Anais
Brasileiros
de
Dermatologia
www.anaisdedermatologia.org.br
INVESTIGATION
Allergic
contact
dermatitis
to
cosmetics:
retrospective
analysis
of
a
population
subjected
to
patch
tests
between
2004
and
2017
夽,夽夽
Mariana
de
Figueiredo
Silva
Hafner
a,∗,
Ana
Carolina
Rodrigues
b,
Rosana
Lazzarini
aaDermatologyClinic,SantaCasadeMisericórdiadeSãoPaulo,SãoPaulo,SP,Brazil bMedicalSciencesCollege,SantaCasadeMisericórdiadeSãoPaulo,SãoPaulo,SP,Brazil
Received10September2019;accepted9April2020
Availableonline17September2020
KEYWORDS Cosmetics; Dermatitis,allergic contact; Patchtests Abstract
Background: Cosmeticsarepartofthedailylifeofthepopulation,andtheirusecanleadto
allergiccontactdermatitis.
Objectives: Toassesstheprofileofpatientsdiagnosedwithallergiccontactdermatitisto
cos-meticstreatedatareferralcenterfor13years,aswellasthecharacteristicsoftheclinical
pictureandallergensinvolved.
Methods: Thiswasaretrospectivestudy,withanalysisofmedicalrecordsofpatientsattended
atthisservice.Theindividualsincludedhadadiagnostichypothesisofallergiccontact
dermati-tistocosmeticsandhadpreviouslybeensubmittedtoepicutaneoustests.
Results: Atotalof1405medicalrecordswere analyzed,403(28.7%)withsuspectedallergic
contactdermatitistocosmeticsand232(16.5%)withconfirmeddiagnosis.Ofthese,208(89.7%)
werewomen,andtheagegroupmostaffectedwas31−60years.Themostcommonlocations
werefacein195cases(25.8%),cervicalregionin116(15.3%),andtrunkin96 (12.6%).The
mainallergensinthecontacttestsweretoluene-sulfonamide-formaldehyderesinin69cases
(29.7%),paraphenylenediaminein54(26.3%),KathonCG®in41(20.7%),andfragrance-mix1
in29(16.4%).In154(66.4%)ofthe232patientswithaconfirmeddiagnosisofallergiccontact
dermatitistocosmetics itwaspossibleto specifythe cosmeticproductresponsible for the
lesions.
Studylimitations: Theabsenceofsomeallergensconsideredimportantintheworldascauses
ofallergiccontactdermatitis,whicharenotreadilyaccessibleamongus.
夽 Howtocitethisarticle:HafnerMFS,RodriguesAC,LazzariniR.Allergiccontactdermatitistocosmetics:retrospectiveanalysisofa
populationsubjectedtopatchtestsbetween2004and2017.AnBrasDermatol.2020;95:696---701.
夽夽StudyconductedattheDermatologyClinic,SantaCasadeMisericórdiadeSãoPaulo,SãoPaulo,SP,Brazil. ∗Correspondingauthor.
E-mail:mariana@hafner.med.br(M.F.Hafner).
https://doi.org/10.1016/j.abd.2020.04.011
0365-0596/©2020SociedadeBrasileiradeDermatologia.PublishedbyElsevierEspa˜na,S.L.U.ThisisanopenaccessarticleundertheCC BYlicense(http://creativecommons.org/licenses/by/4.0/).
Conclusions: The dataoftheanalyzed population(predominanceofyoungwomen),aswell
asthelocationofthelesions(faceandcervicalarea)andthemainallergens involvedwere
consistentwiththosefromtheworldliterature.
©2020SociedadeBrasileira deDermatologia.PublishedbyElsevierEspa˜na,S.L.U.Thisisan
openaccessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).
