Am J Transplant. 2019;00:1–10.  | 1amjtransplant.com

Received:3May2019  |  Revised:3September2019  |  Accepted:7September2019DOI: 10.1111/ajt.15601

B R I E F C O M M U N I C A T I O N

Management of allergy transfer upon solid organ transplantation

Yannick D. Muller1,2,3  | Julien Vionnet2,4 | Franziska Beyeler5 | Philippe Eigenmann6 | Jean‐Christoph Caubet6 | Jean Villard7 | Thierry Berney8  | Kathrin Scherer9 | Francois Spertini10 | Michael P. Fricker11 | Claudia Lang12 | Peter Schmid‐Grendelmeier12 | Christian Benden13 | Pascale Roux Lombard1 | Vincent Aubert10 | Franz Immer5 | Manuel Pascual2 | Thomas Harr1 | the Swiss Transplant Cohort Study†

1DivisionofImmunologyandAllergy,DepartmentofMedicine,UniversityHospitalsandUniversityofGeneva,Geneva,Switzerland2TransplantationCenter,LausanneUniversityHospitalandUniversityofLausanne,Lausanne,Switzerland3DepartmentofSurgery,UniversityofCalifornia,SanFrancisco,California4DepartmentofInflammationBiology,SchoolofImmunologyandMicrobialSciences,King’sCollegeLondon,London,UK5Swisstransplant,Bern,Switzerland6PediatricAllergyUnit,DepartmentofWomen-Children-Teenagers,PediatricAllergyUnit,UniversityHospitalsofGenevaandUniversityofGeneva,Geneva,Switzerland7DepartmentofGenetic,LaboratoryandPathologyMedicine,GenevaUniversityHospitals,Geneva,Switzerland8DivisionofTransplantation,DepartmentofSurgery,GenevaUniversityHospitals,Geneva,Switzerland9DivisionofAllergyandDermatology,UniversityHospitalBasel,Basel,Switzerland10ServiceofImmunologyandAllergy,LausanneUniversityHospitalandUniversityofLausanne,Lausanne,Switzerland11DivisionofRheumatology,ImmunologyandAllergy,Inselspital,Bern,Switzerland12AllergyUnit,DepartmentofDermatology,UniversityHospitalofZürich,Zürich,Switzerland13DivisionofPulmonaryMedicine,UniversityHospitalofZürich,Zürich,Switzerland

ThisisanopenaccessarticleunderthetermsoftheCreativeCommonsAttribution-NonCommercialLicense,whichpermitsuse,distributionandreproductioninanymedium,providedtheoriginalworkisproperlycitedandisnotusedforcommercialpurposes.©2019TheAuthors.AmericanJournalofTransplantationpublishedbyWileyPeriodicals,Inc.onbehalfofTheAmericanSocietyofTransplantationandtheAmericanSocietyofTransplantSurgeons

FranzImmer,ManuelPascual,andThomasHarrareco-seniorauthors.

†TheSwissTransplantCohortStudymembersarelistedintheAppendix.

Abbreviations:IgE-Bcs,IgE-producingBcells;SOT,solidorgantransplantation;SPT,skinpricktest;STCS,SwissTransplantCohortStudy.

CorrespondenceYannickD.MullerEmail:Yannick.muller@unige.ch

Funding informationYDMwassupportedbytheSwissNationalResearchFund(grantno.P300PB_174500),theSwissTransplantCohortStudy(FUP096,CGR73771),andtheUlrichMullerGierokFoundation(CGR73774).

Allergytransferuponsolidorgantransplantationhasbeenreportedintheliterature,althoughonlyfewdataareavailableastothefrequency,significance,andmanage-mentofthesecases.Basedonareviewof577consecutivedeceaseddonorsfromtheSwisstransplantDonor-Registry,3cases(0.5%)offatalanaphylaxiswereidentified,2becauseofpeanutand1ofwaspallergy.Theseraofall3donorsandtheir10pairedrecipients, prospectively collected before and after transplantation for the SwissTransplantCohortStudy,wereretrospectivelyprocessedusingacommercialproteinmicroarrayfluorescenttest.Asearlyas5daysposttransplantation,newlyacquiredpeanut-specificIgEweretransientlydetectedfrom1donorto3recipients,ofwhom1liverandlungrecipientsdevelopedgradeIIIanaphylaxis.Yet,todefinehowallergy

2  |     MULLER Et aL.

1  | INTRODUC TION

Anaphylaxisisafrequentcauseofhospitalizationwithanestimatedannualfatalityrateof≈0.5per1000000.Foodallergybeingthemostcommoncause foranaphylaxis inchildrenandyoungadults,deathdue to foodallergywas found in≈25%of the reportedpa-tients.1Peanutsortree-nutswerethecausativeallergens in>70%ofthecasesinwhichtheresponsibleallergenwasidentified.Otherallergensfrequentlyinvolvedinfatalanaphylaxisarefish,milk,andeggbutalsobeeandwaspvenom,anddrugs.1

Thefirstcasesoftransplant-associatedallergytransferwerere-portedafterhematopoieticstemcell transplantation, likelycausedbyIgE-specificBcellsorThelpertype2cellsthatwerecotransferredwithhematopoieticstemandprogenitorcells.2Subsequently,casesofallergytransferwerealsodescribedaftersolidorgantransplan-tation(SOT),predominantlyafterliver,lung,orcombinedpancreas-kidneytransplantation(Table1).3-11Onlyveryfewdataareavailableastothefrequency,significanceandmechanismsofIgEtransferinthe settingof SOT. In addition, the impactof immunosuppressionon IgE sensitization is poorly understood. The objectives of thisstudywere(1)toidentifythefrequencyandsignificanceofallergytransferbasedonretrospectiveanalysisfromtheSwissTransplantDonorRegistryand theSwissTransplantCohortStudy (STCS); (2)toevaluatewhetherallergytesting isfeasibleearlyafterSOT;and(3)tomakerecommendationsforthediagnosisandmanagementofallergytransplantafterSOT.

