Hospitalized Adults: Therapeutic Management - COVID-19 ...

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HomeManagementClinicalManagementHospitalizedAdults:TherapeuticManagementManagementClinicalManagementClinicalManagementSummaryNonhospitalizedPatients:GeneralManagementNonhospitalizedAdults:TherapeuticManagementHospitalizedAdults:TherapeuticManagementCriticalCareSummaryRecommendationsGeneralConsiderationsInfectionControlHemodynamicsOxygenationandVentilationAcuteKidneyInjuryPharmacologicInterventionsExtracorporealMembraneOxygenationGuidelinePDFsSectionOnly(PDF|2MB)FullGuideline(PDF|4.1MB)SignUpForUpdatesEmailAddressSubmitRelatedContentGuidelinesArchiveHowtoCiteTheseGuidelinesTherapeuticManagementofHospitalizedAdultsWithCOVID-19LastUpdated:December16,2021TableA.DosingRegimensfortheDrugsRecommendedinFigure2TableA.DosingRegimensfortheDrugsRecommendedinFigure2DrugNameDosingRegimenCommentsRemdesivirRDV200mgIVonce,thenRDV100mgIVoncedailyfor4daysoruntilhospitaldischarge.Ifthepatientprogressestomoresevereillness,completethecourseofRDV.ForadiscussiononusingRDVinpatientswithrenalinsufficiency,seeRemdesivir.DexamethasoneDEX6mgIVorPOoncedailyforupto10daysoruntilhospitaldischarge.IfDEXisnotavailable,anequivalentdoseofanothercorticosteroidmaybeused.Formoreinformation,seeCorticosteroids.BaricitinibBaricitinibdoseisdependentoneGFR;durationoftherapyisupto14daysoruntilhospitaldischarge.eGFR≥60mL/min/1.73m2:Baricitinib4mgPOoncedailyeGFR30to<60mL/min/1.73m2:Baricitinib2mgPOoncedailyeGFR15to<30mL/min/1.73m2:Baricitinib1mgPOoncedailyeGFR<15mL/min/1.73m2:Baricitinibisnotrecommended.TofacitinibTofacitinib10mgPOtwicedailyforupto14daysoruntilhospitaldischarge.Useasanalternativeimmunomodulatorydrugifbaricitinibisnotavailableornotfeasibletouse(BIIa).eGFR<60mL/min/1.73m2:Tofacitinib5mgPOtwicedailyTocilizumabTocilizumab8mg/kgactualbodyweight(upto800mg)administeredasasingleIVdose.Inclinicaltrials,athirdoftheparticipantsreceivedaseconddoseoftocilizumab8hoursafterthefirstdoseifnoclinicalimprovementwasobserved.SarilumabUsethesingle-dose,prefilledsyringe(nottheprefilledpen)forSQinjection.Reconstitutesarilumab400mgin100cc0.9%NaClandadministerasanIVinfusionover1hour.Useasanalternativeimmunomodulatorydrugiftocilizumabisnotavailableornotfeasibletouse(BIIa).IntheUnitedStates,thecurrentlyapprovedrouteofadministrationforsarilumabisSQinjection.IntheREMAP-CAPtrial,theSQformulationwasusedtopreparetheIVinfusion.Key:DEX=dexamethasone;eGFR=estimatedglomerularfiltrationrate;IV=intravenous;PO=oral;RDV=remdesivir;SQ=subcutaneousIntroductionTwomainprocessesarethoughttodrivethepathogenesisofCOVID-19.Earlyintheclinicalcourse,thediseaseisprimarilydrivenbythereplicationofSARS-CoV-2.Subsequently,thediseaseappearstobealsodrivenbyadysregulatedimmune/inflammatoryresponsetoSARS-CoV-2thatleadstotissuedamage.Basedonthisunderstanding,therapiesthatdirectlytargetSARS-CoV-2areanticipatedtohavethegreatesteffectearlyinthecourseofthedisease,whereasimmunosuppressive/anti-inflammatorytherapiesarelikelytobemorebeneficialafterCOVID-19hasprogressedtostagescharacterizedbyhypoxia.PatientsWhoDoNotRequireSupplementalOxygenRecommendationsTheCOVID-19TreatmentGuidelinesPanel(thePanel)recommendsagainsttheuseofdexamethasone(AIIa)orothercorticosteroids(AIII)forthetreatmentofCOVID-19.PatientswithCOVID-19whoarereceivingdexamethasoneoranothercorticosteroidforanunderlyingconditionshouldcontinuethistherapyasdirectedbytheirhealthcareprovider.ThereisinsufficientevidencetorecommendeitherfororagainsttheroutineuseofremdesivirforthetreatmentofCOVID-19inhospitalizedpatientswhodonotrequiresupplementaloxygen,butusemaybeappropriateinpatientsathighriskofdiseaseprogression.RationaleforRecommendingAgainsttheUseofDexamethasoneorOtherCorticosteroidsIntheRECOVERYtrial,amulticenter,open-labeltrialintheUnitedKingdom,hospitalizedpatientswithCOVID-19wererandomizedtoreceivedexamethasoneplusstandardofcareorstandardofcarealone(controlarm).1Nosurvivalbenefitfordexamethasonewasobservedamongtheparticipantswhodidnotrequiresupplementaloxygenatenrollment:17.8%ofparticipantsinthedexamethasonearmand14%inthecontrolarmdiedwithin28daysofenrollment(rateratio1.19;95%CI,0.91–1.55).SeeTable4aforadditionalinformation.Basedonthesedata,thePanelrecommendsagainsttheuseofdexamethasone(AIIa)orothercorticosteroids(AIII)forthetreatmentofCOVID-19inhospitalizedpatientswhodonotrequiresupplementaloxygen,unlessthepatienthasanotherindicationforcorticosteroidtherapy.RationaleforDeterminingThatThereIsInsufficientEvidencetoRecommendEitherfororAgainsttheUseofRemdesivirACTT-1wasamultinationalrandomizedcontrolledtrialthatcomparedintravenous(IV)remdesivirtoplaceboinhospitalizedpatientswithCOVID-19.Remdesivirshowednosignificantbenefitinpatientswithmildtomoderatedisease,whichwasdefinedasoxygensaturation>94%onroomairorarespiratoryrate<24breaths/minwithoutsupplementaloxygen(rateratioforrecovery1.29;95%CI,0.91–1.83);however,therewereonly138patientsinthissubgroup.2Inamanufacturer-sponsored,open-labelrandomizedtrialthatincluded596patientswithmoderateCOVID-19,patientswhoreceived5daysofremdesivirhadhigheroddsofabetterclinicalstatusonDay11(basedona7-pointordinalscale)thanthosewhoreceivedstandardofcare(OR1.65;95%CI,1.09–2.48;P=0.02).3TheSolidaritytrialwasalarge,multinational,open-labelrandomizedcontrolledtrialthatcompareda10-daycourseofremdesivirtostandardofcare.About25%ofhospitalizedpatientsinbotharmsdidnotrequiresupplementaloxygenatstudyentry.Theprimaryoutcomeofin-hospitalmortalityoccurredin11of661patients(2%)intheremdesivirarmand13of664patients(2.1%)inthecontrolarm(rateratio0.90;99%CI,0.31–2.58).4PleaseseeTable2aforadditionalinformation.DatasupportingtheclinicalbenefitofearlytreatmentwithremdesiviremergedfromPINETREE,arandomizedplacebo-controlledtrialinnonhospitalizedpatientswithCOVID-19athighriskofclinicalprogression.Participantswererandomizedtoreceive3daysofIVremdesivirorplaceboasoutpatients.Attreatmentinitiation,themediandurationofsymptomswas5days.ByDay28,therewasasignificantdecreaseinhospitalizationand/ordeathamongthepatientswhoreceivedremdesivir:theprimaryendpointoccurredin0.7%ofremdesivirrecipientsversus5.3%ofplaceborecipients(HR0.13;95%CI,0.03–0.59;P=0.008).5Becausethesetrialsproducedconflictingresultsregardingthebenefitsofremdesivir,thePanelfindstheavailableevidenceinsufficienttorecommendeitherfororagainstroutinetreatmentwithremdesivirforallhospitalizedpatientswithmoderateCOVID-19.However,thePanelrecognizesthatcliniciansmayjudgethatremdesivirisappropriateforsomehospitalizedpatientswithmoderatedisease(e.g.,thoseatparticularlyhighriskforclinicaldeterioration).PatientsWhoRequireSupplementalOxygenPatientswhorequiresupplementaloxygen,butnothigh-flowoxygen,noninvasiveventilation(NIV),ormechanicalventilationareaheterogeneousgroup.Someofthesepatientswillhavemilddiseasethatwillimproveafterashortperiodwithorwithouttreatmentwithremdesivir,dexamethasone,orboth;otherswilldevelopprogressivediseasedespitetreatmentandrequireamoreintensivelevelofcare.Thereisnoconsensusonwhichclinicalorlaboratoryparametersallowforreliablerisk-stratificationtoguidetherapyand/oridentifywhichsubsetsofpatientswillexperienceprogressivelunginjuryandhypoxemia.SomestudieshavetriedtodefinethisgroupaccordingtotraditionalriskfactorsforCOVID-19progressionand/orbythepresenceofelevatedinflammatorymarkerslikeC-reactiveprotein(CRP),butevidencetosupportaspecificidentifyingbiomarkerorclinicalthresholdislacking.RecommendationsThePanelrecommendsusing1ofthefollowingoptionsforhospitalizedpatientswhorequiresupplementaloxygen:Remdesivir(e.g.,forpatientswhorequireminimalsupplementaloxygen)(BIIa)Dexamethasoneplusremdesivir(BIIb)Dexamethasone(BI);forpatientsondexamethasonewhohaverapidlyincreasingoxygenneedsandsystemicinflammation,addasecondimmunomodulatorydrug(e.g.,tocilizumaborbaricitinib)(CIIa)Ifdexamethasoneisnotavailable,analternativecorticosteroidsuchasprednisone,methylprednisolone,orhydrocortisonecanbeused(BIII).SeeCorticosteroidsfordosingrecommendations.RationalefortheUseofRemdesivirIntheACTT-1trial,remdesivirwasassociatedwithimprovedtimetorecoveryinthe435participantswhorequiredoxygensupplementationbutnothigh-flowoxygen,NIV,ormechanicalventilation(7daysforremdesivirvs.9daysforplacebo;recoveryrateratio1.45;95%CI,1.18–1.79).Fewerpatientsintheremdesivirarmthanintheplaceboarmprogressedtorequiringhigh-flowoxygen,mechanicalventilation,orextracorporealmembraneoxygenation(ECMO)(17%vs.24%).InaposthocanalysisofdeathsbyDay29,remdesivirappearedtoconferasubstantialsurvivalbenefitinthissubgroup(HRfordeath0.30;95%CI,0.14–0.64).2TheSolidaritytrialreportednodifferenceintherateofin-hospitaldeathsbetweenpatientswhoreceivedremdesivirandthosewhoreceivedstandardofcare(rateratiofordeathintheoverallstudypopulation0.95;95%CI,0.81–1.11;rateratiofordeathinpatientswhodidnotrequiremechanicalventilationatentry0.86;99%CI,0.67–1.11).Therewasnodifferencebetweenpatientswhoreceivedremdesivirandthosewhoreceivedstandardofcareinthepercentageofthosewhoprogressedtomechanicalventilation(11.9%vs.11.5%)orinlengthofhospitalstay.4However,anopen-labeltriallikeSolidarityislesswell-suitedtoassesstimetorecoverythanaplacebo-controlledtrial.IntheSolidaritytrial,becausebothcliniciansandpatientsknewthatremdesivirwasbeingadministered,itispossiblethathospitaldischargewasdelayedinordertocompletethe10-daycourseoftherapy.DisCoVeRywasamultinational,open-labelrandomizedcontrolledtrialthatcomparedupto10daysofremdesivirplusstandardofcaretostandardofcarealoneinhospitalizedpatientswithmoderateorsevereCOVID-19.TherewasnosignificantdifferenceintheoddsofimprovedclinicalstatusbyDay15betweenthepatientsintheremdesivirarmandthestandardofcarearm(OR0.98;95%CI,0.77–1.25).AtDay28,therewerealsonodifferencesbetweenthearmsineithermortality(8%inremdesivirarmvs.9%instandardofcarearm)orclinicalstatus.TheDisCoVeRytrialsharedwiththeSolidaritytrialthemajorlimitationofopen-labeldesign.Additionally,440ofthe832participantsintheDisCoVeRytrial(219intheremdesivirarmand221inthestandardofcarearm)werealsoSolidaritytrialparticipants.6Althoughtheopen-labelSolidarityandDisCoVeRytrialsdemonstratednomortalitybenefitforremdesivir,inthelargerandomizedplacebo-controlledACTT-1trial,remdesivirsignificantlyreducedtimetoclinicalrecovery.Inaposthocanalysis,thisclinicalbenefitofremdesivirwasmostevidentinthosewhohadsymptomsfor≤10days.TheevidencefromtheACTT-1andPINETREEtrialssuggeststhatremdesivirwillhaveitsgreatestimpactwhenadministeredearlyintheclinicalcourse,whichisalsothecaseforantiviralagentsusedtotreatotherviralinfections.5ThePanelrecommendsremdesivir(withoutdexamethasone)asatreatmentoptionforcertainpatientswithCOVID-19whorequireminimalsupplementaloxygenandareintheearlycourseofthedisease(BIIa).Intheseindividuals,thehyperinflammatorystatewherecorticosteroidsmightbemostbeneficialmaynotyetbepresentorfullydeveloped.Althoughseveraltrialsstudieda10-daycourseofremdesivir,2,4a5-daycoursehasbeenshowntobecomparableto10daysoftherapyinhospitalizedpatientswithmoderate-to-severeCOVID-19.3,7Formoreinformation,pleaseseeTable2a.RationalefortheUseofRemdesivirPlusDexamethasoneDataonthesafetyandefficacyofcombinationtherapyconsistingofremdesivirwithcorticosteroidsareprimarilyderivedfromobservationalstudies,withsome(butnotall)suggestingaclinicalbenefitofremdesivirplusdexamethasone.8-10Remdesivirplusdexamethasonehasnotbeendirectlycomparedtodexamethasonealoneinalargerandomizedclinicaltrial.PatientswithsevereCOVID-19maydevelopasystemicinflammatoryresponsethatleadstomultipleorgandysfunctionsyndrome.Thepotentanti-inflammatoryeffectsofcorticosteroidsmightpreventormitigatethesehyperinflammatoryeffects.Thus,thecombinationofanantiviralagent,suchasremdesivir,withananti-inflammatoryagent,suchasdexamethasone,maytreattheviralinfectionanddampenthepotentiallyinjuriousinflammatoryresponsethatisaconsequenceoftheinfection.Basedonthetheoreticalcombinedbenefitofantiviralandanti-inflammatorytherapies,thePanelrecommendsthecombinationofdexamethasoneplusremdesivirasatreatmentoptionforpatientswhorequiresupplementaloxygen(BIIb),despiteimportantlimitationsofobservationaldata.RationalefortheUseofDexamethasoneIntheRECOVERYtrial,treatmentwithdexamethasoneconferredasurvivalbenefitamongparticipantswhorequiredsupplementaloxygenatenrollment.Amongtheseparticipants,fewerparticipantsinthedexamethasonearmthaninthestandardofcarearmdiedwithin28daysofenrollment(23.3%vs.26.2%;rateratio0.82;95%CI,0.72–0.94).1However,theamountofsupplementaloxygenthatparticipantswerereceivingandtheproportionsofparticipantswhorequiredoxygenthroughahigh-flowdeviceorNIVwerenotreported.Itispossiblethatthebenefitofdexamethasonewasgreatestinthosewhorequiredmorerespiratorysupport.Itshouldbenotedthat<0.1%ofpatientsintheRECOVERYtrialreceivedconcomitantremdesivir.Formoreinformation,seeCorticosteroids.Someexpertsprefernottousedexamethasonemonotherapyinpatientswhorequiresupplementaloxygenbecauseofthetheoreticalconcernthatcorticosteroidsmightslowviralclearancewhenadministeredwithoutanantiviraldrug.Corticosteroidshavebeenassociatedwithdelayedviralclearanceand/orworseclinicaloutcomesinpatientswithotherviralrespiratoryinfections.11-13SomestudieshavesuggestedthatcorticosteroidsslowSARS-CoV-2clearance,buttheresultstodateareinconclusive.14-18RationaleforAddingaSecondImmunomodulatoryDrugtoDexamethasoneinCertainPatientsWhoRequireRapidlyIncreasingOxygenSupplementationSeveralmajorrandomizedtrialsevaluatingtheuseofinterleukin(IL)-6inhibitorsorJanusKinase(JAK)inhibitorswithorwithoutcorticosteroidsinpatientswithCOVID-19haveincludedpatientswhorequiredonlylow-flowsupplementaloxygen.However,subgroupanalysesinthesetrialshavenotclearlydefinedwhichpatientsinthisheterogeneousgrouparemostlikelytobenefitfromcorticosteroidswithanotherimmunomodulator.Directcomparisonbetweentrialsisnotpossiblebecauseinsometrials,backgroundtherapies(e.g.,corticosteroids)andinclusioncriteria(e.g.,therequirementforelevatedinflammatorymarkers)differed.Nonetheless,sometrialssuggestthataddingasecondimmunomodulatortodexamethasoneprovidedbenefitsinpatientsrequiringlow-flowsupplementaloxygen.19-21Forexample,theRECOVERYtrialdemonstratedamortalitybenefitforaddingtocilizumabtodexamethasonecomparedtousualcarealone(includingdexamethasone)inasubgroupthatincludedpatientsonlow-flowoxygen.19Similarly,dataonJAKinhibitorsarealsoinconclusive;forexample,theCOV-BARRIERtrialdidnotfindastatisticallysignificantbenefitofbaricitinibversusplaceboinpatientsonlow-flowoxygen,20whereastheplacebo-controlledSTOP-COVIDtrialdemonstratedareductioninrespiratoryfailureordeathinthesubgroupofpatientsonlow-flowoxygenwhoreceivedtofacitinib.21Giventheuncertaintyconcerningwhichpatientsinthisgroupwouldbenefitfromaddingasecondimmunomodulator,suchasbaricitinibortocilizumab,todexamethasonetreatment,thePanelrecommendsconsideringthesetherapiesonacase-by-casebasisforindividualswithrapidlyincreasingoxygenrequirementsandelevatedmarkersofsystemicinflammation(CIIa).BecausetherearenostudiesthatdirectlycomparetheuseofbaricitinibandtocilizumabastreatmentsforCOVID-19,thePanelhasinsufficientevidencetorecommend1drugovertheother.Treatmentdecisionsshouldbebasedonlocalguidance,drugavailability,andpatientcomorbidities.AdditionalConsiderationsBaricitinibortocilizumabshouldonlybegivenincombinationwithdexamethasoneoranothercorticosteroid.Somecliniciansmayassessapatient’sclinicalresponsetodexamethasonebeforedecidingwhetheraddingbaricitinibortocilizumabasasecondimmunomodulatorydrugisnecessary.BecausetherearenostudiesthatdirectlycomparetheuseofbaricitinibandtocilizumabastreatmentsforCOVID-19,thePanelhasinsufficientevidencetorecommend1drugorclassofdrugs(i.e.,JAKinhibitors,anti-IL-6receptormAbs)overtheother.Treatmentdecisionsshouldbebasedonlocalguidance,drugavailability,andpatientcomorbidities.IfbaricitinibandIVtocilizumabarenotavailableornotfeasibletouse,tofacitinibcanbeusedinsteadofbaricitinib(BIIa)andIVsarilumabcanbeusedinsteadofIVtocilizumab(BIIa).ThePanelrecommendsagainsttheuseofbaricitinibincombinationwithtocilizumabforthetreatmentofCOVID-19,exceptinaclinicaltrial(AIII).Becausebothbaricitinibandtocilizumabarepotentimmunosuppressants,thereisthepotentialforanadditiveriskofinfection.Combinationimmunosuppressivetherapy(e.g.,dexamethasonewithbaricitinibortocilizumab)mayincreasetheriskofopportunisticinfectionsorreactivationoflatentinfections;however,randomizedtrialstodatehavenotdemonstratedanincreaseinthefrequencyofinfections.CasesofsevereanddisseminatedstrongyloidiasishavebeenreportedinpatientswithCOVID-19duringtreatmentwithtocilizumabandcorticosteroids.22,23Manyclinicianswouldinitiateempirictreatmentforstrongyloidiasis(e.g.,withtheantiparasiticdrugivermectin)withorwithoutserologictestinginpatientsfromareaswhereStrongyloidesisendemic(i.e.,tropical,subtropical,orwarmtemperateareas).PatientsWhoRequireOxygenThroughaHigh-FlowDeviceorNoninvasiveVentilationRecommendationsThePanelrecommendsusing1ofthefollowingoptionsforhospitalizedpatientswhorequireoxygenthroughahigh-flowdeviceorNIV:Dexamethasone(AI)Dexamethasoneplusremdesivir(BIII)Forpatientswhohaverapidlyincreasingoxygenneedsandhaveincreasedmarkersofinflammation,addeitherbaricitinib(BIIa)ortocilizumab(BIIa)(drugsarelistedalphabetically)to1ofthe2optionsabove.AdditionalConsiderationsIfdexamethasoneisnotavailable,anequivalentdoseofanothercorticosteroidsuchasprednisone,methylprednisolone,orhydrocortisonemaybeused(BIII).SeeCorticosteroidsformoreinformation.Immunosuppressivetherapy(e.g.,dexamethasonewithorwithoutbaricitinibortocilizumab)mayincreasetheriskofopportunisticinfectionsorreactivationoflatentinfections;however,randomizedtrialstodatehavenotdemonstratedanincreaseinthefrequencyofinfections.CasesofsevereanddisseminatedstrongyloidiasishavebeenreportedinpatientswithCOVID-19duringtreatmentwithtocilizumabandcorticosteroids.22,23Manyclinicianswouldinitiateempirictreatmentforstrongyloidiasis(e.g.,withtheantiparasiticdrugivermectin)withorwithoutserologictestinginpatientsfromareaswhereStrongyloidesisendemic(i.e.,tropical,subtropical,orwarmtemperateareas).RationalefortheUseofDexamethasoneIntheRECOVERYtrial,treatmentwithdexamethasoneconferredasurvivalbenefitamongparticipantswhorequiredsupplementaloxygenwithoutmechanicalventilationatenrollment:23.3%oftheparticipantsinthedexamethasonearmversus26.2%inthestandardofcarearmdiedwithin28daysofenrollment(rateratio0.82;95%CI,0.72–0.94).1RationalefortheUseofRemdesivirPlusDexamethasoneAsdiscussedabove,dataonthesafetyandefficacyofcombinationtherapyofremdesivirwithcorticosteroidsareprimarilyderivedfromobservationalstudies,withsome,butnotallsuggestingclinicalbenefitofremdesivirplusdexamethasone.8-10Remdesivirplusdexamethasonehasnotbeendirectlycomparedtodexamethasonealoneinalargerandomizedclinicaltrial.PatientswithsevereCOVID-19maydevelopasystemicinflammatoryresponsethatleadstomultipleorgandysfunctionsyndrome.Thepotentanti-inflammatoryeffectsofcorticosteroidsmightpreventormitigatethesehyperinflammatoryeffects.Thus,thecombinationofanantiviralagent,suchasremdesivir,withananti-inflammatoryagent,suchasdexamethasone,maytreattheviralinfectionanddampenthepotentiallyinjuriousinflammatoryresponsethatisaconsequenceoftheinfection.Basedonthetheoreticalcombinedbenefitofantiviralandanti-inflammatorytherapies,thePanelrecommendsthecombinationofdexamethasoneplusremdesivirasatreatmentoptionforpatientswhorequirehigh-flowoxygenorNIV(BIIb),despiteimportantlimitationsofobservationaldata.RationaleforNotRecommendingRemdesivirMonotherapyIntheACTT-1trial,therewasnoobserveddifferenceintimetorecoverybetweentheremdesivirandplaceboarmsinthesubgroupof193participantswhorequiredhigh-flowoxygenorNIVatenrollment(recoveryrateratio1.09;95%CI,0.76–1.57).AposthocanalysisdidnotshowasurvivalbenefitforremdesiviratDay29,butthetrialwasnotpoweredtodetectthisdifference.2ThePaneldoesnotrecommendusingremdesivirmonotherapyinpatientswhorequirehigh-flowoxygenorNIVbecausethereisuncertaintyregardingwhetherremdesiviraloneconfersaclinicalbenefitinthissubgroup(AIIa).DexamethasonealoneorremdesivirplusdexamethasonearebettertreatmentoptionsforCOVID-19inthisgroupofpatients.Forpatientswhostartremdesivirmonotherapyandthenprogresstorequiringoxygenthroughahigh-flowdeviceorNIV,thePanelrecommendsinitiatingdexamethasoneandcontinuingremdesiviruntilthetreatmentcourseiscompleted.Clinicaltrialsthatevaluatedtheuseofremdesivircategorizedpatientsbasedontheirseverityofillnessatthestartoftreatmentwithremdesivir;therefore,patientsmaybenefitfromremdesivireveniftheirclinicalcourseprogressestoaseverityofillnessforwhichthebenefitsofremdesivirarelesscertain.RationaleforAddingaSecondImmunomodulatoryDrugtoDexamethasoneinCertainHospitalizedPatientsSeverallargeclinicaltrialssuggestthataddingasecondimmunomodulatorydrug,suchasbaricitinibortocilizumab,todexamethasoneprovidesclinicalbenefitinpatientswhorequireoxygensupplementationthroughahigh-flowdeviceorNIV.TheREMAP-CAPandRECOVERYtrials,the2largestrandomizedcontrolledtrialsoftocilizumabtodate,havebothreportedamortalitybenefitfortocilizumabamongpatientswithrapidrespiratorydecompensationwhorequireoxygendeliverythroughahigh-flowdeviceorNIV.19,24Mostpatientsinbothstudiesreceivedcorticosteroids.IntheREMAP-CAPtrial,patientsadmittedtoanintensivecareunit(ICU)withsevere-to-criticalCOVID-19andrapidrespiratorydecompensationwererandomizedtoreceiveopen-labeltocilizumaborusualcare.Theuseoftocilizumabreducedin-hospitalmortality(28%intocilizumabarmvs.36%inusualcarearm)and,during21daysoffollow-up,increasedthemediannumberofdaysfreeofrespiratoryandcardiovascularorgansupport(10daysintocilizumabarmvs.0daysinusualcarearm;OR1.64;95%CI,1.25–2.14).Enrollmentoccurredwithin24hoursofICUadmissionandwithinamedianof1.2daysofhospitalization(IQR0.8–2.8days),suggestingthatthebenefitoftocilizumaboccursinpatientsexperiencingrapidrespiratorydecompensation.TheRECOVERYtrialalsosuggestedamortalitybenefitfortocilizumabplusdexamethasoneinasubsetofpatientsthatincludedthosewhorequiredNIVorhigh-flowoxygen.Inthisstudy,asubsetofparticipantswithhypoxemiaandCRP≥75mg/Lwererandomizedtoreceivetocilizumaborusualcare.Tocilizumabreducedall-causemortalityinthesepatients;byDay28,29%ofparticipantsinthetocilizumabarmversus33%intheusualcarearmhaddied(rateratio0.86;95%CI,0.77–0.96).IntheCOV-BARRIERtrial,1,525hospitalizedpatientswithCOVID-19and≥1elevatedinflammatorybiomarkerwererandomized1:1toreceiveoralbaricitinib4mgorplaceboinadditiontothelocalstandardofcareforupto14days(oruntilhospitaldischarge).20Overall,therewasnodifferenceintheoccurrenceoftheprimaryendpointofprogressiontohigh-flowoxygen,NIV,mechanicalventilation,ordeathbyDay28betweenthebaricitinibarm(27.8%ofpatients)andtheplaceboarm(30.5%ofpatients;OR0.85;95%CI,0.67–1.08;P=0.18).However,all-causemortalitybyDay28was8.1%inthebaricitinibarmand13.1%intheplaceboarm,resultingina38.2%reductioninmortalityforbaricitinib(HR0.57;95%CI,0.41–0.78;nominalP=0.002).Thedifferenceinmortalitywasmostpronouncedinthesubgroupof370patientsreceivinghigh-flowoxygenorNIVatbaseline(17.5%inthebaricitinibarmvs.29.4%intheplaceboarm;HR0.52;95%CI,0.33–0.80;nominalP=0.007).Theoccurrenceofadverseevents,seriousadverseevents,seriousinfections,andvenousthromboemboliceventsinthearmswascomparable.TheACTT-2trialdemonstratedthatbaricitinibusedincombinationwithremdesivirimprovedtimetorecoveryinhospitalizedpatientswithCOVID-19.Theeffectwasmostpronouncedinpatientswhowerereceivinghigh-flowoxygenorNIV.However,patientsreceivingcorticosteroidswereexcludedfromtheACTT-2trial,limitingthegeneralizabilityofthesefindings.Giventheclinicaltrialdata(seeTable4e),thePanelrecommendsaddingbaricitinibortocilizumabasasecondimmunomodulatorytreatmentincombinationwithdexamethasoneforpatientswhoarereceivingoxygensupplementationthroughahigh-flowdeviceorNIV(BIIa).AdditionalConsiderationsBaricitinibortocilizumabshouldonlybegivenincombinationwithdexamethasoneoranothercorticosteroid.Somecliniciansmayassessapatient’sclinicalresponsetodexamethasonebeforedecidingwhetheraddingbaricitinibortocilizumabisnecessary.StudiesthatdirectlycomparebaricitinibtotocilizumabastreatmentsforCOVID-19arenotavailable.Therefore,thereisinsufficientevidenceforthePaneltorecommend1drugovertheother.Treatmentdecisionsshouldbebasedonlocalguidance,drugavailability,andpatientcomorbidities.IfbaricitinibandIVtocilizumabarenotavailableornotfeasibletouse,tofacitinibcanbeusedinsteadofbaricitinib(BIIa)andIVsarilumabcanbeusedinsteadofIVtocilizumab(BIIa).AlthoughapproximatelyathirdofpatientsintheREMAP-CAPandRECOVERYtrialsreceivedaseconddoseoftocilizumabatthediscretionoftheirtreatingphysician,dataonoutcomesbasedonreceiptof1or2dosesisnotavailable.Therefore,thereisinsufficientevidencetodeterminewhichpatients,ifany,wouldbenefitfromanadditionaldoseofthedrug.RationaleforRecommendingAgainsttheUseoftheCombinationofBaricitinibandTocilizumabThePanelrecommendsagainsttheuseofthecombinationofbaricitinibandtocilizumabforthetreatmentofCOVID-19,exceptinaclinicaltrial(AIII),becausethereisinsufficientevidencefortheuseofthiscombination.Giventhatbothbaricitinibandtocilizumabarepotentimmunosuppressants,thereisthepotentialforanadditiveriskofinfection.RationaleforRecommendingSarilumabandDexamethasoneasanAlternativetoTocilizumabandDexamethasoneinCertainHospitalizedPatientsInanupdatedreportfromtheREMAP-CAPtrial,theefficacyoftocilizumabandsarilumabinimprovingsurvivalandreducingthedurationoforgansupportwassimilar.Comparedtononcontemporarycontrolpatientswhoreceivedplaceboplusdexamethasone,patientswhoreceivedsarilumabanddexamethasonedemonstratedreducedmortality,shortertimetoICUdischarge,andmoreorgansupport-freedays.25IntheREMAP-CAPtrial,sarilumabincombinationwithdexamethasone(n=483)wasnoninferiortotocilizumabwithdexamethasone(n=943)withregardstothenumberoforgansupport-freedaysandmortalitywithaprobabilityof99%and98%,respectively.EventhoughtheREMAP-CAPtrialsupportsthatsarilumabandtocilizumabhavesimilarefficacyinthetreatmentofhospitalizedpatientswithCOVID-19,thePanelrecommendssarilumabonlywhentocilizumabisnotavailableorisnotfeasibletouse(BIIa).Therationalesforthisrecommendationare:Theevidenceofefficacyfortocilizumabismoreextensivethanforsarilumab,andCurrently,sarilumabisonlyapprovedasasubcutaneous(SQ)injectionintheUnitedStates.IntheREMAP-CAPtrial,asingledoseofsarilumab400mgforSQinjectionwasreconstitutedin50mlor100mlofnormalsalineandadministeredasanIVinfusionover1hour.RationaleforRecommendingtheUseofTofacitinibPlusDexamethasoneinCertainHospitalizedPatientsIntheSTOP-COVIDtrial,adouble-blindrandomizedplacebo-controlledtrial,useoftofacitinibwasassociatedwithadecreasedriskofrespiratoryfailureanddeath(riskratio0.63;95%CI,0.41–0.97).All-causemortalitywithin28dayswas2.8%inthetofacitinibarm(n=144)and5.5%intheplaceboarm(n=145)(HR0.49;95%CI,0.15–1.63).Approximately80%ofparticipantsineacharmalsoreceivedcorticosteroids.21TheSTOP-COVIDtrialsupportsthattofacitinibplussteroidsiseffectiveinimprovingoutcomesinhospitalizedpatientswithCOVID-19.Bothbaricitinibandtofacitinibbelongtothesameclassofanti-inflammatorydrugs,thekinaseinhibitors,andhaveoverlappingmechanismsofaction.ThePanelrecommendstofacitinibasanalternativetobaricitinibonlywhenbaricitinibisnotavailableornotfeasibletouse(BIIa)becausetheevidenceofefficacyfortofacitinibislessextensivethanforbaricitinib.PatientsWhoRequireMechanicalVentilationorExtracorporealMembraneOxygenationRecommendationsThePanelrecommendsusingdexamethasoneforhospitalizedpatientswithCOVID-19whorequiremechanicalventilationorECMO(AI).ThePanelrecommendsusingdexamethasoneplustocilizumabforpatientswithCOVID-19whoarewithin24hoursofadmissiontotheICU(BIIa).AdditionalConsiderationsIfdexamethasoneisnotavailable,anequivalentdoseofanalternativecorticosteroid(e.g.,prednisone,methylprednisolone,hydrocortisone)maybeused(BIII).ForpatientswhoinitiallyreceivedremdesivirmonotherapyandprogressedtorequiringmechanicalventilationorECMO,dexamethasoneshouldbeinitiatedandremdesivirshouldbecontinueduntilthetreatmentcourseiscompleted.ThePanelrecommendsagainsttheinitiationofremdesivirmonotherapy(AIIa)inpatientswhorequiremechanicalventilationorECMO.Tocilizumabshouldbegivenonlyincombinationwithdexamethasone(oranothercorticosteroidatanequivalentdose).AlthoughsomepatientsintheREMAP-CAPandRECOVERYtrialsreceivedaseconddoseoftocilizumabatthediscretionoftheirtreatingphysician,thereisinsufficientevidencetodeterminewhichpatients,ifany,wouldbenefitfromanadditionaldoseofthedrug.Thecombinationofdexamethasoneandtocilizumabmayincreasetheriskofopportunisticinfectionsorreactivationoflatentinfections.Prophylactictreatmentforstrongyloidiasis(e.g.,withtheantiparasiticdrugivermectin)shouldbeconsideredforpatientswhoarefromareaswhereStrongyloidesisendemic.RationalefortheUseofDexamethasoneMonotherapyAsCOVID-19progresses,asystemicinflammatoryresponsemayleadtomultipleorgandysfunctionsyndrome.Theanti-inflammatoryeffectsofcorticosteroidsmitigatetheinflammatoryresponse,andtheuseofcorticosteroidshasbeenassociatedwithimprovedoutcomesinpeoplewithcriticalCOVID-19.DexamethasonereducesmortalityincriticallyillpatientswithCOVID-19accordingtoameta-analysisthataggregated7randomizedtrialsandincludeddataon1,703criticallyillpatients.26Thelargesttrialinthemeta-analysiswastheRECOVERYtrial,whosesubgroupofmechanicallyventilatedpatientswasincluded.1Fordetailsaboutthemeta-analysisandtheRECOVERYtrial,seeCorticosteroidsandTable4a.Becausethebenefitsofdexamethasoneoutweighthepotentialharms,thePanelrecommendsusingdexamethasoneinhospitalizedpatientswithCOVID-19whorequiremechanicalventilationorECMO(AI).ConsiderationsRelatedtotheUseofDexamethasonePlusRemdesivirCombinationTherapyDexamethasoneplusremdesivircombinationtherapyhasnotbeenevaluatedincontrolledstudies;therefore,thereisinsufficientinformationtomakearecommendationeitherfororagainsttheuseofthiscombinationtherapy.However,thereisatheoreticalreasontoadministerdexamethasoneplusremdesivirtopatientswhohaverecentlybeenintubated.Antiviraltherapymaypreventasteroid-relateddelayinviralclearance.Thisdelayhasbeenreportedinthesettingofotherviralinfections.11,12SomestudieshavesuggestedthatcorticosteroidsslowSARS-CoV-2clearance,butthestudiestodatearenotdefinitive.Forexample,anobservationalstudyinpatientswithnonsevereCOVID-19suggestedthatviralclearancewasdelayedinthosewhoreceivedcorticosteroids,27whereasamorerecentstudyinpatientswithmoderatetosevereCOVID-19foundnorelationshipbetweentheuseofcorticosteroidsandtherateofviralclearance.18Giventheconflictingresultsfromobservationalstudiesandthelackofclinicaltrialdata,somePanelmemberswouldcoadministerdexamethasoneandremdesivirinpatientswhohaverecentlybeenplacedonmechanicalventilation(CIII)untilmoreconclusiveevidencebecomesavailable,basedontheirconcernsaboutdelayedviralclearanceinpatientswhoreceivedcorticosteroids.OtherPanelmemberswouldnotcoadministerdexamethasoneandremdesivirduetouncertaintiesaboutthebenefitofusingremdesivirincriticallyillpatients.RationaleforRecommendingtheUseofTocilizumabPlusDexamethasoneinPatientsWithin24HoursofAdmissiontotheIntensiveCareUnitTheREMAP-CAPandRECOVERYtrials,the2largestrandomizedcontrolledtrialsoftocilizumabtodate,bothreportedamortalitybenefitfortocilizumabinpatientswhoexperiencedrapidrespiratorydecompensationandwererecentlyadmittedtotheICU,includingthosewhorequiredmechanicalventilation.19,24TheREMAP-CAPtrialenrolledpatientswithin24hoursofadmissiontotheICU.PrevioustrialsthatenrolledpatientslaterinthecourseofICUcareand/orwhoreceivedoxygensupport>24hoursafterICUadmissionhavefailedtoshowconsistentclinicalbenefitsfortocilizumab(seeTable4e).Thus,itisunclearwhetherthereisaclinicalbenefitfortocilizumabinpatientswhoreceivedmechanicalventilationfor>24hours.FindingsfromtheRECOVERYtrialsuggestaclinicalbenefitfortocilizumabpluscorticosteroidsamongpatientswithrapidclinicalprogressionwhoreceivedmechanicalventilation.PleaseseetheRationaleforAddingaSecondImmunomodulatoryDrugtoDexamethasoneinCertainHospitalizedPatientssectionaboveforadditionaldetailsontheclinicaltrialdataandrationaleforusingtocilizumabinthissituation.RationaleforRecommendingAgainsttheUseofRemdesivirMonotherapyAclearbenefitofremdesivirmonotherapyhasnotbeendemonstratedinpatientswhorequiremechanicalventilationorECMO.IntheACTT-1trial,remdesivirdidnotimprovetherecoveryrateinthissubgroupofparticipants(recoveryrateratio0.98;95%CI,0.70–1.36),andinaposthocanalysisofdeathsbyDay29,remdesivirdidnotimprovesurvivalinthissubgroup(HR1.13;95%CI,0.67–1.89).2IntheSolidaritytrial,therewasatrendtowardincreasedmortalityamongpatientswhoreceivedmechanicalventilationandwererandomizedtoreceiveremdesivirratherthanstandardofcare(rateratio1.27;95%CI,0.99–1.62).4Takentogether,theseresultsdonotdemonstrateaclearbenefitofremdesivirincriticallyillpatients.ForpatientswhostartremdesivirmonotherapyandthenprogresstorequiringmechanicalventilationorECMO,thePanelrecommendsinitiatingdexamethasoneandcontinuingremdesiviruntilthetreatmentcourseiscompleted.Clinicaltrialsthatevaluatedremdesivircategorizedpatientsbasedontheirseverityofillnessatstudyenrollment;therefore,patientsmaybenefitfromreceivingremdesivireveniftheirclinicalcourseprogressestoaseverityofillnessforwhichthebenefitsofremdesivirarelesscertain.RationaleforRecommendingtheUseofSarilumabandDexamethasoneasanAlternativetoTocilizumabandDexamethasoneinCertainHospitalizedPatientsPleaserefertothePatientsWhoRequireOxygenThroughaHigh-FlowDeviceorNoninvasiveVentilationsectionabovefortherationaleregardingtheuseofsarilumabanddexamethasoneasanalternativetotocilizumabanddexamethasoneincertainhospitalizedpatients.RationaleforDeterminingThatThereisInsufficientEvidencetoRecommendtheUseofBaricitinibinAdditiontoStandardofCareinMechanicallyVentilatedIndividualsAcohortofcriticallyillpatientswasaddedtotheCOV-BARRIERtrialafterthecompletionoftheoriginalstudy.Theresultsforthecohortwerenotincludedintheprimaryresultsofthemaintrial.28Inthisaddendum,101patientsonmechanicalventilationorECMOwererandomized1:1toreceivebaricitinib4mg(n=51)orplacebo(n=50)forupto14daysincombinationwithstandardofcare.Baricitinibsignificantlyreduced28-dayall-causemortality(39.2%inthebaricitinibarmvs.58.0%intheplaceboarm;HR0.54;95%CI,0.31–0.96;P=0.030).However,giventhesmallsamplesize,thePanelconsideredtheevidenceinsufficienttoissuearecommendationforpatientsonmechanicalventilationorECMO.ReferencesRECOVERYCollaborativeGroup,HorbyP,LimWS,etal.DexamethasoneinhospitalizedpatientswithCOVID-19.NEnglJMed.2021;384(8):693-704.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/32678530.BeigelJH,TomashekKM,DoddLE,etal.RemdesivirforthetreatmentofCOVID-19—finalreport.NEnglJMed.2020;383(19):1813-1826.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/32445440.SpinnerCD,GottliebRL,CrinerGJ,etal.Effectofremdesivirvsstandardcareonclinicalstatusat11daysinpatientswithmoderateCOVID-19:arandomizedclinicaltrial.JAMA.2020;324(11):1048-1057.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/32821939.WHOSolidarityTrialConsortium,PanH,PetoR,etal.RepurposedantiviraldrugsforCOVID-19—interimWHOSolidaritytrialresults.NEnglJMed.2021;384(6):497-511.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/33264556.HillJA,ParedesR,VacaC,etal.Remdesivirforthetreatmentofhigh-risknon-hospitalizedindividualswithCOVID-19:arandomized,double-blind,placebo-controlledtrial.Presentedat:IDWeek.2021.Virtual.AderF,Bouscambert-DuchampM,HitesM,etal.RemdesivirplusstandardofcareversusstandardofcarealoneforthetreatmentofpatientsadmittedtohospitalwithCOVID-19(DisCoVeRy):aPhase3,randomised,controlled,open-labeltrial.LancetInfectDis.2021;Publishedonlineaheadofprint.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/34534511.GoldmanJD,LyeDCB,HuiDS,etal.Remdesivirfor5or10daysinpatientswithsevereCOVID-19.NEnglJMed.2020;383(19):1827-1837.