key: cord-0899612-vxtv8cro
authors: Cholankeril, George; Goli, Karthik; Rana, Abbas; Hernaez, Ruben; Podboy, Alexander; Jalal, Prasun; Da, Ben L.; Satapathy, Sanjaya K.; Kim, Donghee; Ahmed, Aijaz; Goss, John; Kanwal, Fasiha
title: Impact of COVID‐19 pandemic on liver transplantation and alcohol‐associated liver disease in the United States
date: 2021-07-26
journal: Hepatology
DOI: 10.1002/hep.32067
sha: 124c3ca40716ddf9a2d45b0edc45d69c808cbd6b
doc_id: 899612
cord_uid: vxtv8cro

BACKGROUND & AIMS: The surge in unhealthy alcohol use during the COVID‐19 pandemic may have detrimental effects on the rising burden of alcohol‐associated liver disease (ALD) on liver transplantation (LT) in the US. We evaluated the impact of the pandemic on temporal trends for LT including ALD. APPROACH & RESULTS: Utilizing data from United Network for Organ Sharing, we analyzed waitlist outcomes in the US through March 1, 2021. In a short‐period analysis, patients listed or transplanted between June 1, 2019 and February 29, 2020 were defined as the “pre‐COVID” era and after April 1, 2020 were defined as the “COVID” era. Interrupted time‐series analyses utilizing monthly count data from 2016‐2020 were constructed to evaluate rate change for listing and LT prior to and during the COVID‐19 pandemic. Rates for listings (P=0.19) and LT (P=0.14) were unchanged during the pandemic despite a significant reduction in the monthly listing rates for HCV (‐21.69%, P <0.001) and NASH (‐13.18%; P <0.001). There was a significant increase in ALD listing (+7.26%; P <0.001) and LT (10.67%; P <0.001) during the pandemic. In the COVID era, ALD (40.1%) accounted for more listings than those due to HCV (12.4%) and NASH (23.4%) combined. The greatest increase in ALD occurred in young adults (+33%) and patients with severe alcoholic hepatitis (+50%). ALD patients presented with a higher acuity of illness, with 30.8% of listings and 44.8% of LT having a MELD‐Na ≥ 30. CONCLUSIONS: Since the start of COVID‐19 pandemic, ALD has become the most common indication for listing and the fastest increasing cause for LT. Collective efforts are urgently needed to stem the rising tide of ALD on healthcare resources.

The exponential increase in the number of reported Coronavirus Disease (COVID-19) cases in the United States (U.S.) has mandated large-scale healthcare practice changes across the country. Although organ transplantation is often a medical emergency, the increasing demand and utilization of hospital resources has adversely impacted the ability of transplant centers to perform these live-saving procedures.

Previous analyses have demonstrated that solid organ transplantation within the U.S. was significantly curtailed by COVID-19.(1) However, the reduction was primarily driven by a substantial decline in kidney and living Accepted Article donor transplantation volumes during the early phases of the pandemic in March and April 2020. 2, 3 While these analyses appreciated a downtrend in transplant volumes among all organ types, an ongoing follow-up was warranted to understand how this trend has impacted liver transplantation (LT) on both a national and regional level.

In particular, patients with alcohol-associated liver disease (ALD) are an important subpopulation to consider. Data from early in the pandemic showed a rise in liquor sales during the pandemic. (2) Other recently published studies showed that increased alcohol consumption which was associated with length of time spent under a shelter-in-place order, increased stress, greater alcohol availability, and diagnoses of depression or depressive symptoms. (3) (4) (5) ALD is already the leading indication for LT in the U.S. (6, 7) The downstream impact of increased unhealthy alcohol use during the pandemic can have substantial, detrimental effects and may have already impacted LT in the U.S.

The landscape for LT in the U.S. has changed dramatically over the past 5 years due to advancements for treating HCV, rising prevalence for NASH and increased leniency for programs to list those with ALD. 2, 6 This has led to declining LT rates for HCV and increasing rates for ALD and NASH. The effect of the COVID-19 pandemic on LT for these etiologies needs to be explored further. Therefore, we aim to evaluate the impact of the COVID-19 pandemic on waitlist outcomes in relation to short-and long-period temporal trends for LT.

