key: cord-1033407-qn3s49gr
authors: Muller, Xavier; Tilmans, Gilles; Chenevas‐Paule, Quentin; Lebosse, Fanny; Antonini, Teresa; Poinsot, Domitille; Rode, Agnes; Guichon, Céline M; Schmitt, Zoé; Ducerf, Christian; Mohkam, Kayvan; Lesurtel, Mickaël; Mabrut, Jean‐Yves
title: Strategies for Liver Transplantation during the SARS CoV‐2 Outbreak Preliminary Experience from a Single Center in France
date: 2020-05-31
journal: Am J Transplant
DOI: 10.1111/ajt.16082
sha: 55e64569bf31233e0ed6cf0dd8d4672e02c7646b
doc_id: 1033407
cord_uid: qn3s49gr

Liver transplantation during the ongoing SARS‐CoV‐2 pandemic is challenging given the urgent need to reallocate resources to other areas of patient care. Available guidelines recommend to reorganize transplant care but data on clinical experience in the context of SARS‐CoV‐2 pandemic are scarce. Thus, we report strategies and preliminary results in liver transplantation during the peak of the SARS‐CoV‐2 pandemic from a single‐center in France. Our strategy to reorganize the transplant program included four main steps: optimization of available resources especially intensive care unit capacity, multidisciplinary risk stratification of liver transplantation candidates on the waiting list, implementation of a systematic SARS‐CoV‐2 screening strategy prior to transplantation and definition of optimal recipient‐donor matching. After implementation of these four steps, we performed 10 successful liver transplantations during the peak of the pandemic with a short median intensive care unit stay (2,5 days), benchmark post‐transplant morbidity and no occurrence of SARS‐CoV‐2 infection during follow‐up. From this preliminary experience we conclude that efforts in resource planning, optimal recipient selection and organ allocation strategy are key to maintain a safe liver transplant activity. Transplant centers should be ready to readapt their practices as the pandemic evolves.

Data on outcomes after SARS-CoV-2 infection in liver transplant (LT) recipients are scarce and the potential impact on LT activity uncertain. While reports on SARS-CoV-2 in long-term solid organ recipients including LT report a case-fatality rate as high as 27.8%, others suggest that LT recipients may be protected by immunosuppression-related mitigation of cytokine release. 1, 2 Besides unanswered questions on SARS-CoV-2 infections in transplant recipients, LT is particularly challenging during this pandemic given the urgent need to reallocate health care resources, such as ventilators, intensive care unit (ICU) beds and staff to treat SARS-CoV-2 infected patients 3 . However, decreased LT activity has to be balanced against the potential negative impact for patients with end-stage liver disease or hepatocellular carcinoma. 4, 5 To face these challenges, guidelines suggest a phased reduction in LT activity based on available resources, ranging from performing only super-urgent transplantation to maintaining an active deceased donation-based program 6, 7 During the peak of the pandemic in France, a total of 7130 patients with SARS-CoV-2 infection required ICU treatment with a baseline availability of 5432 beds 8 . In this context, we present the experience and preliminary outcomes from a LT program in one of the most exposed regions in France. 8 

This is a retrospective analysis of all consecutive adult patients undergoing LT at Croix Rousse University Hospital in Lyon, France during the first month after the beginning of the national SARS-CoV-2 Lock Down on March 16 th 2019.

In accordance with the French National Organ Donor Agency's (Agence Nationale de Biomédecine) and the French Transplantation Society's recommendations to reduce LT activity, we reorganized our LT program based on available resources. 7, 9 This strategy included four major steps: (a) resource planning; (b) multidisciplinary risk stratification of LT candidates on the waiting list; (c) implementation of a systematic pre-LT SARS-CoV-2 screening strategy and (d) definition of optimal recipient-donor matching to achieve benchmark outcomes.

Resource planning

Our university hospital is one of the tertiary reference centers for SARS-CoV-2 infections which forced us to substantially reorganize our liver transplant program. Three separate surgical units were set-up: one for all elective surgery in SARS-CoV-2 negative patients, one for SARS-

This article is protected by copyright. All rights reserved CoV-2 positive patient and a third SARS-CoV-2 negative unit for LT recipients. Of note, the transplant unit had only single rooms to avoid patient contact and post-LT visits by relatives were temporarily suspended. Specific intra-hospital SARS-CoV-2 free pathways especially for ultrasound and CT-scan were established.

