© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020

Click to check for updates

Released: November 9, 2020 CLINICAL BEST PRACTICE ADVICE FOR HEPATOLOGY AND LIVER TRANSPLANT PROVIDERS DURING THE COVID-19 PANDEMIC: AASLD EXPERT PANEL CONSENSUS STATEMENT This is a “living” document that will continue to evolve and will be updated as new information becomes available. DISCLAIMER ...................................................................................................................................................... 2 OVERVIEW AND RATIONALE ................................................................................................................................ 2 EFFECTS OF SARS-COV-2 ON THE LIVER AND EVALUATION OF COVID-19 PATIENTS WITH ELEVATED LIVER BIOCHEMISTRIES ................................................................................................................................................ 2 DIAGNOSIS OF SARS-COV-2 INFECTION................................................................................................................ 4 STABLE OUTPATIENTS WITH LIVER DISEASE AND/OR HEPATOCELLULAR CARCINOMA .................................................... 5 PATIENTS WITH DECOMPENSATED CIRRHOSIS, LIVER TRANSPLANT EVALUATIONS, AND PATIENTS ON THE LIVER TRANSPLANT WAITING LIST ................................................................................................................................................... 7 LIVER TRANSPLANTATION, RESOURCE UTILIZATION, AND ETHICAL CONSIDERATIONS ..................................................... 9 CHALLENGING ISSUES IN LIVER TRANSPLANTATION DURING THE COVID-19 PANDEMIC .............................................. 11 POST-LIVER-TRANSPLANT PATIENTS AND MANAGEMENT OF PATIENTS ON IMMUNOSUPPRESSIVE AGENTS .................... 11 INPATIENTS ..................................................................................................................................................... 14 MEDICATION MANAGEMENT OF PATIENTS WITH COVID-19 AND POTENTIAL DRUG-DRUG INTERACTIONS .................... 15 PROCEDURES .................................................................................................................................................. 19 RESEARCH ...................................................................................................................................................... 19 TRAINEES ....................................................................................................................................................... 20 TELEMEDICINE ................................................................................................................................................ 21 REENTRY AND RETURN TO A PRE-PANDEMIC STATE ............................................................................................... 22 AASLD COVID-19 CLINICAL OVERSIGHT SUBCOMMITTEE ..................................................................................... 23 COVID-19 LIVER DISEASE AND TRANSPLANT REGISTRIES ....................................................................................... 24 HELPFUL RESOURCES ....................................................................................................................................... 24 TABLES .......................................................................................................................................................... 25

Table 1. Diagnostic Methods for SARS-CoV-2 Detection .................................................................................... 25 Table 2. Investigational Treatments for COVID-19 ............................................................................................. 26

FIGURES ......................................................................................................................................................... 29 Figure 1. Approach to the Patient with COVID-19 and Elevated Serum Liver Biochemistries ............................ 29 Figure 2. Approach to Liver Transplant Organ Offers ........................................................................................ 30 Figure 3. Approach to the Liver Transplant Recipient with COVID-19 ................................................................ 31

REFERENCES ................................................................................................................................................... 32

More AASLD resources for COVID-19 and the Liver: https://www.aasld.org/about-aasld/covid-19-and-liver

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 2

Disclaimer This document represents the collective opinion of its authors and approval of the AASLD Governing Board as of the date of publication. Its use is voluntary, and it is presented primarily for the purpose of providing information to hepatology and liver transplant care providers. This document is not a practice guideline and has not been subject to the methodical rigor of a practice guideline. There has not been a systematic evidence review as defined by the Health and Medicine Division of the National Academies of Sciences, Engineering, and Medicine (formerly the Institute of Medicine), nor is the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach utilized. This document does not define a standard of practice or a standard of care. It should not be considered as inclusive of all proper treatments or methods of care, nor is it intended to substitute for the independent professional judgment of the treating provider. Hospitals, clinics and private practices should take into account local standards, practices and environment. Overview and Rationale Coronavirus disease 2019 (COVID-19), the illness caused by the SARS-CoV-2 virus, has impacted every aspect of life and health care in 2020 and for the foreseeable future. Patients with chronic liver disease including cirrhosis may be at higher risk of death from COVID-19, but clinical risk factors in specific liver diseases, such as autoimmune hepatitis (AIH) or liver cancer, or in transplant recipients, are not clearly defined. Given the extraordinary amount of rapidly emerging data on COVID-19, it is difficult for any single clinician to stay abreast of the latest information. The first version of this document was published online on March 23, 2020 and in print in Hepatology on April 16, 2020. This online document has been updated regularly to include rapid changes in information relevant for the hepatology workforce. The goals of this document are to provide data on what is currently known about COVID-19, and how it may impact hepatologists, liver transplant providers, and their patients. Our aim is to provide a template for developing clinical recommendations and policies to mitigate the impact of the COVID-19 pandemic on liver patients and health care providers. As some communities begin a gradual return toward a pre-pandemic state, we must adjust to the “new normal” and provide safe and optimal care in response to changes in our work and surrounding environment. Effects of SARS-CoV-2 on the Liver and Evaluation of COVID-19 Patients with Elevated Liver Biochemistries What we know

