 2017 Elsevier Inc. All rights reserved.

Cabanel, 75739 PARIS CEDEX 15, France.muller@me.com (J.-Y. Muller), elodie.pouchol@efs.sante.fr), quaranta.jf@chu-nice.fr (J.-F. Quaranta), CDrouet@chu-grenoble.frees.fr (B. Clavier), mcejp17@aol.com (M. Carlier),

and Possible Transfusion-Related Acute Lung Injuryrv.2017.07.001

2 G. Andreu et al. / Transfusion Medicine Reviews xxx (2017) xxx–xxx

Contents

Material and Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0TRALI Notification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

TRALI and Possible TRALI Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Severity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

TRALI Incidence Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Incidence per Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Incidence per BC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

Impact of PAS on TRALI Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Statistical Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Overall Description (2007-2013) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

TRALI and Possible TRALI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Patient Demographics, Clinical Context, and Incidence per Transfused Patients . . . . . . . . . . . . . . . . . . . . . . . . . . 0TRALI and AGCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0TRALI with HLA/HNA Antibodies (Antibody-Positive TRALI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

TRALI Incidence per BC Before and After the Implementation of Mitigation Measures Targeting the Antibody-Positive TRALI Category . . . . . 0BC Distributed in France From 2007 to 2013 and TRALI Overall Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0TRALI Incidence in 2007-2009 Versus 2011-2013 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

PAS Impact on TRALI Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

TRALI Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0TRALI Clinical Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0TRALI Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0TRALI Associated With HLA/HNA Incompatibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Impact ofMitigationMeasures of TRALIWhere a Donor Had HLA and/or HNA Antibody and the Recipient Had Cognate Antigen (Antibody-Positive TRALI) . . 0Impact of PASs on PC-Related TRALI Incidence Rates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Conflict of Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

Although defined in 1985 [1], transfusion-related acute lunginjury (TRALI) was incorporated into the French HemovigilanceNetwork (FHN) in 2001 following a report from the UnitedStates Food and Drug Administration stressing the importanceof this adverse transfusion reaction [2]. Until 2004, TRALI wasusually restricted in France to cases where the donor hadhuman leukocyte antigen (HLA) and/or human neutrophil anti-gen (HNA) antibodies and the recipient had the cognate antigen.In 2005, the criteria for TRALI were modified in accordance withthe 2004 consensus conference [3]. In 2006, the French HealthProducts Safety Agency (Agence française de sécurité sanitairedes produits de santé), which became the French National Agen-cy for Medicines and Health Products Safety (Agence nationalede sécurité du médicament [ANSM] in 2012), disseminated infor-mation to the FHN concerning TRALI [4]. This information includ-ed guidelines for clinical and immunological investigations, aswell as a flowchart for TRALI diagnosis and transfusion imput-ability [5]. Two measures to mitigate TRALI were implementednationally in July 2010: First, fresh frozen plasma (FFP) andapheresis platelet concentrates (APCs) were restricted to thefollowing donors: males, nulliparous females, or parous womenwho were negative for HLA class I and II antibodies [6]. Second,whole blood donations from women with known HLA antibodieswere not used to prepare pooled buffy coat platelet concentrates(BCPCs).

In this report, we provide an overall summary of TRALI cases re-ported to the FHN from 2007 to 2013, an analysis of the effectivenessof TRALI mitigation measures applied to FFP and APC by comparingthe period before (2007-2009) vs after (2011-2013), and an analysisof the effect of platelet additive solutions (PASs) on the incidence ofreported TRALI cases.

Please cite this article as: Andreu G, et al, Analysis of Transfusion-RelatedReported to the French Hemovi..., Transfus Med Rev (2017), http://dx.doi.

Material and Methods

TRALI Notification

The reporting of adverse transfusion reactions has been mandatoryin France since 1994 [7], according to previously described rules [8,9].ANSM receives, validates, and gathers acute transfusion reaction notifi-cations using a national database. In those cases of suspected TRALIwhere several blood components (BCs) have been transfused in the pre-vious 24 hours, the list of BC is recorded, but only a single BC can be se-lected in the database as the implicated unit responsible for the adversereaction. In most instances where there is uncertainty regarding theresponsible BC, the last transfused BC before the onset of TRALI is gener-ally listed as the implicated unit. TRALI-specific clinical and immunolog-ical investigation forms are sent to ANSM along with the standardreaction notification. ANSM ensures data completeness, checks thatthe TRALI definition criteria have been respected, and submits difficultcases to a dedicated expert group for adjudication. Specific to thisstudy, all the declared TRALIs initially present in the national databasewere checked by 2 investigators (KB and IS). They identified 147 casesdeserving an additional review process, performed for each case by atleast 5 of the following investigators: GA, BC, MC, CD, GF, PMM, and CR.

TRALI and Possible TRALI DefinitionsThe 2004 consensus conference criteria [3] are applied without

modification.

TRALI. Two TRALI categories are distinguished:

- Antibody-positive TRALI: Case fits clinically with the consensusconference criteria, and the donor has HLA (class I or II) and/orHNA antibodies and the recipient has cognate antigen.

Acute Lung Injury and Possible Transfusion-Related Acute Lung Injuryorg/10.1016/j.tmrv.2017.07.001

3G. Andreu et al. / Transfusion Medicine Reviews xxx (2017) xxx–xxx

- Antibody-negative TRALI: Case fits clinically with the consensusconference criteria, but the immunological investigation is nega-tive or not done.

Possible TRALI. In accordance with the consensus conference criteria [3]and the joint work of the International Society of Blood Transfusion andthe International Hemovigilance Network [10], cases are categorized as“possible TRALI” if there is another clinical cause for acute lung injuryregardless of whether or not the donor has HLA and/or HNA antibodiesand the recipient has the cognate antigen.

SeveritySeverity grades are defined on the basis of therapy required:

- 1 (mild): spontaneous recovery or supplemental oxygen via a facemask;

- 2 (severe): cases requiring noninvasive ventilation or transfer inan intensive care unit;

- 3 (life threatening): cases requiring invasive mechanical ventila-tion with or without additional therapy such as the use ofvasopressors;

- 4 (death): cases where there is a clear temporal relationship be-tween death and TRALI.

ANSM adopted this severity grading in 2010. Previously, “mild” and“severe” cases were combined in a single grade. As we had cases from2007 to 2013, we decided tomerge “mild” and “severe” grades for anal-ysis. In some instances where numbers were too small for statisticalcomparison, we merged “life threatening” and “death” as well.

TRALI Incidence Evaluation

Incidence per Patient

General Population of Transfused Patients. The number of transfused pa-tients is provided in the ANSM annual hemovigilance reports [11-17].

Postpartum Hemorrhage. The Statistics and Economic Studies NationalInstitute provides the annual number of births in France [18]. To evalu-ate the number of births with a maternal hemorrhage requiring bloodtransfusion, we referred to a UK study evaluating the percentage ofbirths with maternal blood loss ≥1000 mL [19].

