key: cord-0787656-bqmz8p8s
authors: De Carlis, Riccardo; Vella, Ivan; Incarbone, Niccolò; Centonze, Leonardo; Buscemi, Vincenzo; Lauterio, Andrea; De Carlis, Luciano
title: Impact of the COVID-19 pandemic on liver donation and transplantation: A review of the literature
date: 2021-03-14
journal: World J Gastroenterol
DOI: 10.3748/wjg.v27.i10.928
sha: 32386f85e4777015edc55f36db42eb844fca7031
doc_id: 787656
cord_uid: bqmz8p8s

The coronavirus disease 2019 (COVID-19) pandemic has upended healthcare systems worldwide and led to an inevitable decrease in liver transplantation (LT) activity. During the first pandemic wave, administrators and clinicians were obliged to make the difficult decision of whether to suspend or continue a life-saving procedure based on the scarce available evidence regarding the risk of transmission and mortality in immunosuppressed patients. Those centers where the activity continued or was heavily restricted were obliged to screen donors and recipients, design COVID-safe clinical pathways, and promote telehealth to prevent nosocomial transmission. Despite the ever-growing literature on COVID-19, the amount of high-quality literature on LT remains limited. This review will provide an updated view of the impact of the pandemic on LT programs worldwide. Donor and recipient screening, strategies for waitlist prioritization, and posttransplant risk of infection and mortality are discussed. Moreover, a particular focus is given to the possibility of donor-to-recipient transmission and immunosuppression management in COVID-positive recipients.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has upended healthcare systems worldwide. During the first pandemic wave, overwhelming hospitals rapidly reallocated their resources and increased their capacity to attend to an exponential increase in the number of critically ill patients, leading to the limitation of oncological and elective surgery [1] . Organ donation and transplantation have also suffered an inevitable decrease [2, 3] . The second pandemic wave in most European countries has posed similar issues regarding resource allocation, although most patients are asymptomatic or present with less severe symptomatology [4] .

In the field of liver transplantation (LT), administrators and clinicians were forced to make difficult decisions regarding whether to suspend or continue a life-saving procedure during the pandemic. Therefore, the main ethical question was whether it was riskier to accept a patient for LT or to wait until the peak of the infection had decreased. The pandemic has also led to additional complexities regarding donor and recipient testing, obliged to design COVID-safe clinical pathways, and promoted telehealth to prevent nosocomial transmission.

An ever-growing number of papers on COVID-19 have been published since its initial outbreak, making it difficult to keep up with the most recent evidence on this topic. However, the amount of high-quality literature on LT remains limited, and particular care should be taken in drawing any conclusions [5] . Indeed, preliminary data during the first pandemic wave were often obtained in difficult conditions, and the race to publication has led, in some cases, to corrections and retractations [6, 7] . Aware of these limitations, in this review, we aim to analyze the impact of the pandemic on LT programs worldwide, mainly focusing on donor and recipient screening, waitlist prioritization, and immunosuppression management in COVID-positive recipients.

The first pandemic wave between February and March 2020 led to a reduction in organ donation compared to the same period in 2019, varying between 0-30% in different countries (Table 1) . For example, early data from Italy -one of the first Western countries dealing with the COVID-19 outbreak -reported a 25% decrease in procured organs during the first month of the outbreak, which paralleled the progressive rise of patients admitted to the intensive care unit (ICU) [8] . Particularly regarding LT, the United Network for Organ Sharing (UNOS) data revealed a more than 25% decrease between February and April 2020, with an inactivation rate of waitlisted patients between 5%-10% [3] . This trend is consistent with the 29% decrease registered in the Eurotransplant network in approximately the same period, which inevitably led to increased death and dropout from the waitlist [9] . Moreover, in most countries, LT activity slowly recovered in the following months from this abrupt reduction due to a second pandemic wave [4, 9] . Three different scenarios have been observed during the pandemic among centers in both Europe and the United States:

This was a last-resort measure in situations where no ICU or healthcare personnel were available [10] . It was estimated that 6% of centers in Europe temporarily halted LT activity due to the lack of donors and logistical problems correlated to the first pandemic wave [2] .