Introduction
The term ‘cosmetics’ is defined by the Brazilian National HealthSurveillanceAgency(AgênciaNacionaldeVigilância Sanitária[ANVISA]) asproductsfor external use,intended toprotectorbeautifydifferentpartsofthebody.TheFood andDrugAdministration(FDA)definesthemasarticlesthat canbe appliedtothehuman bodyfor cleaning, beautify-ing, highlighting features, changing appearance, or even ascomponentsof any of theseproducts, withthe excep-tionofsoaps.1InaccordancewiththeEuropeanlegislation, thetermis usedfora substanceor mixtureof substances intended for application on the external surfaces of the body(skin,hair,nails,lips,andgenitalia),teethand/ororal mucosa,withthepurposeofcleaning,odorization, modifi-cationof appearance,orcorrection ofodorsintheregion of use.2 Thus, this term varies according to the legisla-tionofeachcountryandincludesmakeup,skincareitems, perfumes, hair andnail products, shaving gels or creams, and any personal care products, such as toothpaste and deodorants.3Cosmeticsarepartofthedailylifeofthe pop-ulation,beingmoreusedbywomen,who,onaverage,apply about12productsperday,whichcancontainupto168 dif-ferentcomponents, whilemenuseuptosixproductswith anaverageof85components.4
Although the most common adverse effects caused by theuseofcosmeticsareirritantdermatitis,allergiccontact dermatitis(ACD)alsooccurs,correspondingtoabout1%of thereactions.TheincidenceofACDvariesaccordingtothe region,frequencyofuseofcosmetics,allergenicpowerof the products used,and accesstopatch tests (which con-firmthediagnosis).Theriskfactorforitsoccurrenceisthe increaseintheuseofcosmetics;thus,thepopulationmost affectedisfemalesbetween20and55yearsofage.Itis dif-ficulttoestimatethefrequencyofthiscondition,sincemost individualsdonotseekmedicalserviceswhenexperiencing suchreactionsanddiscontinuetheuseontheirown.1,3
Hygieneproductsandmoisturizersarethemain responsi-bleforthecasesofACDtocosmetics,followedbymakeup, hairproducts,andnailproducts.2Themainassociated aller-gensarefragrancesandpreservatives.4
ACD to cosmetics occurs at the place of direct appli-cation of the product or to which it can be transferred. This transmissioncanoccur throughunintentionalcontact through objects such as towels and phones, through air, andthroughinterpersonalcontact.1Theclinicalpicturecan be acuteor chronic; chronic manifestationsare themost common,duetothelowallergenic powerofthecosmetic components.3
The diagnosis is based on anamnesis, dermatological examination,andpatchtest.Itisimportanttoinvestigate theproductsusedbythepatient,bothathomeandatwork. Afterdiagnosis,itisessentialthatthepatientunderstands
Table 1 Reading of the results of patch tests (ICDRG criteria).
Intensity Morphology Interpretation
--- Noreaction Negative
?+ Milderythema Doubtfulreaction
+ Erythema,infiltration, possiblypapules Poorresponse ++ Erythema,infiltration, papules,vesicles Strongresponse +++ Intenseerythema, infiltration,coalescent vesicles
Verystrongresponse
thatshe/heshouldavoidcontactwiththeallergenandthat theconditionmayreturnwithnewexposures.1,3,4
Thepresentstudyaimedtoassesstheprofileofpatients diagnosedwithACDtocosmeticstreatedatareferralcenter foraperiodof13years,aswellasthecharacteristicsofthe clinicalpicturepresentedandtheallergensinvolved.
Materials
and
methods
Thiswasaretrospectivestudy,withanalysisofthemedical recordsof patients treated at a referenceservice outpa-tient clinic during the period from 2004 to 2017. It was approvedbytheHumanResearchEthicsCommittee(CAAE 94354218.4.0000.5479).
The patients included in the study had a diagnostic hypothesisofACDtocosmeticsandhadpreviouslybeen sub-mittedtoepicutaneoustests.Accordingtotheanamnesis, the series of allergens used in the tests were: Brazil-ian standard panel (30 substances/FDA --- Allergenic/RJ, Brazil),cosmeticspanel(tensubstances/FDA---Allergenic, RJ, Brazil), and when possible, cosmetic products that belongedtothepatientherself/himselfwasalsoincluded. Inallcases,thecontainersusedinthetestswereoftheFinn Chamber(SmartPractice,UnitedStates)orAllergoChamber (Neoflex,SãoPaulo,Brazil)type.Thetestswereappliedand readaccording tothecriteriaoftheInternationalContact DermatitisResearchGroup(ICDRG).
Inordertostandardizethemethodologyandthereading ofthe patch tests,avoiding the occurrence of false posi-tivesand falsenegatives, the ICDRG established that the testsmustbeappliedonthehighportionofthebackofthe patients,andthereadingsmustbetakenafter48and96h. Thereadingcanshownegativeorpositiveresults(1,2,or3 +),asshownintable1.