• The novel coronavirus SARS-CoV-2 is most similar to the beta-coronaviruses, SARS-CoV and MERS-CoV, the causative agents of the SARS outbreak in 2002-2003 and the MERS outbreak beginning in 2012, respectively.

• SARS-CoV-2 is a single, positive-stranded RNA virus that replicates using a virally-encoded RNA-dependent RNA polymerase.

• SARS-CoV-2 binds to and is internalized into target cells through angiotensin-converting enzyme 2 (ACE2), which acts as a functional receptor.1,2

• ACE2 is present in biliary and liver epithelial cells; therefore, the liver is a potential target for infection.3

o Coronavirus particles have been identified in the cytoplasm of hepatocytes associated with typical histological evidence of viral infection.4

• The incidence of elevated serum liver biochemistries in hospitalized patients with COVID-19 ranges from 14% to 83%.5–14

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 3

o Primarily elevated AST and ALT 1-2 times the upper limit of normal (ULN) and normal to modestly elevated total bilirubin early in the disease process.11–13,15

o Liver injury occurs more commonly in severe COVID-19 cases than in mild cases.10,12,16 o Rare cases of severe acute hepatitis have been described in patients with COVID-

19.6,11,12,17 Predictors of peak abnormal liver tests >5x ULN include age, male gender, body

mass index, diabetes mellitus, medications (e.g., lopinavir/ritonavir, hydroxychloroquine, remdesivir, tocilizumab), and inflammatory markers (IL-6, ferritin).12,14

o Liver injury in mild COVID-19 cases is usually transient and does not require specific treatment beyond supportive care.10

• Low serum albumin on hospital admission is a marker of COVID-19 severity.9,12,18–20 • AST is usually higher than ALT and is associated with severe COVID-19 and mortality, which may

reflect non-hepatic injury.8,12,13,16 • Severe liver injury in COVID-19 is uncommon in children; in the rare cases of severe pediatric

COVID-19, increases in ALT or AST, when present, are usually mild (<2x ULN).21,22 • COVID-19 is linked with multisystem inflammatory syndrome in children (MIS-C), with

overlapping features of Kawasaki disease and positive COVID-19 antibody testing suggesting a post-infectious entity.23

• Liver histologic assessment has been limited but thus far is nonspecific and ranges from moderate microvesicular steatosis with mild, mixed lobular and portal activity to focal necrosis.24–26

• An American autopsy series demonstrated histologic findings of macrovesicular steatosis, mild acute hepatitis (lobular necroinflammation) and mild portal inflammation. In addition, SARS-CoV-2 viral RNA was detectable by PCR in 55% of liver samples that were interrogated.26

• Elevated liver biochemistries may reflect a direct virus-induced cytopathic effect and/or immune damage from the provoked inflammatory response and cytokine release syndrome.7,27

• Therapeutic agents used to manage symptomatic COVID-19 may be hepatotoxic but rarely lead to treatment discontinuation.10 These include remdesivir and tocilizumab.28–31

• It is unknown whether SARS-CoV-2 infection exacerbates cholestasis in those with underlying cholestatic liver disease such as primary biliary cholangitis or primary sclerosing cholangitis or with underlying cirrhosis.10

• Patients with chronic lung disease including those with alpha-1 antitrypsin deficiency may be at increased risk of severe COVID-19.

• COVID-19 may predispose patients to thromboembolic disease and anticoagulation may improve outcomes in hospitalized patients.32,33

o An awareness of the high rate of thrombotic events in COVID-19 is necessary as this could potentially adversely impact the outcomes in those with chronic liver disease.

• The impact of nonalcoholic fatty liver disease (NAFLD) on COVID-19 is controversial but metabolic risk factors such as obesity, diabetes mellitus, and hypertension are associated with COVID-19 severity.34,35

• It will be difficult to differentiate whether increases in liver biochemistries are due to SARS-CoV-2 infection itself; its complications, including myositis (particularly with AST>ALT), cytokine release syndrome, ischemia/hypotension; and/or drug-induced liver injury.10,24

• An approach to evaluating the patient with COVID-19 and elevated liver biochemistries is shown in Figure 1.

