key: cord-0878457-6nv3xb9n
authors: Russo, Francesco Paolo; Izzy, Manhal; Rammohan, Ashwin; Kirchner, Varvara A.; Di Maira, Tommaso; Belli, Luca Saverio; Berg, Thomas; Berenguer, Marina Carmen; Polak, Wojciech Grzegorz
title: Global impact of the first wave of COVID-19 on liver transplant centers: A multi-society survey (EASL-ESOT/ELITA-ILTS)
date: 2021-10-13
journal: J Hepatol
DOI: 10.1016/j.jhep.2021.09.041
sha: 5ee3949112bc132cd66611c8a427d975a1704a88
doc_id: 878457
cord_uid: 6nv3xb9n

BACKGROUND AND AIMS: The global impact of SARS-CoV-2 on liver transplantation (LT) practices across the world is unknown. The goal of this survey was to assess the impact of the pandemic on global LT practices. METHOD: A prospective web-based survey (available online from 7(th) September 2020 to 31(st) December 2020) was proposed to the active members of the EASL-ESOT/ELITA-ILTS in the Americas (including North, Central, and South America) (R1), Europe (R2), and the rest of the world (R3). The survey comprised four parts concerning the transplant processes, therapy, living donor, and organ procurement. RESULTS: Of the 470 transplant centers reached, 128 answered each part of the survey, 29 centers (23%), 64 centers (50%), and 35 centers (27%) from R1, R2, and R3, respectively. When we compared the practices during the first six months of the pandemic in 2020 with that a year earlier in 2019, statistically significant differences were found in the number of patients added to the waiting list (WL), the number of WL mortality, and the number of transplantations. At the regional level, we found that in R2 the number of LTs was significantly higher in 2019 (p < 0.01), while R3 had more patients listed, higher WL mortality, and more LTs performed before the pandemic. Countries severely affected by the pandemic (“hit” countries) had a lower number of WL patients (p = 0.009) and LT (p = 0.002) during the pandemic. Interestingly, WL mortality was higher in the pandemic in “non-hit” countries (p = 0.022) compared to 2019. CONCLUSION: The first wave of the pandemic differentially impacted LT across the world, especially with detrimental effects on the “hit” countries. The modifications in the policies for recipient and donor selection, organ retrieval, and postoperative recipient management were adopted at a regional or national level. LAY SUMMARY: The health emergency caused by the Coronavirus has dramatically changed clinical practice during the pandemic. The first wave of pandemic impacted Liver Transplantation across the world differently, especially with detrimental effects on the hit countries. The resilience of the entire transplant network has enabled the support of organ donations and transplants to ultimately improve the lives of patients with end-stage liver disease.

In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China as a serious threat to public health (1) . Since then, SARS-CoV-2 has become a devastating pandemic that has remarkably overwhelmed the healthcare systems around the world, resulting in more than 168 million infections with a death toll exceeding 3.5 million as of May 2021 (2) .

Additionally, the collateral damage of the SARS-CoV-2 pandemic has been extensive, disrupting the management of acute and chronic diseases globally (3) (4) (5) .

The early days of the pandemic had demonstrated that SARS-CoV-2 affected liver transplantation at the level of the infrastructure, as well as the individual patient and provider (6) . The operation of the liver transplantation (LT) program, including evaluation and selection of potential candidates, wait-list management, donor evaluation, transplantation, and subsequent recipient and living donor follow-up, requires substantial resources and infrastructure that were compromised, especially early in the pandemic as demonstrated by few regional studies (7) . In countries with primarily deceased donations, the situation was further complicated as individual liver transplant programs depend on the donor networks to continue liver transplantation (8) . Patients with cirrhosis (9) and recipients of liver transplants (10) are thought to be at a higher risk of morbidity and mortality from SARS-CoV-2. Liver donor to recipient transmission has also been reported (11) .

Frontline healthcare workers have been at a higher risk of SARS-CoV-2 infection (12) , causing a large proportion of the workforce to be temporarily out of J o u r n a l P r e -p r o o f service. These factors have led liver transplant centers worldwide to adopt various strategies hoping to mitigate the risk of their patients and liver transplant care providers. These strategies involved every aspect of the liver transplant process, including managing infected or exposed patients on the wait-list, pausing or limiting transplant and donor operations, implementing new policies regarding retrieval of the donated organs, adjusting post-transplant immunosuppression, and adopting virtual technology for patient follow-up, among other policies (13) . Currently, there is insufficient data on the changes in these practices and/or risk mitigation approaches and policies. Therefore, a task force was formed in mid-2020 by the European Association for the Study of Liver disease (EASL), International Liver Transplantation Society (ILTS), and the European Liver and Intestine Transplant Association (ELITA) of the European Society of Organ Transplantation (ESOT) to investigate the global impact of the first wave of the SARS-CoV-2 pandemic on liver transplant centers and their patient care practices by a multidisciplinary online survey. Here, we report the results of the survey and their implications, which may help the liver transplant centers to operate better if they continue to encounter the sequelae of the current pandemic and optimize these programs for future pandemics.

