key: cord-0798311-n8qwqka8
authors: Rabiee, Atoosa; Sadowski, Brett; Adeniji, Nia; Perumalswami, Ponni; Nguyen, Veronica; Moghe, Akshata; Latt, Nyann; Kumar, Sonal; Aloman, Costica; Catana, Andreea M.; Bloom, Patricia P.; Chavin, Kenneth; Carr, Rotonya M.; Dunn, Winston; Chen, Vincent; Aby, Elizabeth S.; Debes, Jose; Dhanasekaran, Renumathy
title: Liver Injury in Liver Transplant Recipients with Coronavirus Disease 2019 (COVID‐19): US Multicenter Experience
date: 2020-09-22
journal: Hepatology
DOI: 10.1002/hep.31574
sha: 4b0b8095e116921378110fa85aa4f283149da924
doc_id: 798311
cord_uid: n8qwqka8

BACKGROUND: Coronavirus disease 2019 (COVID‐19) is associated with liver injury, but the prevalence and patterns of liver injury in liver transplant (LT) recipients with COVID‐19 is not defined. APPROACH AND RESULTS: We conducted a multicenter study in the US of 112 adult LT recipients with COVID‐19. The median age was 61 years (IQR 20), 54.5% (n=61) were male, and 39.3% (n=44) Hispanic. The mortality rate was 22.3% (n=25); 72.3% (n=81) were hospitalized and 26.8% (n=30) admitted to the ICU. Analysis of peak values of alanine aminotransferase (ALT) during COVID‐19 showed moderate liver injury (ALT 2‐5x ULN) in 22.2% (n= 18) and severe liver injury (ALT > 5x ULN) in 12.3% (n= 10). Compared to age and gender matched non‐transplant patients with CLD and COVID‐19 (n=375), the incidence of acute liver injury was lower in LT recipients (47.5% vs. 34.6%; p=0.037). Variables associated with liver injury in LT recipients were younger age (p= 0.009, odds ratio (OR) 2.06 [1.20‐3.54]), Hispanic ethnicity (p= 0.011; OR 6.01 [1.51‐23.9]), metabolic syndrome (p= 0.016; OR 5.87 [1.38‐24.99]), vasopressor use (p= 0.018; OR 7.34 [1.39‐38.52]) and antibiotic use (p= 0.046; OR 6.93 [1.04‐46.26]). Reduction in immunosuppression (49.4%) was not associated with liver injury (p= 0.156) or mortality (p= 0.084). Liver injury during COVID‐19 was significantly associated with mortality (p= 0.007; OR 6.91 [95% CI: 1.68‐28.48]) and ICU admission (p=0.007; OR 7.93[1.75‐35.69]) in LT recipients. CONCLUSION: Liver injury is associated with higher mortality and ICU admission in LT recipients with COVID‐19. Hence, monitoring liver enzymes closely can help in early identification of patients at risk for adverse outcomes. Reduction of immunosuppression during COVID‐19 did not increase risk for mortality or graft failure.

Coronavirus disease 2019 has now claimed over 750,000 lives around the world, with more than 170,000 deaths in the US alone (1). Data on clinical outcomes and disease severity of COVID-19 in liver transplant (LT) recipients is limited, but initial reports raise concern for high rates of adverse outcomes (2) (3) (4) . Bhoori et al first reported the death of three LT recipients in the epicenter of COVID-19 in Lombardy, Italy in March 2020, and postulated that post-transplant metabolic complications may drive adverse outcomes with COVID-19 rather than immunosuppression (5) . A subsequent study of 38 LT recipients from the international SECURE-CIRRHOSIS registry showed a mortality rate of 24% (6) . Other recent studies have reported mortality rates ranging from 12-20% and have identified factors like older age, comorbid active cancer or renal injury to be predictive of adverse outcomes (2) (3) (4) . The dose or type of immunosuppression does not appear to be associated with adverse outcomes, and most guidelines recommend continuing immunosuppression during COVID-19 (7) . However, real-world data on how immunosuppression was modified during COVID-19 and the impact of these changes on graft function or outcomes are not yet clear.