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 4

Recommendations • Consider etiologies unrelated to COVID-19, including other viruses such as hepatitis A, B and C,

and drug-induced liver injury when assessing patients with COVID-19 and elevated liver biochemistries.14

• To limit unnecessary exposure to COVID-19, ultrasound or other advanced imaging (e.g., MRI/MRCP) should be avoided unless it is likely to change management, e.g., clinical suspicion for biliary obstruction or hepatic/portal venous thrombosis.

• Consider other causes of elevated liver biochemistries, including myositis (particularly when AST>ALT), cardiac injury, ischemia, drug-induced liver injury, and cytokine release syndrome.

• The presence of abnormal liver biochemistries should not be a contraindication to using investigational or off-label therapeutics for COVID-19, although AST or ALT levels >5x ULN may exclude patients from consideration of some investigational agents.

• Regular monitoring of liver biochemistries should be performed in all hospitalized COVID-19 patients, particularly those treated with remdesivir or tocilizumab, regardless of baseline values.

• In patients with AIH or liver transplant recipients with active COVID-19 and elevated liver biochemistries, do not presume disease flare or acute cellular rejection without biopsy confirmation.

• Evaluate all children with elevated AST or ALT for underlying liver diseases and coexisting infections as COVID-19 is not commonly associated with abnormal liver biochemistries in children.21

• Follow guidance in your clinical study protocol and/or by the Food and Drug Administration (FDA) for monitoring of liver biochemistries and discontinuation of study drug used to treat COVID-19.

Diagnosis of SARS-CoV-2 Infection What we know

• Inflammatory markers including D-dimer, C-reactive protein, creatine phosphokinase, and ferritin are frequently elevated in hospitalized patients and may be followed over time.

• A chest computed tomography (CT) scan with bilateral ground glass opacities is highly sensitive for the detection of pneumonia caused by COVID-19 but is non-specific.36

o The American College of Radiology recommends that chest CT should not be used as a first line screening test but rather to confirm the presence of pneumonia in selected hospitalized patients.37–39

• Accurate real-time quantitative polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 relies on sufficient amounts of replicating virus, optimal collection procedures and the collection site (i.e., nasopharyngeal vs. oropharyngeal vs. lower respiratory tract) (Table 1).40

• Nasopharyngeal swabs are more sensitive (63%) than oropharyngeal swabs (32%) while bronchoalveolar lavage (BAL) fluid specimens are the most sensitive (93%) using RT-PCR-based methods, although BAL poses a more significant risk of aerosolizing the virus.41

• On August 15, 2020, the FDA issued an Emergency Use Authorization for a rapid saliva-based test for the detection of SARS-CoV-2.

o The sensitivity of the saliva test in 70 COVID-19 patients was similar to a nasopharyngeal swab (81% vs. 71%).42

• Qualitative, isothermal, non-PCR nucleic acid amplification methods can deliver SARS-CoV-2 test results from a nasal or nasopharyngeal swab in <15 minutes but with higher concern for false negatives.43

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 5

• Testing samples from multiple sites from the patient or repeated testing from one patient site may improve sensitivity and reduce false negative results.40

• Serological tests (antibody and antigen) hold promise as non-invasive, rapid, and convenient means of testing for current or past SARS-CoV-2 infection.44,45

o SARS-CoV-2 antigen testing is less sensitive than PCR but with the advantage of more rapid results and potentially lower cost.45

o Antibody testing may complement PCR testing to improve detection (IgM), detect subclinical infection (IgM or IgG) and identify individuals who have recovered (IgG).40

o Antibody testing may also prove valuable in epidemiological studies, identification of convalescent plasma donors, and in the ongoing development of SARS-CoV-2 vaccines and antiviral treatments.

o Potential drawbacks of serological testing include false negative results early in the disease course, false positive results particularly with IgM testing and potential cross-reactivity with common cold coronaviruses.46

o Reinfection by a phylogenetically distinct strain of SARS-CoV-2 has been demonstrated in humans, suggesting that SARS-CoV-2 may continue to circulate despite herd immunity due to natural infection.47

o Per the Infectious Diseases Society of America (IDSA), antibody results should not be used to make staffing decision or decisions regarding the need for personal protective equipment (PPE) until more evidence is available.46

Recommendations

• Test all patients with suspected COVID-19 with nasopharyngeal swab testing (or saliva if available) using RT-PCR or non-PCR methods.

