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Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced mortality: Findings from the observational multicentre Italian CORIST study

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EuropeanJournalofInternalMedicine000(2020)1–10

ContentslistsavailableatScienceDirect

European

Journal

of

Internal

Medicine

journalhomepage:www.elsevier.com/locate/ejinme

Original

article

Use

of

hydroxychloroquine

in

hospitalised

COVID-19

patients

is

associated

with

reduced

mortality:

Findings

from

the

observational

multicentre

Italian

CORIST

study

The

COVID-19

RISK

and

Treatments

(CORIST)

Collaboration

1 ,∗

Q1

a

r

t

i

c

l

e

i

n

f

o

Keywords: Hydroxychloroquine COVID-19 Disease severity Mortality Inflammation

a

b

s

t

r

a

c

t

Background: Hydroxychloroquine(HCQ)wasproposedaspotentialtreatmentforCOVID-19.

Objective: Weset-upamulticenterItaliancollaborationtoinvestigatetherelationshipbetweenHCQtherapyand COVID-19in-hospitalmortality.

Methods: Inaretrospectiveobservationalstudy,3,451unselectedpatientshospitalizedin33clinicalcenters inItaly,fromFebruary19,2020toMay23,2020,withlaboratory-confirmedSARS-CoV-2infection,were ana-lyzed.Theprimaryend-pointinatime-toeventanalysiswasin-hospitaldeath,comparingpatientswhoreceived HCQwithpatientswhodidnot.WeusedmultivariableCoxproportional-hazardsregressionmodelswithinverse probabilityfortreatmentweightingbypropensityscores,withtheadditionofsubgroupanalyses.

Results: Outof3,451COVID-19patients,76.3%receivedHCQ.Deathrates(per1,000person-days)forpatients receivingornotHCQwere8.9and15.7,respectively.Afteradjustmentforpropensityscores,wefound30% lowerriskofdeathinpatientsreceivingHCQ(HR=0.70;95%CI:0.59to0.84;E-value=1.67).Secondary analy-sesyieldedsimilarresults.TheinverseassociationofHCQwithinpatientmortalitywasparticularlyevidentin patientshavingelevatedC-reactiveproteinatentry.

Conclusions: HCQusewasassociatedwitha30%lowerriskofdeathinCOVID-19hospitalizedpatients.Within thelimitsofanobservationalstudyandawaitingresultsfromrandomizedcontrolledtrials,thesedatadonot discouragetheuseofHCQininpatientswithCOVID-19.

1. Introduction

1

The aminoquinoline hydroxychloroquine (HCQ) has been

exten-2

sivelyused inthetreatmentof malariaandis currentlywidely used

3

totreatautoimmunediseaseslikerheumatoidarthritis(RA),systemic

4

lupuserythematosus(SLE)andanti-phospholipidsyndrome(APS),due

5

toitsimmunomodulatoryandanti-thromboticproperties[1] .More

re-6

cently, a promising role of HCQ has been suggested in viral

infec-7

tions[2] ,sinceitdirectlyinhibitsviralentryandspreadinseveralin

8

vitroandinvivomodels.Duetotheseproperties,HCQhasbeenused

9

inEbolavirusdisease[3,4] ,humanimmunodeficiencyvirus(HIV)

in-10

fection[5] ,SARS-CoV-1infectionandtheMiddleEastRespiratory

Syn-11

drome(MERS)[6 ,7 ]andgainedworldwideattentionasapossible

ther-12

apyinCOVID-19patients[8] .

13

HCQmightinhibittheintracellularglycosylationofACE2,the

re-14

ceptorusedbytheSARS-CoV-2virustoenterthecells,resultingina

15

Correspondingauthorat:DepartmentofEpidemiologyandPrevention,IRCCSNeuromed,Viadell’Elettronica,86077Pozzilli(IS),Italy.

E-mailaddress:licia.iacoviello@moli-sani.org

1 ThemembersofTheCOVID-19RISKandTreatments(CORIST)CollaborationarelistedinAppendix1attheendofthearticle.

reducedligandrecognitionandinternalizationofthevirus[7] andexert- 16

ingapossibleprotectiveroleinSARS-CoV-2infection.Moreover,dueto 17

itsimmunomodulatory,anti-inflammatoryandanti-thromboticeffects, 18

HCQcouldalsomodulatetheseverityofthedisease.However,theexact 19

mechanismforthepotentialbenefitinCOVID-19islargelyspeculative 20

[9] andmightbecounterbalancedbyadverseeffects,mainlycardiovas- 21

cular[10 ,11 ],sothatthenetbalanceofthisdrug’suseremainstobe 22

established. 23

TheAmericanFoodandDrugAdministration(FDA)allowedChloro- 24

quine(CQ)phosphateandHCQtobeprovidedtocertainhospitalized 25

patients becausethese drugsmaypossibly helppatients withsevere 26

COVID-19[12] .TheEuropeanMedicinesAgency(EMA)authorizedthe 27

useofCQandHCQforCOVID-19inclinicaltrialsorasemergencyuse 28

[13] ,while theItalianDrugAgency(AIFA)statedin thisemergency 29

phasethattherapeuticuseofHCQmightbe consideredin COVID-19 30

patients,bothinthosewithmildpresentationmanagedathomeandin 31

https://doi.org/10.1016/j.ejim.2020.08.019

Received28June2020;Receivedinrevisedform19August2020;Accepted20August2020 Availableonlinexxx

(3)

hospitalizedpatients[14] .Inclinicalpractice,HCQratherthan

chloro-32

quinehasbeenusedbecauseofitsmorepotentantiviralpropertiesand

33

bettersafetyprofile[15] .

34

However,inthelightofarecentpublication[16] ,thatwaslater

re-35

tracted[17] ,onthelackofsafetyandefficacyofHCQinthetreatment

36

forCOVID-19patientstheExecutiveGroupoftheSolidarityTrial

de-37

cidedtoimplementatemporarypauseoftheHCQarmwithinthetrial

38

asaprecaution,whilethesafetydataisbeingreviewed[18] .Similarly,

39

theItaliandrugAgencyAIFAdecidedtosuspendtheauthorizationto

40

useHCQforCOVID-19treatmentoutsideclinicaltrials[19] .

41

Recent reviews of clinical trials or observational studies [20–

42

24] havereportedinsufficientandoftenconflictingevidenceonthe

ben-43

efitsandharmsofusingHCQtotreatCOVID-19andconcludedthatas

44

such,itwasimpossibletodeterminethebalanceofbenefitstoharm.

45

Untilnow,althoughseveraltrialshadbeenstartedontheuseofCQand

46

HCQinCOVID-19,onlyfewofthemhavebeenpublished[25] onsmall

47

numbersofpatientsoronsurrogateendpointsorinexposedsubjectsfor

48

prophylaxisuse[26] .

49

Whilewaitingtheresultsfrom ongoingrandomizedclinicaltrials

50

(RCT)todefinetheefficacyinpreventinghardendpointsofthis

treat-51

mentsowidelyusedduringtheemergencyphaseoftheCOVID-19

pan-52

demic,poweredretrospectiveobservationalstudiesperformedin

differ-53

entgeographicalanddiseaseconditionsmaystillbeusefultoshedlight

54

onthisdebate.Tworetrospectiveobservationalstudies,bothconducted

55

intheNewYorkmetropolitanregion,didnotreportanysignificant

as-56

sociationbetweenHCQuseandratesofintubationordeath[27 ,28 ].

57

NodataarepresentlyavailablefromlargecohortsofpatientsinItaly,

58

whichrepresentsoneofthemostaffectedcountriesintermsof total

59

deathsforCOVID-19intheworld[29] .Weundertookamulticenter

Ital-60

iancollaboration[30] toinvestigatetherelationshipbetween

underly-61

ingriskfactorsandCOVID-19outcomes,andtoevaluatetheassociation

62

betweendifferentdrugtherapyanddiseaseseverityand/ormortality.