2  | MATERIAL AND METHODS

2.1 | Donor‐to‐recipient IgE transfer

Weretrospectively reviewed thedataof577consecutivedeceaseddonorsfromtheSwisstransplantDonor-Registry(fromJanuary2012toMay2017)andidentified3donorswhodiedofanaphylaxis.Inthisregistry,theindividualhistoryofsevereallergywasnotrecorded.Wethen collected the prospectively stored sera of each donor-paired

recipientfromtheSTCS(Table2),12aprospectivemulticentercohortincludingSOTperformedinSwitzerlandasofMay2008.Seraoftherecipientsareprospectivelycollectedatbaseline(dayoftransplanta-tion),6and12monthsaftertransplantation.Inaddition,serawerein-dividuallycollectedthroughoutthedifferentcentersatspecifictimepointsaftertransplantation.ToassesstheIgEprofileofthedonorandrecipient’ssera,acommercialproteinmicroarrayfluorescenttestbear-ingrecombinantallergenmolecules (ISAC™,ThermoFisherScientific,Waltham,MA) was used. ISAC standardized units (ISU-E) were as-sessedusingacut-offvaluedefinedat0.35 ISU.All recipientsgavewritteninformedconsentforparticipation.LocalethicsIRBcommittee(ID2017-1058,CCER-GE)andSwisstransplantapprovedthestudy.

2.2 | Immunosuppression and IgE sensitization

Skin prick tests (SPT), specific IgE values, and clinical symptomsweremonitoredin5adultliving-donorkidneytransplantrecipientswith symptomatic allergic rhinoconjunctivitis between November2016andAugust2018.Therhinoconjunctivitisscorewasbasedonthesubject’snasal(runnynose,blockednose,sneezing,itchynose)and eye symptoms (gritty feeling/red/itchy eye and watery eye)usinga3-pointscale(none=0,slightsymptoms=1,moderatesymp-toms=2,andseveresymptoms=3)forthe6symptomclasses.Allrecipientsgavewritteninformedconsent(ID2018-00965,CER-VD).

3  | RESULTS

3.1 | Donor case 1

Oneyoungorgandonordiedofpeanut-allergy-inducedanaphylaxisleadingtocardiacarrestwithsubsequentbraindeath.Uponadmis-sion, tryptase was >100 ng/mL (normal results: <10 ng/mL).Withtheconsentoftherelatives,theheart,lungs,liver,andkidneyswereprocured for transplantation.The liverwas further split and trans-planted into 2 recipients (Figure 1A).Onposttransplant follow-up,thekidneyof1recipienthadtobeexplantedwithinthefirstweek

testingshouldbeperformed in transplant recipientsand tobetterunderstand theimpactofimmunosuppressivetherapyonIgEsensitization,weprospectivelystudied5atopicliving-donorkidneyrecipients.Allpollen-specificIgEand>90%ofskinpricktests remainedpositive7days and3months after transplantation, indicating thatearlydiagnosisofdonor-derivedIgEsensitizationispossible.Importantly,weproposerecommendationswithrespecttosafetyforrecipientsundergoingsolid-organtrans-plantationfromdonorswithahistoryoffatalanaphylaxis.

K E Y W O R D S

allergy,allergytransfer,anaphylaxis,business/management,clinicaldecision-making,clinicalresearch/practice,diagnostictechniquesandimaging,guidelines,IgE,immunoglobulinE,immunosuppression,immunosuppression/immunemodulation,management,organtransplantationingeneral,patientsafety,solidorgantransplantation

     |  3MULLER Et aL.

TAB

LE 1

 Systematicreviewoftheliteratureforallergytransfer

Serie

s 1Se

ries 2

Serie

s 3Se

ries 4

Serie

s 5Se

ries 6

Serie

s 7Se

ries 8

Organ(s)withallergy

tran

sfer

Liver

Liver

Liver

Liver,lung

Liver-kidney

Pancreas-kidney,

liver(no

in

form

atio

n provided)

Lung

Lung

Organ(s)without

alle

rgy

tran

sfer

Kidney,

kidney-pancreas

—Kidneys,heart

Kidney,pancreas

Pancreas-kidney

Kidney

—Kidney,kidney-pancreas

Causeofdonordeath

Anaphylaxis

Anaphylaxis

Anaphylaxis

Car

acc

iden

tAnaphylaxis

Anaphylaxis

Obstructedventricu-

loperitonealshunt

Anaphylaxis

Supposedrespon-

sibleallergenfor

death

Peanut,cashew

nut,sesameseed

Unknown

Pean

ut—

Pean

utPe

anut

—Pe

anut

Donorhistoryof

alle

rgy

Atopicdermatitis,

asthma

Allergytonuts,

kiwi,seafood,and

wheat

Asthma

Asthma,peanut

alle

rgy

—Pe

anut

alle

rgy

Pean

ut a

llerg

yPe

anut

alle

rgy

Anaphylaxisevents

(Mullerclassifica-

tion)intherecipient

POD25(grade

2),POW32

(unclear)

