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Revista Clínica Española
ORIGINAL ARTICLE
Clinical characteristics of patients hospitalized with COVID-19 in Spain: results from the SEMI-COVID-19 Registry 夽
J.M. Casas-Rojo
a, J.M. Antón-Santos
a,∗, J. Millán-Nú˜ nez-Cortés
b,
C. Lumbreras-Bermejo
c, J.M. Ramos-Rincón
d, E. Roy-Vallejo
e, A. Artero-Mora
f,
F. Arnalich-Fernández
g, J.M. García-Bru˜ nén
h, J.A. Vargas-Nú˜ nez
i, S.J. Freire-Castro
j, L. Manzano-Espinosa
k, I. Perales-Fraile
l, A. Crestelo-Viéitez
m, F. Puchades-Gimeno
n, E. Rodilla-Sala
o, M.N. Solís-Marquínez
p, D. Bonet-Tur
q, M.P. Fidalgo-Moreno
r,
E.M. Fonseca-Aizpuru
s, F.J. Carrasco-Sánchez
t, E. Rabadán-Pejenaute
u, M.
Rubio-Rivas
v, J.D. Torres-Pe˜ na
w, R. Gómez-Huelgas
x,∗, en nombre del Grupo SEMI-COVID-19, Network.
1aServiciodeMedicinaInterna,H.U.InfantaCristina,Parla,Madrid,Spain
bServiciodeMedicinaInterna,H.U.GregorioMara˜nón,Madrid,Spain
cServiciodeMedicinaInterna,H.U.12deOctubre,Madrid,Spain
dDepartamentodeMedicinaClínica,UniversidadMiguelHernández,Elche,Alicante,Spain
eServiciodeMedicinaInterna,H.U.LaPrincesa,Madrid,Spain
fServiciodeMedicinaInterna,H.U.Dr.Peset,Valencia,Spain
gServiciodeMedicinaInterna,H.U.LaPaz,Madrid,Spain
hServiciodeMedicinaInterna,H.U.MiguelServet,Zaragoza,Spain
iServiciodeMedicinaInterna,H.U.PuertadeHierro,Majadahonda,Madrid,Spain
jServiciodeMedicinaInterna,H.U.deACoru˜na,ACoru˜na,Spain
kServiciodeMedicinaInterna,H.U.RamónyCajal,Madrid,Spain
lServiciodeMedicinaInterna,H.U.InfantaSofía,SanSebastiándelosReyes,Madrid,Spain
mServiciodeMedicinaInterna,H.RoyoVillanova,Zaragoza,Spain
nFacultaddeMedicina,UniversidadCatólicadeValencia,Valencia,Spain
oServiciodeMedicinaInterna,H.deSagunto,Sagunto,Valencia,Spain
pServiciodeMedicinaInterna,H.U.SanAgustín,Avilés,Asturias,Spain
qServiciodeMedicinaInterna,H.U.SanJuandeAlicante,SantJoand’Alacant,Alicante,Spain
rServiciodeMedicinaInterna,H.U.delHenares,Madrid,Spain
sServiciodeMedicinaInterna,H.U.deCabue˜nes,Gijón,Asturias,Spain
tServiciodeMedicinaInterna,H.U.JuanRamónJiménez,Huelva,Spain
uServiciodeMedicinaInterna,H.U.SanPedro,Logro˜no,LaRioja,Spain
vServiciodeMedicinaInterna,H.U.deBellvitge,L’HospitaletdeLlobregat,Barcelona,Spain
夽 Pleasecitethisarticleas:Casas-RojoJM,Antón-SantosJM,Millán-Nú˜nez-CortésJ,Lumbreras-BermejoC,Ramos-RincónJM,Roy-Vallejo Eetal..CaracterísticasclínicasdelospacienteshospitalizadosconCOVID-19enEspa˜na:resultadosdelRegistroSEMI-COVID-19.RevClin Esp.2020;220:480---494.
∗Correspondingauthor.
E-mailaddresses:[email protected](J.M.Antón-Santos),[email protected](R.Gómez-Huelgas).
1TheremainingSEMI-COVID-19NetworkGroupmembersarelistedintheannex.
2254-8874/©2020ElsevierEspa˜na,S.L.U.andSociedadEspa˜noladeMedicinaInterna(SEMI).Allrightsreserved.
wServiciodeMedicinaInterna,H.U.ReinaSofía,Córdoba,Spain
xServiciodeMedicinaInterna,H.RegionalUniversitariodeMálaga,Málaga,Spain
Received16July2020;accepted16July2020 Availableonline9September2020
KEYWORDS 2019-nCoV;
SARS-CoV-2;
Coronavirus;
COVID-19;
Spain
Abstract:
Background: SpainhasbeenoneofthecountriesmostaffectedbytheCOVID-19pandemic.
Objective: Tocreate aregistry ofpatients with COVID-19 hospitalizedin Spain inorder to improveourknowledgeoftheclinical,diagnostic,therapeutic,andprognosticaspectsofthis disease.
Design:Amulticenterretrospectivecohortstudythatincludesconsecutivepatientshospital- izedwithconfirmedCOVID-19throughoutSpain.Epidemiologicalandclinicaldata,additional tests atadmissionand atsevendays, treatmentsadministered, andprogress at30 days of hospitalizationwerecollectedfromelectronicmedicalrecords.
Results:UptoJune302020,15,111patientsfrom150hospitalswereincluded.Theirmedian agewas69.4years(range:18---102years)and57.2%weremale.Prevalencesofhypertension, dyslipidemia,anddiabetesmellituswere50.9%,39.7%,and19.4%,respectively.Themostfre- quentsymptomswerefever(84.2%)andcough(73.5%).Highvaluesofferritin(73.5%),lactate dehydrogenase(73.9%), andD-dimer(63.8%)aswellaslymphopenia(52.8%)werefrequent.
Themostusedantiviraldrugswerehydroxychloroquine(85.6%)andlopinavir/ritonavir(61.4%).
33.1%developedrespiratorydistress.Overallmortalityratewas21.0%,withamarkedincrease withage(50-59years:4.7%,60−69years:10.5%,70−79years:26.9%,≥80years:46.0%).
Conclusion: TheSEMI-COVID-19Networkprovidesdataontheclinicalcharacteristicsofpatients withCOVID-19hospitalizedinSpain.PatientswithCOVID-19hospitalizedinSpainaremostly severecases,asoneinthreepatientsdevelopedrespiratorydistressandoneinfivepatients died.Thesefindingsconfirmacloserelationshipbetweenadvancedageandmortality.
© 2020Elsevier Espa˜na, S.L.U.andSociedadEspa˜noladeMedicina Interna(SEMI).Allrights reserved.
PALABRASCLAVE 2019-nCoV;
SARS-CoV-2;
Coronavirus;
COVID-19;
Espa˜na
CaracterísticasclínicasdelospacienteshospitalizadosconCOVID-19enEspa˜na:
resultadosdelRegistroSEMI-COVID-19
Resumen
Antecedentes: Espa˜nahasidounodelospaísesmásafectadosporlapandemiadeCOVID-19.
Objetivo: CrearunregistrodepacienteshospitalizadosenEspa˜naporCOVID-19paramejorar nuestroconocimientosobrelosaspectosclínicos,diagnósticos,terapéuticosypronósticosde estaenfermedad.
Métodos: Estudiodecohorteretrospectiva,multicéntrico,queincluyepacientesconsecutivos hospitalizadosconCOVID-19confirmadaentodaEspa˜na.Seobtuvieronlosdatosepidemiológi- cos yclínicos, laspruebascomplementariasal ingresoyalossietedíasdelaadmisión, los tratamientosadministradosylaevoluciónalos30díasdehospitalizacióndelashistoriasclínicas electrónicas.
