Severe COVID-19 pneumonia in Piacenza, Italy — A cohort study of the first pandemic wave

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Severe COVID-19 pneumonia in Piacenza, Italy - A

cohort study of the first pandemic wave

Lorenzo Guglielmetti, Irina Kontsevaya, Maria Leoni, Patrizia Ferrante, Elisa

Fronti, Laura Gerna, Caterina Valdatta, Alessandra Donisi, Alberto Faggi,

Franco Paolillo, et al.

To cite this version:

Lorenzo Guglielmetti, Irina Kontsevaya, Maria Leoni, Patrizia Ferrante, Elisa Fronti, et al.. Severe

COVID-19 pneumonia in Piacenza, Italy - A cohort study of the first pandemic wave. Journal of

Infection and Public Health, Elsevier, 2021, 14 (2), pp.263 - 270. �10.1016/j.jiph.2020.11.012�.

�hal-03123116�

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ContentslistsavailableatScienceDirect

Journal

of

Infection

and

Public

Health

j o ur na l h o me p a g e :h t t p : / / w w w . e l s e v i e r . c o m / l o c a t e / j i p h

Severe

COVID-19

pneumonia

in

Piacenza,

Italy

—

A

cohort

study

of

the

ﬁrst

pandemic

wave

Lorenzo

Guglielmetti

a,b,c,∗

,

Irina

Kontsevaya

d,e,f

_,

_Maria

_C.

_Leoni

c

_,

_Patrizia

_Ferrante

c,g

_,

Elisa

Fronti

c

_,

_Laura

_Gerna

c

_,

_Caterina

_Valdatta

c

_,

_Alessandra

_Donisi

h

_,

_Alberto

_Faggi

c

_,

Franco

Paolillo

c

_,

_Giovanna

_Ratti

c

_,

_Alessandro

_Ruggieri

c

_,

_Marta

_Scotti

c

_,

_Daria

_Sacchini

c

_,

Gloria

Taliani

c,i,j,1

_,

_Mauro

_Codeluppi

c,1

_,

_For

_the

_{COVID-Piacenza}

_Group

2

a_Sorbonne_Université,_INSERM,_U1135,_Centre_{d’Immunologie}_et_des_Maladies_{Infectieuses,}_Cimi-Paris,_équipe_13,_Paris,_France

b_APHP,_Groupe_Hospitalier_{Universitaire}_Sorbonne_Université,_Hôpital_{Pitié-Salpêtrière,}_Centre_National_de_Référence_des_{Mycobactéries}_et_de_la_Résistance

desMycobactériesauxAntituberculeux,Paris,France

c_Infectious_Diseases_Unit,_Piacenza_Hospital,_Piacenza,_Italy d_Research_Center_Borstel,_Borstel,_Germany

e_German_Center_for_Infection_Research,_{Hamburg-Lübeck-Borstel-Riems,}_Borstel,_Germany f_{International}_{Health/Infectious}_Diseases,_University_of_Lübeck,_Lübeck,_Germany

g_Institute_for_{Cross-Disciplinary}_Physics_and_Complex_Systems_IFISC_(UIB-CSIC),_Campus_Universitat_Illes_Balears,_E-07122_Palma_de_Mallorca,_Spain h_Migration_Health_Unit,_Primary_Health_Care_Department,_“Guglielmo_da_Saliceto”_Hospital,_Piacenza,_Italy

i_Infectious_and_Tropical_Disease_Unit,_Department_of_{Translational}_and_Precision_Medicine,_Sapienza_University_of_Rome,_Rome,_Italy j_Anti-COVID_Task_Force_of_the_Italian_Civil_Protection

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received11August2020 Receivedinrevisedform 13November2020 Accepted18November2020 Keywords: SARS-CoV-2 Coronavirus Viralpneumonia

Acuterespiratorydistresssyndrome Mortality

a

b

s

t

r

a

c

t

Background:Piacenzaistheclosestcitytotheﬁrstcoronavirusdisease2019(COVID-19)clusterinItaly andhasthehighestnationalCOVID-19deathratesperpopulation.Theobjectiveofthisstudyistopresent characteristicsandoutcomesofpatientsadmittedtomedicaldepartmentsoftheHospitalofPiacenza duringtheﬁrstwaveoftheepidemic.

Methods:Atotalof218patientswithconfirmedorsuspectCOVID-19andseverepneumoniawere includedfromFebruary21sttoMay15th,2020.Routinely-collectedclinicalandlaboratorydatawere ret-rospectivelyretrievedfromelectronicmedicalfiles.ACoxproportional-hazardsmodelwasfittoassess theassociationoftreatmentandothervariableswithdeath.

Results:Medianageofpatientswas68years;150patients(69%)hadcomorbidities,mainlyhypertension (107,49%).Overall,185(85%)patientshadacuterespiratorydistresssyndrome(ARDS)onadmission, including103(47%)withmoderateorsevereARDS.Chestcomputedtomographyscanshowedbilateral diseasein201(98%)andextensivelunginvolvementin79(50%)patients.Mostpatientsreceivedantiviral treatment(187,86%)andcorticosteroids(134,61%).Allpatientsreceivedrespiratorysupportand64(29%) wereadmittedtointensivecareunit.AsofJune30th,100patients(46%)died,109patients(50%)were discharged,and9patients(4%)werestillhospitalized.InmultivariableCoxanalysis,ageabove65years, havingmorethanonecomorbidity,severeARDS,lowplateletcounts,andhighLDHlevelsatadmission wereassociatedwithmortality,whilehavingdiarrheaatadmissionwasassociatedwithsurvival.The useofantiviralsorcorticosteroidswasnotassociatedwithsurvival.