• Consider retesting patients with a high clinical suspicion for COVID-19 and negative initial test results.

• Point-of-care oropharyngeal swabs and saliva-based tests can also be used to screen for and diagnose COVID-19.

• Reserve testing of BAL samples for intubated patients with high clinical suspicion for COVID-19 despite negative nasopharyngeal, oropharyngeal, or sputum testing.

• CT should not be used to screen for or as a first line test to diagnose COVID-19 because of its lower specificity compared to nasal swabs.39,48

• Antibody testing should not be used for the diagnosis of SARS-CoV-2 infection. • Antibody testing results should not be used as the sole information necessary to make staffing

decisions or decisions regarding the need for PPE.

Stable Outpatients with Liver Disease and/or Hepatocellular Carcinoma What we know

• Asymptomatic adults and children (who are less likely to become ill) with SARS-CoV-2 infection can contribute to the spread of the virus.21,49

• Preliminary data from the CDC on 122,653 COVID-19 cases, including 7,162 (5.8%) with data on underlying conditions, showed that 1/3 of these patients (37.6%) had at least one underlying condition or risk factor for severe disease and poor outcomes.50 Among these patients with underlying conditions, only 41 patients (0.6%) had chronic liver disease, including 7 who required ICU admission.50

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 6

o These data are limited by small numbers and missing data (only 5.8% had available data on underlying conditions). Based on the known prevalence of NAFLD in the US population, the estimated prevalence of chronic liver disease in this study is likely underestimated.

• In a large cohort study of electronic health record data from over 17 million patients (>100,000 with chronic liver disease) in the United Kingdom, chronic liver disease was a risk factor for in-hospital death from COVID-19 (HR 1.61, 95% CI 1.33-1.95).51

• Chronic liver disease was associated with significantly higher mortality (RR 2.8, 95% CI 1.9-4.0) in a cohort of 2780 US patients with COVID-19.52

o The mortality risk was higher in patients with cirrhosis (RR 4.6, 95% CI 2.6-8.3). o Fatty liver disease and nonalcoholic steatohepatitis were the most common etiologies in

the liver disease group and the mortality risk was independent of risk factors such as body mass index, hypertension, and diabetes.

• It is unclear if the association between nonalcoholic fatty liver disease and poor outcomes from COVID-19 is because of comorbidities associated with the metabolic syndrome, chronic inflammation, fibrosis, or a combination of factors.53

• Despite the theoretical possibility that some hepatitis C and hepatitis B antiviral drugs (e.g., velpatasvir, ledipasvir, tenofovir) may have antiviral effects on SARS-CoV-2, there are insufficient data to conclude if these drugs are clinically effective against SARS-CoV-2.54

• There is no evidence that patients with stable chronic liver disease without advanced fibrosis/cirrhosis attributable to hepatitis B and/or C, or cholestatic syndromes such as primary biliary cholangitis or primary sclerosing cholangitis have increased susceptibility to SARS-CoV-2 infection.10

• It is unknown whether patients with hepatocellular carcinoma (HCC) are at increased risk for severe COVID-19 by virtue of their malignancy or treatments.

o A case series reported an association between worse COVID-19 outcomes and a history of non-hepatic types of cancer.55

o Those who underwent recent chemotherapy had an even higher risk of severe COVID-19, but the series also included those without recent chemotherapy.55

• The slow median doubling time of HCC supports a rationale of a short delay in radiological surveillance if necessary in areas of high SARS-CoV-2 prevalence.56

Recommendations

• Consider limiting outpatient visits to only patients who must be seen in person when COVID-19 is prevalent in the community, per local guidance. (See CDC Guidance for Healthcare Facilities.)

o As clinical practices increase the volume of in-person visits, continue to prioritize new adult and pediatric patients with urgent issues and clinically significant liver disease (e.g., jaundice, elevated ALT or AST >500 U/L, recent onset of hepatic decompensation, selected patients with liver cancer, and selected patients for liver transplant evaluation).

o Follow CDC recommendations for PPE. If PPE is unavailable keep a distance of at least 6 feet from the patient.

o Patients, caregivers, and providers should wear masks while in the clinic. Masks should be provided and/or homemade cloth masks should be permitted.

o Stagger patient arrival times, and if possible, room patients immediately on arrival to clinic to avoid patients congregating in the waiting area. If patients or caregivers are in the waiting area, maintain appropriate distancing and decontamination of the waiting area.