LT activity continued even in some highly stressed hospitals without being stopped a priori, but evaluating each organ offer based on the resources available at the moment [11] . Two-thirds of centers in Europe have adopted the policy of selecting only urgent recipients [2] . However, this sickest-first approach poses the risk of prolonged hospital stays for such patients, thus conversely increasing the ICU length of stay [12] . For this reason, some centers have temporarily suspended treating aging patients with comorbidities and surgical complexities to minimize the chance of complications [10, 13, 14] . Likewise, different centers have reduced the use of marginal grafts and those from donation after circulatory death for both fear of poor transplant outcomes and heavier commitment on ICU personnel [3, 15, 16] .

Other centers in areas where COVID-19 prevalence was low -or the infection reached its peak slowly -have continued their activity at a routine or even increased rate compared to 2019, being able in some cases to shunt COVID-19 affected patients elsewhere [17] [18] [19] [20] .

Significant heterogeneity has been noted in the three aforementioned levels of activity across centers within the same country or even the same region. These differences were unrelated to the local prevalence of COVID-19 but more likely reflected a different perception of risk and prioritization of hospital resources [18, 19, 21] . In this context, a phased approach has been proposed to decrease transplant activity based on risk tolerance, hospital capacity, and degree of virus activity in different areas [10] . Nevertheless, it is essential to note that the decision of whether to continue LT activity was made in an emergent situation and based on the very limited evidence available at the moment on the risk of transmission and mortality in LT recipients [5] . These aspects will be analyzed in the following sections.

Living donor LT (LDLT) poses additional issues during the pandemic due to the risk of nosocomial transmission to donors as they recover from major surgery. Given the mainly elective nature of the procedure, most programs have considered postponing LDLT an ethically appropriate action during the pandemic peak [2, 3] . In April 2020, LDLT activity nearly stopped in Spain [4] . According to UNOS data, LDLT has been performed seldomly, comprising only 32 cases throughout April 2020 [3] . However, some centers have continued this practice even in high COVID-19 prevalence regions by creating COVID minimal-exposure pathways and reported favorable outcomes [3, 22, 23] . Surprisingly, data from South Korea showed that LDLT -the main type of transplantation performed in this county -did not significantly decrease even during the peak of the epidemic, thanks to a strict screening and tracing policy based on the experience of the previous Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV) infection [20] .

Most scientific societies worldwide have strongly recommended nucleic acid testing for SARS-CoV-2 to be part of the routine evaluation of both donors and recipients ( Table 2 ). Significant variability in the false-negative rate has been reported in testing for SARS-CoV-2 by nasopharyngeal swabs (NFSs) [3, 24] . For this reason, the results should be interpreted alongside clinical history and chest computed tomography when available. Molecular testing on NFS is the recommended screening method for living donors in centers where LDLT has not been halted [24] . Conversely, bronchoalveolar lavage (BAL) should be preferred for deceased donor screening, as it has a very low false-negative rate [25] . However, it should be considered that BAL may not be logistically feasible and has the greatest sensitivity later in the course of the infection, whereas NPS has the greatest sensitivity during the early period [3, 10] . Donor and recipient testing can significantly extend the timing and complicate the logistics of transplantation. In this context, many local medical centers are now beginning to obtain consistent access to rapid reverse transcription-polymerase chain reaction (RT-PCR) diagnostics [3, 15] . Moreover, machine perfusion has been used to extend preservation times of the liver graft while awaiting SARS-CoV-2 test results to be available [26] . As no molecular test is perfectly sensitive or specific, an additional epidemiological and clinical screening (which includes travel to a high-risk area, contact with a confirmed case, or onset of symptoms) of each case has been suggested [24] . The organs of donors who are positive for the epidemiological and clinical screening are considered high risk and should not be used for transplantation.

