Carrying on with liver transplantation during the COVID-19 emergency: Report from Piedmont region

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ScienceDirect

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ORIGINAL

ARTICLE

Carrying

on

with

liver

transplantation

during

the

COVID-19

emergency:

Report

from

piedmont

region

Margherita

Saracco

a,1

_,

_Silvia

_Martini

a,∗,1

_,

_Francesco

_Tandoi

b

_,

Dominic

Dell’Olio

c

,

Antonio

Ottobrelli

a

,

Antonio

Scarmozzino

d

,

Antonio

Amoroso

c

,

Paolo

Fonio

e

,

Roberto

Balagna

f

,

Renato

Romagnoli

b

a_{Gastrohepatology}_Unit,_AOU_Città_della_Salute_e_della_Scienza_di_Torino,_University_of_Turin,_Turin,_Italy b_General_Surgery_2U,_Liver_{Transplantation}_Center,_AOU_Città_della_Salute_e_della_Scienza_di_Torino, UniversityofTurin,Turin,Italy

c_Regional_{Transplantation}_Center,_Piedmont,_AOU_Città_della_Salute_e_della_Scienza_di_Torino,_University_of Turin,Turin,Italy

d_Molinette_Hospital,_AOU_Città_della_Salute_e_della_Scienza_di_Torino,_Turin,_Italy

e_Radiology_Unit,_AOU_Città_della_Salute_e_della_Scienza_di_Torino,_University_of_Turin,_Turin,_Italy f_Anesthesia_and_Intensive_Care_Unit_2,_AOU_Città_della_Salute_e_della_Scienza_di_Torino,_Turin,_Italy

KEYWORDS SARS-CoV-2; Outbreak; Transplantactivity; Tertiaryhealthcare; Teamworking Summary

Background: TheCOVID-19pandemicisanemergencyworldwide.InItaly,livertransplant activ-itywascarriedon,butdespiteallefforts,a25%reductionofprocuredorganshasalreadybeen observedduringtheﬁrst4weeksoftheoutbreak.

Aims: ToanalyzeifourstrategyandorganizationofLTpathwayduringtheﬁrsttwomonthsof theCOVID-19emergencysucceededinkeepingahighlevelofLTactivity,comparingthenumber ofLTintheﬁrsttwomonthswiththesameperiodoftimein2019.

Methods: WecomparedthelivertransplantsperformedinourCenterbetweenFebruary24th andApril17th,2020withlivertransplantsperformedinthesameperiodin2019.

Abbreviations: AIH,autoimmunehepatitis;ALF,acuteliverfailure;ASSLD,AmericanAssociationfortheStudyofLiverDisease;BAL, bronchoalveolarlavage;CIT,coldischemiatime;CNT,ItalianTransplantAuthority;EAD,earlyallograftdysfunction;EASL,European Asso-ciationfortheStudyoftheLiver;HCC,hepatocellularcarcinoma;HOPE,HypothermicOxygenatedMachinePerfusion;ICU,intensivecare unit;LT,livertransplant;MELD,ModelfortheEnd-stageLiverDisease;NASH,non-alcoholicsteatohepatitis;NPS,nasopharyngealswab; WHO,WorldHealthOrganization.

∗_{Correspondence}_author.

E-mailaddress:smartini@cittadellasalute.to.it(S.Martini).

1 _They_shared_co-ﬁrst_authorship.

https://doi.org/10.1016/j.clinre.2020.07.017

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Results:In 2020,21patientsunderwentlivertransplantationfromdeceaseddonors,exactly astheyear before,withoutstatisticallysigniﬁcant difference.Allpatients survivedinboth groups,andtherateofearlygraftdysfunctionwas24%in2020and33%in2019.In2020Median MELDwashigher(17vs13).Wewereabletoperform3multiorgantransplantsandoneacute liverfailure.Nobodydiedonwaitinglist.TheperformanceofourCenter,despitethe maxi-emergencysituation,wassteadyandthiswastheresultofatremendousteamworkingwithin thehospitalandinourregion.