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 7

o Limit the number of family members/friends who accompany patients to their visits. Have these persons wait outside the clinic unless their presence is required for clinical decision making. Enable critical caregivers to participate in the visit by phone or video if possible.

o Continue to use phone visits or telemedicine as appropriate and available to replace in-person visits.

• Screen all patients for symptoms of COVID-19 or recent exposure (i.e., fever, cough, shortness of breath, sore throat, diarrhea, myalgias, new loss of sense of taste or smell,15,57 contact with known COVID-19 patients, history of recent domestic or international travel) before entry into the clinical space (e.g., phone call 24 hours prior to scheduled visit), and again at registration or as they enter the clinic.

• Check each patient’s temperature and ask about symptoms when they arrive to the clinic or registration desk.

o Patients with fever (>38 °C) or symptoms should be referred to the hospital’s protocol for symptomatic patients.

• Consider evaluating patients with COVID-19 symptoms or known exposure in an outpatient clinic or a site dedicated for this purpose. PPE should be prioritized to that site. Patients with COVID-19 symptoms or known exposure should not be evaluated in the hepatology/liver transplant clinic.

• Follow CDC recommendations for cleaning and disinfecting rooms or areas visited by individuals with suspected or confirmed COVID-19.

• Continue treatment for hepatitis B and hepatitis C if already on treatment. • There is no contraindication to initiating treatment of hepatitis B and C in patients without

COVID-19 as clinically warranted. • Initiating treatment of hepatitis B in a patient with COVID-19 is not contraindicated and should

be considered if there is clinical suspicion of a hepatitis B flare or when initiating immunosuppressive therapy.

• Initiating treatment of hepatitis C in a patient with COVID-19 is not routinely warranted and can be deferred until recovered from COVID-19.

• Continue monitoring in those on or off therapy for HCC and continue radiological surveillance in those at risk for HCC (cirrhosis, chronic hepatitis B) as close to schedule as circumstances allow, although an arbitrary delay of 2 months is reasonable.

o Discuss the risks and benefits of delaying radiological surveillance with the patient and document the discussion.

o These patients should be prioritized for imaging studies. o Avoid HCC surveillance in patients with COVID-19 until infection is resolved.

• Consider virtual visits to discuss diagnosis and management of HCC and other liver tumors. • Proceed with liver cancer treatments or surgical resection when able rather than delaying them

because of the pandemic.

Patients with Decompensated Cirrhosis, Liver Transplant Evaluations, and Patients on the Liver Transplant Waiting List What we know

• Mortality attributable to COVID-19 appears higher in patients with more advanced liver disease.20,51

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 8

• Data from two combined international reporting registries (COVID-Hep and Secure-Cirrhosis) of the first 152 consecutive submissions of COVID-19 patients with chronic liver disease show a high mortality rate of 39.8%.58

o Cause of death in patients with cirrhosis was liver-related in 12.2%, compared to 78.7% pulmonary and 4.3% cardiac.

o Mortality strongly correlated with Child-Turcotte-Pugh (CTP) class: 12.2% without cirrhosis, 23.9% CTP class A, 43.4% CTP class B, 63.0% CTP class C died.

o Hepatic decompensation during COVID-19 was strongly associated with subsequent risk of death (63.2% with new decompensation died vs. 26.2% without decompensation).

o 24.3% with new hepatic decompensation had no respiratory symptoms of COVID-19 at the time of diagnosis.

• A retrospective Italian study of 50 patients with COVID-19 and cirrhosis reported a high rate of hospitalization (96%) and high mortality rate (35% of hospitalized patients).20

o The most common cause of death was respiratory failure (71%); however, end-stage liver disease (with hypoxemic respiratory failure) was the cause of death in 29% of patients.

o Overall, liver function worsened and 46% decompensated during the course of their COVID-19 illness.

o 12% of patients were asymptomatic at presentation and were tested as part of a protocol for contact with positive patients.

o Compared to patients without cirrhosis hospitalized with COVID-19 during the study period, patients with cirrhosis had a higher 30-day mortality rate (18% vs. 34%) and a lower median age at death (80 vs. 70).

o Compared to historical controls (cirrhotic patients hospitalized for acute decompensation because of bacterial infection), patients with COVID-19 were older with lower MELD and CTP scores and a higher 30-day mortality rate (17% vs 34%).

