COVID-19 and the Response of Transplant Centers: the Global Response with an Emphasis on the Kidney Recipient

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KIDNEY TRANSPLANTATION (ML HENRY AND R PELLETIER, SECTION EDITORS)

COVID-19 and the Response of Transplant Centers: the Global Response with an Emphasis on the Kidney Recipient

Yorg Azzi^1,2_&Abigail Brooks^1,2_&Hillary Yaffe^1,2_&Stuart Greenstein^1,2

Accepted: 22 May 2021

#The Author(s), under exclusive licence to Springer Nature Switzerland AG 2021

Abstract

Purpose of the ReviewIn response to the COVID-19 pandemic, vulnerable populations, such as transplant patients, were at greater risk than the regular population. In order to protect these populations, transplant centers enacted new guidelines. We approach this review by looking at how different transplant regions responded to COVID-19 and analyze the unifying themes that have proven invaluable in the subsequent waves.

Recent FindingsWe noticed that most elective surgeries including living donor transplant operations were suspended in most countries. The response to deceased donor transplants varied between countries: in some deceased donor transplants continued with modified donor and recipient criteria, while in other countries this surgery was suspended. There was a general trend of decreasing or holding antimetabolites, treating the virus with hydroxychloroquine and/or azithromycin, and converting outpatient clinics to virtual clinics.

SummaryWe learned how to carefully select donors and recipients, tailor immunosuppressant regiments, and implement telemedicine. The kidney recipient population can be effectively managed in times of crisis with appropriate accommodations and measures. This review can be a model for the transplant community for future pandemics.

Keywords Transplant response to COVID-19 . Kidney recipients and COVID-19 . Review of transplant response to COVID-19 . COVID-19 in the transplant community

Introduction

In the winter of 2020, the first wave of SARS-CoV-2, the virus that causes coronavirus-19 (COVID-19) infection emerged from Wuhan, China. This virus spread rapidly through the world in an unprecedented way that has yet to abate. As the COVID-19 global pandemic erupted, the care of vulnerable populations was one of the primary challenges.

Among them are the solid organ transplant patients, on ac- count of their immunosuppressed status. In particular, the T cell response is significantly suppressed in this population [1••,2•,3,4]. At the outset of the pandemic, when the natural

history of COVID-19 infection could only be conjectured, there was bona fide concern that immunosuppressed patients would be at increased risk for infection with SARS-CoV-2 and would experience unacceptably high mortality rates [3–7]. Faced with this hypothesis, solid organ transplant programs needed to make important decisions about very practi- cal matters [7,8]. Is the inpatient transplant unit sufficiently physically distant from the COVID-19 unit? Should post- operative patients be seen in the outpatient clinic? How should the medical personnel be protected? Should induction immunosuppression not include lymphocyte depleting agents?

Should only some transplants be performed? Should any transplants be performed?

Around the world, transplant centers made individualized decisions about the conduct of their programs, though several themes were mostly consistent: pre-operative testing of recipients and donors for COVID-19 infection, minimizing immunosuppression, rigorous limited recipient selection, and the use of telemedicine in the outpatient setting when possible [1••,3,5,8,9••]. In this paper, we explore the variations on these management strategies, to demonstrate that the This article is part of the Topical Collection onKidney Transplantation

* Stuart Greenstein

SGREENST@montefiore.org

1 Albert Einstein College of Medicine, Bronx, NY, USA

2 Montefiore-Einstein Center for Transplantation, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467-2401, USA

/ Published online: 29 June 2021

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transplant center response to the COVID-19 pandemic devel- oped to address the individual needs of the centers, but ulti- mately reflected the desire to protect patients from any mod- ifiable excessive harm.

We reviewed the published global literature for transplant centers’COVID-19 responses. The detailed findings are sum- marized in Table1.

Transplant Centers ’ Responses by Region

North America—the USA and Canada

Our center—Montefiore Medical Center in the Bronx, New York—halted all kidney transplants starting March 22, 2020, including new evaluations of both recipients and donors. Only emergent liver, heart, and lung transplants were performed.

