1

RecurrenceofSARS-CoV-2PCRpositivityinCOVID-19patients:asinglecenter

experienceandpotentialimplications

JiaHuang,MD1,2*#,LeZheng,PhD3,4*,ZhenLi,PhD2*,ShiyingHao,PhD3,4*,FangfanYe,MD1,2*,JunChen,MD1*,XiaomingYao,MD,PhD5,JiayuLiao,PhD6,SongWang,BS1,ManfeiZeng,MD1,LipingQiu,MD1,FanlanCen,BS1,YajingHuang,BS1,TengfeiZhu,MD1,ZehuiXu,BS1,ManhuaYe,BS1,YangYang,MD1,GuoweiWang,MD1,JinxiuLi,MD1,LifeiWang,MD1,JiuxinQu,MD1,JingYuan,MD1,WeiZheng,MD1,ZhengZhang,PhD1,ChunyangLi,PhD7,8,JohnC.Whitin,PhD9,LuTian,PhD10,HenryChubb,MBBS,PhD9,Kuo-YuanHwa,PhD11,HayleyA.Gans,MD9,ScottR.Ceresnak,MD9,WeiZhang,MD7,8,YingLu,PhD10,YvonneA.Maldonado,MD9,12,QingHe,MD1,ZhaoqinWang,PhD1,YingxiaLiu,MD1,DoffB.McElhinney,MD3,4,KarlG.Sylvester,MD2,HarveyJ.Cohen,MD,PhD9,LeiLiu,MD1#,XuefengB.Ling,PhD2,4#

1NationalClinicalResearchCenterforInfectiousDisease,TheSecondAffiliatedHospitalofSouthernUniversityofScienceandTechnology,Shenzhen,GuangdongProvince,China2DepartmentofSurgery,StanfordUniversitySchoolofMedicine,Stanford,CA,UnitedStates3DepartmentofCardiothoracicSurgery,StanfordUniversitySchoolofMedicine,Stanford,CA,UnitedStates4ClinicalandTranslationalResearchProgram,BettyIreneMooreChildren'sHeartCenter,LucilePackardChildren’sHospital,PaloAlto,CA,UnitedStates5WestChinaHospital,SichuanUniversity,Chengdu,China6DepartmentofBioengineering,UniversityofCaliforniaatRiverside,Riverside,CA,USA7BiomedicalBigDataCenter,WestChinaHospital,SichuanUniversity,Chengdu,China8MedicalBigDataCenter,SichuanUniversity,Chengdu,China9DepartmentofPediatrics,StanfordUniversitySchoolofMedicine,Stanford,CA,UnitedStates10DepartmentofBiomedicalDataScience,StanfordUniversity,Stanford,CA,UnitedStates11DepartmentofMedicine,TheUniversityofHongKong,HongKongSAR,China12DepartmentofHealthResearchandPolicy,StanfordUniversitySchoolofMedicine,Stanford,CA,UnitedStates *Contributedequally #CorrespondingAuthors: JiaHuang,NationalClinicalResearchCenterforInfectiousDisease,TheSecondAffiliatedHospitalofSouthernUniversityofScienceandTechnology,Shenzhen518112,GuangdongProvince,China;Tel:+86-13699858655;Email:

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

2

huangjia10@csu.edu.cnLeiLiu,NationalClinicalResearchCenterforInfectiousDisease,TheSecondAffiliatedHospitalofSouthernUniversityofScienceandTechnology,Shenzhen518112,GuangdongProvince,China;Tel:+86-13510333313;Email:liulei3322@aliyun.com

XuefengB.Ling,StanfordUniversitySchoolofMedicine,Stanford,CA94305,USA;Tel:650-427-9198;Fax:(650)-723-1154;Email:bxling@stanford.edu

Wordcounts:2918

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

3

KeyPoints

QuestionWhatarethecharacteristics,clinicalpresentations,andoutcomesof

COVID-19patientswithPCRretestpositivityafterresolutionoftheinitialinfection

andconsecutivenegativetests?Canweidentifyrecoveredpatients,priorto

discharge,atriskoftherecurrenceofSARS-CoV-2PCRpositivity?

FindingsInthisseriesof414COVID-19inpatientsdischargedtoadesignated

quarantinecenter,69retestpositive(13with2readmissions,and3with3

readmissions).Amultivariablemodelwasdevelopedtopredicttheriskofthe

recurrenceofSARS-CoV-2PCRpositivity.

MeaningRateandtimingoftherecurrenceofPCRpositivityfollowingstrict

quarantinewerecharacterized.Ourpredictionalgorithmmayhaveimplicationsfor

COVID-19clinicaltreatment,patientmanagement,andhealthpolicy.

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

4

ABSTRACT

IMPORTANCEHowtoappropriatelycareforpatientswhobecomePCR-negativefor

severeacuterespiratorysyndromecoronavirus2(SARS-CoV-2)isstillnotknown.

Patientswhohaverecoveredfromcoronavirusdisease2019(COVID-19)could

profoundlyimpactthehealthcaresystemifasubsetweretobePCR-positiveagain

withreactivatedSARS-CoV-2.

OBJECTIVETocharacterizeasinglecenterCOVID-19cohortwithandwithout

recurrenceofPCRpositivity,anddevelopanalgorithmtoidentifypatientsathigh

riskofretestpositivityafterdischargetoinformhealthcarepolicyandcase

managementdecision-making.

DESIGN,SETTING,ANDPARTICIPANTSAcohortof414patientswithconfirmed

SARS-CoV-2infection,atTheSecondAffiliatedHospitalofSouthernUniversityof

ScienceandTechnologyinShenzhen,ChinafromJanuary11toApril23,2020.

EXPOSURESPolymerasechainreaction(PCR)andIgM-IgGantibodyconfirmed

SARS-CoV-2infection.

MAINOUTCOMESANDMEASURESUnivariableandmultivariablestatisticalanalysis

oftheclinical,laboratory,radiologicimage,medicaltreatment,andclinicalcourseof

admission/quarantine/readmissiondatatodevelopanalgorithmtopredictpatients

atriskofrecurrenceofPCRpositivity.