∗ Correspondingauthor:LaboratoiredeBactériologie-Hygiène,FacultédeMédecineSorbonneUniversité,91Boulevarddel’hôpital,75634ParisCedex13,France. E-mailaddresses:lorenzo.guglielmetti@aphp.fr(L.Guglielmetti),ikontsevaya@fz-borstel.de(I.Kontsevaya),M.Leoni2@ausl.pc.it(M.C.Leoni),P.Ferrante@ausl.pc.it

(P.Ferrante),E.Fronti@ausl.pc.it(E.Fronti),L.Gerna@ausl.pc.it(L.Gerna),C.Valdatta@ausl.pc.it(C.Valdatta),a.donisi@ausl.pc.it(A.Donisi),A.Faggi@ausl.pc.it

(A.Faggi),F.Paolillo@ausl.pc.it(F.Paolillo),G.Ratti@ausl.pc.it(G.Ratti),A.Ruggieri@ausl.pc.it(A.Ruggieri),M.Scotti@ausl.pc.it(M.Scotti),D.Sacchini@ausl.pc.it(D.Sacchini),

gloria.taliani@uniroma1.it(G.Taliani),m.codeluppi@ausl.pc.it(M.Codeluppi).

1 _Senior_authors_contributed_equally_to_this_study.

2 _Members_of_the_{COVID-Piacenza}_Group_are_the_following:_Mario_Barbera,_Francesco_Calabrese,_Luigi_Cavanna,_Andrea_{Magnacavallo,}_Carlo_Moroni,_Massimo_Nolli,_Massimo

Piepoli,RobertaSchiavo,MatteoSilva.Afﬁliationsforallmembersis:PiacenzaHospital,Piacenza,Italy.

https://doi.org/10.1016/j.jiph.2020.11.012

1876-0341/©2020TheAuthors.PublishedbyElsevierLtdonbehalfofKingSaudBinAbdulazizUniversityforHealthSciences.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

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L.Guglielmettietal. JournalofInfectionandPublicHealth14(2021)263–270

Conclusions:Overallcasefatalityrates werehighandassociatedwithcomorbidities,extensivelung involvement,ARDSatadmission,andadvancedage.Theuseofantiviralswasnotassociatedwithincreased survival.

Introduction

Coronavirusdisease2019(COVID-19)iscausedbysevereacute respiratory syndromecoronavirus-2 (SARS-CoV-2), detectedfor theﬁrsttime inWuhan,China,in December2019.COVID-19is thoughttohaveafavorableclinicalcourseinmostpatients. How-ever,insomecases,itmayleadtoseverepneumoniaandeventually toacuterespiratorydistresssyndrome(ARDS)[1].Todate,thereis noestablishedantiviraltreatmentforCOVID-19.Manydrugsare currentlyunderinvestigation,whileseveralarebeingemployed inoff-labeluse,andothersareavailableviacompassionateuseor expandedaccessprograms.

As ofOctober 31st, 2020,45667780casesof COVID-19and 1189499deathshavebeenreportedworldwide[2],with594472 casesand37781deathshavingoccurredinItaly[3].Italy,thefirst WesterncountryreportingsustainedCOVID-19transmission,has beendisproportionatelyaffectedbytheepidemic[4–6].Inareasof NorthernItalysurroundingthefirstCOVID-19clusterinthetown of Codogno,publichealthcare systemshavebeenoverwhelmed by theabruptcaseloadincrease [7]. Limitedavailabilityof ven-tilatorysupportinintensivecareunits(ICUs)ofmanyhospitals promptedtheneedtoimplementformsofpatienttriage.Afterthe firstmonthsoftheepidemic,theprovinceofPiacenza,theclosest totheinitialcluster,hadthehighestCOVID-19deathratesper pop-ulationinthecountry[8].InthePiacenzaHospital,thefirstproven casewasreportedonFebruary21st,2020[9].AsICUcapacitywas quicklyexhaustedbyCOVID-19patients,non-ICUmedical depart-ments,andinparticulartheInfectiousDiseasesUnit,hadtoadmit increasingnumbersofcritically-illpatientswhoneededadvanced respiratorysupport.

Multiple case series of COVID-19 patients have been pub-lished,mostlyfromChinaandtheUnitedStates[10–18].However, descriptionsofthecharacteristicsofpatientsinItalyareless com-mon, excludingstudiesfrom theICUsetting [19,20]. Moreover, thereisaneedtocharacterizemanagementandoutcomesofsevere casesadmittedtonon-ICUwards.

In thisstudy,wepresent thecharacteristicsof patientswith severeCOVID-19pneumoniawhowereadmittedtofourmedical departmentsoftheHospitalofPiacenzaduringtheﬁrstepidemic waveoftheoutbreak,aimingtodescribetreatment,casefatality rates,andfactorsassociatedwithmortality.