We conducted an analysis of prospectively collected data from the United Network for Organ Sharing (UNOS) among all adult (age >18 years) liver transplant waitlist registrants and recipients. We defined the nine-month period from June 1, 2019 through February 29, 2020 as the "pre-COVID era". Similarly, we defined the ninemonth period from April 1, 2020 through December 31, 2020 as the "COVID era". To limit confounding from regional variation in the adoption of shelter-in place statutes during March 2020 and its effect on LT, we excluded data from March 1, 2020 through March 31, 2020 from our comparative analyses. Waitlist additions or listings were defined as patients initially listed only during the defined era period. Follow-up data was available until March 1, 2021.

Etiology of liver disease including ALD and severe alcoholic hepatitis (SAH) was determined by distinct primary and secondary diagnostic codes provided by the UNOS registry. Patients listed or transplanted HCV or NASH were also evaluated. Other patient characteristics included sociodemographic characteristics including age, gender, ethnicity/race and clinical characteristics including laboratory Model for End-Stage Liver Disease Accepted Article score (MELD-Na), presence of ascites, hepatic encephalopathy, history of spontaneous bacterial peritonitis, hepatocellular carcinoma (HCC), hemodialysis, mechanical ventilation and U.S. geographic region.

To compare how pandemic-associated changes took place within the context of ongoing trends over the last several years, we constructed a single group interrupted time-series regression models using monthly cumulative count data from the last 5 years (January 1, 2016 -March 1, 2021) to account for long-term time trends in the data. (8, 9) April 1, 2020 represented the start of the COVID-19 pandemic. Predicted rate during the pandemic was determined using cumulative monthly counts in the pre-COVID era from January 1, 2016 through February 28, 2020 and compared to actual rates during the pandemic. Using these models, we analyzed changes in rates for overall and etiology-based (ALD, NASH, and HCV) cumulative listing and transplant trends. In consideration of the idea that consecutive observations in a trend tend to be more similar than observations further apart, our time-series models were corrected for autocorrelation appropriately to favor the assumption that observations are independent.

We also evaluated trends in waitlist and LT rates prior to and during the COVID-19 pandemic in a short-term analyses. We split the pre-COVID and COVID eras into 3-month periods resulting in 6 quarters. The quarterly average number of new waitlist additions, waitlist deaths, and LT surgeries performed in the pre-COVID era (April 1, 2019 to December 31, 2019) were compared to counts during each of the three time periods during the pandemic (April 1, 2020 to June 30, 2020; July 1, 2020 to September 30, 2020; October 1, 2020 to December 31, 2020). We also examined temporal trends in waitlist and LT in subgroups with ALD, SAH, and by geographic region in the U.S.

First, we sought to evaluate how state-to-state variation in the duration of shelter-in-place order statutes for COVID-19 affected listing and transplants performed for high MELD patients (MELD-Na>30) between eras.

Although covariates directly relating to pandemic restrictions or shelter-in-place were not available in the UNOSS database, to address this point we ascertained the timing of shelter-in-place orders for all states, and categorized states based on the implementation and duration of shelter in place during the study time frame 

This article is protected by copyright. All rights reserved and/or transplantation in ALD and non-ALD patients based on whether they were listed/transplanted in states with or without shelter in place orders.

In February 2020, OPTN/UNOS implemented the "acuity circle" policy which prioritizes allocating liver organs to the sickest candidates within a 150-250 nautical mile range from a donor service area. (11) In a secondary analysis, we compared median time from listing to transplant for all, ALD and non-ALD patients in high MELD recipients between eras.

We compared clinical and demographic characteristics between waitlist additions and LT recipients in the pre-COVID-19 era with those in the COVID-19 era. Clinical characteristics among waitlist additions and LT recipients, including those with ALD, were compared in each era using chi-square test for categorical variables and student's t-test (parametric) and Mann-Whitney U test for (nonparametric) continuous variables.

Interrupted time-series analyses were performed using linear regression with Newey-West standard errors to handle autocorrelation in addition to possible heteroskedasticity. Fine and Gray proportional hazard regression models were constructed to evaluate differences in LT rates for ALD and non-ALD in the pre-COVID and COVID eras, respectively. The Gray test and Fine-Gray models allow for the analysis of competing risk events, which, in our study, waitlist removal due to death, clinical deterioration or clinical improvement. Followup time for the pre-COVID era was censored on February 28, 2020 to prevent overlap between the two eras.

Patients listed without at least 2 months of follow-up data in either era were excluded in the regression models.