Liver and Hematopoietic Stem Cells Transplants. The Biomedicine Agency(Agence de la biomédecine) provides annually the number of liver [20]and hematopoietic stem cell (HSC) [21] transplants performed inFrance.

Acute Myeloid Leukemia and Myelodysplastic Syndromes. The Institut na-tional de veille sanitaire (Sanitary Surveillance Institute) published anevaluation of the annual incidence and survival of patients with hema-tologic malignancies in France during the period 2005-2010 [22].

Polytrauma Patients. Basic information comes from a nationwide surveyabout BC recipients in France in 2006 [23]. Raw data were adjusted totake account of the exhaustiveness of the study and theweekly distribu-tion of severe traffic accidents [24].

Thrombotic Microangiopathies. The National Reference Centre for throm-boticmicroangiopathy (TMA) provides an estimation of their incidence [25].

Incidence per BCThe number of BCs distributed by the French Blood Establishment

and the Military Blood Transfusion Centre is provided in the ANSM an-nual hemovigilance reports [11-17].

Please cite this article as: Andreu G, et al, Analysis of Transfusion-RelatedReported to the French Hemovi..., Transfus Med Rev (2017), http://dx.doi.

Impact of PAS on TRALI Incidence

PAS reduces the amount of plasma in platelet concentrates (PCs) to20%-30% of the total PC volume, instead of N98% when PAS is not used.This reduction in plasma cannot fully guarantee prevention of TRALI be-cause even less than 20mL of residual plasma is sufficient to precipitateTRALI in the case of red cells concentrates (RCCs) [26]. However, wewondered whether use of PAS in PC might prevent some antibody-positive TRALI cases in the presence of weak antibodies or if PAS mayprevent some antibody-negative and possible TRALI cases resultingfrom the presence of low concentrations of nonimmunoglobulinmolecules capable of provoking TRALI such as biologically active lipids[27-28]. We therefore compared the incidence of PC-related TRALIwith and without PAS during the period 2008-2013.

Statistical Analysis

Fisher or χ2 tests were used to compare incidence data. Welch t testwas used to compare age distribution and number of BCs transfused inTRALI cases vs the general population of transfused patients. Pearsoncorrelation test was used to investigate a correlation between thenumber of BCs transfused and TRALI severity. For all comparisons, theresults were considered significant at P b .05. All analyses were explor-atory and not predefined. No correctionwasmade for multiple compar-isons, and so we risked false discovery of significant differences. Weused the online statistical software provided by Pierre and Marie CurieUniversity [29].

Results

Overall Description (2007-2013)

TRALI and Possible TRALITwenty-three of the initial 403 TRALI declarations were excluded

after review, mainly on account of coexisting signs of circulatory over-load. Among the remaining 380 cases, 378 were analyzed (the precisetype of responsible PC was not mentioned in 2 cases). The majority ofcases, 251 (66%), were associatedwith RCC. Twenty-three (6%)were as-sociated with BCPC, 56 (15%) with APC, 44 (12%) with FFP, and 4 (1%)with apheresis granulocyte concentrates (AGCs). Seventy-five anti-body-positive TRALI cases (20%), 100 antibody-negative TRALI cases(26%), and 203 possible TRALI (54%) cases were reported. Thus, justover half of our cases had other clinical factors thatmay have precipitat-ed acute respiratory distress syndrome (ARDS). See Table 1.

Patient Demographics, Clinical Context, and Incidence per TransfusedPatients

Age and Sex. As shown in Table 2, antibody-positive, antibody-negative,and possible TRALI cases occurred in patients of all ages but were re-ported in a significantly younger population than the general popula-tion of transfused patients, P b .001 (Welch t test). The male-to-femaleratiowas 0.88, a value not significantly different from that of the generalpopulation of transfused patients (0.92) [16-17].

Number of Transfused BCs.When all 3 TRALI categories combined (anti-body positive, antibody negative, and possible)were comparedwith thegeneral population of transfused patients, several factors were signifi-cantly different (Table 3). Specifically, cases reported as TRALI receivedsignificantly more BCs: 56/378 (15%) patients received N10 BCs com-pared with only 33/3434 (1%) of the general transfused population.TRALI patients also received more BCs with a high plasma volume (PC,FFP, and AGC): 225/378 (60%) vs 680/3434 (20%). TRALI patients alsoreceived a greater variety of BCs (RCC and/or PC and/or FFP and/orAGC): 154/378 (41%) of TRALI cases vs 207/3434 (6%) of general trans-fused patients. Fewer TRALI patients received only red cells: 152/378

Acute Lung Injury and Possible Transfusion-Related Acute Lung Injuryorg/10.1016/j.tmrv.2017.07.001

4 G. Andreu et al. / Transfusion Medicine Reviews xxx (2017) xxx–xxx

(40%) vs 2754/3434 (80%). Of note, because these factors are associatedwith each other, they should not be regarded as independent correlateswith reported TRALI cases. The above factors were also not able to dis-tinguish among antibody-positive TRALI, antibody-negative TRALI, orpossible TRALI. Indeed, the 3 TRALI categories were not statistically dif-ferent for any of the above comparisons.

Number of Transfused BCs and TRALI Severity. As the number of trans-fused BCs is a quantitative variable with a non-normal distribution,and the severity grades an ordinal qualitative variable, we explored acorrelation between these variables by calculating the Pearson ρ coeffi-cient, which is 0.14, corresponding to a significant correlation: P =.0078. However, this result should be considered cautiously becausecorrelation does not mean a causal link, because the observed coeffi-cient was only 0.14, and because the number of transfused BCs is an in-dependent confounding factor associated with more critically illpatients.

Clinical Context and Incidence per Transfused Patients. Table 4 showsTRALI incidence per 1000 patients in selected clinical conditionswhere we identified a significantly higher TRALI incidence comparedwith the general population of transfused patients. These clinical situa-tions occurred in 127 of 378 (34%) TRALI cases, whereas they represent-ed only 271 427/3 757 257 (7%) of the general transfusion population.They share 3 common features. First, these selected patient groups re-ceived many BCs, either during a short time period (eg, postpartumhemorrhage, liver transplant, polytrauma patients) or over a period ofweeks (TMA treated with plasma exchange) or even years (AML, HSCtransplants). During the transfusion episode where TRALI occurred,these 127 patients received a mean of 7.8 (1-38) BCs (Q1 = 2,median = 4, Q3 = 11, IQR = 9), whereas the remaining 251 reported

Fig 1. Age distribution of TRALI and general population of patients transfused. The 2 referenceamong the 3450 patients investigated in this study. - Patients transfused in 2013 [17]: Age isdistribution of the 2007-2013 TRALI cases is shown in 3 ways: - Total TRALI population (n =127) - Patients with a clinical condition not considered at higher risk to develop TRALI (n = 2transfused patient population and the TRALI population not considered at risk: P = .12. - A hrisk TRALI population: P = 4.1 10−22. - Age distribution comparison of the 3 TRALI categoriesthe “at-risk” group never reaches significance. - Similarly, age distribution of the 3 TRALI ca137)—inside the “non–at-risk” group never reaches significance.

