Potential impact of COVID-19 on colorectal diseasemanagement Coloproctology Journal of

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w w w . j c o l . o r g . b r

Journal of

Coloproctology

Special Article

Potential impact of COVID-19 on colorectal disease management

Fábio Guilherme Campos

^a,∗

, Henrique Sarubbi Fillmann

^b

aUniversidadedeSãoPaulo,HospitaldasClínicas,DivisãodeCirurgiaColorretal,DepartamentodeGastroenterologiaem,SãoPaulo,SP, Brazil

bDivisionofColorectalSurgery,DepartmentofSurgeryofFaculdadedeMedicina,UniversidadePUCRS,PortoAlegre,RS,Brazil

a r t i c l e i n f o

Articlehistory:

Received1June2020 Accepted10June2020 Availableonline19June2020

Keywords:

Coronavirus COVID-19 Colorectalcancer

Inﬂammatoryboweldisease

a bs t r a c t

Thecurrentrecommendationsformanagementofcolorectaldiseasesarestillevolving, duetothelimitedexperienceonthisissue.Asthenewcoronaviruscanbetransmitted throughbreathdroplets,bycontactandorofecally,thereisnoconsensusofhowthisfact mayaffecttheinvestigationandtreatmentofanorectaldiseases.Thus,high-qualitymul- ticenterstudiesareurgentlyneededtoprovidebetterinformationtobothpatientsandthe multiprofessionalteam,inordertobuildaneffectivepandemicresponseplaninourspe- cialty.Asagreateroperativeriskforinfectedpatientshasalreadybeendemonstrated,the nextstepliesontheidentificationofnewtherapeuticstrategiesthatcouldminimizethis effectonanindividualbasis.ThereisapresentunderstandingthattheCOVID-19pandemic shouldchangesometraditionalpractices.Therefore,thesurgicaltreatmentofsuspected orknownCOVID-19casedemandsspecificinsights.Thisarticleanalysespotentialinflu- encesregardingthetreatmentofpatientswithColorectalCancer(CRC)andInflammatory BowelDiseases(IBD).Atpresent,electivesurgerymustbeavoided,andthecolorectalsur- geonmustcarefullyevaluatetherisksandbenefitsofsuchdecision.Withinthiscontext, achangetowardnonsurgicalandlessaggressivemodalitiesofCRCtreatmentmayhelpto postponedefinitivetreatment.Wealsodiscusstheconcernsregardingtheviralinfection amongthepopulation,theinfluenceonclinicalsymptomsandtheproposedmodifications ontherapeuticschemes.

licenses/by-nc-nd/4.0/).

∗ Correspondingauthor.

E-mail:fgmcampos@terra.com.br(F.G.Campos).

https://doi.org/10.1016/j.jcol.2020.06.002

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ImpactopotencialdaCOVID-19nomanuseiodasdoenc¸ascolorretais

Palavras-chave:

Coronavírus COVID-19 Câncercolorretal Doenc¸asinﬂamatórias intestinais

r e s u mo

Asrecomendaçõesatuaisparamanuseiodasdoençascolorretaisaindaestãoemevolução, devidoàlimitadaexperiêncianessetema.Comoonovocoronavíruspodesertransmitido emgotículasdarespiração,porcontatoouporviaoro-fecal,aindanãoexisteconsensode comoestefatopodeafetarainvestigaçãoeotratamentodedoençasanorretais.Assim, sãonecessáriosestudosmulticêntricosdequalidadeparaprovermelhorinformaçãoao pacienteeequipemultiprofissional,possibilitandoaformulaçãodeumarespostaefetiva àpandemiaemnossaespecialidade.Umavezqueoriscooperatóriodepacientesinfec- tadosémaior,opassosubsequenteresideemidentificarnovasestratégiasterapêuticas quepossamminimizaresseefeitoindividualmente.Assim,reconhece-seatualmenteque apandemiapeloCOVID-19devealteraralgumaspráticastradicionais.Consequentemente, otratamentocirúrgicodeumdoenteinfectadooususpeitodemandareflexõesespecíficas.