63

Wereportheretheresultsobtainedin3,451 hospitalizedCOVID -19

64

patientsreceivingornotHCQtreatment.

65

2. Materialandmethods

66

2.1. Setting

67

Thisnationalretrospectiveobservationalstudywasconceived,

co-68

ordinatedandanalysedwithintheCORISTProject(ClinicalTrials.gov

69

ID:NCT04318418,30].Thestudywas approvedby theinstitutional

70

ethicsboardoftheIstitutodiRicoveroeCuraaCarattereScientifico

71

(IRCCS)Neuromed,Pozzilli,andofallrecruitingcentres.Dataforthe

72

presentanalyseswereprovidedby33hospitalsdistributedthroughout

73

Italy(listedinthesupplementaryfile).Acceptancetoparticipateinthe

74

projectortoprovidedataforthepresentanalysiswasnotrelatedto

75

theuseofCQ/HCQ.Eachhospitalprovideddatafromhospitalized

pa-76

tientswhohadapositivetestresultfortheSARS-CoV-2virusatany

77

timeduringtheirhospitalizationfromFebruary19toMay23,2020.

78

Thefollow-upcontinuedthroughMay29,2020.

79

2.2. Datasources

80

Wedevelopedacohortcomprising3,971patientswith

laboratory-81

confirmedSARS-CoV-2infectioninanin-patientsetting.The

SARS-CoV-82

2statuswasdeclaredbasedonlaboratoryresults(polymerasechain

re-83

actiononnasopharyngealswab)fromeachparticipatinghospital.

Clin-84

icaldata were abstractedat one-timepoint from electronicmedical

85

recordsorcharts,andwerecollectedusingeitheracentrallydesigned

86

electronic worksheet or a centralized web-baseddatabase. Collected

87

dataincludedpatients’demographics,laboratorytestresults,

medica-88

tionadministration,historicalandcurrentmedicationlists,historical

89

andcurrent diagnoses,andclinicalnotes. Inaddition,specific

infor-90

mationonthemostseveremanifestationofCOVID-19occurredduring

91

hospitalizationwasretrospectivelycaptured.Maximumclinicalsever- 92

ityobservedwasclassifiedasmildpneumonia;orseverepneumonia;or 93

acuterespiratorydistresssyndrome(ARDS)[31] .Specifically,weob- 94

tainedthefollowinginformationforeachpatient:hospital;dateofad- 95

missionanddateofdischargeordeath;age;sex;thefirstrecordedinpa- 96

tientlaboratorytestsattheentry(creatinine,C-reactiveprotein);past 97

andcurrent diagnoses(myocardialinfarction, heartfailure,diabetes, 98

hypertension,respiratorydiseaseandcancer)andcurrentdrugthera- 99

piesforCOVID-19– HCQ,lopinavir/ritonavirordarunavir/cobicistat, 100

remdesevir,tocilizumaborsarilumab,corticosteroids,heparin,andfor 101

comorbidities(insulin,anti-hypertensivetreatments,aldosteronerecep- 102

torantagonists,diuretics,statins,sacubitril/valsartan).Adiagnosisof 103

pre-existing cardiovascular disease was basedon history of myocar- 104

dialinfarctionorheartfailure.Chronickidneydiseasewasclassified 105

as: stage1: kidneydamagewithnormalor increasedglomerular fil- 106

tration rate (GFR) (>90 mL/min/1.73 m2); stage 2: mild reduction 107

in GFR (60-89 mL/min/1.73 m2); stage 3a: moderate reduction in 108

GFR(45-59mL/min/1.73 m2);stage3b:moderatereductionin GFR 109

(30-44 mL/min/1.73 m2); stage 4: severe reduction in GFR (15-29 110

mL/min/1.73m2);stage5:kidneyfailure(GFR<15mL/min/1.73m2 111

ordialysis).Forstatisticalanalysis,stages3aand3bandstages4and 112

5werecombined.GFRwascalculatedbytheChronicKidneyDisease 113

EpidemiologyCollaboration(CKD-Epi)equation.Patientsweredefined 114

asreceivingHCQiftheywerereceivingitatadmissiontohospitalor 115

receiveditduringthefollow-upperiod.AccordingtotheAIFAguidance 116

[14] ,HCQwasadministeredatdoseof400mgx2/dayorx4/daythe 117

firstday,and200mgx2/dayfromtheseconddayonwardsforatleast 118

5toamaximumof10days,accordingtotheclinicalevolutionofthe 119

disease. 120

2.3. Statisticalanalysis 121

Thestudyindexdatewasdefinedasthedateofhospitaladmission. 122

IndexdatesrangedfromFebruary19,2020toMay23,2020.Thestudy 123

endpointwasthetimefromstudyindextodeath.Thenumberofpa- 124

tientswhoeitherdied,orhadbeendischargedalive,orwerestilladmit- 125

tedtohospitalasofMay29,2020,wererecorded,andhospitallengthof 126

staywasdetermined.Patientsalivehadtheirdatacensoredonthedate 127

ofdischargeorasthedateoftherespectiveclinicaldatacollection.Data 128

werecensoredat35daysoffollowupinn=330(8.3%)patientswitha 129

followupgreaterthan35days. 130

Oftheinitialcohortof3,971patients,350patientswereexcluded 131

fromtheanalysisbecausetheyhadatleastonemissingdataatbaseline 132

orlosttofollowuponHCQuse(N=94),otherdrugtherapiesforCOVID- 133

19(n=265),timetoevent(n=59),outcome(death/alive,n=8),COVID- 134

19 severity(n=4),age(n=4withmissingdataandn=2withage<18 135

years)orsex(n=2).Oftheremaining3,621patients,170patientsdied 136

orweredischargedwithin24hoursafterpresentation,andwerealso 137

excludedfromtheanalysis. 138

Attheend,theanalysedcohortconsistedofn=3,451patients.Inpa- 139

tientsnotincludedintheanalysis(n=520),asuniquedifferencewiththe 140

analysedgroup,theprevalenceofdiabetics(19.9%vs14.8%,P=0.0066) 141

and,toalessextent,ofmen(62.3%vs58.3%,P=0.081)washigher.Out 142

of3,541patients,295(8.5%)hadatleastamissingvalueforcovariates. 143

Distributionofmissingvalueswasasfollows:n=178forC-reactivepro- 144

tein;n=69forGFR;n=74forhistoryofischemicdisease;n=64forhis- 145

toryofchronicpulmonarydisease;n=51fordiabetes;n=51forhyper- 146

tensionandn=56forcancer.Weusedmultipleimputationtechniques 147

(SASPROCMI,n=10imputeddatasets;andPROCMIANALYZE)tomax- 148

imizedataavailability.Assensitivityanalysis,wealsoconductedacase- 149

completeanalysison3,156patients. 150

Coxproportional-hazardsregressionmodelswereusedtoestimate 151

theassociationbetweenHCQuseanddeath.Sincemultipleimputation 152

was applied,thefinalstandarderrorwas obtainedusingtheRubin’s 153

rulebasedontherobustvarianceestimatorinCoxregression[32] .The 154

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European Journal of Internal Medicine 000 (2020) 1–10

feldresiduals,andnoviolationwasidentified.Toaccountforthe

non-156

randomizedHCQadministrationandtoreducetheeffectsof

confound-157

ing,thepropensity-scoremethodwasused.Theindividualpropensities

158

forreceivingHCQtreatmentwereassessedwiththeuseofa

multivari-159

ablelogistic-regressionmodelthatincludedage,sex,diabetes,

hyperten-160

sion,historyofischemicheartdisease,chronicpulmonarydisease,GFR,

161

C-reactiveprotein,hospitalsclusteringanduseofotherdrugtherapies

162

forCOVID-19(lopinavir/ritonavirordarunavir/cobicistat,remdesivir,

163

corticosteroids,tocilizumaborsarilumab).AssociationsbetweenHCQ

164

treatmentanddeathwasthenappraisedbymultivariableCox

regres-165

sionmodelswiththeuse ofpropensity-score andfurthercontrolling

166

forhospitalsclusteringasrandomeffect(frailtymodel).Theuseofa

167

frailtymodelwas chosenassuggested in[33] .Theprimary analysis

168

usedinverseprobabilitybytreatmentweighting;thepredicted

proba-169

bilitiesfromthepropensity-scoremodelwasusedtocalculatethe

sta-170

bilizedinverse-probability-weighting weight[34] . Stabilized weights

171

werenormalizedso thatthey addedup the actualsample size.

