www.bjorl.org
Brazilian
Journal
of
OTORHINOLARYNGOLOGY
ORIGINAL
ARTICLE
The
role
of
aspirin
desensitization
in
patients
with
aspirin-exacerbated
respiratory
disease
(AERD)
夽
Jonas
Willian
Spies,
Fabiana
Cardoso
Pereira
Valera,
Daniel
Loiola
Cordeiro,
Taís
Nociti
de
Mendonc
¸a,
Marcelo
Gonc
¸alves
Junqueira
Leite,
Edwin
Tamashiro,
Luiza
Karla
Arruda,
Wilma
Terezinha
Anselmo-Lima
∗DepartmentofOphthalmology,OtorhinolaryngologyandHeadandNeckSurgery,FaculdadedeMedicinadeRibeirãoPreto, UniversidadedeSãoPaulo(USP),RibeirãoPreto,SP,Brazil
Received9December2014;accepted16April2015 Availableonline21September2015
KEYWORDS
Desensitization immunological; Aspirin; Sinusitis; Nasalpolyps
Abstract
Introduction:Aspirin-exacerbatedrespiratorydisease(AERD)consistsofaclassictetrad: mod-erate/severeasthma,chronicrhinosinusitis,nasalpolyps,andintolerancetoaspirinorother nonsteroidalanti-inflammatorydrugs.Clinicalcontrolwithdrugs,surgery,anddesensitization aretreatmentoptions.
Objective: Toevaluatetheefficacyandtolerabilityofaspirindesensitizationinpatientswith AERD.
Methods:Periodic symptom assessment and endoscopy in patients with AERD undergoing surgerywhoweredesensitized.
Results:Seventeenpatientsweredesensitized.Eightpatientscompletedthedesensitization andwerefollowedforaminimumofaone-yearperiod(mean3.1years).Thesepatientsshowed improvementinallsymptoms.Moreover,surgicalreassessmentwasnotindicatedinanyofthese patientsandtherewasadecreaseincostswithmedicationandprocedures.Eightpatientsdid notcompletedesensitization,mainlyduetoprocedureintoleranceanduncontrolledasthma, whereasanotherpatientwaslosttofollow-up.
Conclusion: Aspirindesensitization,whentolerated,waseffectiveinpatientswithAERDand withpoorclinical/surgicalresponse.
© 2015Associac¸˜aoBrasileira de Otorrinolaringologiae CirurgiaC´ervico-Facial.Publishedby ElsevierEditoraLtda.Allrightsreserved.
夽 Pleasecitethisarticleas:SpiesJW,Valera FCP,CordeiroDL,deMendonc¸a TN,LeiteMGJ,TamashiroE,et al.Theroleofaspirin
desensitizationinpatientswithaspirin-exacerbatedrespiratorydisease(AERD).BrazJOtorhinolaryngol.2016;82:263---8.
∗Correspondingauthor.
E-mail:wtalima@fmrp.usp.br(W.T.Anselmo-Lima). http://dx.doi.org/10.1016/j.bjorl.2015.04.010
PALAVRAS-CHAVE
Dessensibilizac¸ão imunológica; Aspirina; Sinusite; Poliposenasal
Opapeldadessensibilizac¸ãoàaspirinaempacientesportadoresdedoenc¸a respiratóriaexacerbadaporaspirina(DREA)
Resumo
Introduc¸ão:A doenc¸a respiratória exacerbada por aspirina é composta pela tétrade clás-sica: asma moderada/grave, rinossinusite crônica, pólipos nasais e intolerância à aspirina ou outro anti-inflamatório não esteroide. Controle clínico com medicamentos, cirurgias e dessensibilizac¸ãosãoopc¸õesdetratamento.
Objetivo:Avaliaraeficáciaetolerabilidadedadessensibilizac¸ãoàaspirinaempacientescom doenc¸aexacerbadaporaspirina.
Método: Avaliac¸ão periódica dos sintomas e exame endoscópico em pacientes comdoenc¸a respiratóriaexacerbadaporaspirinasubmetidosàcirurgiaedessensibilizados.