POD8(grade3)

POD

10

and

28

(grade1)

Liver:POM2

(grade4),lung:

POM3(grade3)

POM3(grade3)

—POW<4(4episodes,

uptograde4)

POD4(asthmaticcrisis),

POW5-16(asthmatic

crisis),POM7(grade3)

Tim

e to

alle

rgy

test

POW9-10

POW4

POD>28

Liver:POD1,lung:

POM

4POW>12

POW4

POW8

POW>28

Dur

atio

n of

alle

rgy

(supposed)

>48wk

>3wk

>4wk

Liver:<8mo,lung:

>18mo

>12wk

<24wk

<1.5y

>7y

SkinTest

Posi

tive

for

peanut,cashew,

sesame(POW6)

Negative

Posi

tive

for

peanut(POD28)Liver:negative

(POM8),lung:

posi

tive

for p

ea-

nut(POM4-18)

—Po

sitiv

e fo

r pea

nut

(POM1),negative

(POM6)

Posi

tive

for p

eanu

t (POM2),negative

(1yafterTx)

Posi

tive

for p

eanu

t (POM>7),negative(5y

afterTx)

IgE

sero

logy

Negative

Negative

Negative

Liver:positivefor

rArah3(POD1),

negative(POM5),

lung

: pos

itive

for

rArah1-2-3(POM

4-8-18)

Posi

tive

for

peanut(POM3)PositiveforrAra

h1-2(POM1),

negative(POM6)

Negative

Negative(5yafterTx)

Oralchallenge

—Po

sitiv

e fo

r walnuts(grade3,

POW4-5)

—Liver:negative

(POM8)

—Negative(POM6)

Negative(1.5yafter

Tx)

Positive(asthmaticcrisis)

7yafterTx

Imm

unos

uppr

essi

onTacrolimus,

Azathioprine,

Glucocorticoids

Tacrolimus,MMF,

Glucocorticoids

Cyclosporine,

Glucocorticoids

Liver:Cyclosporine,

MMF,

Glucocorticoids,

lung:Tacrolimus,

MMF

Glucocorticoids

Cyclosporine,

Azathioprine,

Glucocorticoids

—Azathioprine,

Cycl

ospo

rine

Cyclosporine,Azathioprine,

Glucocorticoids

(Continues)

4  |     MULLER Et aL.

posttransplant because of multiple surgical complications and thepatientwassubsequentlyexcludedfromtheanalysis.Recombinantpeanut-specificIgEknowntobemajorelicitorsofclinicallyrelevantallergy13couldbedetectedinthedonor(Arah1:42ISU-E,Arah2:85ISU-E,Arah3:36ISU-E,andArah6:61ISU-E),andinbothliver(LiverR1,LiverSplitR2)andlungrecipients(LungR3),butneitherinthekidneynorintheheartrecipientsofthesamedonor(Figure1B,C).

In the caseof LiverR1, an inadvertentoral ingestionof2pea-nutsonpostoperativeday(POD)11resultedinstomachpain,vom-iting, and transient dyspnea. LungR3underwent anoral challengeonPOD30with a startingdoseof6mgpeanut (=1.5mgpeanutproteinED05).Afterthefifthdose,thepatientdevelopedurticaria,acuteasthma,andstomachpain.TheoralchallengewasnegativeinLiverR2.However,thetestwasperformed9monthsaftertransplan-tationwhenpeanut-specificIgEwerenotdetectableanymoreinthepatient’ssera.

LiverR1 and LungR3 responded to treatment with antihista-mines, glucocorticoids, and inhaled salbutamol. Two years aftertransplantation,anoral challengewithpeanutswaswell toleratedby recipient LiverR1 after SPT had become negative, whereasLungR3refusedarepeatoralchallenge.Ofnote,recipientswithdenovotransferred-IgEwereatopicasdefinedherebythepresenceofspecificIgEagainst,pollen,animaldander,orhousedustsmites(Figure1D).ThesedataindicatedthatdenovooccurrenceofspecificIgEtorecombinantpeanutallergenIgE(Arah1,2,3,and6)maypre-dictallergytransferinSOT.

3.2 | Donor cases 2

The second donor had a history ofwasp allergy and developedcardiacarrestafterawaspstingdespitetheself-applicationofepi-nephrine.Analysisoftheserauponadmissionshowedatryptaselevelof3.95ng/mLwithoutsignificantelevationofspecificIgEstocrudeandrecombinantwaspvenomallergens(rVesv51.1ISU-E,wasp IgEnegative).An ISACperformed inboth thedonorand2recipients(kidneyandlung)didnotshowanyIgEtransfer.Inthiscase,failuretodocumentanelevationofthetryptaseorspecificIgEsdoesnotexcludethediagnosisofIgE-mediatedanaphylaxisinlightofthepersonalhistory,14,15althoughanon-IgE-mediatedana-phylaxis(mastcellrelease,IgG-orcomplemented-mediated)mightbepossible.Overall, thesedata suggest that if the exact natureof an allergy is not appropriately documented in the donor, thepretestprobabilityofidentifyingallergytransferislikelyreduced.