Data were collected according to a standard form adopted by the service, in which information such as age,sex,profession,durationofthecondition,locationof
Table2 Distributionof232patientsaccordingtothe
loca-tionoftheinjuries.
Location Numberof
patients
%
Face 195 25.8
Cervicalarea 116 15.3
Trunk(sternum,breasts,scapula) 96 12.6
Upperlimbs 75 9.9 Hands 60 7.9 Lowerlimbs 49 6.4 Scalp 44 5.8 Abdomen/flanks 44 5.8 Feet 27 3.5 Armpits 24 3.1 Lumbarregion 11 1.4 Inguinal/genitalregion 10 1.3 Buttocks 9 1.2 Total 760a 100.0
aSomepatientshadmorethanoneaffectedregion.
lesions,and results of patchtests arerecorded. The col-lecteddatawasanalyzedinanExcelspreadsheet.
Results
Atotalof1405medicalrecordswereanalyzed,amongwhich 403(28.7%)weresuspectedofhavingACDduetocosmetics and232(16.5%)hadthisdiagnosisconfirmed.Inthisgroup, 208 (89.7%) were female and 24 (10.3%) were male. The referredhistoryperiodvariedfrom1to528months,witha meandurationof32.9months.
The patients’ agesranged from3to 88years; theage groupmostaffected wasfrom31−60 years,withamean ageof44.4years.
Table4 CosmeticidentifiedasresponsibleforACDin154 patients. Cosmetic % Sex F M Nailpolish 32.3 75 − Hairdye 17.2 36 4 Fragrances/perfumes 7.3 15 2
Shampooandhairproducts 6.0 12 2
Moisturizingcream 4.7 7 4
Deodorant 4.3 7 3
Sunscreen 1.3 3 −
Soap 0.9 1 1
Hairstraighteningtreatment 0.4 1 −
Insomepatients,morethanonecosmeticwasimplicatedinthe etiologyofACD.
Themostcommonlocationswerethefacein195cases (25.8%),thecervicalregionin116(15.3%),andthetrunkin 96(12.6%),asdescribedintable2.Somepatientspresented morethanoneaffectedarea.
Amongthe232patientswithACDtocosmetics,82(35.3%) werediagnosedbythecosmeticpanel,65(28%)bythe asso-ciationofstandardpanelandextrasubstances,55(23.7%) by the association between cosmeticand standard panel, and30(12.9%)bythestandardpanel.
Themainallergenswithpositiveresultsinthepatchtests were toluene-sulfonamide-formaldehyde resin in 69 cases (29.7%),paraphenylenediaminein54(26.3%),KathonCGin 41(20.7%),andfragrance-mix1in29(16.4%),asshownin table3.
In154(66.4%)ofthe232patientswithaconfirmed diag-nosis of allergic contact dermatitis by cosmetics it was possibletospecifythecosmeticproductresponsibleforthe lesions,asshownintable4.
Table3 Distributionofpositivepatchtestsamongthe232patientsdiagnosedwithACDtocosmetics.
Positivesubstance % Sex Positivesubstance % Sex
F M F M R-TSFa 29.7 69 0 Hydroquinone 2.1 5 0 Paraphenylenediamine 26.3 54 7 Triethanolamine 2.1 4 1 KathonCG®b 20.7 41 7 BHTd 1.7 4 0 Fragrance-mix1 16.4 29 9 Lanolin 1.7 4 0 Formaldehyde 8.2 19 0 Bronopole 1.7 4 0 Colophony 7.7 15 3 Chloroacetamide 1.7 4 0
BalsamofPeru 6.0 11 3 AmercholL-101 1.3 2 1
Parabens 3.4 6 2 Propyleneglycol 1.3 3 0
Irgasanc 3.0 6 1 Sorbicacid 0.9 2 0
Ammoniumthioglycolate 3.0 7 0 ImUf 0.9 2 0
Quaternium-15 2.6 6 0 Chlorhexidine 0.4 1 0
Somepatientshadmorethanonepositivesubstanceonthepatchtest.
aToluenesulfonamide-formaldehyderesin.
b Methylisothiazolinone+methylchloroisothiazolinone. c Triclosan.
d Butylhydroxytoluene.
e 2-bromo-2-nitropropane-1,3-diol. f Imidazolidinylurea.
