w w w . r e u m a t o l o g i a . c o m . b r
REVISTA
BRASILEIRA
DE
REUMATOLOGIA
Original
article
Guidelines
for
the
management
and
treatment
of
periodic
fever
syndromes:
periodic
fever,
aphthous
stomatitis,
pharyngitis
and
adenitis
syndrome
Maria
Teresa
R.A.
Terreri
a,∗,
Wanderley
Marques
Bernardo
b,
Claudio
Arnaldo
Len
a,
Clovis
Artur
Almeida
da
Silva
c,
Cristina
Medeiros
Ribeiro
de
Magalhães
d,
Silvana
B.
Sacchetti
e,
Virgínia
Paes
Leme
Ferriani
f,
Daniela
Gerent
Petry
Piotto
a,
André
de
Souza
Cavalcanti
g,
Ana
Júlia
Pantoja
de
Moraes
h,
Flavio
Roberto
Sztajnbok
i,
Sheila
Knupp
Feitosa
de
Oliveira
j,
Lucia
Maria
Arruda
Campos
c,
Marcia
Bandeira
k,
Flávia
Patricia
Sena
Teixeira
Santos
l,
Claudia
Saad
Magalhães
maSectorofPediatricRheumatology,DepartmentofPediatrics,UniversidadeFederaldeSãoPaulo(Unifesp),SãoPaulo,SP,Brazil bCenterforDevelopmentofMedicalTeaching,MedicineSchool,UniversidadedeSãoPaulo(USP),SãoPaulo,SP,Brazil cPediatricRheumatologyUnit,Children’sInstitute,MedicineSchool,UniversidadedeSãoPaulo(USP),SãoPaulo,SP,Brazil dHospitaldaCrianc¸adeBrasíliaJoséAlencar(HCB),Brasília,DF,Brazil
eIrmandadedaSantaCasadeMisericórdiadeSãoPaulo,SãoPaulo,SP,Brazil
fServiceofImmunology,AllergyandPediatricRheumatology,DepartmentofPediatrics,FaculdadedeMedicinadeRibeirãoPreto,
UniversidadedeSãoPaulo(USP),RibeirãoPreto,SP,Brazil
gServiceofRheumatology,HospitaldasClínicas,UniversidadeFederaldePernambuco(UFPE),Recife,PE,Brazil hUniversidadeFederaldoPará(UFPA),Belém,PA,Brazil
iServiceofRheumatology,NucleusAdolescents’HealthStudies,UniversidadedoEstadodoRiodeJaneiro(UERJ),RiodeJaneiro,RJ,Brazil jServiceofPediatricRheumatology,InstitutodePuericulturaePediatriaMartagãoGesteira,UniversidadeFederaldoRiodeJaneiro
(UFRJ),RiodeJaneiro,RJ,Brazil
kHospitalPequenoPríncipe,Curitiba,PR,Brazil
lServiceofRheumatology,HospitaldasClínicas,UniversidadeFederaldeMinasGerais(UFMG),BeloHorizonte,MG,Brazil mPediatricRheumatologyUnit,FaculdadedeMedicinadeBotucatu,UniversidadeEstadualPaulista(Unesp),Botucatu,SP,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received7July2015 Accepted30August2015 Availableonline20October2015
Keywords:
Syndromeofperiodicfever, aphthousstomatitis,pharyngitis, andcervicaladenitis
a
b
s
t
r
a
c
t
Objective:Toestablishguidelinesbasedonscientificevidenceforthemanagementof peri-odicfever,aphthousstomatitis,pharyngitisandadenitis(PFAPA)syndrome.
Descriptionoftheevidencecollectionmethod:TheGuidelinewaspreparedfrom5clinical ques-tionsthatwerestructuredthroughPICO(Patient,Interventionorindicator,Comparison andOutcome),tosearchinkeyprimaryscientificinformationdatabases.Afterdefiningthe potentialstudiestosupporttherecommendations,theseweregraduatedconsideringtheir strengthofevidenceandgradeofrecommendation.