Sec-172

ondaryanalysesusedpropensity-scorestratification(n=5strata)or

mul-173

tivariableCoxregressionanalysisormultivariable logisticregression

174

analysescomparingdeathversusalivepatients,oraccountedfor

hos-175

pitalsclusteringviastratificationorbyrobustsandwichestimator.

Pre-176

establishedsubgroupanalyseswereconductedaccordingtoageorsex

177

ofpatients,degreeofCOVID-19severityexperiencedduringthe

hospi-178

talstay,C-reactiveproteinatbasalorotherdrugtherapiesfor

COVID-179

19.Hospitalswereclusteredaccordingtotheirgeographical

distribu-180

tion, as illustrated in Table 1 . To quantify the potential for an

un-181

measuredconfoundertorenderapparentstatisticallysignificanthazard

182

rationon-significant,theE-value wascalculated[35] . Analyseswere

183

performedwiththeaidoftheSASversion9.4statisticalsoftwarefor

184

Windows.

185

3. Results

186

Weincludedinthefinalcurrentanalyses3,451patientswhowere

187

hospitalizedwithconfirmedSARS-CoV-2infectionat33clinicalcentres

188

acrossItalyandeitherdied,hadbeendischarged,orwerestillin

hospi-189

talasofMay29,2020.Ofthesepatients,2,634(76.3%,rangeamong

190

hospitals53.2%to93.6%)receivedHCQ.Timingofthefirstdoseof

191

HCQafterpresentationtothehospitalwas1dayforthelargemajority

192

ofcentres,and2to3daysfortheothers.HCQwasadministeredinall

193

centresatthedoseof400mg/day(inonecentrehoweveritwasusedat

194

thedoseof600mg/dayandinanotheratthedoseof600mg/daybut

195

onlyinpatientsyoungerthan65years).Durationoftreatmentranged

196

from5to15days(with10daysasthemodalvalue).Thedrugusedwas

197

HCQinallhospitals.

198

BaselinecharacteristicsaccordingtoHCQuseareshowninTable1.

199

PatientsreceivingHCQweremorelikelyyounger,menandhadhigher

200

levelsofC-reactiveproteinandlesslikelyhadischemicheartdisease,

201

cancerorstages3aorgreaterchronickidneydisease(Table1).Patients

202

receivingHCQmorelikelyreceivedanotherdrugforCOVID-19

treat-203

ment(78.4%;lopinavir/ritonavirordarunavir/cobicistat,remdesevir,

204

tocilizumaborsarilumab,corticosteroids),incomparisonwithnon-HCQ

205

patients(46.3%;P<0.0001;Table 1 ).

206

Theunadjusteddifferencesanddifferencesadjustedbypropensity

207

scoresbetweenHCQ-treatedandnon-HCQtreatedpatientsforeach

vari-208

ableincludedinthepropensityscoreareshowninFig.1.Allthe

pre-209

treatmentdifferencesdisappearedafteradjustmentbypropensityscore

210

weighting.TheC-statisticofthepropensity-scoremodelwas0.74.