EsseartigoanalisainfluênciaspotenciaisrelacionadasaotratamentodoCâncerColorretal (CCR)eDoençasInflamatóriasIntestinais(DII).Noatualmomento,cirurgiaseletivasdevem serpostergadaseocirurgiãocolorretaldeveavaliarcuidadosamenteosriscosebenefícios dessadecisão.Nessecontexto,umamudançanadireçãodemodalidadesnão-cirúrgicase menosagressivasdoCCRpodefavoreceraprorrogaçãodotratamentodefinitivo.Aquitam- bémsediscutemaspreocupaçõessobreainfecçãoviralempacientescomDII,suainfluência sobreossintomasclínicoseasmodificaçõespropostasnosesquemasterapêuticos.

´eumartigoOpenAccesssobumalicenc¸aCCBY-NC-ND(http://creativecommons.org/

licenses/by-nc-nd/4.0/).

Introduction

TheCoronavirusDisease(COVID-19)hasspreadgloballyand quiterapidlysinceitwasreportedasaglobalhealthemer- gencyand identiﬁedasapandemic.Afterthat, thereisan urgentneedtoassessitsimpactondiseasesandthetreatment ofcolorectaldisorders.

Thisﬁndingbringsseveralchallengestothecolorectalsur- geon.Whentreatingapatient,thisindividualmighthaveno infection,haveaninfectionnotyetdiagnosedoradetected infection.Thus,inaddition tocaretoavoidcontamination oftheteamandthepatient,wemusttakeintoaccountthe needtochangesomecriteriaforsurgicalindicationsoreven operative procedures. That is because viral infection may require clinical or surgical interventions that are different fromtheconventionalones,astheinfectionisassociatedwith additionalrisksthatculminateinasigniﬁcantincreaseinmor- bidityandmortality.

Thepresentreviewaimedtoreviewtheexperiencesand resultspublishedintheliteratureinrelationtothetreatment ofcolorectal tumorsandinﬂammatorybowel diseases,two importantconditionsofourspecialty,ofwhichmanagement willeventuallyhavetoincorporatenewtherapeuticstrategies.

Is it necessary to change surgical procedures?

Incaseofaninfectedpatient,arecentdiscussionconcernsthe decisiontoavoidperformingananastomosisinhigh-risksitu- ations(lowanastomosis,diabetics,preoperativeradiotherapy,

theelderly),inordertoreducecomplicationsandhospitaliza- tioncosts.¹However,thisoptionmustbeweighedagainstthe demandforafuturehospitalizationtoreconstructintestinal transit(inadditiontothepsychologicalconsequencesasso- ciatedwithastoma).Forthisreason,thisdecisionmustbe individualizedand shared, based onthe team’sexperience andclinicalconditionsatthetimeofsurgery.

Another presented proposal concerns the management of cases with intestinal obstruction, a situation in which oneproposesevaluatinglessaggressivealternatives,suchas stentplacementorintestinalbypasswithastoma,without resection.²However,onemustrememberthatthemanage- mentofanintestinalstomacanincreasetheriskofinfection throughthehandlingofcontaminatedstool.Digestivetran- sitreconstructionproceduresshouldbepostponed,astheydo notrepresentanemergencycontingency.Similarly,itisneces- sarytoconsiderpotentiallycontaminatedsurgicalspecimens whentheyaresenttothepathologist.

In the current situation,the COVID-19infection should bepartofthedifferentialdiagnosiswheninvestigatingpost- operative fever. This is particularly important when low symptomaticorasymptomaticpatientsinfectedwithSARS- CoV-2 require urgent surgery and cannot be effectively screened.

Patients with fever of unknown etiology or respiratory symptomsshouldbeisolated,submittedtoachestCTscan and laboratorytests. Theuncertainty about the etiologyof postoperativefevercanbereducedbytheuniversal testing ofall surgicalpatients.Even ifthe patienthasbeen tested negativeinthepreoperativeperiod,furthertestsmustbeper- formed.

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Table1–Treatmentprioritycategoriesaccordingto tumortypes.

Priority Tumortypes

High Obstructive,perforatedtumors,withrepetitive bleeding

Middle StagesI,IIandIIIcoloncancer StageIrectalcancerorstagesII-IIIafter neoadjuvanttreatment

Low EarlyrectalcanceraftercompleteRT/CT response

ProphylacticsurgeryforhereditaryCRCcases

Initial recommendations for the management of colorectal cancer (CRC)

Overall, cancer patients can be fragile and show different degreesofmalnutritionandimmunosuppression,duetothe neoplasmitselfortoantineoplastictherapies.Thisgroupis estimatedtohaveatwo-foldriskofcontractingSARS-CoV-2, whencomparedtothegeneralpopulation.²

Thesurgicaltreatmentofthesepatientsaddsimportant dilemmas,asthesurgerycantriggerimportantcomplications and its delay can affect prognosis.It iscrucialto evaluate theoperativerisksandthechancesofrespiratoryinfection, asCOVID+patients are moreprone toinfection associated withsurgery,adjuvanttreatmentorimmunosuppression.This entirescenario must beexplained and discussed withthe patient.

