key: cord-0861736-5nrjtr08
authors: Polak, Wojciech G.; Fondevila, Constantino; Karam, Vincent; Adam, Rene; Baumann, Ulrich; Germani, Giacomo; Nadalin, Silvio; Taimr, Pavel; Toso, Christian; Troisi, Roberto I.; Zieniewicz, Krzysztof; Belli, Luca S.; Duvoux, Christophe
title: Impact of COVID‐19 on liver transplantation in Europe: Alert from an early survey of European Liver and Intestine Transplantation Association (ELITA) and European Liver Transplant Registry (ELTR)
date: 2020-07-01
journal: Transpl Int
DOI: 10.1111/tri.13680
sha: a87f28993fba12ced198b565fb7e9989a1372a94
doc_id: 861736
cord_uid: 5nrjtr08

There are scarce data on the impact of COVID‐19 pandemic on liver transplantation (LT) in Europe. The aim of this study was to obtain a preliminary data on incidence, management and outcome of COVID‐19 in liver transplant recipients and candidates in Europe. An internet‐based survey was sent to the centers affiliated with ELTR. 109 out of 149 (73%) of ELTR centers located in 28 European countries (93%) responded. 94 (86%) of the centers tested all donors and 75 (69%) centers tested all LT recipients for SARS‐Cov‐2. 73 (67%) centers selected recipients for LT in the COVID‐19 pandemic, whereas 33% did not. Eighty‐eight centers reported COVID‐19 infection in 57 LT candidates and in 272 LT recipients. Overall crude incidence of COVID‐19 among LT candidates and recipients was estimated 1.05 % (range 0.5%‐20% and 0.34% (range 0.1%‐4.8%), respectively and it was significantly higher among candidates (p<0.001). Crude rate of death was 18% (10/57) among candidates and 15% (36/244) among recipients. This first large‐scale European snapshot study clearly shows that both LT candidates and recipients are at a high risk for COVID‐19. These results plead for an early and pro‐active screening of COVID‐19 symptoms in these populations.

Authors' contribution:

WGP -designed and performed the study, analyzed data, wrote the manuscript CF -designed and performed the study, wrote the manuscript VK -collected and analyzed data, wrote the manuscript RA -designed and performed the study, wrote the manuscript UB -designed and performed the study, critically revised the manuscript GG -designed and performed the study, critically revised the manuscript SN -designed and performed the study, critically revised the manuscript PT -designed and performed the study, critically revised the manuscript CT -designed and performed the study, critically revised the manuscript RIT -designed and performed the study, critically revised the manuscript KZ -designed and performed the study, critically revised the manuscript LB -designed and performed the study, critically revised the manuscript

Since the declaration on 11 th March 2020 by the World Health Organization of the SARS-Cov-2/COVID-19 pandemic, a considerable amount of publications and data regarding clinical presentation, natural history of the disease and risk factors driving prognosis in general population have been accumulated [1] [2] [3] . However, there is still scarce data regarding specific populations with unique risks, such an organ transplant recipients [4] [5] [6] . Whether immunosuppression is associated with more aggressive patterns of infection versus general population, or on the contrary, may protect against the dramatic innate, inflammatory immune response that arises with relative frequency in the course of the disease is unknown [7] [8] .

A recent short communication reported on 3 severe cases of COVID-19 leading to death among a cohort of 111 COVID-19 liver transplant recipients in Lombardy, providing initial indication of a potentially aggressive disease pattern in this population [9] . recipients as well as on strategies adopted by LT centers to cope with LT in this unprecedented period.

An internet-based survey was sent to the main investigator and all the co-investigators registered in the ELTR platform, in accordance with ELTR regulations. The survey consists of two parts ( Figure 1 ). The first questionnaire (SurveyMonkey 1: SM1) contained 17 items (Supplemental file 1). Apart from center identifying information and case volume , all the other items were multiple-choice questions related to how SARS-Cov-2 affected LT donor, candidate and recipient management at each center. In the second questionnaire (SurveyMonkey 2: SM2), in order to obtain more concrete data

This article is protected by copyright. All rights reserved regarding symptomatic COVID-19 infection among LT candidates and recipients, 14

questions was sent in parallel and scheduled to be updated on a regular basis over the period of the epidemic (Supplemental file 2). Symptomatic COVID 19 cases in LT candidates/recipients were defined as patients presenting with relevant clinical symptoms and positive swab PCR and/or highly suggestive lung injury on thoracic CT scan. Data from the second questionnaire has been updated through April 24, 2020.