A prospective cross-sectional web-based survey (available online from 7 th September 2020 to 31 st December 2020) was designed by a group of investigators dedicated to the care of patients in need of liver transplants from three international societies: EASL, ESOT-ELITA, and ILTS. The The study protocol conformed to the ethical guidelines and was approved by the institutional review board of Vanderbilt University Medical Center, USA. The survey was available on the websites of all three societies, and all members of the societies were invited by email to respond, ensuring not to duplicate the emails or the personnel at each center. The survey was also promoted via social media platforms (Twitter and Facebook accounts of the participating societies). The J o u r n a l P r e -p r o o f participants were given a choice to disclose their transplant center names and contact information, and 97% of the participants disclosed the information. Non-respondents were contacted at least twice.

The survey was divided into four independent parts. Section 1 assessed the influence of the pandemic on LT programs across the globe, evaluating different topics such as wait-listing, transplant volumes, mortality, and others, compared to that in the same period in the previous year. Section 2 evaluated the impact of special precautions, modifications, and demands required for the continuation of services during the first wave of the pandemic. Section 3 dealt with different aspects of living donations during the pandemic. Finally, Section 4 highlighted the effects of the pandemic on deceased liver donations, especially regarding strategies to recover organs (Supplementary Section 1).

Data was collected and categorized into three regions: the Americas (including North, Central, and South America) (R1), Europe (R2), and the rest of the world (R3).

Data was expressed as a median and interquartile range, while categorical variables were expressed as percentages. Continuous variables were compared by unpaired Student's T-test, Mann-Whitney U-test, or Wilcoxon signed paired test for related variables. Distribution was assessed by normality plots and the Shapiro-Wilk test. Categorical variables were compared by determining X 2 values by performing Fisher's exact test. Trends in the number of patients listed for liver transplantation, mortality in the waiting list, and the number of liver transplants performed between similar periods before and after the pandemic were expressed as a ratio (e.g., variable between 1st January and 1st July in 2019/variable between 1st January and 1st July in 2020) and changes were assessed by multivariable linear regression after adjusting for COVID19 case-fatality rate, living donor activity and country. Analysis of subgroups was performed for assessing outcomes according to the continents "hit" versus "non-hit" countries, and volume of living donor activity. Continents 

A total of 470 liver transplant centers were reached across the world. Among these, 128 Table 1) . A further sub-analysis to assess the impact of the geographical heterogeneity of the pandemic on regional LT services across countries and continents showed that Asia had fewer wait-listed patients in 2020 than at a similar period in the previous year (33.3% vs 63.3%, p = 0.040) ( Table 2) . Europe also showed a non-significant trend with fewer wait-listed patients in 2020 (59.4% and 31.3% centers in 2019 and 2020, respectively) ( Table 2 ). In 2020, the wait-list mortality was higher in Asia (58.6% vs 20.7%, p = 0.041), while Europe showed a non-significant trend (27.4% vs. 51.6% centers with a mortality rate in 2019 and 2020, respectively) ( Table 2) . Correspondingly, a higher number of LT were performed in 2019 than in 2020 in Asia and Europe (p = 0.011 for both continents), while these trends were not observed in the Americas (Table 2) . However, corrections for post hoc comparisons showed no significant difference across the continents (corrected significance of p-value ≤ 0.006). With low respondents from Africa and Australia, these continents were excluded from the analyses ( Table 2 Table 2 ). "Hit" vs. "non-hit" countries COVID19 case-fatality rate of 3.4% was considered the best cut-off for "hit" versus "nonhit" countries with a 95% of probability to fall between 0.028 and 0.051 bounds based on the main outcomes of liver transplant activity. 3) during the pandemic as compared to 2019. Interestingly, the pre-pandemic mortality rate in wait list was higher in the "non-hit" countries than in the "hit" countries (54% vs 24.4%, p=0.022 and 50% vs 27.1%, p=0.124, respectively). However, only waitlisted patients and the number of LT performed in "hit countries" were significantly diminished in pandemic era after post hoc comparison correction (corrected p-value ≤ 0.013) (Supplementary Section 2 Figure 3 ).