We started doing new donor and recipient evaluations for kidney transplant via telemedicine in May 2020.With the pandemic surge winding down around June 2020 in New York City, we performed our first living donor kidney transplant in the first week of June, followed by two deceased donor kidney transplants in the same week. Currently, we are still performing both living and deceased donor kidney transplants with careful selection of recipients and donors and tailoring immunosuppression and induction to immunological risk, the psychosocial needs and living situation of the recipient, and infectious risk.

All other transplant centers in the USA discontinued living donor kidney transplants, except those on the West Coast since they were not initially as hard hit with cases as the East Coast. While some centers continued doing deceased donor transplants on a case-by-case basis, considering the lev- el of emergency of the transplant, some centers only continued to transplant those with a lower risk of delayed graft function.

Our center initially reported a mortality rate of 28% among our kidney transplant recipients with COVID-19 [10••]. In a subsequent report, we reported an overall mortality of 20%

and in-hospital mortality of 38% [11••]. Other centers in New York reported similar mortality. For immunosuppression management, the antimetabolite dose was reduced or held for most patients. Hydroxychloroquine and/or azithromycin dominated the therapeutic arsenal used. All outpatient management was switched to virtual visits via telemedicine. The handling of transplants in Canada during the pandemic mir- rored that of the USA.

Asia—China

Wuhan, China, closed on January 23, 2020, due to the impending threat of COVID-19. However, the impact of COVID-19 in organ transplant recipients was minor in the Hubei Province. There were only 22 confirmed cases in organ

transplant recipients (19 liver and 2 kidney) [1••]. The differ- ence in infection rate in the transplant community compared to the rest of the community at large was credited to years of effective transplant recipient education, including practicing effective self-protection with mask compliance, hand wash- ing, and social distancing. In response to the overwhelming healthcare demands, all organ donation stopped on January 23, 2020.

Due to the lockdown of the surrounding areas, transplant outpatient management was converted to remote follow-up.

Online consultation was implemented and labs collected from home were sent to transplant centers for interpretation, including dose adjustments of calcineurin inhibitors (CNI).

COVID-19-positive transplant patients were treated by a reduction or discontinuation of immunosuppression along with supportive treatment (often with low-dose methylpred- nisolone) based on the severity of the lung lesions. The mortality rate was low for COVID-19-positive transplant recipients, with one death among the 22 patients. In the single- center study from Tongji Hospital, Zhu et al. describe pneumonia in COVID-19-positive renal transplant recipients and assess their center’s treatment. They managed patients by discontinuing antimetabolites and CNIs and adding on antivi- ral medications [2•].

On May 25, 2020, organ transplantation resumed as the risk of COVID-19 dwindled and healthcare systems had suf- ficient resources.

Asia—Hong Kong

COVID-19 first emerged in Hong Kong in January 2020 after the Chinese New Year. Resource utilization shifted to treat the influx of COVID-19 cases, so the liver transplant department at Queen Mary Hospital reduced living donor liver transplant (LDLT) cases in half [1••]. However, LDLT for urgent con- ditions was permitted, and the center found itself utilizing LDLT grafts for fulminant cases, who ordinarily would have received deceased donor grafts, actually doubling the LDLT rate of the prior year. There was a vast change in deceased donor liver transplantation (DDLT), with only 2 DDLT oc- curring in the month of February [1••].

The center required that both potential living donors and recipients were screened for COVID-19 infection if they had symptoms or a history of recent travel. For deceased donors, screening was only performed in the presence of clinical symptoms or a recent travel history [1••].

Asia—Japan

Japan’s response to organ transplantation was based on the urgency of the transplant. Heart, lung, and emergent liver transplantation continued, while kidney, pancreas, and small bowel transplantation was stopped [1••].

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Table1GlobalresponseoftransplantcenterstoCOVID-19 RegionAsia CountryChina Response1/23/20Suspendedallorgantransplantationandresumedtransplantationon5/25/20[1••] ClinicalstudyPatientnumberClinicaloutcomesInpatienttreatmentOutpatientmanagement Coronavirusdisease2019pneumonia inimmunosuppressedrenaltransplant recipients:asummaryof10confirmed casesinWuhan,China Zhuetal.[2] Wuhan,China(TongjiHospital) 10patientsMortality1/10(10%) Hospitalized10/10(100%) AKI5/10(50%) Discharged8/10(80%) DiscontinuedMMF9/10(90%) DiscontinuedCNI7/10(70%) ReduceddoseofCNI8/10(80%) IVIG7/10(70%) Antiviraltherapy10/10(100%)

