The novel coronavirus disease 2019 (COVID-19), the clinical syndrome caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a profound impact on all aspects of transplantation in the United States and worldwide. The infection continues to spread at an alarming rate around the world, having reached over 3.3 million deaths globally and over 580,000 deaths in the United States alone as of May 2021. Although mortality from COVID-19 is primarily related to pulmonary complications, there are numerous extrapulmonary manifestations of the disease, including gastrointestinal and hepatic. Patients with preexisting medical comorbidities including chronic liver disease (CLD) and cirrhosis are likely to be at high risk of severe disease and death when compared with healthy patients and those without liver disease. There has been significant interest in the outcomes of patients with COVID-19 among liver transplantation candidates and recipients, as well as the impact the pandemic has had on the rates and logistics of the transplantation itself. Here, we review what we have learned in the first year of this pandemic about the impact of COVID-19 in liver transplantation and identify key knowledge gaps to guide research in this area.
The Impact of the COVID-19 Pandemic on the Practice of Liver Transplantation
Many aspects of health care have changed dramatically during the pandemic, with practices in liver transplantation being no exception. Most centers rapidly converted to telehealth for the majority of their patient visits. In the first quarter of 2020, there was a significant impact of the pandemic on the number of liver transplantations performed (Fig. 1), number of additions to the liver transplantation waiting list, and number of liver transplantation waitlist inactivations as the pandemic evolved throughout the United States. Adding additional complexity, these data must be interpreted in the context of the virtually simultaneous change in the liver allocation system in February 2020. This initial decline in transplantation activities was likely fueled by concerns about donor and recipient safety, as well as the safety of the transplantation teams and unknowns about the resources available in transplantation centers as the virus spread geographically and access to viral testing was very limited. In addition, there was a notable increase in number of waitlist inactivations because of COVID-19 precautions at this same time. Between March 15, 2020 and April 30, 2020, states with the highest incidence of COVID-19 cases saw 33% fewer new listings for liver transplantation than expected, with 34% fewer deceased donor liver transplantations (DDLTs). Over this period, transplantation centers in these states had 59% more waitlist deaths than expected.
Interestingly, even within geographic areas with similar COVID-19 rates, there were significant variations in transplantation practices between individual centers. When changes in adult DDLT in the month preceding and following the onset of widespread COVID-19 infection in the United States were evaluated, there was an 11.0% decrease in deceased donors from February 2020 to March 2020 overall, with a resultant decrease in adult DDLTs nationally of 24.7%. When region and center were considered, there was much greater variability seen in 2020 compared with 2019 when looking at transplantation practices within the same region, despite similar rates of COVID-19 at these centers. This was observed among regions with high and low rates of COVID-19, although notably with some of the highest within-region variability seen in that with the highest burden of COVID-19 cases (such as region 9). It is not clear what accounts for these differences, though it is possible that center-specific resources, COVID-19 transmission among transplantation team members, and center leadership philosophy regarding risk may have played a role.
Despite the risks and unknowns, these early effects of the pandemic on transplantation and waitlist rates are largely seen only in the first 2 months of the pandemic. Subsequently, even as COVID-19 cases spread between states, waitlist registrations, rates of transplantation, and waitlist mortality were very near that expected in new high-incidence areas. Some of this restoration of transplantation volume may be attributed to the rapid implementation of guidance surrounding COVID-19 from the United Network for Organ Sharing (UNOS) as well as medical societies. With the adoption of COVID-19 testing in donors and recipients based on society guidelines, increased access to personal protective equipment, and especially now with health care workers having been offered vaccination against COVID-19, concerns about risk of transmission to the transplantation team in the perioperative period are diminished. Figure 1 shows the number of liver transplantations performed in the United States from January 2020 to May 2021, highlighting key events related to COVID-19.
There was a particularly sharp initial decline in living donor liver transplantation early in the pandemic, which has also subsequently recovered. As reported also in countries where living donor liver transplantation is the main source of liver allografts, with improved safety protocols and testing, these operations are likely safe if the local hospital resources are not overwhelmed. Overall, we believe living donor liver transplantation evaluation and programming should continue, especially in the context of widespread vaccination, with additional precautions as described here for donor testing to ensure safety of the potential donor, recipient, and transplantation team.
CLD, Cirrhosis, and Liver Transplantation Candidates
Since the early reports of the clinical characteristics of COVID-19, it has been clear that liver injury as measured by both elevations in liver enzymes and post-mortem pathology has been common, perhaps a particular threat to patients with decompensated liver disease. Liver enzyme elevations have been reported in up to 63.0% of patients hospitalized with COVID-19 infection, with a more severe disease course including higher rates of intensive care unit (ICU) admission, intubation, renal replacement therapy, and mortality seen in patients with marked elevations. In addition, there have been reports of less common but more severe forms of liver disease in the context of COVID-19 that could create additional indications for liver transplantation, including acute liver failure as well as progressive cholangiopathy.
Patients with CLD and cirrhosis have also been greatly affected by COVID-19 (Table 1). While patients with CLD do not appear to be overrepresented in the largest epidemiological cohorts, it does appear that patients with CLD overall are at increased risk of severe disease and death. This has been demonstrated in large data set analyses, where CLD is associated with increased rates of hospitalization and a significantly higher risk of mortality when compared with patients without liver disease, with the greatest risk among patients with cirrhosis. From subsequent studies with more granular patient data, it is likely that both the etiology of CLD and the disease severity impact this risk, and it is possible that cirrhosis is underdiagnosed in these larger data sets.