3.3 | Donor cases 3

The third donor had an anaphylactic reaction with cardiac ar-rest supposedly mediated by peanut ingestion. On admission,tryptasewaselevated(38.1ng/mL)whereasserumIgE(measuredby UniCAP™, ThermoFisher) to peanut (3.04 kUI/L), hazelnut(6.74kUI/L),almond(1.14kUI/L),cashewnut(1.27kU/L),andpis-tachio (3.24UI/L)wereonlymoderatelyelevated. Interestingly,in the sera of the donor a high level of nAct d1 (actindin) was

Serie

s 1Se

ries 2

Serie

s 3Se

ries 4

Serie

s 5Se

ries 6

Serie

s 7Se

ries 8

Atopicstatusofthe

reci

pien

t —

——

Liver:-,lung:

nega

tive

——

Posi

tive

—

Age/Sexofthe

reci

pien

t 60

/m54

/m28

/fLiver:62/f,lung:

54/f

35/m

32/f

47/f

42/f

Reference(PMID)

1254

6616

19424047

11753913

Liver:21668638,

lung:22172896

9297112

24919754

21766079

1892

6410

Refe

renc

ePhanetal(ref10)

Vagefietal(ref9)

Trot

ter e

t al

(ref7)

Dewachteretal

(ref5),Schuller

etal(ref4)

Legendreetal

(ref3)

Berryetal(ref6)

Bhinderetal(ref11)

Khalidetal(ref8)

MMF,mycophenolatemofetil;PMID,PubmedID;POD,postoperativeday;POM,postoperativemonth;POW,postoperativeweek;Tx,transplantation.

TAB

LE 1

 (Continued)

     |  5MULLER Et aL.

TAB

LE 2

 Baselineclinicaldataoftherecipients.AtopicstatuswasassessedbythepresenceofspecificIgEagainst,pollen,animaldander,orhousedustsmitesusingcommercialprotein

microarraybearingrecombinantallergenicmolecules(ISAC)

Reci

pien

ts o

rgan

Don

orBa

selin

e di

seas

eA

topi

c st

atus

Age

at T

x (y

)In

duct

ion

imm

unos

uppr

essi

onM

aint

enan

ce im

mun

osup

‐pr

essi

on (6

mo)

Mai

nten

ance

im‐

mun

osup

pres

sion

(1

2 m

o)

Heart

1(peanut)

Dilatedcardiomyopathy(anthracycline-

inducedsarcoma)

Negative

11ATG,Glucocorticoids,

TAC,MMF

TAC,MMF,Glucocorticoids

TAC,MMF,

Glucocorticoids

Lung

1(peanut)

Cysticfibrosis

Posi

tive

25Basiliximab,CsA,MMF,

Glucocorticoids

TAC,MPA,Glucocorticoids

TAC,MPA,

Glucocorticoids

Liverleft

1(peanut)

Bilia

ry a

tres

iaPo

sitiv

e1

Basiliximab,

Glucocorticoids,TAC

Glucocorticoids,TAC

TAC

Liverright

1(peanut)

Primarybiliarycholangitis

Posi

tive

17Basiliximab,TAC,MMF

TAC,MMF

TAC,MMF

Kidneyleft

1(peanut)

Hypertension/renovascular

glom

erul

oscl

eros

isNegative

76Thymoglobulin,TAC,

MMF,Glucocorticoids

TAC,MMF,Glucocorticoids

TAC,MMF,

Glucocorticoids

Lung

2(wasp)

Cysticfibrosis

Posi

tive

20Basiliximab,TAC,MMF,

Glucocorticoids

TAC,MMF,Glucocorticoids

TAC,MMF,

Glucocorticoids

Kidneyleft

2(wasp)

Glomerulonephritis/vasculitis

Negative

58Basiliximab,TAC,MMF,

Glucocorticoids

Basiliximab,TAC,MMF,

Glucocorticoids

Basiliximab,

TAC,MMF,

Glucocorticoids

Heartandkidney

3(peanut)

Ischemicheartdisease,Hypertension/

reno

vasc

ular

glo

mer

ulos

cler

osis

Negative

49ATG,Glucocorticoids,

CsA,MMF

Glucocorticoids,CsA,MMF

Glucocorticoids,

CsA,MMF

Liver(left)

3(peanut)

Sclerosingcholangitis

Negative

5Basiliximab,TAC,

Glucocorticoids

TAC,MMF

TAC,MMF

Kidneypancreas

3(peanut)

Diabeticnephropathy(type1DM)

Negative

49Thymoglobulin,TAC,

MPA,Glucocorticoids

TAC,MPA

TAC,MPA

CsA,cyclosporine;DM,diabetesmellitus;MMF,mycophenolatemofetil;MPA,mycophenolicacid;TAC,tacrolimus;TX,transplantation.

6  |     MULLER Et aL.

found, a serologicalmarker that can be associatedwith severeallergic reactions tokiwi.16However, the serological analysisofthe3recipientsofthisdonor(ie,pancreas-kidney,heart-kidney,andliver)showednopeanutandkiwiIgEat6months’posttrans-plantation. Interestingly,thedonorwasalsohighlysensitizedtoanimals (rCanf1:87 ISU-E, rCanf5 46 ISU-E, rEqu c1: 19 ISU-E),ash/olivepollen(rOlee129ISU-El),andmites(rDerp136ISU-E),incontrasttotherecipients inwhomnoneofthesespecific IgEweredetected.Notably,noneoftherecipientswasatopiceither(basedonserology).Inthiscase,akiwi-inducedanaphylaxiscouldnotbeexcluded,emphasizingtheimportanceofassessingtheal-lergyprofileofthedonoratthetimeoftransplantation.