RESULTS16.7%(95CI:13.0%-20.3%)patientsretestPCRpositive1to3timesafter

discharge,despitebeinginstrictquarantine.Thedrivingfactorsintherecurrence

predictionmodelincluded:age,BMI;lowestlevelsofthebloodlaboratorytests

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

5

duringhospitalizationforcholinesterase,fibrinogen,albumin,prealbumin,calcium,

eGFR,creatinine;highestlevelsofthebloodlaboratorytestsduringhospitalization

fortotalbilirubin,lactatedehydrogenase,alkalinephosphatase;thefirsttestresults

duringhospitalizationforpartialpressureofoxygen,whitebloodcelland

lymphocytecounts,bloodprocalcitonin;andthefirsttestepisodicCtvalueandthe

lowestCtvalueofthenasopharyngealswabRTPCRresults.AreaundertheROC

curveis0.786.

CONCLUSIONSANDRELEVANCEThiscaseseriesprovidesclinicalcharacteristicsof

COVID-19patientswithrecurrentPCRpositivity,despitestrictquarantine,ata16.7%

rate.Useofarecurrencepredictionalgorithmmayidentifypatientsathighriskof

PCRretestpositivityofSARS-CoV-2andhelpmodifyCOVID-19casemanagement

andhealthpolicyapproaches.

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

6

Introduction

Giventhesuddenemergenceandrapidcommunitytransmissionofsevereacute

respiratorysyndromecoronavirus2(SARS-CoV-2)beingobservedworldwide,a

strategyofsocialdistancingandshelterinplacehasbeenwidelyadoptedinaneffort

tocurbthespreadofCOVID-19acrossspaceandtime1,2.Thequarantiningof

patientstestingpositiveforSARS-CoV-2virusisconsideredmandatoryinorderto

preventcontinuedviralspread(contagion).Inlast6months,manyofCOVID-19

patientshavesinceclinicallyrecoveredandbeendischargedfromthehospital,butit

remainsunclearthedegreetowhichpatientswithCOVID-19(clinicalsymptomsand

PCRtestpositivity)remaincontagiousandoratriskfordiseaserelapse.Therising

concernisthatCOVID-19dischargedpatientsmaybeatriskofviralreactivationto

infectothersasasymptomaticcarriers,orbere-infectedthemselves.Inanattempt

tobetterunderstandtheseconcerns,varyingquarantinestrategieshavebeen

implementedduringthetransitionofCOVID-19recoveringpatientsfromhealthcare

tonon-healthcaresettingsinthiscurrentpandemic.

Recently,theearlyexperiencesof116casesconfirmedbynasopharyngealswab

testing,potentiallyresultingfromeither“reactivated”or“re-infected”SARS-CoV-2,

wasreportedinSouthKorea3,4.Inresponse,theWorldHealthOrganization(WHO)

commentedthatthereiscurrently“noevidence”demonstratingthatpeoplewho

haverecoveredfromthecoronavirusarenotatriskofre-infection5.

However,limitedinformationisavailableregardingviralsheddingkineticsand

livevirusisolation.VariabilityinPCRmethodologywillresultindifferentthresholds

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

7

oftheassayforRNAdetection,butinonestudytheSARS-CoV-2RNAthresholdupon

PCRtestingneedstobegreaterthan106copiespersample6.Todate,therehave

beennoreportsoflivevirusisolationfrompatientsofPCRretestpositivity.

Importantly,though,pathologicalevidenceoflikelyviableSARS-CoV-2viruswithin

pneumocyteswasrecentlyobtainedfromanindividualwhodiedunexpectedlyfrom

cardiacarrestaftershowingclinicalrecoveryandthreeconsecutivenegativePCR

nasopharyngealswabs.7

Inordertoassistwithpandemicmanagement,abetterunderstandingofthe

recurrenceofSARS-CoV-2andassociatedpotentialinfectivityinthesettingofstrict

quarantineiscritical.Similarly,toassistinmanagingindividuals,settingquarantine

strategiesandadjudicatinglimitedhealthcareresources,predictionmodelsare

neededtobetterdefinetherisk,timing,andrelevanceofviralPCRretestpositivity.

Unansweredquestionsinclude:timebetweennasopharyngealswabtestnegative

andlengthofeffectivequarantine,andhowinfectiousisaninfectedpersonwho

recurredwithPCRpositivityaftertestingnegative.Pragmaticmodelsshouldseekto

definewhenrecoveredpatientscanbeinfectious,includinginthecohortof

individualswhorecurwithPCRpositivityrelativetotestinginterval.Thus,limited

resourcescanbeconcentratedontheisolationofthesepotentialSARS-CoV-2

carriers,withimmediatebenefitsforthepatient,thepopulationandthehealthcare

system.

Thisstudycharacterizesasinglecentercohortofconsecutivepatientswith

COVID-19whowerefollowedafterrecoveryandPCRnegativityandshowntohave

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

8

oneormorerecurrentpositivePCRresultdespitecontinuedquarantine.Theprimary

objectivewastodescribethekineticsofSARS-CoV-2PCRinalargecohortofinfected

individualsandbetterunderstandtherelevanceofrecurrentpositiveresults.The

secondaryobjectivewastodevelopapredictionalgorithmtoidentifypatientsat

highriskoftherecurrentPCRpositivityandprovidepracticaldatathatmayimpact

medicaloperation,healthcarepolicy,andcasemanagement.

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

9

Methods

Studydesignandparticipants

ThestudycohortincludedconsecutiveCOVID-19patientsadmittedtoThe

SecondAffiliatedHospitalofSouthernUniversityofScienceandTechnology,

Shenzhen,ChinasinceJanuary11,2020.ThelastfollowupdatewasApril23,2020.