Results:806articleswereretrievedandevaluatedbytitleandabstract;fromthese,32articles wereselectedtosupporttherecommendations.
∗ Correspondingauthor.
E-mail:teterreri@terra.com.br(M.T.R.A.Terreri). http://dx.doi.org/10.1016/j.rbre.2015.09.004
Guidelines Childhood Fever
Autoinflammatorysyndromes
Recommendations: 1.PFAPAisadiagnosisofexclusionestablishedonclinicalgrounds,and onemustsuspectofthisprobleminchildrenwithrecurrentandperiodicfebrileepisodes ofunknownorigin,orwithrecurrenttonsillitisinterspersedwithasymptomaticperiods, especially in children ingood general conditionand with preservation of weight and heightdevelopment.2.Laboratoryfindingsarenonspecific.Additionaltestsdonotreveal pathognomonicchanges.3.Theevidencesupportinganindicationforsurgicaltreatment (tonsillectomywithorwithoutadenoidectomy),isbasedontwonon-blindedrandomized clinicaltrialswithsmallnumbersofpatients.4.Theuseofprednisoneattheonsetoffever inpatientswithPFAPAprovedtobeaneffectivestrategy.Thereisstillneedformore quali-fiedevidencetosupportitsuseinpatientswithPFAPA.5.Despitepromisingresultsobtained instudieswithIL-1inhibitors,suchstudiesarelimitedtoafewcasereports.
©2015ElsevierEditoraLtda.Allrightsreserved.
Diretrizes
de
conduta
e
tratamento
de
síndromes
febris
periódicas:
síndrome
de
febre
periódica,
estomatite
aftosa,
faringite
e
adenite
Palavras-chave:
Síndromedefebreperiódica, estomatiteaftosa,faringitee adenitecervical
Diretrizes Infância Febre
Síndromesautoinflamatórias
r
e
s
u
m
o
Objetivo:EstabelecerdiretrizesbaseadasemevidênciascientíficasparamanejodaSíndrome defebreperiódica,estomatiteaftosa,faringiteeadenite(PFAPA).
Descric¸ãodométododecoletadeevidência: ADiretrizfoi elaboradaapartirde5questões clínicasqueforamestruturadaspormeiodoP.I.C.O.(Paciente,Intervenc¸ãoouIndicador, Comparac¸ãoeOutcome),combuscanasprincipaisbasesprimáriasdeinformac¸ãocientífica. Apósdefinirosestudospotenciaisparasustentodasrecomendac¸ões,estesforamgraduados pelaforc¸adaevidênciaegrauderecomendac¸ão.
Resultados: Foramrecuperados,eavaliadospelotítuloeresumo,806trabalhos,sendo sele-cionados32artigos,parasustentarasrecomendac¸ões.
Recomendac¸ões:1.OdiagnósticodaPFAPAéclínicoedeexclusão,devendoasuspeitaser con-sideradaemcrianc¸asqueapresentamepisódiosfebrisdeorigemindeterminadarecorrentes eperiódicosouamidalitesderepetic¸ão,intercaladoscomperíodosassintomáticos, sobre-tudoemcrianc¸asembomestadogeralecomdesenvolvimentopondero-estaturalmantido; 2.Osachadoslaboratoriaissãoinespecíficos.Nãoexistemalterac¸õespatognomônicasnos examescomplementares;3.Aevidênciaquesustentaaindicac¸ãodotratamentocirúrgico (tonsilectomiacomousemadenoidectomia)ébaseadaemdoisensaiosclínicos random-izadosnãocegosqueincluírampequenonúmerodepacientes;4.Ousodeprednisonano iníciodoquadrofebrilempacientescomPFAPAmostrousereficaz.Melhoresevidências aindasãonecessáriasparaapoiarseuusonaPFAPA;5.Apesardosresultadosobtidosde estudoscominibidoresdeIL-1ßserempromissores,estessãolimitadosapoucosrelatosde casos.
©2015ElsevierEditoraLtda.Todososdireitosreservados.