Conclusions: TeamworkingallowedourCenter tomaintainits activitylevel,takingcareof patientsbeforeandafterlivertransplantation.Sharingourexperience,wehopetobehelpful tootherCenters thatarefacingthepandemicand,ifanotherpandemiccomes,tobemore preparedtodealwithit.

Introduction

The COVID-19 pandemic caused by SARS-CoV-2 virus is a public health emergency affecting all aspects of medical care. On January 30th,2020, the World Health Organiza-tion(WHO)declaredittobeaglobalhealthemergencyand sinceMarch13thEuropebecametheepicenterofthe pan-demic.BytheendofFebruary2020,Italyhadexperienceda rapidspreadofthevirus,startingfromitsNorthernregions, witha dailyincrease inthe number of cases anddeaths. OnFebruary24th,2020aWHO-ledteamofexpertsarrived in Italyin orderto assistthe local health authorities. On the8thof Marchthe Italiangovernment instituteda con-tainmentredzoneenclosingthemostaffectedareasandin thefollowingdaysfurtherdecreesextendedstrictlockdown measurestothe wholecountryin ordertocontrast SARS-CoV-2spread.Allnon-urgentandnon-oncologicalactivities were suspended in national health service hospitals and planned surgeries were postponed. A growing number of wardsandintensivecareunit(ICU)bedswerequickly ded-icatedtothecare ofCOVID-19 patients.On April17th,in Italytherewere172.434conﬁrmedcases,42.727healedand 22.745deaths and thePiedmont alonecounted 450cases per100.000inhabitantswith19.803conﬁrmedcases,3.634 healed and 2.171 deaths [1]. According to the European AssociationfortheStudyoftheLiver(EASL)[2]and Amer-icanAssociation fortheStudyof LiverDisease(AASLD)[3] livertransplant(LT) activity,as an acutecare treatment, shouldnotbepostponed,evenintheCOVID-19era. Prelimi-narydatainpost-LTpatients[4,5]didnotshowanincreased riskofsevereCOVID-19disease,despiteimmunosuppression mayprolongviralshedding[6].Cirrhoticpatientsmightbe moresusceptibletovirusinfectionbecauseoftheir dysfunc-tionalimmuneresponseandtransplantationinSARS-CoV-2 positive recipients is currently not recommended [2,3]. Consequently,theItalianTransplantAuthority(CNT) recom-mendsthatallpauci/symptomaticrecipientsandalldonors ought to be tested for SARS-CoV-2 RNA (nasopharyngeal swab,NPSorbronchoalveolarlavage,BAL)[7]immediately pre-LTandthosewhotestpositivearetobeconsidered med-icallyineligiblefor transplantation/donation;screening of asymptomaticrecipientsofdeceaseddonorswilldependon

localresources availability.Despite alleffortstopreserve transplantactivity,a25%reductionofprocuredorganshas alreadybeenobservedinItalyduringtheﬁrst4weeksofthe outbreak[8].

Our working hypothesis is that our organization of LT pathwayduringtheﬁrsttwomonthsoftheCOVID-19 emer-gency succeeded in keeping a high level of LT activity, despitethereductionofprocuredorgans.

We aimed to analyze the number of LT performed betweenFebruary24th,2020andApril17th,2020withthe sameperiodoftimein2019,inourhigh-volumetransplant Center(median150LT/year).

Materials

and

methods

Studypopulation

Inthisobservationalcohortstudy,weconsecutivelyenrolled allpatientswhounderwentLTinourCenter,betweenthe 24thofFebruary2020andthe17thofApril2020.Inaddition, we retrospectivelyanalyzedtheLTsperformed in2019, in thesameperiodoftime.Thevariablesassessedinthestudy populationandtheirdonorsareshowninTable1.