AlldischargedCOVID-19patientsweresubjectedtostrictquarantineatadesignated

centerfor14days.SARS-CoV-2quantitativereversetranscriptionpolymerasechain

reaction(qRT-PCR)RNAtestingwasperformedevery3to5daysduringboth

hospitalizationandquarantine.Follow-upathomequarantinewasmandatedforan

additional14dayswithweeklySARS-CoV-2qRT-PCRtesting.Uponpositive

nasopharyngealswabtesting,accordingtothelocalhealthpolicy,thesepatients

wereimmediatelyreadmittedbacktothehospital(SupplementaryFigure1).This

studywasapprovedbytheEthicsCommitteeoftheSecondAffiliatedHospitalof

SouthernUniversityofScienceandTechnology.Writteninformedconsentwas

obtainedfromallpatients.

Demographicfeatures,comorbidities,clinicalsymptoms,vitalsigns,laboratory

findingsandtreatmentsduringthefirsthospitalizationwerecollected.Sequentially

fromadmission,nasopharyngealswabtestingwasperformedevery3daysduring

hospitalization.Reportedtreatmentinformationincludesmedicines,intensivecare

unit(ICU)admissions,andrespiratorysupportandventilationusage.

AdmissionanddischargecriteriaofCOVID-19pneumonia

Diagnosis,diseaseseverity,treatmentandfollow-upcriteriaforCOVID-19

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

10

infectionwerebasedonthepreliminarydiagnosisandtreatmentprotocols(6th

edition)fromtheNationalHealthCommissionofChina8.Diagnosticcriteriafor

COVID-19pneumoniaincludedepidemiological(demographicsandcomorbidities)

history,typicalclinicalmanifestations(fever,respiratorysymptoms)andlaboratory

diagnosis.Pulmonaryrespiratorysyndromeseveritywasclassifiedinto4categories:

(1)mild:mildrespiratorysymptoms,noimagingfindingsofpneumonia;(2)

moderate:fever,respiratorysymptoms,imagingfindingsofpneumonia;(3)severe:

shortnessofbreath,respiratoryrate>30breaths/min,systemicoxygensaturation

<93%atrestonroomair,ratioofthesystemicarterialpartialpressureofoxygento

thefractionofoxygenininspiredair≤300mmHg,or>50%progressionofradiologic

pulmonarylesionsover24to48hours;(4)critical:needingmechanicalventilation,

extracorporealmembraneoxygenation,orotherorgansupporttherapyintheICU.

Thedischargecriteriaincluded:beingafebrileforatleastthreedays,resolved

respiratorysymptoms,improvementofradiologicalabnormitiesinCTorX-ray,and

twoconsecutivenegativeSARS-Cov-2qRT-PCRtestssampled>1dayapart.All

patientsweredischargedunderstrictmonitoringconditions:patientswerekeptfor

14daysatadesignatedcenterfollowedbyanother14daysathome,inquarantine,

andalldischargedpatientsweretestedwithrepeatedroutineSARS-CoV-2qRT-PCR

detectionsinnasopharyngealswabsamples.Accordingtothelocalquarantinepolicy,

patientswithapositiveSARS-CoV-2qRT-PCRnasopharyngealtestwereimmediately

readmittedbacktothehospital.

SARS-CoV-2tests

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

11

Earlymorningnasopharyngealswabs(fromJanuary12,2020)andanalswabs

(fromFebruary2,2020)wereanalyzedevery3daysduringthehospitalization,every

3to5daysduringmandatedquarantineatadesignatedcenter,andweeklyduring

quarantineathome.Bronchoalveolarlavagewashingwassampledfrompatients

withsevereillnessorundergoingmechanicalventilation.TotalRNAwasextracted

fromtheclinicalspecimensusingtheQIAampRNAViralKit(Qiagen,Heiden,

Germany).AqRT-PCRTestKit(productcode.GZ-D2RM25,ShanghaiGeneoDx

BiotechCo.,Ltd)targetingtheORF1abandNgenesofSARS-CoV-2wasused.Acycle

threshold(Ct)valuelessthan37wasinterpretedaspositiveforSARS-CoV-2RNA9.

SARS-CoV-2antibodyChemiluminescentmicroparticleimmunoassay(CMIA)kit

(Innodx,Xiamen,China;catalogno.Gxzz20203400198)wasusedtodetect

SARS-CoV-2IgMandIgGinplasma.

Outcome

Patientswhohadapositivenasopharyngealswabtestduringpost-discharge

follow-upandwerereadmittedtohospitalweredefinedas'case'.Patientswhodid

nothavepositiveresultsofnasopharyngealswabtestafterdischargewereanalyzed

as‘control’patients.

StatisticalanalysisandmodellingtopredictrecurrenceofPCRpositivity

Featuresincludingdemographics,comorbidities,symptoms,vitalsigns,

laboratoryfindings,andtreatmentswereassembledformodelling.Univariable

analysiswasperformedonz-score-normalizedfeatures,andlogisticregressionwas

usedtocalculatetheoddsratiosandPvaluesforfeaturefiltering.Formultivariate

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

12

modelbuilding,agradientboostingtreealgorithmXGBoostwasusedfor

constructingamultivariablepredictionmodel10-16.Thebaselinelearneristhe

classificationandregressiontreeandthenumberoftreesisselectedvia

cross-validationtoavoidover-fitting.Thederivedmodelscorerangedfrom0to100

describingtheprobabilityofrecurrenceafterdischarge.Therecurrenceprediction

modelwasevaluatedusingareaunderthereceiver-operating-characteristiccurve

(ROCAUC),sensitivity,andspecificityfromthe10-foldcross-validations.Statistical

analyseswereperformedusingRsoftware(version3.5.1).

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

13

Results

Baselinecharacteristics

Thestudycomprisedatotalof417consecutivepatientsadmittedtothehospital

withCOVID-19whowerecategorizedtohavemild(N=16),moderate(N=309),

severe(N=73),orcritical(N=19)conditionsofpulmonaryrespiratorysyndrome.

