key: cord-317707-r0q7ipa6
authors: Saracco, Margherita; Martini, Silvia; Tandoi, Francesco; Dell’Olio, Dominic; Ottobrelli, Antonio; Scarmozzino, Antonio; Amoroso, Antonio; Fonio, Paolo; Balagna, Roberto; Romagnoli, Renato
title: Carrying on with Liver Transplantation during the COVID-19 emergency: Report from Piedmont Region
date: 2020-08-07
journal: Clin Res Hepatol Gastroenterol
DOI: 10.1016/j.clinre.2020.07.017
sha: 
doc_id: 317707
cord_uid: r0q7ipa6

BACKGROUND: The COVID-19 pandemic is an emergency worldwide. In Italy, Liver transplant activity was carried on, but despite all efforts, a 25% reduction of procured organs has already been observed during the first 4 weeks of the outbreak. AIMS: To analyze if our strategy and organization of LT pathway during the first two months of the COVID-19 emergency succeeded in keeping a high level of LT activity, comparing the number of LT in the first two months with the same period of time in 2019. METHODS: We compared the Liver transplants performed in our Center between February 24(th) and April 17(th), 2020 with Liver transplants performed in the same period in 2019. RESULTS: In 2020, 21 patients underwent Liver transplantation from deceased donors, exactly as the year before, without statistically significant difference. All patients survived in both groups, and the rate of early graft dysfunction was 24% in 2020 and 33% in 2019. In 2020 Median MELD was higher (17vs 13). We were able to perform 3 multiorgan transplants and one acute liver failure. Nobody died on waiting list. The performance of our Center, despite the maxi-emergency situation, was steady and this was the result of a tremendous team working within the hospital and in our Region. CONCLUSIONS: Team working allowed our Center to maintain its activity level, taking care of patients before and after Liver transplantation. Sharing our experience, we hope to be helpful to other Centers that are facing the pandemic and, if another pandemic comes, to be more prepared to deal with it.

The COVID-19 pandemic caused by SARS-CoV-2 virus is a public health emergency affecting all aspects of medical care. On January 30 th , 2020, the World Health Organization (WHO) declared it to be a global health emergency and since March 13 th Europe became the epicenter of the pandemic. By deaths. 1 According to the European Association for the Study of the Liver (EASL) 2 

Association for the Study of Liver Disease (AASLD) 3 liver transplant (LT) activity, as an acute care treatment, should not be postponed, even in the COVID-19 era. Preliminary data in post-LT patients 4 , 5 did not show an increased risk of severe COVID-19 disease, despite immunosuppression may prolong viral shedding. 6 Cirrhotic patients might be more susceptible to virus infection because of their dysfunctional immune response and transplantation in SARS-CoV-2 positive recipients is currently not recommended 2,3 . Consequently, the Italian Transplant Authority (CNT) recommends that all pauci/symptomatic recipients and all donors ought to be tested for SARS-CoV-2 RNA (nasopharyngeal swab, NPS or bronchoalveolar lavage, BAL) 7 immediately pre-LT and those who test positive are to be considered medically ineligible for transplantation/donation; screening of asymptomatic recipients of deceased donors will depend on local resources availability. Despite all J o u r n a l P r e -p r o o f efforts to preserve transplant activity, a 25% reduction of procured organs has already been observed in Italy during the first 4 weeks of the outbreak. 8 Our working hypothesis is that our organization of LT pathway during the first two months of the COVID-19 emergency succeeded in keeping a high level of LT activity, despite the reduction of procured organs.

We aimed to analyze the number of LT performed between February 24 th , 2020 and April 17 th , 2020 with the same period of time in 2019, in our high-volume transplant Center (median 150 LT/year).

In this observational cohort study, we consecutively enrolled all patients who underwent LT in our Center, between the 24 th of February 2020 and the 17 th of April 2020. In addition, we retrospectively analyzed the LTs performed in 2019, in the same period of time. The variables assessed in the study population and their donors are shown in Table 1 .

Pursuant to Italian law, Regional Transplantation Centers are the custodians of donor/recipient biomedical data also for research purposes. All study procedures complied with the ethical standards of the 2000 Declaration of Helsinki and the Declaration of Istanbul 2008.

By the end of February 2020, the number of patients coming to our transplant clinic was limited to subjects with urgent issues and phone visits or telemedicine as appropriate replaced in-person appointments. Arrival times were staggered in order to avoid patients congregating in the waiting areas. Before entry, all patients were screened for COVID-19 symptoms or recent exposure and each patient's temperature was checked. A pre-triage form had to be filled out before every procedure.

Outpatient LT diagnostic workups were carried out by using COVID-free pathways. As already published, we recommended to our patients frequent handwashing and sanitization, avoid public places and overcrowded situations and wear a surgical mask to prevent of SARS-CoV-2 infection. [9] [10] [11] In our hospital 7 wards (5 internal medicine, pneumology and cardiology), 4 out of 5 ICUs and 1 out of 4 Radiology Unit were progressively dedicated to COVID patients; On April 17 th in the district of Turin there were 9.503 confirmed cases.

In our liver sub-intensive unit, we were allowed to continue to admit patients with severe decompensated liver disease, and from March 31 st every patient before admission was tested for SARS-CoV-2 RNA by NPSs in order to guarantee a COVID-free unit. Furthermore, among the 5 intensive care units of our hospital, the one dedicated to transplants was maintained COVID-free, by testing each transplant recipient in advance with SARS-CoV-2 RNA in NPS or BAL, starting from the 22 nd of March.

The only source of our donors are deceased donors after brain or cardiac death and all of them were screened for SARS-CoV-2, according to CNT guidelines. A deceased donor graft was defined suboptimal if donor age was ≥65 years and/or had macrovesicular steatosis ≥15%. 12 The degree of fatty infiltration of the graft were assessed on liver biopsies routinely obtained at the end of transplant surgery. In our center, from 2016, grafts from brain death donors characterized by increased risk profile (donors >80 years and/or obese donors) as well as from donors after cardiac death undergo Hypothermic Oxygenated Machine Perfusion (HOPE) before implantation, to reduce ischemiareperfusion injury. Recently, normothermic machine perfusion (OrganOx) was also used.

After LT, immunosuppression consisted of tacrolimus, mycophenolate mofetil and steroids, as per our standard protocol. Early allograft dysfunction (EAD) was defined according to Olthoff: 13 total J o u r n a l P r e -p r o o f bilirubin level  10 mg/dL or international normalized ratio  1.6 on postoperative day 7 or aspartate aminotransferase or alanine aminotransferase level > 2000 IU/L within the first 7 days after transplant.

Categorical variables were represented as number (n) and percentage (%) and compared using Fisher's exact test or Chi-square test. Quantitative variables were shown as median and interquartile range (25th-75th percentiles, IQR) and their distribution was evaluated with D'Agostino & Pearson test; parametric data were evaluated by t-test, non-parametric data were evaluated by Mann-Whitney U test. P<0.05 in a two-tailed test was considered statistically significant.

Between February 24 th , 2020 and April 17 th , 2020, among 22 admissions in our 7-bed sub-intensive liver unit, a 40-year-old woman, who was listed during hospitalization, developed fever during hospitalization and tested positive for SARS-CoV-2 RNA in NPSs. Immediately transferred to a COVID unit, she came back to our unit after 7 days and 2 negative SARS-CoV-2 RNA in NPS and underwent LT the day after readmission to our unit.

At the beginning and at the end of the enrollment period 51 and 52 patients, respectively, were actively on the LT waiting list. None of the patients on the LT waiting list had to be admitted to hospital for COVID-19 and the on-list mortality rate was 0%. During the study period, 21 first LTs were consecutively performed in our Center. The majority of the recipients were male, with a median age of 56 years (IQR 51-65). The median biochemical Model for end-stage Liver disease (MELD) at LT was 17 (IQR 12-22). Twenty patients were affected by cirrhosis (20% viral-, 35% alcohol-, 25% autoimmune/cholestatic-related) and 45% of them also by hepatocellular carcinoma (HCC). Two out J o u r n a l P r e -p r o o f of the twenty patients underwent combined liver-kidney transplant and one combined lung-liverpancreas transplant. One patient was transplanted for HBV-related acute liver failure (ALF) ( Table   1 ). Four out of 21 patients (19%) were hospitalized at the time of LT and the ALF patient was in the ICU on ventilator/respiratory support. Looking at the donors: 86% of the graft were recruited in our regional area. The median donor age was 58 years (IQR 38-72) and 48% of the grafts were suboptimal. The median cold ischemia time was 452 minutes (IQR 346-473). Ex vivo normothermic machine perfusion was employed for one graft, and hypothermic perfusion for 3 grafts. 95% of livers came from brain-dead donors and one from a donor after cardiac death. After LT, 1 out of the 21 recipients was found positive for SARS-CoV2 on NPS on his 5 th day post-LT, after his bed neighbor, who was recovering from liver resection, had tested positive the day before. His oxygen saturation was persistently normal and CT scan was negative for pneumonia. We transferred the patient immediately to the COVID unit, where precautionary hydroxychloroquine 400 mg twice daily was administered for 16 days. Mycophenolate mofetil dosing was reduced from 1500 mg/day to 1000 mg/day and target tacrolimus trough level was set at 5-7 ng/ml. He was discharged after 18 uneventful days in COVID unit, and the SARS-CoV2 on NPS is still positive, without specific symptoms.