3.4 | Diagnosis of IgE sensitization early after transplantation

Sofar, it remainsunclearwhether IgEandallergytransferareaf-fected by the immunosuppressive therapy. Also, the importantquestionaboutwhetherdetectionof IgEsensitization ispossibleearly after transplantation is unanswered.17 The overall numberofIgEsensitizationsofall5atopicrecipientsremainedunchanged

within the first 6 months after transplantation (Figure 1E). Wethereforedecidedtostudytheimpactofimmunosuppressivether-apyonIgEandallergymaintenance.Tothispurpose,weperformeda prospective follow-up analysis on5 symptomatic patientswithpre-existing allergic rhinoconjunctivitis undergoing living donorkidneytransplantation.Noneofthepatientshadbeentreatedwithantihistamines at the time of transplantation. All 5 patients re-ceived a standard induction and maintenance immunosuppressive therapywithbasiliximabandmethylprednisolonefollowedbyoraltacrolimus, prednisone, and mycophenolate mofetil (Figure 2A).SPTandserological analysiswereperformedbefore,7days, and3monthsafter transplantation, respectively.Surprisingly, the im-munosuppressivetherapyonlymoderatelyaffectedtheskintests(SPT)results7daysaftertransplantation(Figure2B,C)andhadnoimpactonthespecificandtotal IgE levels (Figure2D,E).Twenty-twoof23and21/23ofSPTremainedpositive7daysand3monthsafter transplantation, respectively.Finally, the rhinoconjunctivitisscore (dailynasal andeye symptomsusinga4-point scale:none,mild,moderate,andsevere)beforeand3monthsaftertransplanta-tiondidnot showa significant improvement (Figure2F).Overall,theseresultsindicatethatIgEsensitizationisweaklyaffectedearly

F I G U R E 1  Allergytransferanalysisindonorandrecipients.A,Overviewof3seriesofdonorswhodiedbecauseoffatalanaphylaxis.GreenchartsshowpatientswithIgEtransferandredchartspatientswithoutdetectableIgEtransfer.Dashedlineshighlightrecipientswithpositiveoralchallenge.§showsatopicrecipients.AtopicstatuswasassessedbythepresenceofspecificIgEagainst,pollen,animaldander,orhousedustmitesusingcommercialproteinmicroarraybearingrecombinantallergenicmolecules(ISAC).B,DonorsseraanalysiswithISAC.GreenrecombinantIgEhighlightsthosewhoweretransferredintorecipients(leftYaxis).Yellowbars(rightYaxis)representthetryptase(ng/mL)measuredindonorsduringtheirhospitalization.C,IgEfollow-upovertimeinrecipients(liverrecipient1[LiverR1],liverrecipient2[LiverSplitR2],lungrecipient[LungR3])ofseries1comparedtodonor.D,PercentageofatopicrecipientswithorwithoutIgEtransfer.E,Absolutenumberofsensitizationsbeforeand6monthsaftertransplantationinallatopicrecipients(series1-3)

     |  7MULLER Et aL.

after transplantation and canbedetectedbasedon SPT and IgEserologiesdespiteimmunosuppressivetherapy.

4  | DISCUSSION

4.1 | Mechanisms of allergy transfer after SOT

Asreviewedintheliterature(Table1),allergytransferwasdem-onstrated after liver, lung, andpancreas transplantation, but sofar not in heart and kidney recipients alone. One could there-fore speculate that allergy transfer is a donor organ–specificphenomenon.Interestingly, inthecaseseriesreportedbyBerryet al, allergy transfer occurred in thepancreas-kidney recipientbut not in the recipient of an isolated kidney, possibly becauseof thecotransplantationofa smallbowelportion togetherwiththepancreas.6Thesedatasuggestthatkidneyandhearttissuesare less likely to contain sufficient IgG1-memory B cells (IgG1-MBcs)and/orIgE-producingBcells(IgE-Bcs)(Figure3).Thus,the

majorityofallergen-specific IgE in theblooddoesnotoriginatefromblood-derivedB/plasmacells,suggestingthatlocalIgEpro-ductionintissuesisindeedthemajorsourceofallergen-specificIgE.18Furthermore, it isknownthatpersistenceofsometissue-resident T cell clones can be organ-specific (ie, influenza-spe-cificCD8+Tcellsarepredominantlyfoundinthelungswhereashepatitis-specific CD8 are predominantly found in the liver).19 ThefactthatplasmaticIgEcanbedetectedasearlyas24hoursafter transplantation and that it persists up to severalmonths/years suggests that the primarymechanism lies in the transferofIgE-producingcellsratherthaninpassivetransferofIgEonly,becausethehalf-lifeoffreecirculatingIgEisknowntobeonly2to 4 days.20 Interestingly, several groups reported positive SPTwithoutelevationofbloodIgE,suggestingthatIgEalonecanbealso passively transferred and secondarily binds tomastocytes,which increases IgEhalf-life (Table1andFigure3).21Thus,SPTandIgEserologicalanalysiscanbecomplementaryinthediagno-sis of allergy transfer.

F I G U R E 2  Allergypersistencein5symptomaticatopicpatients.A,Immunosuppressionprotocolofthe5recipientsovertime.B,Representativeskinpricktestresults7daysaftertransplantationin1oftherecipients.C,Areasinmm2ofthepositiveskinprickteststhedaybeforetransplantation7and90daysaftertransplantation.D,LeveloftotalIgEovertime(daybeforetransplantation,7and90daysaftertransplantation).E,LevelofrecombinantIgEovertime(daybeforetransplantation,7and90daysaftertransplantation).F,Rhinoconjunctivitissymptomsscorebeforeand90daysaftertransplantation

8  |     MULLER Et aL.