Thefollowingareconsideredessentialmeasuresincases ofcolorectalneoplasms:

- Keepingminimumnutritionalconditions;

- Avoidimmunesystemworseningbytheimplementedtreat- ments;

- Avoidprolongedhospitalizationandvisitsthatfavorcon- tamination;

- Adopttherapeuticplanningthatdoesnotrequireaspeciﬁc surgicalschedulethatmaynotbepossible;

- Includethepatientinmultidisciplinarydiscussiongroups;

- Providepsychologicalassistance.

Surgery is the therapeutic method with the greatest beneﬁtsinterms of survival.However, possiblealternative measurestoradicalsurgeryshouldbediscussedinearlyor veryadvancedstages,andpatientsshouldbereferredtoter- tiaryhospitalswithintensivecare.³ Similarly,it istheonly alternativeformanagingcomplicationscausedbytheneopla- sia.

Tomakeiteasier,wecanproposetheseparationofpatients accordingtotheirtreatmentpriority(Table1).

Insituationswherehospitalresourcesarealldedicatedto thecareofinfectedpatients,operativeindicationsshouldbe restrictedto urgentcasesonly(perforation, localor gener- alizedperitonitis,obstruction,bleedingtumorsthatrequire repeatedtransfusion).Inthisway,thetreatmentofmalignant polyps,largenon-obstructive polyps,prophylacticsurgeries inpatientswithgeneticdiseasesandrarer tumors,suchas small-sizedneuroendocrinetumors,wouldbepostponed.⁴

Obstructivetumorswilleventuallyrequirethecreationof astomaandchemotherapyindication.Inthesecases,special caremustbetakenduringthehandlingofthestomainorder toreduceinfectionamongtheteam.Thebigproblemliesin caseswherethesurgeryhasacurativeintention,only.Allsit- uationsshouldbediscussedonacase-by-casebasis,taking into accountthe oncologicalrisk,thechanceofevolvingto anobstructive conditionand alsoofinducingimmunosup- pression, whichcouldbeharmful.⁵ Ininitiallesionswitha goodprognosis(T1-2,N0),itispossibletodelaythesurgery, althoughnotforlong,aimingtominimizetheriskofcompli- cationsandprogression.Theadministrationofneoadjuvant therapyinthesecasesisnotstandardized.^6,7

Inintermediatecases,itisdifﬁculttoestimatetheimpact ofthedelay.Whentreatmentisdelayedformorethan90days sincethediagnosis,itcanaffectsurvival⁸ incomparisonto treatmentimplementedbetween3and6weeks.⁹Duringthe pandemic,itisestimatedthatthisperiodcannotberespected, possiblyinﬂuencingresultsinthemediumandlongterms, sincethetimebetweenthediagnosisandsurgeryisconsid- eredameasureoftreatmentquality.

Thosewithadvancedcolonictumorsmayundergoneoad- juvant chemotherapy (5-FU or oxaliplatin) until the peak of the pandemic has occurred, before proposing any radi- cal treatment. Remember that the beneﬁtof tumors with MicrosatelliteInstability(MSI)islimitedorevenharmful.¹⁰

Asforprecancerousrectallesionsorearlytumors,there isthealternativeofresectionusinglessinvasiveendoscopic techniquessuchasEMRorESD.Inthemoreadvancedcases, the biggestproblemwillnotnecessarilybethenewlydiag- nosed patient, but the one who has ﬁnished radiotherapy andchemotherapy.Aftercompletingtheneoadjuvanttreat- ment,patientswithstageII–IIIrectaltumorscanbeoperated, butsurgerycanalsobedelayedincasesthatrespondedwell or completely. At the oncologist’s discretion, adding more cyclesofchemotherapymayfurtherextendtheintervalbefore surgery.T3-4orN+tumorsthatcompletedtheneoadjuvant treatment without achieving a full tumorresponse should beoperatedsoasnottomissthechanceofhavingacura- tiveprocedure,withagreaterchanceofcurethantheriskof infection.^4,11