Materialsandmethods

Studypopulationandoversight

Consecutive patients admitted to four non-ICU medical departments(InfectiousDiseases,EmergencyMedicine,andtwo COVID-19Unitscreatedduringtheepidemic)ofthe“Guglielmoda Saliceto”HospitalinPiacenzabetweenFebruary21st,2020,and May15th,2020,wereincludedinthissingle-center,retrospective, observationalstudy.Inclusioncriteriaforthestudywerethe fol-lowing:(1) conﬁrmedCOVID-19caseswithpositive Sars-CoV-2 polymerase-chain-reaction(PCR)test,orsuspectCOVID-19cases withhighlysuggestiveradiologicevidenceonchesthigh-resolution computed tomography(HRCT), in theabsenceofan alternative diagnosis,and(2)severeCOVID-19pneumonia.Children(<18years

old)werenotincluded.ThestudywasapprovedbythelocalEthics Committee(AreaVasta EmiliaNord).Requirementforinformed consentwaswaivedbytheEthicsCommittee.

Studydeﬁnitions

ConfirmedandsuspectCOVID-19cases,andcaseswithsevere COVID-19 pneumonia were defined according toWHO criteria [21,22].ConfirmedCOVID-19casesweredefinedaspatientswith apositivePCRtestforSARS-CoV-2.SuspectCOVID-19caseswere defined as patients with acute respiratory illness, chest HRCT evidenceoflesionscompatiblewithCOVID-19,andresidencein anareareportingcommunitytransmissionofCOVID-19disease duringthe14dayspriortosymptomonset.SevereCOVID-19 pneu-moniawasdefinedaspneumoniawithoxygensaturationonroom airof93%orlessathospitaladmission.

Studyprocedures

COVID-19 cases were conﬁrmed using reverse transcriptase real-timePCRonnasopharyngealswabspecimen.HRCTscanswere routinelyperformedathospitaladmissiontodiagnosepulmonary COVID-19 and toassess theextent of lung involvement. HRCT scanswerereadbyexpertradiologists,whoassessedopticallythe proportionoflungparenchymainvolvedbyviralpneumonia(i.e. interstitialinvolvement,ground-glassopacities,crazy-paving pat-tern,etc.),asdescribedpreviously[23].Bloodtests(includingblood gastesting)wereperformedattheClinicalLaboratoryofthe Pia-cenzaHospital.Resultsfromsamplescollectedonadmissionoron thefollowingdaywereconsideredasbaselineresultsandincluded intheanalysis.

Datacollection

Routinely-collecteddatawere retrieved retrospectivelyfrom electronic medical ﬁles, cross-checked and collated in an anonymizeddatabase.Collecteddataincludeddemographic and clinicalcharacteristicsofpatients,laboratoryandradiologic exam-inations,treatmentandoxygensupportreceived,andoutcomes. Treatmentdatawereonlyavailablefortheperiodofhospitalstay atthemedicaldepartments,butnotduringthestayintheICU.Data collectionwascompletedanddatawerelockedonJune30th,2020. Statisticalanalysis

Results of continuous data were reported as median and interquartilerange(IQR),whilecategoricaldatawerereportedas countsandproportions.Missingdatawerenotimputed.Survival analysiswasperformedtodescribethetimefromhospitalization todeathand Kaplan-Meiercurves wereestimated for probabil-ityofsurvivalafterhospitalization,overallandbyvariousstrata. Testsbetweenstrataweredonebythelog-ranktest.The associ-ationofexplanatoryvariables(patientcharacteristics,symptoms, comorbidities,laboratoryandradiologicexams,andtreatments) withdeathwasanalyzedusingamultivariateCoxproportional haz-ardsmodel.Variableswereinitiallyincludedintothemultivariate Coxproportionalhazardsmodeliftheypredictedtheoutcomeat

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Table1

Baselineclinicalcharacteristicsandcomorbiditiesof218patientshospitalizedwith severeCOVID-19pneumonia.

n(%) Demographiccharacteristics

Sex,male 172(79)

Age,years,median(IQR)[range] 68(59−76)[19−102]

Clinicalpresentationathospitaladmission

Fever 203(93)

Dyspnea 159(73)

Cough 111(51)

Fatigue 36(17)

Diarrhea 41(19)

Timefromsymptomstohospitaladmission,days, median(IQR) 7(5−10) Comorbidities Metabolicdisease Obesity(BMI>30) 52(24) Diabetesmellitus 46(21) Cardiovasculardisease Hypertension 107(49)

Othercardiovasculardisease 56(26)

Cerebrovasculardisease 16(7) Pulmonarydisease COPD 17(8) Bronchialasthma 6(3) Cancer Solidcancer 17(8) Onco-hematologiccancer 10(5)

Chronickidneydisease 20(9)

Chronicliverdisease 3(2)

HIVinfection 2(1)

Iatrogenicimmunosuppression 5(2)

Numberofcomorbidities

None 68(31)

One 59(27)

Morethanone 91(42)

Totalnumber,median(IQR) 1(0−4)

IQR=interquartilerange;BMI=bodymassindex;COPD=chronicobstructive pul-monarydisease;HIV=humanimmunodeﬁciencyvirus.

ap-value≤0.20inunivariateanalysisandiftheyfulﬁlledthe pro-portionalhazardsassumption;astepwisebackwardshierarchical approach wasappliedfor variableselectioninthemultivariable model. Hazardratios(HRs)werereported withstandard errors and95%-conﬁdenceintervals(CI).Noroutineimputationofmissing explanatoryvariableswasdone.