Early studies have reported that COVID-19 is associated with liver injury, which, in turn, is predictive of severe disease (8) (9) (10) . However, it is not clear if SARS-CoV-2, the virus that causes COVID-19, causes liver injury in a direct fashion, or if other factors like hepatotoxic medications and comorbid metabolic conditions play a major role. LT recipients present a unique challenge since they are immunosuppressed and hence might not be able to mount an adequate immune response against the virus. Moreover, their immunosuppression is likely to be modified during COVID-19, placing them at risk for acute rejection. In addition, the propensity for drug-drug interactions is higher in these patients, raising concern for hepatotoxicity from medications used during the management of COVID-19. More studies are needed to understand the risk for graft injury in liver transplant recipients who acquire COVID-19.

This article is protected by copyright. All rights reserved

Here, we report data from a large US multi-center study of LT recipients with COVID-19, and define their patterns of liver enzyme abnormalities, determine the impact of changes in immunosuppression, and identify predictors of liver injury and mortality.

This article is protected by copyright. All rights reserved

This is a multicenter observational cohort study on clinical outcomes of COVID-19 in patients who have undergone liver transplantation. This study was carried out by the consortium of investigators to study COVID-19 in chronic liver disease (COLD) (registered Clinicaltrials.gov NCT04439084).

Inclusion criteria for this study constituted: age over 18 years, laboratory confirmed diagnosis of COVID-19 and history of liver transplantation (Fig S1) . The COLD registry collected de-identified data on patients within the inclusion criteria diagnosed with COVID-19 before May 30, 2020. Only patients with COVID-19 confirmed by PCR-based laboratory diagnosis were included. All participating institutions independently identified patients meeting inclusion criteria and collected data. Death was attributed to COVID-19 if it was clinically related to the COVID-19 illness and there were no other unrelated causes of death (11).

We collected de-identified data using 170 structured and text variables in 10 different categories: demographic data, clinical course of COVID-19, comorbidities, laboratory tests within 6 months before the diagnosis of COVID-19, at diagnosis of COVID-19, and after COVID-19, transplant status, immunosuppression, hepatotoxic medications, vasopressor use (if >12 hours) and treatment of COVID-19. For the analysis on liver injury, only patients who had laboratory values for liver tests prior to-and during COVID-19 infection were included. A control group of nontransplant patients with chronic liver disease (CLD) who also had laboratory values for liver tests at the same points was employed ( Fig S1) .

A predefined statistical data analysis plan was used. Continuous variables are expressed as medians and interquartile ranges (IQR) or mean and standard deviation, as appropriate. Categorical variables are summarized as counts and percentages. The statistical significance of differences between groups was evaluated using the independent t-test or the Mann-Whitney U test for continuous variables, and the chi-square test for categorical variables.

This article is protected by copyright. All rights reserved

The primary outcome studied was the presence of acute liver injury. Since changes in AST, bilirubin or albumin can be due to multiple non-hepatic factors, we used ALT, a more specific marker for acute liver injury, to define liver injury. ALT values at the peak of COVID-19 disease were used to define acute liver injury as follows: no liver injury = ALT values <2 times the upper limit of normal (ULN); moderate liver injury 2-5 times ULN; severe liver injury > 5x ULN (10) . Patients with both moderate and severe liver injury were classified as having acute liver injury. The cutoffs for normal values of ALT were 19 U/L for women and 30 U/L for men (12) . The secondary outcome was allcause mortality. Severe COVID-19 was defined as admission to the ICU, receipt of vasopressors or mechanical ventilation. To determine the independent risk factors for the primary outcome, we performed multinomial logistic regression analyses. After considering the number of outcome events, the multivariable-adjusted models were confined to variables that were based on clinical plausibility, statistical significance in the univariate model, and had less than 10% missingness.