In 2019, over the same period of time, at the beginning and at the end of the enrollment period 60 and 71 patients, respectively, were actively on the LT waiting list; the mortality rate on the LT waiting list was 0% and we performed the same number of LTs (19 first transplant and 2 re-transplants), compared with 2020. 71% of the patients was male, with a median age of 58 years (IQR 56-62). The median biochemical MELD at LT was 13 (IQR 9-18) with an HCC rate of 38%. The etiology of liver cirrhosis was viral for 52% of the cases, alcohol related for 24%. The median donor age was 60 years (IQR 51-63), all of them were brain-dead and 76% of the graft were recruited into our regional area.

The median cold ischemia time was 431 minutes (IQR 393-495) and 33% of the grafts were suboptimal. Ex-vivo hypothermic machine perfusion was used in 29% of the grafts. All patients survived in both groups, and the rate of EAD was 24% in 2020 and 33% in 2019 (Table   1) . We did not find any statistically significant difference between the two cohorts.

We compared LT activity in our Center during the first 2 months of COVID-19 pandemic, starting since February 24 th , with the same period of the year before. Italy has been the first European country to face the severe COVID-19 pandemic since February 2020 and our National Healthcare System, which offers universal access to health care to all residents, is facing a tremendous pressure. Hospitals and health workers were asked to suspend all non-urgent activities and to postpone all planned surgery in order to give over beds to the treatment of COVID-19 patients. In accordance with AASLD and EASL recommendations, 2,3 transplant surgery was excluded from these limitations, in order not to compound the outbreak lethality with risking the lives of patients who need a life-saving LT. This requires stringent criteria for prioritizing patients who are more likely to die on the wait list and a delicate balance with the risk of hospital-acquired COVID-19. In order to optimize resource utilization and to avoid transplantation in virus-positive patients, every effort has been made to prevent SARS-CoV-2 infection in patients before and after LT and the SARS-CoV-2 molecular screening for donors and symptomatic recipients became mandatory.

In our Country deceased donors are the prevalent organ resource and a restriction in the number of available ICU beds necessarily influenced the donation activity; in fact, during the first 4 weeks of COVID-19 outbreak the number of procured organs dropped by 25%, as reported by CNT.

From 1990 more than 3000 LTs have been carried out at our Center and the annually LT volume is around 150. The Unit is located into a region strongly hit by COVID-19 (454 cases per 100,000 1 1 inhabitants and 50 deaths per 100,000). In our study we evidenced that, despite the emergency public health situation, we performed during the first 2 months the same number of LT of the year before, without mortality on the waiting list and early post-transplant. Median MELD was higher as well as the complexity of patients: we managed 3 multiorgan transplants and one acute liver failure, without significantly impacting on the ICU hospitalization days (median ICU-stay value: 5 days in 2020 vs 4 days in 2019, P=0.69) and all patients survived in both groups. Furthermore, the majority of the donors were recruited in our regional area, one of the hardest hits by the virus, and we were able to manage machine perfusion in 19% of the cases inside our hospital. We did not change our standard immunosuppression regimen, according to published data which show that immunosuppression was not a risk factor for mortality associated with SARS (2002 SARS ( -2003 or MERS (2012-present), 3,4 even if it may prolong viral shedding in post-transplant patients with COVID-19. 3, 6 We strongly believe that the steady performance of our Center, despite the maxi-emergency situation, was the result of a tremendous team working within the hospital and in the Piedmont Region. Our healthcare Director (AS) rapidly switched in our tertiary referral hospital many medical doctors and departments previously dedicated to different specialties, into new COVID-19 units, progressively increasing in number and size. Our transplant hepatologists were spared from the full-time management of COVID-units, in order to take care of outpatient and inpatient transplant patients.

Our liver sub-intensive care and transplant intensive unit were included into a COVID-free pathway within the hospital and a strong collaboration between transplant hepatologists and surgeons made possible the prioritization of patients more in need of transplant and to optimize the recipient/donor match. Furthermore, regional ICUs were able to preserve beds and intensivists for the management of a precious resource like a potential organ donor. Despite all our efforts to maintain a transplant COVID-free pathway, two transplant patients, one before and one after LT were tested SARS-CoV-2 virus positive during hospitalization and both were safely discharged home. In conclusion, Italy is facing an unprecedented health care emergency situation due to the COVID-19 pandemic. Team working with close involvement of several specialties such as hepatologists, surgeons, anesthesiologists and radiologists allowed our single regional Center to maintain its activity level, taking care of patients before and after LT. We think that LT, being a life-saving procedure, should be not suspended when it is possible. Sharing our experience, we hope to be helpful to other Transplant Centers that are now facing the COVID-19 emergency.

Financial support: Authors declare they received no financial support for this manuscript. 

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