StatisticalanalysiswasperformedusingStatasoftwareversion 15.0(StataCorp).

Results

Overall,245provenorsuspectCOVID-19caseswereadmitted tothefournon-ICUmedicaldepartmentsofthePiacenzaHospital duringthestudyperiod,outofwhich218hadsevereCOVID-19 pneumoniaandwereincludedinthestudy.

Demographicandclinicalcharacteristicsofthepatients

BaselineclinicalcharacteristicsareshowninTable1.Median ageofadmittedpatientswas68years(IQR,59−76;range,19−102 years);172(79%)patientsweremale.Mediantimefromﬁrst symp-tomstohospital admissionwas7 days(IQR,5−10days).Fever (203patients,93%),dyspnea(159patients,73%),andcough(111 patients, 51%) were the most common symptoms followed by fatigue(36patients,17%)anddiarrhea(41patients,19%).One hun-dredandﬁftypatients(69%)hadcomorbiditieswithmorethanhalf ofthem(91patients,42%)havingmorethanoneknown comorbid-ity.Themostcommoncomorbiditywashypertension(107patients, 49%),followedbyothercardiovasculardiseases(56patients,26%), obesity(52patients,24%),anddiabetesmellitus(46patients,21%).

Pulmonarydiseasewasreportedin23patients:chronic obstruc-tivepulmonarydisease(COPD)in17(8%)andbronchialasthma in6patients(3%).Otherreportedcomorbiditiesincludedchronic kidney(20patients, 9%)andliver(3patients,2%)disease, cere-brovasculardisease(16patients,7%),solidcancer(17patients,8%), HIVinfection(2patients,1%),andiatrogenicimmunosuppression (5patients,2%).

Virology,radiology,andlaboratoryresultsonadmission

Asshown inTable 2,216(99%) patientshad a positive PCR forSARS-CoV-2fromanasopharyngealswab.Twopatientstested negativeon admission, but had a HRCT scan showingbilateral interstitialdiseaseandclinicalandepidemiologicalhistorywhich was suggestive of COVID-19. The test could not be repeated since these patients died in the first day after admission. All 206patientswithavailablechestHRCTscan performedon hos-pitaladmissionhad signsof interstitiallung disease,201(98%) of them with bilateral involvement. The median proportion of lung parenchyma affected by viral pneumonia was 48% (IQR, 30–60; range, 5–90%),with 79 patients(50%) havingextensive lungdisease,definedas50%ormoreoflungparenchymaaffected. Twenty-five(12%)patientshadpleuraleffusion.Allpatientshad blood oxygensaturationof 93% or less onroom air on admis-sion. Arterial blood gas analysis found that 33 (15%) patients had anarterial oxygenpartialpressure/fractional inspired oxy-gen(PaO2/FiO2) ratiohigherthan 300mmHg,82patients(38%) had200−300mmHg,50patients(23%)had100−200mmHg,and 53patients(24%)hadlessthan100mmHg,correspondingtono ARDS,mildARDS,moderateARDS,andsevereARDS,respectively. Resultsof thebaseline blood testsareshown in Table2. Com-paredtoreferencevalues, medianvalues oflymphocyte counts were decreased, while prothrombin time, lactate dehydroge-nase,ferritin,C-reactiveprotein,D-dimer,andinterleukin-6were increased.

Treatmentandrespiratorysupport

Table3summarizesthetreatmentreceivedbypatients.Most patients(187, 86%)received antiviral treatmentand 169 (78%) receivedacombinationoftwoormoreantivirals.Mediantimefrom onsetofsymptomstotheinitiationofantiviraltreatmentwas8 days(IQR,6–10days);mediandurationofantiviraltreatmentwas 6days(IQR,3–9days).Overall,181patients(83%)received hydrox-ychloroquine,118patients(54%)receiveddarunavir/cobicistat,92 patients(42%) receivedlopinavir/ritonavir, and 5 patients (2%) received remdesivir. Additionally, 134 patients (61%) received corticosteroids.Mediantimefromﬁrstsymptomstostartof corti-costeroidtreatmentwas10days(IQR,8−13days)withamedian treatmentdurationof6days(IQR,3−10days).Azithromycinwas usedaspartoflarge-spectrumantibiotictreatmentin149patients (68%),andtocilizumabwasgivento14patients(6%).Low molec-ularweightheparinwasadministeredto172patients(79%)ata prophylacticdoseandto20patients(9%)atahigherdose. Over-all,60patients(28%)receivedACEinhibitors,sartan,orboth,for thetreatmentofhypertension.Duringhospitalization,allpatients wereadministeredrespiratorysupport.Table3showsthehighest levelofrespiratorysupportwhichwasprovided:anyamongnasal cannula,Venturimask,ormaskwithreservoirfor58patients(27%); high-ﬂownasalcannulafor14patients(6%);non-invasive ventila-tionsupportwithcontinuouspositiveairwaypressurehelmetsfor 88patients(40%);trachealintubationfor58patients(27%). Over-all,64patients(29%)weretransferredfromtheInfectiousDiseases wardtoICU;mediantimefromhospitalizationtoICUadmission was5days(IQR,3−9days).