TransanalTotalMesorectum(TaTME)excisionprocedures requireinsufﬂationwithahighCO₂ﬂow,exposingthemedical teamtoaerosolizedviralparticles.Consequently,itwouldbe prudenttoavoidthisaccessrouteduringthepandemic.¹²

Eventually, the adoption of newneoadjuvant treatment protocols willallow the deﬁnitive treatment tobe delayed for up to12 weeks, without majorconsequences.¹³ Atthe MemorialSloan-KetteringCancerCenteremNovaYork,the reassessmentofpracticesintheemergencysituationthatwe arecurrentlyexperiencingledtotheadoptionofshort-course radiationtherapytothedetrimentoftotalneoadjuvantther- apy,despitebeingassociatedwithlesstumormassreduction.

Theadoptionoftherapeuticstrategiesinvolvingshort-course radiationtherapyhastheadvantageofreducingthepatient’s exposuretothehospitalenvironment.¹⁴

Eventually,apatientwithalessadvancedtumordevelops acompleteresponse,asituationinwhichalowerchanceof newtumorgrowthisrecognized.¹⁵ Thissituation wouldbe potentially ideal,despiteallthecontroversythatinvolvesa

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Table2–Strategiessuggestedforthetreatmentofcolorectalcancerinitsdifferentstages.

Tumor Staging Conduct

EarlyCRC T1N0M0 Endoscopicresection,transanalexcisionordelaysurgery

EarlyCRC T2N0M0 Delaysurgery

Locallyadvancedcolontumor T3-4 Chemotherapy?

Locallyadvancedmid-rectaltumor T4N0orTqqN+ NeoadjuvantCRT

T3N0M0 NeoadjuvantCRTordelay

Locallyadvancedhighrectaltumor T0N0completeresponse Surgerywith/withoutneoadjuvantCRTorWatchandwaitProtocol

conductthatisdivergentfromthetraditionalone,allowing theorgantobepreservedandthepatientnottobeexposedto surgicalrisk,withclearbeneﬁtsfortheelderly.

Table2depictsasummaryofthestrategiessuggestedfor thetreatmentofcolorectalcancerinitsdifferentstages.¹¹

Whenconsideringtherisksandbeneﬁtsofanintervention, onemustbecarefullyassessthemonanindividualbasis.Sur- gicaldelay,associatedornotwithadjuvanttreatment,maybe possibleaslongasthereisanagreement.Anotherimportant measureistominimizethepatient’sexposuretootherpeople andthehospitalenvironment.

Duetothelimitednumberofpublicationswithevidence, therearestillnointernationalrecommendationsthatindicate thebesttherapeuticstrategyinallsituations.Here,wehave onlyoutlinedthechallengesthatcanbefoundandlistedthe practicalsuggestionsproposedsofar.Butwerecognizethat onlytimewillbringmoreappropriateanswerstothecountless doubtsthatintrigueusatthismoment.

Inﬂammatory bowel disease management during the pandemic

Introduction

OnMarch11,2020,theWorld HealthOrganizationdeclared that Coronavirus-19 Disease (COVID-19) was a pandemic.

Threeweekslatertherewerealready1,000,000affectedindi- vidualsandmorethan46,000deathsworldwide.Thisdisease affectspeopleinallagegroups,beingmoreprevalentinmales andhasamoreunfavorableevolutioninpeoplewithchronic comorbiditiessuchasdiabetes,respiratorydiseases,obesity andhypertension.¹⁶

ThemainclinicalmanifestationsofCOVID-19arefeverand respiratorysymptoms;however, weknowthatasigniﬁcant partofaffectedpatientswillexperiencesymptomsrelatedto thedigestivetract.Thesesymptomsseemtoberelatedtothe swallowingofthevirusandtheexpressionoftheAngiotensin- 2ConvertingEnzymeinintestinalcells.Recentstudieshave demonstrated the presence ofthe virus in the stool, even afterthedisappearanceofrespiratorysymptomsandeventhe absenceofthevirusintheoropharynx.¹⁷