Description
of
the
method
of
evidence
collection
TheGuideline was preparedfrom 5relevant clinical ques-tionsrelatedtothemanagementofperiodicfever,aphthous stomatitis,pharyngitisandadenitis (PFAPA)syndrome.The questionswerestructuredbytheuseofPICO(Patient, Inter-ventionorindicator,ComparisonandOutcome),allowingthe generation of strategies for searching evidence (described after each question, with the number of recovered arti-cles),inthemainprimarydatabasesofscientificinformation (Medline/Pubmed, Embase,Lilacs/Scielo, CochraneLibrary). The recovered evidence has been selected from a critical evaluationusingdiscriminatoryinstruments(scores):JADAD and GRADE for randomizedclinical trials, and New Castle
Ottawa scale for observational studies. After defining the potentialstudiestosupporttherecommendations,these arti-cleswereratedbasedonthestrengthofevidenceandgrade ofrecommendation,accordingtotheclassificationofOxford (availableinwww.cebm.net),includingavailableevidenceof greateststrength.
Summary
of
grades
of
recommendation
and
strength
of
evidence
A. Experimental orobservational studies ofhigher consis-tency.
C. Casereports(non-controlledstudies).
D. Expertopinionwithoutexplicitcriticalappraisal,orbased onphysiologyorbenchresearch.
Objective
Toestablish guidelinesbased onscientificevidenceforthe managementofperiodicfever,aphthousstomatitis, pharyn-gitisandadenitissyndrome.
Whenshouldwesuspectthatanindividualisacarrier
ofperiodicfever,aphthousstomatitis,pharyngitis
andadenitissyndrome?
Strategy
(PharyngitisORPharyngitidesORSoreThroatOR Lymphadeni-tisORAdenitisORStomatitis,AphthousORFeverORPFAPA) ANDPeriodicity*n=336.
DescribedbyMarshallforthefirsttimein1987,periodic fever,aphthousstomatitis,pharyngitisandadenitissyndrome –PFAPAistheautoinflammatorysyndromebelongingtothe groupofthe mostcommonrecurrent febrilesyndromes in childhood,althoughitsexactprevalenceisnotknown1(C).
Thisisarecurrent,febrile,self-limitingdisease,well charac-terizedfrom aclinical pointofview basedon casereports andcaseseriesdescriptions2(C).TheonsetofPFAPAalmost
alwaysoccursbeforetheageoffive,andinmostpatientsthe clinicalpictureresolvesspontaneouslybefore10–12yearsof age.Rarecaseshavebeenreportedinadulthood3,4(C).PFAPA
displaysayetunknownetiology,however,increased expres-sionofgenesrelatedtoIL-1,interferonandchemokineshave been found duringfebrile periods5 (D). A significant
num-berofpatientswithPFAPAsyndromehaveapositivefamily history of recurrence offebrile episodes suggesting a pos-sible geneticorigin; however, no mutation hasnever been identified6(C).
PFAPAsyndromeischaracterizedbythepresenceof sud-denrecurrentepisodesofhighfever,lastingfrom2to8days andwhich arerepeated every2–12weeks,accompaniedby aphthousulcers,pharyngitis,sometimeswithexudate,or cer-vicallymphadenopathy(upper cervicalregion),withmobile andpainless lymphnodesinthe absenceofupper respira-torytractinfection3(C).Patientsusuallycomplainofmalaise
hoursbeforethe onset ofanattack. Pharyngitisand cervi-cal adenitis are present in80–100% of these patients, and aphthousstomatitiscanbeseenin60–70%.Otherassociated symptomsareabdominalpain,arthralgia,headache,nausea orvomiting7(C).Forthediagnosisofthissyndrome,thereis
noneedofthepresenceofthewholegroupofsymptoms,and oneshouldruleoutthepossibilityofanepisodeofupper respi-ratorytractinfection;thepatientmustpresentasymptomatic periodsbetweenattacksandmaintainnormalpsychomotor growthanddevelopment8(D).