Please cite this article as: Andreu G, et al, Analysis of Transfusion-RelatedReported to the French Hemovi..., Transfus Med Rev (2017), http://dx.doi.

TRALI cases received a mean of 4.3 (1-42) BCs (Q1 = 1, median = 2,Q3= 4, IQR= 3). Second, patients in these selected clinical groups re-ceived a wider range of BCs: 70/127 (55%) received at least 2 differentBCs compared with 83/251 (33%) of the TRALI cases which did nothave these selected clinical conditions. These patient groups were alsoyounger, especially when considering postpartum hemorrhage, TMA,liver transplants, stem cell transplant patients, and polytrauma patients.Only the AML patients had an age distribution close to the general pop-ulation of transfused patients. The 127 patients in these selected clinicalgroups were evenly distributed for the 3 TRALI categories representing33%, 36%, and 33% for antibody-positive, antibody-negative, and possi-ble TRALI categories, respectively.

Age Distribution of TRALI Patients.Wenext compared TRALI patients to 2well-documented populations: transfused patients on a single day in2006 [23] and throughout the year 2013 [17]. The TRALI populationwas investigated as a whole (n = 378); as the 2 subgroups selectedfrom the previous section (n = 127 and n = 251). The results areshown in Figure 1. The 2 general populations of transfused patients in2006 and 2013 were very similar, with a median age of 70 and 73years, respectively. The median age of the whole TRALI population(n = 378) was 55 years, which was significantly younger than the2006 population (P b .001). The median age from selected clinicalgroups was 37 years, which was a highly significant difference fromthe 2006 general population (P b .001). The median age of the remain-ing subgroup was 63 years, not significantly different from the 2006population (P = .12).

TRALI and AGCsThree female patients received AGCs for uncontrolled infections: a 9-

year-old patient with immune deficiency and 2 patients (53 and 78

populations are: - Patients transfused in 2006 [23]: Age is documented in 3381 patientsdocumented in 440 805 patients among the 538 159 patients transfused that year. Age378) - Patients with a clinical condition considered at higher risk to develop TRALI (n =51) Statistical analysis (Welch test) shows: - No significant difference between the 2006ighly significant difference between the 2006 transfused patient population and the at-—antibody positive (n = 25), antibody negative (n = 36). and possible (n = 66)—insidetegories—antibody positive (n = 50), antibody negative (n = 64), and possible (n =

Acute Lung Injury and Possible Transfusion-Related Acute Lung Injuryorg/10.1016/j.tmrv.2017.07.001

Table 1Distribution of TRALI cases according to the involved BCs and TRALI categories

A. Distribution of TRALI cases as notified to the Hemovigilance Network

BC RCC BCPC APC FFP AGC Total

TRALIcategory

Ab pos Ab neg p Ab pos Ab neg p Ab pos Ab neg p Ab pos Ab neg p Ab pos Ab neg p

Year 2007 5 6 11 1 2 3 3 4 3 3 412008 5 11 19 1 1 4 2 4 5 522009 5 10 17 1 6 1 5 1 1 472010 6 9 31 1 4 3 1 3 4 6 682011 9 11 20 1 1 1 1 5 3 2 2 562012 9 14 20 3 2 2 3 2 7 622013 7 3 23 1 2 3 3 5 1 3 1 52

Total 46 64 141 4 8 11 15 13 28 9 14 21 1 1 2 378251 23 56 44 466% 6% 15% 12% 1%

B. Distribution of TRALI cases taking account of patients with I- and p TRALI who received several BC types

BC RCC BCPC APC FFP AGC Several BC typestransfused

Total

TRALIcategory

Ab pos Ab neg p Ab pos Ab neg p Ab pos Ab neg p Ab pos Ab neg p Ab pos Ab neg p Ab neg p

Year 2007 5 4 6 1 2 3 3 4 1 2 3 7 412008 5 8 12 1 4 1 3 5 4 9 522009 5 6 7 1 6 1 2 1 5 13 472010 6 6 16 1 1 3 1 2 1 3 6 22 682011 9 9 15 1 1 5 1 2 5 8 562012 9 8 15 1 1 2 2 1 9 14 622013 7 3 12 1 2 1 2 5 2 1 2 14 52

Total 46 44 83 4 4 4 15 11 22 9 3 8 1 1 2 34 87 378173 12 48 20 4 12167% 5% 19% 8% 2%

Fresh frozen plasma was prepared from apheresis donation, either quarantined or treated with methylene blue or amotosalen.Abpos, antibody positive: clinical TRALIwhere a donor hasHLA and/orHNA antibody and the recipient has cognate antigen; Abneg, antibody negative: clinical TRALIwhere noHLA and/orHNA antibody is detected in donors; p, possible TRALI as defined by the 2004 consensus conference.

5G. Andreu et al. / Transfusion Medicine Reviews xxx (2017) xxx–xxx

years old) with AML and chemotherapy-induced leukopenia. The 53-year-old patient developed TRALI twice, after a 3-day interval. In all in-stances, TRALI occurred within 2 hours after the end of the granulocytetransfusion. Immunological investigation was negative (HLA and HNA)in the 9-year-old and the 53-year-old patients. The 78-year-old patienthad anti-HLA-B8, and the granulocyte donor was positive for the HLA-B8 antigen. “Reverse TRALI,” a rare condition described in 1976 [30],was suspected. Very few cases of reverse TRALI have been published[31-32], and they never involve leukodepleted BCs [33]. Reverse TRALIhas not been reported in countries using universal leukodepletion[34]. This case may be a unique example of “reverse TRALI” in thiscase series. Similar to another published case [35], the symptoms ap-peared early during the AGC transfusion and required invasivemechan-ical ventilation (severity grade 3). Although few in number, these 4episodes in 3 patients suggest that the incidence of TRALI following

Table 2Basic demographics (sex and age) of all TRALI cases notified between 2007 and 2013a, b

TRALI category

Ab pos Ab neg Possible

n 75 100 203

Sex M F 34 41 42 58 101 102Sex ratio M/F 0.83 0.72 0.99

Age (y) Mean 56 52 53Median 61 53 55SD 22 22 21Range 13 93 9 mo 90 1 mo 89

Patients of each TRALI category (antibody positive, antibody negative, and possible) consideredt test (Welch) antibody-positive TRALI: P = .046, antibody-negative TRALI: P = 3.7 10−5, posConversely, age of patients in the 3 TRALI categories (antibody positive, antibody negative, and

a Data provided by 2012 and 2013 ANSM hemovigilance reports [16-17].b n = 3381. Data from Quaranta et al [23].

