EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Coronavirus disease 2019 has resulted in significant morbidities and mortalities in nearly all parts of the world. There remain major concerns about management, timing, and safety of liver transplant in patients who have recovered from COVID-19. We aimed to study the clinical course and outcomes of patients with liver cirrhosis who recovered from COVID-19 and underwent liver transplant from deceased donors.
Materials and Methods: A retrospective study was conducted on liver transplant recipients who underwent liver transplant from April 1, 2020, to January 30, 2021. We evaluated all recipients of liver transplant from deceased donors during this period in the COVID-19 pandemic.
Results: There were 14 patients with decompensated liver cirrhosis who had recovered from COVID-19 as documented by reverse transcription-polymerase chain reaction test for SARS-CoV-2. Mean duration from COVID-19 to transplant surgery was 56.14 ± 29.96 days. Mortality occurred in 3 patients, and of whom 2 had been hospitalized and received medications for COVID-19 before transplant. Five patients had positive reverse transcription-polymerase chain reaction results for SARS-CoV-2 after liver transplant.
Conclusions: This is a large reported series of patients with liver cirrhosis who have received liver transplant after recovery from COVID-19. We provided evidence that liver transplant from deceased donors should be considered in patients recovered from COVID-19, especially in those with deterioration of clinical status.

Key words : Decompensated cirrhosis, Liver transplantation, Mortality

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in drastic morbidities and mortalities throughout the world.¹ Successful management of patients with chronic liver disease has been negatively affected during the COVID-19 pandemic.^2,3 Many aspects of liver transplant programs were disrupted, including pretransplant evaluation of donors and recipients, management of transplant operation rooms and intensive transplant units, and posttransplant follow-up of patients, especially early in the course of the COVID-19 pandemic.⁴ It was also initially suspected that patients with liver cirrhosis and liver transplant recipients were more susceptible to severe COVID-19.^5,6 In parallel, several restrictions have been implemented in liver transplant programs for both donors and recipients, and the number of liver transplants has decreased compared with the pre-COVID-19 era.⁷ However, as the COVID-19 pandemic continued, many liver transplant centers gradually resumed activities by using preventive protocols.⁸ Presently, after more than 2 years, the pandemic has been largely controlled after vaccination of the general population, a high level of acquired immunity, and provision of a third round of vaccine doses. However, COVID-19 is still present, and if immunity were to wane, then a new episode of viral transmission could occur, especially during winter months.⁹ One challenge is increasing numbers of patients with decompensated liver cirrhosis who had been infected with SARS-CoV-2 and recovered. Despite improvements, major concerns remain about management, timing, and safety of liver transplant in this group of patients. Herein, we described the clinical course and outcomes of patients with liver cirrhosis who recovered from COVID-19 and underwent liver transplant from deceased donors.

Materials and Methods

We conducted a retrospective analysis of liver transplant recipients who underwent liver transplant from April 1, 2020, to January 30, 2021, at Shiraz Transplant Center, Shiraz, Iran. We evaluated all liver transplant recipients from deceased donors in this period during the COVID-19 pandemic.

Our local protocol directed that both donors and transplant candidates undergo a complete evaluation for new onset of symptoms related to COVID-19 (fever, cough, dyspnea, gastrointestinal symptoms), chest computed tomography (CT) scan, and reverse transcription-polymerase chain reaction (RT-PCR) test for SARS-CoV-2. For the RT-PCR test, 2 swab samples were taken from nasopharynx and oropharynx of patients and transferred into viral medium vials. Patients were considered to have COVID-19 if they had a positive RT-PCR result for SARS-CoV-2 on nasopharyngeal or oropharyngeal swabs. If a liver transplant candidate had positive RT-PCR results, abnormal CT findings, or symptoms, then the liver transplant surgery was postponed for 2 weeks. After 2 weeks, the candidate was reevaluated again for symptoms, and RT-PCR and chest CT scan were performed. We proceeded to liver transplant if RT-PCR tests were negative and spiral chest CT scans were normal for both the deceased donor and the transplant candidate.

Clinical data of patients were recorded, including age, sex, underlying liver disease, date of liver transplant, Model for End-Stage Liver Disease (MELD) score, time of COVID-19 positivity, time interval from COVID-19 positivity to liver transplant surgery, lung involvement during COVID-19 course, symptoms related to COVID-19, medications used for COVID-19, and outcomes of liver transplant. All liver transplant recipients received methylprednisolone pulse therapy as induction of immunosuppression and tacrolimus-based immunosuppression as mainte-nance regimen.

Data are presented as mean values (with SD) for numeric variables and as counts (with percent) for categorical variables. We analyzed survival rates of patients with Kaplan-Meier analysis. We used log-rank test to compare survival after liver transplant in those with versus without lung involvement during COVID-19 illness. Statistical analyses were performed with SPSS (version 20.0).

The study protocol was approved by the institutional review board of Shiraz Transplant Center, Abu-Ali Sina Hospital, Shiraz, Iran. The study was performed in accordance with the Helsinki Declaration as revised in Seoul 2008.

During the study period, 220 liver transplants were performed at our center. There were 50 living donor liver transplants and 170 deceased donor liver transplants. We noted 14 liver transplant recipients who had recovered from COVID-19, as documented by positive RT-PCR results for SARS-CoV-2 before liver transplant. There were 9 men (61.5%) and 5 women (38.4%). All patients were adults who received livers from deceased donors. Mean age of patients was 44.14 ± 9.81 years. Mean MELD score was 25.64 ± 6.67. Underlying liver diseases, clinical characteristics of patients, and outcomes after liver transplant are shown in Table 1. Autoimmune liver diseases (autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cholangitis) were the most common causes of liver cirrhosis leading to transplant in this group of patients.

