Non-Steroidal Anti-Inflammatory Drug Hypersensitivity in Children

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www.elsevier.es/ai

Allergologia

et

immunopathologia

SociedadEspa˜nola deInmunolog´ıaCl´ınica,

Alergolog´ıayAsmaPedi´atrica

ORIGINAL

ARTICLE

Non-steroidal

anti-inﬂammatory

drug

hypersensitivity

in

children

C. Alves

a_,_∗

_,

_A.M.

_Romeira

a

_,

_C.

_Abreu

b

_,

_P.

_{Carreiro-Martins}

a_,c

_,

E. Gomes

b

_,

_P.

_Leiria-Pinto

a_,c

a_Dona_Estefânia_Hospital,_Centro_Hospitalar_de_Lisboa_Central,_Rua_Jacinta_Marto,_1169-045_Lisbon,_Portugal b_Centro_Hospitalar_do_Porto,_Largo_Prof._Abel_Salazar,_4099-001_Oporto,_Portugal

c_CEDOC,_Respiratory_Research_Group,_Nova_Medical_School,_Campo_dos_Mártires_da_Pátria,_130,_1169-056_Lisbon,_Portugal

Received13January2016;accepted1April2016 Availableonline27July2016

KEYWORDS Allergy; Children; Drugprovocation test; Hypersensitivity; NSAID Abstract

Introduction:There are rather few publications about hypersensitivity reactions to non-steroidal anti-inflammatorydrugs (NSAID) inthepaediatric age.In this study,we aimedto assessthefrequencyofconfirmedNSAIDhypersensitivityinchildrenwithapreviousreported reactiontoNSAID inordertoinvestigate therole ofthedrug provocationtest (DPT)inthe diagnosticworkupandtoexplorethefactorsassociatedwithconfirmedNSAIDhypersensitivity.

Methods:Weconductedaretrospectiveanalysisoftheclinicalﬁlesfromeverypatientunder 18yearsoldwhoattendedtwoPortuguesepaediatricallergyoutpatientclinics,fromJanuary 2009toAugust2014,duetoasuspectedNSAIDhypersensitivity.

Results:Weincluded119patients,withamedianageofnineyears(P25---P75:5---14).Ibuprofen

wasthecommonestimplicatedNSAIDinthepatients’reports(n=94---79%).AfterDPT,NSAID hypersensitivitywasconfirmedinnine(7.6%)patients,excludedin93(78.2%)andwas incon-clusivein17(14.3%).Inthemajority(n=95---79.8%),thereactionoccurredinthefirst24hafter intake.Eighty-fourpatients(70.6%)reportedonlycutaneousmanifestationsand18(15.1%)had systemicsymptoms.AnaphylaxisrepresentedarelativerisktoNSAIDhypersensitivity confirma-tion.Noassociationwasfoundforatopyandthenumberofpreviousreactions.

Conclusion:In ourstudy,NSAID hypersensitivitywas confirmedinasmall proportionofthe patients with a previous reported reaction. Ibuprofen was the most implicated drug with urticaria/angio-oedemaasthecommonestmanifestation.Anaphylaxiswasassociatedwith con-firmeddrughypersensitivity.Thedrugprovocationtestwasessentialtoestablishthediagnosis. ©2016SEICAP.PublishedbyElsevierEspaña,S.L.U.Allrightsreserved.

∗_{Corresponding}_author.

E-mailaddress:catia@catia-alves.net(C.Alves).