Please cite this article as: Andreu G, et al, Analysis of Transfusion-RelatedReported to the French Hemovi..., Transfus Med Rev (2017), http://dx.doi.

AGC transfusion was extremely high. In the period studied, 1925 AGCswere transfused in France; the incidence was 2 TRALIs per 1000 AGCs,that is, more than 50-fold higher than any other BC.

TRALI with HLA/HNA Antibodies (Antibody-Positive TRALI)HLA investigation was not performed in 26/378 cases (7%), most of

them (n= 25) being cases labeled as possible TRALI. HNA antibody in-vestigation was documented in only 46/378 (12%) of all cases. Overall,75/378 (20%) of suspected reported TRALI caseswere antibody positive.The responsible BCs were RCC (n = 46), BCPC (n = 4), APC (n = 15),FFP (n= 9), and AGC (n= 1). In 11 cases, there was HLA incompatibil-ity with 2 different donors: 2 RCCs (n= 4), 2 FFPs (n= 4), 1 RCC and 1APC (n= 1) arbitrarily classified as APC related, and 2 donors in a BCPC(n= 2). These 11 patients received amean of 13 BCs vs 5.4 BCs in thosewith only 1 identified HLA antibody incompatibility.

All TRALIcategories

Transfused generalpopulation

Transfused general population vsall TRALI categories

378 1 082 753a

177 201 518.075 564 6780.88 0.92 χ2 P = ns53 64b t test (Welch) P = 4.6 10−4

55 7021 211 mo 93 1 d 106

separately are significantly younger than the general transfused population:sible TRALI: P = 1.0 10−7.possible) does not differ significantly.

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Table 3BCs transfused in the 24 hours prior to TRALI onset and comparison with the general transfused population

BCs transfused Antibody-positiveTRALI

Antibody-negativeTRALI

PossibleTRALI

All TRALIcategories

Patientstransfused2006a

Patients transfused 2006 vs allTRALI categories

Patient no. 75 100% 100 100% 203 100% 378 100% 3434 100% Statistical test P

Mean BCs transfused (range) 6.5 (1-42) 5.0 (1-34) 5.3 (1-38) 5.4 (1-42) 2.2 (1-28) t (Welch) P = 1.06 10−18

Number of BCs transfused(all types)

1 or 2 transfused BCs 36 48% 54 54% 102 50% 192 51% 2762 80% χ2 P = 5.0 10−79

3 to 10 BCs transfused 24 32% 34 34% 72 36% 130 34% 639 19%N 10 BC transfused 15 20% 12 12% 29 14% 56 15% 33 1%

Type of BC transfused, aloneor in association

AGC 1 1% 1 1% 2 1% 4 1% 0 0% b

RCC 25 33% 46 46% 81 40% 152 40% 2754 80.2% Fisher P = 1.1 10−12

PC 13 17% 16 16% 26 13% 55 15% 415 12.1% P = .19 (ns)FFP 2 3% 3 3% 8 4% 13 3% 58 1.7% P = .025RCC + PC 6 8% 7 7% 9 4% 22 6% 101 2.9% P = 8.9 10−3

RCC + FFP 14 19% 7 7% 38 19% 59 16% 79 2.3% P = 1.8 10−22

PC + FFP 1 1% 2 2% 3 1% 6 2% 12 0.3% P = 6.4 10−3

RCC + PS + FFP 13 17% 18 18% 36 18% 67 18% 15 0.4% P = 1.5 10−50

No. of different BC types 1 BC type 41 55% 66 66% 117 58% 224 59% 3227 94% χ2 P = 5.6 10−144

2 BC types 21 28% 16 16% 50 25% 87 23% 192 5.6%3 BC types 13 17% 18 18% 36 18% 67 18% 15 0.4%

RCC alone vs otherBC ± RCC

RCC 25 33% 46 46% 81 40% 152 40% 2754 80% χ2 P = 2.5 10−67

PC/FFP/AGC/RCC 50 67% 54 54% 122 60% 226 60% 680 20%

Distribution of BC types transfused in all TRALI cases is highly different from the general transfused population, except for isolated PC transfusion alone, representing less than 15% of alltransfusions.Each TRALI category (antibody positive, antibody negative, and possible) considered separately is highly statistically different from the general transfused population for:

- the total number of BC transfused 24 hours prior the onset of TRALI.- all the BC types combinations.- Conversely, the 3 TRALI categories (antibody positive, antibody negative, and possible) do not differ significantly between each other for these criteria (χ2 test):- total number of BC transfused 24 hours prior the onset of TRALI: P = .66.- number of different BC types: P = .37.a Data from Quaranta et al [23].b AGC not considered in the statistics (too small numbers).

6 G. Andreu et al. / Transfusion Medicine Reviews xxx (2017) xxx–xxx

HLA/HNA Specificities and Reaction Severity. Specificities observed wereHLA class I (n = 31), class II (n = 23), both class I and II (n = 19),and HNA3a (n = 1). Their distribution according to severity isshown in Table 5, with no significant difference of severity distri-bution among HLA class I, class II, or a mixture of class I and IIantibodies.

Table 4TRALI incidence per 1000 patients according to the clinical circumstances of blood transfusion

Population No. of patients I

All TRALI categories Total transfused

All patients 378 3 757 257 0Postpartum hemorrhage 44 74 893 0Acute myeloid leukemia 27 55 000 0Liver transplantation 9 7777 1HSC allogeneic graft 9 11 411 0Polytrauma 27 97 000 0Thrombotic microangiopathy 5 7000 0HSC autologous graft 6 20 346 0Total at-risk patients 127 273 427 0Patients not identified at risk 251 3 483 830 0

RR, relative risk.Estimation of the total transfused population in the 2007-2013 period in France is 3 757 257 [1Postpartumhemorrhage: There have been 5 761 000 births in France between 2007 and 2013 [174 893 cases.Acutemyeloid leukemia: Estimation of annual incidence is 2800 (upper estimate), and that of sannual prevalence estimation is 7850, that is, 55 000 patients from 2007 to 2013.Liver transplantation: A total of 7777 liver transplants were performed in France from 2007 toHematopoietic stem cells allogeneic graft: A total of 11 411 were performed in France from 20Polytrauma: In the reference study [23], 33 polytraumas were transfused on a single day (Thuactivity, this value was raised by 10% and by an additional 5% to take account of the incidenceThromboticmicroangiopathies (hemolytic uremic syndrome and thrombotic thrombocytopenic[25]. We retained the upper value of 1000 annual cases, that is, 7000 in the 2007-2013 period.Autologous hematopoietic stem cells graft: 20 346 were performed in France from 2007 to 201All the clinical circumstances mentioned in the table show a significantly higher TRALI incidenTRALI cases in patientswithmyelodysplastic syndromewere also evaluated (n = 18), but the hthe general transfused population (P = .07).Other clinical conditions, such as liver cirrhosis (15 TRALI cases) or malaria (3 TRALI cases), coufused in these conditions could be found.