Deathoccurred3of417(0.7%)patientsduringinitialhospitalization.Ofthe

remaining414patientsalive,69[16.7%(95CI:13.0%-20.3%),case]patientswere

withrecurrenceofnasopharyngealswabPCRpositivityandhad≥1readmission(s).

Demographics,clinicaldata,PCRdata,andoutcomesfromthefirsthospitalization

aresummarized(Table1,Table2andSupplementaryFigure2).Statistically

significantdifferencesbetweencaseandcontrolpatientswereobservedforpatient

age,bodymassindex,andclinicalseverityofpulmonaryrespiratorysyndrome

duringthefirsthospitalization.Casepatientsweregenerallyyoungerthanthe

controls(Pvalue<0.001).Themajority(93%)ofcasepatientshadmildormoderate

pulmonaryrespiratorysyndromeatthefirstadmission,andhadrespiratory

symptomsincludingcoughandincreasedsputumatthereadmissionofPCR

positivity.Only2ofthe69patients,negativeforothernon-COVID-19infections,

werefebrilewithtypicalclinicalmanifestationssatisfyingthefirstadmissioncriteria.

Patientclinicalhistory:admission,discharge,quarantine,andreadmission

The timeline of clinical events including admission, discharge, quarantine and

readmissionaresummarized(Figure1,casesaredividedintosubgroupsaccordingto

numberofreadmissions;SupplementaryFigure3).Atotalof69patientswerere-test

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

14

positive for SARS-CoV-2 RNAduring the followup period. Themedian time (days)

fromnewonsetof symptomstoeither the firstpositivenasopharyngeal swabPCR

test after admission or PCR test negative after treatment was 3 or 12 days,

respectively.Distributionoftime(days) fromnewonsetofsymptomstoeitherthe

firstpositiveswabtestorthefirstdischargewasanalyzed(SupplementaryFigure3

andSupplementaryFigure4).

The69casepatientshad1(N=53),2(N=13),or3(N=3)readmissionsforpositive

nasopharyngealswabre-tests,mostofwhomhadmild/moderatediseaseduringthe

firstadmission(Figure1).AsofApril23rd,67ofthe69totalcaseshavebeen

dischargedfollowingtwoconsecutivenegativeSARS-CoV-2swabtests,while2

patientsremainedwithintheirsecondhospitalization.Duringthesecondperiodof

post-dischargeobservation,16patientstestedpositiveonceagainforSARS-CoV-2

RNA,indicatingamediantimeof8.5daysfromtestnegativetoretestpositive,

demonstratingashorterinter-episodeperiodthanthefirstrecurrence.Three

patientstestedpositiveforthefourthtimefollowingthreequarantineperiodswitha

mediantimeofonly5.5daysfrompriortestnegativetoretestpositive.

RecurrenceofPCRpositivitywasanalyzedasafunctionoftime(days)between

thefirstnasopharyngealswabtestnegativeduringthefirsthospitalizationandretest

positiveduringthefollowupperiod(Figure2A,median19days,range6-52days).

Withinthecasegroup,70%retestedpositivewithin5-25daysafterthefirstnegative

test,withapeakoccurringat10-15days(22%).

Serologyresultsincaseandcontrolpatients

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

15

Ofnote,asubsetof154patientshadIgG/IgMantibodytestingattheinitial

discharge,amongwhich85and153wereIgGandIgMpositive,respectively.1/154

hadrepeatednegativeantibodytests(N=5)ofbothIgMandIgGagainstSARS-CoV-2.

Thissuggeststhatconvalescentpatients,includingagingpopulations6,mayfailto

developSARS-CoV-2specificIgMandIgG.Ofthe154patientstested,40(100%)of

thecasegroupwereIgGpositive,and30(75%)wereIgMpositive(Figure2Band

SupplementaryFigure5).

PredictingrecurrenceofPCRpositivityatdischarge:modeldevelopmentand

performance

Themodelwasbuiltwith69casesand345controls.Eighteenclinicalfactors

wereselectedbasedonPvaluesandutilizedbytheXGBoostalgorithmforthefinal

model(SupplementaryTable1AandSupplementaryText1).

ThepredictionmodeldisplayedanoverallAUCof0.786basedon10-fold

cross-validation(SupplementaryTable1B).Todeterminetheaccuracyand

demonstratetheutilityofthemodeltopredictafuturerecurrenceofPCRpositivity,

ananalysisof‘daystoPCRpositivity’ofhigh-riskpatientswasunder-taken.This

analysissupportsourhypothesisthatourpredictionisfeasibleandmaygive

actionableinformationatthetimeofthefirstoftheconsecutivenasopharyngeal

swabnegativetestsduringthehospitalization(Figure3)oratthedischargetime

(SupplementaryFigure6).

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

16

Discussion

GiventherapidlyevolvingCOVID-19pandemic,itiscriticaltodevelopan

understandingoftherecurrenceofPCRpositivityrelativetoseverityofclinical

presentationandviralparticledetection.Thecurrentstudyisimportantsincethe

datashowthatasignificantpercentageofinfectedandrecoveredindividualswill

haverecurrentPCRNPswabpositivitydespitestrictquarantine.Toourknowledge,

thisstudyisamongthefirsttoconductacomprehensiveassessmentofPCRkenetics

withregularserialviralRNAtestinginthesettingofstrictquarantine.Wealso

proposeacasefindingmodeltoidentifypatientsathighriskforCOVID-19viral

retestpositivitytoassistinthedeterminationofhealthcaresystemutilizationand

healthpolicyplanning.

The16.7%nasopharyngealswabretestpositiveratehasnotbeenpreviously

reported.Giventhemandatedquarantinefordischargedpatientsatadesignated

centerforaminimumof14daysfollowedbyanother14daysathome(total28days

ofstrictsocialdistancing,shelter-in-place),theobservedoverallrateandmultiple

recurrenceofpositiveviraltestingareunlikelytobefromre-infection.Thiscontrasts

withtherecentlycasereportsinSouthKorea4,5,whereinrecoveredpatientswere

homequarantinedandrecurrenceofPCRpositivitytherecouldhavearisenfrom

eitherdormantvirusreactivationorre-infection.