Resultados: Hastael30dejuniode2020seincluyeron15.111pacientesde150hospitales.Su medianadeedadfue69,4a˜nos(rango:18-102a˜nos)yel57,2%eranhombres.Lasprevalencias dehipertensión,dislipemiaydiabetesmellitusfueron50,9%,39,7%y19,4%,respectivamente.
Lossíntomasmásfrecuentesfueronfiebre(84,2%)ytos(73,5%).Fueronfrecuenteslosvalores elevadosdeferritina(73,5%),lactatodeshidrogenasa(73,9%)ydímeroD(63,8%),asícomola linfopenia(52,8%).Losfármacosantiviralesmásutilizadosfueronlahidroxicloroquina(85,6%) yellopinavir/ritonavir(61,4%).El33,1%desarrollódistrésrespiratorio.Latasademortalidad globalfuedel21,0%,conunmarcadoincrementoconlaedad(50-59a˜nos:4,7%,60-69a˜nos:
10,5%,70-79a˜nos:26,9%,≥80a˜nos:46%).
Conclusiones:ElRegistroSEMI-COVID-19proporcionainformaciónsobrelascaracterísticasclíni- cas de los pacientes con COVID-19 hospitalizados en Espa˜na. Los pacientes con COVID-19 hospitalizados enEspa˜nasonensumayoríacasosgraves,yaqueunodecadatrespacientes desarrollódistrésrespiratorioyunodecadacincopacientesfalleció.Nuestrosdatosconfirman unaestrecharelaciónentrelaedadavanzadaylamortalidad.
© 2020Elsevier Espa˜na, S.L.U. y SociedadEspa˜nola de Medicina Interna (SEMI). Todos los derechosreservados.
Introduction
Spain is one of the countries withthe highest number of patientswithsevereacuterespiratorysyndromecoronavirus 2(SARS-CoV-2)intheworld.SincethefirstCOVID-19case wasconfirmedinthecountryonJanuary31,2020,253,908 caseshavebeendiagnosedand28,403patientshavediedas ofJuly13,2020.1
Current knowledge about COVID-19 is incomplete and fragmented.Cohort studies fromvarious countries2---7 sug- gestthattheriskfactorsandprognosisofthisdiseasemay notbeabletobeextrapolatedtoothergeographicalareas, asthey couldbeinfluencedby specificpublichealth con- ditions or race-relatedissues. To date, therearenosolid therapeuticrecommendations,astheresultsfromongoing clinical trialsonthe efficacy of antiviraland immunosup- pressantdrugsarepending.8---10
TheSEMI-COVID-19Networkarisesasaninitiativeofthe SpanishSociety ofInternalMedicine(SEMI)toimprovethe quality of treatment for SARS-CoV-2. The main objective oftheregistryistogenerate,inashortperiodof time,a large,multicentercohortwithdetailedinformationonthe epidemiology,clinicalprogress,andtreatmentreceivedby patients.This willallow for the development of prognos- ticmodelsandtheassessment oftheefficacyofdifferent treatmentregimensusedinreal-worldclinicalpractice.
Methods
StudydesignObservationalstudy
TheSEMI-COVIDRegistryisanongoingretrospectivecohort comprisingmostconsecutivepatientswithconfirmedCOVID- 19hospitalizedanddischargedinSpainfromMarch1,2020 uptotheend of thepandemic. InclusionbeganonMarch 24 and is ongoing. Follow-up at one month wasdone via telephone.
Studypopulationandparticipants
AllconsecutivepatientswithconfirmedSARS-COV-2infec- tion who had been discharged or died after hospital admission were eligible for inclusion. COVID-19 was con- firmedeitherbya positiveresultonreal-timepolymerase chainreaction(RT-PCR)testingofanasopharyngealorspu- tumsampleorbyapositiveresultonserologicaltestingand compatibleclinicalpresentation.
Inclusioncriteriafortheregistrywere:a)patientage≥
18years,b)confirmeddiagnosisofCOVID-19,c)firsthospital admissioninaSpanishhospitalparticipatinginthestudy,d) hospitaldischargeorin-hospitaldeath.
Exclusion criteria were subsequent admissions of the samepatientanddenialorwithdrawalofinformedconsent.
Patients were treated at their attending physician’s discretion,accordingtolocalprotocolsandclinicaljudge- ment.Patientsincludedinopen-labelclinicaltrialscouldbe includedintheregistry,providedthatallinformationabout treatment was available. Given its observational nature,
inclusioninthe registryentailednofurtherinconvenience tothepatientsincluded.
Registryinformation
An online electronic data capture system (DCS)has been developed,whichincludes adatabasemanageralongwith procedures for theverification of data andcontrasting of informationagainsttheoriginalmedicalrecordinorderto ensurethebestpossiblequalityofdatacollection.
Patient identifiable data are dissociated and pseudonymized. Direct identifiers are not collected in the DCS,butratheran alphanumericsequence of charac- tersthatincludesacodeforidentificationoftheresearcher and a correlative number is used. Each researcher must maintain a protected registry (patient log) that is for his/her sole use. The purpose of this protected registry is tobeabletoconfirm data withthemedicalrecordsso thatadditionalinformationmaybegathered,ifnecessary, aswell astoperformqualitycontrols. Thissystem allows forpatientprivacytoberespected,ethicalconsiderations tobemet,anddataprotectionregulationstobecomplied with.
Thedatabaseplatform ishostedonasecure server.All informationcontainedinthedatabase,theconfigurationof theinformationwithinthedatabase,aswellasthedatabase itselfarefullyencrypted.Everyclient-serverdatatransfer isencryptedthroughavalidTLScertificate. Dailybackups areperformedinordertoensuredataintegrity.
Datacollection
Data are collected retrospectively and include approxi- mately 300 variablesgrouped under variousheadings: (1) inclusioncriteria,(2)epidemiologicaldata,(3)RT-PCRand serology data, (4) personal medical and medication his- tory, (5) symptoms and physical examination findings at admission, (6) laboratory (blood gases, metabolic panel, complete blood count, coagulation) and diagnostic imag- ingtests,(7)additionaldataatsevendaysafteradmission or at admissiontotheintensive care unit(ICU),(8) phar- macologicaltreatment duringthehospitalization(antiviral drugs,immunomodulators,antibiotics)andventilatorysup- port,(9)complicationsduringthehospitalization,and(10) progress afterdischarge and/or30 daysfromdiagnosis. A listofvariablescanbefoundinAppendixA.
Studymanagement
TheSpanishSocietyofInternalMedicine(SEMI,foritsinitials inSpanish)isthesponsorofthisstudy.Theresearchersthat coordinatethestudyfromeachhospitalareSEMImembers andwereasked toparticipatein thestudyonavoluntary basiswithoutreceivingremuneration.
Database monitoring is performed by the study’s sci- entific steering committee and an independent external agency. Logistics coordination and data analysis are also carriedoutbyexternalindependentagencies.
Fig.1 Geographicaloriginofpatients,byAutonomousCommunity.
Dataanalysis
Participatingpatients’demographic,clinical,epidemiologi- cal,laboratory,anddiagnosticimagingdatawereanalyzed as well as their clinical progress. Quantitative variables areexpressedasmedian[interquartilerange].Categorical variables are expressed as absolute frequencies and per- centages.Mortalityisexpressedascasefatalityrate(CFR).