4.2 | Persistence of sensitization and allergy

The persistence of sensitization after allergy transfer in SOT re-cipientsovertime ispoorlyunderstood. Inourseries,LiverR1haddetectable IgE for >393 days (Figure 1C), which turned negative2yearsafter transplantation,whereas inLiverSplitR2peanut-spe-cific IgEwerepositivefor<53days.LiverR1receivedanextendedlivergraftandeventuallyincreasednumberofpassengerleukocytes,butontheotherhandLiverSplitR2hasneverbeenexposedtopea-nut before peanut-specific IgE levels turned negative. Thus, earlyexposure to allergen after SOTmay lead to expansionof IgE-Bcs,

or alternatively switch from IgG1-MBcs into IgE-producing cells22 (Figure3).

Interestingly, in lung transplant recipients, allergy transferseems to persist longer than in liver recipients (Table 1), proba-blyduetothehighamountof immunecells inhumanlungtissueincluding 100 000 mast cells per gram of tissue.21Khalidetalre-ported a lung recipient who developed an acute asthma attackwithout other symptoms of anaphylaxis 7 years after transplan-tationuponexposuretopeanutswithnegativeSPTandnegativepeanut-specificIgE(Table1,Series8).Thiscorroboratesolderdatashowingthatpreviouslynonasthmaticrecipientscanbecomeasth-maticafterlungtransplantationfrommildlyasthmaticdonors.23

Finally,resultsfromhematopoieticstemcelltransplantationsug-gest thatmaturedTh2-likecellsorhematopoieticprogenitor stemcells are also sufficient to induce and maintain long-term allergytransferfor(more)than16years.24Thus,durationandpersistenceofthetransferredallergystatusovertimemaydependontheorgantransplantedandmechanismsofallergytransfer.

4.3 | Immunosuppression and allergy

Importantly,ourdataandthatofothers(Table1) indicatethattheconventionalimmunosuppressiondoesnotaffectIgE-sensitization.This finding isnot surprisingsincedonor-specific IgG-producingBcellscanmediateacuteand/orchronicallograftrejection,whichare2 conditions that are associatedwith limited response to therapydespite several lines of treatments.25,26Interestingly,itisalsoknownthatIgG-producing“passengerlymphocytes”canmediateacutehe-molysisor idiopathic thrombocytopenicpurpurawithin the first2weeksafterlivertransplantation.27-29

It has been previously shown that sensitization and allergysymptoms inchildrenafterSOTmightnotbecontrolledby immu-nosuppression.Onthecontrary,therateofsensitizationinpatients

F I G U R E 3  Mechanismsforallergytransfer.IgE,immunoglobulinE;MC,mastocyte;IgE-Bcs,IgE-producingBcells;Th,Thelpercells;IgG1-MBcs,IgG1memoryBcells

F I G U R E 4   Recommendation for patient management in case of solid organtransplantationfromdonorswhodiedbecauseoffatalanaphylaxis.IgE,immunoglobulinE

     |  9MULLER Et aL.

treatedwithtacrolimuswasevenincreased.30,31Ourdatafromthe5 living-donor kidney recipients with allergic rhinoconjunctivitissupporttheobservationthatdiagnosisofdonor-derivedIgEsensi-tizationbasedonIgEandSPTispossibleearlyaftertransplantationdespiteanimmunosuppressiveregimenbasedonbasiliximabinduc-tion,methylprednisolone/prednisone, tacrolimus, andmycopheno-latemofetilasmaintenancetreatment.FurtherstudiesassessingtheimpactonSPTandIgEofothercommonlyusedimmunosuppressivedrugs(ie,thymoglobulin,azathioprine,orrapamycin)arewarranted.

4.4 | Management and patient care

Insummary,increasedattentionhastobegiventotheriskofallergytransferafterSOT.Unfortunately,theexactfrequencyandclinicalconsequences of IgE transfer remain poorly understood becausetheallergy/atopystatusofthedonorsandrecipientsarerarelycon-sequently assessed. This is a limitation of the present study, be-causewe focusedondonorswith fatalanaphylaxisonly. Incasesofpossibleorprobablefatalanaphylaxis,specificIgEtestinginthedonorshouldbeperformedas1of the first-line investigations toevaluatethepossibilityofallergytransfer(Figure4).Asdonorswithahistoryofsevereallergymaydieofotherreasonsthananaphy-laxis (Table1),wewouldalsosuggest tocarefullyexplorehistoryofsevereallergicreactiontofood,hymenopteravenom,anddrugswiththefamilyofthedonor,albeitconciserecommendationsinthissettingaredifficulttoimplementinlightofourcurrentknowledge.

Regarding the recipients of organ donors with fatal anaphy-laxis,thosereceivingaliver,lung,andpancreasshouldbecloselymonitored after transplantation. Furthermore,weencourage ini-tiallycheckingtheatopicstatusoftherecipientbyusingaqualita-tiveserologicalscreeningtest(eg,Phadiatop)andmeasurementoftotalIgE,becauseatopicpatientsmaybeatahigherriskofallergytransfer. Strict avoidance of eliciting food allergens is stronglyadvisedandemergencymedication (including self-injectableepi-nephrinedevice)shouldbeprescribed.Adetailedallergywork-upaswellasfollow-upofthesensitizationprofileisimportant.Incaseofdonor-derivedIgEsensitizationtransfer,SPTandIgEshouldbemonitored over time. Food challenge should only be consideredwhenSPTandIgEhaveturnednegative(Figure4)orincasesoflowpersisting food-specific IgEswhen IgEs to recombinantallergensknowntoinducesevereanaphylaxisarebelowthethresholdlevel.

