Desordens olfativas e gustativas na COVID-19: uma revisão sistemática

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www.bjorl.org

Brazilian

Journal

of

OTORHINOLARYNGOLOGY

REVIEW

ARTICLE

Olfactory

and

taste

disorders

in

COVID-19:

a

systematic

review

夽

Klinger

V.T.

da

Costa

a_,_∗

_,

_Aline

_Tenório

_Lins

_Carnaúba

b

_,

Katianne

Wanderley

Rocha

b

_,

_Kelly

_Cristina

_Lira

_de

_Andrade

c

_,

Sonia

M.S.

Ferreira

b

_,

_Pedro

_de

_L.

_Menezes

c

a_Universidade_Federal_de_Alagoas_(UFAL),_Maceió,_Alagoas,_Brazil b_Centro_{Universitário}_Cesmac,_Maceió,_Alagoas,_Brazil

c_Universidade_Estadual_de_Ciências_da_Saúde_de_Alagoas_(UNCISAL),_Maceió,_Alagoas,_Brazil

Received11May2020;accepted14May2020 Availableonline9June2020

KEYWORDS COVID-19; SARS-CoV-2; Olfactorydisorders; Tastedisorders; Olfactiondisorders Abstract

Introduction:TheSARS-CoV-2viruscausesCOVID-19,anditisresponsibleforthelargest pan-demicsincethe1918H1N1inﬂuenzaoutbreak.Theclassicsymptomsofthediseasehavebeen welldeﬁned bytheWorldHealthOrganization;however,olfactory/gustatory disordershave beenreportedinsomestudies,buttherearestillseveralmissingpointsintheunderstanding andintheconsensusabouttheclinicalmanagementofthesecases.

Objective: Toidentifyevidenceinthescientiﬁcliteratureaboutolfactory/gustatorydisorders, theirclinicalpresentation,prevalenceandpossiblespeciﬁctreatmentsassociatedwith COVID-19.

Methods:AsystematicreviewofarticlespublisheduptoApril25,2020wasperformedin Med-line,CochraneClinicalTrials,ScienceDirect,Lilacs,ScopusandGoogleSchoolar,OpenGrey.eu, DissOnline,TheNewYorkAcademyofMedicineandResearchGate.Inclusioncriteria:(1)Studies onpatientswithCOVID-19;(2)RecordsofCOVID-19signs/symptoms,andolfactory/gustatory functions. Exclusioncriteria:(1)Studiesonnon-human coronavirus;(2) Reviewarticles;(3) Experimentalstudies(inanimalsorinvitro);(4)Olfactory/gustatorydisordersinitiatedprior toSARS-CoV-2 infection.The riskassessmentofbiasofthe selectedstudieswasperformed usingtheNewcastle-Ottawascale.

Results:Sixarticlesfromthe1788recordsmettheinclusioncriteriaandwereanalyzed.Atotal of1457patientsofdifferentethnicitieswereassessed;ofthem,885(60.7%)and822(56.4%) had smell andtastedisorders, respectively,with women beingmostoften affected.There

夽 _Please_cite_this_article_as:_Costa_KV,_Carnaúba_AT,_Rocha_KW,_Andrade_KC,_Ferreira_SM,_Menezes_PL._Olfactory_and_taste_disorders_in COVID-19:asystematicreview.BrazJOtorhinolaryngol.2020;86:781---92.

∗_{Corresponding}_author.

E-mail:klingercostamcz@gmail.com(K.V.Costa).

PeerReviewundertheresponsibilityofAssociac¸ãoBrasileiradeOtorrinolaringologiaeCirurgiaCérvico-Facial. https://doi.org/10.1016/j.bjorl.2020.05.008

1808-8694/©2020AssociaçãoBrasileiradeOtorrinolaringologiaeCirurgiaCérvico-Facial.PublishedbyElsevierEditoraLtda.Thisisanopen accessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).

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wereolfactory/gustatory disordersevenwithoutnasalobstruction/rhinorrheaandbeginning evenbefore the signs/symptomsofCOVID-19;the recovery ofsmell/taste, when itoccurs, usually happened inthe first two weeks after COVID-19 resolution.There is evidencethat olfactory/gustatorydisordersarestrongpredictorsofinfectionbySARS-CoV-2,anditispossible torecommendpatientisolation,asearlyasofthemedicalconsultation,preventingthespread ofthevirus.Noscientificevidencehasbeenidentifiedforeffectivetreatmentsforanyofthe disorders.

Conclusion:Olfactory/gustatory disordersmay occur at varyingintensities andprior tothe generalsymptomsofCOVID-19andshouldbe consideredaspartoftheclinical featuresof COVID-19,eveninmildcases.Thereisstillnoscientiﬁcevidenceofspeciﬁctreatments for suchdisordersinCOVID-19disease.

© 2020 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). PALAVRAS-CHAVE COVID-19; SARS-CoV-2; Distúrbiosolfativos; Distúrbiosdopaladar; Distúrbiosdoolfato

DesordensolfativasegustativasnaCOVID-19:umarevisãosistemática

Resumo

Introdução: OvírusSARS-CoV-2causaaCOVID-19eéresponsávelpelamaiorpandemiadesdeo surtodeinfluenzaH1N1de1918.Ossintomasclássicosdadoençajáforambemdefinidospela OrganizaçãoMundialdaSaúde;entretanto,distúrbiosolfativo-gustativostêmsidorelatadosem algunsestudos,masaindacomváriaslacunasnoentendimentoenoconsensosobreacondução clínicadessescasos.

Objetivo:Identificarevidênciasnaliteraturacientíficasobreosdistúrbiosolfativo-gustativos acercadaapresentaçãoclínica,prevalênciaepossíveistratamentosespecíficosassociadosà COVID-19.