The first questionnaire ( Categorical variables, were summarized as frequencies and percentages, and groups were compared by Chi-squared test. P-value of <0.05 was considered significant.

One hundred nine out of 149 (73%) of ELTR centers located in 28 European countries (93%) responded the survey SM1 ( Figure 1 ).

This article is protected by copyright. All rights reserved Eighty six percent of the centers tested all donors for SARS-Cov-2, while 8% did not ( Figure 2A ). Remaining centers (6%) temporary halted all transplant activity due to the lack of donors and/or other collateral effects the pandemic. The majority centers (91%) responded that they did not transplant livers from SARS-Cov-2 positive donors. Only 3% centers responded that they did or would consider transplanting organs from SARS-Cov-2 positive donors ( Figure 2B ): 51% to high urgent candidates only, 2 % to high MELD candidates only, and remaining 47% to any potential LT candidates ( Figure 2C ). In centers performing living donor liver transplantation, 54% responded that they tested their donors for SARS-Cov-2, whereas 32% did not ( Figure 2D ). If the living donor turned out to be SARS-Cov-2 positive, 53% of the centers responded that they would delay donation after donor recovery >2 weeks ( Figure 2E ), and additional 39% would extend that delay to >4 weeks (data not shown).

Among responders, 69% tested all liver transplant recipients for SARS-Cov-2 at the moment a liver became available for transplantation , while 30% performed no test( Figure   3A ). If the test resulted positive, 55% of responders cancelled LT, 34% re-allocated the liver to another potential recipient and only 5% responded that they would proceed with LT as originally planned ( Figure 3B ). In case of unknown status of SARS-Cov-2 in the potential liver recipient 42% centers went forward with LT, 22% canceled LT and 18% reallocated the liver to another recipient ( Figure 3C ).

During the height of COVID-19 pandemic, 33% centers did not select potential recipients for LT, 32% selected only high MELD or high urgency patients, 26% selected only high urgency patients, 7% selected only high MELD patients, 1% selected only children and 1% selected only high urgency children ( Figure 3D ).

If COVID-19 were to be diagnosed post-transplant, 44% of responders modified immunosuppression therapy, 42% modified immunosuppression and started antiviral treatment, and 14% started only antiviral treatment without modification of immunosuppression regimen ( Figure 3E ).

Among the 149 active ELTR centers, 117 completed the SM2 (79%) providing data from 80% of ELTR countries. Fifty-seven cases of symptomatic COVID-19 among LT candidates and 272 cases of COVID-19 among LT recipients were identified. No cases

This article is protected by copyright. All rights reserved symptomatic cases were detected among candidates and recipients at 49% centers (57/117) and 74% centers (86/117), respectively..

Evolution of the overall number of COVID-19 cases reported to the survey is shown in Based on these figures, the overall crude incidence of symptomatic COVID-19 in the LT candidates was estimated to be 1.05% (57/5440) ranging from 0.5% to 20% across centers. Among LT recipients, the incidence was estimated to be 0.3% (244/71,516), ranging from 0.1% to 5%. The incidence of symptomatic COVID-19 infection was significantly higher in LT candidates compared to LT recipients (p<0.001). It was also significantly higher among LT candidates compared to the general population (p<0.001) as shown in Figure 6 . The incidence of symptomatic COVID-19 infection among LT recipients was not different compared to the general population.

Eight LT candidates and 33 LT recipients were admitted to intensive care over the observation period, corresponding to a crude incidence for intensive care admission of 14% for both groups.

Mortality rates among LT candidates, LT recipients, and in the general population, overall and by country, are shown in Figure 7 . Among the 57 and 244 COVID-19 cases reported pre-LT and post-LT, 10 and 36 patients, respectively, died due to COVID-19 or its

This article is protected by copyright. All rights reserved complications corresponding to a crude rate of death of 18% (10/57) among LT candidates and 15% (36/244) among LT recipients.