Recommendation
PFAPA is a diagnosis of exclusion established on clinical grounds,andonemustsuspectofthisprobleminchildren with recurrent and periodic febrile episodes of unknown
origin,orwithrecurrenttonsillitis,interspersedwith asymp-tomatic periods,especiallyinchildrenwith agoodgeneral conditionandwithpreservationofweightandheight devel-opment.Othermonogenicauto-inflammatorydiseasessuch asaperiodicsyndromeassociatedwithtumornecrosisfactor receptor(TRAPS)andmevalonatekinasedeficiency,shouldbe takeninconsiderationinthedifferentialdiagnosis.
Whattestsshouldberequiredfortheevaluation
ofpatientswithperiodicfever,aphthousstomatitis,
pharyngitisandadenitissyndrome?
Strategy
(PharyngitisORPharyngitidesORSoreThroatOR Lymphadeni-tisORAdenitisORStomatitis,AphthousORFeverORPFAPA) ANDPeriodicity*AND(Diagnosis/Broad[filter])n=150.
Laboratoryfindings are nonspecificandthe diagnosisof PFAPA syndrome is established on clinical grounds.9 (C).
Although not producing pathognomonic changes, comple-mentarytestsshouldberequestedtosupporttheexclusionof otherdiagnoses.Crisesareoftenassociatedwithleukocytosis andmoderateneutrophiliaandhigherythrocyte sedimenta-tionrate(ESR)andC-reactiveprotein(CRP),whichnormalize in the intervals between episodes10 (C). Hemoglobin levels
arenormal,andplateletlevelsmaybenormalorslightly ele-vated.Atonsilsecretionculturemaybeperformedtoexclude diseasesthatmayexhibitsimilarsymptoms,especially strep-tococcalinfection11(D).
Recommendation
LaboratoryfindingsarenonspecificandPFAPAisadiagnosisof exclusionestablishedonclinicalgrounds.Nopathognomonic changesarefoundwithadditionaltests.
Whatistheroleofsurgicalapproach(tonsillectomywith
orwithoutadenoidectomy)inthetreatmentofperiodic
fever,aphthousstomatitis,pharyngitisandadenitis
syndrome?
Strategy
(PharyngitisORPharyngitidesORSoreThroatOR Lymphadeni-tisORAdenitisORStomatitis,AphthousORFeverORPFAPA) ANDPeriodicity*AND(Therapy/Broad[filter])n=93.
Severalcaseserieshaveshowngoodresults,withreportsof completeresolutionofsymptomsinpatientswithPFAPAwho underwentsurgery(tonsillectomy)12–16 (C).However,thereis
controversyregardingthisapproach17(C).Asystematicreview
analyzingevidenceontheroleoftonsillectomyor adenoidec-tomy intreatingchildrenwithPFAPA syndromefoundthat thesuccessofthesurgicalapproachiswidelyvariable,with studiesdemonstratingcompleteresolutionofsymptoms,and others which did not identify any clinical improvement18
(A). A meta-analysis published in 2010 noted that, when comparingtheclinicaltreatmentwithcorticosteroidsversus
tonsillectomy,boththerapieswereequallyeffectivein treat-ingPFAPA.However,surgicalinterventionwasconsideredthe bestchoiceinthelongrun19(A).Takingintoaccountthe
PFAPAclearlyaffecttheirqualityoflifeorinthosewithpoor responsetomedicaltreatment.
Arandomizedclinicaltrialcarriedoutinordertoassessthe effectivenessoftonsillectomyinchildrenwithameanageof 4.1years(n=26)andwhohadsufferedatleastfiveepisodes relatedtoPFAPAsyndromefoundthatallchildrenwhohad undergonetonsillectomy(n=14)werefreeofsymptomsafter a6-month follow-up,withdisappearance offeverepisodes. Ontheotherhand,inthegroupunderclinicalsurveillance onlyinhalfofthesepatientsthesymptomssubsided(6/12)20
(B).Fourofthe14childrenwhounderwentsurgicaltreatment showedafebrileepisodecompatiblewithperiodicfeverwithin sixmonthsaftersurgeryversus34episodesreportedbyall chil-dreninthecontrolgroup(0.05episodesperchild/monthin thesurgicalgroupversus0.47episodesperchild/monthinthe controlgroup,basedona6-monthperiodoffollow-up).Aftera 6-monthfollow-up,42%ofthechildrenascribedtothecontrol groupweresubmittedtosurgicaltreatmentduetopersistence ofsymptoms.Inthisstudy,nocomplicationsrelatedtosurgery wereidentified20(B).