COVID-19patientswithmultiplerecurrenceofPCRpositivityhavenotbeen

previouslyreported.ThirteenandthreecasesrecurredtwoandthreetimeswithPCR

positivity,respectively,makingitlikelythatthere-emergenceofPCRpositivityisdue

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

17

tocyclingbetweendormancyandreactivationofSARS-CoV-2,and/ortheresurfacing

ofthevirusfromthelowertracttotheuppertractoftherespiratorysystem.

However,itmustbenotedthatthepositiveSARS-CoV-2testdoesnotequatewith

infectivity.SincethecurrentstandardforSARS-CoV-2testpositivityispredicatedon

viralloaddetectionbyPCR6,sampletestinginthecasecohortof<106copiesper

samplemaynotrepresentalivevirusisolate.Unlessequippedwithalivevirus

isolate,wecannotbecertainwhethertheseretestpositivepatientswerecapableof

infectingothers(contagious)giventhattheywerequarantinedatadesignated

center.

Ninety-threepercentoftheretestpositivepatientshadmildormoderate

severitydiseaseduringtheirfirsthospitalization.Noobvioustrendingwasfoundin

thiscaseseriesbetweentheinitialviralloadandfirstadmissionsymptoms,e.g.

temperature(SupplementaryFigure7).Thisisinlinewithapreviousreportthat

describedlackofcorrelationbetweentransmissibilityofCOVID-19and

exceeding-positive-threshold-levelsofSARS-CoV-2sheddingintheupperrespiratory

tract17.Thetworeadmittedfebrilepatientswithtypicalclinicalmanifestations

satisfyingthefirstadmissioncriteriamayhavebeencapableoftransmissiongiven

thepresenceofpositivitywithbothviralloadtestingandCOVID-19admission

symptoms.Thekeyrationaleofthelocalhealthpolicyforimplementingthe

describedstrictcenter-basedquarantineistopreventtransmission.Ourfindings

demonstratethattheeffectivenessofthisquarantinestrategyinthemanagementof

thepandemicmaybecrucialinminimizinglatetransmission.Theyalsoprovide

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

18

insightintothecasemanagementofretestedpositivepatientswithorwithout

typicalCOVID-19symptoms3,17-31andimmunity.

Themodelidentifiedserumconcentrationsofcholinesterase,calcium,andeGFR

aspredictors,andelevationofthethreemarkersassociatedwiththeriskof

recurrenceofPCRpositivity.Previousstudiesfoundthatincreasedlevelsof

cholinesterase,calcium,andeGFRwereassociatedwithmildCOVID-1932-34.Inour

study,mildormoderatepatientsmorelikelytorecurwithPCRpositivitypost

discharge.Thus,theassociationsofthebloodmarkersandcaseoutcomesrevealed

byourmodelappeartobeconsistentwithpreviousfindings.

DeterminingthoseathighestandlowestrisksofrecurrenceofPCRpositivity

maybeanessentialcomponentofanystrategytoenablereadmissions,guide

interventions,preventtransmissions,andoptimizelimitedcareresourceutilization.

Theanalysisdescribedhereinbuildsonourpreviouslyvalidatedmachine-learning

modelstopredicthospitalreadmission35,36todevelopCOVID-19readmissionrisk

predictiontool37.Thealgorithmdescribedhereenablesdifferentcasemanagement

strategiesforvariousriskscorethresholds,andfacilitatestheincorporationof

differentassumptionsabouttheimpactoftheinterventionandquarantine

(SupplementaryFigure1).Atdischarge,thosepatientsflaggedbythealgorithmtobe

athighestriskmayneeddifferentfollow-upordifferentscreeningstrategies.Most

critically,thetimeandtreatment-dependenttrajectorytocompletelycleardormant

and/orliveSARS-CoV-2needstobeestablished.

Thedrivingfactorsforthismodelcanbecollectedinanyinpatientsettings,and

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

19

thereforeitisportableinternationallyforimmediatevalidationtoprovideclinical

utilityinthecurrentCOVID-19pandemic.

Limitations

Thisstudyhasseverallimitations.First,thestudypopulationonlyincluded

COVID-19patientswithinasinglecenterinSouthernChina.Second,theIgM/IgG

testswerenotperformedonallpatientsduetothelateintroductionoftheantibody

test.Thirdly,formodelvalidation,multi-centerprospectiveanalysesonadditional

patientswillberequired.Fourthly,andmostimportantly,the(re)infectiousabilityof

SARS-CoV-2measuredpositivebythenasopharyngealswabtestneedstobe

quantified.Livevirusisolationfromretestpositivepatientsstillrequiresfurther

effortinordertoquantifyriskassociatedwithrecurrenceofPCRpositivityataviral

RNAlevel.

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

20

Conclusions

ThiscaseseriesdemonstratesthatrecurrenceofSARS-CoV-2RNApositivity

followinghospitaldischargeisrelativelycommon,witha16.7%rate.Younger

patientswithlesssevereindexillnessweremorelikelytoretestpositive.More

informationwillberequiredtounderstandtherelevanceofthesefindings,which

willbecriticalforinformingthemanagementofthepandemic.Ourprediction

algorithmtoidentifypatientsathighriskofrecurrenceofPCRpositivitymay

facilitatehealthpolicy.

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

21

ConflictofInterestDisclosures:Theauthorsdeclarethatthereisnoconflictof

interest.

Funding/Support:ThisworkwassupportedbygrantsSZSM201812065from

SanmingProjectofMedicineinShenzhen(JiaHuang);Bill&MelindaGates

Foundations(LeiLiu);and81501651fromNationalNaturalScienceFoundationof

China(JiaHuang).

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

22

References1. SjodinH,Wilder-SmithA,OsmanS,FarooqZ,RocklovJ.Onlystrictquarantinemeasurescan

curbthecoronavirusdisease(COVID-19)outbreakinItaly,2020.EuroSurveill.2020;25(13).