Resultados: Dezessetepacientes foram dessensibilizados, dos quais oito pacientes comple-taram a dessensibilizac¸ão e foram acompanhadospelo tempo mínimo de 1 ano (média de 3,1anos).Todosreferirammelhoradetodosossintomas;não houvenenhumaindicac¸ãode reabordagem cirúrgica, ehouve reduc¸ão de gastos commedicac¸ões eprocedimentos. Out-rosoito pacientesnãocompletaram adessensibilizac¸ão,principalmente porintolerância ao procedimentoedescontroledaasma,enquantooutropacienteperdeuoseguimento. Conclusão:A dessensibilizac¸ãoàaspirina, quandotolerada,mostrou-seeficaznospacientes comdoenc¸arespiratóriaexacerbadaporaspirinacomrespostaclínica/cirúrgicainsatisfatória. ©2015Associac¸˜aoBrasileira deOtorrinolaringologiaeCirurgiaC´ervico-Facial.Publicadopor ElsevierEditoraLtda.Todososdireitosreservados.
Introduction
Aspirin-exacerbated respiratory disease (AERD), also described in the literature as Samter’s triad and aspirin-induced asthma (AIA), is a clinical syndrome whose symptoms are induced by a non-allergic hypersensitiv-ity reaction, independent of IgE,1---5 to aspirin and/or
other non-steroidal anti-inflammatory drugs (NSAIDs),
cyclooxygenase-1 (COX-1) enzyme inhibitors. It was
origi-nallydescribedbyWidaletal.6in1922andbySamterand
Beer7 in 1967. The classical presentation comprises the
tetrad:moderate tosevere asthma, chronic hypertrophic
eosinophilicrhinosinusitis,sinonasalpolyps,andintolerance
toaspirinorotherNSAIDs.1
Symptom onset usually occurs in adulthood, usually
beforetheageof40,1,3andthenumberofaffectedwomen
ishigher thanthat of men.1,2 Thereis nodescribed
asso-ciationwithethnicityandfamilyhistoryisrarelypresent.3
Studiesshowthatitsprevalenceinthegeneralpopulation
is 0.3%---0.9%, reaching 10%---20% in patients with asthma,
affecting 30%---40% of asthmatics withnasal polyposisand
chronicrhinosinusitis.1,3
The physiopathology of AERD is not fully known. The
first theory, proposed by Szczeklik in 1988, associated a
viral respiratory infection as a trigger for AERD.4 More
recentstudieshaveshownthereleaseofcytokinesinvitro
by lymphocytes infected with respiratory syncytial virus,
parainfluenzavirus,andrhinovirus.Cytokinesrecruit,
stim-ulate,andactivateinflammatorycells.4,5
Anotherfactor appears tobe theincreased expression
of specific cytokines associated with activation and
sur-vival of eosinophils in nasal polyps, such asinterleukin 5
(IL-5),GM-CSF(granulocyte-macrophagecolony-stimulating
factor),andeotaxin,whichwouldincreasetheintensityof
localeosinophilicinflammation.
It is believed that patients with AERD have genetic
polymorphismsthat leadtoreducedactivityof theCOX-1
isoenzyme and increased affinity of leukotriene
recep-tors, with low production of PGE2 (prostaglandin E2)
and low COX-2 expression in nasal polyps. Since PGE2
hasanti-inflammatoryactivity,theinhibitionof eosinophil
chemotaxisanditsactivation,andadecreasedproduction
of this prostaglandin (PG) would contribute tothe
devel-opment of more severe eosinophilic inflammation. These
alterations in thearachidonic acidmetabolism leadtoan
imbalance in the PG/leukotriene ratio in these patients,
causing inflammatory alterations in the upper and lower
airways.8---11
Theingestion of aspirin (acetylsalicylicacid)or NSAIDs
by a sensitive patient inhibits COX-1 and results in the
exacerbation of the inflammation already present in the
upper andlower airways,with awide spectrumof
sever-ity and manifestationsthat range fromconjunctivitis and
rhinitis to laryngospasm and bronchospasm.1 Initially, the
clinical manifestation of AERD is nasal congestion, which
may be reported by the patient as an upper-airway viral
infectionthatneverresolved.Hyposmiaoranosmiaoccurs
in most patients with AERD.3 This rhinitis develops into
chronic hypertrophic eosinophilic pansinusitis and
emer-gence of nasal polyps, which recur even after surgical
excision. Asthma may already be present from childhood
or young adulthood, or occur after three months to five
yearsofsymptomonset,andisusuallymoderatetosevere.
Hypersensitivity skintests areusuallynegativein patients
with AERD, indicating higher prevalence in non-atopic
History of asthma triggered by ingestion of aspirin or
otherNSAIDsissuggestiveofAERD.Thechallengetestisthe
gold standard forthe diagnosis.1---5,11 Theoral route is the
most used,becauseitis moresensitive and itsspecificity
is similartothat ofthe nasal,bronchial, and intravenous
routes.