Ethicalaspects
Personal data are processed in strict compliance with Spanish Law 14/2007, of July 3, on Biomedical Research;
Regulation (EU)2016/679 ofthe EuropeanParliament and oftheCouncilof27April2016ontheprotectionofnatural personswithregardtotheprocessingofpersonaldataand onthefreemovementofsuchdata,andrepealingDirective 95/46/EC(GeneralDataProtectionRegulation);andSpan- ishOrganicLaw3/2018,ofDecember5,ontheProtection ofPersonalDataandtheGuaranteeofDigitalRights.
The SEMI-COVID-19 Registry has been approved by the ProvincialResearchEthicsCommitteeofMalaga(Spain).
In accordance withapplicable regulations, the Spanish Agencyof Medicines andMedical Products(AEMPS,for its initialsinSpanish)hasruledthatduetoitsnature,thestudy onlyrequiredtheapprovaloftheEthicsCommitteeandnot theAutonomousCommunity,asinotherstudies.
Informed consent was obtained from all the patients.
Whenitwasnotpossibletoobtaininformedconsentinwrit- ingduetobiosafetyconcernsorifthepatienthadalready beendischarged,informedconsentwasrequestedverbally andnotedonthemedicalrecord.
The STROBEstatementguidelineswerefollowedin the conductandreportingofthestudy.
Results
AsofJune30,2020,15111patientshospitalizedin150hos- pitalsthroughoutSpainwereincludedintheregistry(Fig.1).
The epidemiological characteristics of population studied aredescribed in Table 1.The medianage was 69.4years (range:18---102 years)and 57.2%were male. Male gender waspredominantinallagerangesexceptforpatients≥90 years,inwhichfemalesaccountedfor56.7%ofthetotal.
A high level of comorbidity was observed (61.4% with moderate or severe Charlson Comorbidity Index scores).
Furthermore, 16.5% of patients had moderate or severe dependencyforactivitiesofdailyliving(Barthelindexscore
<60).The most common comorbidities werehypertension (50.9%),dyslipidemia(39.7%),obesity(21.2%),anddiabetes mellitus(19.4%).
Table2summarizestheclinicalandradiologicalfindings upon admission to the emergency department. The most commonclinical manifestationswerefever (84.2%),cough (73.5%),dyspnea (57.6%), and asthenia(43.6%). Anosmia, dysgeusia,andhyporexiawerelesscommon.Gastrointesti- nalmanifestationswerequitecommon,especiallydiarrhea.
Attriage,only52.1%ofpatientswerefebrileandalmosthalf showedsomedegreeof respiratoryfailure(oxygensatura- tion<90%in17.9%,respiratoryrate>20breathsperminute in31.1%).Lunginvolvementwaslesscommonuponexamina- tionthanintheradiographicfindings:crepitantraleswere present in53.2% of patientswhereas pneumoniaor inter- stitialinfiltrateswereobservedonchestX-raysin86.8%of patients.
Laboratory findings at admission are also shown in Table2.Decreasedlymphocytesandeosinophilcountswere ofnote:themedianvalueswere940and0×106/L,respec- tively. High lactate dehydrogenase (LDH), D-dimer, and ferritinlevels were observed in 73.9%,63.8%, and 73.5%, respectively.
Treatment andcomplicationsduring hospitalizationare summarized in Table 3. A wide variety of drugs with purported antiviral effects have been used, the most frequent of which were hydroxychloroquine (85.6%) and lopinavir/ritonavir (61.4%). Remdesivir was only used in 68patients(0.5%).Antibioticswerealsowidelyindicated, mainly beta-lactam antibiotics (71.7%) and azithromycin
Table1 Demographicandcomorbiditydata.
Variable Absolutefrequency(%).
*Median[Interquartile range]
N
Age(years) 69.4[56.4;79.9]* 15111
18−29 250(1.7%)
30−64 6027(39.9%)
65−79 5096(33.7%)
≥80 3738(24.7%)
Gender 15111
Male 8643(57.2%)
Female 6478(42.8%)
Race/Ethnicity 14889
Caucasian 13437(90.2%)
Other 1452(9.8%)
Healthcareworker 608(4%) 15093
Age-adjustedCharlsonComorbidity Index
14733
Nocomorbidities 1753(11.9%)
Mild 3927(26.7%)
Moderate 4115(27.9%)
Severe 4938(33.5%)
Degreeofdependency 14938
Independentormild 12460(83.4%)
Moderate 1410(9.4%)
Severe 1068(7.1%)
Tobaccouse 14419
Hasneversmoked 9995(69.3%)
Formersmoker 3659(25.4%)
Smoker 765(5.3%)
Alcoholusedisorder 690(4.7%) 14631
Obesity(BMI≥30kg/m2) 2910(21.2%) 13758
Hypertension 7689(50.9%) 15111
Dyslipidemia 5990(39.7%) 15104
Diabetesmellitus 2924(19.4%) 15095
Cancer(solidtumor,leukemia, lymphoma)
1610(10.7%) 15078
Cardiovasculardisease(atrial fibrillation,anginapectoris,heart failure)
3001(19.9%) 15076
Anginapectoris 534(3.5%) 15107
Atrialfibrillation 1687(11.2%) 15095
Heartfailure 1086(7.2%) 15107
Myocardialinfarction 894(5.9%) 15111
Obstructivelungdisease(COPD,asthma) 2071(13.7%) 15091
COPD 1038(6.9%) 15106
Asthma 1098(7.3%) 15101
Obstructivesleepapnea/hypopnea syndrome
903(6.0%) 15038
KnownHIVinfection(withorwithout AIDScriteria)
103(0.7%) 15075
Moderate-severechronickidneydisease 917(6.1%) 15102
(60.8%).Immunomodulatorydrugswerealsocommon,prin- cipally corticosteroids (35.2%), beta-interferon (11.3%), andtocilizumab(8.4%).Low-molecular-weightheparinwas used in 83.4% of patients, generally at prophylactic doses.
Manypatientsrequiredsupport:highflownasalcannula wasusedin8.0%ofpatients,noninvasivepositive-pressure ventilationin 4.9%,andinvasivemechanicalventilation in 6.6%.Themaincomplicationwasacuterespiratorydistress syndrome(ARDS), which33.1% ofpatientsdeveloped, fol-
Table2 Clinical,laboratory,anddiagnosticimagingfindingsuponadmission.
Variable Absolutefrequency(%).
*Median[Interquartile range]
N
Clinicalpresentation
Feverorlow-gradefever 15081
None 2388(15.8%)
Low-gradefever(<38◦C) 3131(20.8%)
Fever(>=38◦C) 9562(63.4%)
Cough 15079
No 3997(26.5%)
Yes,dry 8751(58%)
Yes,withexpectoration 2331(15.5%)
Fatigue 6507(43.6%) 14915
Diarrhea 3554(23.7%) 14991
Anorexia 2915(19.6%) 14845
Shortnessofbreath 8684(57.6%) 15067
Anosmia 1040(7.1%) 14710
PhysicalExamination
Oxygensaturation(pulseoximetry,%) 94[91;97] 14705
<90 2628(17.9%)
≥90 12077(82.1%)
Oxygensaturation/FiO2ratio(%) 442.9[404.8;457.1]* 14411
Temperature,oC 37[36.3;37.8]* 14646
<37◦C 7026(48%)
37-37.9◦C 4520(30.9%)
≥38◦C 3100(21.2%)
Hypotension(systolicbloodpressure<100mmHg) 907(6.3%) 14464
Tachycardia(>100beatsperminute) 3751(24.8%) 15140
Tachypnea(>20breathsperminute) 4590(31.1%) 14769
Confusion 1803(12%) 14992
Crackles 7854(53.2%) 14754
Chestx-ray 14949
Nopulmonaryinfiltrates 1973(13.2%)
Unilateralpulmonaryinfiltrates 3058(20.5%)
Bilateralpulmonaryinfiltrates 9918(66.3%)
Completebloodcount
Whitebloodcellcount,(x106/L) 6300[4780;8520]* 15015
Absolutecount(x106/L)
Neutrophils 4600[3200;6700]* 14944
Lymphocytes 940[690;1300]* 14990
>1200 4818(32.1%)
1000-1200 2249(15%)
800-1000 2729(18.2%)
<800 5194(34.6%)
Eosinophils 0[0;20]* 14786
Monocytes 400[300;600]* 14866
Hemoglobin(g/dL) 13.9[12.6;15]* 15016
Platelets(x106/L) 190000[148000;247000]
*
15012
ArterialBloodGases
pH 7.5[7.4;7.5]* 7764
PCO2(mmHg) 34[30.7;39]* 7851
PO2(mmHg) 66[56;77.6]* 7509
pO2/FiO2ratio(%) 288.6[233.3;342.9]* 7203
Basicmetabolicpanel
Glucose(mg/dL) 112[98;136]* 14547
Serumcreatinine(mg/dL) 0.9[0.7;1.2]* 14977
Urea(mg/dL) 37[27;55]* 12095
Table2(Continued)
Variable Absolutefrequency(%).