The ICU capacity was a key consideration. As referral tertiary center for SARS-CoV-2 disease, the overall number of ICU beds was increased by 67% during the early phase of the outbreak. The majority of the ICU beds were dedicated to SARS-CoV-2 infected patients and 17%

of the ICU beds were dedicated to patients without SARS-CoV-2 infection including surgical patients and LT recipients. The ICU capacity available for LT including available beds, ventilators and renal replacement therapy (RRT) were continuously reassessed during weekly multidisciplinary meetings. survival. 13 The BAR score combines 6 independent donor and recipient characteristics associated with post-LT survival. 14 The score balances one risk factor by optimal matching of the others, for example high MELD with short cold ischemia and low donor age. 

Our transplant center was situated in a high SARS-CoV-2 incidence zone, with 10-20 SARS-CoV-2 infected patients hospitalized per 100.000 inhabitants (Figure 1 ). Compared to the monthly average over the past five years, LT activity during the 30-day study period decreased by 29% in France (77 LT vs. 108 LT ) while LT activity increased by 42% at our center (10 LT vs. 7 LT). 8

This article is protected by copyright. All rights reserved

In total, 39% (13 out of 33) of LT candidates on the waiting list were temporarily put on hold. These patients were either planned for a multiorgan transplant, had HCC controlled by bridging therapy or had severe cardiovascular or respiratory comorbidities. The median MELD on the waiting list was 14 (IQR 10-20) and the median CLIF-C-ACLF score was 7 (IQR 6-8).

A total of 10 successful DBD LT in adult recipients were performed during the study period. Recipients had a median age of 51 years (IQR 38-60 years) with a median MELD score of 19 (IQR 12-28). The majority had compensated ELD (70%) and was admitted from home. Three recipients were inpatients with a MELD score >25 points: one had ACLF grade 1 and two had ACLF grade 2. Overall, HCC was present in 40% of the recipients. (Table 2 ) with a short median ICU stay of 2,5 (IQR 2-6) days. The median total hospital stay was 14 (IQR 13-21) days.

The standard immunosuppressive protocol was followed for all patients. One liver graft recipient underwent liver biopsy for abnormal liver tests on post-LT day 30 and was diagnosed with an acute rejection classified BANFF 6 which was successfully treated by corticosteroids bolus.

During the 39 days of median post-LT follow-up no case of SARS-CoV-2 was diagnosed in the 10 LT recipients.

We report a single-center experience with LT during the peak of the SARS-CoV-2 outbreak in (Table 3 ).

The first question at the beginning of the SARS-CoV-2 pandemic was: should LT activity be maintained? On one hand, LT during the pandemic may have surpassed available capacities in ventilators, RRT and ICU staff and thus jeopardized treatment options for SARS-CoV-2 infected patients. 9, 15 In addition, the risk of SARS-CoV-2-related morbidity and mortality in the context of immunosuppression is being actively debated within the transplant community with only few data from single cases available 1, 2, 16, 17, 18, 19 . On the other hand, from a patient perspective, suspending LT may have a negative impact on patients with ELD or HCC without any other curative treatment option. 4, 5 After balancing these considerations, we opted to maintain a LT activity by following center-specific decisional steps based on available guidelines. (Table 3) A first step was the reorganization of the LT program and a continuous evaluation of available resources. Despite the significant increase in ICU beds required for SARS-CoV-2 infected patients, we were able to maintain SARS-CoV-2-free ICU dedicated to LT and surgical oncology (17% of total ICU beds). In addition, to further prioritize LT activity, major elective interventions (e.g major hepatectomy, esophagectomy) in frail patients with potential long ICU stays were reduced according to the national guidelines. 20, 21 The LT ward was reorganized into single rooms and medical staff wore face masks and scrubs and were tested and quarantine if they showed SARS-CoV-2 symptoms. While logistically challenging, setting-up these SARS-CoV-2 free pathways to mitigate in-hospital transmission should be the first priority to allow a safe LT activity for both recipients and medical staff. 21 A second step was a case by case evaluation and risk stratification of every LT candidate on the waiting list, resulting in a 39% reduction of actively listed candidates. As reported in other LT centers, candidates listed for multiorgan transplants or retransplantations were temporarily put on hold due to an expected higher morbidity and to transitory shortage in blood products and RRT equipment. 11, 22 In contrast, LT candidates with MELD > 25 or ELD with poor prognosis but expected benchmark outcomes and short ICU stay were kept active on the waiting list. Of note, the median overall hospital stay was longer than the expected benchmark because of the mitigation strategies in place in France and reduced rehabilitation capacities.