Please cite this article as: Andreu G, et al, Analysis of Transfusion-RelatedReported to the French Hemovi..., Transfus Med Rev (2017), http://dx.doi.

TRALI Incidence per BC Before and After the Implementation of MitigationMeasures Targeting the Antibody-Positive TRALI Category

BC Distributed in France From 2007 to 2013 and TRALI Overall IncidenceTable 6 displays the number of BC distributed in France from 2007 to

2013. Data from SD plasma have not been recorded because no TRALI

ncidence/1000 patients Selected at-risk patient groups vs generalpopulation (Fisher test)

P RR IC 95%

.10

.59 5.5 10−24 8.2 (5.8-11.3)

.49 8.3 10−14 6.8 (4.4-10.2)

.16 1.1 10−8 16.1 (7.3-31.0)

.79 2.6 10−7 11.0 (4.9-21.1)

.27 1.6 10−8 3.9 (2.5-5.8)

.71 1.9 10−5 9.9 (3.2-23.4)

.29 4.0 10−3 4.1 (1.5-9.0)

.46 2.5 10−50 6.5 (5.2-8.1)

.07

1-17].8]. Assuming postpartumhemorrhage N1000mL occurs in 1.3% of births [19], it represents

urvival at 1, 3, and 5 years is, respectively, 42%, 25% and 21% [22]. Therefore, themaximum

2013 [20].07 to 2013 [21].rsday), a raw annual estimation of 12 000. As the study involved ca. 90% of the nationalof polytrauma related to traffic accidents on weekends [24].purpura): Estimation of their annual incidence is between5 and 10 permillion inhabitants

3 [21].ce than the general transfused population.igher TRALI incidence (0.15/1000 patients) was not found to be significantly different from

ld not be evaluated because no reliable information on the total number of patients trans-

Acute Lung Injury and Possible Transfusion-Related Acute Lung Injuryorg/10.1016/j.tmrv.2017.07.001

Table 5Antibody-positive TRALI: distribution of antibodies specificities and TRALI severity grades

Severity grade Antibodies detected in donors

HLA HNA

Class I Class II Class I + II

1 & 2 Nonsevere & severe 13 9 9 13 Life threatening 16 12 9 04 Death 2 2 1 0

Total 31 23 19 1

Statistical analysis shows no significant difference between HLA antibody class (I, II, andI + II) and TRALI severity grade:- Either by 2 × 2 comparison of every severity grade (Fisher test):• Class I vs class II: P = 1 in all instances.• Class I vs class I + II: P = .77 (grades 1 and 2) and P = 1 (grades 3 and 4).• Class II vs class I + II: P = .75 (grades 1 and 2) and P = 1 (grades 3 and 4).- Or by merging grades 3 and 4 severity grades (χ2 test: P = .86).

Table 6Number of BCs distributed in France in the 2007-2013 period

Year RCC BCPC APC FFP AGC Total BC

2007 2 192 810 55 836 192 265 179 435 321 2 620 6672008 2 287 350 62 139 192 784 193 025 224 2 735 5222009 2 343 804 76 649 186 752 229 125 245 2 836 5752010 2 378 241 107 772 170 325 299 286 286 2 955 9102011 2 449 506 142 281 150 365 275 096 296 3 017 5442012 2 517 097 154 955 145 728 320 563 323 3 138 6662013 2 499 000 158 173 148 069 262 825 230 3 068 297Total 16 667 808 757 805 1 186 288 1 759 355 1925 20 373 1812007-2009 6 823 964 194 624 571 801 601 585 790 8 192 7642011-2013 7 465 603 455 409 444 162 858 484 849 9 224 507

RCC use increased by 15% between 2007 and 2012 and remained stable in 2013.BCPC use was multiplied by a factor 3 in the whole period, whereas APC was reduced by28%. This is the result of a voluntary policy. Globally, the use of PC increased by 23% inthe period.FFP use increased by 48% in the whole period. However, when taking account of theamount of SDplasma distributed (not included in the table), the actual therapeutic plasmaincrease is 28%.The reference numbers for incidence calculation are indicated in the 2 bottom lines.

7G. Andreu et al. / Transfusion Medicine Reviews xxx (2017) xxx–xxx

case has been reported for this blood product either in France or in an-other country [36-40]. The total number of BCs distributed was 20 373181, and 380 TRALI cases were reported. Therefore, the incidence ofTRALI during the years 2007-2013 was 18.7 per 1 million BCs.

TRALI Incidence in 2007-2009 Versus 2011-2013Table 7 displays estimates of the incidence of TRALI in the selected

periods. Mitigation measures specific for BCPC-related antibody-positive TRALI cases had no detectable effect: the incidence variedfrom 5.1/million BCs before to 4.4/million BCs after, a difference that

Table 7TRALI incidence according to TRALI categories and to BCs before and after specific mitigation m

BC RCC BCPC

TRALI category Ab pos Ab neg p Ab pos Ab neg

2007-2009 No. of TRALI 15 27 47 1 22011-2013 25 28 63 2 62007-2009 No. of BC distributed 6 823 964 194 6242011-2013 7 465 603 455 4092007-2009 Incidence/106 BCs 2.2 4.0 6.9 5.1 10.32011-2013 3.3 3.8 8.4 4.4 13.22007-2009 vs 2011-2013(Fisher test)

P = 0.2 0.9 0.3 1 1

APC is the BC with the highest TRALI all categories incidence (52.5 per million in the first perioWhen considering APC-related antibody-positive TRALI alone, the decrease from 21 to 0 per mcategory, preventive measures have been efficient.FFP-related antibody-positive TRALI shows similar data: incidence decrease from 15 to 0 per mBCPC-related antibody-positive TRALI incidence is not significantly reduced despite the prevenRCC-related antibody-positive TRALI incidence is not significantly modified, as expected (no spIn addition, as expected, for antibody-negative TRALI and possible TRALI, alone or in associatio

Please cite this article as: Andreu G, et al, Analysis of Transfusion-RelatedReported to the French Hemovi..., Transfus Med Rev (2017), http://dx.doi.

was not significant. The reported incidence was zero for APC-relatedantibody-positive TRALI cases since 2011 and for FFP-related antibody-positive TRALI cases since 2009. A reduction from 21/million (APC)and 15/million (FFP) to 0/million was statistically significant, P = .002and .0003, respectively. However, when comparing all categories ofTRALI, no significant impact of mitigation measures was detectable.For all 3 TRALI categories combined, there were 17.0/million BCs beforemitigationmeasures and 18.1/million after. Considering only antibody-positive TRALI cases, there were 4.5/million BCs before mitigation mea-sures and 2.9/million after, P = .1 (Fisher test).