Inanothernon-blinded,randomized,clinicaltrial,which alsoanalyzedtheroleoftonsillectomy(withadenoidectomy), childrendiagnosedwithPFAPAsyndrome(n=39)were allo-catedforsurgicaltreatment(n=19)orclinicalfollow-uponly (control group n=20), and both groups received treatment withcorticosteroids21(B).Inthisstudy,attheendofan
18-monthperiodoffollow-uptheauthorsidentifiedacomplete resolutionofsymptomsin13 patients;12ofthesepatients (12/19)had been randomized forsurgical treatment. Over-all,12 episodes ofPFAPA syndrome were identified in the groupundergoingsurgeryversus179episodesrecordedinthe controlgroupduringthe18-monthfollow-up(0.04episodes perchild/monthinthesurgicalgroupversus0.5episodesper child/monthinthecontrolgroup;RR=0.07;95%CI:0.04–0.13). The proportion of patients who experienced resolution of symptomswithsurgeryversusclinicalfollow-upwas63% ver-sus5%respectively21(B).
Recommendation
Theevidencesupportingtheindicationforsurgicaltreatment (tonsillectomy withor without adenoidectomy) ofpatients withPFAPAsyndromeisbasedontwonon-blinded, random-izedclinicaltrialsthatincludedsmallnumbersofpatients22,23
(A).Althoughthesestudiesdemonstrateeffectivenessof sur-gical treatment with immediate and long-term resolution ofsymptoms relatedto this syndrome,each case must be assessed individually, and further studies should be con-ducted.Takingintoaccountthepossibilityofasurgicalrisk relatedtotonsillectomy,someauthorssuggest thatsurgery shouldbeconsideredinthosepatientsinwhomthe symp-tomsofPFAPAclearlyaffecttheirqualityoflifeorinthose withpoorresponsetomedicaltreatment.22
Whatistheroleofcorticosteroidsinthetreatment
ofperiodicfever,aphthousstomatitis,pharyngitis
andadenitissyndrome?
Strategy
(PharyngitisORPharyngitidesORLymphadenitisORAdenitis ORStomatitis,Aphthous)AND(Fever,PeriodicORPeriodicity
ORSyndromeORPFAPA)AND(SteroidsORGlucocorticoid*OR PrednisoneORDexamethasone)=208.
Seriesandcasereportshavedemonstratedtheoccurrence offeverresolutioninlessthan6h,andoftheothersymptoms inlessthan48hafteraninitialdoseofprednisone1–2mg/kg, withaseconddoseof0.5–1mg/kgthatmayberepeatedifthe diseasehasnotbeencontrolledwithin48–72h3,7,24–27(C).
A caseseries with12 children showedimmediate fever improvementinninepatientsafterthedoseofprednisone, andtheintervalbetweenattackswasextendedfrom21days (meanintervalpriortotreatment)to133daysposttreatment (p=0.007)2 (C).And adecrease of50% inthe timebetween
attackswasalreadyassignedtocorticosteroids.4
InadultswithPFAPA,prednisoneatadoseof60mg/day administeredattheonsetofsymptoms,improvedfever;anda significantimprovementofothersymptoms,particularlywith respecttoadecreaseoftonsillarexudateandoralulcers,was alsoobserved.Duringfollow-up,eightofthe15patients evalu-atedexhibitedanincreasedincidenceofcrisisepisodes,with recurrenceat3-weekintervals afterthebeginning of treat-mentwithcorticosteroids4(C).