http://dx.doi.org/10.1016/j.aller.2016.04.004

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Introduction

Non-steroidalanti-inﬂammatorydrugs(NSAID)areawidely

used group of medications withantipyretic and analgesic

properties. This leads to frequent reports of

hypersensi-tivity reactions to NSAIDs (NSAID-H) by adults as well as

children.Thereportedprevalenceofhypersensitivity

reac-tionstoNSAIDsinthegeneralpopulationis0.3%inadults,

withsimilarresultsinchildren.1_In_Portugal,_the_prevalence

ofself-reportedNSAID-Hwas0.5%amongchildrenattending

day-carecentres.2

Apreviousstudy,whichwasperformedinPortugalamong

children,showedthat,althoughadversedrugreactionsare

frequently described in this population, after a thorough

investigation,atruedrughypersensitivitywillbeconﬁrmed

inonlyafewcases.3

In patients evaluated due to a possible NSAID-H, the

investigation conﬁrmed this suspicion in a minority of

them.4,5 _The _drug _provocation _test _(DPT) _with_the _culprit

drug is considered the gold standard to diagnose NSAID

hypersensitivity.6,7_The_prevalence_of_{immunologically}

medi-atedreactionstoNSAIDsrangesfrom0.1%to3.6%.8

There are rather few studies in the paediatric

popu-lation regarding NSAID hypersensitivity reactions. Atopy,

immediate-typereactions or respiratorysymptomsas

pre-viousmanifestationshavebeenidentiﬁedasriskfactorsby

someauthors.5

The aim of our study was to assess the frequency of

conﬁrmed NSAIDhypersensitivity in childrenwith a

previ-ousreportedreaction toNSAID,toinvestigate theroleof

the drug provocation test (DPT) in the diagnostic workup

andtoexplorethefactorsassociatedwithconﬁrmedNSAID

hypersensitivity.

Methods

Studydesign,settingandparticipants

We conductedaretrospective analysisof theclinical ﬁles

fromevery patient under18 years oldwho attendedtwo

PortugueseImmunoallergyDepartments(oneinLisbonand

anotherinOporto),fromJanuary2009toAugust2014,due

toasuspectedNSAIDhypersensitivity.

The participating centres were the Immunoallergy

DepartmentofDonaEstefâniaHospital,CHLC,inLisbonand

theImmunoallergyDepartmentof MariaPiaHospital,CHP,

inOporto,whicharethetwomainpublicpaediatricallergy

centresinPortugal.

Datacollection

Datawasretrospectivelycollectedbyastandardised

ques-tionnaire in order to gather information about NSAID

reactions and diagnostic test results. Inboth allergy

cen-tres, the usual diagnostic workup includes a ﬁrst clinical

assessmentofthereportedreactionfollowedbyaDPT.

The standardised questionnaire comprised questions

regarding the chronology of the reaction (acute --- if the

reactionoccurredintheﬁrst24haftertheintake;delayed

--- if it occurred after 24h),7,8 _implicated _drugs, _clinical

presentation,numberofpreviousreactions,ageatthetime

of the ﬁrst reaction, drug provocation test result, atopic

status(deﬁnedasatleastonepositiveskinpricktest---SPT

---to aero/foodallergens) and previous diagnosis of

aller-gicdiseases(asthma,atopiceczema,allergicrhinitis,food

allergyandchronicurticaria).Anaphylaxiswasdeﬁnedasa

severe,life-threateninggeneralisedorsystemic

hypersensi-tivityreaction,accordingtotheliterature.9

Drugprovocationtest

Iftherewasnocontraindication,7,8,10_NSAID_provocation_test

wasperformedtoconﬁrmorexcludethepresenceof

hyper-sensitivityandtoclassifythereaction.

OpenDPTs wereconducted byan experiencedallergist

according to the recommendations of the ENDA

(Euro-peanAcademyofAllergologyandClinicalImmunologyDrug

Hypersensitivity Interest Group).10 _The _diagnostic

work-up included single-blind, placebo-controlled DPT if the

reportedsymptomsweresubjectiveoriftheopenDPT

per-formed ended in an unclear result. Incremental doses of

thedrugwereadministratedatintervalsof30---60min,

stop-pingassoonastheﬁrstobjectivesymptomsoccurredorat

theendoftheintakeofthedeﬁneddosesoftheprotocol.

Theﬁrstadministrationwasusually1/10of the

therapeu-ticdose, according to the weightand age, and the total

cumulativedosewassimilartotheusualmaximalindividual

intakedose (adjusted toweight and age).Symptoms and

vitalsigns weremonitored before, duringand at the end

oftheDPT.Threehourswastheminimalperiodof

surveil-lanceafterthelastdrugadministration.Written informed

consentwasobtainedfromtheparentsorguardiansbefore

theprocedure.