• In a multicenter study of inpatients with cirrhosis+COVID-19 compared with age/gender-matched patients with COVID-19 alone and cirrhosis alone, patients with cirrhosis and COVID-19 had a higher risk of death compared to patients with COVID-19 alone, but not significantly higher than the risk of death from cirrhosis alone without COVID-19.59

o Patients with cirrhosis+COVID-19 had equivalent respiratory symptoms, chest findings, and rates of intensive care transfer and ventilation compared with patients with COVID-19 alone.

o Patients with cirrhosis+COVID-19 were less likely to present with GI symptoms, while patients with cirrhosis alone were more likely to develop cirrhosis-related complications.

o The only significant predictor of mortality was the Charlson Comorbidity Index. • The complex decision making involved in whether or not to proceed with transplantation has

been more challenging because of the COVID-19 pandemic. • It is essential that transplant centers continuously assess their local situation and its impact on

patients awaiting transplantation. • COVID-19 has had a significant impact on the transplant waiting list and transplant center

practice patterns.60 • Risk stratification continues to be important to identify patients who need to be evaluated for

transplantation or complete their evaluation during the COVID-19 pandemic, including patients with high MELD scores, risk of decompensation, or tumor progression.

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 9

Recommendations • Continue to prioritize patients coming to clinic for transplant evaluations who have HCC or those

patients with severe disease and high MELD scores who are likely to benefit from immediate liver transplant listing.

o Telemedicine can continue to be used to evaluate less urgent patients. • Continue to assess which listed patients need to be seen in person based on local prevalence of

SARS-CoV-2 and individual patient factors such as MELD. • Conduct patient transplant education and social work, dietitian, and financial consultations by

video conference, telemedicine, or telephone whenever possible. • Avoid multiple patients in one room for patient education.

o Consider developing internet-based education sessions for patients and family members that can be deployed either by in-room computers or at home prior to patient evaluation.

• Consider telemedicine alternatives in place of outreach clinics. • Obtain labs and imaging only as clinically necessary.

o Patients should not be asked to update labs or imaging simply to update or maintain their MELD score. Recent Organ Procurement and Transplantation Network (OPTN) policy changes provide guidance on how to maintain candidate MELD when updated clinical data are not obtained.

• Ensure that patients have refills available for essential medications. Provide prescriptions for 90-day supplies instead of 30-day supplies. Many insurance companies are waiving early medication refill limits.

• Consider instructing patients to avoid attending in-person community recovery support meetings such as Alcoholics Anonymous and provide alternative telephone or online resources.

• Advise patients to limit travel during the COVID-19 pandemic. • Consider providing documentation to patients, providers, and organ procurement teams to ease

essential travel where travel restriction policies are in place. • Have a low threshold for admitting to the hospital patients on the transplant waiting list who are

symptomatic with COVID-19. • Test patients with new onset hepatic decompensation for SARS-CoV-2.

Liver Transplantation, Resource Utilization, and Ethical Considerations What we know

• Resource utilization and ethical considerations are inherently tied to liver transplantation. This is a critical and challenging area for which protocols and policies need to be carefully considered and developed. There is no over-arching policy that can or should be applied to every transplant center; these issues will need to be discussed and developed locally.

• Although the Centers for Medicare and Medicaid Services (CMS) recommended limiting all non-essential planned surgeries and procedures, they specifically excluded transplant surgery from this recommendation and categorize transplant surgery as Tier 3b (“do not postpone”).

o The status of medical and surgical procedures is changing as state executive orders and local policies are evolving.

• Despite an initial decrease in liver transplantations at the onset of the COVID-19 pandemic, particularly in living donor liver transplantations, liver transplant volumes in the US have since rebounded to 2019 levels.

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 10

• All Organ Procurement Organizations are testing donors for SARS-CoV-2 RNA using nasopharyngeal, BAL, or both, and those who test positive are medically ineligible for organ donation.

• There is a significant false negative testing rate and transplant programs should consider symptoms of COVID-19 in a potential donor or recipient to be strongly suggestive of infection despite negative testing.

o Additional data including chest imaging and inflammatory markers (e.g., C-reactive protein, ferritin, IL-6) should be considered.

• Transplantation in SARS-CoV-2-positive transplant candidates is currently not routinely recommended until at least 14 days after clinical recovery.

o Limited data suggest there is a significant increase in postoperative morbidity and mortality related to SARS-CoV-2 infection, and for emergent surgery in particular.

o The risks of emergent liver transplantation for patients with acute liver failure who test positive for SARS-CoV-2 are not known.

• The Scientific Registry of Transplant Recipients (SRTR) will be modifying the evaluation metrics for transplant programs and organ procurement organizations (OPOs) and has recommended to remove any patient and donor data from the performance metrics following the declaration of a national emergency on March 13, 2020.