Método: Revisãosistemáticadeartigospublicadosaté25deabrilde2020nasbasesdedados: Medline,CochraneClinicalTrials,ScienceDirect,Lilacs,ScopuseGoogleSchoolar,OpenGrey.eu, DissOnline,TheNewYorkAcademyofMedicineeReasearchGate.Foramcritériosdeinclusão:1) EstudoscomindivíduoscomCOVID-19;2)Registrodossinais/sintomasdaCOVID-19edasfunções olfativo-gustativa.Foramcritériosdeexclusão:1)Estudossobrecoronavírusnão humano;2) Artigosderevisão;3)Estudosexperimentais(emanimaisouinvitro);4)Distúrbios olfativos-gustativosiniciadospreviamenteàinfecçãopeloSARS-CoV-2.Aavaliaçãoderiscodeviésdos estudosselecionadosfoifeitapormeiodaescaladeNewcastle-Ottawa.

Resultados: Seisartigosdos1.788registrosforamselecionados.Umtotalde1.457pacientes de diversas etnias foi avaliado; desses, 885 (60,7%) apresentaram perda do olfato e 822 (56,4%)perdadopaladar,sendoasmulheresasmaisafetadas.Osdistúrbiosolfativo-gustativos estiveram presentes mesmo sem obstrução nasal/rinorreia e com início mesmo antes dos sinais/sintomasclínicosdaCOVID-19;arecuperaçãodoolfato/paladar,quandoocorre, geral-mentese dánasduasprimeiras semanasapósaresoluçãodadoença.Háevidências queos distúrbiosolfativo-gustativossejamfortespreditoresdeinfecçãopeloSARS-CoV-2,podendo-se recomendaroisolamentodopaciente,jáapartirdaconsultamédica,paraevitaradisseminação dovírus.Nãoforamidentificadasevidênciascientíficasparatratamentoseficazesparanenhum dosdistúrbios.

Conclusão:Podemocorrer distúrbios olfativo-gustativosem intensidadesvariáveis eprévios aossintomasgeraisdaCOVID-19,devemserconsideradoscomopartedossintomasdadoença, mesmoemquadrosleves.Nãoháaindaevidênciascientíficasdetratamentosespecíficospara taisdistúrbiosnaCOVID-19.

© 2020 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Publicado por Elsevier Editora Ltda. Este é um artigo Open Access sob uma licença CC BY (http:// creativecommons.org/licenses/by/4.0/).

Introduction

Smellandtasteareessentialsensoryfunctionsbothforgood qualityof lifeandfor itspreservation, byidentifying

sev-eralharmfulodorsandﬂavors.ViralUpperRespiratoryTract Infections(URTIs)canleadtoOlfactory(OD)andGustatory (GD)Disordersofvaryingdegreesandduration,1_which_can

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virus and parainﬂuenza, respiratory syncytial virus, ade-novirus and the severe acute respiratory syndrome virus (SARS-CoV-2).2

Coronavirusdisease2019(COVID-19)becameaviral pan-demicthatemergedfromEastAsiaduetoSARS-CoV-2.3 _In

Brazil,thenumberofcasescontinuestoincrease,withmore than66,000conﬁrmedcasesbytheendofApril20204_;

how-ever,itisestimatedthatthenumberisevenhigher,asthe numberofdiagnostictestsperformedisstillinsufﬁcientfor thenationaldemand.

In COVID-19, the most common otorhinolaryngological symptoms arecoughing, sore throatand dyspnea; rhinor-rheaandnasalcongestionhavealsobeenfound; however, therearereportsofOD/GD5,6_and_that_they_are_present_even

before molecular conﬁrmation of SARS-CoV-2 infection.6,7

These observationswere maderecently, in countries that startedtoperformmoleculartestsforCOVID-19more exten-sively,inwhichpatientsinfectedwithSARS-CoV-2reported severeODandGDwithoutrhinorrheaornasalobstruction.In thebeginning,COVID-19wasnotsuspectedinsomeofthese patients,astheydidnothavefever,coughoranyother clas-sicgeneralsigns/symptomsofCOVID-19.TheODandGDin COVID-19stillshowgapsintheirunderstandingofboththe clinicalspectrumandthetreatmenttobeproposed.

The advancementof knowledgeonaspecific topiccan befacilitatedthroughsystematicreviews(SR),whichmake itpossibletoidentify,analyzeandsynthesizethebest sci-entificevidenceforbestclinicalpractices,especiallyinthe faceofnewclinicalscenariossuchasthecurrentCOVID-19 pandemic, inthat randomizedcontrolledstudiesand pre-cise recommendations for their management are not yet available.TheobjectiveofthisSRistoidentifyevidenceof current knowledge on olfactory-gustatorydisorders about theclinical presentation, prevalenceand possiblespecific treatmentsassociatedwithCOVID-19.

Methods

The creation of this Systematic Review (SR) aimed to answerthefollowingquestion:‘‘Whatistheassociationof olfactory/gustatory disorders,includingtheir clinical pre-sentations andtreatments, with COVID-19?’’,constructed with the help of the PICO strategy. This SR is in agree-ment withthe ‘‘Preferred ReportingItems for Systematic ReviewsandMeta-AnalysesStatement(PRISMA)’’checklist.8

TheprotocolwasregisteredonApril24,2020atthe Interna-tionalProspectiveRegisterofSystematicReviews---Prospero database (https://www.crd.york.ac.uk/PROSPERO/) under registrationnumberCRD42020181524.