*Median[Interquartile range]
N
Lactatedehydrogenase(U/L) 321[246;432]* 13053
<250 3410(26.1%)
250-400 5634(43.2%)
>400 4009(30.7%)
Aspartateaminotransferase(U/L) 35[25;52]* 11974
Alanineaminotransferase(U/L) 29[19;46]* 14145
C-reactiveprotein(mg/L) 60.2[19;127.9]* 14483
Lactate(mmol/L) 1.6[1.1;2.4]* 6824
Procalcitonin(ng/mL) 0.1[0.1;0.2]* 7159
Interleukin-6(IL-6)(pg/mL) 29.8[11.5;65.4]* 1993
D-dimer(ng/mL) 11749
<500 4251(36.2%)
500-1000 3610(30.7%)
>1000 3888(33.1%)
Serumferritin(g/L) 5978
<300 1584(26.5%)
300-650 1583(26.5%)
>650 2811(47%)
qSOFAindex 0[0;1]* 14129
Lowrisk≥1 12817(90.7%)
Highrisk≥2 1312(9.3%)
lowed by bacterial pneumonia and sepsis. Although 2680 patients developed severe ARDS, only 1255 (8.3%) were transferredtoanintensivecareunit.
Themedianfollow-upperiodwas40days(range:0---102 days).Attheendoffollow-up,78.8%hadbeendischarged, 21.0%haddied,and0.2%continuedhospitalized(afterread- mission).Theaveragelengthofhospitalstayfordischarged patientswas10.4days(range:1---62days).Therateofread- missionwithin30dayswas3.9%(573patients).
Discussion
Inthis study,we analyze a large seriesof patients hospi- talizedwithCOVID-19inSpain whohave beenincluded in theSEMI-COVID-19Registry.This firstcohortincludes con- secutive patients admitted to hospitals throughout Spain whowere dischargedor died. Similartoalmost allWest- ernseries,ourpatientswerepredominantlymale,elderly, andwithmultiplecomorbidities.
Recently,thefirstconclusionsabouttheimpactofCOVID- 19inMadrid,theepicenterofthepandemicinSpain,were drawnfromalargecohortof2226patientsfromLaPazUni- versityHospitalofMadrid.11Thestrengthsandweaknesses ofthis study both arise fromitssingle-centerdesign: the dataaremoreconsistentandabletobeanalyzed,butare also less able to be extrapolated to the general popula- tionandpronetolocalbiases,suchasdifferentpopulation demographicsorfeaturesspecifictothatparticularhospi- tal.
Ourserieshasahigherproportionofmales,ashasbeen describedinmostmulticentercohortsandcontrarytothe workbyBorobiaetal.11 The higherproportionoffemales
atLaPazUniversityHospitalmaybearesultofthespecific demographicfeaturesofitsreferencepopulation andthus doesnotreflectthedifferencesaccordingtosexpreviously describedinotherviralinfectionsingeneralandspecifically inCOVID-19.
In addition, our cohort includes older patients with a greaternumberofcomorbidities.Inourseries,themedian age was69years(61 inMadridcohort11), whichis clearly higherthanGuanetal.’sChineseseries,4moderatelyhigher than Richardson etal.’s NewYork series,7 and lowerthan Dochertyetal.’sUKseries.8Themostfrequentcomorbidi- ties(hypertension,diabetes,obesity,dementia,andothers) are similartothose thathave been previously described, butallweremoreprevalentamongourpatients.Theyare summarizedinTable4.
Inourcohort,themainsymptomsreporteduponadmis- sion (fever, cough, dyspnea, and asthenia) were similar to those reported in other studies,4---8 although myalgia andanosmia werelesscommon.This couldpotentially be explained by a difference in admission criteria: patients without lung involvement were managed as outpatients fromemergencydepartmentsand,therefore,onlythemost severecaseswereadmitted.
Inourseries,mortality, asdefined byCFR,wassimilar towhatwasobservedintheMadridcohort,11someChinese series,2---6 andtheUSA cohort,7 but wasmuchhigher than theItaliancohort9andlowerthanwhathasbeendescribed intheUK.8
ThedifferencebetweenourseriesandtheItalianseries warrantssomeexplanation,aswesharemanydemographic features withItaly and the timing and magnitude of the COVID-19 pandemic have been similar. The difference in
Table3 Treatmentandcomplicationsduringhospitalization.
Variable Absolutefrequency(%) N
Antimicrobialtherapy
Hydroxychloroquine 12915(85.6%) 15084
Lopinavir/Ritonavir(LPV/r) 9254(61.4%) 15072
Azithromycin 9146(60.8%) 15036
Beta-lactamantibiotics 10795(71.7%) 15050
Remdesivir 68(0.5%) 14968
Immunomodulatorytherapy
Systemiccorticosteroids 5287(35.2%) 15034
InterferonBeta-1B(IFNb) 1689(11.3%) 15008
Tocilizumab 1276(8.5%) 15038
Anakinra 91(0.6%) 14939
Immunoglobulin 70(0.5%) 14821
Ventilatorysupport
Highflownasalcannula 1197(8.0%) 14989
Invasivemechanicalventilation(IMV) 998(6.6%) 15057
Non-invasivemechanicalventilation(NIMV) 733(4.9%) 15051
Anticoagulanttherapy
Low-molecular-weightheparinduringhospitalization 15016
No 2645(17.6%)
Low(prophylactic)dose 9713(64.7%)
High(anticoagulant)dose 1648(11%)
Intermediatedose 1010(6.7%)
Complications
Acuterespiratorydistresssyndrome(ARDS) 15057
No 10077(66.9%)
Mild 1203(8.0%)
Moderate 1097(7.3%)
Severe 2680(17.8%)
Bacterialpneumonia 1680(11.1%) 15075
Sepsis 937(6.2%) 15080
IntensiveCareUnitadmission 1255(8.3%) 15129
Outcome
Discharge 11928(78.8%) 15140
Death 3181(21.0%) 15140
Readmission 573(3.9%) 14709
Notdischargedattheendoffollow-up(afterreadmission) 31(0.2%) 15140
mortality may reflect differentstudy inclusion criteriaor differenthospital admissioncriteria. Lessstrict admission or inclusion criteria yield a greater number of patients included in the registry, thus lowering the CFR. Indeed, population-basedstudies,whichincludemorepatientswith milder disease, have lower CFRs than hospital-centered series.9Conversely, stricter admissionor inclusioncriteria leadtogreaterseverityamongthepatientsanalyzedandan increaseintheCFR.