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Table2

Baselinediagnostictestresultsof218patientshospitalizedwithsevereCOVID-19pneumonia.

n(%) Nwithavailableresults

PositivePCRforSARS-CoV-2 216(99) 218

Respiratoryimpairmentathospitaladmission

Oxygensaturation≤93% 218(100) 218

Arterialbloodgastest

PaO2/FiO2≥300mmHg 33(15) 218

PaO2/FiO2≥200and<300mmHg 82(38) 218

PaO2/FiO2≥100and<200mmHg 50(23) 218

PaO2/FiO2<100mmHg 53(24) 218

ChestHRCTscanathospitaladmission

Anyinterstitiallungdisease 206(100) 206

Bilaterallunginvolvement 201(98) 206

Proportionofaffectedlungparenchyma(visualassessment),%,median(IQR)[range] 48(30−60)[5−90] 158

Extendedlunginvolvement(≥50%) 79(50) 158

Anypleuraleffusion 25(12) 206

Bloodlaboratorytest,unit(referencerange) Hematologic

Whitebloodcells,×103_/␮l,_median_(IQR)₍₄₋₁₀₎ _7.5_(6.0−9.8) ₂₁₈

Hemoglobin,g/dl,median(IQR)(13−17) 13.6(12.2−14.8) 218

Platelets,×103_/␮l,_median_(IQR)_(150−450) ₁₉₇_(157−265) ₂₁₈

Lymphocytes,×103_/␮l,_median_(IQR)_(1,5−4) _0.84_{(0.62−1.11)} ₂₁₈

Biochemistry

Bloodcreatinine,mg/dl,median(IQR)(0.6−1.2) 0.99(0.83−1.25) 218

Totalbilirubin,mg/dl,median(IQR)(0−1.1) 0.67(0.51−0.90) 206

Prothrombintime,INR,median(IQR)(0.8−1.1) 1.29(1.20−1.37) 207

Partialthromboplastintime,ratio,median(IQR)(0.8−1.2) 0.97(0.89−1.05) 123

Lactatedehydrogenase,U/l,median(IQR)(0−248) 440(325−574) 207

Ferritin,ng/mL,median(IQR)(12−300) 1033(488−1991) 92

C-reactiveprotein,mg/dl,median(IQR)(0−0.5) 13.0(7.7−18.8) 218

Procalcitonin,ng/mL,median(IQR)(<0.5) 0.38(0.16−0.92) 100

D-dimer,ng/mL,median(IQR)(≤500) 1277(733−4947) 55

Interleukin-6,pg/mL,median(IQR)(<6.4) 64(13−205) 40

PCR=polymerasechainreaction;IQR=interquartilerange;HRCT=highresolutioncomputedtomography;PaO2=arterialpartialoxygenpressure;FiO2=fractionalinspired oxygen;INR=internationalnormalizedratio.

Outcomes

As of June 30th, 2020, 209 (96%) out of 218 patients had a treatment outcome (Table 3). A total of 100 patients (46%) died, 93 (43%) within 28 days after admissionto the hospital. Overall, 68 (31%) died in the wardand 33 (15%) in ICU. Fig. 1 showsKaplan–Meiercurvesformortality,overallandstratifiedby age(log-rank,p<0.0001),extensionoflungparenchymaaffected by pneumonia at chest HRCT scan (log-rank, p<0.0001), and PaO2/FiO2ratioonadmission(log-rank,p<0.0001).One hundred-ninepatients(50%)weredischargedtoarehabilitationfacilityor senthome.Amongthesepatients,mediandurationof hospitaliza-tionwas18days(IQR,11−27days).Fourpatients(2%)werestillin ICUand5patients(2%)werestillinanon-ICUward.Fig.2 summa-rizesthetimecourseofdiseaseandtreatmenthistoryofpatients, stratifiedacrossfourdifferentgroupsaccordingtofinaloutcome (deathordischarge)andtoadmissiontoICU.

Associationoftreatmentandothervariableswithmortality

Table4 showstheresultsof multivariableCox proportional-hazardsmodelanalysingtheassociationofexplanatoryvariables withdeath.Overall,thefollowingvariables wereindependently associated with death: age above 65 years at admission (HR 4.08; 95% CI 2.37–7.03),more than one comorbidity (HR 1.84; 95% CI 1.04–3.26),severe ARDS at admission(HR 3.66;95% CI 1.47–9.07),plateletcount<197×103_/_␮l _at_admission_(HR_2.23;

95%CI1.42–3.48),andLDH>440U/latadmission(HR1.98;95%CI 1.19–3.29).Diarrheaatadmissionwasassociatedwithsurvival(HR 0.31;0.13–0.72).Ofnote,antiviraltreatmentwasnotassociated withincreasedsurvival,regardlessofwhetherdifferentdrugswere entered as individual variables (hydroxychloroquine: HR 0.65; 95%CI0.33–1.30;lopinavir/ritonavir:HR0.66;95%CI0.41–1.08;

darunavir/cobicistat:HR0.62;95%CI0.37–1.06)orgroupedasa singlevariable(antiviraltreatment:HR0.81;95%CI0.43–1.53). Corticosteroidusewasassociatedwithsurvival andincludedin theﬁnalmodel,althoughtheassociationdidnotreachstatistical signiﬁcance(HR0.72;95%CI0.46–1.14).