211

3.1. Primaryoutcome

212

Outof3,628patients,576died(16.7%),2,390weredischargedalive

213

(69.3%)and485(14.1%)werestillatthehospital.Themedian

follow-214

up was14 days (interquartilerange8to22;range 2to35;55,388

215

person-days).Deathrate(per1,000person-days)was8.9inHCQand

216

15.7innon-HCQpatients(Table2).Atunivariableanalysis,hazardra- 217

tioformortalitywas0.56(95%CI:0.47to0.67).Intheprimarymul- 218

tivariableanalysiswithinverseprobabilityweightingaccordingtothe 219

propensityscore,HCQusewasassociatedwitha30%(95%CI:16%to 220

41%)reductionindeathrisk(Fig.2,Table2,E-value=1.67).Secondary 221

multivariableanalysesyieldedverysimilarresults(Table2),aswellas 222

case-completeanalysesrestrictedtothe3,156patientswithoutmissing 223

data(Table2).Consideringsecondarymultivariableanalysesoverall, 224

HRformortalityassociated withHCQranged between0.64to0.70, 225

accordingtotypeofanalyses.Controlofhospitalsclusteringwithdif- 226

ferentapproachesalsoyieldedsimilarresultsfortheprimaryanalysis 227

(HR=0.71,95%CI:0.59to0.85whenhospitalsclusteringwasstratified 228

forandHR=0.69,95%CI:0.54to0.88withtherobustsandwichesti- 229

mator). 230

SubgroupanalysesarepresentedinTable3.HCQuseremainedcon- 231

sistentlyassociatedwithreducedmortalityinalmostallsubgroups.The 232

inverseassociationofHCQwithinpatientmortalityisslightlymoreevi- 233

dentinwomen,elderlyandinpatientswhoexperiencedahigherdegree 234

ofCOVID-19severity.Itwasabsentin-patientwithC-reactiveprotein 235

<10mg/LandclearlyconfinedtopatientswithelevatedC-reactivepro- 236

tein(Table3). 237

4. Discussion 238

Inalargecohortof3,451patientshospitalizedforCOVID-19in33 239

clinicalcentersalloverItaly,coveringalmostcompletelytheperiodof 240

thehospitalizationforCOVID-19,theuseofHCQwasassociatedwith 241

asignificantbettersurvival.In-hospitalcrudedeathratewas8.9per 242

1,000person-day forpatientsreceivingHCQand15.7forthosewho 243

didnot.Afteradjustmentforknownpossibleconfounders,weobserved 244

a30%reductionintheriskofdeathinpatientsreceivingHCQtherapy 245

ascomparedwiththosewhodidnot. 246

Ourfindings provideclinicalevidenceinsupportof guidelinesby 247

ItalianandseveralinternationalSocietiessuggestingtouseHCQther- 248

apy in patients with COVID-19. However,the observed associations 249

shouldbeconsideredwithcaution,astheobservationaldesignofour 250

studydoesnotallowtofullyexcludingthepossibilityofresidualcon- 251

founders.Largerandomizedclinicaltrialsinwell-definedgeographical 252

andsocio-economicconditionsandinwell-characterizedCOVID-19pa- 253

tients,shouldevaluatetheroleofHCQbeforeanyfirmconclusioncan 254

bereachedregardingapotentialbenefitofthisdruginpatientswith 255

COVID-19. 256

Over 76%of patients receivedHCQ either aloneor in combina- 257

tion with other drugs. They were more likely to be younger, men 258

andwithhigherlevelsofCreactiveproteinatentry,whilelesslikely 259

hadpre-existingcomorbiditiessuchasischemicheartdisease,cancer 260

andseverechronickidneydisease,ascomparedtopatientsnotreceiv- 261

ingthedrug.Weadjustedouranalyses forpossible confounders,in- 262

cludingage,sex,diabetes,hypertension,historyofischemicheartdis- 263

ease,chronicpulmonarydisease,chronickidneydisease,C-reactivepro- 264

tein andadditionaltreatments for COVID-19,and tookinto account 265

possible differences across centresbyeitheradjustmentor stratifica- 266

tion. Tominimize biasduetotheobservationaldesign, weuseddif- 267

ferentanalyticalapproachesaimingatcreatinganoverallbalancebe- 268

tweencomparisongroups.Finally,wetriedtolimitbiasduetomiss- 269

ing data by using a multiple imputation approach, but in no case, 270

the resultwas changed. Despite all these precautions, we recognize 271

thepossibility,however,ofresidualunmeasuredconfoundersaffecting 272

results. 273

Systematic reviews of small clinical trialshad reported contrast- 274

ing results that were however scarcely reliable becauseof poor de- 275

signs [20–25] . TheHCQ dosestested in a Chinese randomizedclin- 276

ical trial[25] were approximately doubleas comparedto thatused 277

in our study(1200 mg vs 800 mg as loadingdose, 800mg vs400 278

mg as maintenancedose) for twice thetime (14-21 days versus 7- 279

10 days). National guidelines in Italy suggest to use HCQ 200 mg 280 3

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Table1

GeneralcharacteristicsofCOVID-19patientsatbaseline,accordingtohydroxychloroquineuse.

Hydroxychloroquine

Characteristic No (N = 817) Yes (N = 2,634) P-value unadjusted ∗

Age -median (IQR-yr.) 73 (58-83) 66 (55-77) < .0001

Gender - no (%) < .0001 Women 361 (44.2%) 940 (36.7%) Men 456 (55.8%) 1,694 (64.3%) Diabetes - no (%) 0.71 No 633 (77.5%) 2,090 (79.3%) Yes 162 (19.9%) 515 (19.6%) missing data 22 (2.7%) 29 (1.1%) Hypertension - no (%) 0.31 No 378 (46.3%) 1,294 (49.1%) Yes 416 (50.9%) 1,312 (49.8%) missing data 23 (2.7%) 28 (1.1%)

Ischemic heart disease - no (%) < .0001

No 610 (74.7%) 2,190 (83.1%) Yes 179 (21.9%) 398 (15.1%)

missing data 28 (3.4%) 46 (1.8%)

Chronic pulmonary disease - no (%) 0.21

No 666 (81.5%) 2,225 (84.5%) Yes 127 (15.5%) 369 (14.0%) missing data 24 (2.9%) 40 (1.5%) Cancer - no (%) 0.036 No 694 (84.9%) 2,338 (88.8%) Yes 101 (12.4%) 262 (9.9%) missing data 22 (2.6%) 34 (1.3%) CKD stage ∗∗ - no (%) < .0001 Stage 1 241 (29.5%) 970 (36.8%) Stage 2 281 (34.4%) 991 (37.6%) Stage 3a or stage 3b 180 (22.0%) 487 (18.5%) Stage 4 or stage 5 89 (10.9%) 143 (5.4%) missing data 26 (3.2%) 43 (1.6%) C Reactive Protein - no (%) 0.0003 < 1 mg/L 104 (12.7%) 256 (9.7%) 1-3 mg/L 120 (14.7%) 301 (11.4%) > 3 mg/L 549 (67.2%) 1,943 (73.8%) missing data 44 (5.4%) 134 (5.1%)

Lopinavir or Darunavir use < .0001

No 621 (76.0%) 1,203 (36.7%) Yes 196 (24.0%) 1,431 (64.3%)

Tocilizumab or Sarilumab use < .0001

No 755 (92.4%) 2,160 (82.0%) Yes 62 (7.6%) 474 (18.0%) Remdesivir use 0.0015 No 808 (98.9%) 2,551 (96.9%) Yes 9 (1.1%) 83 (3.1%) Corticosteroids use < .0001 No 596 (73.0%) 1,655 (62.8%) Yes 221 (27.0%) 979 (37.2%) Clusters of hospitals < .0001

Northern regions (except Milan) (n) 169 (20.7%) 616 (23.4%) Milan (m) 161 (19.7%) 525 (19.9%) Center regions (except Rome) (c)) 303 (37.1%) 747 (28.4%) Rome (r) 94 (11.5%) 390 (14.8%) Southern regions (s) 90 (11.0%) 356 (13.5%)

(n)includehospitalsofNovara,Monza,Varese,Pavia,CremonaandPadova;(m)include Hu-manitasClinicalandResearchHospital,CentroCardiologicoMonzino,andhospitalsofSan DonatoMilanese(Milano)andCiniselloBalsamo(Milano);(c)includehospitalsofModena, Ravenna,Forlì,Firenze,Pisa,ChietiandPescara;(r)includeNationalInstituteforInfectious Dis-eases“L.Spallanzani” andUniversità CattolicadelSacroCuore;(s)includehospitalofNapoli, Pozzilli(Isernia),AcquavivadelleFonti(Bari),Foggia,Taranto,Catanzaro,CataniaandPalermo

Chi-squaretest.∗∗Stage1:Kidneydamagewithnormalorincreasedglomerularfiltrationrate

(GFR)(>90mL/min/1.73m2);Stage2:MildreductioninGFR(60-89mL/min/1.73m2);Stage

3a:ModeratereductioninGFR(45-59mL/min/1.73m2);Stage3b:ModeratereductioninGFR

(30-44mL/min/1.73m2);Stage4:SeverereductioninGFR(15-29mL/min/1.73m2);Stage5:

Kidneyfailure(GFR<15mL/min/1.73m2ordialysis).

twice daily for at least 5-7 days in patients over 70 years and/or

281

withco-morbidities(chronicobstructivepulmonarydisease,diabetes,

282

cardiovasculardisease)evenwithmildrespiratorysymptomsorwith

283

radiographically documented pneumonia or in severe patients [36] .

284

Thelowerdosesof HCQusedin ourcenters,assuggested byItalian

285

official guidelines [19 ,36 ], mayhave been both more effective and 286

safer. 287

Tworecentlypublishedlargeobservationalstudies,bothfromlarge 288

hospitalsinNewYorkCity,showednoassociationbetweenHCQuse 289

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European Journal of Internal Medicine 000 (2020) 1–10

Table2

IncidenceratesandhazardratiosfordeathinCOVID-19patients,accordingtohydroxychloroquineuse.

Multiple imputation analysis (N = 3,451)

Death (N = 576) Patient at risk (N = 3,451) Person-days Death Rate (x1,000 person-days)

Hydroxychloroquine

No- no. (%) 190 (23.3%) 817 (100%) 12,084 15.7 Yes- no. (%) 386 (14.7%) 2,634 (100%) 43,304 8.9

Hazard ratio for death (HCQ versus non HCQ) HR (95% CI)

Crude analysis 0.56 (0.47 to 0.67) Multivariable analysis ∗ 0.70 (0.58 to 0.85)

Propensity score analysis, inverse probability weighting ∗∗ ( primary analysis ) 0.70 (0.59 to 0.84)

Propensity score analysis, stratification (n = 5 strata) ∗∗ 0.67 (0.56 to 0.81)

Odds ratio for death (HCQ versus non HCQ) OR (95% CI) Propensity score analysis, inverse probability weighting ∗∗ 0.67 (0.54 to 0.82)

Case Complete Analysis (N = 3,156)

Death (N = 510) Patient at risk (N = 3,156) Person-days Death Rate (x1,000 person-days)

Hydroxychloroquine

No- no. (%) 170 (22.9%) 741 (100%) 11,050 15.4 Yes- no. (%) 340 (14.1%) 2,415 (100%) 39,274 8.7

Hazard ratio for death (HCQ versus non HCQ) HR (95% CI)