Another explanation couldbe that theseobservational works could not control for factors related to race, includingthe percentage and origin of immigrantpopula- tions or healthcare-system disparities. In fact, racial and demographic factors may in part explain the differences in severity and mortality between Chinese and Western series.2---8
Demographicfactors,suchasageorcomorbidities,may partiallyexplainthedifferencesinmortalityandcanbecon- trolledforbymeansofmultivariateanalysis.Pressureonthe
healthcaresystemcanresultindifferentmortalityrates,as wasshowninChinabyLiangetal.,12whocomparedtheCFR bothwithinandoutsideofHubeiprovince(CFRof7.3%vs.
0.3%,respectively).
InItaly,9 thepandemicplacedthegreatestpressureon theregionofLombardywhereasinSpain,ithasbeenmore widelydistributed. Nevertheless, themajority of patients inourseriesarefromhospitalsinMadrid,whichhasbeen oneof themost affectedregions andwhere thesituation iscomparabletothatofnorthernItaly.Whetherthereisa geographicalinfluencewillbefurtherexploredinadditional studies.
As has been shown in all series, a high percentage of patientshadabnormallaboratory valuesthatwereconsis- tentwithanabnormalinflammatoryprofile.2---8Inourseries, lymphopeniaandelevatedlevelsofD-dimer,LDH,andfer- ritinwerethemostfrequentfindings.Also,alargepartof ourpatientsreceivedtreatmentthathaspurportedantivi- ralactivityagainstSARS-CoV-2.Ourmulticenterregistryhas
J.M.Casas-Rojoetal.
Table4 ComparisonofbaselinecharacteristicsandoutcomeofpatientswithCOVID-19includedinseriesfromdifferentcountries.
Guanetal.4 Zhouetal.6 Docherty etal.8
Onderetal.9 Richardsonetal.7 Borobiaetal.11 SEMI-COVID-19
City/Country/Typeof study
Wuhan/ China/ multicenter cohort
Wuhan/ China/ multicenter cohort
UK/ multicenter cohort
Italy/ItalianNational InstituteofHealth
NewYork/USA/ multicentercohort
Spain/single-center cohort
Spain/multicenter cohort
Numberofcases 1099 191 20133 22512 5700 2226 15111
Medianageinyears [IQR]
47[35-58] 56(46-67) 73[58-82] --- 63[52-75] 61[46---78] 69.4
[56.4-79.9]
Malesex 58.1% 62.0% 59.9% --- 60.3% 48.2% 57.2%
Comorbidity
Hypertension 15.0% 30.0% --- 56.0% 41.3% 50.9%
Obesity --- --- 10.5% --- 41.7% 10.9% 21.2%
Diabetes 7.4% 19.0% 24.6% --- 33.8% 17.1% 19.4%
Abnormalchestx-ray 59.0% 59%-75% --- --- --- --- 86.8%
Clinicaloutcomes AcuteRespiratory DistressSyndrome
3.4% 31.0% --- --- --- 4.9% 33.1%
ICUadmission 5.0% 26.0% 17.0% --- 12.2% 10.6% 8.3%
Mortality 1.4% 28.3% 26.0% 7.2% 21.0% 20.7% 21.0%
Mortalitybyagegroup (years)
No(%) CFR% No(%) CFR% No(%) CFR% No(%) CFR%
<30 --- --- --- 0 0 97(3.7) 4.1% 1(0.2) 0.6% 7(0.2) 2.8%
30-39 --- --- --- 4(0.3) 0.3 211(8.1) 3.8% 0(0.0) 0.0% 7(0.2) 1.0%
40-49 --- --- --- 10(0.6) 0.4 353(13.5) 6.2% 4(0.9) 1.5% 38(1.2) 2.6%
50-59 --- --- --- 43(2.7) 1.0 515(19.8) 10.3% 14(3.0) 3.8% 114(3.6) 4.7%
60-69 --- --- --- 139(8.6) 3.5 533(20.5) 15.8% 36(7.8) 11.0% 311(9.8) 10.5%
70-79 --- --- --- 578(25.6) 12.8 451(17.3) 32.1% 122(26.5) 34.1% 975(30.7) 26.9%
≥80 --- --- 850(52.3) 20.2 441(16.9) 53.7% 283(61.5) 55.4% 1719(54.2) 46.0%
IQR:interquartilerange;ICU:intensivecareunit;CFR%:casefatalityratepercentage:SEMI:SpanishSocietyofInternalMedicine.
beendesignedtoallowformultivariateanalysisoftheprog- nosticvalueoftheseabnormallaboratoryfindingsaswellas treatmentreceivedduringhospitalization.
Notably,inourseries,therewasamuchhigherproportion ofpatientswithARDS (moderateorsevere: 25.1%or3777 patients)thanpatientswhowereadmittedtoanICU(8.3%, 1255 patients).This suggeststhat only approximatelyone outofeverythreepatientswithARDSwasadmittedtoan ICU.
Wehavediscussedthisfindingindetailandhaveevalu- atedsomepossibleconfoundingfactorsandbiases.Onthe onehand,patientsadmitteddirectlytoanICUorwhodied in an ICU may have notbeen included in our cohort and thusalteredourICUadmissionrate.Patientswhohavestill notbeendischargedhavenotbeenincludedinourcohort.
Therefore, patients whoare currently hospitalizedin the ICUthusalsofalselylowerourICUadmissionrate.Patients withARDSmayhavediedbeforebeingtransferredtoanICU orhavepresentedwithcriteriathatisnotcompatiblewith treatment in an ICU, but evenstill, this does not explain how 2522 out of 3777 patients with moderate or severe ARDSweredischargedwithouthavingbeenadmittedtoan ICU.
Anotherplausibleexplanationcouldbetheoverloadingof thehealthcaresystem,atleastinthemostaffectedregions of the country. It is known that the number of ICU beds hasincreasedsubstantiallyduringtheCOVID-19pandemicin Spain.Itislikelythatinadditiontoincreasingthenumberof ICUbeds,somesemi-intensivecareareaswereestablished withinhospitals.Inourpersonalexperience,manyhospitals have designed ‘‘semi-intensive’’ or ‘‘intermediate care’’
wards in orderto provide ventilatory support topatients when ICU expansion was no longer feasible. This finding warrantsfurtherexamination.
The collaborative effortof the SEMI-COVID-19Network Group has provided us witha large amount of data from a sizeable number of patients. Among the strengths of our registry are its multicenter design; its wide geo- graphical dispersion, which limits local biases (selection, admission, treatment availability, ICU availability, etc.) and increases its external validity; and its large size, which provides statistical power for confirming hypothe- ses.
Thisstudyalsohaslimitations.First,dataarecollected by a large number of researchers fromdifferent centers, whichcouldleadtoheterogeneityindatacollectionandval- idation.Second,theregistryincludes consecutivepatients from participating centers, which limitspatient selection bias but introduces another selection bias according to participating centers. Third, our registry, though exten- sive(morethan300variables),collectsonlybasicdatafor enhancingourknowledgeofCOVID-19,butlacksthelevelof detailrequiredfordeeperanalysisofveryspecificaspects.
Lastly,themainlimitationofthisstudyisitsobservational design, which does not allow for establishing causalrela- tionships.
Thisisthelargestreportedseriesofhospitalizedpatients in Spain withconfirmed COVID-19 disease and one of the largestregistriesintheworldtodate.Thoughourfindings arecurrentlypreliminaryandmustbeexploredingreater
detail,theSEMI-COVID-19Network working groupandthe SEMI-COVID-19 Registrywill surely become a key tool for helpingcliniciansandresearchersimproveknowledgeofthis novel disease which has threatened not only the lives of manypatientsandtheproperfunctioningofourhealthcare systems,butalsothefoundationsofoureconomyandway oflife.