All statistical analyses and data visualizations were performed using STATA Version 13.0 (College Station, TX). Statistical significance was met with a P-value <0.05. This study was approved by the Institutional Review Board at Baylor College of Medicine.

Cumulative year-to-date totals for waitlist additions, waitlist dropout (defined as removal from the waitlist due to death or clinical deterioration), and liver transplants in the U.S. were similar in 2019 and 2020 (Supplementary Figure 1) . Although the number of LT had initially declined during the start of the pandemic, LT volume recovered from May 2020 onwards. Aggregate quarterly totals for 2020 shown in Table 1 demonstrate that the LT recovery was seen across all U.S. regions including the Northeast and Mid-Atlantic, regions that experienced the largest reduction in transplant volume. However, this recovery was not uniform. Compared to pre-COVID era, the Mid-Atlantic and Southeast regions experienced a reduction in number of transplants performed. In contrast, the Southwest region experienced both an increase in waitlist additions and transplants in the COVID era. Compared to pre-COVID era, waitlist dropout was lower in the COVID era, which was also observed in nearly all U.S. regions ( Table 1 ).

Overall Clinical characteristics of waitlist additions and LT recipients in the pre-and COVID eras are shown in Table 2 .

Both waitlist additions and liver transplant recipients were younger during the COVID era. In addition, there was a higher percentage of listings with Medicaid and private insurance and a lower percentage of Medicare insurance.

Gender, ethnicity/race, and geographic region of listing/transplant were not significantly different between eras.

During the COVID era, the percentage with ALD significantly increased, accounting for 40% of listings and liver transplants. The percentage of waitlist additions with ALD (40.1%) surpassed that for HCV (12.4%) and NASH (23.4%) combined. Median MELD-Na scores at listing (18 vs. 19, P <0.001) and at transplant (23 vs. 24, P < 0.001) were also higher in the COVID era. The percentage of patients with a high MELD-Na scores > 30 at listing (pre-COVID era: 19.9%. vs. COVID era: 22.1%; P <0.001) and at transplant (pre-COVID era: 30.1% vs COVID era: 33.4%; P <0.001) increased significantly during the pandemic.

Clinical characteristics of patients listed or transplanted with ALD are shown in Table 3 . Between eras, young adults (18-34 years and 35-50 years) experienced a modest 2.8% absolute increase but accounted for 35.4% of listings in the COVID era. There was also a corresponding decrease in the number of ALD listed or transplanted aged 65 and above. Similar to the overall comparison, gender, race/ethnicity and geographic region distributions were similar between the pre-COVID and COVID eras. Median MELD-Na at listing (22 vs. 23, P < 0.001) and transplant (27 vs. 28, P <0.001) increased for ALD during the COVID era. The percentage of ALD patients listed with MELD-Na > 30 increased from 26.6% in pre-COVID to 30.8% in the COVID era, a

This article is protected by copyright. All rights reserved 15 .8% relative increase from prior. In addition, the percentage of ALD transplanted with MELD-Na > 30 increased from 38.6% to 44.8%, a 16.1% relative increase. A higher proportion of ALD patients required hemodialysis at listing and transplant in the COVID era. The percentage of patients hospitalized on the general medical floor or ICU at the time of transplant also increased from 39.8% to 45.8% between eras (Table 3) .

Listings and transplants for SAH increased from July 2020 onwards, and were nearly twice the numbers of listings and transplants in 2019 (Table 1) . Overall, SAH listings (pre-COVID era n=131 vs. COVID era n=207) and transplants (pre-COVID era n=110 vs. COVID era n=168) increased by 58.0% and 52.7%, respectively. There were no differences in age or MELD-Na scores at listing or transplant for SAH in either era. Table 1 ). In the pre-COVID era, ALD patients had 50% higher removal rate due to clinical improvement (sHR: 1.50, 95% CI: 1.17-1.92; P =0.001) than non-ALD. Conversely, during the COVID era this relationship inverted with ALD experiencing a 50% lower rate for clinical improvement (sHR: 0.49, 95% CI: 0.33-0.75; P =0.001) compared to non-ALD.