Crude analysis 0.56 (0.46 to 0.67) Multivariable analysis ∗ 0.71 (0.59 to 0.86)

Propensity score analysis, inverse probability weighting ∗∗ 0.64 (0.53 to 0.76)

Propensity score analysis, stratification (n = 5 strata) ∗∗ 0.68 (0.56 to 0.82)

Odds ratio for death (HCQ versus non HCQ) OR (95% CI) Propensity score analysis, inverse probability weighting ∗∗ 0.67 (0.54 to 0.82)

Abbreviations: HR, hazard ratios;CI, confidence intervals. ∗Controlling forage, sex,diabetes, hypertension, historyof

ischemic heart disease, chronic pulmonary disease, chronic kidney disease, C-reactive protein, lopinavir/ritonavir or darunavir/cobicistat,tocilizumaborsarilumab,remdesivirorcorticosteroidsuseasfixedeffectsandhospitalsclusteringas randomeffect.∗∗Includinghospitalsclusteringasrandomeffectcovariate.

studyofGelerisetal.[27] ,thepercentageuseofHCQwaslowerthanin

291

Italy;moreover,inbothUSstudies[27 ,28 ]thedrugwasmorefrequently

292

administeredtopatientswithpreviousillnessesandamoresevere

pre-293

sentationofthedisease.Ourcohortincludedmilderpneumoniapatients

294

thantheUSpopulation,duetobetween-countrydifferencesin

indica-295

tionstothedrugforthebeginningoftherapy(e.g.,mildpneumoniain 296

ItalyversusonlyseverepneumoniaandARDSintheUS).Concomitant 297

useofotherdrugsforCOVID-19wasverylowinonestudy[27] andwas 298

notreportedintheotherstudy[28] .Inourcohort,patientsreceiving 299

HCQweremorelikelytreatedwithanotherdrugforCOVID-19treat- 300

Fig.1. TheunadjustedstandardizeddifferencesandstandardizeddifferencesadjustedbypropensityscoresbetweenHCQ-treatedandnon-HCQtreatedpatientsfor thevariablesincludedinthepropensityscore.Alldifferencesforthematchedobservationsarewithintherecommendedlimitsof–0.25and0.25,whichareindicated byreferencelines.

(7)

Fig.2. Survivalcurvesaccordingtohydroxychloroquineuse.Thecurvesareadjustedbypropensityscoreanalysis(inverseprobabilityfortreatmentweighting)and hospitalindexasrandomeffect,andaregeneratedusingthefirstimputeddataset.Theotherimputeddatasetsaresimilarandthusomitted.

Table3

Hazardratiosformortalityaccordingtohydroxychloroquineuseindifferentsubgroups.

Hydroxychloroquine NO (N = 817) Hydroxychloroquine YES (N = 2,634)

Subgroups No. death/patient at risk No. death/patient at risk HR (95% CI) ∗

Women 80/361 116/940 0.63 (0.46 to 0.86)

Men 110/456 270/1,694 0.74 (0.60 to 0.93)

Age < 70 years 22/357 93/1,542 0.76 (0.50 to 1.16)

Age ≥ 70 years 168/460 293/1,092 0.68 (0.56 to 0.83)

Highest degree of COVID-19 severity experienced at hospital

Mild pneumonia or less 28/424 40/1,358 0.70 (0.41 to 1.18) Severe pneumonia 80/253 172/764 0.76 (0.58 to 0.99) Acute respiratory distress syndrome 82/140 174/512 0.68 (0.52 to 0.90)

Use of other COVID-19 treatmentsˆ

No 101/439 64/570 0.63 (0.45 to 0.88)

Yes 89/378 322/2,064 0.77 (0.61 to 0.99)

C-Reactive Protein at basal ∗∗

< 10 mg/L 56/412 125/1,138 1.23 (0.86 to 1.77)

≥ 10 mg/L 123/361 241/1,362 0.59 (0.47 to 0.73)

Abbreviations:HR,hazardratios;CI,confidenceintervals;∗Propensityscoreanalysis,inverseprobabilityweighting,including

hos-pitalclusteringasrandomeffectcovariate;multipleimputedanalysis.

ˆLopinavir/ritonavirordarunavir/cobicistatortocilizumaborsarilumaborremdesivirorcorticosteroids.

∗∗MissingdataforN=178.Frequenciesandhazardratiosarebasedonacasecompleteanalysis(N=3,273)withoutmissingdatafor

C-reactiveProtein;multipleimputedanalysis(N=3,451)yieldedverysimilarresults.

ment(78.4%),incomparisonwithnon-HCQpatients(46.3%).Anyway,

301

ourfindingsareadjustedforconcomitantotherdrugsuse.

302

WhiletheUSstudieswereconfinedtoonehospitalonlyoradefined

303

relativelysmallareaintheCountry,ourstudyincluded33hospitals

304

distributedalloverItaly,coveringregionswithahighnumberofcases

305

andahighintra-hospitalmortalityandregions withalowerburden

306

ofthedisease.TheparticipatingItalianclinicalcentershavedifferent

307

healthcarefacilities,differentsize,specialization,andownership,and

308

thereforequitecloselyrepresentthereal-lifeItalianapproachto

COVID-309

19.Moreover,theydifferedforthepercentageofuseofHCQandfor

310

therateofin-hospitalmortalitythatrangedbetween34.1and1.5per

311

1,000persons/day.Toconsiderthisvariability,weadjustedthe

analy-312

sisforrecruitingcenterandperformedanumberofsubgroupanalyses.

313

Inallcircumstances,theassociationbetweenHCQuseandareduced

314

riskofdeathofabout30%wasmaintained.Quiteinterestingly,the

in-315

verseassociationofHCQwithinpatientmortalitywasmoreevidentin 316

elderly,inpatientswhoexperiencedahigherdegreeofCOVID-19sever- 317

ityorespeciallyhavingelevatedC-reactiveprotein,suggestingthatthe 318

anti-inflammatorypotentialofHCQmayhavehadmoreimportantrole 319

ratherthanitsantiviralproperties.HCQ,indeed,besideanantiviralac- 320

tivity,mayhavebothanti-inflammatoryandanti-thromboticeffects[8] . 321

Thiscanjustifyitseffectinreducingmortalityrisk,sinceSars-Cov-2can 322

inducepulmonarymicrothrombiandcoagulopathy,thatareapossible 323

causeofitsseverity[37 ,38 ]andthelackinpreventingSARS-CoV-2in- 324

fectionafterexposure[26] 325

Nevertheless,largerandomizedclinicaltrialsontheefficacyofHCQ 326

onhardend-pointsarestilllackingandthelargestobservationalstudy 327

showing no effect in reducing mortalityhas beenretracted [16 ,17 ], 328

Agencies have suspended clinical trials on the efficacy of HCQ on 329

(8)

European Journal of Internal Medicine 000 (2020) 1–10

inclinicaltrials,intheabsenceofanample,sereneandbalanced

dis-331

cussionatinternationallevel.

332

Veryrecently,alargeRCThasbecomeavailableasapre-print

pub-333

lication[39] ,reportingnobeneficialeffectofHCQinpatients

hospital-334

izedwithCOVID-19.However,thedoseofHCQusedinthattrialwas

335

almostthedoubleofthatadministeredinourreallifeconditions.A

re-336

ducedmortalitywasalsoobservedbyotherobservationalstudiesusing

337

loworintermediatedosesofHCQ[40 ,41 ].

338

Moreover, in our studypatients takingHCQ more frequently

re-339

ceivedotheranti-COVIDdrugs,whoseinteractioninreducingmortality

340

cannotbecompletelyruled-out.Ofnote,despitethehigherdosageused,

341

theRCTdidnotshowanyexcessinventriculartachycardiaor

ventric-342

ularfibrillationintheHCQarm(39).