Inarandomizedclinicaltrial28(B)with41children,
treat-mentwithlowdosesofprednisonewascomparedwithhigher dosesofthisdrug.Thechildrenweredividedintotwogroups toreceive0.5mg/kg/dayor2mg/kg/day.Inthefirstgroup,the feverceasedin8–12h,andinthesecondgroupin6–8h.The othersymptomsdisappearedafter24hinbothgroups.There was no increase in the interval between crises with pred-nisoneinthesetwodoses.Theadverseeffectsobservedwere restlessnessandsleepdisturbance,whichcanbeminimized byadministeringthedoseofthecorticosteroidatleast4–6h beforebedtime.
Recommendation
Theuseofprednisoneatadoseof1–2mg/kgbodyweightat theonsetoffeverinpatientswithPFAPAhasprovedeffective in a number of series and case reports and in a random-izedstudy.Despitethesmallsamplesinthesetrials,andalso takinginto accountthatthesewerenonplacebo-controlled studies,theuseofprednisoneondemandprobablyisavalid therapeuticstrategyforcrisesofthissyndrome,withalow riskofadverseevents.29Thebestevidenceisstillneededto
supportitsuseinPFAPApatients.
WhatistheroleofIL-1inhibitorsinthetreatment
ofperiodicfever,aphthousstomatitis,pharyngitis
andadenitissyndrome?
Strategy
(PharyngitisORPharyngitidesORLymphadenitisORAdenitis ORStomatitis,Aphthous)AND(Fever,PeriodicORPeriodicity ORSyndromeORPFAPA)AND(Interleukin1Receptor Antag-onistProteinORAnakinraORKineretORAntrilORReceptors, Interleukin)n=19.
Onestudylookedatthebloodprofile,inflammatory mark-ers and cytokine levels in 15 children with PFAPA in and off-febrileepisodes. Theabilityofmonocytes tosecrete IL-1wasassessedbyELISA;andactivesecretionofIL-1was visualizedbyWesternblotting.Duringfebrileperiods, stim-ulated monocytes secreted significantly more IL-1 versus
off-febrile episodes. The authors concluded that an IL-1 releasedysregulationbymonocytesoccursinpatientswith PFAPAsyndrome,andapproximately20%hadNLRP3variants, suggestingthatinflammasome-relatedgenesmaybeinvolved inthisauto-inflammatorysyndrome31(C).Inonecasereport,
a27-yearoldadultpatientwhoexhibitedresistanceagainst conventional treatmentwith prednisoneand tonsillectomy andfeaturingmorethan10attacks/yearwastreatedwiththe IL-1inhibitor,anakinra,atadoseof100mg/day.Aftera 6-monthfollow-up,thepatientremainedasymptomatic,with nosignalofrecurrence32(C).
Inarandomizedclinicaltrialwith21children,blood sam-plesofchildrenwithPFAPA,ofchildrenwithotherhereditary periodicfever,andofhealthychildrenwereanalyzed.Inthose patientswithPFAPAasignificantelevationofC3,IL-18and IL-1 in febrile periodswas noted. In the same study, five patients withPFAPA were treated with arecombinant IL-1 receptorantagonist;inallpatients,aquickclinicalresponse wasobserved5(B).
Recommendation
WhiletheresultsobtainedwithIL-1inhibitorsare promis-ing,thestudiesare limitedtoafewcasereports,requiring randomizedclinicaltrialstodefinetheroleofIL-1inhibitors inthemanagementofPFAPA.
Conflict
of
interests
MariaTeresaR.A.TerreriandFlavioRobertoSztajnbokserve asspeakersforNovartis.ClovisArturAlmeidadaSilvahasa conflictofinterestswithConselhoNacionaldeDesenvolvimento Científico eTecnológico (CNPq 302724/2011-7), Federico Foun-dationandNúcleode ApoioàPesquisa“SaúdedaCrianc¸aedo Adolescente”,USP(NAP-CriAd).Theotherauthorsdeclareno conflictofinterests.
r
e
f
e
r
e
n
c
e
s
1. MarshallGS,EdwardsKM,ButlerJ,LawtonAR.Syndromeof periodicfever,pharyngitis,andaphthousstomatitis.JPediatr. 1987;110(1):43–6.PMID:3794885.