The management of patients diagnosed with AERD
includes nasal surgeries, ASA desensitization, and
rec-ommendations on how to completely avoid the use of
non-selectiveCOXinhibitors.Forthosemakingthischoice,
itisnecessarytohavefullknowledgeofallthedrugsthat
inhibitthispathway,includingthosewithcross-reactivity.It
isnoteworthythatselectiveinhibitorsofCOX-2canbeused
inpatients withAERD;however, duetothe albeitremote
possibilityof cross-reactions, it is recommended that the
firstdoseofthesedrugsbeadministeredinaprivateclinic
orhospital.1
However,eveniftheyavoidtheuseofCOX-1inhibitors,
patients withAERD usually have progressive worseningof
respiratory disease, even with aggressive surgical
treat-ment and topical and/or systemic corticosteroids and
anti-leukotrienes.2,13---15 Itis alsonoteworthythatavoiding
theuseofaspirinisnotalwayspossible,asin
cardiovascu-lardiseasemanagement.Thechanceofrecurrenceofnasal
polyposisandtheneedfornewendoscopicparanasalsinus
surgery(EPSS)ishighinpatientswithAERD,comparedwith
patientswithnasalpolyposiswhoaretoleranttoaspirin.16
Currently,thereisnobiomarkerthatcanpredictthe
dis-easeand airwayremodelingactivity.Recently,therehave
been studies that identified serum periostin increases as
a useful biomarker for the assessment of airflow
limita-tion in asthmatic patients, indicating Th2 inflammatory
response.17,18
The aimofthestudywastoevaluatetheeffectiveness
ofASAdesensitizationinpatientswithAERDtreatedatthe
RhinosinusologyClinic,aswellastheirtolerancetothe
pro-cedure.
Methods
The study was approved by the Research Ethics
Com-mittee, Process No. 13091313.7.0000.5440. Patients who
had chronic rhinosinusitis with nasal polyps (CRSwNP),
moderate/severe asthma, and history compatible with
hypersensitivity to aspirin were evaluated from 2008 to
2013.Thepatientsremainedmoderatelysymptomaticeven
ifsubmittedtoshortpulsesofsystemiccorticosteroids,
top-icalcorticosteroidtherapy(bothapplicationsineachnostril
twice a day), and antileukotriene oncea day. All
under-wentoralchallengetestwithASA,accordingtothespecific
service protocol, establishing the diagnosis of AERD. Of
these,16acceptedtheASAdesensitizationprotocol,which
was conducted at the Hospital Allergy and Immunology
Clinic.FourweeksafterEPSS,patients werehospitalized,
properlyadvisedontheneedfortheprocedure,andsigned
theinformedconsent.
Desensitizationprotocol
Initially,venousaccesswasperformedthroughaperipheral
vein. The following medications were available at the
bedside for any systemic reaction: methylprednisolone
125mgIV,salbutamolnebulizer(10---20gts),ranitidine50mg
IVorcimetidine300mgIV,adrenaline1:10000.3mLIM,and
promethazine50mg(1amp)IV.The pre-medicationswere
prednisone20mgevery12handmontelukast (SingulairTM)
10mgevery12h,48hpriortodesensitization,whichwere
maintainedduringhospitalization.Theuseofbeta-blockers
or ACE inhibitors was not allowed. Procedures were also
performedforrespiratory/cardiovascularassessment:
a. Vitalsignseveryhourduringdesensitizationand,
when-evernecessary;
b. BasalFEV1throughspirometry.A20%reductioninFEV1
waspre-calculatedbymultiplyingFEV1inlitersby0.8;
c. Previousspirometry (FEV1) at each dose of aspirin, at
eachhourandwhennecessary.Ifthepatienthadsevere
dyspneaordecreaseinFEV1>20%,salbutamol
nebuliza-tionwasperformed;
d. IfSBP<90mmHg,adrenaline1:10000.3mLwas
adminis-teredIM;
e. Rhinorrhea, nasal congestion, and flushing: FEV1 and
blood pressure (BP) werechecked and verified,if
rhi-norrheawasaccompaniedbyadecreaseinFEV1>20%or
systolicBP<90mmHg,andprotocolwasfollowedas
pre-viouslydescribed. Forrhinorrhea, nasal congestion, or
flushingnotaccompaniedbytheabovementioned
symp-toms,promethazine50mgIVwasadministered.
Aspirindesensitization.