Discussion
Cosmeticsareproductsuseddailybyalargeportionofthe population, making them frequent causes of contact der-matitis,bothinirritativeandallergicforms.
ThefrequencyofACDtocosmeticsintheserviceinthe assessedperiodwas16.5%amongpatientswhounderwent patchtests.Theseratesareequivalenttothedataof the groupsthatstudythissubject,rangingfrom1%to17.8%of allACDcases.Thesefiguresdependonthelocationofthe study,thefrequency of useof cosmeticsin theevaluated population,theavailabilityofmedicalservicesand,mainly, accesstopatchtestsandallergens thatcause dermatitis. The data presented here reflect the frequency of such a diagnosisinauniversityservicewithaccesstopatchtests.4 Regardinggender,thestudyincluded208women(89.7%) and24men(10.3%).Thisfactisinaccordancewith litera-turedata,corroboratingtheideathatthegreaternumber ofcosmetics usedby womenfavorsthegreaterfrequency of sensitization, although the use of these products has increasedamongmen.4,5
Thetimeofevolutionofthedermatosisuntilthearrival attheservicewas44months,onaverage,whichreflectsthe pooraccessofthepublicservicepopulationtopatchtests, delayingthediagnosisandimplyinggreatermorbidity.Other studiesshowmeanintervalsof23and29months.5
The two regions of the body most affected were the faceandneck,coincidingwiththeareasofgreatestcontact withcosmetics,bothbydirectapplicationandby indirect contact.2
ACDtocosmeticscanbecausedbydifferentcomponents of the formulations, suchasactive ingredients, preserva-tives,fragrances,emulsifiers,andvehiclecomponents.
Among the active principles, toluene-sulfonamide-formaldehyderesin(R-TSF)wasthemostcommonamongall allergenssurveyedinthesample(29.7%).Thesecaseswere exclusivelydiagnosedamongwomen.This resin ispresent innailenamels,allowingfordurabilityafterapplication.It isanallergenstillprevalentinBrazil,althoughfewercases havebeenobservedinthepresentservice.
Paraphenylenediamine(PPDA),presentinpermanentand semi-permanent hair dyes, wasthesecond most frequent amongwomen and men. Although the scalp is thick, this allergen is capable of causing reactions that are often intense and severe. Lesions can also occur on the face, eyebrows,neck, andears, without affecting thescalp. In addition,thisallergeniscommonlyincludedinimpurehenna tattoos,causingsensitizationinchildren.4
Ammoniumthioglycolate,areducingagentusedinhair straighteningandpermingproducts,iswidelyusedinBrazil, especiallyinproceduresperformedinthedomestic environ-ment.Itaccountedfor3%ofcasesofACDtocosmetics.Itis anuncommonallergen,butin2017aJapanesestudyshowed 4.8%ofpatientswithreactionstoproductsappliedtohair thatwerepositivetothisagent.6
Preservatives had a significant number of reactions, and isothiazolinones were the most frequent. Kathon CG® (methylisothiazolinone+methylchloroisothiazolinone) accountedfor20.7%ofpositivetests.Itisacommon preser-vative in water-based products, such as creams, lotions, shampoos,andbabywipes.Itcanalsobefoundinproducts
forindustrial use,such aswallpaints, cuttingoils, glues, textiles, and leather. Contact dermatitis induced by this preservativemainly affects theface and hands in adults. Inchildren,themostaffectedregionsaretheperioraland genitalregions,andthebuttocks,duetotheirpresencein wetwipes.7
Unpublisheddata fromthis service indicate a 17% fre-quency of sensitization to Kathon CG® in the general population.Thisfrequencywashigherinthepresentstudy, asitincludedaspecificgroupofACDbycosmetics(inwhich thisallergenismorecommon).Thefrequencyof sensitiza-tionincreasedsubstantiallyfrom2011onwardsintheUnited States and Europe; in Brazil, Scherrer and Rocha demon-strated an increase in sensitization from3.35% to 11.14% between2006and2012.8
Formaldehyde is a well-known antiseptic used as a preservative in cleaning products, cosmetics (e.g., shampoos and soaps) and topical medicines. Due to theirallergenic andcarcinogenicpotential, formaldehyde-releasingpreservativescanbeusedinstead.Inthecurrent study,8.2%ofthecasespresentedsensitizationto formalde-hyde,somerelatedtotheuseofhairstraighteningproducts. AlthoughprohibitedbytheANVISAasastraightener,itisstill usedininformalsettings,atunknownconcentrations. The frequenciesofsensitizationtoformaldehyderangefrom2% to3%inEuropeandfrom8%to9%intheUnitedStates; there-fore,thefrequencyobservedinthepresentstudyissimilar tothe one observed in the United States. The frequency of sensitization to formaldehyde-releasing agents such as quaternium-15(2.6%), bronopol(1.7%), andimidazolidinyl urea(0.9%)waslow.