PAS Impact on TRALI Incidence

Data related to the use of PAS in PC since 2008 are presented inTable 8. PAS has been used in more than 98% of PCs in 2012-2013 com-pared with less than 50% in 2008-2009. This evolution was voluntary,first following a recommendation from French Health Products SafetyAgency in the year 2000 in reference to the potential for Creutzfeld-Jakob disease transmission by blood transfusion [41] and after the ob-servation that use of PAS was linked to a dramatic reduction in allergicreactions in patients [42]. Rates of TRALI associated with PC with PASwere compared with rates without PAS as follows. BCPC-related TRALIcases were compared throughout the 2008-2013 period under the as-sumption that no intervention was introduced to mitigate BCPC-related TRALI (see previous section). Rates of APC-related antibody-negative TRALI and possible TRALI were also compared throughoutthe 2008-2013 period, as these categories were not influenced by theTRALI mitigation measures. In contrast, rates for APC-related antibody-positive TRALI were compared only during the period 2008-2009, asmitigation measures implemented in 2010 were introduced and couldhave therefore affected the comparison of PAS-positive vs PAS-negative products.

Results are shown in Table 9.For platelet concentrates prepared with a pool of buffy coats, the

reduction in the incidence of reported TRALI associated with PAS wassimilar for each TRALI category: a factor of 4.4, 4.4, and 5.7 forantibody-positive TRALI, antibody-negative TRALI, and possible TRALI,respectively. Because the number of events is low, the decrease in inci-dence was statistically significant only for possible TRALI cases, P =.028.When combining all 3 TRALI categories, the reduction in incidencebecomes significant, P = .003. However, for APCs, any reduction inTRALI incidence was found to be weak, not significant, or nonexistent.

Discussion

In the reviewprocess done prior to our analysis, themain reasons formodification of initial conclusions were, on one hand, the presence of

easures implementation targeted to antibody-positive TRALI

APC FFP All BC

p Ab pos Ab neg p Ab pos Ab neg p Ab pos Ab neg p

1 12 6 12 9 4 3 37 39 636 0 6 13 0 6 12 27 46 94

571 801 601 585 8 191 974444 162 858 484 9 223 658

5.1 21.0 10.5 21.0 15.0 6.6 5.0 4.5 4.8 7.713.2 0.0 13.5 29.3 0.0 7.0 14.0 2.9 5.0 10.20.7 0.002 0.8 0.4 0.0003 1 0.1 0.1 0.9 0.09

d and 42.8 in the second).illion is significant (P = .002). As all specific measures were targeted against this TRALI

illion is significant: P = .0003.tive measures.ecific preventive measures were implemented).n, there is no significant incidence modification whatever the BC is.

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Table 8Number of APCs and PCs prepared with a pool of buffy coats distributed in France from2008 to 2013 with and without PAS

PC PAS No. of PC distributed Total PC

2008 2009 2010 2011 2012 2013

BCPCNo 3842 13 220 22 220 3257 3459 3008 49 006Yes 58 313 63 478 85 542 139 020 151 487 155 161 653 001

APCNo 129 969 120 902 117 654 37 299 9410 1918 417 152Yes 63 091 65 885 52 664 113 066 136 316 146 152 577 174

8 G. Andreu et al. / Transfusion Medicine Reviews xxx (2017) xxx–xxx

circulatory overload signs besides ARDS and, on the other hand,preexisting risk factor for ARDS, both sometimes difficult to detect.Therefore, we think that our additional review process reduced drasti-cally the number of misdiagnosed TRALI cases in our series.

TRALI Incidence

Among the 378 cases reported to the FHNas suspected TRALI, the re-sponsible BC was identified without ambiguity in 257/378 cases (68%),wherein patients either received only 1 BC or were classified asantibody-positive TRALI (Table 1A and B). This proportion was similarto that observed by the Canadian Blood Service in 2001-2009: 99/136(72%) [43], and in the Netherlands in 2006-2013: 80/109 (73%) [44].All AGCs were unambiguous. When comparing the BC distribution ofantibody-negative and possible TRALI in the unambiguous group(n = 179: 127 RCC, 8 BCPC, 33 APC, and 11 FFP) and in the groupwhere patients received multiple different BCs (n = 121: 78 RCC, 11BCPC, 8 APC, and 24 FFP), the distributionwas not significantly differentfor RCC (P= .24) and BCPC (P=011) but was significantly different forAPC (P= .003) and FFP (P= .0003). In other words, as reported to theFHN, the number of APC-related TRALI may be underestimated, where-as the number of FFP-related TRALI may be overestimated. However,this observation should not interfere with a comparison of the overallincidence of TRALI with available data in the literature.

We selected 9 National Hemovigilance reports from 8 countries[17,44-51]. We also selected 10 publications from other studies that re-ported results either from single hospitals or from clinical departmentswithin a single hospital [52-61]. As shown in Table 10, the reported in-cidence of TRALI varies from 786/million to 15 362/million BCs in re-ports from clinical departments, from 4.3/million to 755/million BCs inreports from single hospitals, and from 2.6/million to 17.6/million BCsin reports from hemovigilance networks. Studies from clinical

Table 9Relationship between the use of PAS and the incidence of PC-related TRALI

PAS in PC No. of events TRALIincidence/millio

No Yes No

BCPC PC distributeda 49 006 653 001Ab pos TRALI 1 3 20.4Ab neg TRALI 2 6 40.8possible TRALI 3 7 61.2Ab pos & Ab neg TRALI 3 9 61.2Ab pos & possible TRALI 4 10 81.6Ab neg & possible TRALI 5 13 102.0All TRALI 6 16 122.4

APC PC distributedb 250 871 128 976TRALI I+ 8 2 31.9PC distributeda 417 152 577 174TRALI I- 5 5 12.0TRALI p 10 15 24.0

For BCPC, incidence reduction factor is similar for each TRALI category: 4.4, 4.4, and 5.7 for antThis incidence decrease is significant for possible TRALI: P = .028.When considering any association of the 3 TRALI categories, the incidence reduction is alwaysFor APC, no effect of TRALI incidence is observed.

a PC distributed in the years 2008 to 2013.b APC distributed in the years 2008 and 2009 could only be considered.

Please cite this article as: Andreu G, et al, Analysis of Transfusion-RelatedReported to the French Hemovi..., Transfus Med Rev (2017), http://dx.doi.

departments report selected patients at increased risk with muchhigher incidence rates. All hospital studies displayed large variationsin incidence values. The method to identify cases of TRALI is of thehighest importance, and the work from Toy et al [61] is the most rigor-ous. However, considering that this work comes from a tertiary referralhospital, it likely includes patients at higher risk than the general popu-lation of transfused patients. Thus, it is possible that this work overesti-mates the incidence in a general transfusion population. Nevertheless,the different incidence rates reported in the literature strongly suggestthat all hemovigilance networks miss many TRALI cases.