Searchstrategy

The strategies aimed at a complete search, including descriptors (Medical Subject Headings - Mesh) and free terms, which consisted of: COVID-19, 2019-nCoV, 2019 novel coronavirus pneumonia, SARS-CoV, SARS-CoV-2,sars coronavirus,coronavirus,coronavirusinfection,coronavirus COVID-19, novel coronavirus), COVID-19 clinical features, olfactorydisorders,olfactiondisordersandtastedisorders. Toidentifytherelevantarticlesfortheproposedquestion,a searchstrategywasdeveloped:(COVID-19OR2019-nCoVOR

2019novel coronavirus pneumoniaOR SARS-CoVOR SARS-CoV-2 OR sars coronavirus OR coronavirus OR coronavirus infection OR coronavirus COVID-19 OR novel coronavirus) AND(COVID 19clinicalfeatures ORolfactorydisordersOR olfaction disorders OR taste disorders); this strategy was adaptedtothedatabases,andthecorrespondingtermswere appliedinPortugueseandSpanishatLilacsdatabase.There wasnorestrictiononthelanguageofpublication.The com-pletesearchstrategyisshowninthesupplementarymaterial (Appendix1).

BetweenApril 2 and25,2020,the followingelectronic databases were searched: Medline via PubMed, Cochrane Clinical Trials, ScienceDirect, Lilacs, Scopus and Google Schoolar,as well asthe grayliterature OpenGrey.eu, Dis-sOnline,TheNewYork AcademyofMedicine andResearch Gate.Topreventcitationbias,therewasnomanualsearch fortheincludedarticlesandspecialistsintheﬁeldwerenot contacted.9

After the search, the references of each database were exported to the Mendeley® _program

(https://www.mendeley.com/) aiming to identify all arti-clesinduplicate,promotegreaterselectionreliabilityand proceedtotheeligibilitycriteriastep.

Eligibilitycriteria

Thefollowinginclusioncriteriawereconsidered:(1) Obser-vationalstudieswithindividualsdiagnosedwithcoronavirus infection and (2) recording of the signs and symptoms of COVID-19, with clinical aspects related to olfactory and/orgustatoryfunction.Thefollowingexclusioncriteria wereconsidered:(1)Studiesonnon-humancoronavirus;(2) Reviewarticles;(3)Experimentalstudies (inanimalsor in vitro);(4)ClinicalreportofOD/GDwithonsetpriortothe SARS-CoV-2infection.

Dataextraction

Thesearchforthearticleswascarriedoutbytwo review-ers.Thetitlesandabstractsoftheretrievedarticleswere independently assessedby two researcherswho werenot blindedtotheauthorsorthetitlesofjournals.Thefull ver-sionsofthepotentiallyeligiblearticleswereretrievedfor furtherevaluationandwerecarriedoutinthreestages: 1. Identiﬁcationandreadingoftitlesindifferentelectronic

databases.Articlesthatclearlydidnotmeetanyofthe inclusionorexclusioncriteriawereexcluded.

2. Reading ofthe abstractsof thestudiesselected inthe firstphase.Likewise,articlesthatclearlydidnotmeet anyoftheinclusionorexclusioncriteriawereexcluded. 3. All studies that were not excluded in these first two stageswerereadinfullfortheselectionoftheonesthat wouldbeincludedinthisSystematicReview(SR). The main datafor each article wasfullycollectedand insertedintoadatabasecreatedintheMicrosoftOfficeExcel 2010®_software._There_were_no_{disagreements}_between_the

evaluators.Astandard formfor data storage wascreated basedon themodel adopted by Cochrane.10 _For_a _better

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Table1 TheNewcastle-Ottawascaleadaptedforcross-sectionalobservationalstudies.

Iselection:(maximum:5stars)

1.Representativenessofthesample

(a)Trulyrepresentativeofthemeaninthetargetpopulation(allsubjectsorrandomizedsample) (b)Alittlerepresentativeofthemeaninthetargetpopulation(non-randomizedsample)

2.Selectedusergroups

(a)Relevantselectionofindividualstoexcludefactorsthatinﬂuenceoutcomes(suchascertaindiseasesormedications thathaveanegative/positiveeffectonanycondition)

3.Samplesize

(a)Justiﬁedandsatisfactory(Powerofcalculationincluded)

4.Diagnosis

(a)Characterizationofthediagnosis (b)Determinationofexposure

IIcomparability(maximum:2stars)

1.Thesubjectsindifferentgroupsofresultsarecomparable,basedonthestudydesignoranalysis.Confoundingfactors arecontrolled

(a)Thestudycontrolsthemostimportantfactor(selectone) (b)Controlofthestudyforanyadditionalfactors

IIIresults(maximum:3stars)

1.Determinationofthemethod

(a)Validatedmeasurementmethod

(b)Measurementmethodnotvalidated,butthemethodisavailableordescribed

2.Statisticaltests

(a)Thestatisticaltestusedtoanalyzethedataisclearlydescribedandappropriate,andthemeasurementofthe associationisshown;includingSD/SEandtheprobabilitylevel(p-value)

Total(maximum:10stars)

following variables of the selectedarticles: Title, author, studylocation,studydesign,samplesize(N),patients’mean ageandethnicity,boththediagnosticmethodandthemost prevalentgeneralsigns/symptoms andtheseverity ofthe clinicalpictureofCOVID-19,methodsusedinthe olfactory-gustatoryevaluationandtheprevalenceofODandGD.The outcomessoughtinthestudieswereboththedemographic data,prevalenceandclinicalexpressionsofOD/GD,aswell aspossiblespeciﬁctreatmentsforsuchdisordersinpatients diagnosedwithCOVID-19.

Riskofbiasassessment

Theriskofbiaswasassessedaccordingtothe recommenda-tionsinthemanualandtheNewcastle-Ottawascaleadapted forcross-sectionalobservationalstudies.11_Study_quality_was

independentlyassessed bytworesearchersandthe diver-genceswereevaluatedbyconsensus.The maximumscore tobeachievedwas10pointsandtheitemsevaluatedonthe scalewere:(1)Representativenessofthesample;(2)Sample size;(3)Characterizationofthediagnosis;(4)Riskexposure assessment (risk factor); (5) Comparability, toinvestigate whetherindividualsindifferentgroupsofresultsare compa-rable, based on the study design or analysis, control of confoundingfactors;(6)Evaluation ofresults and(7) Sta-tisticaltest(Table1).