Dose
Day1
8:00AM Aspirin20mgorally
10:00AM Aspirin40mgorally 12:00PM Aspirin60mgorally
2:00PM Aspirin81mgorally
Day2
8:00AM Aspirin81mgorally
10:00AM Aspirin160mgorally 12:00PM Aspirin325mgorally
2:00PM Aspirin650mgorally
Thepatientwasobservedfor3hafterthefinaldose,and thenwasdischargedwiththefollowingmedications:
1. Aspirin650mgevery12h,orally;
2. ProtonpumpinhibitororH2blockerwasconsideredfor gastricprotection;
3. Regularlyusedmedications.
Thedailydoseof1300mgwasmaintainedforsixmonths, andafterthat,thedosewasdecreasedaccordingtoclinical parameters(meanof375---975mg/day).Becausethe desen-sitizedstate is maintainedfor only twotofivedaysafter aspirinusecessation,whentheuseisbelow325mg/dayfor morethan48h,intakeshouldnotberesumed,due tothe riskofseverereactions.
Clinic of Rhinosinusitis every three months in the first semester,andeverysixmonthsthereafter.Atthesereturn consultations,thepatientswereevaluatedforthepresence ofsinonasalsymptoms(nasalobstruction,anterioror poste-riorrhinorrhea,facialpain,hyposmia,cacosmia,andother sinonasalsymptoms),andthenasofibroscopyfindings (pres-enceofpolypoiddegenerationintheethmoidroof,middle meatus, polyps, secretion). The mean interval between recurrencerequiringsurgerybeforeandafter desensitiza-tion, timeuntil the diagnosis of AERD and the results of immediatehypersensitivityskintests,performed toassess theassociationwithatopy,werealsoevaluated.
Agroupofeightpatientsundergoingdesensitizationdid notcompletetheprocedure,ordidnotpersistwiththelater useofthedrug.Patientswhorefusedtoundergo desensiti-zationorwerelosttofollow-up,orwhowerestillundergoing follow-upforaperiodlessthanayearafterdesensitization werenotincludedinthisstudy.
Results
PatientswithCRSwNPandmoderate/severeasthma submit-tedtoEPSSwereassessed.AmongalldiagnosedwithAERD, seventeenofthem,whohadalreadybeensubmittedtoat leastone surgery, accepted and underwentthe desensiti-zationprotocol.Onepatientwaslosttofollow-upandwas excludedfromthestudy.Ofthe16remainingpatients,eight
completedtheprocedure,whileeightothershadthe treat-mentinterrupted.
Oftheeightpatientswhocompletedoneyearof desen-sitization,thereweretwomalesandsixfemales.Themean time fromsymptom onset and AERD diagnosis, aswell as patients’ ages at the start of desensitizationand time of follow-uparedescribedinTable1.Themeanfollow-upwas
3.1 years after desensitization (ranging between one and
fiveyears).Symptomassessmentandnasofibroscopyfindings
beforeandafterdesensitizationareshowninTable2.
Noneofthepatientsfollowedafterdesensitizationhad
anewsurgicalindication.Eightdidnotcompleteordidnot
persistwithdesensitization.Therewasapredominance of
women(six womenandtwomen),withameanageof 50
years,9 months.The mean numberof surgeries was1.75
(range fromone tofour procedures) prior to
desensitiza-tion.Threepatientsdidnotcompletedesensitizationdueto
adversereactionsanddecompensatedasthma.Threeothers
discontinuedtheuseafterlessthanonemonthofaspirinin
fulldoseduetoasthmaworsening.Therewasalsoapatient
whodiscontinued use due tosuspecteddengue fever and
anotherabandonedtreatmentduetofearofanewsurgery.
Discussion
Aspirin desensitizationis an alternativethat hasshownto
be effective in the management of patients with AERD.
Table1 PatientswhocompletedASAdesensitization.
Patient Gender Age(years) Ageatdesensitization (years)
Timeuntildiagnosis ofAERD(years)
Newsurgicalindication afterdesensitization
1 F 55.5 50.9 14
---2 F 55.9 54.2 14
---3 F 43.8 39 10
---4 F 61.1 59.9 8
---5 F 51.2 46.1 19
---6 M 32.6 30.5 6
---7 M 55 54 5
---8 F 44.1 42.1 8
---F,female;M,male.
Table2 Symptomsandnasofibroscopyfindingsineightpatientsundergoingaspirindesensitizationduringfollow-up.