TheDPTwasconsideredpositiveifitreproducedthe

pre-viousreportedreactionorelicitedobjectivemanifestations.

ANSAID-Hconﬁrmation wasassumed whenthepatient

hadapositiveDPTwiththeimplicatedoralternativeNSAID.

ANSAID-HwasexcludediftheDPTwiththeimplicateddrug

wasnegative.Theinvestigationwasconsideredinconclusive

whenDPTwasnegativewiththealternativeNSAIDbutaDPT

withtheculpritNSAID wasnotperformed (in thiscase, a

singleNSAID-Hcannotbeexcluded),orwhenaDPTwasnot

performedatall(duetotheparent’srefusal).

Statisticalanalysis

Anexploratoryanalysisofthevariablesofinterest(gender,

age,presenceofatopyandallergicconditions,typeofdrug,

manifestationsandchronology,NSAIDtolerance)wascarried

out.TheMann---WhitneyUtestwasusedforcomparisonsof

differencesbetweenmedians.Achi-squaredtest orFisher

ExactTestwasusedtocomparethecategoricalvariables.

Thelevelofsigniﬁcanceconsideredwas˛=0.05.Statistical

analysiswasperformedusingIBMSPSSStatisticsVersion23®

(NewYork,USA).

Results

Weincluded119children,51.3%boys,withamedianageof

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Table1 Demographiccharacteristicsofpatientsand clin-icalmanifestationsofthereportedreaction.

Numberofpatients

Gender

Male 61(51.3%)

Female 58(48.7%)

Medianage(years) 9.0(P25---75---5---14)

Atopy 53(44.5%) Allergicdiseases Rhinitis 58(48.7%) Asthma 46(38.7%) Atopiceczema 8(6.7%) Chronicspontaneous urticaria 4(3.4%) Foodallergy 3(2.5%) HistoryofDHR

WithasingleNSAID 111(93.3%) WithmultipleNSAID 8(6.7%)

Historyofreportedreactions

Onereaction 72(60.5%) Twoormorereactions 47(39.5%)

ChronologyofDHRaccordingtohistory

Acute 102(85.7%) Delayed 2(1.7%) Donotrecall 15(14.7%) Symptoms Mucocutaneous 84(70.6%) Urticaria/Urticariaand Angio-oedema 49 Angioedema/Facialor periorbitaloedema 35 Maculopapularexanthema 27 Others 6 Respiratory 12(10.1%) Bronchospasm,cough, wheezing 12 Gastro-intestinal 5(4.2%) Vomiting 5 Diarrhoea 1 Systemic 18(15.1%) Malaise/pallor/dizziness 1 Anaphylaxis 17

DHR---drughypersensitivityreaction;NSAID---non-steroidal anti-inﬂammatorydrug.

60.5%hadapreviousdiagnosisofallergicdiseases. Accord-ingtotheclinicalreports,111patients(93.3%)describeda reactiontoasingleNSAID(Table1).

Priortotheinvestigation,70(58.8%)patientshadproven

tolerability to at least one alternative NSAID (which was

veriﬁedafterthereportedreaction--- thepatienttookan

alternativeNSAIDafterthereportedreactionbutprevious

tothisinvestigation):60(85.7%)referredtoleranceto

para-cetamol,eight(11.4%)toacetylsalicylic acid(ASA), three

(4.3%) to metamizole, two (2.9%) to ibuprofen and one

(1.4%)tonimesulide.

Table2 NumberofpatientsandsuspectedNSAIDinvolved. ImplicatedNSAID Numberofpatients

Ibuprofen 94 Paracetamol 20 ASA 7 Nimesulide 4 Metamizol 1 Etoricoxib 1 Ketorolac 1

NSAID---non-steroidalanti-inﬂammatorydrugs;ASA--- acetylsal-icylicacid.

Inoursample,47(39.5%)patientsreportedtwoormore previousreactions(41withthesamedrugandsixwith dif-ferentNSAID)(Table1).