Aftertheseevaluations,theselectedstudieswere sub-mitted toa statistical analysis toverify the possibilityof

building ameta-analysis.This analysiscombines and sum-marizes theresults of severalstudies, thus increasingthe accuracyandpowerofevidenceoftheresults.

Results

Includedstudies

In the ﬁrst phase of this SR, 1788 articles were found in sixdatabasesandnone inthegrayliterature.After elimi-nating1023studiesinduplicate,765wereselectedforthe readingoftitlesandabstracts.Atotalof749wereexcluded accordingtotheestablishedselectioncriteria(62studieson non-humancoronavirus,301duetolackofdataonclinical aspects,375literaturereviewsand11experimentalstudies

in vitro) and16 articleswere selectedtoberead in full. Afterthereading,10articleswereexcludedastheydidnot havedataonsmell/taste(Table2).Therefore,sixfull arti-cleswereincludedinthequalitativeanalysis(Table3).The entirearticleselectionprocessisdescribedinFig.1,which showsthePrismaﬂowdiagramforinclusion.

Riskofbiasassessment

The analysis of the quality of the included articles and, consequently, of therisk of bias,is shown in Table 4. All included studies are characterized as observational and cross-sectional studies. Moreover, in the ﬁnal evaluation,

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Table2 Fulltextsexcludedfromtheanalysis.

Author Location Year Reasonforexclusion

Chenetal. China 2020 Absenceofdataonsmell/taste

Chengetal. China 2019 Absenceofdataonsmell/taste

Huangetal. China 2020 Absenceofdataonsmell/taste

Jinetal. China 2020 Absenceofdataonsmell/taste

Pivaetal. USA 2020 Absenceofdataonsmell/taste

Tianetal. China 2020 Absenceofdataonsmell/taste

Wangetal. China 2020 Absenceofdataonsmell/taste

Youngetal. Singapore 2020 Absenceofdataonsmell/taste

Zhengetal. China 2019 Absenceofdataonsmell/taste

Zhuetal. China 2020 Absenceofdataonsmell/taste

Table3 Studiesselectedaccordingtotheinclusionandexclusioncriteriaestablishedinthesystematicreview.

Article Title Author Location Studydesign n

1 NeurologicalManifestationsof HospitalizedPatientswith

COVID-19inWuhan,China:a retrospectivecaseseriesstudy

Maoetal.12 _China _{Retrospective} ₂₁₄

2 Olfactoryandgustatory

dysfunctionsasaclinical presentationof

mild-to-moderateformsofthe coronavirusdisease

(COVID-19):amulticenter Europeanstudy

Lechienetal.13 _Belgium,_France,

SpainandItaly

Multicentric (transversal)

417

3 SmellDysfunction:A

BiomarkerforCOVID-19

Moeinetal.14 _Iran _{Cross-sectional,}

observational

60

4 AssociationofChemosensory

DysfunctionandCOVID-19in PatientsPresentingwith Inﬂuenza-likeSymptoms

Yanetal.15 _USA _{Cross-sectional,}

observational

59

5 Self-reportedolfactoryloss associateswithoutpatient clinicalcourseinCOVID-19

Yanetal.16 _USA _{Retrospective} ₁₂₈

6 Lossofsmellandtastein combinationwithother symptomsisaStrongpredictor ofCOVID-19infection

Mennietal.17 _United_Kingdom _Survey ₅₇₉

Total 1457

all obtained a percentage of quality equal to or greater than80% (8/10),and fourofthe sixarticlesobtained the maximumscoreof90%(9/10).

Only oneofthestudies carriedoutacensusstudy,the otherstudiesdidnotperformarandomselectionofpatients, whichcompromisestherepresentativenessofthesamples, buttookintoaccountthesamplesize.

Allstudieswereconcernedwiththeparticipants’ selec-tion,deﬁningtheinclusionandexclusioncriteria,inorder toexcludefactorsthatcouldinﬂuencetheresultsfound.

Thesizeofthestudiedsampleswasadequatetothe cen-trallimittheoremforallstudies,andonlytwostudieshad samplessmallerthan300subjects.

Thecharacterizationofthediagnosisandthe determina-tionofexposurewereverywelldescribedinallstudies.All studiescontrolledatleastonevariable,allowinganefﬁcient comparisonamongallstudies.

Theevaluationoftheresultswascarriedoutinallstudies throughaspeciﬁc reportandthemethods weredescribed andvalidatedinallstudies.

Finally,allstudies showedappropriatestatisticaltests, withdescriptionofthestatisticaltests,thelevelsof signif-icanceandtheapplicationsused.

Itwasnotpossibletoperformameta-analysisinthisSR becausethearticlesincludedhadverydifferent methodolo-giesandmeasuresresultingfromthetests.

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Identification

Screening

Eligibility

Induction

Articles identified in the databases (n = 1.788) medline:124 lilacs:01 science direct: 877

scopus: 42 cochrane clinical trials:0 google scholar (n = 744)

Articles in gray literature

(n = 0)

Remaining articles after duplicates were removed (n = 765)

Eligible articles (n 16)

Articles deleted after reading the title and summary (n = 749) Non-human coronavirus (n = 62)

No relation to the clinical aspects (n 301) Literature review (n 375) In vitro experimental studies

Full-text articles assessed for eligibility (n = 06)

Articles excluded after reading the full text (n = 10) Lack of clinical data on smell

and/or taste

Studies included in the qualitative synthesis (n = 06)

Studies included in the quantitative synthesis

(meta-analysis) (n = 0)

Figure1 Diagramofidentiﬁcationandselectionﬂow.