Six patients had asymptomatic infections of COVID-19. Eight patients had at least 1 symptom related to COVID-19; among them only 1 patient was severely symptomatic, with fever, cough, and dyspnea. A total of 5 patients were hospitalized during the course of their infection with COVID-19, of whom 3 patients received specific medications for COVID-19 including hydroxychloroquine and high-dose steroids. No patients required invasive ventilator support, and noninvasive ventilation was used for 1 patient during course of COVID-19. Three patients had lung invol-vement (2 mild and 1 severe) on chest CT scans during the course of their COVID-19, and 5 patients were hospitalized for COVID-19 before liver transplant.

The median time interval from COVID-19 to liver transplant was 50 days (interquartile range, 15-98 days). One patient underwent liver transplant only 15 days after COVID-19 because of worsening clinical status and died 12 days after liver transplant. Mortality occurred in 3 patients, and 2 of them had been hospitalized and received medications for COVID-19 before transplant. Mean survival duration was 313.21 ± 41.85 days after liver transplant among our patients. Mean survival duration was 360.54 ± 32.58 days in patients without lung involvement during COVID-19 compared with 62.33 ± 41.09 days in patients with lung involvement during COVID-19 (P = .017) (Figure 1). Five patients had positive RT-PCR results for SARS-CoV-2 after liver transplant. Outcomes of our patients related to COVID-19 are shown in Table 2.

Herein, we described a series of 14 patients with liver cirrhosis who underwent liver transplant after recovery from COVID-19. Mortality occurred in 3 patients in the early posttransplant period, of whom 2 patients had lung involvement while infected with COVID-19 before liver transplant. All of these 3 patients had bilateral pneumonia in the posttransplant period with sepsis and multiorgan failure. Two of these 3 patients had positive nasopharyngeal RT-PCR tests for SARS-CoV-2 after liver transplant. Short-term survival after liver transplant was significantly longer in patients who did not have lung involvement compared with those who had lung involvement during COVID-19 infection.

Although outcomes of liver transplant recipients infected by COVID-19 have been reported in several studies during the pandemic,¹⁰ there remains a scarcity of data about clinical outcomes of liver transplant in patients recovered from COVID-19. Liver transplant after recovery from COVID-19 has been reported in only a few patients. Niess and colleagues described a patient with liver cirrhosis who underwent liver transplant from a deceased donor 36 days after onset of COVID-19 symptoms.¹¹ Another patient with liver cirrhosis caused by autoimmune hepatitis was reported who underwent liver transplant from a deceased donor as early as 9 days after recovery from COVID-19.¹² Dhand and colleagues reported a patient with alcoholic cirrhosis who received a liver transplant 70 days after COVID-19 from a deceased donor.¹³ A series of 10 patients with living donor liver transplants has been reported in which the patients had been infected and recovered from COVID-19 before transplant.¹⁴ Belli and colleagues reported 26 patients infected with COVID-19 who underwent liver transplant after a median time of 78.5 days; no reinfection after liver transplant was reported in this cohort, and 1 mortality was reported.¹⁵ Another recent study reported 51 patients who tested positive for COVID-19 at various time points before liver transplant, of whom 48 patients received liver transplant from living donors and 3 received liver transplant from deceased donors in a median time interval of 99 days.¹⁶

Many liver transplant guidelines have suggested living donor liver transplant as the method of choice during the COVID-19 era.¹⁷ Our results showed feasibility of deceased donor liver transplant for patients recovered from COVID-19. The timing of liver transplant after COVID-19 remains uncertain. Most guidelines recommend postponement of liver transplant for at least 4 weeks in such patients. In our series, we had 3 patients with a time gap of less than 4 weeks between COVID-19 and liver transplant. Two of these patients survived, and 1 patient, who had lung involvement during COVID-19, succumbed to complications after liver transplant. Furthermore, the median interval from COVID-19 to liver transplant was shorter in our series compared with previous reports. Therefore, the timing between COVID-19 and liver transplant might not be the single contributing factor to determine outcomes in the posttransplant period. Other factors such as lung involvement during COVID-19 and having symptoms during the course of COVID-19 might be more important factors. Although any robust recommendation remains unstated, it might be reasonable to perform liver transplant in cirrhotic patients with COVID-19 as early as 15 days after the disease, in asymptomatic patients who show no lung involvement in chest CT scan and show negative results from RT-PCR test. These details require further clarification in future studies.

Five patients again tested positive for SARS-CoV-2 by RT-PCR after liver transplant, of whom 2 patients succumbed to death due to multiorgan failure and 3 patients had very mild symptoms or were totally asymptomatic. Because patients are typically in a state of immunosuppression before and after liver transplant, prolonged shedding of the virus is a reasonable expectation for this phenomenon as described among other immunosuppressed populations.¹⁸ There are 2 patients reported in the literature with prolonged viral shedding after liver transplant without negative effects on outcomes of transplant.^11,19 On the other hand, recurrence of positive results for SARS-CoV-2 has been reported in patients with COVID-19, especially in those with low levels of antibody against SARS-CoV-2.²⁰ Our results showed that a positive RT-PCR result for SARS-CoV-2 after liver transplant is prevalent even in those who had been previously infected, although it is not clear whether this is due to recurrence or prolonged viral shedding. Clinical significance of this observation and its effect on posttransplant outcomes should be investigated in future studies.

Liver transplant from deceased donors can be performed in patients recovered from COVID-19, especially in those with increasing MELD scores and deterioration of clinical status. When necessary, liver transplant might be considered even earlier than 4 weeks, especially in those who are asymptomatic or mildly symptomatic with no lung involvement during COVID-19. Long-term outcomes of patients in such an approach should be investigated in future studies.

Volume: 20 Issue: 10 October 2022

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