Temporal Trend Analyses Table 4 shows the results of the interrupted time series models. The monthly rate for overall listings (mean difference -18.27 waitlist additions per month, -1.74%; P =0.194) and transplants (+11.04 waitlist additions per month, +1.57%; P =0.146) did not significantly change after COVID-19. (Table 4 ). For ALD, rate for listings increased significantly in the COVID era by 7.26% (+28.56 waitlist additions per month; P <0.001). Similarly, rate for ALD transplants also increased by 10 There was a significant increase in overall high MELD listings and transplants in states with longer shelter-inplace orders of 40-80 days. In regards to ALD, both high MELD listings and transplants significantly increased with longer duration of shelter-in-place of 40-80 days (pre-COVID era: 23.1% vs COVID era: 28.1%; P <0.001) and >80 days (pre-COVID era: 19.8% vs COVID era: 22.2%; P <0.001) but remained unchanged for non-ALD.

Median time from listing to transplant for high MELD patients (at time of listing) significantly decreased among all patients including ALD and non-ALD patients during the COVID era, which also coincided with the start of the acuity circle allocation policy (Supplementary Table 1 ). (11)

The COVID-19 pandemic has had far reaching impact on many aspects of health and healthcare. We found evidence for a substantial and rising burden of ALD since the onset of the pandemic. In our comprehensive analyses of national waitlist and transplantation data, we found that over 40% of listings were due to ALD. For the first time, ALD accounted for more listings than HCV and NASH combined. In parallel, we found a shift in the severity of liver disease at the time of listing and transplantation, MELD-Na score at listing and transplant was significantly higher in the COVID era and much of this trend was due to the higher severity of liver disease seen in patients with ALD. The percentage of ALD patients listed or transplanted with a MELD-Na > 30 significantly increased by over 15% during the pandemic. Our data also show that ALD patients had an advantage over patients with other etiologies but this disparity grew substantially in the COVID-era. ALD patients had a 50% higher probability of LT rate than patients with other liver disease. Collectively, these data show that COVID-19 pandemic has accelerated the rising burden of ALD with substantial impact on the LT allocation system.

During the COVID era, overall MELD-Na scores at listing and transplant increased. Over 20% of all waitlist additions in the COVID era had a MELD-Na score > 30. This increase in MELD-Na and severity of hepatic decompensation at presentation and transplant was largely due to the fact that over 30% of listings and 40% of transplants for ALD had a MELD-Na score > 30; an ominous rising trend which could suggest a larger contribution form alcoholic hepatitis as well. There was also a noticeable shift in the population demographic towards a younger age and Medicaid insurance. In addition, we found that listings and transplants with a diagnosis code for SAH nearly doubled since July 2020, possibly another effect of the pandemic on unhealthy alcohol use, particularly among young adults. Several trials have demonstrated favorable outcomes of early LT for SAH.(12) (13) , (14) In light of these data, transplant centers have increasingly adopted ALD and SAH as an indication for early LT among carefully selected patients whom may not have achieved 6-month sobriety. (15) (16) However, our time-series analysis shows that this change in clinical practice over the past few years for ALD is unlikely to explain the current trends seen during the pandemic. Instead, our data suggest a sharp rise

This article is protected by copyright. All rights reserved in underlying rate of ALD and SAH during the pandemic and not just an increased consideration for early LT in patients with SAH.

In our sensitivity analyses, we found an association between longer duration of shelter in place and higher severity of disease at the time of listing for ALD. This was not the case for non-ALD etiologies. These data provide support to the causal effect of pandemic (and related restrictions) on the sharp rise in ALD and related hepatic decompensation. This is a cause for concern for the lack of appropriate linkage-of-care for ALD patients during the pandemic. Due to "stay at home" regulations, patients with alcohol use disorder (AUD) and ALD who are high-risk for relapse might no longer have structured non-alcohol-related activities and in-person behavioral counseling programs that were previously readily available. This coupled with the delay in routine health care could have had deleterious effects on patients at risk for unhealthy alcohol use. While there has been a call for LT to centers to adapt to the pandemic by considering leniencies for ALD liver transplant candidates who may not have appropriate access to care, this strategy will not curtail the anticipated problem. 2 Few patients with ALD receive recommended care for AUD.(3) Access to these services is ever more crucial during the pandemic. Our data call for a well-coordinated multi-disciplinary effort involving policy stakeholders and healthcare providers to tackle these alarming trends. It could include use of telehealth and patient outreach programs that address AUD while simultaneously managing liver disease. Without these efforts, AUD and ALD may have a longstanding negative impact on our healthcare system including the liver allocation system well after the pandemic has subsided. (17) Our study is limited by its retrospective design, inability to evaluate onset of disease presentation, acute on chronic liver disease, and variation in policies at LT centers in the U.S. for ALD and SAH as an indication for liver transplantation. In February 2020, UNOS implemented a policy limiting a candidate's maximum exception score to each center's a median MELD-Na at LT minus 3 (MMaT-3). (18) This policy was implemented to reduce the inequity in access for LT between HCC and non-HCC patients and would prioritize non-HCC. This policy may have increased rate for LT among non-HCC patients including ALD patients.