Dataanalysis

Regardingthe overall characteristics of the included arti-cles(Table3),thesixstudieswerepublishedin2020,one inChina,12_one_in_Europe,13_one_in_Iran,14_two_in_the_United

States15,16 _and _one _in _the _United _Kingdom.17 _The _Chinese

study(Maoetal.)12 _{retrospectively}_evaluated₂₁₄_patients

fromthreehospitalsinWuhan;theEuropeanstudy(Lechien etal.)13_{cross-sectionally}_evaluated₄₁₇_patients_in_a

multi-centricmodel;theIranianstudy(Moeinetal.)14 _studied₆₀

patientswithCOVID-19and60subjectsinthecontrolgroup, matchedforageandgender;thetwoNorth-American stud-ieswerecarriedoutbythesamegroupofresearchers(Yan

etal.)15,16_; _while _the _British_study _(Menni _et_al.)17

evalu-ated,throughacensusstudy,579COVID-19positiveand1123 COVID-19negativepatients.Thedemographicdata,general symptomsandtheprevalence ofODandGD inpatientsin thesixstudiesaredepictedinTable5.

Intotal,thesixstudiesevaluated1457patients(Table3). In the study by Mao et al.,12 _the _sample _consisted _only

of Chinese patients; in the study by Lechien et al.,13

most of the sample consisted of European patients; in the study by Moein et al.,14 _all _patients _were

Ira-nians; in the two studies by Yann et al.,15,16 _most

patientswere North-American; andin thestudy by Menni et al.,17 _the _ethnicity _of _the _study _participants _was _not

recorded.

The exam used for diagnosing COVID-19 in the six studies was the RT-PCR (Real-Time Reverse-Transcription

PolymeraseChainReaction).Regardingthemostprevalent overallsigns/symptomsofCOVID-19,thereweredifferences betweengroups; fever wasthe mostprevalentsignin the studiesbyMaoetal.12_and_by_Moein_et_al.14_;_fatigue_was_the

ﬁrstsymptomintheﬁrststudybyYanetal.15_and_of_Menni

etal.17_;_coughing _was_the_ﬁrst_sign _in_the_second _study_by

Yanetal.16_and_in_the_study_by_Lechien_et_al.13_(Table_5).

Mao et al.12 _carried _out _the _study _at _three _hospitals

designated for the care of patients withCOVID-19, which belonged totheUnion Hospital of Huazhong University of ScienceandTechnologyinWuhan,China.Clinicaldatawere extractedfromelectronicmedicalrecordsandreviewedby a trained medical team. Neurological symptoms fall into threecategories: skeletalmuscle symptoms,symptomsor diseasesoftheCentralNervousSystem(CNS)andPeripheral NervousSystem(PNS)symptoms,includingODandGD.Data onallneurologicalsymptomswereveriﬁedbytwotrained neurologists. Ofthe214patientsstudied, 126(58.9%)had mild-moderatedisease,127(59.3%)werefemales andthe mean age of the group was 52.7±15.5 years. Compared to the patients with mild-moderate disease, critically-ill patientswereolder(58.7±15.0vs.48.9±14.7years)and showedfewertypicalsymptoms,suchasfeverin40(45.5%)

vs.92(73%)andcoughingin30(34.1%)vs.77(61.1%).GD wasidentiﬁed in12 (5.6%),and OD in 11(5.1%) patients; regarding these disorders, there were only references to hypogeusia and hyposmia and they were the main symp-tomsreportedbypatientswithPNSalterations,with12/19 (63%),11/19 (57.8%);respectively. Therewerenorecords

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T able 4 Quality assessment of cross-sectional studies using the Newcastle-Ottawa Scale (adapted). Article Selection a Comparability (control of the most important factor) b R esult c Final evaluation d Sample repre-sentativeness R elevant selection Sample size Determination of exposure/diagnosis V alidated measurement method Statistical test Mao et al. 12 1 1 0 3 1 2 1 9 Lechien et al. 13 1 1 0 3 1 2 1 9 Moein et al. 14 1 0 0 3 1 2 1 8 Ya n aet al. 15 1 0 0 3 1 2 1 8 Ya n bet al. 16 1 1 0 3 1 2 1 9 Menni et al. 17 1 1 1 3 1 2 1 9 a Maximum score (5 points). b Maximum score (2 points). c Maximum score (3 points). d Maximum score (10 points).

regardingtheonsetofolfactory/gustatorydisorders, dura-tion,resolutionorspeciﬁctreatments.

Lechien et al.13 _carried _out _the _multicentric

Euro-pean study through the COVID-19 Task Force of the Young-Otolaryngologists of the International Federations of Oto-rhino-laryngological Societies (YO-IFOS) in six Bel-gian,threeItalianandtwoFrenchhospitals.Patientswith olfactory-gustatorydisordersofwhichonsetoccurredprior tothepandemic, patientswithout laboratory diagnosis of COVID-19,patientswhowereintheintensivecare unitat the time of the study (due to their health status) were excluded.Therefore,thesampleconsistedonlyofpatients withmildtomoderatedisease.Clinicaldatawerecollected prospectivelyduringtheotorhinolaryngologicalconsultation orby telephonefor patients undergoinghome treatment. Inthis study,patients ﬁlled outa questionnaire based on ‘‘ThesmellandtastecomponentoftheNationalHealthand NutritionExaminationSurvey’’andthesimpliﬁedversionof the‘‘Questionnaireof OlfactoryDisorders-Negative State-ments’’(sQOD-NS).18_Of_the₄₁₇_patients,₃₈₉_(93.3%)_were