PursuanttoItalianlaw,RegionalTransplantationCenters arethecustodiansofdonor/recipientbiomedicaldataalso for researchpurposes.Allstudyprocedurescompliedwith theethicalstandardsofthe2000DeclarationofHelsinkiand theDeclarationofIstanbul2008.

Clinicalprotocol

BytheendofFebruary2020,thenumberofpatients com-ing to our transplant clinic was limited to subjects with urgent issues and phone visits or telemedicine as appro-priatereplacedin-personappointments.Arrivaltimeswere staggered in order to avoid patients congregating in the waitingareas.Beforeentry,allpatientswerescreenedfor COVID-19symptomsorrecentexposureandeach patient’s temperature was checked. A pre-triage form had to be ﬁlledout before everyprocedure. Outpatient LT diagnos-ticworkupswerecarriedoutbyusingCOVID-freepathways.

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COVID-19andlivertransplantation 3 Table1 Recipientanddonorcharacteristics.

2020(n=21) 2019(n=21) P-value Recipientcharacteristics Male 16(76%) 15(71%) .99 Age,years 56[51—65] 58[56—62] .72 Etiologyofcirrhosis .15 Viral 4(20%) 11(52%) Alcoholic 7(35%) 5(24%)

AIHandcholestaticdisorders 5(25%) 1(5%)

NASH 2(10%) 1(5%) Others 2(10%) 3(14%) EtiologyofALF Viral 1(5%) 0 HCCincirrhoticpatients 9(45%) 8(38%) .75 Bloodtype .63 A 12(57%) 11(52%) B 2(10%) 5(24%) AB 1(5%) 1(5%) 0 6(29%) 4(19%)

Multipleorganstransplant 3(14%) 1(5%) .61

MELDatLT 17[12—22] 13[9—18] .13

Donorcharacteristic

Age,years 58[38—72] 60[51—63] .45

Donoraftercardiacdeath 1(5%) 0 .99

Suboptimalgraft 10(48%) 7(33%) .53

Regionaldonors 18(86%) 16(76%) .69

Transplantoperation

Exvivomachineperfusion 4(19%)a ₆_(29%) _.72

ColdIschemiaTime,minutes 452[346—473] 431[393—495] .99

Post-transplantcourse

EAD 5(24%) 7(33%) .73

ICU-stay,days 5[4—7] 4[3—6] .69

Hospital-stay,days 11[10—17] 13[8—21] .82

Dischargehome 20b_(95%) ₂₁_(100%) ₁

Abbreviations:AIH,autoimmunehepatitis;EAD,earlygraftdysfunction,accordingtoOlthoff;HCC,hepatocellularcarcinoma;ICU,

intensivecareunit;LT,livertransplantation;MELD,ModelfortheEnd-stageLiverDisease;NASH,non-alcoholicsteato-hepatitis.

a _One_out_of_four_with_normothermic_machine_perfusion.

b _One_still_hospitalized_(combined_{lung-liver-pancreas}_transplant).

Asalreadypublished,werecommendedtoourpatients fre-quenthandwashingandsanitization,avoidpublicplacesand overcrowdedsituationsandwearasurgicalmasktoprevent ofSARS-CoV-2infection[9—11].

Inourhospital7wards(5internalmedicine,pneumology andcardiology), 4out of 5ICUs and1 outof 4 Radiology Unit were progressively dedicated to COVID patients; On April17thinthedistrictofTurintherewere9.503conﬁrmed cases.

Inourliversub-intensiveunit,wewereallowedto con-tinue to admit patients withsevere decompensated liver disease,andfromMarch31steverypatientbeforeadmission wastestedforSARS-CoV-2RNAbyNPSsinordertoguarantee aCOVID-freeunit.Furthermore,amongthe5intensivecare unitsofourhospital,theonededicatedtotransplantswas maintainedCOVID-free,bytestingeachtransplantrecipient inadvancewithSARS-CoV-2RNAinNPSorBAL,startingfrom the22ndofMarch.