Discussion

Weherebyreporthighcasefatalityratesinpatientsaffected bysevereCOVID-19pneumoniawhowerehospitalizedinnon-ICU wardsinItaly,despitethefrequentuseofantiviraldrugsandaccess tonon-invasiveventilationsupport.

Inourstudy,79%ofpatientsweremale,similarlytowhathas beendescribedforICUpatientsinItaly[20].Overall,85%ofpatients inourstudyhadARDSonadmission,including47%withmoderate orsevereARDS.TheseratesofARDS,muchhigherthaninprevious studieswithasimilarsetting[10,17,18,24],aremorecomparableto ICUcohorts[11,12,16,20,25],andmayaccountforthehigh mortal-ityobservedinourstudy(Fig.1d).Themediantimefromonset ofsymptomstohospitalizationwas7 days,suggestingthatour patientsdevelopedsevereillnessinashorttime.Medianagewas 68years,whichishighercomparedtostudiesfromItaly[20],China [10,13,15,24,25],Singapore[26],andtheUnitedStates[11,12,14], andtosurveillancedatafromItaly[3].Inaddition,69%ofpatients hadatleastonecomorbidity,whichisconsistentwithdatafroman ICU-basedstudyfromItaly[20],higherthaninstudiesfromChina [10,13,17,18], althoughnotablylowerthaninacohort fromthe UnitedStates[14].Asinpreviousreports,themostcommon comor-biditieswerecardiovascularandmetabolicdiseases.Therefore,our observationconﬁrmsthatolderage(Fig.1b)andcomorbiditiesare associatedwithpooroutcomes[16–18,24,27,28].Anotherrelevant ﬁndingwasthat,amongpatientswhounderwentHRCTon admis-sion,halfhad50%ormoreoflungparenchymaaffectedand98%

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Fig.1.MortalityofpatientswithsevereCOVID-19pneumonia.

Kaplan-Meiercurvesofmortalityover56daysafterhospitaladmissionof218patientshospitalizedwithsevereCOVID-19pneumonia.Thefiguresrepresent:(a)overall mortality,withdashedlinerepresenting95%confidenceintervalandamediantimetodeathof27days;(b)mortalitystratifiedbyage(log-rank,p<0.0001);(c)mortality stratifiedbytheproportionoflungparenchymaaffectedbyinterstitialdiseaseatchestcomputedtomographyscanonadmission(N=158)(log-rank,p=0.0001);(d)mortality stratifiedbyP/Fratioonadmission(log-rank,p<0.0001).Dotsindicatecensoring.

CT=chestcomputedtomography;P/F=arterialpartialoxygenpressure/fractionalinspiredoxygen.

Fig.2.TimecourseofpatientswithsevereCOVID-19pneumonia.

Timecourseofsymptoms,hospitaladmission,intensivecareunit(ICU)admissionanddischarge,initiationanddiscontinuationofantiviralandcorticosteroidtherapy,and deathordischargeofpatientshospitalizedwithsevereCOVID-19pneumonia.Patientsaredividedinfourgroupsaccordingtotheiroutcomeandtointensivecareunit admission:(a)patientswhowerenotadmittedtoICUandweredischargedhomeortoarehabilitationfacility(N=78);(b)patientswhowereadmittedtoICUandwere dischargedhomeortoarehabilitationfacility(N=22);(c)patientswhowereadmittedtoICUanddied(N=67);(d)patientswhowerenotadmittedtoICUanddied(N=29). Alldurationsrepresentmedianvaluesforeachgroupandarereportedindays.Patientswithnoassignedoutcome(N=9)arenotshown.

ICU=intensivecareunit. ICU=intensivecareunit.

hadbilateraldisease.Ithasbeenshownthatthescoreofpulmonary involvementisassociatedwithICUadmission/death[23]andthe resultsfromourstudysupportthisconclusion,aswellasthe rou-tineuseofHRCTtoassesstheextensionofpulmonaryCOVID-19at hospitaladmission(Fig.1c).Onclinicalgrounds,almostallpatients

hadfever,oftenassociatedwithrespiratorysymptoms,while gas-trointestinalsymptomswerepresentinaminorityofpatients.This isinlinewithpreviousreports[10,12,24,26].

Onadmission,mostpatientshadreducedlymphocytecounts andanincreaseinlaboratorymarkerslinkedtoinﬂammation,such

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Table3

Treatment,respiratorysupportreceived,andoutcomesbyJune30th,2020,of218 patientshospitalizedwithsevereCOVID-19pneumonia.

n(%) Treatmenta

Antivirals

Anyantiviral 187(86) Combinationofmorethanoneantiviral 169(78) Timefromsymptomstoantiviraltreatmentstart,days,

median(IQR)(N=187)

8(6−10) Antiviraltreatmentduration,days,median(IQR)(N=187) 6(3−9) Hydroxychloroquine 181(83) Darunavir/cobicistat 118(54) Lopinavir/ritonavir 92(42) Remdesivir 5(2) Corticosteroids Anycorticosteroid 134(61) Timefromsymptomstocorticosteroidtreatmentstart,

days,median(IQR)(N=134)

10(8−13) Corticosteroidtreatmentduration,days,median(IQR)

(N=134)

6(3−10) Others

Azithromycin 149(68) Tocilizumab 14(6) Lowmolecularweightheparin,prophylaxis 172(79) Lowmolecularweightheparin,highdose 20(9)