The earliest multicenter cohorts to explore outcomes among patients with cirrhosis, though relatively small, were from China and Italy, the first epicenters of the pandemic. Following these initial reports, larger studies from the United States and multinational cohorts have further refined our understanding of the relationship between CLD, cirrhosis, and COVID-19 outcomes. The first of these is the COVID-19 in Chronic Liver Disease (COLD) consortium, which included 867 patients across 21 US centers with CLD (71.5% with cirrhosis, 10.7% with decompensated cirrhosis) and confirmed SARS-CoV-2 infection. In this cohort, decompensated cirrhosis was associated with an increased risk of severe COVID-19 infection and higher mortality. Higher mortality was also seen in alcohol-related liver disease (ALD), patients with hepatocellular carcinoma (HCC), and several medical comorbidities including older age, diabetes mellitus, hypertension, chronic obstructive pulmonary disease, and current smoking. Similar findings were seen in the SECURE-Liver Registry (formerly SECURE-Cirrhosis) and the COVID-Hep registry, which included 745 patients with CLD from 29 countries. Within this cohort, patients with cirrhosis (n = 386) had a mortality rate of 32.0% compared with only 8.0% in patients with CLD but no cirrhosis. Among patients with cirrhosis, there was a stepwise increase in mortality with increasing Child-Turcotte-Pugh (CTP) class. Multivariable analysis showed older age, cirrhosis (with any CTP class), and ALD to be associated with increased risk for mortality.
However, it is also clear that this literature must be interpreted in the context of carefully selected control groups to understand what is driving these outcomes. In a US-based multicenter study comparing patients with cirrhosis and COVID-19 with 2 age- and sex-matched comparator groups, patients with cirrhosis and COVID-19 had higher mortality than those without cirrhosis with COVID-19, but similar mortality rates when compared with patients with cirrhosis without COVID-19, perhaps indicating that cirrhosis itself is driving the high inpatient mortality rates. In a recent international study comparing outcomes among patients with autoimmune hepatitis (AIH) and COVID-19 with a propensity score–matched cohort of patients with other etiologies of CLD and COVID-19, cirrhosis was again identified as the strongest predictor for severe COVID-19 in patients with AIH.
Treatment of COVID-19 in Transplantation Candidates
Data for the treatment of COVID-19 specifically among patients with cirrhosis and decompensated cirrhosis are limited. There remain concerns about the potential hepatotoxicity of several SARS-CoV-2 therapies, particularly remdesivir and interleukin 6 (IL6) inhibitors such as tocilizumab. Remdesivir has been associated with elevation in aspartate aminotransferase and/or alanine aminotransferase in 10.0%-11.0% of patients treated for SARS-CoV-2 in the trials to date, though grade 3-4 elevations in liver enzymes were rare and not greater than those in the control populations in the phase 3 trials. However, remdesivir is currently recommended to be discontinued among patients with liver enzyme elevation over 10 times the upper limit of normal or if symptomatic liver disease is diagnosed. The use of remdesivir in patients with CLD and cirrhosis has not been reported outside of 1 case report, where a patient with decompensated cirrhosis received the medication without adverse effects.
There are also numerous studies regarding tocilizumab-related hepatotoxicity in the rheumatology literature, including reports of up to 71.0% of patients with liver injury in this context. In the trials currently published of tocilizumab for the treatment of COVID-19, liver enzyme elevations were reported in over 15.0% of patients, although these reflect only significant enzyme elevations. In other series, for example, liver enzyme elevations were seen in over 80.0% of patients who received tocilizumab during their hospitalization. However, it is challenging to understand whether there is a direct tocilizumab-related liver injury in many cases given the many competing etiologies of acute liver injury (ALI) in this population, especially among hospitalized patients.
Despite these concerns, there have been no reports to suggest that patients with CLD and cirrhosis should not receive these COVID-19-directed therapies. Given the significant mortality associated with severe COVID-19, the increased risk of severe disease in the context of liver enzyme elevation, and the limited therapeutic options available, it will be important to report outcomes among these patients who receive these agents.
SARS-CoV-2 Testing of Donors and Recipients at Transplantation
Screening of donors (both deceased and living) and recipients at the time of transplantation is now widely performed, although not yet standardized outside of society consensus statements. All patients who present for transplantation should be tested for SARS-CoV-2 with a nasopharyngeal polymerase chain reaction (PCR) test prior to undergoing the operation. Current recommendations advise against transplantation in recipients with active COVID-19 and recommend proceeding to transplantation ideally 2-3 weeks after symptoms have resolved and only if at least 1 nasopharyngeal PCR test is negative, with some physicians recommending 2 negative tests.
All donors should also undergo a nasopharyngeal PCR test prior to acceptance of the organ offer. In lung transplantation donors a lower respiratory specimen is also required, with this policy change being implemented after a case of SARS-CoV-2 transmission from a lung transplantation donor to recipient was reported. Potential living donors with prior SARS-CoV-2 infection should have at least 1 negative SARS-CoV-2 RNA test; if repeat testing remains positive, proceeding to donation should be considered only if they are asymptomatic and the infection was between 21 and 90 days prior to donor evaluation, as this is felt to reflect viral shedding and not new or active infection.
One unique challenge in testing is the prolonged viral shedding that has been observed in patients with end-stage liver disease, especially among those with nonalcoholic fatty liver disease, where PCR testing can remain positive beyond the period expected in the general population.