This article is protected by copyright. All rights reserved

We identified 112 liver transplant recipients who were diagnosed with COVID-19 before May 30, 2020 from 15 US medical centers. The median age of the cohort was 61 years (IQR 20), and 54.5% (n = 61) were male. This racially and ethnically diverse study cohort was 39.3% (n = 44) Hispanic, 27.7% 

The all-cause mortality in our cohort was 22.3% (n = 25). Overall, 72.3% (n = 81) were hospitalized and the median length of hospital stay was 6.5 days (IQR 10). Among the hospitalized patients, 37.0% (n = 30) were admitted to the intensive care unit (ICU) and 29.6% (n=24) received vasopressors. Supplemental oxygen was given to 52.7% (n=59) and 23.2% (n=26) were placed on mechanical ventilation. The most common medications used for treatment of COVID-19 were hydroxychloroquine (37.5%) or azithromycin alone (27.7%). Table 1 shows the clinical and demographic features of the cohort stratified by clinical outcomes.

Our objective was to study the patterns and predictors of acute liver injury in transplant recipients, peak values during COVID-19. One patient had a documented diagnosis of acute cellular rejection and, hence, was excluded from further analysis of etiology of liver injury. We compared the

This article is protected by copyright. All rights reserved incidence of liver injury with a control group of 375 non-transplant patients with chronic liver disease (CLD 32.5 [IQR 44]); p=0.043). Correspondingly, the incidence of acute liver injury (peak ALT > 2 ULN) was higher in non-transplant patients with CLD than LT recipients (47.5% vs. 34.6%; p=0.037).

Amongst LT recipients, all three liver enzymes (AST, ALT and alkaline phosphatase) showed 

We wanted to determine predictors of liver injury during COVID-19 in LT recipients. The majority of LT recipients had peak ALT < 2x ULN (65.4% [n = 53]); while moderate elevation in ALT 2-5x ULN was seen in 22.2% (n = 18) and severe elevation > 5x ULN in 12.3% (n = 10). Table 2 shows the proportion of liver injury seen in the different clinical and demographic subgroups. On univariate analysis,

patients with more severe COVID-19 i.e. patients who were admitted to the ICU (p = 0.002), received vasopressors (p < 0.001) or were mechanically ventilated (p < 0.001) were more likely to have acute liver injury (ALT <2x ULN). We obtained a detailed list of several classes of potentially hepatotoxic medications the patients had received (Table S1 ). Among them, receipt of antibiotics was associated with risk for liver injury (p = 0.016), while use of statins, proton pump inhibitors (PPI) or acetaminophen was not. None of the medications used to treat COVID-19 were associated with liver injury.

Multivariate logistic regression was performed to identify independent predictors of liver injury (ALT Reducing tacrolimus (p = 0.735) or holding mycophenolate (p = 0.617) were not associated with liver injury (Table 2) . Overall, reduction in immunosuppression during COVID-19 was not associated with liver injury (p = 0.156) or risk for mortality (p = 0.084).

This article is protected by copyright. All rights reserved

We evaluated predictors of overall mortality in LT recipients with COVID-19 ( 

Liver injury has been reported in a significant proportion of nontransplant patients with COVID-19 but data on transplant recipients is scarce. Liver transplant recipients are at particular risk for graft injury given their immunocompromised state, high prevalence of metabolic comorbidities, and risk for drug-drug interactions leading to hepatotoxicity. Our multicenter observational study of 112 patients explores clinical outcomes and patterns of liver injury in LT recipients with COVID-19. We found that 34.6% of the LT recipients had liver injury during COVID-19, with liver enzyme elevations predominantly in a hepatocellular pattern. Age, Hispanic ethnicity, metabolic syndrome, vasopressor and antibiotic use predicted liver injury, highlighting the multifactorial nature of this process.