Funding information
TheSpanishSocietyofInternalMedicine(SEMI,foritsinitials inSpanish)is the sponsorof thisstudy.This work hasnot receivedanyspecific fundingfrompublic,commercial, or non-profitentities.
Conflicts of interest disclosure
Theauthorsdeclarethattherearenoconflictsofinterest.
Acknowledgements
Wewholeheartedlythankalltheinvestigatorswhopartic- ipateintheSEMI-COVID-19Network Group.Wealsothank theSEMI-COVID-19RegistryCoordinationCenter,S&HMedi- calScienceService,fortheirdataqualitycontrolandlogistic andadministrativesupport.
Anexo. List of the SEMI-COVID-19 Network members
Coordinator of the SEMI-COVID-19 Registry: José Manuel CasasRojo.
SEMI-COVID-19 Scientific Committee Members: José ManuelCasasRojo,JoséManuelRamosRincón,CarlosLum- breras Bermejo, Jesús Millán Nú˜nez-Cortés, Juan Miguel AntónSantos,RicardoGómezHuelgas.
SEMI-COVID-19 Registry Coordinating Center: S & H MedicalScienceService.
MembersoftheSEMI-COVID-19Group:
H. U. 12 deOctubre. Madrid.Paloma Agudode Blas, CoralArévaloCa˜nas,BlancaAyuso,JoséBascu˜nanaMorejón, Samara Campos Escudero, María Carnevali Frías, Santi- ago Cossío Tejido, Borja de Miguel Campo, Carmen Díaz Pedroche, Raquel Díaz Simón, Ana García Reyne, Lucia JorgeHuerta,AntonioLaluezaBlanco,JaimeLaureiroGon- zalo,Carlos Lumbreras Bermejo,Guillermo Maestro de la Calle, BárbaraOtero Perpi˜na, Diana ParedesRuiz, Marcos Sánchez Fernández, Javier Tejada Montes. H. U. Grego- rioMara˜nón.Madrid.LauraAbarcaCasas,ÁlvaroAlejandre deO˜na,RubénAlonsoBeato,LeyreAlonsoGonzalo,Jaime Alonso Mu˜noz, Christian Mario Amodeo Oblitas, Cristina AusínGarcía,MartaBaceteCebrián,JesúsBaltasarCorral, MaríaBarrientosGuerrero,AlejandroBendalaEstrada,María CalderónMoreno,PaulaCarrascosaFernández,RaquelCar- rillo,SabelaCasta˜nedaPérez,EvaCervillaMu˜noz,Agustín Diego Chacón Moreno, María Carmen Cuenca Carvajal, Sergio de Santos, Andrés Enríquez Gómez, Eduardo Fer- nándezCarracedo,MaríaMercedesFerreiro-MazónJenaro,
Francisco Galeano Valle, Alejandra García, Irene Gar- cía Fernández-Bravo, María Eugenia García Leoni, María Gómez Antúnez, Candela González San Narciso, Anthony AlexanderGurjian,LorenaJiménezIbá˜nez,CristinaLavilla Olleros,CristinaLlamazaresMendo,SaraLuisGarcía,Víctor Mato Jimeno, Clara Millán Nohales, Jesús Millán Nú˜nez- Cortés, Sergio Moragón Ledesma, Antonio Mui˜no Miguez, CeciliaMu˜nozDelgado,LucíaOrdieresOrtega,SusanaPardo Sánchez,Alejandro Parra Virto, María Teresa Pérez Sanz, Blanca Pinilla Llorente, Sandra Piqueras Ruiz, Guillermo SoriaFernández-Llamazares,MaríaToledanoMacías,Neera Toledo Samaniego, Ana Torres do Rego, María Victoria VillalbaGarcía,GraciaVillarreal,MaríaZuritaEtayo.H.Uni- versitaride Bellvitge. L’Hospitalet de Llobregat. Xavier Corbella,AbelardoMontero,José MaríaMora-Luján. C.H.
U. de Albacete. Albacete. José Luis Beato Pérez, María LourdesSáezMéndez.H.U.LaPaz-Cantoblanco-CarlosIII.
Madrid.JorgeÁlvarezTroncoso,FranciscoArnalichFernán- dez, FranciscoBlanco Quintana, Carmen Busca Arenzana, SergioCarrascoMolina,AranzazuCastellanoCandalija,Ger- mán Daroca Bengoa, Alejandro de Gea Grela, Alicia de LorenzoHernández,AlejandroDíezVidal,CarmenFernán- dezCapitán,MaríaFranciscaGarcíaIglesias,BorjaGonzález Mu˜noz, Carmen Rosario Herrero Gil, Juan María Herrero Martínez, Víctor Honta˜nón, María Jesús Jaras Hernández, Carlos Lahoz, Cristina Marcelo Calvo, Juan Carlos Martín Gutiérrez,MónicaMartínez Prieto,Elena Martínez Robles, AraceliMenéndezSalda˜na,AlbertoMorenoFernández,José María Mostaza Prieto, Ana Noblejas Mozo, Carlos Manuel O˜noro López, Esmeralda Palmier Peláez, Marina Palomar Pampyn,MaríaAngustiasQuesadaSimón,JuanCarlosRamos Ramos,LuisRamosRuperto,AquilinoSánchezPurificación, TeresaSanchoBueso,RaquelSorriguietaTorre,ClaraItziar SotoAbanedes,YerayUntoriaTabares,MartaVarasMayoral, Julia Vásquez Manau. Complejo Asistencial de Segovia.
Segovia. Eva María Ferreira Pasos, Daniel Monge Monge, AlbaVarelaGarcía.H.U.PuertadeHierro.Majadahonda.
Madrid. María Álvarez Bello, Ane Andrés Eisenhofer, Ana Arias Milla, Isolina Ba˜nos Pérez, Javier Bilbao Garay, Sil- viaBlancoAlonso,JorgeCalderónParra,AlejandroCallejas Díaz,JoséMaríaCaminoSalvador,MaCruzCarre˜noHernán- dez, Valentín Cuervas-Mons Martínez, Sara de la Fuente Moral,MigueldelPino Jiménez,AlbertoDíazdeSantiago, ItziarDiegoYagüe,IgnacioDonateVelasco,AnaMaríaDuca, Pedro Durán del Campo,Gabriela Escudero López, Esther Expósito Palomo, Ana Fernández Cruz, Esther Fiz Benito, AndreaFraile López, AmyGalánGómez, SoniaGarcíaPri- eto,ClaudiaGarcíaRodríguez-Maimón,MiguelÁngelGarcía Viejo,JavierGómezIrusta,EdithVanessaGutiérrezAbreu, Isabel Gutiérrez Martín, Ángela Gutiérrez Rojas, Andrea GutiérrezVillanueva,JesúsHerráizJiménez,PedroLaguna delEstal, Ma Carmen Máinez Sáiz, Cristina Martín Martín, MaríaMartínezUrbistondo,FernandoMartínezVera,Susana MellorPita,PatriciaMillsSánchez,EstherMonteroHernán- dez, AlbertoMora Vargas, Cristina Moreno López, Alfonso Ángel-MorenoMaroto,VíctorMoreno-TorresConcha,Ignacio MorrásDeLaTorre,ElenaMú˜nezRubio,AnaMu˜nozGómez, RosaMu˜nozdeBenito,AlejandroMu˜nozSerrano,JoséMaría PalauFayós,IlduaraPintosPascual,AntonioRamosMartínez,
Isabel Redondo Cánovas del Castillo,Alberto Roldán Mon- taud,LucíaRomero Imaz,Yolanda RomeroPizarro,Mónica Sánchez Santiuste, David Sánchez Ortiz, Enrique Sánchez Chica,PatriciaSerranodelaFuente,PabloTutordeUreta, Ángela Valencia Alijo, Mercedes Valentín-Pastrana Aguilar, Juan Antonio Vargas Nú˜nez,José ManuelVázquez Comen- dador,GemaVázquezContreras,CarmenVizosoGálvez.H.