Inconclusion,wedemonstratethatSPTandIgEanalysiscanbeperformedasearlyas7daysaftertransplantation.Therefore,post-poning theallergological investigation isunnecessary.Prescriptionofantihistaminesshouldbeomittedinanycase7dayspriortoSPTas per standard recommendation.17 Finally, goodmedical practicewouldincludeafoodchallengetoprovetolerance(Figure4).

ACKNOWLEDG MENTS

We would like to thank all the physicians, nurses, pharmacists,and laboratory technicians involved in themanagementof thepa-tients and all the colleagueswhohelped in collecting information

relevanttothiswork.Thisstudyhasbeenconductedintheframe-workoftheSwissTransplantCohortStudy,supportedbytheSwissNational Science Foundation and the Swiss University Hospitals(Unimedsuisse) and their respective transplant centers, and Swisstransplant.

DISCLOSURE

Theauthorsofthismanuscripthavenoconflictsofinteresttodis-closeasdescribedbytheAmerican Journal of Transplantation.

DATA AVAIL ABILIT Y S TATEMENT

Thedatathatsupportthefindingsofthisstudyareavailableonre-questfromthecorrespondingauthor.Thedataarenotpubliclyavail-ableduetoprivacyorethicalrestrictions.

ORCID

Yannick D. Muller https://orcid.org/0000-0003-0513-7156

Thierry Berney https://orcid.org/0000-0002-4230-9378

R E FE R E N C E S

1. TurnerPJ,GowlandMH,SharmaV,etal. Increase inanaphylaxis-relatedhospitalizationsbutnoincreaseinfatalities:ananalysisofUnited Kingdom national anaphylaxis data, 1992–2012. J Allergy Clin Immunol. 2015;135(4):956-963.e1. https://doi.org/10.1093/annonc/mdw013.

2. AgostiJM,SprengerJD,LumLG,etal.Transferofallergen-specificige-mediatedhypersensitivitywithallogeneicbonemarrowtrans-plantation. N Engl J Med. 1988;319(25):1623–1628. https://doi.org/10.1056/NEJM198812223192502.

3. LegendreC,Caillat-ZucmanS,SamuelD,et al.Transferof symp-tomaticpeanutallergytotherecipientofacombinedliver-and-kid-ney transplant. N Engl J Med.1997;337(12):822–825.

4. Schuller A, Barnig C, Matau C, et al. Transfer of peanut allergyfollowing lung transplantation: a case report. Transplant Proc. 2011;43:4032-4035.

5. DewachterP,VézinetC,Nicaise-RolandP,etal.Passivetransienttransferofpeanutallergybylivertransplantation.Am J Transplant. 2011;11:1531-1534.

6. BerryA,CampsenJ,ShihabF,FirsztR.TransferofpeanutIgEsensi-tisationaftercombinedpancreas-kidneytransplant.Clin Exp Allergy. 2014;44:1020-1022.

7. Trotter JF, Everson GT, Bock SA, Wachs M, Bak T, Kam I.Transferenceofpeanutallergythroughlivertransplantation.Liver Transpl.2001;7:1088-1089.

8. KhalidI,ZorattiE,StagnerL,BetensleyAD,NemehH,AllenspachL.Transferofpeanutallergy from thedonor toa lung transplantrecipient. J Heart Lung Transplant.2008;27:1162-1164.

9. Vagefi PA, Blazick E, Hamilos D, Ades A, Cosimi AB, Hertl M.Transference of food allergy after adult liver transplantation. Transplantation.2009;87:1426.

10. PhanTG,StrasserSI,KooreyD,etal.Passivetransferofnutallergyafter liver transplantation. Arch Intern Med.2003;163:237-239.

11. BhinderS,HefferMJ,LeeJK,ChaparroC,TarloSM.Developmentof transient peanut allergy following lung transplantation: a casereport. Can Respir J.2011;18:154-156.

10  |     MULLER Et aL.

12. KollerMT,vanDeldenC,MüllerNJ,etal.Designandmethodol-ogyoftheSwissTransplantCohortStudy(STCS):acomprehensiveprospectivenationwidelong-termfollow-upcohort.Eur J Epidemiol. 2013;28:347-355.

13. Kukkonen AK, Pelkonen AS, Mäkinen-Kiljunen S, Voutilainen H,MäkeläMJ. Ara h 2 andAra 6 are the best predictors of severepeanut allergy: a double-blind placebo-controlled study. Allergy. 2015;70:1239-1245.

14. GoldbergA,Confino-CohenR.TimingofvenomskintestsandIgEdeterminationsafterinsectstinganaphylaxis.J Allergy Clin Immunol. 1997;100:182-184.

15. CastellsM.Diagnosisandmanagementofanaphylaxisinprecisionmedicine. J Allergy Clin Immunol.2017;140:321-333.

16. BublinM,PfisterM,RadauerC,etal.Component-resolveddiagno-sisofkiwifruitallergywithpurifiednaturalandrecombinantkiwi-fruit allergens. J Allergy Clin Immunol.2010;125(687–694):694.e1.