This article is protected by copyright. All rights reserved A third step was the implementation of a screening strategy to avoid peri-LT SARS-CoV-2 infection. In contrast to some centers which only test symptomatic recipients, we opted for systematic testing in all recipients prior to LT. 9, 23 For the first three recipients, we used RT-PCR and quickly added chest CT-Scan to the systematic screening protocol, based on data showing good sensitivity of chest CT-scan for detecting symptomatic and asymptomatic SARS-CoV-2 infected patient. 24 Chest-CT slots were available 24/24h and in collaboration with our virology laboratory we were able to have pre-LT results from RT-PCR within less than 6 hours. Since recipients selected for LT were admitted to the hospital at least 6 hours before the transfer to the operating room, no significantly delay due to pending test results occurred. Additionally, potential liver graft donors were screened by RT-PCR and chest CT during their ICU stay and a negative SARS-CoV-2 status was mandatory to initiate the organ donation process. 7 There were thus no delays due to SARS-CoV-2 diagnostics once the donation was initiated.

Finally, the organ allocation strategy played a major role. Our results showed optimal donor-recipient matches (median BAR score 8) with liver grafts procured from very young donors presenting a low DRI. This allowed balancing the high pre-LT risk in two recipients with a MELD> 25 by the use of optimal grafts. One explanation of the availability of such grafts may be the selection policy of the donor centers, focusing efforts on these young donors. Furthermore, similar to the transfer of SARS-CoV-2 infected patients from hospitals with insufficient ICU capacity to less affected hospitals across France during the study period, we also observed reallocation of liver grafts from regions with a high number of hospitalized SARS-CoV-2 patients to our center ( Figure 1 ). 25 For example, recipient N.8 (Table 1 ) received a liver graft declined by a center from a region with a high SARS-CoV-2 incidence because the initial recipient was screened SARS-CoV-2 positive. We conclude that all transplant centers should be ready to accept or decline liver grafts according to their local SARS-CoV-2 dynamics in order to guarantee optimal utilization of available grafts. In this context, centers may anticipate a back-up recipient in case of SARS-CoV-2 positive screening in the initial recipient. Furthermore, as a consequence of reallocation of liver grafts, cold ischemia time may be extended as in the case of recipient N.8

were total static cold storage duration was 10 hours. This may increase the risk of allograft dysfunction or primary non-function and centers may consider using ex-vivo machine perfusion strategies to recondition grafts with extensive ischemic damage 26 .

This retrospective single-center report has inherent limitations. Regarding the small patient Table 1 . Characteristics of ten consecutive liver transplantations performed during the peak of the SARS-CoV-2 pandemic at a single-center Table 2 . Post-transplant outcomes at hospital discharge compared to the available benchmark Table 3 . Center-specific decisional steps to maintain a liver transplant activity based on international guidelines Accepted Article 

COVID-19 in solid organ transplant recipients: a single-center case series from Spain

COVID-19 in long-term liver transplant patients: preliminary experience from an Italian transplant centre in Lombardy

Liver transplantation in an ICU dominated by COVID-19. Liver Transplant

Lest we forget

Risk of COVID-19 for patients with cancer

American Association for the study of liver diseases : Clinical insights for hepatology and liver transplant providers during the COVID-19 pandemic

Point de situation au 21 avril 2020 : Activité de prélèvement et de greffe d'organes et de tissus durant l'épidémie de COVID 19

COVID-19 : point épidémiologique du 9

COVID-19: A global transplant perspective on successfully navigating a pandemic

Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis

Accepted Article This article is protected by copyright. All rights reserved

Defining Benchmarks in Liver Transplantation: A Multicenter Outcome Analysis Determining Best Achievable Results

Characteristics associated with liver graft failure: the concept of a donor risk index

Simple Predictor of Post Liver Transplant Mortality for Optimization of Donor/Recipient Matching

Are there better guidelines for allocation in liver transplantation? A novel score targeting justice and utility in the model for end-stage liver disease era

Clinical Best Practice Advice for Hepatology and Liver Transplant Providers During the COVID-19 Pandemic: AASLD Expert Panel Consensus Statement

Novel Coronavirus-19 (COVID-19) in the immunocompromised transplant recipient: #Flatteningthecurve

Coronaviruses and immunosuppressed patients. The facts during the third epidemic. Liver Transplant

Clinical characteristics and immunosuppressants management of coronavirus disease 2019 in solid organ transplant recipients

Fatal outcome in a liver transplant recipient with COVID-19

COVID-19 epidemic: proposed alternatives in the management of digestive cancers : A French Intergroup clinical point of view

Accepted Article This article is protected by copyright. All rights reserved 21

Early Impact of COVID-19 on Transplant Center Practices and Policies in the United States

COVID-19: Thoughts and comments from a Tertiary Liver Transplant Center in France

Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases

France's TGV speeds Covid-19 patients to spare hospital beds

Machine perfusion strategies in liver transplantation

Accepted Article

Local Regional National National National Local National National National