Onlineconsultation RegionAsia CountryHongKong Response50%reductioninLDLT(continues inurgentconditions) DecreasedDDLT IncreasedLDLTforliverfailure[1••] RegionAsia CountryJapan ResponseContinueslife-savingtransplantation forstatus1liverrecipients Suspendedallkidney,pancreas,and boweltransplants[1••] RegionAsia CountrySouthKorea ResponsePartialsuspensionofLDKT(especiallyif desensitizationforABOorHLAincompatibility) ContinuedurgentLDKTandDDKT[1••] RegionAsia CountryMongolia Response3/20suspendedlivingdonortransplantation except1patient[1••] RegionAsia CountrySingapore ResponseDiscontinuedLDKTexcept1patientwhoneeded whowasunabletogetdialysisaccess DiscontinuedDDKTexceptthoseonprioritywaitlist forfailingdialysisaccessorpureredcellaplasia Livertransplantationifmeetcriteriaformedicalurgency[1••] RegionAsia CountryIndia ResponseLDKTandLDLTsuspendedinMumbaiandoutsideMumbaiatthediscretionofthehospital DDKTsuspendedinMumbaiandtheregion ContinuedDDLT[1••] RegionMiddleEast CountryTurkey ResponsePostponedalltransplantationexcepturgentcases(acuteliverfailure)[3] ClinicalstudyPatientnumberClinicaloutcomesInpatienttreatmentOutpatientmanagement COVID-19inkidneytransplant recipients: amulticenterexperienceinIstanbul Demiretal.[4] Istanbul,Turkey(IstanbulUniversity)

40patientsMortality5/40(12.5%) Hospitalized39/40(98%) ICUstay7/40(18%) AKI14/40(35%) Graftfailure0/40(0%) Discontinuedantimetabolites40/40(100%) DiscontinuedmTOR-Is4/40(10%) DiscontinuedCNIs11/40(27.5%) Favipiravir18/40(45%) Tocilizumab5/40(12.5%) Anakinra3/40(7.5%) Antibiotics24/40(60%)

In-personiflocal,otherwisetelehealth RegionMiddleEast

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Table1(continued) CountrySaudiArabia ResponseContinuedDDRTandLDRT,butdiscontinuedLDRTwhen3kidneyrecipientspresentedsymptomatically.ContinuedonlyurgentLDLT(definedasMELD> 25,HCCbeyond.MilanCriteriabutwithinUCSFcriteria,acutefulminantliverfailure,andrecurrentdecompensations) Discontinuednon-urgentLDLT[3] ClinicalstudyPatientnumberClinicaloutcomesInpatienttreatmentOutpatientmanagement Coronavirusdisease-19:disease severityand outcomesofsolidorgantransplant recipients: differentspectrumsofdiseasein differentpopulations? Alietal.[5] Riyadh,SaudiArabia(KingFaisal Specialist Hospital&ResearchCenter) 67patients 44kidney/15liver/8lung Mortality2/67(3%)

Hospitalized47/67(70%) ICUadmission7/47 (15%) AKI9/47(19%) Discontinuedantimetabolites47/47(100%) Hydroxychloroquine39/47(83%) Azithromycin42/47(89%) Tocilizumab11/47(23%) Dexamethasone9/47(19%)

N/A RegionMiddleEast CountryEgypt ResponseDiscontinuedmajorityoftransplantation[3] RegionMiddleEast CountryKuwait ResponseDiscontinuedLDRTandLDLTtransplants excepttoavoiddialysis[3] RegionMiddleEast CountryIran ResponseN/A ClinicalstudyPatientnumberClinicaloutcomesInpatienttreatmentOutpatient management Areportof85casesofCOVID-19and abdominal transplantationfromasinglecenter: whatarethe associatedfactorswithdeathamong organ transplantationpatients Malekhosseinietal.[6] Shiraz,Iran(AbuAliSinaHospital)

85patients 66liver/16kidney/2kidney– pancreas,and1liver/kidney

Mortality17/85(20%),Hospitalized56/85 (66%)ICUadmission19/56(34%)Hydroxychloroquine 30/85(35%) Lopinavir–ritonavir 4/85(5%) Tavanex4/85(5%) Tamiflu2/85(2%) Azithromycin23/85 (27%) Imipenem4/85 (27%) Cotrimoxazole3/85 (4%) Fluconazole2/85 (2%) Vancomycin2/85 (2%) Salbutamol1/85 (1%)