Respiratorysupport

Highestlevelofrespiratorysupportduringhospitalization

Nasalcannula,Venturimask,maskwithreservoir 58(27) High-ﬂownasalcannula 14(6) CPAPhelmet 88(40) Trachealintubation 58(27)

ICU

TotaladmittedtoICU 64(29) TimefromhospitaladmissiontoICUadmission,days,

median(IQR)(N=64)

5(3−9)

Outcomes

Death

Total 100(46)

Atday28afterhospitaladmission 93(43) Timefromhospitaladmissiontodeath,days,median(IQR)

(N=100)

8(5−17) Dischargefromhospital(homeorrehabilitationfacility)

Total 109(50)

Timefromhospitaladmissiontodischarge,days,median (IQR)(N=109)

18(11−27) Outcomenotassigned

Total 9(4)

StillinICUatdatalock 4(2) Stillinhospitalatdatalock 5(2) IQR=interquartile range; CPAP=continuous positive airway pressure; ICU=intensivecareunit.

a_This_table_summarizes_treatment_received_before_and_during_admission_at_the

medicaldepartments(i.e.itdoesnotincludetreatmentreceivedintheIntensive CareUnit).

aslactatedehydrogenase,ferritin,C-reactiveprotein,D-dimer,and interleukin-6.These ﬁndingsareconsistentwithprevious stud-iesindicatingthedecreaseofantiviralimmuneresponseandthe triggerofthecytokinestorm[10,13,14,24,28]

The vastmajority ofpatientsincludedin thestudyreceived at least one antiviral and mostof them a combination oftwo,

usually hydroxychloroquine and a boosted protease inhibitor (lopinavir/ritonaviror darunavir/cobicistat). In addition, 61% of patientswere treated with corticosteroids. These high rates of treatmentwerebasedonlocalguidelines[29]andunderstandable inlightoftheclinicalseverityatpresentation.Todate,however, theevidencebackingtheefficacyofthesedrugsislimited.Intwo randomizedcontrolledtrials,lopinavir/ritonavirfailedtoshow effi-cacycomparedtostandard-of-care[30,31].Theinvivoactivityof hydroxychloroquineagainstCOVID-19,despitehighexpectations, hasnotbeenconfirmedinalargerandomized,controlledclinical trial[32].Inourstudy,theuseoftheseantivirals,often adminis-teredincombination,wasnotassociatedwithincreasedsurvival, reinforcingthestrongreservesontheefficacyofthesedrugsfor treatmentofsevereCOVID-19pneumonia[33].Corticosteroidsare currentlya mainstayoftreatmentofsevereCOVID-19 pneumo-nia:whilenobenefithad beenfoundinthetreatmentofother coronaviruses[34], multiplerandomized, controlled trials have shownthatcorticosteroidsimprovesurvivalratesinpatientswho needoxygensupportforCOVID-19[35]. Morepromising agents likeremdesivir[36]andtocilizumab[37]wereprescribedtosmall numbersofpatientsand couldnotbeassessedinthis study.In ourstudy,corticosteroidusewasassociatedwithsurvival,butthis findingdidnotreachstatisticalsignificance.Thismaybepartially explainedbytheheterogeneoustimingofstart andduration of treatmentwithcorticosteroidsinourcohort,andbythesmall sam-plesize.

Themainfindingfromourstudyisanoverallcasefatalityrate of46%,similartoratesreportedforICUpatients[11,12,16,20,25] and much higher than those reportedin studies from non-ICU wards[10,13–15,24,26].Mortalityratesareoftendifficultto com-parebetweenthesetwogroupsofstudies,alsobecauseindications forintensivecareandmechanicalventilationmaychangegreatly amongdifferentsettings[38].Indeed,mostofourpatientshave characteristicsthatwouldhavemadethemlikelyeligibleforICU directlyatthetriagelevel,hadtherenotbeenarequestoverload duetotheepidemicwave.Mostdeathsoccurredquickly,halfin thefirst7daysofhospitalizationandthemajoritywithinthefirst 28days(Fig.1a).Therearemultiplepossibleexplanationsforthe highcasefatalityrateweobserved.Aboveall,thecharacteristics ofpatientsinourstudyaresimilartothoseofICUcohorts:high ratesofcomorbidities,extensivelunginvolvement,high propor-tionofARDSatadmission,andadvancedage–allfactorsassociated withmortality.Asamatteroffact,duringthepeakoftheepidemic inPiacenzaHospital,COVID-19patientswhoneededventilatory supportwereoftenallocatedtonon-ICUwards,liketheInfectious DiseasesorEmergencyMedicineUnits,whichactedasadefacto sub-intensivecareward.Thisstudydescribesthefirstwaveofthe epidemic,includingthepeakof COVID-19admissions,and it is remarkablehownon-ICUwardswerequicklytransformedtocope withtheemergency,indicatingavirtuouslearningcurve.Indeed, ahighproportionofpatientsinourcaseseriesdiedwithoutbeing admittedtotheICU,similarlytowhathasbeenreportedpreviously inChina[39],likelyreflectingthelackofICUresources.Finally,it

Table4

Associationoftreatmentandothervariableswithdeath,assessedusingamultivariableCoxproportional-hazardsmodel(N=218).