Parentsreported a previous adverse reaction toother

drugclassin24(20%)ofthechildren,mostlytoantibiotics

(n=17).

At the time of the ﬁrst reported reaction, 84 (70.6%)

patientshadonly mucocutaneousmanifestationsafterthe

intake of the implicated NSAID, 18 (15.1%) had systemic

symptoms(17anaphylaxis),12(10.1%)hadisolated

respira-torymanifestationsandﬁve(4.2%)referredgastrointestinal

symptoms(Table1).

ThemostcommonimplicatedNSAIDinthepatients’

reac-tionreportswasibuprofen(N=94;79%)(Table2).

Thecharacteristics oftheﬁrstreactionand theresults

oftheinvestigationperformedinthepatientswhoreported

anaphylaxisaredetailedinTable3.

TheDPTdiagramispresentedinFig.1.Inoursample,99

(83.2%)patientswerechallengedwiththeimplicatedNSAID

(positiveinﬁveDPT)and19(16%)withanalternativeNSAID

duetoseverityofthereactions/patientrefusal(positivein

four).OnepatientrefusedtheDPTwiththeimplicateddrug

ashealreadyhadaknowntolerancetoanalternativeNSAID.

ThepresenceofNSAIDhypersensitivitywasconﬁrmedin

ninepatients (7.6%)(Table4),excluded in93 (78.2%)and

inconclusivein17(14.3%)patients.

Oftheninepatientswithproven NSAID-H,seven hada

previous diagnosis of an allergicdisease (ﬁveatopic,

sen-sitised to house dust mites). Of the 93 patients without

NSAID-H,30hadconﬁrmedsensitisationtohousedustmites.

Patientswith conﬁrmed hypersensitivity were older at

the time of the ﬁrst reaction (p=0.008) than patients in

which NSAID-H was excluded. A reported history of

ana-phylaxiswasassociatedwithconﬁrmedNSAID-H(p=0.029)

(RR=5.48,95%CI1.69---17.8,p=0.0047).Nostatistically

sig-niﬁcantdifferenceswerefoundforasthma,urticaria,atopy

andanumberofpreviousreactions.However,patientswith

asthmaorrhinitispresentedahigherfrequencyofconﬁrmed

NSAID-H(11.9%versus6.7%forasthmaand14%versus3.8%

forrhinitis)thanthosewithout allergicrespiratorydisease

(Table5).

Discussion

Inthepresentstudy,wefounda7.6%frequencyof

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Table3 Clinicalmanifestationsofthereportedreaction,implicateddruganddrugprovocationtestsresultsintheanaphylaxis cases. PatientID Clinical manifestation NSAID (implicated) DPT(implicated drug) DPT(alternative NSAID) Diagnosis A Angio-oedema/Facialor periorbitaloedema; Bronchospasm,cough, wheezing

Paracetamol Positive ASAandNimesulide ---Negative

Conﬁrmed

B Maculopapularexanthema; vomiting

Ibuprofen Negative --- Excluded

C Urticaria;vomiting Ibuprofen Negative --- Excluded

D Nasalandocularsymptoms; vomiting

E Urticaria;Bronchospasm, cough,wheezing;vomiting

F Chesttightness,dysphonia, dysphagia;facial

angioedemaandurticaria

G Angio-oedema/Facialor periorbitaloedema; angio-oedemaofthelarynx

Ibuprofen Nimesulide

Notperformed ASA---Positive Conﬁrmed

H Angio-oedema/Facialor periorbitaloedema; Bronchospasm,cough, wheezing

Ibuprofen Notperformed Nimesulide---Positive Conﬁrmed

I Maculopapularexanthema; Bronchospasm,cough, wheezing

Ibuprofen Notperformed Nimesulide ---Negative

Inconclusive

J Maculopapularexanthema; Oropharyngealpruritus

Ibuprofen Notperformed Meloxicam---Negative Inconclusive K Urticaria;Bronchospasm,

cough,wheezing;vomiting

Paracetamol Negative --- Excluded

L Angio-oedema/Facialor periorbitaloedema; Bronchospasm,cough, wheezing

ASA Notperformed Nimesulide ---Negative

Inconclusive

M Urticaria;Bronchospasm, cough,wheezing;vomiting

N Urticaria;vomitingand diarrhoea

O Urticaria;Bronchospasm, cough,wheezing; Angio-oedema/Facialor periorbitaloedema