Recommendations

• Develop a hospital-specific policy for organ acceptance. o Ensure hospital administrators are aware of the CMS Tier 3b designation for transplant

surgery (“Do not postpone”). o Consider resource utilization including ICU beds, operating rooms, ventilators,

hemodialysis equipment, PPE and supply of blood products (especially platelets and type-specific packed red cells) in the decision to proceed with liver transplantation.

o Consider changes in local COVID-19 prevalence data to determine if transplantation should be restricted/suspended.

• Consider notifying patients that the COVID-19 pandemic may impact their waiting time on the transplant list.

• Notify patients that family and visitor access to them during their hospital stay may be limited or prohibited.

• Screen potential donors for exposure and clinical symptoms/fever compatible with COVID-19 (regardless of test results or availability).61

o Alternatives to PCR-based testing such as chest radiography may also be considered. • Screen potential recipients with an acceptable organ offer for COVID-19 symptoms/fever before

they are called in from home for transplantation. • Test all recipients and donors for SARS-CoV-2 before transplantation, if testing is available.

o Consider the risk of false negatives, disease prevalence, and testing turnaround time in your area.

o Review as much donor history as possible for fever, respiratory symptoms and radiographic findings.

• Consider having backup transplant recipients wait at home or away from the transplant center. • Ideally, transplantation in SARS-CoV-2-positive transplant candidates should be delayed for at

least 14-21 days after symptom resolution and 1 or 2 negative SARS-CoV-2 diagnostic tests. o The decision to proceed with transplantation in a SARS-CoV-2-positive candidate must

be individualized based on several factors including the urgency of transplantation, the

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 11

presence of respiratory symptoms, and the risk of exposing transplant personnel to SARS-CoV-2.

• See the latest updates regarding COVID-19 related OPTN policy changes. • An approach to liver transplant organ offers is shown in Figure 2.

Challenging Issues in Liver Transplantation During the COVID-19 Pandemic

• Should we decide who is more in need of limited resources, i.e., COVID-19 patients vs. patients in urgent need of liver transplantation? It is impossible to weigh the value of the life of a patient with COVID-19 against that of a patient in need of life-saving liver transplantation. We should not compound the negative impact of the pandemic by risking the lives of patients in need of liver transplantation. Our goal is to ensure that an appropriately staffed ICU bed is available for every patient who requires one.

• An argument that has been advanced to justify deferring some transplants is a concern about immunosuppressing patients during the COVID-19 pandemic. However, immunosuppressed patients may not be at increased risk for severe COVID-19.22,62 Nevertheless, immunosuppressed patients have higher viral titers and may be more infectious than immunocompetent individuals.61

• CMS clarified that transplants fall into Tier 3b and should not be postponed. • Other issues to consider in hospitals with a high prevalence of COVID-19 include the risk

of nosocomial transmission during the transplant admission, difficulty obtaining procedures or other resources when complications arise, and limitations on family/caregiver visitation for a postoperative period that often relies on the engagement of caregivers.

• These ethical issues may arise in transplant programs when the community incidence of infection is high and hospitalized COVID-19 patients utilize more resources, and predominantly center on the need for limited ICU beds, ventilators, and blood products. Each program will need to establish its institutional capacity to perform liver transplantation and a process for determining whether or not to proceed when an organ is available.

• These decisions should ideally be made in consultation with local medical ethics committees.63

Post-Liver-Transplant Patients and Management of Patients on Immunosuppressive Agents What we know

• Data suggest that the immune response may be the main driver for pulmonary injury attributable to COVID-19 and that immunosuppression may be protective.8,22,64

• Posttransplant immunosuppression was not a risk factor for mortality associated with SARS (2002-2003) or MERS (2012-present).22

• Several studies have shown a mortality benefit with the use of corticosteroids for the treatment of critically ill patients with COVID-19.65,66

• Immunosuppression may prolong viral shedding in posttransplant patients with COVID-19.61

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 12

• A retrospective report from Italy of 10 patients with AIH on immunosuppression and with COVID-19 suggests that the course of COVID-19 may be similar to non-immunosuppressed patients.62

o 4 patients had cirrhosis, 1 who was decompensated (the only one who died). o 2 patients were on high-dose corticosteroids for treatment of acute onset of AIH. o Prednisone was increased in 2 patients, decreased in 3 patients, and 1 patient stopped

taking prednisone. o 6 patients were hospitalized, including 5 with pneumonia and 3 required non-invasive

ventilation. o Liver biochemistries remained normal in all hospitalized patients except the 2 on high-

dose steroids for treatment of acute AIH (liver biochemistries improved in these 2 patients).

o The authors suggested that pre-emptive reduction in immunosuppression during COVID-19 can be potentially harmful.