Paraben sensitizationwas observedin 3.4% of patients and,althoughithasbecomeacenterofcontroversyamong cosmeticusers,ithasbeenthesafestandcheapest preser-vative agent on the market since 1924. It is present in mostcosmeticproducts,toothpastes,mouthwashes, clean-ing products, and food. The frequency of sensitization rangesfrom0.6%to2.3%inthestudiesoftheNorthAmerican group.9
Irgasan(triclosan)accountedfor 3%ofpositivetests,a higherfrequencythanthatoftheliterature(below1%).This productisusedasapreservativeinpersonalcareandsports products,bedding,andtoys.10
Otherpreservatives,suchasBHT(antioxidant), chloroac-etamide, sorbic acid, and chlorhexidine, presented low frequencies,andwereconsidereduncommoncausesofACD. Fragrancesareamongthemostcommonallergensin cos-meticsand,in thisstudy, accounted for 16.4%of positive tests.This value waslowerthan that observed inthe lit-erature,wherethesesubstancesaccountfor30%to40%of casesof allergytocosmetics. Fragrance-mix 1,balsam of Peru,andcolophony areconsidered asmarkersof ACD to fragranceinBrazil.
Among the mixes, only the fragrance-mix 1 (cinnamic alcohol, cinnamic aldehyde, hydroxycitronellal, amylcin-namaldehyde,geraniol,eugenol, isoeugenol,andoakmoss absolute)wasanalyzedinthecurrentstudy,afactthatcould reduce the diagnosis of ACD by fragrances by 15% to33% whencomparedwithforeignstudies,inwhichfragrance-mix 2isroutinelyusedinpatchtests.11
BalsamofPeruisanaturalresincomposedofmorethan 250differentchemicalsubstancesandisusedasafragrance
fixator.Inthepresentstudy,thefrequencyofsensitization tothissubstance was6%andwasrelatedtocasesof sen-sitizationtofragrancesin sixcases(43%),while theother eighthad isolated positivity. It is estimated that at least 50%ofcasesofallergytofragranceshavepositivereactions tobalsamofPeru,asobservedinthepresentstudy.2
Colophony is a plant-based resin composed of a com-plexmixtureof acidic(90%)andneutral(10%)resins.The abieticand dehydroabietic acids are themost important, andtheallergensareproductsoftheiroxidation.Thisresin has multiple uses; its use in perfumes is uncertain, but cross-reactionsbetween substancesarewell described.In thestudiedgroup,18patients (7.7%)weresensitivetoit, andin17cases(7.3%)therewasconcurrentreactionwith fragrance-mix 1. A study by the same group that studied fragrancesensitization,publishedin 2018, showed10% of concurrentpositivetests.12
Theproductsusedasvehiclesincosmeticswere responsi-bleforninecasesofACD(2.8%).Amongthese,lanolin(1.7%) andAmerchol L-101(1.3%) arenoteworthy. The former is extractedfromsheep’swoolandwidelyusedincosmetics andtopicalmedicines.The latterisacommercialproduct that contains lanolin alcohols obtained from its hydroly-sis.Althoughboth arefrequentlyimplicatedintheACDof patientswithulcersofthelowerlimbsand,morerecently inpatientswithatopicdermatitis,theyalsoappearas aller-genstocosmetics,asdemonstratedinthepresentstudy.13 Incosmeticstheycanbepresentindeodorants,eye cosmet-ics,depilatories,lipsticks,lotions,andmoisturizingcreams, inadditiontoshampoosandconditioners.