Theonlysourceofourdonorsaredeceaseddonorsafter brainor cardiacdeathand allof them werescreened for SARS-CoV-2,accordingtoCNTguidelines.Adeceaseddonor graft wasdefined suboptimal if donorage was≥65 years and/orhadmacrovesicularsteatosis≥15%[12].Thedegree offattyinfiltrationofthegraftwereassessedonliver biop-siesroutinelyobtainedattheendoftransplantsurgery.In ourcenter,from2016,graftsfrombraindeathdonors cha-racterizedbyincreasedriskprofile(donors>80yearsand/or obesedonors) aswell asfrom donorsafter cardiac death undergoHypothermicOxygenatedMachinePerfusion(HOPE) beforeimplantation,toreduceischemia-reperfusioninjury. Recently,normothermic machineperfusion (OrganOx) was alsoused.

After LT, immunosuppression consisted of tacrolimus, mycophenolate mofetil and steroids, asper our standard protocol. Early allograft dysfunction (EAD) was deﬁned accordingtoOlthoff[13]:totalbilirubinlevel≥10mg/dLor

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internationalnormalizedratio≥1.6onpostoperativeday7 oraspartateaminotransferaseoralanineaminotransferase level>2000IU/Lwithintheﬁrst7daysaftertransplant.

Statisticalanalysis

Categoricalvariableswererepresentedasnumber(n)and percentage (%) and compared using Fisher’s exact test or Chi-square test. Quantitative variables were shown as medianandinterquartilerange(25th—75thpercentiles,IQR) and their distribution was evaluated with D’Agostino & Pearsontest;parametricdatawereevaluatedbyt-test, non-parametricdatawereevaluatedbyMann—WhitneyUtest. P<0.05inatwo-tailedtestwasconsideredstatistically sig-niﬁcant.

Results

BetweenFebruary24th,2020andApril17th,2020,among 22 admissions in our 7-bed sub-intensive liverunit, a 40-year-old woman, who was listed during hospitalization, developedfever duringhospitalizationandtestedpositive forSARS-CoV-2RNA inNPSs. Immediatelytransferredtoa COVIDunit,shecame backtoourunitafter 7daysand2 negativeSARS-CoV-2RNAinNPSandunderwentLTtheday afterreadmissiontoourunit.

Atthebeginningandattheendoftheenrollmentperiod 51 and52 patients, respectively, wereactively onthe LT waiting list. None of the patients on the LT waiting list hadto be admitted tohospital for COVID-19 and the on-listmortalityratewas0%.Duringthestudyperiod,21ﬁrst LTswereconsecutivelyperformedinourCenter.The major-ityof therecipients weremale, witha median ageof 56 years(IQR51—65).ThemedianbiochemicalModelfor end-stageLiverdisease(MELD)atLTwas17(IQR12—22).Twenty patientswereaffectedbycirrhosis(20%viral-,35%alcohol-, 25%autoimmune/cholestatic-related)and45%ofthemalso byhepatocellular carcinoma(HCC).Twooutofthetwenty patients underwent combined liver-kidney transplant and onecombinedlung-liver-pancreas transplant.One patient wastransplantedfor HBV-related acuteliverfailure (ALF) (Table1).Fouroutof21patients(19%)werehospitalizedat thetimeofLTandtheALFpatientwasintheICUon venti-lator/respiratorysupport.Lookingatthedonors:86%ofthe graftwererecruitedinourregionalarea.Themediandonor agewas58 years(IQR38—72)and 48%of thegraftswere suboptimal. The median cold ischemia time was 452min (IQR 346—473). Ex vivo normothermic machine perfusion wasemployedforonegraft,andhypothermicperfusionfor 3 grafts. 95% of livers came from brain-dead donors and one froma donor after cardiac death. After LT, 1 out of the21recipientswasfoundpositiveforSARS-CoV2onNPS on his 5th day post-LT, after his bed neighbor, who was recoveringfromliverresection,hadtestedpositivetheday before.Hisoxygen saturationwaspersistentlynormaland CTscan wasnegative for pneumonia. We transferred the patientimmediatelytotheCOVIDunit,where precaution-aryhydroxychloroquine400mgtwicedailywasadministered for16days.Mycophenolatemofetildosingwasreducedfrom 1500mg/dayto1000mg/dayandtarget tacrolimustrough level was set at 5—7ng/ml. He was discharged after 18

uneventfuldaysin COVIDunit,andtheSARS-CoV2onNPS isstillpositive,withoutspeciﬁcsymptoms.