Sincethisdiseasepresentsitselfasapandemic,itisnatural forpatientswithInﬂammatoryBowelDisease(IBD)toexpress aspecialconcernregardingtheirsituation.Wemustremem- berthatthedrugcontrolofIBDsfundamentallyinvolvesthe continued and chronicuse ofimmunosuppressive medications.Inthisarticle,wewillattempttoclarifysomedoubts pertaining to the inherent risk of contamination of these patients,thosewithactivediseaseandtheonesinremission,

theneedtochangetheprescriptionoftheirmedicationsto preventcontagionandhowtomanagethosewithIBDwho maybeaffectedbyCOVID-19.¹⁸

IBDandriskofcontractingCOVID-19

Inflammatory bowel diseases, more specifically ulcerative colitis and Crohn’s disease, are characterized by chronic gastrointestinalinflammation,whichaffectmillionsofpeo- pleworldwide.Mostoftheseindividuals requiretheuseof immunosuppressive medications that increase the risk of severalinfections.Corticosteroids,immunomodulators,bio- logicalagentsandseveralothercommonlyusedmedications areassociatedwithhigherratesofviral,bacterialandfungal infections.Therefore,itislogicaltoassumethatSARS-CoV-2 infectionandthedevelopmentofCOVID-19isgreateramong individualswithIBD.Despitethepotentialriskforthedevelop- mentofCOVID-19inthesepatients,thisfacthasnotyetbeen observed.PatientswithIBDdonotseemtohaveanincreased riskofacquiringSARS-CoV-2infectionordevelopingCOVID- 19.¹⁹

ThefactthattheindividualhasanactiveIBDorisinremis- sionalsodoesnotseemtomakeanydifferenceinrelationto theriskofdevelopingCOVID-19.However,itseemslogicalthat agreateffortshouldbemadetokeepthesepatientsinremis- sion;thusavoidingtheincreaseinmedications,theneedfor exams,hospitalizationsand,eventually,moreinvasiveproce- dures.

PatientswithIBDwhodonothaveSARS-CoV-2infection should nothave theirmedications suspended. There isno evidenceofprophylacticbeneﬁtforthisconduct.¹⁷

EvolutionofIBDinpatientswithCOVID-19

TheevolutionofIBDdoesnotseemtobealteredinpatients withCOVID-19.Todate,noworsening intheinﬂammatory activityinindividualswithCrohn’sdiseaseorulcerativecol- itis that havebeen contaminated bySARS-CoV-2 has been observed.Thepatient’soverallevolutionwilldependfunda- mentallyontheseverityofthetwodiseasesseparately.²⁰

DrugmanagementofIBDduringthepandemic

OneoftheimportantquestionsraisedbypatientswithIBD and alsobytheirmedicalteamsiswhattodoand howto managedrugtherapyduringthepandemic.Westilldonot haveenoughdatatobeabletosupportaconductunequivo- cally;however,onethingisveryclear:themanagementwill dependfundamentallyontheclinicalpresentationofIBDand

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theformofSARS-CoV-2infection.Therefore,wedivideddrug managementintodifferentsituations:

Patient with IBD without SARS-CoV-2 infection: IBD patientsarenotatincreasedriskofdevelopingCOVID.Thus, itisstronglysuggestedthattheymaintaintheirmedication withoutchangingdosesorintervals.Itisessentialatthispoint thattheymaintaintheclinicalandendoscopicremissionof thedisease.

IBDrecurrenceisextremelydangerousatthistime,asit may leadthe patientto require the use ofcorticosteroids, hospitalizationsandevenpossibleinvasiveprocedures,which aresituationsthatshouldbeavoidedatthispoint.Moreover, patientsmustmaintainstrictsocialisolationandadequate hygienemeasures.PatientsusingInﬂiximabshouldnotswitch toAdalimumab,aimingtoavoidgoing totheinfusioncen- ters,as it isknown that the riskof IBDrecurrence during the exchange exceeds the risk of contagion during these displacements.²¹

Patients withIBD who test positive forSARS-CoV-2 but remain asymptomatic of viral infection: In this situation, thereisa real possibilityofthe developmentofCOVID-19.