Ibuprofen Notperformed Meloxicamand nimesulide ---Negative Inconclusive P Angio-oedema/Facialor periorbitaloedema; Bronchospasm,cough, wheezing;vomiting

Ibuprofen Positive Notperformed ---toleranceto paracetamol, conﬁrmedafterthe reactionbutbefore thisinvestigation

Conﬁrmed

Q Urticaria;Bronchospasm, cough,wheezing; hypotension

NSAID---non-steroidalanti-inﬂammatorydrug;ASA---acetylsalicylicacid;DPT---drugprovocationtest.

Totalcumulativedoseswere:ibuprofen10mg/kguntil600mg,paracetamol15mg/kguntil1000mg,nimesulide100mgandASA20mg/kg until1000mg.

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99 patients DPT with the culprit

NSAID DPT positive in 5 patients DPT negative in 93 patients Investigation inconclusive in 1 patient(DPT inconclusive) 19 patients DPT with an alternative NSAID DPT positive in4 patients Investigation inconclusive in 15 patients (DPT inconclusive) 1 patient refused the DPT 119 Patients

Figure1 Drugprovocationtestdiagram.DPT---drugprovocationtest.

Table4 CharacterisationofthepatientswithconﬁrmedNSAID-H. PatientID Ageatthe

ﬁrstreaction Implicated NSAID Typeof reaction Numberof previous reactions Manifestation NSAIDDPT DPT manifestation A 12yrs Male

5yrs Paracetamol Acute ≥4 Anaphylaxis Culprit Bronchospasmand nasalsymptoms G 17yrs Male 13yrs Ibuprofen Nimesulide

Acute 2 Anaphylaxis Alternative---ASA Facial angio-oedema H

11yrs Male

10yrs Ibuprofen Acute 1 Anaphylaxis Alternative ---Nimesulide Facialand periorbital angio-oedema P 14yrs Male

14yrs Ibuprofen Acute 1 Anaphylaxis Culprit Periorbital angio-oedemaand ocularpruritus R

7yrs Female

6yrs Ibuprofen Acute 1 Urticaria; Angio-oedema/Facialor periorbital oedema

Culprit Urticariaand periorbital oedema S

13yrs Female

11yrs Ibuprofen Acute 1 Urticaria Alternative ---Nimesulide Hypotensionand dizziness T 8yrs Male

7yrs Nimesulide Acute 1 Urticaria; Angio-oedema/Facialor periorbital oedema Alternative ---Paracetamol Urticaria,facial angio-oedema, bronchospasm, coughand wheezing U 13yrs Female

13yrs Ketorolac Acute 1

Angio-oedema/Facialor periorbital oedema; Maculopapular exanthema

Culprit Facialand periorbital angio-oedema V 8yrs Male 6yrs Ibuprofen Paracetamol

Notclariﬁed ≥4

Angio-oedema/Facialor periorbital oedema Culprit (paracetamol) Labial angio-oedema

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Table5 CharacterisationofthepatientsthathadconﬁrmedandexcludedNSAID-H. ConﬁrmedNSAID-H patients(N=9) ExcludedNSAID-H patients(N=93) p-Value