There is no consensus on time and testing requirements before recovering organs from donors who had previously documented COVID-19 infection. Waiting periods after the resolution of symptoms vary between 14-28 d, and most groups specifically recommend repeating a single or two negative tests before proceeding to donation [10, 27] . The use of liver grafts from donors testing positive for COVID-19 is widely considered unacceptable [4, 10, 24] . However, their use is hotly debated for superurgent patients. Some authors have suggested that for selected patients with imminently life-threatening organ failure, transplants from deceased donors with asymptomatic or mild SARS-CoV-2 infection may offer a favorable risk-benefit balance [14, 28, 29] . The two main arguments in favor of this position were as follows:

SARS-CoV-2 was initially thought to be less likely to infect the liver due to lower expression in the hepatocytes of angiotensin-converting enzyme 2 (ACE-2), the cell surface receptor for SARS-CoV-2. This was considered consistent with the limited initial autopsy studies, which failed to demonstrate SARS-CoV-2 in the liver [28, 29] .

To date, there have been no reports of recognized transmissions of SARS-CoV-2 following blood transfusion, even in immunosuppressed patients [28, 30] . Moreover, Hong et al reported the case of a patient who underwent LDLT without knowing that the donor was infected with COVID-19 at the time of the procedure. Donor-derived transmission to the recipient was not identified, and retrospective RT-PCR for SARS-CoV-2 from the liver biopsy confirmed no evidence of viral infection in the liver [22] .

Conversely, other authors advise against the use of livers from COVID-19-positive donors in any case [31] . In this context, the main arguments are as follows: 

The expression of ACE-2 in cholangiocytes was found to be comparable to that in alveolar type 2 cells [32] . Wang et al recently demonstrated that SARS-CoV-2 can directly infect hepatocytes, most likely through alternative extra-ACE-2 receptors, causing conspicuous cytopathy [33] . Moreover, Lagana et al [34] reported a case of likely COVIDrelated hepatitis in a pediatric recipient whose living donor subsequently tested positive for COVID-19, although no RT-PCR for SARS-CoV-2 was performed on liver biopsy.

The impossibility of clearly defining the risk of transmission prevents the recipient from providing adequate informed consent. This is further accentuated by the absence of effective prophylaxis [31] .

Staff members contracting the disease or in quarantine can result in the shutdown of a program for weeks. Organ recovery teams moving across centers and regions are exposed to the risk of transmission, and they must take appropriate respiratory and contact precautions throughout the procedure, even if the donor tested negative [15, 20] .

To reduce the exposure of recovery teams, many transplant centers have started relying on local teams and information sharing between centers via secure digital platforms [3] . Theoretically, the possibility exists to transplant these organs in patients who recovered from COVID-19 infection or received the vaccine, thus having developed a protective antibody titer [35] . Nevertheless, cases of reinfection with different SARS-CoV-2 clades have been documented, and this practice still entails healthcare workers' exposure [36] .

Qin et al [37] first reported the case of an LT recipient who experienced COVID-19 infection in the perioperative period and was discharged without sequelae after 56 days. Two reports from the same high-prevalence Italian region reported extremely low infection rates of 1.25% and 1.5% among 640 adult and 200 pediatric LT recipients, respectively [38, 39] . The apparently lower risk of COVID-19 infection among LT recipients compared to the general population could be explained partly by the higher degree of surveillance [38] . A survey from Germany has shown that during the pandemic, LT recipients used personnel protective equipment and practiced social distancing significantly more frequently than waitlist candidates [40] . Moreover, many transplant centers preferred suspending family visits during the posttransplant course and providing postdischarge follow-up care via telehealth [41] . However, the incidence of infection among LT recipients might also be underestimated due to the milder disease expression in these patients [38] . Therefore, short-term LT recipients seem to present fewer atypical symptoms, frequently of the gastrointestinal type, most likely because higher immunosuppression attenuates typical COVID-19 presentation [42, 43] . In fact, a nationwide experience in Spain revealed that LT patients had almost double the incidence rates of COVID-19 compared with the age-and gender-matched general population [44] .