N/A RegionEurope CountryDenmark

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Table1(continued) ResponseDDKTandDDLTcontinued LDKTcontinuedinsomecenters andsuspendedinothers Suspended SPK[1••] RegionEurope CountrySweden ResponseN/A ClinicalstudyPatientnumberClinicaloutcomesInpatienttreatmentOutpatientmanagement InitialreportfromaSwedishhigh- volume transplantcenterafterthefirstwaveof the COVID-19pandemic Felldinetal.[7] Gothenburg,Sweden(University ofGothenburg) 53patients 31kidney/5lung/5heart/8liver/4 dualorgans

Mortalityrate5/53(9.4%) In-hospitalmortalityrate 5/37(14%) Hospitalized37/52(70%) ICUadmission8/37 (22%) Dialysis12/37(32%) SevereCOVID-19disease 12/37(32%) Mechanicalventilation 7/37(19%) DiscontinuedorreducedMMF23/35(66%) ReducedCNI11/53(21%) Hydroxychloroquine+tocilizumab1/37(3%) LMWH27/37(73%) Apixaban1/37(3%) SupplementalO221/37(57%)

N/A RegionEurope CountryUK ResponseRoutinetransplantationcontinued Acuteliverfailurelistedandtransplanted Cancelledroutinetransplantassessment Continuationofpediatriclivertransplantation SuspendedallLDLT Suspendedallelectivepost-transplantsurgicalcases[1••] ClinicalstudyPatientnumberClinicaloutcomesInpatienttreatmentOutpatientmanagement Outcomesofrenaltransplantrecipients with SARS-CoV-2infectionintheeyeof thestorm: acomparativestudywithwaitlisted patients Mohamedetal.[8] London,UK (BartsHealthNHSTrust)

28patientsMortality9/28(32%) Hospitalized25/28(89%) ICUstay5/25(20%) AKI14/25(56%) DiscontinuedMMF19/21(90%) HalvedMMF1/21(5%) DiscontinuedAZA3/3(100%) Nochangeinantimetabolite3/24(12.5%) Steroidincreased12/27(44%) Hydrocortisone1/28(4%)

Virtualclinics Medicationssentviamail 24honlinesupport RegionEurope CountryFrance(Paris) ResponseContinuedorganprocurementincludingDCDdonors[1••] ClinicalstudyPatientnumberClinicaloutcomesInpatienttreatmentOutpatientmanagement COVID-19infectioninkidney transplant recipients:diseaseincidenceand clinicaloutcomes

66patientsMortality16/66(24%) Hospitalized60/66(91%) ICUstay15/66(22%) AKI28/66(42%) RRT7/28(25%) DiscontinuedonlyMMF/MPA/AZA38/61(62%) DiscontinuedonlyCNI2/57(4%) Belataceptinfusionpostponed1/6(17%) Nochangeinimmunosuppression24/66(36%) Discontinuedallimmunosuppression1/66(2%) Cancelledallf/uappointmentsforliver Telehealthclinicsforkidney

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Table1(continued) EliasM,PievaniD,RandouxC,etal. [9••] Paris,France(SaintLouisHospital)

Hydroxychloroquine7/66(11%) Tocilizumab1/66(2%) Eculizumab2/66(3%) ClinicalstudyPatientnumberClinicaloutcomesInpatienttreatmentOutpatientmanagement AninitialreportfromtheFrenchSOT COVIDRegistrysuggestshigh mortality duetoCOVID-19inrecipientsof kidneytransplants Caillardetal.[10••] Strasbourg,France(Strasbourg UniversityHospital)

279patientsMortalityat30days (23%) Hospitalized243/279 (87%) Ventilated72/243(30%) O2therapy152/210(72%) ICUstay88/243 (36%) AKI106/243(44%) RRT27/243(11%) Graftloss9/243 (4%) CNIdiscontinued58/202(29%) Antimetabolitediscontinued136/192(71%) mTOR-Idiscontinued18/29(62%) Belataceptdiscontinued7/15(47%) Azithromycin71/243(29%) Otherantibiotics153/243(63%) Antifungaldrugs6/243(2.5%) Remdesivir2/243(1%) Lopinavir/ritonavir11/243(4.5%) Oseltamivir6/243(2.5%) Hydroxychloroquine60/243(25%) Tocilizumab12/243(5%)