Beforedesensitization Threemonths Sixmonths 12months
Symptoms
Nasalobstruction 7 1 1 2
Rhinorrhea(before/after) 6 2 1 3
Facialpain 1 --- ---
---Hyposmia/anosmia 7 --- --- 1
Cacosmia 1 --- ---
---Nasalpruritus 3 --- --- 3
Nasofibroscopyfindings
Secretion 3 --- ---
---Polypoiddegenerationoftheethmoidceiling --- 1 1 3
Polypoiddegenerationofthemiddlemeatus --- 2 2
---Studies have shown that the desensitization results in significant improvement of all AERD symptoms, reduction of rhinosinusitis, better control, and reduced doses of corticosteroids used to treat asthma, anosmia/hyposmia improvement,19 decreased need for revision sinonasal
surgery, improved tomographic image and quality of life
of patients, as well as reduced costs, both regarding
proceduresandmedications.19,20
Long-termtreatmentwithaspirincausesdownregulation
of IL-4 and subsequent downregulation of the
cysteinyl-leukotriene receptors in lymphocytes, which, ultimately,
lead to a decrease in the Th2 inflammatory response.
Another important aspect of this therapy is the decrease
inMMP-9(matrixmetalloproteinase9),whichisimportant
intheairwayremodelingprocess.19 Desensitizationcanbe
considered thefirst choiceof treatment forpatients with
AERD and recalcitrant nasal polyposis, need for repeated
sinus surgery, need for systemic corticosteroids, or those
withanymedicalconditionrequiringchronicaspirinuse.21
Therecurrenceofnasalpolyposisaftersurgeryisalmost
three-foldhigherinpatientswithAERD,whencomparedto
thosewithoutit.22Otherstudieshaveshownthat
desensiti-zationincreasedthemeanlengthofsurgicalreintervention
from three to approximately six years,23,24 with
signifi-cant improvement in quality of life, olfactory function,
decreasednasalpolyps,andasthmacontrol.24Inthepresent
study,alleightpatientsthatmaintaineddesensitizationfor
at leastone year showedsignificant improvementof
clin-icalparametersandnasofibroscopyfindings.Aftera mean
follow-upof3.1years,nopatientwassubmittedtoanew
surgicalapproach.
Desensitization is not risk-free and requires several
precautionsduetopossiblecomplications.Evenwhen
con-ducted in a hospital under stringent medical care and
frequent outpatient consultations, many patients do not
toleratetheprocedure.This representsthemain causeof
patientrefusal whentheyareinvitedtoundergo
desensi-tization. Berges-Gimenoet al.25 (2003) found that67% of
patients benefited fromthe therapy withaspirin during a
one-yearfollow-upand14%discontinuedtheuseofASAdue
tosideeffects,whereas11%discontinuedduetopregnancy
orelectivesurgery.Itisimportanttoemphasizeitscorrect
continuoususe.Ifpatientsdiscontinuetreatment,they
can-notre-startthemedicationontheirown,becauseoftherisk
ofseverereactions.
Inthepresentstudy,inthegroupofpatientswho
discon-tinueddesensitization,threeofeightpatientswereunable
to finish it, due to adverse reactions and worsening of
asthma. The other three had uncontrolled asthma after
lessthanonemonthusingaspirin625mgtwicedaily,which
required discontinuation.There arestillfactors that
can-notbepredictedorareindependentfrommedicalaction,
suchaswhatoccurredwithapatientwithsuspecteddengue
feverwhohadtointerruptthemedicationduetotheriskof
Reye’ssyndrome.
Desensitizationiscapableofalteringthenaturalcourse
of AERD26 and should be included in the treatment of
patients with the disease27; however, it should not be
considered as an option to replace a new surgical
inter-vention. The main goal is to postpone a new surgery
or even make it less aggressive, thereby decreasing the
risks for the patient.Another goal is tolessen morbidity,
through symptom improvement and decrease in acute
episodes. Although this was not a randomized,
double-blind, placebo-controlled trial, this study showed that
aspirin desensitization is an effective option for patients
withAERDwhomeettheindicationsfor thisprocedure.It
dependsonanexcellentdoctor---patientrelationship, with
fullcommitmentbythepatienttouseaspirin
uninterrupt-edly; thepatient must be verywell advised regarding all
potential risks/side effects and the fact that treatment
cessationmayresultinthelossofallthathasbeengained,
withgreatpossibilityofdiseaserecurrence.
Conclusion
Despitethe small sample size, aspirin desensitizationhas
showntobeaneffectivealternativetreatmentforpatients
with poor clinical response. More studies, performed for
alongerperiod oftime,are necessary tobetterevaluate
theeffectivenessofaspirindesensitizationinpatientswith
AERD.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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