Another subgroup analysis of LDLT centers categorized as low volume (≤ 30% LDLT activity) and high volume (> 30% LDLT activity) showed that the influence of the pandemic was more obvious in high volume LDLT centers. There were significantly fewer wait-listed patients (27% vs 70.3%, p=0.005 in 2020 vs 2019) ( Table 4 ) and fewer LTs performed in high volume LDLT centers (35% vs 62.5%, p=0.013) ( Table 4 ) after the pandemic compared to that in 2019. The "low volume"

LDLT centers were predominantly from the Americas and Europe and had a similar number of waitlisted patients, but a lower number of LTs performed in 2020 compared to that in 2019 (34.7% vs 59.7%, p=0.006 in 2020 vs 2019, respectively). However, the wait-list mortality in both high and low volume LDLT centers was similar across the two periods (57.1% vs 25.7%, p=0.089 and 47.8% vs 29%, p=0.123, respectively) ( Table 4 ). Moreover, the waitlist mortality was not associated with COVID19 case-fatality rate once adjusted for country and LDLT activity. Data was confirmed after no data were available on the 4 th donor.

Between 18.2% and 36.4% of the recipients tested positive for SARS-CoV-2 after LT with a mortality rate of R1 = 25%, R2 = 20%, and R3 = 8.3% across the three regions. Only 23% of the centers retested donors/recipients for COVID at discharge. 

Nearly all transplant centers depended heavily on virtual technology during the pandemic, and very few centers did not use telemedicine (R1 = 0%, R2 = 12.3%, and R3 = 14.3%).

SARS-CoV-2, an invisible microorganism, has put the whole world under pressure, with devastating health, human and economic costs (14) . Yet, it is crucial to recognize that the frequency of pandemics have increased over the past twenty years and it is unlikely that SARS-CoV-2 will be J o u r n a l P r e -p r o o f the last global health crisis that we witness, as discussed by Drs. Morens and Fauci in their recent publication "Emerging Pandemic Diseases: How We Got to COVID-19". (15) . Therefore, the lessons learned from the current pandemic including the impact on the individual areas of medical practice could be critical knowledge for the future in the instance of the new health crisis.

Although it has been recognized that SARS-CoV-2 pandemic had a profound impact on the healthcare system, data about the global impact of the virus on LT practices across the world are limited.

The survey showed an early cessation of activity in LT centers, generally for four weeks. (25), feeling distressed or anxious is understandable for many going through such unprecedented times. Clearly, for those who are vulnerable, it is important to be vigilant to mitigate the risks to mental health difficulties. We also need to consider longer term preventive approaches more broadly, so that we are more responsive to the chronic outcomes of the current pandemic as well as being better prepared for future public health crises.

As expected, the regions most affected by the pandemic were the ones that had fewer patients Immunosuppression in these patients may result in adverse outcomes, and the optimal diseasefree interval is currently unknown (31) (32) (33) (34) (35) . For the reduction of immunosuppression to prevent SARS-CoV-2 infection, most centers evaluated recipients on a case-by-case basis. The EASL guidelines confirmed these findings, suggesting that reduction should only be considered under special circumstances (e.g., medication-induced lymphopenia or bacterial/fungal superinfection in case of severe COVID-19) (36). The results from the ELITA-ELTR multicenter study demonstrated that the use of tacrolimus was associated with better survival in 243 symptomatic liver transplant recipients (37) . Recent data from Spanish transplant centers showed that the baseline immunosuppression using mycophenolate was an independent predictor of severe COVID-19 and it was dose-dependent (38) .

We also found a discrepancy in the prophylactic use of subcutaneous anticoagulants to prevent thromboembolism. In most of the European centers and few centers from other regions, heparin or heparin-like drugs were routinely administered in transplant patients.

Another issue raised by the survey was whether donors/recipients were tested for Sars-CoV- Table 3 Center with higher number of listed patients, higher mortality in the WL for LT and higher LT performed, comparing 2019 vs 2020 in hit vs non-hit countries

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We sincerely and deeply acknowledge all respondents for their precious participation in this timesensitive survey (all the centers are listed in the Supplementary Section 3, 

 Table 4 Center with higher number of listed patients, higher mortality in the WL for LT and higher LT performed, comparing 2019 vs 2020 in low LDLT activity vs high LDLT activity J o u r n a l P r e -p r o o f  Liver transplantation was severely affected in every aspect by SARS-CoV2 pandemic  An international multi-society taskforce evaluated the real impact of SARS-CoV2's first wave  The pandemic detrimentally impacted transplant operations in heavily hit countries  Transplant centers' resilience led to efficient accommodations in clinical practice  These observations may serve to handle future emergencies of this magnitude J o u r n a l P r e -p r o o f