In2019,overthesameperiodoftime,atthebeginning andattheendoftheenrollmentperiod60and71patients, respectively,wereactivelyontheLTwaitinglist;the mortal-ityrateontheLTwaitinglistwas0%andweperformedthe samenumberofLTs(19ﬁrsttransplantand2re-transplants), comparedwith2020.71%ofthepatientswasmale,witha medianageof58years(IQR56—62).Themedian biochemi-calMELDatLTwas13(IQR9—18)withanHCCrateof38%. Theetiologyoflivercirrhosiswasviralfor52%ofthecases, alcoholrelatedfor24%.Themediandonoragewas60years (IQR51—63), allof them werebrain-dead and76% of the graft were recruited into our regional area. The median cold ischemiatimewas431min(IQR393—495)and33% of the graftsweresuboptimal. Ex-vivo hypothermicmachine perfusionwasusedin29%ofthegrafts.

Allpatientssurvivedinbothgroups,andtherateofEAD was24%in2020and33%in2019(Table1).Wedidnotﬁndany statisticallysigniﬁcantdifferencebetweenthetwocohorts.

Discussion

We comparedLT activity in our Centerduring the ﬁrst 2 monthsofCOVID-19pandemic,startingsinceFebruary24th, withthesameperiodoftheyearbefore.Italyhasbeenthe ﬁrstEuropeancountrytofacethesevereCOVID-19pandemic since February 2020 and ourNational Healthcare System, whichoffersuniversalaccesstohealthcaretoallresidents, isfacingatremendouspressure.Hospitalsandhealth work-erswereaskedtosuspendallnon-urgentactivitiesandto postponeallplannedsurgeryinordertogiveoverbedstothe treatmentofCOVID-19patients.InaccordancewithAASLD and EASL recommendations [2,3], transplant surgery was excludedfromtheselimitations,inordernottocompound theoutbreaklethalitywithriskingthelivesofpatientswho needalife-savingLT.Thisrequiresstringentcriteriafor pri-oritizing patients who aremore likely todie on the wait listandadelicatebalancewiththeriskofhospital-acquired COVID-19.Inordertooptimizeresourceutilizationandto avoidtransplantationinvirus-positivepatients,everyeffort hasbeenmadetopreventSARS-CoV-2infectioninpatients beforeandafterLTandtheSARS-CoV-2molecularscreening fordonorsandsymptomaticrecipientsbecamemandatory.

InourCountrydeceaseddonorsaretheprevalentorgan resource anda restrictionin the numberof available ICU bedsnecessarily inﬂuenced thedonationactivity; in fact, duringtheﬁrst4weeksofCOVID-19outbreakthenumber ofprocuredorgansdroppedby25%,asreportedbyCNT.

From1990morethan3000LTshavebeencarriedoutat ourCenterandtheannuallyLTvolumeis around150.The Unitis locatedintoaregionstronglyhitbyCOVID-19(454 casesper100,000inhabitantsand50deathsper100,000). Inourstudyweevidencedthat,despitetheemergency pub-lichealthsituation,weperformedduringtheﬁrst2months thesamenumberofLToftheyearbefore,withoutmortality onthewaitinglistandearlypost-transplant.MedianMELD washigheraswellasthecomplexityofpatients:we man-aged3multiorgan transplantsandoneacuteliverfailure, without signiﬁcantly impacting onthe ICU hospitalization days (median ICU-stay value: 5 days in 2020 vs 4 days in

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COVID-19andlivertransplantation 5 2019,P=0.69)andallpatientssurvivedinbothgroups.