Cancelledallf/uappointmentsforliver Telehealthclinicsforkidney ClinicalstudyPatientnumberClinicaloutcomesInpatienttreatmentOutpatientmanagement Biomarkersofcytokinerelease syndrome predictdiseaseseverityandmortality Benotmaneetal.[11••] Publicationdate:11,09,2020 France

49patientsMortality9/49(19.5%) Hospitalized41/49(84%) ICUstay14/41(34%) AKI31/41(76%)

DiscontinuedMMF/MMPA35/35(100%) DiscontinuedmTOR-Is6/6(100%) Belataceptpostponed½(50%) DiscontinuedCNI15/36(42%) Hydroxychloroquine15/41(37%) Azithromycin26/41(65%) Lopinavir–ritonavir5/41(12%) Highdosecorticosteroids14/41(34%) Tocilizumab4/41(10%)

Cancelledallf/uappointmentsforliver Telehealthclinicsforkidney RegionEurope CountryFrance(Strasbourg) Response3/9/20discontinuedDDKTandLDKT[1••] RegionEurope CountryItaly ResponseN/A ClinicalstudyPatientnumberClinicaloutcomesInpatienttreatmentOutpatientmanagement KidneytransplantpatientswithSARS- CoV-2 infection:theBresciaRenalCOVID TaskForceexperience Bossinietal.[12] Brescia,Italy(SpedaliCiviliHospital)

53patientsMortality15/45(33%) Hospitalized45/53(85%) ICUstay10/45(22%) AKI15/45(33%) RRT3/15(20%) Discharged27/45(60%) ARDS27/45(60%) Immunosuppressionadjustmentsinhospitalized patients34/45(76%) F/uimmunosuppressionadjustments17/20(85%) ReducedsteroidsandCNI13/17(76%) ReducedCNIandMMF2/17(12%) Samedosesteroids+reduceddoseCNI1/17(6%) Samedosesteroids+introducedmTOR-I1/17(6%) Lopinavir/ritonavir18/53(34%) Darunavir+ritonavir14/53(26%) Hydroxychloroquine39/53(74%)

N/A ClinicalstudyPatientnumberClinicaloutcomesInpatienttreatmentOutpatientmanagement Asinglecenterobservationalstudyof the clinicalcharacteristicsandshort-term

20patientsMortality5/20(25%) Hospitalized20/20 (100%) Discontinuedimmunosuppression20/20(100%) Initiatedmethylprednisolone16mg/day20/20 (100%)

N/A

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Table1(continued) outcome of20kidneytransplantpatients admittedfor SARS-CoV2pneumonia Albericietal.[13] Brescia,Italy(SpedaliCiviliHospital) ICUstay4/20(20%) AKI6/20(30%) RRT1/6(17%) Discharged3/20(15%)

Antiviraltherapy+hydroxychloroquine19/20(95%) Lopinavir/ritonavir3/20(15%) Darunavir+ritonavir8/20(4%) Tocilizumab6/12(50%) RegionEurope CountryGermany ResponseSuspendedmostLDKT ContinuedDDKT Highurgencypediatriclivertransplantation DDLTinlowerurgentsituationsoncase-by-casebasis Transportoforgansacrosscountryborders continueswithsomerestrictions[1••] RegionEurope CountryNetherlands Response3/13/20 SuspendedLDKTandDDKTatthelargesttransplantcenter(includingpatientsscheduledtoundergobloodgroupABO-incompatiblekidneytransplantation alreadytreatedwithalemtuzumabbeforethedecisiontostopacutekidneytransplants) 3/23/20 ContinuedDDKTatsmallercenters Livertransplantationcontinued[1••] RegionEurope CountrySpain ResponsePostponedallLDtransplantation[1••] ClinicalstudyPatientnumberClinicaloutcomesInpatienttreatmentOutpatientmanagement RespiratoryandGICOVID-19 phenotypes inkidneytransplantrecipients Crespoetal.[14] Barcelona,Spain(HospitaldelMar)