TRALI Clinical Risk Factors

TRALI clinical risk factors identified by Toy et al [61] were liver sur-gery, chronic alcohol abuse, shock, higher peak airway pressure whilebeing mechanically ventilated, current smoking, and positive fluid bal-ance. Chronic alcohol abuse, shock, current smoking, and positive fluidbalance have been associatedwith possible TRALI aswell [62].We iden-tified postpartum hemorrhage, polytrauma, liver transplantation, AML,allogeneic and autologous stem cell transplantation, and TMA as associ-atedwith TRALI. Our approach, based on national statistics, is not able todetect some of the clinical factors identified by Toy et al [61], exceptliver surgery for transplantation. Postpartum hemorrhage has notbeen associated with TRALI in the literature. Our 44 cases came from36 different hospitals over a period of 7 years, which illustrate that nosingle hospital could be expected to observe this association even if in-vestigating over a long period of time.

However, the quality of the different patients' population numbersevaluation is not homogeneous: based on single estimation, it is lowin AML, polytrauma, and TMA; it is better in postpartum hemorrhageas the 1.3% estimation from Stones et al [19], is close to the 1.2% estima-tion from Quaranta et al [23], and is excellent in liver and HSCtransplants.

More importantly, our statistical approach is not able to identifywhether these clinical situations represent independent risk factorsfor TRALI or are confounding factors, as they all received a great numberof BCs of multiple types.

TRALI Classification

The 2004 consensus conference criteria [3] have been decisive tostandardize the classification of TRALI. The category of “possibleTRALI”—a specific group of patients exposed to another risk factor for

n PCIncidence reduction factor Fisher test (P) 95% Confidence

interval

Yes

4.6 4.4 .259.2 4.4 .10

10.7 5.7 .028 1.0 25.013.8 4.4 .046 0.8 17.615.3 5.3 .013 1.2 18.519.9 5.1 .007 1.4 15.324.5 5.0 .003 1.6 13.4

15.5 2.1 .51

8.7 1.4 .7526.0 0.9 1

ibody-positive, antibody-negative, and possible TRALI, respectively.

significant.

Acute Lung Injury and Possible Transfusion-Related Acute Lung Injuryorg/10.1016/j.tmrv.2017.07.001

Table 10Estimation of TRALI incidence according to various sources: national hemovigilance data and hospital studies

Country Institution Patientpopulation

Studyperiod

Year ofpublication

Ref. Ab posTRALIpreventivepolicy

TRALIcategories(Ab pos, Abneg, &possible)

No. of TRALIobserved

No. of BCdistributed/transfused

TRALIincidence/millionBCs

Canada (exceptQuébec)

National/RegionalHemovigilanceNetwork

All countries/regions

2012 2013 [50] Yes All 16 909 595 17.6

France 2013 2014 [17] Yes All 52 3 068 297 16.9Switzerland 2013 2014 [49] Yes All 5 358 343 14.0Canada (Québec) 2012 2013 [51] Yes All 4 341 024 11.7Netherland 2013 2014 [44] Yes All 6 565 136 10.6New Zealand 2013 2014 [47] Yes All 1 136 995 7.3Australia 2012 2013 [46] Yes All 4 1 062 434 3.8United Kingdom 2013 2014 [48] Yes All 10 2 758 495 3.6Germany 2013 2014 [45] Yes All 14 5 337 947 2.6Canada

Tertiary hospital

All hospitals 1991-1995 2003 [58] No All 90 119 093 755UK All hospitals 1993-2002 2003 [57] No All (FFP only) 10 94 800 105USA 2 Hospitals 2009 2012 [61] Yes Ab pos & Ab neg 10 123 731 81USA All hospitals 2001-2007 2010 [59] No NS 2 415 775 4.8USA All hospitals 2007-2008 2011 [60] Yes All 1 233 685 4.3The Netherlands

Tertiary hospital

Pediatrics 2009-2012 2015 [56] Yes All 21 1367 15 362

The NetherlandsIntensivecare unit

2004-2007 2010 [52] Yes All 6 485 12 371

UKAbdominalaorta aneurysm

2004-2007 2008 [53] Yes NS 14 1750 8000

The Netherlands CABG 2007-2009 2011 [54] Yes All 16 2631 6081USA

Pulmonary &critical care

2003 2006 [55] NoPossible 14

89021573

USAAb pos &Ab neg

7 786

NS, not specified.With a single exception indicated in the table [57], all BC-related TRALIs have been investigated.TRALI incidence evaluation drastically differs according to the method of investigation:

- National/Regional Hemovigilance networks: Incidence is constantly low (b20/million BCs) and varies from country to county by a factor 7.- Institutional studies involving tertiary hospitals as a whole: Incidence is higher (median value 81/million BCs) but varies among institutions by a factor 175.- Institutional studies targeting a selected patient population: Incidence is much higher (median value 8000/million BCs) but varies among studies by a factor 20.

9G. Andreu et al. / Transfusion Medicine Reviews xxx (2017) xxx–xxx

ARDS—was intended to provide a more rigorous framework for the defi-nition of TRALI and to facilitate data analysis. However, many cliniciansand hemovigilance correspondents are still puzzled by this classification,prompting some of them to consider possible TRALI as a misdiagnosis.

A modification of TRALI nomenclature has been recently proposed[63] in an attempt to clearly distinguish TRALI cases as “antibodymediat-ed,” “non–antibody mediated,” or “no further classification possible,” thelatter in caseswhere no immunological investigation is available. This ap-proach is designed to drop the term possible TRALI, renaming this categoryas transfused ARDS. The proposed newnomenclature is based on at least 5arguments, among them the observation that the risk of TRALI but notpossible TRALI increases with an increasing number of BC and that possi-ble TRALI is associated with a higher mortality rate.

However, our data are discrepant with these 2 arguments. We ob-served that some characteristics of TRALI and possible TRALI patientsare statistically similar, including patient age, the proportion of at-riskpatients, the average number of BCs transfused, and the proportion ofdifferent BC types. It has been reported in the literature that possibleTRALI is more severe than TRALI, with a 42% vs 17% one-month mortal-ity rate [64]. Interestingly, in analyzing mortality, the FHN addressesonly cases where a direct link between TRALI and death is identified,and mortality rates appear similar: 8/203 (4%) for possible TRALI com-pared with 6/175 (3.4%) for the combination of both antibody-positiveand antibody-negative TRALI. One-month survival data are only avail-able for 146 of the 378 TRALI cases, and in that subgroup, 1-monthmor-tality is 25/81 (31%) in possible TRALI and 14/65 (21%) for antibody-positive and antibody-negative TRALI combined. Although these figuresare not significantly different, the trend is compatiblewith the literatureand suggests that, as a direct consequence of its definition, possibleTRALI occurs in more clinically severe cases than either antibody-positive or antibody-negative TRALI cases.