17. BachertC,JorissenM,BertrandB,KhaltaevN,BousquetJ.Allergicrhinitisanditsimpactonasthmaupdate(ARIA2008).TheBelgianperspective. B‐ENT.2008;4:253-257.

18. Eckl-Dorna J, Pree I, Reisinger J, et al. The majority of aller-gen-specific IgE in the blood of allergic patients does not orig-inate from blood-derivedB cells or plasma cells.Clin Exp Allergy. 2012;42:1347-1355.

19. KumarBV,ConnorsTJ,FarberDL.HumanTcelldevelopment,local-ization,andfunctionthroughoutlife.Immunity.2018;48:202-213.

20. DreskinSC,GoldsmithPK,StroberW,ZechLA,GallinJI.MetabolismofimmunoglobulinEinpatientswithmarkedlyelevatedserumim-munoglobulinElevels.J Clin Invest.1987;79:1764-1772.

21. ColemanJW,GodfreyRC.ThenumberandaffinityofIgEreceptorsondispersedhumanlungmastcells.Immunology.1981;44:859-863.

22. HeJ-S,SubramaniamS,NarangV,etal.IgG1memoryBcellskeepthememoryofIgEresponses.Nat Commun.2017;8:641.

23. CorrisPA,DarkJH.Aetiologyofasthma:lessonsfromlungtrans-plantation. Lancet.1993;341:1369-1371.

24. KhanF,HallstrandTS,GeddesMN,HendersonWR,StorekJ.Isal-lergicdiseasecurableortransferablewithallogeneichematopoieticcell transplantation. Blood.2009;113:279-290.

25. MullerYD,AubertJ-D,VionnetJ,etal.Acuteantibody-mediatedrejection 1 week after lung transplantation successfully treatedwith eculizumab, intravenous immunoglobulins, and rituximab.Transplantation.2018;102:e301-e303.

26. MullerYD,GhalebN,RotmanS,etal.Rituximabasmonotherapyforthetreatmentofchronicactiveantibody-mediatedrejectionafterkidneytransplantation[letter].Transpl Int.2018;31(4):451-455.

27. RamseyG,NusbacherJ,StarzlTE,LindsayGD.IsohemagglutininsofgraftoriginafterABO-unmatchedlivertransplantation.N Engl J Med.1984;311:1167-1170.

28. NadarajahL,AshmanN,ThuraisinghamR,BarberC,AllardS,GreenL. Literature review of passenger lymphocyte syndrome follow-ing renal transplantation and two case reports. Am J Transplant. 2013;13:1594-1600.

29. FriendPJ,McCarthy LJ, Filo RS, et al. Transmission of idiopathic(autoimmune)thrombocytopenicpurpuraby livertransplantation.N Engl J Med.1990;323:807-811.

30. Dehlink E,Gruber S, Eiwegger T, et al. Immunosuppressive ther-apydoesnotprevent theoccurrenceof immunoglobulinE-medi-atedallergies inchildrenandadolescentswithorgan transplants.Pediatrics.2006;118:e764-e770.

31. Lebel MJ, Chapdelaine H, Paradis L, Des Roches A, Alvarez F.Increase in de novo food allergies after pediatric liver transplan-tation: tacrolimus vs. cyclosporine immunosuppression. Pediatr Transplant.2014;18:733-739.

How to cite this article:MullerYD,VionnetJ,BeyelerF,etal;theSwissTransplantCohortStudy.Managementofallergytransfer upon solid organ transplantation. Am J Transplant. 2019;00:1–10. https://doi.org/10.1111/ajt.15601

APPENDIX The members of the Swiss Transplant Cohort Study are: PatriziaAmico, John-David Aubert, Vanessa Banz, Guido Beldi, ChristianBenden, Christoph Berger, Isabelle Binet, Pierre-Yves Bochud,SandaBranca,HeinerBucher, ThierryCarell, EmmanuelleCatana,YvesChalandon,SabinadeGeest,OlivierdeRougemont,MichaelDickenmann,Michel Duchosal, Laure Elkrief, Thomas Fehr, SylvieFerrari-Lacraz,ChristianGarzoni,PaolaGascheSoccal,ChristopheGaudet, Emiliano Giostra, Déla Golshayan, Karine Hadaya, JörgHalter,DimitriHauri,DominikHeim,ChristophHess,SvenHillinger,HansH.Hirsch,GüntherHofbauer,UyenHuynh-Do,FranzImmer,RichardKlaghofer,MichaelKoller(Headofthedatacenter),BettinaLaesser, Guido Laube, Roger Lehmann, Christian Lovis, PietroMajno;OriolManuel,Hans-PeterMarti,PierreYvesMartin,MicheleMartinelli, Pascal Meylan, (Head, Biological samples managementgroup), Philippe Morel, Nicolas J. Mueller (Chairman ScientificCommittee),AntoniaMüller,ThomasMüller,BeatMüllhaupt,ManuelPascual (Executive office), Jakob Passweg, Klara Posfay-Barbe,Juliane Rick, Eddy Roosnek, Anne Rosselet, Silvia Rothlin, FrankRuschitzka,UrsSchanz,StefanSchaub,AureliaSchnyder,ChristianSeiler,JanSprachta;SusanneStampf,JürgSteiger(Head,ExecutiveOffice), Guido Stirnimann, Christian Toso, Christian Van Delden(ExecutiveOffice),Jean-PierreVenetz,JeanVillard,MadeleineWick(STCScoordinator),MarkusWilhelm,PatrickYerly.