Meanageattheﬁrstreaction(years)a _9.4 _5.5 _0.008

Gender Female(n=47) 3(6.4%) 44(93.6%) 0.657 Male(n=55) 6(10.9%) 49(89.1%) Anaphylaxisb _With_(n₌₁₃₎ ₄_(30.8%) ₉_(69.2%) _0.029 Without(n=89) 5(5.6%) 84(94.4%) Atopy With(n=44) 5(11.4%) 39(88.6%) 0.430 Without(n=58) 4(6.9%) 54(93.1%) Asthma With(n-42) 5(11.9%) 37(88.1%) 0.360 Without(n=60) 4(6.7%) 56(93.3%) Rhinitis With(n=50) 7(14%) 43(86%) 0.140 Without(n=52) 2(3.8%) 50(96.2%) Urticaria With(n=4) 0 4(100%) 0.530 Without(n=98) 9(9.2%) 89(90.8%) Numberofprevious reactions 1(n=61) 6(9.8%) 55(90.2%) 0.660 ≥2(n=41) 3(7.3%) 38(92.7%)

a _Four_patients_in_whom_NSAID-H_was_excluded_did_not_recall_the_age_at_the_time_of_the_ﬁrst_reaction. b _Reported_to_the_implicated_NSAID.

urticaria and angio-oedema were the commonest clinical

manifestations.

ChildrenoftenhaveahistoryofNSAIDreactions,

partic-ularly toibuprofen. According totheliterature,in 86%of

thesinglereactorsandin56%ofcross-reactors,aNSAID-H

isnotconﬁrmed.6_It_is_believed_that_concomitant_conditions

suchas infections, fever, or theuse of other drugs might

playaroleinthepathophysiologyofthereaction,eliciting

symptomsinthesepatients.6,8

A well-documented clinical history is essential for the

correctdiagnosisofNSAID-Handshouldincludeadescription

ofthesymptoms,timeintervalbetweendrugadministration

and the symptoms onset, implicated drugs, drugs

toler-atedafterthereaction,routeofadministration,numberof

episodesandunderlyingdiseases.8_However,_a_diagnosis_of

NSAID-Hsupportedsolelybytheclinicalhistorymayleadto

overdiagnosis.4

Ahistoryofrepeatedpreviousreactionswasreportedto

predictafutureresponsetoNSAID.7_In_our_study,_similarly_to

thestudybyYilmazetal.6_the_number_of_previous_reactions

wasnotassociatedwithapositiveDPTresult.

Itwassuggestedthatibuprofencouldbeusedtodetect

thecross-reactivetypeofNSAID-Hinchildren.6_According_to

ourresults,ibuprofenwasthemostfrequentreported

cul-pritinsuspectedreactionsandthecommonestdruginvolved

inchallenge-provenNSAID-H.ThisisinlinewithZambonino

etal.1_and_Guvenir_et_al.4_This_is_partially_explained_because

in thepaediatric age theprescription of NSAIDs is largely

restrictedtoafewdrugs,namely ibuprofenand

paraceta-mol.

During the investigation of a suspected NSAID-H, it is

important tocheck for paracetamoltolerance in all

chil-drenwithcross-intolerancetoNSAIDsbecausetherearefew

medicationsapprovedforthetreatmentoffeveror

inﬂam-mationatyoungerages.1_It_has_been_shown_that_reactivity

toparacetamolamongNSAID-Hpatientsrangesfrom0%to

25%.8,11_In_the_present_study,₂_out_of₉_patients_(22%)_with

conﬁrmedNSAID-Hreactedtoparacetamol.