2. ParmetWE,SinhaMS.Covid-19-TheLawandLimitsofQuarantine.NEnglJMed.

2020;382(15):e28.

3. AlizargarJ.Riskofreactivationorreinfectionofnovelcoronavirus(COVID-19).JFormosMed

Assoc.2020.

4. SmithJ.SouthKoreareportsmorerecoveredcoronaviruspatientstestingpositiveagain.

https://www.reuters.com/article/us-health-coronavirus-southkorea/south-korea-reports-mo

re-recovered-coronavirus-patients-testing-positive-again-idUSKCN21V0JQ.Published2020.

Accessed.

5. GstalterM.WHOsaysthere's'noevidence'recoveredcoronaviruspatientswon'tget

reinfected.

https://thehill.com/homenews/news/494628-who-says-theres-no-evidence-recovered-coron

avirus-patients-wont-get.Published2020.Accessed.

6. WolfelR,CormanVM,GuggemosW,etal.Virologicalassessmentofhospitalizedpatients

withCOVID-2019.Nature.2020.

7. YaoXH,HeZC,LiTY,etal.PathologicalevidenceforresidualSARS-CoV-2inpulmonary

tissuesofaready-for-dischargepatient.CellRes.2020.

8. NationalHealthCommissionofthePeople’sRepublicofChinaandNationalAdministrationof

TraditionalChineseMedicine.DiagnosisandTreatmentSchemeforNovelCoronavirus

Pneumonia(Trial).

http://www.nhc.gov.cn/xcs/zhengcwj/202002/8334a8326dd94d329df351d7da8aefc2.shtml.

Published2020.AccessedFeburary19,2020.

9. YangY,YangM,ShenC,etal.Evaluatingtheaccuracyofdifferentrespiratoryspecimensin

thelaboratorydiagnosisandmonitoringtheviralsheddingof2019-nCoVinfections.medRxiv.

2020.

10. GuoY,ZhengG,FuT,etal.AssessingStatewideAll-CauseFutureOne-YearMortality:

ProspectiveStudyWithImplicationsforQualityofLife,ResourceUtilization,andMedical

Futility.JMedInternetRes.2018;20(6):e10311.

11. YeC,FuT,HaoS,etal.PredictionofIncidentHypertensionWithintheNextYear:Prospective

StudyUsingStatewideElectronicHealthRecordsandMachineLearning.JMedInternetRes.

2018;20(1):e22.

12. WangX,ZhangY,HaoS,etal.Predictionofthe1-YearRiskofIncidentLungCancer:

ProspectiveStudyUsingElectronicHealthRecordsfromtheStateofMaine.JMedInternet

Res.2019;21(5):e13260.

13. YeC,WangO,LiuM,etal.AReal-TimeEarlyWarningSystemforMonitoringInpatient

MortalityRisk:ProspectiveStudyUsingElectronicMedicalRecordData.JMedInternetRes.

2019;21(7):e13719.

14. YeC,LiJ,HaoS,etal.Identificationofeldersathigherriskforfallwithstatewideelectronic

healthrecordsandamachinelearningalgorithm.IntJMedInform.2020;137:104105.

15. ZhengL,WangO,HaoS,etal.Developmentofanearly-warningsystemforhigh-riskpatients

forsuicideattemptusingdeeplearningandelectronichealthrecords.TranslPsychiatry.

2020;10(1):72.

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

23

16. HaoS,FuT,WuQ,etal.EstimatingOne-YearRiskofIncidentChronicKidneyDisease:

RetrospectiveDevelopmentandValidationStudyUsingElectronicMedicalRecordDataFrom

theStateofMaine.JMIRMedInform.2017;5(3):e21.

17. GandhiM,YokoeDS,HavlirDV.AsymptomaticTransmission,theAchilles'HeelofCurrent

StrategiestoControlCovid-19.NEnglJMed.2020.

18. AnP,SongP,WangY,LiuB.AsymptomaticPatientswithNovelCoronavirusDisease

(COVID-19).BalkanMedJ.2020.

19. ChengX,LiuJ,LiN,etal.OtolaryngologyProvidersMustBeAlertforPatientswithMildand

AsymptomaticCOVID-19.OtolaryngolHeadNeckSurg.2020:194599820920649.

20. HeD,ZhaoS,LinQ,etal.TherelativetransmissibilityofasymptomaticCOVID-19infections

amongclosecontacts.IntJInfectDis.2020;94:145-147.

21. HuangL,ZhangX,ZhangX,etal.RapidasymptomatictransmissionofCOVID-19duringthe

incubationperioddemonstratingstronginfectivityinaclusterofyoungstersaged16-23

yearsoutsideWuhanandcharacteristicsofyoungpatientswithCOVID-19:Aprospective

contact-tracingstudy.JInfect.2020.

22. LiG,LiW,HeX,CaoY.AsymptomaticandPresymptomaticInfectors:HiddenSourcesof

COVID-19Disease.ClinInfectDis.2020.

23. McGinnisGJ,NingMS,NitschPL,etal.RapidDetectionofAsymptomaticCOVID-19byCT

Image-GuidanceforStereotacticAblativeRadiotherapy.JThoracOncol.2020.

24. MengH,XiongR,HeR,etal.CTimagingandclinicalcourseofasymptomaticcaseswith

COVID-19pneumoniaatadmissioninWuhan,China.JInfect.2020.

25. PangKH,OsmanNI.AsymptomaticCOVID-19infectioninapatientevaluatedforureteric

colic:Radiologicalfindingsandimpactonmanagement.Urology.2020.

26. SamsamiM,ZebarjadiBagherpourJ,NematihonarB,TahmasbiH.COVID-19Pneumoniain

AsymptomaticTraumaPatients;Reportof8Cases.ArchAcadEmergMed.2020;8(1):e46.

27. TeheranAA,CameroG,PradoR,etal.PresumptiveasymptomaticCOVID-19carriers'

estimationandexpectedperson-to-personspreadingamongrepatriatedpassengers

returningfromChina.TravelMedInfectDis.2020:101688.