MiguelServet.Zaragoza.GonzaloAcebesRepiso,UxuaAsín Samper, María Aranzazu Caudevilla Martínez, José Miguel García Bru˜nén, Rosa García Fenoll, Jesús Javier González Igual,LauraLetonaGiménez, MónicaLlorenteBarrio,Luis Sáez Comet. H. U. La Princesa. Madrid. María Aguil- era García, EsterAlonso Monge, Jesús Álvarez Rodríguez, ClaudiaÁlvarezVarela, MiquelBernizGòdia,Marta Briega Molina,MartaBustamanteVega,JoséCurbelo,Aliciadelas Heras Moreno, Ignacio Descalzo Godoy, Alexia Constanza Espi˜no Álvarez, Ignacio Fernández Martín-Caro, Alejan- dra Franquet López-Mosteiro, Gonzalo Gálvez Márquez, María J. García Blanco, Yaiza García del Álamo Hernán- dez, Clara García-Rayo Encina, Noemí Gilabert González, CarolinaGuillamoRodríguez,NicolásLabradorSanMartín, Manuel MolinaBáez, Carmen Mu˜nozDelgado, Pedro Parra Caballero, Javier Pérez Serrano, Laura Rabes Rodríguez, PabloRodríguezCortés,CarlosRodríguezFranco,EmiliaRoy- Vallejo, MónicaRuedaVega, AresioSancha Lloret,Beatriz SánchezMoreno,MartaSanzAlba,JorgeSerranoBallester, Alba Somovilla, Carmen SuarezFernández, Macarena Var- gas Tirado, Almudena Villa Martí. H. U. de A Coru˜na. A Coru˜na.AliciaAlonsoÁlvarez,OlayaAlonsoJuarros,Ariadna Arévalo López, Carmen Casariego Casti˜neira,Ana Cereza- les Calvi˜no, Marta Contreras Sánchez, Ramón Fernández Varela, Santiago J. Freire Castro, Ana PadínTrigo, Rafael PrietoJarel,FátimaRaadVarea,LauraRamosAlonso,Fran- cisco Javier Sanmartín Pensado, David Vieito Porto. H.
ClínicoSanCarlos.Madrid.InésArmenterosYeguas,Javier Aza˜naGómez,JuliaBarradoCuchillo,IreneBurruezoLópez, NoemíCabelloClotet,AlbertoE.CalvoElías,ElpidioCalvo Manuel, Carmen María Cano de Luque, Cynthia Chocron Benbunan, Laura Dans Vilan, Ester Emilia Dubon Peralta, Vicente Estrada Pérez,Santiago Fernández-Castelao,Mar- cosOliverFragielSaavedra,JoséLuisGarcíaKlepzig,Maria del Rosario Iguarán Bermúdez, Esther Jaén Ferrer, Rubén Ángel Martín Sánchez, Manuel Méndez Bailón, Maria José Nu˜nez Orantos, Carolina Olmos Mata, Eva Orviz García, David Oteo Mata, Cristina Outon González, Juncal Pérez- Somarriba,PabloPérezMateos,MariaEstherRamosMu˜noz, Xabier Rivas Regaira, I˜nigo Sagastagoitia Fornie, Alejan- droSalinasBotrán,MiguelSuárezRobles,MaddalenaElena Urbano, MiguelVillarMartínez. H. InfantaSofía. S.S.de los Reyes. Madrid. Rafael del Castillo Cantero, Rebeca FuerteMartínez,Arturo Mu˜nozBlanco,JoséFranciscoPas- cual Pareja, Isabel Perales Fraile, Isabel Rábago Lorite, Llanos Soler Rangel, Inés Suárez García, José Luis Valle López. H. U. Dr. Peset. Valencia. Juan Alberto Aguilera Ayllón,ArturoArteroMora,MaríadelMarCarmonaMartín, MaríaJoséFabiáValls,MaríadeMarFernándezGarcés,Ana BelénGómezBelda,IanLópezCruz,ManuelMadrazoLópez, Elisabeth Mateo Sanchís, Jaume Micó Gandía, LauraPiles Roger, Adela María Pina Belmonte, Alba Viana García. H.
Clínico de Santiago. Santiago de Compostela. María del Carmen Beceiro Abad, María AuroraFreire Romero, Sonia Molinos Castro, Emilio Manuel Páez Guillan, María Pazo Nú˜nez,PaulaMaríaPesqueiraFontán.H.U.RamónyCajal.
Madrid. Luis Fernando Abrego Vaca, Ana Andréu Arnanz, Octavio Arce García, Marta Bajo González, Pablo Borque Sanz,AlbertoCozarLlisto,SoniadePedroBaena,BeatrizDel HoyoCuenda,MaríaAlejandraGamboaOsorio,IsabelGar- cíaSánchez,AndrésGonzálezGarcía,Oscar AlbertoLópez Cisneros, Miguel Martínez Lacalzada, Borja Merino Ortiz, JimenaRey-García, ElisaRieraGonzález, CristinaSánchez Díaz, Grisell Starita Fajardo, Cecilia Suárez Caranto˜na, AdriánViteriNoel,SvetlanaZhilinaZhilina.C.Asistencialde Zamora.Zamora.CarlosAldasoroFrías,LuisArribasPérez, MaríaEsther Fraile Villarejo, BeatrizGarcía López,Víctor Madrid Romero, Emilia Martínez Velado, Victoria Palomar Calvo,SaraPintosOtero,CarlotaTu˜nóndeAlmeida.H.Royo Villanova.Zaragoza.NicolásAlcaláRivera,AnxelaCrestelo Vieitez,EstherdelCorral,JesúsDíezManglano,IsabelFiteni Mera,MaríadelMarGarcíaAndreu,MartínGericóAseguino- laza, Claudia Josa Laorden, Raúl Martínez Murgui, Marta TeresaMatía Sanz. H. U.Infanta Cristina. Parla. Madrid.
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U. San Juan de Alicante. San Juan de Alicante. David Balaz,David BonetTur,CarlesGarcíaCervera,David Fran- cisco García Nú˜nez, Vicente Giner Galva˜n, Angie Gómez Uranga, Javier Guzmán Martínez, Isidro Hernández Isasi, LourdesLajaraVillar,JuanManuelNú˜nezCruz,SergioPala- ciosFernández,JuanJirgePerisGarcía,AndreaRia˜noPérez, JoséMiguelSeguíRipoll,PhilipWikman-Jorgensen.H.U.San Agustín.Avilés.AndreaÁlvarezGarcía,VíctorArenasGar- cía, Alba Barragán Mateos,Demelsa Blanco Suárez,María Ca˜no Rubia, Jaime Casal Álvarez, David Castrodá Copa, JoséFerreiroCeleiro,NataliaGarcíaArenas,RaquelGarcía Noriega,JoaquínLlorenteGarcía,IreneMaderueloRiesco, PaulaMartínezGarcía,MaríaJoséMenéndezCalderón,Diego EduardoOlivo Aguilar, Marta Nataya SolísMarquínez, Luis TrapiellaMartínez,AndrésAsturTrece˜noGarcía,JuanValdés Bécares.H.deSagunto.Sagunto.Valencia.ZinebKarroud Zamrani, José Maréa Pascual Izuel, Enrique Rodilla Sala.