Therefore, some measures must be taken.Patients should decreaseprednisonedosetolessthan20mg/dayand,ifpos- sible,switch tobudesonide.Thiopurines,methotrexateand tofacitinib canbe temporarilysuspended. Anti-TNF,Ustek- inumabandvedolizumabshouldhavetheirdosesdelayedfor 2weeks.Duringthisperiod,the viralinfection evolutionis possible,and the applicationshouldbe restartedafterthis periodinpatientswhodidnotdevelopCOVID-19.Wemust keepinmindthatthevirusremainspresentinthestooleven afteritsdisappearancefromthenasopharynx,buttheclinical relevanceofthisfactisnotyetclear.²¹

PatientswithIBDwhodevelopCOVID-19:Inthissituation, theuseofaminosalicylates(oralortopical),dietarymanage- ment and antibiotics can be safely used. Oralbudesonide seemstobesafeaswellandcanbemaintainedifitisreally necessaryandshowsbeneﬁtincontrollingIBD.Systemiccor- ticosteroidsshouldbestoppedrapidly,takingintoaccountthe riskofadrenalfailure.Thiopurines,methotrexateandtofac- itinib should be suspended. Anti-tnf, anti-interleukin and anti-integrinshaveanacceptablesafety proﬁlebutmustbe suspendedinthepresenceofCOVID-19.²²

Colonoscopy:strategyinIBDpatientsduringthepandemic

Routineendoscopicprocedures forIBDmonitoring, aswell asfordetectingdysplasiaand earlycolorectal cancerdiag- nosisshouldbedelayedatthistime. Themainindications forendoscopic procedures inpatients withIBD duringthe pandemicwouldbe:(a)Suspectedinfectionbyclostridiumor cytomegalovirus;(b)Radiologicalsuspicionofcolorectalneo- plasiaduetomorphologicalalterationofthemucosa.^23–25 SurgicalproceduresinpatientswithCOVID-19

ThesurgicaltreatmentofIBDduringapandemicexposesthe patientand thesurgicalteam toahighriskofcontamina- tion.Patientsshouldbeadvisedandencouragedtoremainin socialisolationandtoavoidhospitalenvironmentswhenever possible.Additionally,electivesurgeriesoccupyhospitalbeds

inwardsandICUsthatcouldbeverynecessaryforinfected patients.²⁶

Unfortunately, emergencies will continue to occur in patients with IBD and many of them will have to be treatedsurgically.Therefore,patientswithperianalabscesses, intestinal obstruction, perforation with peritonitis, severe intestinalhemorrhage,fulminantcolitisandtoxicmegacolon, might needurgentsurgicaltreatment. Somepatientsdiag- nosedwithcolorectalcancermayalsoneedurgentsurgical intervention.^27,28

Someconductsare usefuland necessarywhenitcomes to surgical treatment. The number of people in the oper- ating room should be limited to the minimum necessary.

Thereisnoabsolutecontraindicationtotheuseofminimally- invasivetechniques;however,thereseemstobeadecreasein thetolerancetoconversiontoopensurgery.²⁸Preferably,the surgeryshouldperformedbyanexperiencedsurgeonrather thanmoreinexperiencedandresidentsurgeons.Finally,spe- cialcaremustbetakenduringpatientintubation,peritoneal insufﬂation, excessive use ofelectrocautery, aerosolization, aspirationandtransoperativeendoscopywhennecessary.^28,29 Todate,thepostoperativemortalityinpatientswhotested positiveforSARS-CoV-2ismuchhigherthanthatobservedfor otherpatients.Aretrospectivestudyof34IBDpatientssubmit- tedtosurgeryshoweda20%mortalityinelectivesurgeries.

Obviously, avery large number ofvariables mustbe taken into account,but untilwehaveamoreconcreteideaabout thesemorbiditiesandmortality,itseemsreasonabletopost- pone,wheneverpossible,electivesurgeriesinpatientswith IBDduringthepandemic.^29,30

Conclusion

Manyofthedatapresentedhereinaredebatableandsubjectto changeoncethepandemicentersitsﬁnalphaseandchanges inconductare betterappreciated, withahighernumberof cases.Itisuptothespecialisttorecognizetheneedtokeep uptodateanddevelopactivitieswithacoordinatedmultidis- ciplinarygroupthatcanmakethebestdecisionstakinginto accounttheshortandlong-termimpactoftheviraldisease.It isalsonecessarytoperformspeciﬁcresearchonthetopicto establishnormsandrecommendationswithahigherlevelof evidence.

Conﬂicts of interest

Theauthorsdeclarenoconﬂictsofinterest.

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