28. WuZY.[Asymptomaticandpre-symptomaticcasesofCOVID-19contributiontospreading

theepidemicandneedfortargetedcontrolstrategies].ZhonghuaLiuXingBingXueZaZhi.

2020;41(00):E036.

29. YeF,XuS,RongZ,etal.DeliveryofinfectionfromasymptomaticcarriersofCOVID-19ina

familialcluster.IntJInfectDis.2020;94:133-138.

30. YuX,YangR.COVID-19transmissionthroughasymptomaticcarriersisachallengeto

containment.InfluenzaOtherRespirViruses.2020.

31. ZhangJ,WuS,XuL.AsymptomaticcarriersofCOVID-19asaconcernfordiseaseprevention

andcontrol:moretesting,morefollow-up.BiosciTrends.2020.

32. CaoM,ZhangD,WangY,etal.ClinicalFeaturesofPatientsInfectedwiththe2019Novel

Coronavirus(COVID-19)inShanghai,China.medRxiv.2020.

33. XiangJ,WenJ,YuanX,etal.Potentialbiochemicalmarkerstoidentifyseverecasesamong

COVID-19patients.medRxiv.2020.

34. ChengY,LuoR,WangK,etal.Kidneydiseaseisassociatedwithin-hospitaldeathofpatients

withCOVID-19.KidneyInt.2020;97(5):829-838.

35. HaoS,WangY,JinB,etal.Development,ValidationandDeploymentofaRealTime30Day

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

24

HospitalReadmissionRiskAssessmentToolintheMaineHealthcareInformationExchange.

PLoSOne.2015;10(10):e0140271.

36. JinB,ZhaoY,HaoS,etal.Prospectivestratificationofpatientsatriskforemergency

departmentrevisit:resourceutilizationandpopulationmanagementstrategyimplications.

BMCEmergMed.2016;16:10.

37. KansagaraD,EnglanderH,SalanitroA,etal.Riskpredictionmodelsforhospitalreadmission:

asystematicreview.JAMA.2011;306(15):1688-1698.

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

25

Figurelegends

Figure1.Thistimelinesummarizesthemedianduration(days)fromtheonsetof

symptomstoclinicaleventsandrecurrenceofnasopharyngealswabPCRpositivity.

Patientsaregroupedbythenumberof(re)admissions.Clinicaleventsinclude

admission,nasopharyngealswabtestednegative,discharge,andquarantineended

duetoeitherretestpositiveorreleasetohome.

Figure2.Thesecolumnchartsshowthedistributionofpatientsaccordingtothe

duration(days)fromthefirstnegativeconsecutivenasopharyngealswabtesttothe

firstpositiveretestduringstrictpost-dischargequarantine.A)COVID-19patients

withrecurrenceofPCRpositivity(thecasegroup).B)Thesubsetofcasegroup(N=40)

whohadIgMandIgGantibodytestingperformedattheinitialdischarge.Allcase

patientswiththeantibodytestswereIgGpositive.

Figure3.High-riskpatientshadnasopharyngealswabpositiveretestsandwere

readmittedtohospital.TheX-axisindicatesthedurationoftime(days)fromthefirst

negativenasopharyngealswabtesttothefirstpositiveretestduringstrict

post-dischargequarantine.TheY-axisindicatesthepercentageofhigh-riskpatients

whowereretestedpositiveandreadmittedtohospitalwithinthespecifiedduration

oftimeafterthefirstnegativetest.Threethresholdsforhigh-riskpatientswere

applied,givinganoverallsensitivityof93%,81%,and68%,respectively.

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

26

Figure 1.This timelinesummarizes themedianduration (days) fromtheonsetof symptomstoclinical eventsand recurrence of nasopharyngeal swab PCRpositivity. Patients are grouped bythe number of (re)admissions. Clinical events include admission, nasopharyngeal swab testednegative,discharge,andquarantineendedduetoeitherretestpositiveorreleasetohome.

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

27

Figure2.Thesecolumnchartsshowthedistributionofpatientsaccordingtotheduration(days)fromthefirstnegative consecutivenasopharyngeal swabtesttothe first positiveretestduringstrictpost-dischargequarantine.A)COVID-19patientswithrecurrenceofPCRpositivity(thecasegroup).B)Thesubsetofcasegroup(N=40)whohadIgMandIgGantibodytestingperformedattheinitialdischarge.AllcasepatientswiththeantibodytestswereIgGpositive.

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

28

Figure 3.High-risk patientshad nasopharyngeal swab positive retests andwere readmitted tohospital.TheX-axisindicatesthedurationoftime(days)fromthefirstnegativenasopharyngealswabtesttothefirstpositiveretestduringstrictpost-dischargequarantine.TheY-axisindicatesthepercentage of high-risk patients who were retested positive and readmitted tohospitalwithinthe specifieddurationof timeafter the firstnegative test. Three thresholds forhigh-riskpatientswereapplied,givinganoverallsensitivityof93%,81%,and68%,respectively.

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

29

Table 1.Demographicsandbaseline characteristics of COVID-19 patients with (i.e. the casegroup)andwithout(i.e.thecontrolgroup)recurrenceofSARS-CoV-2PCRpositivity.

Characteristics Control,N=345 Case,N=69 Pvalue

Age,n(%)

<0.001

0-29yrs 47(13.6) 23(33)

30-54yrs 164(47.5) 34(49)

55-86yrs 134(38.8) 12(17)

Male,n(%) 167(48.4) 28(41) 0.2

BMI,kg/m2 23.2(21.3,25.6) 21.9(20.0,24.5) 0.03

COVID-19severityat1stadmission,n(%)

0.008

Mild 13(3.8) 3(4)

Moderate 248(71.9) 61(88)

Severe 68(19.7) 5(7)

Critical 16(4.6) 0(0)

Clinicalhistory,n(%)

Hypertension 71(20.6) 14(20) 0.9

Diabetes 31(9.0) 3(4) 0.2

Coronaryheartdisease 25(7.2) 1(1) 0.1

Cancer 6(1.7) 0(0) 0.6

Chroniclungdisease 14(4.1) 2(3) 0.9

Chronicliverdisease 11(3.2) 2(3) 0.9

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

30

Table2.Clinicalcharacteristics,laboratorytests,treatments,andoutcomesofCOVID-19patientswith (i.e. the case group) and without (i.e. the control group) recurrence of SARS-CoV-2 PCRpositivity during the 1sthospitalization.Data are presented in form of n (%) or median (IQR),unlessotherwisestated.Forstatisticalanalyses,theMann-WhitneyUtestwasusedtocomparecontinuous variables and Fisher’s exact test was performed to compare categorical variablesbetweengroups.