While death rates did not vary significantly between candidates and recipients, mortality due to COVID-19 was significantly higher among LT patients than among the general population (79,039 deaths among 939,741 infections -8%; P<0.05 versus LT candidates and <0.001 versus LT recipients).

Although a considerable amount of data about the incidence and severity of COVID-19 in the general population have accumulated over the past 2 months, data regarding COVID-19 in transplant populations are still scarce [4, 5, 9] . A preliminary report provided an initial indication that severe forms of COVID-19 may lead to death among LT patients, but the magnitude of the problem up until this point has remained relatively unclear [9] . 

This article is protected by copyright. All rights reserved without limitations, our preliminary data also suggest that symptomatic COVID-19 may be observed significantly more frequently in both LT candidates and recipients than in the general population.

The rate of admission to intensive care and deaths related to COVID-19 were high in both LT candidates and LT recipients and did not differ significantly between these two groups. Mortality related to COVID-19 was 18% among LT candidates and 15% among LT recipients,was significantly higher than mortality estimated among the general adult population (8%). Of note, data on the incidence of symptomatic COVID-19 infection and associated mortality rates were unadjusted yet and should be interpreted with caution.

More studies are needed to define risk factors for a poor outcome following COVID-19

infection in the LT setting, in order to effectively use limited medical resources and avoid futile treatment.

It is well-known that among the general population symptomatic cases of COVID-19 and cases resulting in death bear direct relation with male sex increasing age, and obesity. It is also known that male sex is more frequent among the LT population in general, among which approximately 70% of LT candidates and recipients are men [15] . Although gender and age were not available for the whole survey population (data collection in progress), preliminary analysis of a subset of LT candidates and recipients (data not shown) has revealed, a higher percentage of men among LT candidates (93%) and LT recipients (67%) and mean ages of 59±15 and 62±14 years for each group, respectively. One cannot, therefore exclude the possibility that the apparently higher incidence of symptomatic and severe forms of COVID-19 compared to general population as observed in this survey is driven by higher percentage of men among LT candidates and LT recipients and higher mean ages for each group.

To overcome this issue, collection of more detailed data in our study population, including age, sex, co-morbidities, clinical presentation, and management of COVID-19 infection, is in progress and will be the basis of another futurereport.

Another part of our study focused on the current practices among LT centers in Europe regarding donor and recipient management in the period surrounding the peak of COVID-19 infection. Not surprisingly, the majority of the centers are performing PCR tests on nasopharyngeal swab among both deceased donors (86%) and recipients (69%) in order to detect presence of SARS-Cov-2, which is in a line with the recommendations of Accepted Article transplant societies [16] . However, as recently reported the transplant centers also face a lack of empiric evidence on COVID-19 and standardized protocols to ruled out SARS-Cov-2 infection [17] . Another striking information from the survey is that 6% of liver transplant centers in Europe temporarily halted LT activity due to lack of the donors and other collateral effects of the pandemic (e.g., lack of non-COVID intensive care, general ward, and even operating room space to safely care for LT patients in the perioperative period 

This article is protected by copyright. All rights reserved 

Behillil Set al. Clinical and virological data of the first cases of COVID-19 in Europe: a case series

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Covid-19 and Kidney Transplantation

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

COVID-19 in a lung transplant recipient

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

HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression

Case report of COVID-19 in a kidney transplant recipient: Does immunosuppression alter the clinical presentation?

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

COVID-19 In Spain: Transplantation In The Midst Of The Pandemic

The COVID-19 outbreak in Italy: Initial implications for organ transplantation programs

\ all the other 126 contributing centers (www.eltr.org) and the European Liver and Intestine Transplant Association (ELITA)

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

Solid Organ Transplantation Programs Facing Lack of Empiric Evidencein the COVID-Accepted Article

The authors would like to acknowledge Dr. Amelia Hessheimer for a critical review of this manuscript.ELITA would like to express gratitude to all ELTR centers contributing for this survey