343

Therefore,itwillbe veryimportanttocompareresults ofstudies

344

withdifferentmodeofuseanddosesofHCQ,differentcharacteristics

345

oftreatedanduntreatedpatientsanddifferentacademicorreal-world

346

conditions.

347

4.1. Strengthsandlimitations

348

Amajorstrengthofthisstudyisthelarge,unselectedpatientsample

349

from33hospitals,coveringtheentireItalianterritory.Patientsampling

350

coveredalltheovert epidemicperiod inItaly. Severalstatistical

ap-351

proacheswereusedtoovercomebiasesduetotheobservationalnature

352

oftheinvestigation.

353

Thisstudyhashowever,severalrecognizedlimitations.Thestudy

354

populationpertainstoItaly,andtheresultsobtainedmaynotbe

appli-355

cabletootherpopulationswithapossiblydifferentgeographicaland

356

socio-economicconditionsandnaturalhistoryofCOVID-19.Duetothe

357

retrospectivenatureofthestudy,someparameterswerenotavailable

358

inallpatients,andallin-hospitalmedicationsmighthavebeennotfully

359

recorded.Moreover,althoughguidelinesontheuseofHCQin

COVID-360

19patientshadbeenpublishedinItalysincethefirstphaseofthe

pan-361

demic,individualcenterscouldhavedeviatedfromrecommendations

362

anduseddifferentdosesortreatmentschemes.Wehavenoinformation

363

ontheHCQdosesusedindividuallynoroftheirpossibleassociationwith

364

azithromycin.Moreover,adverseeventspossiblyrelatedtodrugtherapy

365

werenotcollected,thuswecannotexcludebiasduetotherapy

inter-366

ruptionbecauseofsideeffects;wedonotknowwhethersomedeaths

367

couldhavebeenduetocardiovascularcomplicationsofHCQ.However,

368

recentdataonItalianwardsshowedthatCOVID-19patientsreceiving

369

HCQandazithromycinhadaQTc-intervallongerthanbeforetherapy,

370

butdidnotexperience,duringtheirhospitalstay,anyarrhythmic

com-371

plications,suchassyncopeorlife-threateningventriculararrhythmias

372

[42] ,afindingalsoreportedbytheRCTmentionedabove(39).

373

Finally,thepossibilityofunmeasuredresidualconfoundingcannot

374

becompletelyruled-out.However,theE-valueforthelowerboundary

375

oftheconfidenceintervalofourmainresultis1.67,indicatingthatthe

376

confidenceintervalcouldbemovedtoincludethenullbyastrong

un-377

measuredconfounderassociatedwithbothHCQtreatmentanddeath

378

withariskratioof1.67-foldforeach,aboveandbeyondallthe

mea-379

suredconfounders.Weakerconfounders,however,couldnotdoso.

380

5. Conclusions

381

Ourstudy,includingalargereallifesampleofpatientshospitalized

382

withCOVID-19alloverItaly,showsthatHCQuse(200mgtwice/day)

383

wasassociatedwitha30%reductionofoverallin-hospitalmortality.

384

Intheabsenceofclear-cutresultsfromcontrolled,randomizedclinical

385

trials,ourdatado notdiscouragetheuse of HCQin inpatientswith

386

COVID-19.Giventheobservationaldesignofourstudy,however,these

387

resultsshouldbetransferredwithcautiontoclinicalpractice.

388

Sourceoffunding

389

None.

390

DeclarationofCompetingInterests 391

None. 392

CRediTauthorshipcontributionstatement 393

AugustoDiCastelnuovo:Conceptualization,Datacuration,Inves- 394

tigation, Supervision, Writing - review & editing, Writing - original 395

draft.SimonaCostanzo:Investigation,Supervision,Writing-review 396

& editing.AndreaAntinori:Investigation,Supervision,Writing-re- 397

view&editing.NausicaaBerselli:Investigation,Supervision,Writing 398

-review&editing.LorenzoBlandi:Investigation,Supervision,Writing 399

-review&editing.RaffaeleBruno:Investigation,Supervision,Writing 400

-review&editing.RobertoCauda:Investigation,Supervision,Writ- 401

ing-review&editing.GiovanniGuaraldi:Investigation,Supervision, 402

Writing-review&editing.LorenzoMenicanti:Investigation,Super- 403

vision,Writing -review& editing.IlariaMy:Investigation,Supervi- 404

sion,Writing-review&editing.GiustinoParruti:Investigation,Su- 405

pervision, Writing-review&editing. GiuseppePatti:Investigation, 406

Supervision,Writing-review&editing.StefanoPerlini:Investigation, 407

Supervision, Writing -review& editing.Francesca Santilli:Investi- 408

gation,Supervision,Writing-review&editing.CarloSignorelli:In- 409

vestigation,Supervision,Writing-review&editing.EnricoSpinoni: 410

Investigation,Supervision,Writing-review&editing.GiulioG.Ste- 411

fanini:Investigation,Supervision,Writing-review&editing,Formal 412

analysis.AlessandraVergori:Investigation,Supervision,Writing-re- 413

view & editing. WalterAgeno: Investigation, Supervision, Writing- 414

review& editing.Antonella Agodi:Investigation,Supervision,Writ- 415

ing-review&editing.LucaAiello:Investigation,Supervision,Writ- 416

ing-review&editing.Piergiuseppe Agostoni:Investigation,Super- 417

vision,Writing-review&editing.SamirAlMoghazi:Investigation, 418

Supervision,Writing-review&editing.MarinellaAstuto:Investiga- 419

tion,Supervision,Writing-review&editing.FilippoAucella:Inves- 420

tigation, Supervision,Writing-review&editing.GretaBarbieri:In- 421

vestigation,Supervision,Writing-review&editing.AlessandroBar- 422

toloni:Investigation, Supervision,Writing -review& editing. Mari- 423

alauraBonaccio:Investigation,Supervision,Writing-review&editing. 424

PaoloBonfanti:Investigation,Supervision,Writing-review&editing. 425

FrancescoCacciatore:Investigation,Supervision,Writing-review& 426

editing.LuciaCaiano:Investigation,Supervision,Writing-review& 427

editing.FrancescoCannata:Investigation,Supervision,Writing-re- 428

view&editing. LauraCarrozzi:Investigation,Supervision,Writing- 429

review&editing.AntonioCascio:Investigation,Supervision,Writing 430

-review&editing.ArturoCiccullo:Investigation,Supervision,Writ- 431

ing-review&editing.AntonellaCingolani:Investigation,Supervision, 432

Writing-review&editing.FrancescoCipollone:Investigation,Super- 433

vision,Writing-review&editing.ClaudiaColomba:Investigation,Su- 434

pervision,Writing-review&editing.FrancescaCrosta:Investigation, 435

Supervision,Writing-review&editing.ChiaraDalPra:Investigation, 436

Supervision, Writing-review& editing.GianBattistaDanzi: Inves- 437

tigation, Supervision,Writing-review& editing.DamianoD’Ardes: 438

Investigation,Supervision,Writing-review&editing.KatleendeGae- 439

tanoDonati: Investigation,Supervision, Writing -review& editing, 440

Writing -originaldraft. PaolaDel Giacomo:Investigation,Supervi- 441

sion,Writing-review&editing.FrancescoDiGennaro:Investigation, 442

Supervision, Writing-review& editing.Giuseppe DiTano:Investi- 443

gation,Supervision,Writing-review&editing. GiampieroD’Offizi: 444

Investigation,Supervision,Writing-review&editing.TommasoFilip- 445

pini:Investigation,Supervision,Writing-review&editing.Francesco 446

Maria Fusco:Investigation,Supervision, Writing-review& editing. 447

Ivan Gentile:Investigation,Supervision,Writing -review& editing. 448

AlessandroGialluisi:Investigation, Supervision,Writing -review& 449

editing.GiancarloGini:Investigation,Supervision,Writing-review& 450

editing.ElviraGrandone:Investigation,Supervision,Writing-review 451

& editing.Leonardo Grisafi:Investigation,Supervision,Writing- 452

review&editing.GabriellaGuarnieri:Investigation,Supervision, 453 7

(9)

Writing-review&editing.SilviaLamonica:Investigation,

Super-454

vision,Writing-review&editing.FrancescoLandi:Investigation,

455

Supervision,Writing-review&editing.ArmandoLeone:

Investi-456

gation,Supervision,Writing-review&editing.GloriaMaccagni:

457

Investigation,Supervision,Writing-review&editing.Sandro

Mac-458

carella:Investigation,Supervision,Writing-review&editing.