However, we show no statistical difference in the percentage of patients transplanted with HCC prior to or during the pandemic. The acuity circle allocation policy was implemented at the start of the pandemic to help prioritize high MELD patients for LT. In those regards, we found a significant decrease in median time from listing to transplant among high MELD patients regardless of etiology. This may suggest that this allocation policy may be contributing to increased LT rates for ALD during the pandemic, since ALD disproportionately had a higher percentage of high MELD patients compared to other etiologies. Long-term data is needed to further evaluate the effect of the acuity circle allocation policy on LT outcomes.

Due to center variability in the listing diagnosis, our analysis may actually underestimate the number of patients listed and transplanted for SAH. We were unable to evaluate specific patient and donor (offers and acceptances) characteristics, including COVID-19 status, which are crucial to decision-making for transplant programs. In addition, we were unable to evaluate center-specific factors on decision-making for candidates,

This article is protected by copyright. All rights reserved which was likely heterogenous during this unprecedented pandemic. In our sensitivity analyses, we categorized the duration of shelter-in-place orders according to the state for each transplant center. We acknowledge the caveat that some patients may reside in a different state from their transplant center which may confound our findings regarding the association between duration of shelter-in-place orders and high MELD listings.

There has been an unprecedented rise in rates of listings and transplants for ALD since the beginning of COVID-19 pandemic. ALD has accounted for more listings than NASH and HCV combined together. The higher severity of liver disease at listing and an increasing proportion of young adults among waitlisted patients are ominous signs and suggest a higher contribution from severe alcoholic hepatitis than indicated by UNOS data. Innovative health care modalities, such as telemedicine and remote health monitoring, could potentially be leveraged to address problems of excessive at-home drinking that is likely taking place. From a broader perspective, COVID-19-related stressors, such as unemployment, that have been associated with increased alcohol use should also be carefully considered when caring for patients. Clinicians should ensure that patients with ALD are receiving appropriate and timely linkage-to-care including referral to transplantation for those meeting clinical criteria for LT. Our analysis might only be showing the early effects of increased alcohol consumption that began at the start of the pandemic, and the impact of unhealthy alcohol use may be felt for several years to come. 

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A 6-Month Report on the Impact of the Organ Procurement and Transplantation Network/United Network for Organ Sharing Acuity Circles Policy Change

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Model to Calculate Harms and Benefits of Early vs Delayed Liver Transplantation for Patients With Alcohol-Associated Hepatitis

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MELD-Na, hepatic decompensation, hemodialysis and mechanical ventilation/life support) for

MELD-Na, hepatic decompensation, hemodialysis and mechanical ventilation/life support) for liver transplant recipient reported at time of transplant Abbreviations: MELD-Na

Abbreviations: ALD, alcohol-associated liver disease

HCV, hepatitis C virus infection

nonalcoholic steatohepatitis Figure Legends Figure 1. Cumulative incidence rates for liver transplantation among patients listed for ALD and non-ALD in the pre-COVID and COVID eras

Supplementary Figure 1. Cumulative year-to-date totals of waitlist removals (death, +/-clinical deterioration), waitlist additions and liver transplants

Waitlist dropout -removal due to death or clinical deterioration

We would like to acknowledge the United Network for Organ Sharing, a non-profit organization that administrates the Organ Procurement and Transplantation Network, for providing us with a custom database from which our data was collected and analyzed. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy of or interpretation by the United Network for Organ Sharing/Organ Procurement and Transplantation Network or the U.S. Government.

This article is protected by copyright. All rights reserved Table 3 . Comparison of demographic and clinical characteristics among waitlist additions and liver transplant recipients with alcohol-associated liver disease prior to and during the COVID-19 pandemic.

Pre-COVID Era COVID Era Pre-COVID

This article is protected by copyright. All rights reserved

This article is protected by copyright. All rights reserved