European,263(63.1%)werefemales,allwithmildto moder-atepicturesofCOVID-19andwithameanageof36.9±11.4 years. In the evaluated sample, 85.6% and 88.8% of the patientsreportedODandGD,respectively;therewasa sig-nificantassociationbetween thetwodisorders(p<0.001). Of the 357 patients with OD, 284 (79.6%) had anosmia, 73(20.4%) had hyposmia, 45 (12.6%) hadphantosmia and 115(32.4%) hadparosmia. ODappeared before,during or aftertheothersigns/symptomsofCOVID-19in11.8%,22.8% and65.4% ofcases,respectively.Among patientsthathad alreadyrecovered fromCOVID-19, 63% of them remained withOD.Amongthepatientswhorecoveredtheirsenseof smell,33%,39.6%,24.2%and3.3%didsointheperiodsof 1---4,5---8,9---14andmorethan15daysofresolutionofthe COVID-19picture,respectively.Inanosmiacases,olfactory functionnormalizedoverthefirsteightdaysafterdisease resolutionin 67.8% of cases. An association wasobserved between fever and anosmia (p=0.014). Women were sig-nificantly more affected by OD (with both hyposmia and anosmia)andGDthanmen(p=0.001).Regardingthe treat-mentforOD,salinenasallavage,nasalcorticosteroidsand oralcorticosteroids wereusedby16.7%,8.1% and2.5%of thepatients,respectively;GDsweretreatedin1.4%ofcases withl-carnitineortraceelementsassociatedwithvitamins. Noresultswereobservedregardingtheeffectivenessofsuch specifictreatmentsforODandGD.

Moein etal.14 _carried_out_the _study _with₆₀

SARS-CoV-2positivepatientswhowereadmittedtoMasihDaneshvari HospitalinTehran,Iran.Atthetimeoftheolfactorytest, everyonewashospitalizedduringtherecoveryperiodofthe disease.Acontrolgroupwascreatedwith60healthy sub-jects,paired bygenderandage withthe60patients with theinfection.ThePersianversionoftheUniversityof Penn-sylvaniaSmellIdentiﬁcationTest(UPSIT),with40odors,was usedinthisstudy(SensonicsInternational,HaddonHts.,NJ, USA)withthehelpofatrainedexaminer;thetestprovides anabsolute dysfunctionindex(anosmia, severehyposmia, moderatehyposmia,mildhyposmia,normosmia,faking),as well as the relative dysfunctionbased on normative per-centileclassiﬁcationsadjustedforageandgender.Ofthe60 patientsstudiedwithCOVID-19,25(42%)hadmild,29(48%) hadmoderate and6(10%) hadsevere disease; 40(66.6%)

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weremalesandthemeanageofthegroupwas46.5±12.1 years.Ofthe60 patients,OD wasidentiﬁedin 59(98.3%) andGDin 14(24%),incontrasttothecontrolgroup,that showedODin18%oftheindividuals;ofthe60patients,15 (25%)hadanosmia,20(33%)hadseverehyposmia,16(27%) hadmoderatehyposmia,8(13%)hadmildhyposmia,and1 (0.2%)wasnormal.The59 patientswithOD reportedthat thedisorderstartedatthesametimeorimmediatelyafter theonsetofthesigns/symptomsofCOVID-19.Therewere nodetaileddataonthetypeofgustatorydisorderorspeciﬁc treatmentsforOD/GDinthestudiedsample.

In their ﬁrst study, Yan et al.15 _evaluated ₅₈ _patients

at the University of California San Diego Health hospital withpositivelaboratory testsfor COVID-19 and203 nega-tivetests.TheODsandGDswereassessedwiththehelpof aquestionnaireusingaplatform(Qualtrics®_)._The_questions

werebasedona10-pointcontinuous barfor theolfactory function,meaning: 0(anosmia), 10 (normalsmell), anda 10-pointbarfor thegustatory function,meaning:0 (ageu-sia),10 (normal gustatoryfunction); the lowerthescore, thegreater theseverity ofOD and GD.Of the58 studied patients with COVID-19, 54 (93.1%) had mild disease, 29 (50%) weremales and 38 (64.4%) were under50 years of age.Lossofsmellandtastewasreportedin40(68%)and42 (71%)of COVID-19 positive individuals, respectively. In 12 (22%)patients,ODwasalreadypresentatthebeginningof thecondition.Thesmellandtastefunctionimpairmentwas independentlyandstrongly associatedwithCOVID-19 pos-itivity (Anosmia:Adjusted Odds Ratio --- Aor=10.9;95%CI: 5.08---23.5; Ageusia: Aor=10.2; 95%CI: 4.74---22.1). Com-paredtoothersymptomsofCOVID-19infection,lossofsmell and taste showed the greatest magnitudes of association withCOVID-19positivity(Anosmia:OR=10.9;95%CI:5.6---21, 0;Ageusia:OR=11.9;95%CI:6.1---23.2).Ofthepatientswho reportedOD,43(73.6%)reportedanosmiaresolutionat dif-ferentintervalsafterrecoveryfromCOVID-19(18.4%inthe ﬁrst week; 36.8% in the second week, and 18.4% in the thirdorfourthweek);15(26.4%)ofthecasesdidnotshow olfactionrecovery.Noresultswereobservedregardingthe resolutionoftheGDconditionorspeciﬁctreatmentsforboth disorders.

Intheir second study,Yan etal.16 _{retrospectively}

eval-uated 128 patients with a positive laboratory test for COVID-19recordedintheSanDiegoHospitalsystem.Smell andtastewereself-assessedinrelationtotheperiodofthe disease and were comparedto the levels beforethe dis-ease(lossofsmell/tastevs.normalfunction);atﬁrst,these datawereextractedfrompatients’medicalrecords;when absent,theinterviewwasperformedviaemailortelephone. Of the128 patients withCOVID-19, 102 (79.7%) had mild disease, 67 (52.3%) were females and the mean age was 48.25±16.75 years. Of the 128 patients, 75 (58.6%) had OD and70 (54.6%) hadGD. Patients whoreportedloss of smellwereten timesless likelytobehospitalizeddue to COVID-19(OR=0.09;95%CI:0.01---0.74)whencomparedto thosewithout lossof smell.ODswerenotassociatedwith anyothermeasuretypicallyrelatedtothedecisiontoadmit thepatient,suggesting that lossof smellis truly a factor thatcanbeusedasamarkerformildermanifestationsof COVID-19.Thus,theauthorssuggestthatODmaybea clini-calmarkertohelpstratifydiseaseseverityatthebeginning ofSARS-CoV-2infection.Therewasnodetaileddataonthe

type of GD present or speciﬁc treatments for any of the disordersinthestudiedsample.