In this work, asfound by other authors,1,12,13 _urticaria

andangio-oedemawerethemost frequentmanifestations

reportedby the patients, with facialangio-oedema, with

orwithoutgeneralisedurticaria,asthemostcommon

clin-icalpresentation.8,11 _In _the _majority _of _the _patients _with

cutaneousmanifestations(94.0%),NSAID-Hwasconﬁrmedin

onlyﬁvepatients.Thelowfrequencyofconﬁrmeddiagnosis

hasbeen reportedby other authors,suggesting that even

in patients with a history of urticaria/angio-oedema, the

diagnosticprocedurecouldsafely startwiththeoffending

NSAID.14

Anaphylaxisisusuallyconsideredacontraindicationfor

DPTbecauseoftheriskassociated.IntheworkofZambonino

etal.1_the_DPT_with_the_culprit_drug_was_not_performed_in

patientswhoreportedanaphylaxis.However,inthestudyof

Yilmazetal.6_a_report_of_anaphylaxis_was_not_associated_with

theDPTresult.Inourwork,17patientsreportedanaphylaxis

astheclinicalmanifestation.However,thehypersensitivity

wasonlyconﬁrmedinfour.TheseDPTwereperformedinthe

majority of anaphylaxis reported cases, asother possible

causes, such asviral infections or other drugs, couldnot

beruledout.Mostdrugchallengeswerenegative,although

thisclinicalpresentationwasassociatedwithmorepositive

resultsthanhavebeendescribedintheliterature.7

Inwhat concernsatopy, severalstudies have shown an

association between NSAID-H, allergic diseases (asthma,

rhinitis)andatopysensitisationinchildrenandadults,which

has been considered a signiﬁcant risk factor for NSAID-H

inyoung children.1,11,15---17 _An _association _particularly _with

house dust mite sensitisation has been described.18 _The

exactmechanism remains unclear.15,17 _However,_this

asso-ciationwasnotfoundbyotherauthors.4,14

Inourstudy,patientswithconﬁrmedNSAID-Hpresented

ahigherfrequencyofasthmaandrhinitisthanpatientswith

excludedNSAID-H.Almosthalf(44.5%)ofourpatientswere

atopic.Nevertheless, thesedifferences were not

statisti-callysigniﬁcantpossiblyduetothelownumberofpositive

(7)

In our sample, genders were equally distributed (58

girls and 61 boys). However, in the nine patients with

NSAID-H,sixweremale.Thesedataareconsistentwith

pre-viousreports.11 _The_male_{preponderance}_may_be_explained

consideringtheassociation ofNSAID-Hwithatopyandthe

somewhatincreasedprevalenceofatopicdiseasesinboys.11

Regardingthemedianageatthetimeof theﬁrst

reac-tion,patientswithconﬁrmedNSAID-Hwereolderthanthose

forwhichthediagnosiswasexcluded.Thisdifference,which

waspreviouslydescribed,19_could_be_related_to_the_fact_that

youngerchildren aremore susceptibleto viralinfections,

causingskineruptionsandleadingtoadeceptivediagnosis

ofNSAID-H.

DPTisthegoldstandardfor theNSAID-Hdiagnosis,7,8,10

andanegativeresultshouldbereassuringtothe patient.

Nonetheless, patients frequently continue to avoid the

tested NSAID after a negative result,20 _emphasising _the

importanceofaneffectivecommunicationbetweenpatients

and physicians. There are few published studies about

NSAID-Hin children.Forthisreason,weconsiderthatthe

present study provides additional information about this

topic,reinforcingtheneedtoundergoaninvestigationbya

DPTwiththeimplicatedNSAID.

Conclusion

Wefound a low frequency (7.6%) oftrue NSAID-H in

chil-drenwithapreviousNSAIDreaction.Ibuprofenwasthemost

frequentlyimplicateddrugandurticariaandangio-oedema

were the commonest clinical manifestation. Anaphylaxis

was a relative risk to conﬁrmed drug hypersensitivity.

Despitethis,inthefaceofreportedanaphylaxis,theclinical

historymightnotbesufﬁcienttoestablishaﬁnaldiagnosis

ofNSAID-H.Thedrugprovocationtestprovedtobeessential

intheNSAID-Hdiagnosisworkupandshouldbeconsidered,

evenwhensystemicsymptomsarereported.

Ethical

disclosures

Conﬁdentialityofdata.Theauthorsdeclarethattheyhave

followedthe protocols of theirwork centre onthe

publi-cation of patient data and that all the patients included

inthestudyhavereceivedsufﬁcientinformationandhave

giventheirinformedconsentinwritingtoparticipateinthat

study.

Righttoprivacyandinformedconsent.Theauthorshave

obtained the informed consent of the patients and/or

subjectsmentionedinthearticle.Theauthorfor

correspon-denceisinpossessionofthisdocument.

Protection of human and animal subjects.The authors

declarethatnoexperimentswereperformedonhumansor

animalsforthisinvestigation.

Conﬂicts

of

interest

Nonedeclared.

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