Please cite this article as: Andreu G, et al, Analysis of Transfusion-RelatedReported to the French Hemovi..., Transfus Med Rev (2017), http://dx.doi.

HLA investigation was not done in 25/203 (12%) possible TRALIcases vs only 1/175 (0.6%) of TRALI cases,whichmay suggest a less thor-ough evaluation in cases of possible TRALI. As a result, HLA incompati-bility was present in 75/174 (43%) of TRALI cases and in 24/178 (13%)of possible TRALI cases. Our data reflect the observation of others [65]that TRALI and possible TRALI sharemany clinical featureswhen studiedat the level of hemovigilance networks recognizing that such aggregatedata may not always include details on the presence or absence of anARDS risk factor. Tracking cases of “possible TRALI”may still have resid-ual value: critically ill patients [32] are probably being “overdiagnosed”as possible TRALI by strictly applying the consensus conference criteria;in the future, should new measures to mitigate “non–antibody mediat-ed” TRALI arise, the effect of such measures on “possible TRALI” (or“transfused ARDS” in case of nomenclature change) can be measured.Regardless of the nomenclature, improvedmethods formaking an accu-rate diagnosis of ARDS truly resulting from transfusion are needed.

TRALI Associated With HLA/HNA Incompatibility

There is a debate on theprecise contribution of HLA class I antibodiesin TRALI. Some authors consider class I antibodies as sufficient to causeTRALI [66-68], whereas others disagree [61]. We did not detect a differ-ence in TRALI severity between cases associatedwithHLA class I, class II,or both I and II antibodies. Our data are compatible with prior reportsidentifying an active role of either HLA class I or class II antibodies inthe genesis of TRALI [69-70]. The proportion of antibody-positive andantibody-negative TRALI cases demonstrating HLA incompatibility was75/174 (43%), which is lower than some reports: 15/17 (88%) [45] and62/91 (68%) [71]. This difference may be related to the technique usedfor HLA antibody detection [70]. Our data come from 15 different HLAlaboratories, most of them using a bead-based technique. However, as

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10 G. Andreu et al. / Transfusion Medicine Reviews xxx (2017) xxx–xxx

no standardization has been defined except for apheresis donor selec-tion starting from 2010, it is difficult to analyze the effect of detectiontechniques in our data.

Impact of MitigationMeasures of TRALIWhere a Donor Had HLA and/or HNA An-tibody and the Recipient Had Cognate Antigen (Antibody-Positive TRALI)

Mitigationmeasures targeted at antibody-positive TRALIwere foundto be effective for the first time in the UK for FFP, when the incidence ofTRALI decreased through the use ofmale-only plasma from 15.5/millionunits in 1999-2003 to 3.2/million FFP units in 2004-2006 [72]. Numer-ous subsequent publications described similar results with FFP and PC[43,49,52,60,73-79]. No antibody-positive TRALI cases have been re-corded with FFP and APC after implementation of mitigation measuresin France. Our data with respect to APC were even better than those re-ported elsewhere [80] perhaps as a consequence of the permanent ex-clusion from blood donation of donors with a history of transfusionsince 1997 in France (Circulaire DGS/DH/AFS n° 97-662 du 30septembre 1997 relative à l'information des médecins prescripteurs deproduits sanguins labiles et des malades transfusés vis-à-vis de lamesure d'ajournement définitif du don de sang des receveurs deproduits sanguins labiles, text not published), with a subsequent higherprobability that male donors and nulliparous female donors would befree of HLA antibodies. No FFP-related antibody-positive TRALI caseshave been recorded by the FHN since 2009. This is not unexpected be-causemanyblood transfusion centers began usingmale-only FFP before2010. However, we observed 2 failures in FFP selection in cases desig-nated as possible TRALI (2012 and 2013) where HLA antibodies (1class I and 1 class II) were detected in female donors. This observationis similar to the UK experience of four failures observed in 2008 and2009 [81].

No effect of TRALI mitigation policies was observed for BCPC. In ad-dition, in a BCPC-related possible TRALI case recorded in 2011, we de-tected 2 donors with HLA antibodies, 1 class I and 1 class II. Insummary, although a significant reduction in APC and FFP-relatedantibody-mediated TRALI was observed, mitigation measures had noimpact on FFP/BCPC-related antibody-negative TRALI cases or possibleTRALI cases, or on RCC-related TRALI and RCC-related possible TRALI.

Impact of PASs on PC-Related TRALI Incidence Rates

To our knowledge, our data are the first to bring concrete informa-tion on the possible impact of PAS on the incidence of TRALI. For APC,no effect was observed. For BCPC, there was an association betweenPAS and reduced TRALI incidence when combining antibody-positiveTRALI, antibody-negative TRALI, and possible TRALI categories. We jus-tify combining data from the 3 categories on the basis of a low totalnumber of cases and the similar reduction in the incidence of reportedTRALI for the 3 categories. Our results may be criticized, however, be-cause among the 22 BCPC-related TRALI cases studied, 11 received an-other BC (Table 1B) and therefore may represent episodes of TRALInot actually related to BCPC. When considering separately the 11 unam-biguously BCPC-related TRALI cases, we observed 3 cases (1 antibody-positive TRALI and 2 possible TRALIs) without PAS vs 8 cases (3antibody-positive TRALIs, 4 antibody-negative TRALIs, and 1 possibleTRALI) with PAS. The corresponding incidences are 3/49 006 (61/million)without PAS and 8/653 001 (12/million) with PAS, a difference thatremained significantly different: P= .037 (Fisher test). The difference inpossible impact of PAS between APC and BCPCmay relate to the residualplasma volume present [82]: 20 to 25mL per buffy coat vs 150mL in APC.

Conclusion

Mitigation measures for APC and FFP-related antibody-positiveTRALI were found to be effective, with no single case reported aftertheir implementation compared with a prior incidence of 13/million

Please cite this article as: Andreu G, et al, Analysis of Transfusion-RelatedReported to the French Hemovi..., Transfus Med Rev (2017), http://dx.doi.

and 10/million for APC and FFP, respectively. In contrast, no effect ofmitigation strategies was observed for BCPC. Our data also suggestthat PAS may reduce the incidence of TRALI for BCPC, with values de-creasing from122.4/millionwithout PAS to 24.5/millionwith PAS. How-ever, no risk reduction was observed for APC. As shown in Table 7, FFP/APC donor selection and the use of PAS in BCPC did not prevent RCC-related TRALI and did not affect the rate of APC/FFP-related antibody-negative TRALI and possible TRALI cases, which represented 117/139(84%) of all reported cases in the years 2007-2009. Looking to the future,improved methods to categorize TRALI should lead to new approachesto reduce the incidence of this important complication of transfusion.We hope that this report will contribute to the development of researchtargeted to reduce, if not eradicate, all categories of TRALI.

Conflict of Interest

None (all the authors).

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