Mennietal.17_performed_a_census_study_using_the_RADAR

COVID-19applicationwith579patientswhotestedpositive for SARS-CoV-2 in the UK and 1123 negativeones. Of the 579patients,allhadmilddisease,400(69%)werefemales and the mean age was 40.79±11.84 years. OD and GD were present in341 (59%) patientspositive for COVID-19, compared to 202 (18%) that tested negative for the dis-ease,resultinginanoddsratio(OR)ofCOVID-19diagnosis (95%CI=6.59[5.25;8.27],p=1.90×10---59).The combina-tion of loss of smell and taste, fever, persistent cough, fatigue,diarrhea,abdominalpainandlossofappetitewas predictive for a positive COVID-19 test, witha sensitivity of 0.54(0.44;0.63);speciﬁcity of0.86(0.80; 0.90): ROC-AUC=0.77 (0.72; 0.82) in the set of tests and ROC-AUC cross-validation=0.75(0.72;0.77).Overall,without adjust-ments, loss of smell and taste had a positive predictive valueof61.7%.Theresultssuggestthatlossoftaste/smell is a strong predictorof SARS-CoV-2 infection.There were nodetaileddataonthesubtypeof ODand GD,onsetand resolution inrelation totheCOVID-19severity, or speciﬁc treatmentsforanyofthedisorders.

Discussion

The current SR wasdesigned to identify evidence in the scientiﬁc literature about both olfactory/gustatory disor-ders in relation to the clinical presentation, prevalence and possible speciﬁc treatments associated with COVID-19.

The six studies showed different prevalence rates for OD and GD. The study withthe greatest divergencefrom the others regarding the prevalence of OD and GD was the Chinese study by Mao et al.,12 _in _which _the

preva-lenceofODwas19timeslowerthaninthestudybyMoein et al.14 _and ₁₄ _times _lower _than _in _the _study _by _Lechien

etal.13 _These _differences _can _be_explained_by _two

possi-bilities: (1)The study models,becausewhile the Chinese study, with lower prevalence rates of OD and GD, was based only ondata from medicalrecords in which gusta-tory/olfactorycomplaintsmayhavebeenneglected,while the other studies usedtoolsaimed at assessingsmell and taste; (2) Chinese patients, in fact, had few olfactory-gustatorycomplaints.

We observed that in the Chinese, Iranian and North-American studies, the mean age was older than in Europeanstudies;suchdivergencecanbeexplainedbythe sample composition regarding the severity of COVID-19, since the Asian and North-American studies had patients with the severe form of the disease, more common in older patients and those withcomorbidities,19---22 _while _in

the European groups there were only mild to moderate cases.

The clinical behavior of OD and GD varied in sev-eral aspects:it was observed that anosmia was the most prevalentODanditsonsetcanoccurevenbeforethe symp-toms/signsofCOVID-19.Thereisevidencethatlossofsmell maynotonlybeaclinicalmarkerfor SARS-CoV-2infection but can also help to stratify the degree of illness at the onsetof infection.Consideringthe difﬁcultiesin terms of

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and taste disorders in COVID-19: a systematic review 789

Table5 Demographicdata,overallclinicaldata,olfactory-gustatorydiagnosticmethod,prevalenceofolfactoryandgustatorydisordersinpatientsinthethreeselected studies.

Article Author N:n(%) Age(±SD) Ethnicity,n(%) Diagnosisof COVID-19 Severityof COVID-19,n(%) Overall symp-toms/signsin COVID-19,n(%) Olfactory/ gustatory evaluation method Prevalence,n(%) 1 Maoetal.12 _214:₁₂₇ (59.3)♀;87 (40.7)♂ 52.7(±15.5) years Asian214 (100) RT-PCRa _Severe₈₈ (41.1) Fever132 (61.7) Analysisof clinicalrecords inpatients’ ﬁles Gustatorydisorder12 (5.6) Drycough107 (50) Mild-moderate 126(58.9) Anorexia68 (31.8) Olfactorydisorder11 (5.1) 2 Lechien etal.13 417:263 (63.1)♀;154 (36.9)♂ 36.9(_±11.4) years Europeans389 (93.3) RT-PCRa _{Mild-moderate} 417(100) Drycough325 (78)

sQOD-NSb _Olfactory_disorder₃₅₇ (85.6) African descendants15 (3.6) Myalgia241 (58) South-American11 (2.7) Anorexia216 (52) Gustatorydisorder342 (82) North-American1 (0.2) Fever200(48) Asian1(0.2) 3 Moein etal.14 60:20 (33.3)♀;40 (66.6)♂60 (control) 46.55 (±12.17) years

Asian60(100) RT-PCRa _Mild₂₅₍₄₂₎ _Fever₄₆₍₇₇₎ _UPSITc _Olfactory_disorder₅₉ (98.3) Moderate29 (48) Drycough35 (58) Severe6(10) Shortnessof breath31(52) Gustatorydisorder14 (24) 4 Yanetal.15 _58:₃₈ (64.4)♂;20 (35.6)♀;203 COVID-19 negatives <50years:38 (65.5) North-Americans58 (100) RT-PCRa _Mild₅₄_(93.1) _Fatigue₄₈ (81.4)

Questionnaire Gustatorydisorder41 (71.2)

>50years:21 (34.5)

Moderate/severe 4(6.9)

Fever41(69.5) Olfactorydisorder40 (67.8)

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Costa

KV

et

al.