Moreover, liver injury was independently associated with risk for mortality and ICU admission.

Hence following liver enzymes closely can help in the early identification of LT recipients at risk for adverse outcomes with COVID-19. Type of immunosuppression did not have an impact on mortality or liver injury. Real-world data from our study shows that immunosuppression was modified in 50% of the patients during COVID-19, but only one patient experienced acute rejection and none of the patients experienced graft failure. These data are reassuring and will hopefully guide physicians taking care of LT recipients with COVID-19.

Recent studies in the non-transplant general population have shown that liver injury is relatively common during COVID-19 with rates ranging from 15-53% (8, 10) . In our study, we show that around a third of LT recipients sustained acute liver injury during COVID-19, but despite being immunocompromised, this rate was lower than that of our non-transplant cohort with CLD (47.5%).

There has been significant concern that SARS-CoV-2 may cause cholestatic liver injury since angiotensin-converting enzyme 2 (ACE2), the host cell receptor for the virus, has been reported to be expressed on cholangiocytes (13) . But data, including results from our study, consistently show a predominantly hepatocellular pattern of injury (13) (14) (15) . This raises the possibility that SARS-Co-V2 may cause direct hepatocellular damage, as recently reported by Wang et al (16) . Other nonhepatotropic viruses have also been shown to be associated with similar pattern of liver injury. In fact, the rate of liver injury in viral infections from SARS (50.3%) and other human coronaviruses

This article is protected by copyright. All rights reserved (HCoV) (36.0%) were higher than COVID-19 (22.5%) (8) . However, most of this data is from nontransplant patients. In transplant recipients, even though SARS-Co-V and MERS-Co-V have rarely been reported to cause transaminitis (17, 18) , our study clearly shows that SARS-Co-V2 is associated with liver injury in a substantial proportion of LT recipients.

Drug induced liver injury (DILI) is a major cause for abnormal liver tests. We collected extensive history of various classes of potentially hepatotoxic medications used during the clinical course of COVID-19. We show that patients in the ICU who received vasopressors were more likely to have liver injury, highlighting the association of liver injury with hypotension in severe COVID-19. We identified use of antibiotics, several of which are known to cause DILI, to be another risk factor for liver injury. However, use of acetaminophen, PPIs and statins were not associated with liver injury and these medications can be safely continued during COVID-19. Moreover, medications commonly used to treat COVID-19 were not associated with significant liver injury, and this should encourage physicians to continue to offer such treatment in this patient population even in the presence of mild to moderate ALT elevations.

The overall mortality in our study was 22.3% (n=25). A similar mortality rate of 20.5% has been reported from 482 solid organ transplant (SOT) recipients in the US (19) . The CDC reports that the general US population has a COVID-19 mortality rate of 5% (20) . However, the median age of LT recipients who acquire COVID-19 is higher at 60.1 years compared to the reported median age of 48 years in the general population (20) . Furthermore, metabolic comorbidities like diabetes and hypertension, which are known to increase COVID-19 severity, were present in almost 50% of the LT recipients in our cohort while it was present in less than a third of the general population with COVID-19 (20) . A recent study does report that mortality among COVID-19 SOT recipients is similar to the general population, after controlling for age and other comorbidities (21) . Another study from Spain of 111 LT recipients, showed that the mortality rates were actually lower in LT recipients than the matched general population (22) . Based on these studies, it appears that transplant itself is not a risk factor of higher COVID-19 mortality, but coexisting comorbidities are. In our study, we report

This article is protected by copyright. All rights reserved that liver injury is associated with COVID-19 severity. Thus, closely monitoring liver tests can enable earlier identification of patients at risk for adverse outcomes. New promising treatment directed against SARS-Co-V2 which reduces the severity of COVID-19 can potentially also decrease the incidence of liver injury.