H. deMataró. Mataró. Raquel Aranega González, Ramon Boixeda,CarlosLoperaMármol,MartaParraNavarro,Ainhoa RexGuzmán, AleixSerrallongaFustier.H. U.Son Llàtzer.
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SantJoanDespí.JoséLoureiroAmigo,MelaniPesta˜naFer- nández,NicolasRhyman,NuriaVázquezPiqueras.H.U.C.
deAsturias.Oviedo.VíctorAsensiÁlvarez,ItxasneCabezón Estévanez, María Folgueras Gómez, María Martínez Sela, Lucía Meijide Rodríguez, Claudia Moran Casta˜no, Noelia Morán Suárez, Sara Rodríguez Suárez, Silvia Suárez Díaz, LuciaSuárezPérez,CarlosVázquez,CarmenYlleraGutiér- rez. H. U. Virgen de las Nieves. Granada. Pablo Conde Baena,JoaquínEscobar Sevilla,LauraGallo Padilla,Patri- ciaGómez Ronquillo, Pablo González Bustos, María Navío Botías, Jessica Ramírez Taboada, Mar Rivero Rodríguez.
H. San Juan de la Cruz. Úbeda. Marcos Guzmán Gar- cía,FranciscoJavierVicenteHernández.H.CostadelSol.
Marbella.Málaga. VictoriaAgustín Bandera,MaríaDolores MartínEscalante.H.InfantaMargarita.Cabra.MaríaEsther GuisadoEspartero,LorenaMonteroRivas,MaríadelaSierra NavasAlcántara,RaimundoTirado-Miranda.ComplejoAsis- tencialUniversitariodeLeón.León.RosarioMaríaGarcía Die,ManuelMartin Regidor,Ángel LuisMartínez González, Alberto Muela Molinero, Raquel Rodríguez Díez, Beatriz Vicente Montes. Hospital Clínic Barcelona. Júlia Calvo Jiménez,AinaCapdevilaReniu,IreneCarbonellDeBoulle, EmmanuelColomaBazán,JoaquimFernándezSolà,Cristina GabaraXancó,JoanRibotGrabalosa,OlgaRodríguezNú˜nez.
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Madrid.AlejoEriceCalvo-Sotelo.HospitalValledelNalón.
Ria˜no (Langreo). Sara Fuente Cosío, César Manuel Gallo Álvaro, JuliaLobo García, Antía Pérez Pi˜neiro. H. U. del
Vinalopó.Elche. FranciscoAmorós Martínez,ErikaAscu˜na Vásquez,José CarlosEscribano Stablé,AdrianaHernández Belmonte,AnaMaestrePeiró,RaquelMartínezGo˜ni,M.Car- men PachecoCastellanos, BernardinoSoldan Belda, David Vicente Navarro. H. Alto Guadalquivir. Andújar. Bego˜na CortésRodríguez.H.FrancescdeBorja.Gandía.Valencia.
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Toledo.AnaMaríaAlguacilMu˜noz,MartaBlancoFernández, Verónica Cano, Ricardo Crespo Moreno, Fernando Cuadra García-Tenorio,BlancaDíaz-TenderoNájera,RaquelEstévez González,MaríaPaz GarcíaButenegro,AlbertoGatoDíez, VerónicaGómezCaverzaschi,PiedadMaríaGómezPedraza, Julio González Moraleja, Raúl Hidalgo Carvajal, Patricia JiménezAranda,RaquelLabraGonzález,ÁxelLeguaCapara- chini, Pilar López Casta˜neyra,Agustín Lozano Ancín,José DomingoMartinGarcía,CristinaMorataRomero,MaríaJesús Moya Saiz, Helena Moza Morí˜nigo, Gemma Mu˜niz Nicolás, Enriqueta Mu˜noz Platón, Elena Ortiz Ortíz, Raúl Perea Rafael,PilarRedondoGalán,MaríaAntoniaSepúlvedaBerro- cal,PilarToledanoSierra,JesúsVázquezClemente,Carmen YeraBergua. H.U. deCanarias.Santa CruzdeTenerife.
JulioCesar Alvisa Negrín,José Fernando ArmasGonzález, Lourdes González Navarrete, Iballa Jiménez, María Can- delaria Martín González, MiguelNicolás Navarrete Lorite, Paula Ortega Toledo, Onán Pérez Hernández, Alina Pérez Ramírez. H. de Poniente. Almería.Juan Antonio Montes Romero,EncarnaSánchezMartín,JoséLuisSerranoCarrillo de Albornoz, ManuelJesús Soriano Pérez. H. Sierrallana.
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RaquelGómezMéndez,AnaRodríguezÁlvarez.H.SanPedro deAlcántara. Cáceres. Ángela AgeaGarcía, Javier Galán González,Luis GámezSalazar,EvaGarcía Sardón,Antonio GonzálezNieto,ItziarMonteroDías,SeleneNú˜nezGaspar, Álvaro Santaella Gómez. H. U. del Sureste. Arganda del Rey.Madrid.JonCabrejasUgartondo,Ana BelénMancebo Plaza, Arturo Noguerado Asensio, Bethania Pérez Alves,
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deÉibar.Éibar.EsperanzaMonteroAparicio.H.JoanMarch.
Bunyola(Mallorca).CristinaGallego Lezaun.H.Comarcal de Blanes.Blanes. Pere Comas Casanova.H. Santa Ana.
Motril.Granada.JesúsPalomaresRodríguez.H. deZafra.
Zafra. Juana Carretero Gómez. H. G. U. Los Arcos del Mar Menor. San Javier. Diana Pi˜nar Cabezos. H. García Orcoyen. Estella. Maríadel Carmen Martínez Velasco.H.
U. de Gran Canaria Dr. Negrín. Las Palmas G. C. Alicia Conde.C.H.U.deCáceres.Cáceres.MartaCorreaMatos.
H.deBarbastro. Barbastro. JuanSalas Jarque.Fundació Sant Hospital de la Seu d’Urgell. La Seu d’Urgell. Luis EnriqueCajamarcaCalva.H. C.MedinadelCampo.Med- inadelCampo. DavidMorchónSimón.H.U. SantaLucía.
Cartagena.PedroJoséGarcíaLópez.H.ComarcaldeInca.
Inca.MaríaSoledadSanzParras.H.deBarbanza.Ribeira.
LaraMaríaMateoMosquera.H.G.U.ReinaSofía.Murcia.
JoséJoaquínHernándezRoca.H.delVendrell.ElVendrell.
Ana Lacal Martínez. H. U. Río Hortega. Valladolid. Luis CorralGudino. H.U.VirgendelaVictoria.Málaga.María JoséBenítezToledo.H.U.ReyJuanCarlos.Móstoles.José AntonioRuedaCamino.H.SanJuandeDiosdelAljarafe.
Bormujos. Ana Laura BlancoTaboada. Centro Médico de Asturias.Oviedo.FidelAsensioFierro.ClínicaSanMiguel.
Pamplona.Pamplona.RaquelRodil.
IAS Sta. Caterina. Salt. Sara García Torras. H. Insular Ntra.Sra. delos Reyes.Valverde(El Hierro).Ana María TorresVega.ComplejoHospitalarioUniversitarioOurense.
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Madrid.JuanGallegoGaliana.
Appendix A. Supplementary data
Supplementary data associated with this arti- cle can be found, in the online version, at doi:
10.1016/j.rceng.2020.07.003.
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