An-459

dreaMadaro:Investigation,Supervision,Writing-review&

edit-460

ing.MassimoMapelli:Investigation,Supervision,Writing-review

461

&editing.RiccardoMaragna:Investigation,Supervision,Writing

-462

review&editing.LorenzoMarra:Investigation,Supervision,

Writ-463

ing-review&editing.GiulioMaresca:Investigation,Supervision,

464

Writing-review&editing.ClaudiaMarotta:Investigation,

Super-465

vision,Writing-review&editing.FrancoMastroianni:

Investiga-466

tion,Supervision,Writing-review&editing,Methodology.Maria

467

Mazzitelli:Investigation,Supervision,Writing-review&editing.

468

AlessandroMengozzi:Investigation,Supervision,Writing-review

469

&editing.FrancescoMenichetti:Investigation,Supervision,

Writ-470

ing-review&editing.MariannaMeschiari:Investigation,

Super-471

vision,Writing-review&editing.FilippoMinutolo:Investigation,

472

Supervision,Writing-review&editing.ArturoMontineri:

Investi-473

gation,Supervision,Writing-review&editing.RobertaMussinelli:

474

Investigation, Supervision, Writing - review & editing. Cristina

475

Mussini: Investigation,Supervision, Writing - review& editing.

476

MariaMusso:Investigation,Supervision,Writing-review&

edit-477

ing.AnnaOdone:Investigation,Supervision,Writing-review&

478

editing.MarcoOlivieri:Investigation,Supervision,Writing-review&

479

editing,Software.EmanuelaPasi:Investigation,Supervision,Writing

480

-review&editing.FrancescoPetri:Investigation,Supervision,

Writ-481

ing- review& editing. BiagioPinchera: Investigation, Supervision,

482

Writing-review&editing.CarloA.Pivato:Investigation,Supervision,

483

Writing-review&editing. VenerinoPoletti:Investigation,

Supervi-484

sion,Writing-review&editing.ClaudiaRavaglia:Investigation,

Su-485

pervision,Writing-review&editing.MassimoRinaldi:Investigation,

486

Supervision,Writing-review& editing.AndreaRognoni:

Investiga-487

tion,Supervision,Writing-review&editing.MarcoRossato:

Investi-488

gation,Supervision,Writing-review&editing.IlariaRossi:

Investiga-489

tion,Supervision,Writing-review&editing.MariannaRossi:

Inves-490

tigation,Supervision,Writing-review&editing.AnnaSabena:

Inves-491

tigation,Supervision,Writing-review&editing.FrancescoSalinaro:

492

Investigation,Supervision,Writing-review&editing.Vincenzo

San-493

giovanni:Investigation,Supervision,Writing-review&editing.Carlo

494

Sanrocco:Investigation,Supervision,Writing-review&editing.Laura

495

Scorzolini:Investigation,Supervision,Writing-review&editing.

Raf-496

faellaSgariglia:Investigation,Supervision,Writing-review&editing.

497

PaolaGiustinaSimeone:Investigation,Supervision,Writing-review&

498

editing.MicheleSpinicci:Investigation,Supervision,Writing-review

499

&editing.EnricoMariaTrecarichi:Investigation,Supervision,Writing

500

-review&editing.AmedeoVenezia:Investigation,Supervision,

Writ-501

ing-review&editing.GiovanniVeronesi:Investigation,Supervision,

502

Writing-review&editing,Formalanalysis.RobertoVettor:

Investiga-503

tion,Supervision,Writing-review&editing.AndreaVianello:

Investi-504

gation,Supervision,Writing-review&editing.MarcoVinceti:

Investi-505

gation,Supervision,Writing-review&editing.LauraVocciante:

Inves-506

tigation,Supervision,Writing-review&editing.RaffaeleDeCaterina:

507

Conceptualization,Investigation,Supervision,Writing-review&

edit-508

ing,Writing-originaldraft.LiciaIacoviello:Conceptualization,Data

509

curation,Investigation,Investigation,Supervision,Writing-review&

510

editing,Writing-originaldraft.

511

Acknowledgments

512

Wethanktheparticipatingclinicalcentresincludedinthiscohort.

513

ThisArticleisdedicatedtoallthepatientswhosufferedordied,often

514

insolitude,duetoCOVID-19;theirtragicfategaveusmoralstrengthto

515

initiateandcompletethisresearch.

516

TheAuthorsaloneareresponsiblefortheviewsexpressedinthisAr- 517

ticle.Theydonotnecessarilyrepresenttheviews,decisions,orpolicies 518

oftheInstitutionswithwhichtheyareaffiliated. 519

Appendix1 520

Augusto Di Castelnuovoa, Simona Costanzob, Andrea Antinoric, 521

Nausicaa Bersellid, Lorenzo Blandie, Raffaele Brunof,g, Roberto 522

Caudah,i,GiovanniGuaraldij,LorenzoMenicantie,IlariaMyk,Giustino 523

Parrutil, Giuseppe Pattim, Stefano Perlinin,o, Francesca Santillip, 524

Carlo Signorelliq, Enrico Spinonim, Giulio G. Stefaninik, Alessandra 525

Vergorir,WalterAgenos,AntonellaAgodit,LucaAiellou,Piergiuseppe 526

Agostoniv,w,Samir AlMoghazix, MarinellaAstutot, FilippoAucellay, 527

Greta Barbieriz, AlessandroBartoloniaa, MarialauraBonacciob, Paolo 528

Bonfantiab,ac, Francesco Cacciatoread, Lucia Caianos, Francesco 529

Cannatak, Laura Carrozziae, Antonio Cascioaf, Arturo Cicculloh, 530

Antonella Cingolanih,i, Francesco Cipollonep, Claudia Colombaaf, 531

Francesca Crostal, Chiara Dal Praag, Gian Battista Danziah, Dami- 532

ano D’Ardesp, Katleen de Gaetano Donatih, Paola Del Giacomoh, 533

Francesco Di Gennaroai, Giuseppe Di Tanoah, Giampiero D’Offiziaj, 534

TommasoFilippinid,FrancescoMariaFuscoak,IvanGentileal,Alessan- 535

dro Gialluisib, GiancarloGinis, ElviraGrandoney, Leonardo Grisafim, 536

Gabriella Guarnieriam, Silvia Lamonicah, FrancescoLandiu,Armando 537

Leonean, Gloria Maccagniah, SandroMaccarellaao, Andrea Madaroap, 538

Massimo Mapelliv,w, Riccardo Maragnav,w, Lorenzo Marraan, Giulio 539

Marescaaq,ClaudiaMarottaai,FrancoMastroianniap,MariaMazzitelliar, 540

Alessandro Mengozziz, Francesco Menichettiz, Marianna Meschiarij, 541

Filippo Minutoloas, ArturoMontineriat, Roberta Mussinelliq, Cristina 542

Mussinij, Maria Mussoau, AnnaOdoneq, Marco Olivieriav, Emanuela 543

Pasiaw,FrancescoPetriab,BiagioPincheraal,CarloA.Pivatok,Venerino 544

Polettiax, Claudia Ravagliaax, Massimo Rinaldiap, Andrea Rognonim, 545

Marco Rossatoag, Ilaria Rossip, Marianna Rossiab, Anna Sabenan, 546

Francesco Salinaron, VincenzoSangiovanniak, CarloSanroccol,Laura 547

Scorzoliniay, Raffaella Sgarigliaaq, Paola Giustina Simeonel, Michele 548

Spinicciaa, Enrico Maria Trecarichiar, Amedeo Veneziaap, Giovanni 549

Veronesis, Roberto Vettorag, Andrea Vianelloam, Marco Vincetid,az, 550

LauraVoccianteaq,RaffaeleDeCaterinaai,LiciaIacoviellob,s 551 aMediterraneaCardiocentro,Napoli.ItalybDepartmentofEpidemi- 552