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/32459919.WongCKH,LauKTK,AuICH,etal.OptimaltimingofremdesivirinitiationinhospitalizedCOVID-19patientsadministeredwithdexamethasone.ClinInfectDis.2021;Publishedonlineaheadofprint.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/34420051.BenfieldT,BodilsenJ,BrieghelC,etal.ImprovedsurvivalamonghospitalizedpatientswithCOVID-19treatedwithremdesiviranddexamethasone.Anationwidepopulation-basedcohortstudy.ClinInfectDis.2021;73(11):2031-2036.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/34111274.MozaffariE,ChandakA,ZhangZ,etal.RemdesivirtreatmentinhospitalizedpatientswithCOVID-19:acomparativeanalysisofin-hospitalall-causemortalityinalargemulti-centerobservationalcohort.ClinInfectDis.2021;Publishedonlineaheadofprint.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/34596223.ArabiYM,MandourahY,Al-HameedF,etal.CorticosteroidtherapyforcriticallyillpatientswithMiddleEastrespiratorysyndrome.AmJRespirCritCareMed.2018;197(6):757-767.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/29161116.StockmanLJ,BellamyR,GarnerP.SARS:systematicreviewoftreatmenteffects.PLoSMed.2006;3(9):e343.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/16968120.RodrigoC,Leonardi-BeeJ,Nguyen-Van-TamJ,LimWS.Corticosteroidsasadjunctivetherapyinthetreatmentofinfluenza.CochraneDatabaseSystRev.2016;3:CD010406.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/26950335.ChenY,LiL.InfluenceofcorticosteroiddoseonviralsheddingdurationinpatientswithCOVID-19.ClinInfectDis.2021;72(7):1298-1300.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/32588884.LiS,HuZ,SongX.High-dosebutnotlow-dosecorticosteroidspotentiallydelayviralsheddingofpatientswithCOVID-19.ClinInfectDis.2021;72(7):1297-1298.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/32588877.DingC,FengX,ChenY,etal.EffectofcorticosteroidtherapyonthedurationofSARS-CoV-2clearanceinpatientswithmildCOVID-19:aretrospectivecohortstudy.InfectDisTher.2020;9(4):943-952.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/32986226.LiuJ,ZhangS,DongX,etal.CorticosteroidtreatmentinsevereCOVID-19patientswithacuterespiratorydistresssyndrome.JClinInvest.2020;130(12):6417-6428.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/33141117.SpagnuoloV,GuffantiM,GalliL,etal.Viralclearanceafterearlycorticosteroidtreatmentinpatientswithmoderateorseverecovid-19.SciRep.2020;10(1):21291.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/33277573.RECOVERYCollaborativeGroup.TocilizumabinpatientsadmittedtohospitalwithCOVID-19(RECOVERY):arandomised,controlled,open-label,platformtrial.Lancet.2021;397(10285):1637-1645.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/33933206.MarconiVC,RamananAV,deBonoS,etal.EfficacyandsafetyofbaricitinibforthetreatmentofhospitalisedadultswithCOVID-19(COV-BARRIER):arandomised,double-blind,parallel-group,placebo-controlledPhase3trial.LancetRespirMed.2021;9(12):1407-1418.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/34480861.GuimaraesPO,QuirkD,FurtadoRH,etal.TofacitinibinpatientshospitalizedwithCOVID-19pneumonia.NEnglJMed.2021;385(5):406-415.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/34133856.LierAJ,TuanJJ,DavisMW,etal.Casereport:disseminatedstrongyloidiasisinapatientwithCOVID-19.AmJTropMedHyg.2020;103(4):1590-1592.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/32830642.MarcheseV,CrosatoV,GullettaM,etal.StrongyloidesinfectionmanifestedduringimmunosuppressivetherapyforSARS-CoV-2pneumonia.Infection.2021;49(3):539-542.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/32910321.REMAP-CAPInvestigators,GordonAC,MounceyPR,etal.Interleukin-6receptorantagonistsincriticallyillpatientswithCOVID-19.NEnglJMed.2021;384(16):1491-1502.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/33631065.TheREMAP-CAPInvestigators,DerdeLPG.Effectivenessoftocilizumab,sarilumab,andanakinraforcriticallyillpatientswithCOVID-19:theREMAP-CAPCOVID-19immunemodulationtherapydomainrandomizedclinicaltrial.medRxiv.2021;Preprint.Availableat:https://www.medRxiv.org/content/10.1101/2021.06.18.21259133v2.WHORapidEvidenceAppraisalforCOVID-19TherapiesWorkingGroup,SterneJAC,MurthyS,etal.AssociationbetweenadministrationofsystemiccorticosteroidsandmortalityamongcriticallyillpatientswithCOVID-19:ameta-analysis.JAMA.2020;324(13):1330-1341.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/32876694.LiQ,LiW,JinY,etal.Efficacyevaluationofearly,low-dose,short-termcorticosteroidsinadultshospitalizedwithnon-severeCOVID-19pneumonia:aretrospectivecohortstudy.InfectDisTher.2020;9(4):823-836.Availableat:https://www.ncbi.nlm.nih.gov/pubmed/32880102.ElyEW,RamananAV,KartmanCE,etal.BaricitinibplusstandardofcareforhospitalisedadultswithCOVID-19oninvasivemechanicalventilationorextracorporealmembraneoxygenation:resultsofarandomised,placebo-controlledtrial.medRxiv.2021;Preprint.Availableat:https://www.medRxiv.org/content/10.1101/2021.10.11.21263897v2.GuidelinePDFsSectionOnly(PDF|2MB)FullGuideline(PDF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