414patientsHospitalized380/414 (92%) ICUadmission50/414 (12%) Intubation73/414(18%) Hydroxychloroquine369/414(89%) Azithromycin206/414(50%) Glucocorticoids203/414(49%) Lopinavir/ritonavir140/414(34%) Tocilizumab(anti-IL6)77/414(19%)

Cancelledallnon-urgentappointments, labtests,andprocedures Telehealth ClinicalstudyPatientnumberClinicaloutcomesInpatienttreatmentOutpatientmanagement COVID-19insolidorgan transplantation: amatchedretrospectivecohortstudy and evaluationofimmunosuppression management Miaronsetal.[15] Barcelona,Spain(Valld’Hebron HospitalUniversitari)

46patients 30kidney/13lung/3liverMortality17/46(37%) Hospitalized46/46 (100%) ICUadmission10/46 (22%) ARDS9/46(20%)

Discontinuedtacrolimus22/36(61%) Discontinuedeverolimus7/7(100%) Discontinuedsirolimus4/4(100%) Hydroxychloroquine44/46(96%) Hydroxychloroquine+azithromycin41/46(89%) Lopinavir–ritonavir23/46(50%) Darunavir–cobicistat17/46(37%) Interferonbeta3/46(7%) Tocilizumab21/46(46%) Remdesivir1/46(2%)

N/A ClinicalstudyPatientnumberClinicaloutcomesInpatienttreatmentOutpatientmanagement COVID-19inElderly Kidneytransplantrecipients Crespoetal.[16] Barcelona,Spain(HospitaldelMar)

16patientsMortality8/16(50%) Hospitalized15/16(94%) ICUstay2/16(13%) AKI5/15(33%) mTOR-Idiscontinued4/5(80%) MMFdiscontinued8/8(100%) CNIdiscontinued8/14(71%) Hydroxychloroquine13/16(81%) Cancelledallnon-urgentappointments, labtestsandprocedures Telehealth

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Table1(continued) Steroids6/16(37.5) Ritonavir-lopinavir/darunavir5/16(31%) Tocilizumab4/16(25%) Antibiotics(azithromycin)14/16(88%) ClinicalstudyPatientnumberClinicaloutcomesInpatienttreatmentOutpatientmanagement Clinicalcharacteristicsandriskfactors for severeCOVID-19inhospitalized kidney transplantrecipients:amulticentric cohortstudy Favaetal.[17] Barcelona,Spain(HospitalUniversitari deBellvitge) 104patientsMortality28/104(27%) Hospitalized104/104 (100%) ICUstay24/104(23%) AKI47/100(47%) ARDS47/104(55%) Discontinuedatleastoneimmunosuppressiveagent 95/104(91.3%) IVsteroids55/104(53%) Hydroxychloroquine101/104(97%) Lopinavir/ritonavir50/104(48%) Azithromycin67/104(64%)

Cancelledallnon-urgentappointments, labtests,andprocedures Telehealth RegionEurope CountrySwitzerland Response3/13/20 6-stageplan: 1.DiscontinuedallLDtransplantation 2.DiscontinuedallDDPTandislettransplants,discontinueallDCDdonors 3.DiscontinuedDDKT 4.Liver,lung,andheartbasedonurgentstatus 5.Onlyurgenttransplants 6.Discontinuealltransplants 3/22/20 Discontinuedalltransplantandprocurementsexcepturgentcaseslikefulminanthepatitis[1••] RegionOceania CountryAustralia ResponseSuspendedLDKT SuspendedDDKT[1] RegionOceania CountryNewZealand ResponseContinuedDDKTat2/3transplantcenters DiscontinuedLDKT[1••] RegionAfrica CountrySouthAfrica ResponseDiscontinuedLDKTandDDKTingovernmenthospitals ContinuedDDKTinprivatehospitals DiscontinuedLDKTinprivatehospitals[1••] RegionNorthAmerica CountryCanada ResponseMontreal:SuspendedLDKT SuspendedDDKTexceptrecipients>70andhighlysensitized Toronto:3/16/20SuspendedLDKT SuspendedDDKTexceptactivepatientsonthewaitinglistmedicallyurgentorcPRA>99%[1••] RegionNorthAmerica CountryUSA