During the initial phases of the COVID-19 pandemic, it was not clear how, or if, immunosuppression should be reduced in LT recipients with COVID-19. Following evaluation of early reports, several societies published guidelines recommending continuation of immunosuppression at stable doses for most patients (7, 23, 24) . Real-world data from our study shows that immunosuppression was actually modified in 50% of the patients, but only one patient experienced acute rejection. As expected, immunosuppression was more likely to have been reduced in patients with more severe COVID-19 i.e. those who were in the ICU on vasopressors. Nonetheless, decreases in immunosuppression were not associated with liver injury or mortality. These data are reassuring and will hopefully guide physicians taking care of LT recipients with COVID-19.

To our knowledge, our study represents one of the largest multicenter cohorts of LT recipients from the US. Another strength of our study is that we evaluated serial changes in ALT to more accurately identify those with liver injury. Different studies have used varying definitions of liver injury, we used standard definitions for ALT cut-offs (12) that have also been used by other groups (8, 10) . We believe that ALT is a more specific marker of liver injury in this context since AST can originate from the heart, which is also known to be affected during COVID-19 (25) . One limitation of our study is potential referral bias, since most of the centers contributing patients to our cohort are tertiary referral centers, but we did include both outpatients and inpatients in this cohort and have captured patients with mild and severe COVID-19. Another limitation is the lack of a control group of the general population with COVID-19, which prevents us from analyzing whether transplant recipients are at higher risk for mortality. Nonetheless, our study furthers our understanding of patterns and incidence of liver injury in LT recipients when compared to a control group of non-transplant patients with CLD. Lastly, longer term follow up will be needed to study the course of liver injury

This article is protected by copyright. All rights reserved after COVID-19 resolution, but we do present reassuring data from a subgroup of patients who have already recovered.

In conclusion, we show that liver injury is common and is independently associated with mortality with COVID-19. We recommend that liver enzymes should be closely monitored in LT recipients with COVID-19, as they can serve as predictors of outcome. We perform a detailed analysis of various potentially overlapping causes of liver injury and determine that it is mostly driven by hepatotoxic medications and severity of COVID-19. Although antibiotics have been commonly utilized in the direct management of COVID-19, as well as secondary infections, judicious antibiotic stewardship remains a target in infected LT recipients and may reduce risk of liver injury. Further, avoiding hypotension in patients admitted to ICU can potentially mitigate liver injury. Decisions regarding modifications to immunosuppression regimens in LT recipients with COVID-19 need to be made on a case-by-case basis, but our study shows that immunosuppression can be safely reduced, if necessary. While our subgroup analysis shows that liver injury appears to be transient and mostly resolves following recovery from COVID-19, extended follow up will be needed to understand long term effects. 

This article is protected by copyright. All rights reserved 

COVID-19 in Liver Transplant Recipients: An Initial Experience from the

COVID-19 in an international European liver transplant recipient cohort

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

Determining risk factors for mortality in liver transplant patients with COVID-19

One world, one pandemic, many guidelines: management of liver diseases during COVID-19

Liver injury is independently associated with adverse clinical outcomes in patients with COVID-19

Characteristics of liver tests in COVID-19 patients

Acute Liver Injury in COVID-19: Prevalence and Association with Clinical Outcomes in a Large US Cohort

Guidance for certifying deaths due to coronavirus disease 2019 (COVID-19) [Internet]. National Center for Health Statistics

Standard liver tests

Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection

Liver injury in COVID-19: The current evidence

Clinical Features of COVID-19-Related Liver Functional Abnormality

SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19

Severe Acute Respiratory Syndrome (SARS) in a liver transplant recipient and guidelines for donor SARS screening

MERS CoV infection in two renal transplant Accepted Article This article is protected by copyright. All rights reserved recipients: case report

COVID-19 in solid organ transplant: A multi-center cohort study

Coronavirus Disease 2019 Case Surveillance -United States

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

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

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

Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper

Coronavirus Disease 2019 (COVID-19) and Cardiac Injury