Fur-thermore,themajorityofthedonorswererecruitedinour regional area, one of the hardest hits by the virus, and we wereabletomanagemachineperfusion in19% of the casesinside ourhospital.Wedidnotchange ourstandard immunosuppression regimen, according to published data which showthat immunosuppressionwasnotarisk factor for mortality associated with SARS (2002—2003) or MERS (2012-present)[3,4],evenifitmayprolongviralshedding inpost-transplantpatientswithCOVID-19[3,6].

We strongly believe that the steady performance of ourCenter,despitethemaxi-emergencysituation,wasthe result of a tremendous team working within the hospi-tal and in the Piedmont Region. Our healthcare Director (AS)rapidlyswitchedinourtertiaryreferralhospitalmany medicaldoctors anddepartmentspreviously dedicated to differentspecialties,intonewCOVID-19units,progressively increasinginnumberandsize.Ourtransplanthepatologists weresparedfromthefull-timemanagementofCOVID-units, inordertotakecareofoutpatientandinpatienttransplant patients.Ourliversub-intensivecareandtransplant inten-sive unitwereincluded into aCOVID-freepathway within thehospitalandastrongcollaborationbetweentransplant hepatologistsandsurgeonsmadepossibletheprioritization ofpatientsmoreinneedoftransplantandtooptimizethe recipient/donor match. Furthermore, regional ICUs were abletopreservebedsandintensivistsforthemanagement ofapreciousresourcelikeapotentialorgandonor.Despite alloureffortstomaintainatransplantCOVID-freepathway, twotransplantpatients,onebeforeandoneafterLTwere testedSARS-CoV-2virus positiveduringhospitalizationand bothweresafelydischargedhome.

Some limitations need tobe acknowledged. The small number of enrolled patients, limited period of the study andthemonocentricexperience.TheexperienceofMaggi etal.[14]aswell thepreliminaryanalysisof Italian Soci-ety for Organ Transplantation [15]showed that thereis a variability in the emergency management even between the Italian regions. Lombardy has 10.002.615 inhabitants [16] and four active liver transplant programs (Ospedale NiguardainMilan,FondazioneIRCCSPoliclinicoinMilan, Isti-tutodeiTumoriinMilanandOspedaliRiunitiinBergamo). Thisistheregionthatwashitfirst,withthehighestnumber ofcasesinItaly(OnApril17ththerewere64.135confirmed cases and11.851 deaths,641 cases/100.000 inhabitants). Piedmonthas4.392.526inhabitants[16]andtheliver trans-plant activity is focused in a single center, in Turin. The COVID-19 outbreak arrived in Piedmont with a delay of around two weeks, and on April 17th, 2020 19.803 con-firmed cases and 2.171 deaths were recorded, with 450 cases/100,000inhabitants.Thedelayoftheepidemicpeak andthecentralizationofLTactivitycouldexplainthe dif-ferentresultsreportedfromtheLombardycentersandours. Agopianetal.alsoreportedagreatvariabilityinLTactivity fromdifferentregionsinUS[17].

In conclusion, Italy is facing an unprecedented health care emergencysituation due tothe COVID-19pandemic. Teamworkingwithcloseinvolvementofseveralspecialties suchashepatologists,surgeons,anesthesiologistsand radi-ologistsallowed oursingleregionalCentertomaintainits activitylevel, takingcare ofpatients beforeandafter LT. WethinkthatLT, beingalife-savingprocedure, shouldbe

notsuspendedwhenitispossible.Sharingourexperience, wehopetobehelpfultootherTransplantCentersthatare nowfacingtheCOVID-19emergency.

Conﬂict

of

interest

Allauthorshavenoconﬂictofinteresttodeclare.

Financial

support

Authorsdeclaretheyreceivednoﬁnancialsupportforthis manuscript.

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