2. FederHM,SalazarJC.Aclinicalreviewof105patientswith PFAPA(aperiodicfeversyndrome).ActaPaediatr.
2010;99(2):178–84.Review.PMID:19889105.
3. PadehS,BrezniakN,ZemerD,PrasE,LivnehA,LangevitzP, etal.Periodicfever,aphthousstomatitis,pharyngitis,and adenopathysyndrome:clinicalcharacteristicsandoutcome.J Pediatr.1999;135(1):98–101.PMID:10393612.
4. PadehS,StoffmanN,BerkunY.Periodicfeveraccompaniedby aphthousstomatitis,pharyngitisandcervicaladenitis syndrome(PFAPAsyndrome)inadults.IsrMedAssocJ. 2008;10(5):358–60.PMID:18605359.
5. StojanovS,LapidusS,ChitkaraP,FederH,SalazarJC,Fleisher TA,etal.Periodicfever,aphthousstomatitis,pharyngitis,and
adenitis(PFAPA)isadisorderofinnateimmunityandTh1 activationresponsivetoIL-1blockade.ProcNatlAcadSciUS A.2011;108(17):7148–53.PMID:21478439.
6.CochardM,CletJ,LeL,PilletP,OnrubiaX,GuéronT,etal. PFAPAsyndromeisnotasporadicdisease.Rheumatology (Oxford).2010;49(10):1984–7.PubMedPMID:20601652. 7.ThomasKT,FederHMJr,LawtonAR,EdwardsKM.Periodic
feversyndromeinchildren.JPediatr.1999;135(1):15–21.PMID: 10393598.
8.HoferM,MahlaouiN,PrieurAM.Achildwithasystemic febrileillness–differentialdiagnosisandmanagement.Best PractResClinRheumatol.2006;20(4):627–40.Review.PMID: 16979528.
9.SampaioI,MarquesJG.Periodicfeverwithaphthous stomatitis,pharyngitisandadenitis:reportof21cases.Acta MedPort.2011;24(1):37–42.Portuguese.PMID:21672440. 10.FørsvollJA,OymarK.C-reactiveproteinintheperiodicfever,
aphthousstomatitis,pharyngitisandcervicaladenitis (PFAPA)syndrome.ActaPaediatr.2007;96(11):1670–3.PMID: 17937691.
11.FederHMJr.Periodicfever,aphthousstomatitis,pharyngitis, adenitis:aclinicalreviewofanewsyndrome.CurrOpin Pediatr.2000;12(3):253–6.Review.PMID:10836162. 12.GalanakisE,PapadakisCE,GiannoussiE,KaratzanisAD,
BitsoriM,HelidonisES.PFAPAsyndromeinchildren evaluatedfortonsillectomy.ArchDisChild.2002;86(6):434–5. PMID:12023179.
13.WongKK,FinlayJC,MoxhamJP.RoleofTonsillectomyin PFAPASyndrome.ArchOtolaryngolHeadNeckSurg. 2008;134(1):16–9.PMID:18209129.
14.LicameliG,JeffreyJ,LuzJ,JonesD,KennaM.Effectof adenotonsillectomyinPFAPAsyndrome.ArchOtolaryngol HeadNeckSurg.2008;134(2):136–40.Review.PMID:18283154. 15.LicameliG,LawtonM,KennaM,DedeogluF.Long-term
surgicaloutcomesofadenotonsillectomyforPFAPA syndrome.ArchOtolaryngolHeadNeckSurg. 2012;138(10):902–6.PMID:23069819.
16.KyvsgaardN,MikkelsenT,KorsholmJ,VeirumJE,HerlinT. Periodicfeverassociatedwithaphthousstomatitis, pharyngitisandcervicaladenitis.DanMedJ. 2012;59(7):A4452.PMID:22759839.