Rabiee et al [45] recently reported a liver injury rate of 34.6% among COVID-19positive LT recipients, which was higher than that of the general population but lower than that of nontransplant patients with chronic liver disease. Likewise, mortality among LT recipients testing positive for COVID-19 varies between 0%-23% in most studies (Table 3 ) and seems higher than that in the general population but lower than that in cirrhotic patients, where it was estimated to be between 34%-40% [15, 41, 46] . Male sex, advanced age, and metabolic comorbidities, which are known to increase COVID-19 severity, are more frequent among LT recipients than among the general population and could account for this difference [2, 47] . However, risk factors that may increase mortality among LT recipients are not completely clear. Preliminary data from Italy and the European Liver Transplant Registry (ELTR) suggested that mortality could be higher among recipients with a longer time since transplantation, which was not confirmed by the analysis of the COVID-hep and SECURE-Cirrhosis registries [42, 48, 49] . It seems, however, that biological age and comorbidities rather than time from transplantation are most strongly correlated with death [42] . Different studies have confirmed the association between age and mortality among LT recipients with COVID-19 [42, 50] . Bhoori et al [49] first reported increased mortality among LTs who tested positive for COVID-19 with metabolic-related comorbidities, such as hypertension, chronic kidney disease, and diabetes. While the analysis of the COVID-hep and SECURE-Cirrhosis registries confirmed this finding, Becchetti et al [43] found no correlation between comorbidities and mortality in their series.

Clinicians should be aware of the high reported rates of fear and anxiety regarding COVID-19 in LT recipients and the consequent risk of scarce compliance with immunosuppressive medication [40, 51] . The immunocompromised status seemed not to affect mortality during previous coronavirus-related infections, such as SARS-CoV in 2003 and MERS-CoV in 2015 [39] . Moreover, the pathogenesis of severe COVID-19 was found to be mainly explained by the immune-mediated inflammatory reaction rather than direct cellular damage [52] . Thus, immunosuppression could theoretically have a protective role in LT patients [49, 53] .

There is limited guidance related to immunosuppression management during the pandemic. Societies advise against the reduction of maintenance immunosuppressive therapy to prevent SARS-CoV-2 infection. Some authors have initially suggested a reduction in the use of lymphocyte depletion therapy for induction immunosuppression during the pandemic to reduce the risk of nosocomial infection [5, 51] .

The management of immunosuppression in LT recipients testing positive for COVID-19 is currently under debate. In the aforementioned report by Qin et al [37] , tacrolimus and steroids were gradually titrated and then increased due to the suspicion of acute rejection. The retrospective analysis of different series during the first pandemic wave showed that immunosuppression was modified in nearly half of the cases, most frequently among patients with moderate and severe COVID-19, but rarely discontinued. Frequently reported changes were mycophenolate withdrawal, steroid dosing increase, and calcineurin inhibitor reduction [2, 54, 55] . However, the target trough levels of the immunosuppressants were rarely reported in these studies [56] .

An analysis of data from the COVID-Hep and SECURE-Cirrhosis registries has shown that the immunosuppressive regimen used had no impact on the outcome of COVID-19 [42] . Moreover, Becchetti et al [43] reported no impact on the disease course whether immunosuppression was decreased or left unchanged. Therefore, most transplant societies have recommended the continuation of immunosuppression at stable doses for asymptomatic or mildly symptomatic patients [45, 55] . A Spanish nationwide prospective study recently showed that mycophenolate was an independent predictor of severe COVID-19, particularly at doses higher than 1000 mg/d, and complete withdrawal of mycophenolate at COVID-19 diagnosis ameliorated the risk of severe COVID-19 [44] . This datum was, however, not confirmed in another study [42] .