Propyleneglycolisasyntheticalcoholthatcanbeused asanemollient,solvent,preservativeandemulsifier,being foundinvariousproductssuchascosmetics,personalcare products,medicines (includingcorticosteroids), food,and recently in electronic cigarettes. In this study, test posi-tivitywas observed in 1.3% of patients; this finding is in agreementwiththeliterature,wherethefrequencyvaries between0.8%and3.5%ofcases.14
Another positive allergen in the tests was tri-ethanolamine,an emulsifierusedincosmetics andtopical medications,positive in2.1%ofcases,a valuebelowthat observedbySilvaetal.ina2012publication.15Inthatwork, the authors observed 9.52% positivity for this substance. Results may vary between different locations due to the useofdifferentcosmeticsandevenduetopatients’access topatchtests.
Inthepresentstudy,itwaspossibletoidentifythe prod-ucts that were responsible for the condition in 66.4% of patientsdiagnosedwithACDtocosmetics(Table4).Inthese cases,thecurrent relevanceofthepatchtestsperformed wasprobableorcertain.Probablerelevancewasdefinedas teststhatwerepositivefor allergens(andsometimes also for the patient’s own cosmetics) and there was proof of thecompositionoftheproductsinuse(compatiblesources ofexposure);therelevancewasconsideredcertainwhen, in additiontothe criteria mentioned, therewas a recur-renceoftheconditionafterre-exposuretotheproductthat causedthecondition.Intheremaining33.6%,relevancewas consideredpossible,becausedespitepositivetestsfor cos-meticallergensandthehistoryofexposuretosourcesthat areknowntocontainthem,the exactcomposition ofthe productsinusewasnotavailable.
Nail polishes were the most common, followed by hair dyes, perfumes, shampoos and other hair products, bodymoisturizers,deodorants,sunscreens,soaps,andhair straighteningproducts,popularlyknownasprogressivehair brush.Theculpritcosmeticsvaryaccordingtoconsumption habits,hygienehabits,andculturalandreligioustraditions. AstudycarriedoutinIndiawithpatientspresentingACDto cosmeticshasindicatedfacecreams,hairdyes,andsoapsas themostcommon.InBrazil,paintingnailsisacommonhabit amongwomen,makingenamelscommonACDagents.5Itis worthmentioningthatincasesthatwerepositiveforR-TSF in enamelsand PPDAin hairdyes,it iseasier toestablish theprobable or certaindiagnosis, sincethesearespecific allergensoftheseproducts.Inturn,incasesthatwere pos-itivetofragrancesandpreservatives,thediagnosisisoften possible, andthespecific cosmeticsthat causethe condi-tionarenotsoeasilyidentifiable,asthepossiblesourcesof exposurearemultiple.
A limitation of the present study wasthe inclusion of onlyallergensfromstandardBrazilianandcosmeticpanels, although it is known that there are still other sensitiz-ers frequently found in cosmetics. Currently, there are extended panels,which allow testing of a widerrange of substances (such as fragrance-mix 2, cocoamidopropylbe-taine, and methyldibromo glutaronitrile, among others); however, astheywerenot availablein thisservice during mostoftheanalysisperiod,theywerenotincludedinthe study.
Conclusions
The frequency of ACD for cosmetics was 16.5% among patientswhounderwentpatchtests.Theanalyzed popula-tionwaspredominantlyfemale,whoseagerangedfrom31to 60years,withinvolvementofthefaceandcervicalregion; these findings arein agreement withthe literature data. The main allergens involved were toluene-sulfonamide-formaldehyde resin, paraphenylenediamine, Kathon CG®, andfragrance-mix1.However,thestudyhadsome limita-tions, suchasthe absenceof someallergens for analysis, which are currently considered important worldwide as causingACD,andwhoseaccessisstillrestrictedinthis set-ting.Evenintheabsenceoftheseallergens,itwaspossible todrawaprofileofthecosmeticsthatcauseACDinasample oftheBrazilianpopulation.
Financial
support
Nonedeclared.
Authors’
contributions
Mariana de Figueiredo Silva Hafner:Approval of the final versionofthemanuscript;conception andplanning ofthe study;effectiveparticipationinresearchorientation.
AnaCarolinaRodrigues:Obtaining,analyzing,and inter-pretingthedata.
RosanaLazzarini:Conceptionandplanningofthestudy; elaborationandwritingofthemanuscript;criticalreviewof theliterature.
Conflicts
of
interest
Nonedeclared.
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