Table5(Continued)

Article Author N:n(%) Age(_±SD) Ethnicity,n(%) Diagnosisof COVID-19 Severityof COVID-19,n(%) Overall symp-toms/signsin COVID-19,n(%) Olfactory/ gustatory evaluation method Prevalence,n(%) 5 Yanetal.16 _128:₆₇ (52.3)♀;61 (47.7)♂ 48.25 (±16.75) years North-Americans8 (30.8) RT-PCRa _Mild₁₀₂ (79.7) Drycough112 (87.5) Medical record, e-mailand telephone Olfactory disorder75 (58.6%) African descendants3 (11.5) Fever90(70.3) South-American7 (26.9) Moderate/ severe26 (20.3) Fatigue90 (70.3) Gustatory disorder70 (54.6%) Asian4(15.4) Others4(15.4) 6 Menniey al.17 579:400 (69)♀;179 (31)♂;1123 negativefor COVID-19 40.79 (_±11.84) years Not evaluated RT-PCRa _Mild₅₇₉ (100) Fatigue458 (80.1) RADAR COVID-19 Application Olfactory/gustatory disorder343 (59.4) Drycough335 (58) Shortnessof breath:194 (49.4)

♂,male;_♀,female;SD,standarddeviation.

a _Real-time_reverse_{transcription}_polymerase_chain_reaction.

b _The_smell_and_taste_component_of_the_National_Health_and_Nutrition_examination_Survey_(simpliﬁed_version_of_the_{Questionnaire}_of_Olfactory_{Disorders-Negative}_Statements). c _The_University_of_Pennsylvania_Smell_{Identiﬁcation}_Test.

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publichealthfortheperformanceandacquisitionofresults inatimelymannerbyRT-PCR,theevaluationofthese disor-dersintimesofCOVID-19pandemiccanbeusefultoguide immediateisolation,evenbeforehavingaccesstothetest result,favoringthepreventionofthedisseminationofthe virus. AopposedtoOD thatoccurswithother viral infec-tions,ODinmostpatientswithCOVID-19wasnotassociated withnasalobstructionorrhinorrhea.ODrecoveryoccurs,in mostcases,withintheﬁrsttwoweeks,whileonly3.3% man-agetorecovertheirsenseof smell/tasteafterthisperiod and it is not yet known whether the others who persist withODcanrecovertheirsenseofsmellinthelongterm. The olfactory neuroepithelium hasconsiderable regenera-tivecapacity,leadingtospontaneousimprovementofsmell, atvaryingdegrees,overtime23_if_the_stem_cell_layer_is_not

markedlydamaged.24---26 _Regarding _the _GD, _detailed

infor-mationwasnotfound;however,theassociationofGDswith ODswassigniﬁcant,andtherecoveryoftastedependedon therecoveryofthesmell.

The variability of the clinical spectrum of OD/GD in COVID-19isbroadandcertainlydeﬁnedbybiological char-acteristics, viral, cellular and molecular, of patients that varyaccordingtoethnicity.Ofthesixassessedstudies,the twostudies thatdidnotincludesevereformsof COVID-19 consisted of European patientsonly; however, they main-tained high prevalence rates of OD and GD. Mutations in surface proteins (Spike protein (S) and Nucleocapsid pro-tein (N) of SARS-CoV-2 in different regions of Chinahave already been observed,27 _and _can _modify _the _biological

behavior of the virus in relation to tissue afﬁnity.20 _The

Angiotensin-Converting Enzyme 2 (ACE2) acts asa recep-tor for SARS-CoV-2, especially in the olfactory bulb,28

so that some of its variants observed in different eth-nicities could reduce its ability to receive the virus S proteinbymodifyingitssusceptibility,symptomsand clin-ical outcomes29_; _there _are _relatively _high _expressions _of

ACE2andtransmembraneserineprotease2(TMPRSS2)inthe humanolfactoryepithelium30_;_the_non-neuronal_expression

ofACE2/TMPRSS2maypossiblymaketheolfactory epithe-lium a reservoir of viruses.30 _The _expression _of _TMPRSS2

seemsto behigher comparedtothat of ACE2and occurs in both neurons and non-neuronal cells in the olfactory epithelium and with a mosaic pattern, suggesting that some olfactory neurons may be more vulnerable to viral infection.31,32

Regardingspeciﬁctreatments,therewasnoevidenceof speciﬁcdrugsthatwereeffectivefortherecoveryof olfac-tory/gustatoryfunctions.Nasallavagewaspredominantin thestudiedgroups.

Therefore, patients withCOVID-19 of different ethnic-ities were evaluated, with high prevalence of impaired smell/taste, with women being the most signiﬁcantly affected gender; unlikeother viral etiologies, SARS-CoV-2 canleadtolossofolfactory/gustatoryfunctionseven with-outthepresenceofnasalobstruction/rhinorrheaandwith theonsetofOD/GDevenbeforetheclinicalsigns/symptoms ofCOVID-19.ThereisevidencethatOD/GDarestrong pre-dictors of infection by SARS-CoV-2, and it is possible to recommendthe isolationof thepatientasof themedical consultation andstillwithout the resultof thelaboratory

test,topreventthedisseminationofthevirus.The recov-eryof smell/taste,when itoccurs, usually doessowithin thefirsttwoweeksaftertheresolutionofCOVID-19.No sci-entificevidencehasbeenidentifiedforeffectivetreatments foranyofthedisorders.

Conclusion

The studies have shown that both olfactory and gusta-tory disorders of varying intensities and in which onset occurred prior to the general symptoms of SARS-CoV-2 infection may occur, and such disorders should be con-sidered as part of the symptoms that may be present, even in mild cases of COVID-19. There is still no scien-tiﬁcevidence of speciﬁc treatments for suchdisorders in COVID-19.

Conﬂicts

of

interest

Theauthorsdeclarenoconﬂictsofinterest.

Appendix

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pneumoniaORSARS-CoVORSARS-CoV-2ORsarscoronavirus ORcoronavirusORcoronavirusinfectionORcoronavirus COVID-19ORnovelcoronavirus)AND(COVID-19clinical featuresORolfactorydisordersORolfactiondisordersOR tastedisorders)

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GOOGLESCHOLAR

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