Characteristics Control,N=345 Case,N=69 PValue

Symptoms,n(%)

Fever 228(66.1) 43(62) 0.6Cough 33(9.6) 28(41) <0.0001

Sputum 15(4.3) 15(22) <0.0001Dizziness 9(2.6) 3(4) 0.4

Headache 6(1.7) 7(10) 0.002Nasopharyngealsoreness 14(4.1) 9(13) 0.007

Shortnessofbreath 2(0.6) 1(1) 0.9Tightness 9(2.6) 4(6) 0.3

Bloating 2(0.6) 0(0) 0.9Diarrhea 8(2.3) 3(4) 0.4

Fatigue 26(7.5) 8(12) 0.2Chestpain 2(0.6) 1(1) 0.4

Muscleorbodyaches 49(14.2) 2(3) 0.008Chills 5(1.4) 5(7) 0.02

Nauseaandvomiting 3(0.9) 1(1) 0.5Imagingfeature,n(%)

Lungconsolidation 68(19.7) 11(16) 0.5Ground-glassopacity 282(81.7) 60(87) 0.4

Pulmonaryinfiltration 255(73.9) 58(84) 0.2Pleuraleffusion 13(3.8) 2(3) 0.7

MedicationTreatment,n(%) Methylprednisolone 91(26.4) 8(12) 0.006

Immunoglobulin 97(28.1) 8(12) 0.002Tocilizumab 9(2.6) 0(0) 0.2

Oseltamivir 54(15.7) 7(10) 0.3Ribavirin 71(20.6) 9(13) 0.1

Interferon 287(83.2) 54(78) 0.3Lopinavir/Ritonavir 271(78.6) 49(71) 0.2

Arbidol 102(29.6) 11(16) 0.03Favipiravir 32(9.3) 3(4) 0.2

Hydroxychloroquinesulfate 21(6.1) 5(7) 0.9Antibiotics 69(20) 7(10) 0.04

Table2continuesinnextcolumn

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

31

Continuedfrompreviouscolumn

Characteristics Control,N=345 Case,N=69 PValue

Supportingtreatment,n(%)

High-flownasalcannulaoxygentherapy 16(4.6) 1(1) 0.3Non-invasiveventilation 27(7.8) 0(0) 0.02

Invasiveventilation 16(4.6) 0(0) 0.05Extracorporealmembraneoxygenation 2(0.6) 0(0) 0.9

Continuousrenalreplacementtreatment 5(1.4) 0(0) 0.9Bloodroutine,n(%)

Hemoglobin,<13.7g/dL(male) <11.9g/dL(female)

31(9.0) 4(6) 0.5

Totalwhitebloodcellcount

<3.5×109/L 58(16.8) 8(12) 0.4>9.5×109/L 11(3.2) 2(3) 0.9

Lymphocytecount,<1.1×109/L 103(29.9) 12(17) 0.04Neutrophilcount,>6.3×109/L 16(4.6) 2(3) 0.7

Plateletcount,<125×109/L 29(8.4) 8(12) 0.4Bloodbiochemistry,n(%)

Sodium,<135mmol/L 21(6.1) 4(6) 0.9Potassium,<3.5mmol/L 29(8.4) 4(6) 0.6

Urea,>9.5mmol/L 3(0.9) 1(1) 0.5Creatinine,>111,μmol/L 6(1.7) 0(0) 0.6

Albumin,<40g/L 51(14.8) 5(7) 0.1ALT,>45U/L 27(7.8) 6(9) 0.8

AST,>45U/L 36(10.4) 1(1) 0.02Lactatedehydrogenase,>250U/L 113(32.8) 12(17) 0.01

Creatinekinase,>310U/L 7(2.0) 2(3) 0.6Infection-relatedbiomarkers,n(%)

Erythrocytesedimentationrate,>20mm/h 151(43.8) 22(32) 0.08Interleukin6,>7p/mL 97(28.1) 11(16) 0.04

Procalcitonin 0.040.1ng/mL 335(97.1) 61(88)

≥0.1to<0.25ng/mL 10(2.9) 4(6) ≥0.25to≤0.5ng/mL 0(0) 1(1)

>0.5ng/mL 0(0) 1(1) C-reactiveprotein,>8mg/L 151(43.8) 21(30) 0.04

Table2continuesinnextcolumn

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint

32

Continuedfrompreviouscolumn

Characteristics Control,N=345 Case,N=69 PValue

Coagulationfunction,n(%) Prothrombintime,≥16s 3(0.9) 1(1) 0.5

D-dimer 0.5≤0.5μg/mL 265(77.0) 55(80)

>0.5and≤1μg/mL 58(16.8) 8(12) >1μg/mL 22(6.4) 4(6)

SARS-CoV-2antibodyatdischargea 0.23HavingIgG/IgMtested,n 114(33.0) 40(58)

IgGpositive,n(%) 113(99.1) 40(100) IgMpositive,n(%) 55(48.2) 30(75)

ClinicalOutcomes ICUadmission 34(9.9) 0(0) 0.002

Lengthofhospitalization 20(12) 20(12) 0.5aIgG/IgMtestswereperformedatdischargesinceFebruary12,2020.

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2020. ; https://doi.org/10.1101/2020.05.06.20089573doi: medRxiv preprint