Hazardratio 95%conﬁdenceinterval Pvalue

Variables

Age>65yearsatadmission 4.08 2.37–7.03 <0.001

Diarrheaatadmission 0.31 0.13–0.72 0.007

Morethanonecomorbidity 1.84 1.04–3.26 0.036

SevereARDSatadmission 3.66 1.47–9.07 0.005

Plateletcount<197×103_/␮l_at_admission _2.23 _1.42–3.48 _<0.001

LDH>440U/latadmission 1.98 1.19–3.29 0.008

Modeladjustedbysex,presenceofbilateraldiseaseatcomputedtomographyscan,andtreatmentwithcorticosteroids. LDH=lactatedehydrogenase;ARDS=acuterespiratorydistresssyndrome.

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hasbeenpostulatedthathighpollutionlevelsintheareamayhave increasedfatalityratesinNorthernItaly[40]—anelementwhich deservesfutureresearch.

Thisstudyhasmultiplelimitations.Asdescribedabove,the spe-cificepidemiccircumstancesandpatientselectionmustbetaken intoaccount.Thesefindingsmaythereforenotberepresentativeof theoverallcharacteristicsandoutcomesofCOVID-19casesin Pia-cenzaandofsevereCOVID-19pneumoniaingeneral.Inaddition, 4%ofpatientswerestillhospitalized,withoutafinaloutcome,at datalock.Finally,theretrospectivenatureofthestudyexplainsthe highratesofmissinginformationforsomelaboratorytests.

Inconclusion,thisstudydescribesthefeaturesofpatientswith severeCOVID-19pneumonia,theiroutcomes,andfactors associ-atedwithmortality.Theseresultswarnabouttheconsequencesof hospitaladmissionoflargeﬂuxesofpatientsthatmayoverwhelm thehealthcaresystem,despiteswiftresponseandoptimaluseof availableresources.Itseemsthereforeparamounttoimplement adequatepreventionpolicies,whileoptimizinghospital prepared-ness,andincreasingthecapacitiesofmedicalandICUwardsfor themanagementoffuturepandemicwaves.Ourresultsalso high-lightthedireneedforaneffectiveantiviraltreatmentforCOVID-19 pneumonia.Hopefully,forthcomingrandomizedcontrolledclinical trials(NCT04315948,NCT04330690)willallowidentifying promis-ingtreatmentoptions.

Funding

Thereisnospeciﬁcfundingtodeclareforthisstudy.Thework ofthecorrespondingauthor(LG)intheHospitalofPiacenzawas supportedbytheItalianSocietyofInfectiousandTropicalDiseases (SIMIT).

Competinginterests

Nonedeclared.

Ethicsapproval

ThestudywasapprovedbythelocalEthicsCommittee(Area VastaEmiliaNord).Requirementforinformedconsentwaswaived bytheEthicsCommittee.

Availabilityofdataandmaterial

Datamaybemadeavailablebycontactingdirectlythe corre-spondingauthor.

Authorcontributions

LGmadeasubstantialcontributiontotheconceptionanddesign ofthework,totheacquisition,analysisandinterpretationofdata forthework,performedstatisticalanalysis,wrotethemanuscript, critically revisedthemanuscript for importantintellectual con-tent, gaveﬁnalapproval ofthecurrentversiontobepublished, andagreestobeaccountableforallaspectsoftheworkinensuring thatquestionsrelatedtotheaccuracyorintegrityofanypartofthe workareappropriatelyinvestigatedandresolved.

IKmadeasubstantialcontributiontotheanalysisand inter-pretation of datafor thework,wrote themanuscript, critically revised themanuscript for important intellectualcontent,gave ﬁnalapprovalofthecurrentversiontobepublished,andagrees tobeaccountableforallaspectsoftheworkinensuringthat ques-tionsrelatedtotheaccuracyorintegrityofanypartoftheworkare appropriatelyinvestigatedandresolved.

GTandMCmadeasubstantialcontributiontotheconception anddesignofthework,totheanalysisandinterpretationofdata forthework,criticallyrevisedthemanuscriptforimportant intel-lectualcontent,gaveﬁnal approvalofthecurrentversion tobe published,andagreetobeaccountableforallaspectsofthework inensuringthatquestionsrelatedtotheaccuracyorintegrityof anypartoftheworkareappropriatelyinvestigatedandresolved.

Allotherauthorsgaveasubstantialcontributionstothe inter-pretationofdataforthework,revisedthemanuscriptforimportant intellectualcontent,gaveﬁnalapprovaloftheversiontobe pub-lished,andagreetobeaccountableforallaspectsoftheworkin ensuringthatquestionsrelatedtotheaccuracyorintegrityofany partoftheworkareappropriatelyinvestigatedandresolved.

Acknowledgements

Theauthorsaregratefultothehealthcareworkersofthe Infec-tious Diseases Unit, Emergency Medicine department, and the otherCOVID-19departments,ofthe“GuglielmodaSaliceto” Hos-pitalinPiacenza,Italy,andtoallthepatientswhowereincludedin thestudy.AspecialacknowledgementtoMarcelloTavio(Ancona, Italy),Marco Rizzi(Bergamo,Italy),andtotheItalian Societyof InfectiousandTropicalDiseases(SIMIT)forsupportingthe corre-spondingauthorfortheworkinPiacenza.

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