17.ParikhSR,ReiterER,KennaMA,RobersonD.Utilityof tonsillectomyin2patientswiththesyndromeofperiodic fever,aphthousstomatitis,pharyngitis,andcervicaladenitis. ArchOtolaryngolHeadNeckSurg.2003;129(6):670–3.PMID: 12810475.
18.LeongSC,KarkosPD,ApostolidouMT.Istherearoleforthe otolaryngologistinPFAPAsyndrome?Asystematicreview.Int JPediatrOtorhinolaryngol.2006;70(11):1841–5.Review.PMID: 16908073.
19.PeridisSI,PilgrimG,KoudoumnakisE,AthanasopoulosI, HoulakisM,ParpounasK.PFAPAsyndromeinchildren:a meta-analysisonsurgicalversusmedicaltreatment.IntJ PediatrOtorhinolaryngol.2010;74(11):1203–8.PMID:20832871. 20.RenkoM,SaloE,Putto-LaurilaA,SaxenH,MattilaPS,
LuotonenJ,etal.Arandomized,controlledtrialof tonsillectomyinperiodicfever,aphthousstomatitis, pharyngitis,andadenitissyndrome.JPediatr. 2007;151(3):289–92.PMID:17719940.
21.GaravelloW,RomagnoliM,GainiRM.Effectivenessof adenotonsillectomyinPFAPAsyndrome:arandomizedstudy. JPediatr.2009;155(2):250–3.PMID:19464029.
22.GaravelloW,PignataroL,GainiL,TorrettaS,SomiglianaE, GainiR.Tonsillectomyinchildrenwithperiodicfeverwith aphthousstomatitis,pharyngitis,andadenitissyndrome.J Pediatr.2011;159(1):138–42.Review.PMID:21300374. 23.BurtonMJ,PollardAJ,RamsdenJD,ChongLY,VenekampRP.
pharyngitisandcervicaladenitissyndrome(PFAPA).Cochrane DatabaseSystRev.2014;9:CD008669.PMID:25209127. 24.LagosFAR,FauraFJS.Periodicfever,aphthousstomatitis,
pharyngitis,cervicaladenitissyndrome.AtenPrimaria. 2012;44(11):684–5.
25.TasherD,SomekhE,DalalI.PFAPAsyndrome:newclinical aspectsdisclosed.ArchDisChild.2006;91(12):981–4.PMID: 16595648.
26.KrólP,BöhmM,SulaV,DytrychP,KatraR,NemcováD,etal. PFAPAsyndrome:clinicalcharacteristicsandtreatment outcomesinalargesingle-centrecohort.ClinExpRheumatol. 2013;31(6):980–7.PMID:24237762.
27.DeCuntoC,BritosM,EymannA,DeltettoN,LiberatoreD. Periodicfever:adescriptionoftwelvepatientswithperiodic fever,aphthousstomatitis,pharyngitisandcervicaladenitis (PFAPA).ArchArgentPediatr.2010;108(5):445–8.PMID: 21132234.
28.YazganH,GültekinE,YazıcılarO,SagunÖF,UzunL. Comparisonofconventionalandlowdosesteroidinthe treatmentofPFAPAsyndrome:preliminarystudy.IntJPediatr Otorhinolaryngol.2012;76:1588–90.PMID:22858452.
29.TerHaarNI,LachmannH,ÖzenS,WooP,UzielY,ModestoC, etal.Treatmentofautoinflammatorydiseases:resultsfrom theEurofeverRegistryandaliteraturereview.AnnRheum Dis.2013;72(5):675–85.PMID:22753383.
30.StojanovS,HoffmannF,KeryA,RennerED,HartlD,LohseP, etal.CytokineprofileinPFAPAsyndromesuggests
continuousinflammationandreducedanti-inflammatory response.EurCytokineNetw.2006;17:90–7.PMID: 16840027.
31.KollyL,BussoN,vonScheven-GetA,BagnoudN,MoixI, HolzingerD,etal.Periodicfever,aphtousstomatitis, pharyngitis,cervicaladenitissyndromeislinkedto dysregulatedmonocyteIL-1production.JAllergyClin Immunol.2013;131(6):1635–43.PMID:
23006543.