Belli et al [50] showed that the use of tacrolimus was independently associated with reduced mortality among LT recipients testing positive for SARS-CoV-2. The biological explanation of this effect is still unknown but may be due to the inhibition of viral replication and interaction with the inflammatory cascade triggered by the infection. Based on this background, a Spanish randomized clinical trial has been started to test the effect of tacrolimus plus steroids in the management of COVID-19 occurring in immunocompetent patients (ClinicalTrials.gov Identifier: NCT04341038).

In light of the aforementioned data on transmission and mortality among LT patients, some authors have attempted a quantitative approach to the question of whether to continue transplant activity during the pandemic. Chew et al [16] proposed a score to guide the regulation of LT activity despite the competing needs of the pandemic through the 3 aforementioned scenarios based on 4 main ethical instances: waiting list mortality, donor and graft safety, recipient outcome, and healthcare resources available. Likewise, in the field of kidney transplantation, a machine learning algorithm has recently been developed to quantify the benefit-to-harm ratio of immediate transplant vs delay until after the pandemic [57] . COVID-19, like other pandemics, tends to come in several waves over a protracted period until hopefully subsiding through vaccination and herd immunity. These quantitative tools are potentially helpful in decision-making during pandemic peaks but still need to be fully validated. During the interpeak phases, every effort should be made to restore LT activity to regular rates and indications to prevent accumulated death and dropout from the waitlist over the long term. March 14, 2021

Volume 27 Issue 10

The COVID-19 pandemic has heavily affected health care systems worldwide and, despite some exceptions, has generally led to a reduction in LT activity, with different rates in different countries. Donor and recipient molecular screening for SARS-CoV-2 has become a routine practice in LT to prevent infection in the peritransplant period, although the possibility of using positive donors in super-urgent patients is currently debated. LT recipients seem to have an increased risk of being infected with SARS-CoV-2 but a milder and frequently atypical presentation. Mortality, in particular, seems comparable with the general population if corrected for concurrent risk factors. Immunosuppression could exert a protective effect against the most severe forms of COVID-19, and complete withdrawal or significant reduction in immunosuppression may not be useful, thus increasing the risk of acute rejection. The decision of whether to continue or suspend LT activity during the pandemic should be based on the actual strain on the healthcare system, waitlist priority, risk of posttransplant infection, and mortality.

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Perioperative Presentation of COVID-19 Disease in a Liver Transplant Recipient

Health Status of Patients Who Underwent Liver Transplantation During the Coronavirus Outbreak at a Large Center

The Facts During the Third Epidemic

Between fear and courage: Attitudes, beliefs, and behavior of liver transplantation recipients and waiting list candidates during the COVID-19 pandemic

Outcome of COVID-19 in liver transplant recipients: A preliminary report from Northwestern Italy

Outcomes following SARS-CoV-2 infection in liver transplant recipients: an international registry study

COVID-19 in an international European liver transplant recipient cohort

Epidemiological pattern, incidence, and outcomes of COVID-19 in liver transplant patients

Liver Injury in Liver Transplant Recipients With Coronavirus Disease

High rates of 30-day mortality in patients with cirrhosis and COVID-19

COVID-19 in solid organ transplant recipients: No difference in survival compared to general population

COVID-19 in liver transplant recipients: preliminary data from the ELITA/ELTR registry

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

Duvoux C; ELITA-ELTR COVID-19 Registry. Protective role of tacrolimus, deleterious role of age and comorbidities in liver transplant recipients with Covid-19: results from the ELITA/ELTR multi-center European study

Impact of COVID-19 on the care of patients with liver disease: EASL-ESCMID position paper after 6 months of the pandemic

Microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome (MicroCLOTS): an atypical acute respiratory distress syndrome working hypothesis

Does interval time between liver transplant and COVID-19 infection make the difference?

Impact of immunosuppressive therapy on the severity of COVID-19 in solid organ transplant recipients

Modulating immunosuppression in liver transplant patients with COVID-19

Letter to the Editor: Perioperative Presentation of COVID-19 in a Liver Transplant Recipient

Identifying scenarios of benefit or harm from kidney transplantation during the COVID-19 pandemic: A stochastic simulation and machine learning study

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