ologyandPrevention,IRCCSNeuromed,Pozzilli(IS).ItalycUOCIm- 553

munodeficienze Virali, National Institute for Infectious Diseases “L. 554

Spallanzani”,IRCCS.Roma.ItalydSectionofPublicHealth,Department 555

of Biomedical, MetabolicandNeuralSciences,Universityof Modena 556

andReggioEmilia,Modena.ItalyeIRCCSPoliclinicoSanDonato,San 557

DonatoMilanese.ItalyfDivisionofInfectiousDiseasesI,FondazioneIR- 558

CCSPoliclinicoSanMatteo,Pavia.ItalygDepartmentofClinical,Sur- 559

gical, Diagnostic,andPaediatricSciences,Universityof Pavia,Pavia. 560

Italy hFondazionePoliclinico UniversitarioA. Gemelli IRCCS,Roma. 561

ItalyyiUniversità CattolicadelSacroCuore-DipartimentodiSicurezza 562

eBioeticaSedediRoma,Roma.ItalyjInfectiousDiseaseUnit,Depart- 563

mentofSurgical,Medical,DentalandMorphologicalSciences,Univer- 564

sityofModenaandReggioEmilia,Modena.ItalykHumanitasClinical 565

andResearchHospitalIRCCS,Rozzano-Milano.ItalylDepartmentofIn- 566

fectiousDisease,AziendaSanitariaLocale(AUSL)diPescara,Pescara. 567

Italy mUniversityof Eastern Piedmont, MaggioredellaCarità Hospi- 568

tal,Novara.ItalynEmergencyDepartment,IRCCSPoliclinicoSanMat- 569

teoFoundation,Pavia.ItalyoDepartmentofInternalMedicine,Univer- 570

sityof Pavia, Pavia.Italy pDepartmentof MedicineandAging,Clin- 571

icaMedica,“SS.Annunziata” HospitalandUniversityofChieti,Chieti. 572

ItalyqSchoolofMedicine,Vita-SaluteSanRaffaeleUniversity,Milano. 573

ItalyrHIV/AIDSDepartment,NationalInstituteforInfectiousDiseases 574

“LazzaroSpallanzani”-IRCCS,Roma.ItalysDepartmentofMedicineand 575

Surgery, University of Insubria, Varese. Italy tDepartment of Medi- 576

cal and Surgical Sciences and Advanced Technologies “G.F. Ingras- 577

sia”,UniversityofCatania;AOUPoliclinico-VittorioEmanuele, Cata- 578

nia. Italy uUOC. Anestesiae Rianimazione. Dipartimento di Chirur- 579

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European Journal of Internal Medicine 000 (2020) 1–10

diologicoMonzinoIRCCS, Milano.ItalywDepartmentofClinical

Sci-581

ences andCommunity Health, Cardiovascular Section, Universityof

582

Milano,Milano.ItalyxInfezioniSistemichedell’Immunodepresso,

Na-583

tionalInstitute for Infectious Diseases L.Spallanzani, IRCCS, Roma.

584

ItalyyFondazioneI.R.C.C.S“CasaSollievodellaSofferenza”,San

Gio-585

vanniRotondo,Foggia.ItalyzDepartmentofClinicaland

Experimen-586

tal Medicine,Azienda Ospedaliero-Universitaria Pisana,and

Univer-587

sity of Pisa, Pisa. Italy aaDepartment of Experimental and Clinical

588

Medicine. University of Florence, Firenze. Italy abUOC Malattie

In-589

fettive, Ospedale San Gerardo, ASST Monza, Monza. Italy acSchool

590

ofMedicineandSurgery,Universityof Milano-Bicocca,Milano. Italy

591

adDepartmentofTranslationalMedicalSciences.UniversityofNaples,

592

Federico II,Napoli. ItalyaeCardiovascularandThoracic Department,

593

AziendaOspedaliero-UniversitariaPisana,andUniversityofPisa,Pisa.

594

ItalyafInfectiousandTropicalDiseasesUnit-DepartmentofHealth

Pro-595

motion,Mother andChildCare, InternalMedicineandMedical

Spe-596

cialties (PROMISE) -Universityof Palermo,Palermo. Italy agClinica

597

Medica 3, Department of Medicine- DIMED, Universityhospital of

598

Padova,Padova. ItalyahDepartmentof Cardiology,Ospedale di

Cre-599

mona,Cremona.ItalyaiMedicalDirection, IRCCSNeuromed,Pozzilli

600

(IS).ItalyajUOCMalattieInfettive-Epatologia,NationalInstitutefor

In-601

fectiousDiseases L.Spallanzani, IRCCS, Roma.ItalyakUOCInfezioni

602

Sistemicheedell’Immunodepresso,AziendaOspedalieradeiColli,

Os-603

pedaleCotugno.Napoli. ItalyalDepartmentof ClinicalMedicineand

604

Surgery.UniversityofNaples“FedericoII”,Napoli.ItalyamRespiratory

605

PathophysiologyDivision,DepartmentofCardiologic,Thoracicand

Vas-606

cular Sciences,University of Padova, Padova. Italy anUOC di

Pneu-607

mologia, P.O. San Giuseppe Moscati, Taranto. Italy aoASST Milano

608

Nord- Ospedale Edoardo Bassini, CiniselloBalsamo.Italy ap

COVID-609

19Unit.EEOspedaleRegionaleF.Miulli,AcquavivadelleFonti(BA).

610

ItalyaqUOCMedicina -POS.Mariadi LoretoNuovo-ASL Napoli1

611

Centro.NapoliarInfectiousandTropicalDiseasesUnit.Deparmentof

612

MedicalandSurgicalSciences“MagnaGraecia” University,Catanzaro.

613

ItalyasDipartimentodiFarmacia,Università diPisa,Pisa,Italy.atU.O.

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C.MalattieInfettive eTropicali,P.O.“SanMarco”,AOU

Policlinico-615

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Respiratorio,NationalInstituteforInfectiousDiseases“L.Spallanzani”,

617

IRCCS, Roma. Italy avComputer Service, University of Molise,

Cam-618

pobasso.Italy.awMedicinaInterna.OspedalediRavenna.AUSLdella

619

Romagna,Ravenna.ItalyaxUOCPneumologia.DipartimentodiMalattie

620

ApparatoRespiratorioeTorace.OspedaleMorgagni-PierantoniForlì,

621

Forlì. Italy ayUOC Malattie Infettive ad Alta Intensità di Cura,

Na-622

tionalInstituteforInfectiousDiseases“L.Spallanzani”,IRCCS,Roma.

623

ItalyazDepartmentofEpidemiology,BostonUniversitySchoolofPublic

624

Health,Boston.USA.

625

Supplementarymaterials

626

Supplementarymaterialassociatedwiththisarticlecanbefound,in

627

theonlineversion,atdoi:10.1016/j.ejim.2020.08.019 .

628

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