• A retrospective report described the outcomes of 90 solid organ transplant recipients with COVID-19 treated as outpatients or inpatients in New York City.19

o The report included 13 liver transplant recipients (9 with mild/moderate COVID-19 and 4 with severe disease).

o Nosocomial transmission was suspected in 3 patients including 1 liver transplant recipient who was undergoing inpatient treatment for refractory rejection.

o Immunosuppressive medications were reduced in most hospitalized patients: Antimetabolite decreased or held in 88%, steroids decreased or held in 7%, and calcineurin inhibitor decreased or held in 18%.

o 34% required ICU admission, 35% required mechanical ventilation, 24% died (52% of the ICU patients), and 54% were discharged at the time of publication.

o There was no reported acute cellular rejection. • A group from Lombardy, Italy described 6 liver transplant recipients from their program who

were diagnosed with COVID-19.64 o 3 long-term liver transplant recipients died of COVID-19-related pneumonia and ARDS. o All were >65 years with hypertension, obesity, diabetes, and hyperlipidemia. o 3 recently transplanted (<2 years) patients had mild COVID-19 and did not require

hospitalization. • A prospective study of 111 liver transplant recipients with COVID-19 from Spain showed an

increased risk of acquiring SARS-CoV-2 (almost double the rate in the age/gender matched general population) but lower mortality rates than the matched general population.67

o Baseline immunosuppression containing mycophenolate, particularly doses >1000 mg/day, was an independent predictor of severe COVID-19 (RR 3.94, 95% CI 1.59-9.74, P=.003).

• 151 liver transplant recipients were described in an analysis of two combined international COVID-19 reporting registries (COVID-Hep and Secure-Cirrhosis).68

o 124 (82%) were hospitalized, 47 (31%) required intensive care, and 28 (19%) died. o In propensity score-matched analysis comparing liver transplant recipients to non-

transplant recipients (adjusting for age, sex, creatinine, obesity, hypertension, diabetes, and ethnicity), liver transplant status did not significantly increase the risk of death in patients with SARS-CoV-2 infection.

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 13

o In multivariable logistic regression, age, creatinine, and non-liver cancer were significantly associated with risk of death among liver transplant recipients.

• Data have been reported from the first 103 patients of a European registry (ELITA/ELTR) of liver transplant recipients with COVID-19.69

o 15 (15%) were admitted to intensive care, 68 (66%) were admitted to a general ward, and 20 (19%) were monitored at home.

o 16 (16%) died, including 4 (44%) of the 9 who were on mechanical ventilation. o No patients <60 years old died. o More patients who were transplanted at least 2 years ago died than did those

transplanted within the last 2 years (not statistically significant). • Data from the US multicenter COLD consortium of 112 liver transplant recipients were also

recently reported.70 o Overall, 25 (22.3%) died, 81 (72.3%) hospitalized, and 30 (26.8%) required ICU-level

care. o In multivariable analysis, the strongest predictors of death were the presence of

diabetes and the presence of acute liver injury. o The risk of death was not higher among liver transplant recipients compared to controls

with chronic liver disease. • Anti-IL-6 therapeutics have not been shown to increase the risk of acute cellular rejection. • Reducing the dosage or stopping immunosuppressants may cause a flare in a patient with AIH or

precipitate acute rejection in a liver transplant recipient.62 o The NIH COVID-19 treatment guidelines recommend that oral corticosteroid therapy

used prior to COVID-19 diagnosis for another underlying condition should not be discontinued.71

Recommendations

• In post-transplant patients without COVID-19: o Do not make anticipatory adjustments to current immunosuppressive drugs or dosages. o Emphasize prevention measures posttransplant patients already know well: frequent

hand washing, cleaning frequently touched surfaces, staying away from large crowds, staying away from individuals who are ill, etc.

o Advise patients not to travel during the COVID-19 pandemic.61 o Minimize in-person visits for posttransplant patients by maximizing use of telemedicine. o Consider advocating for telework options, appropriate excuses from work or leaves of

absence for posttransplant patients and their primary caregivers. • In post-transplant patients with COVID-19:

o Consider lowering the overall level of immunosuppression, particularly anti-metabolite dosages (e.g., azathioprine or mycophenolate) based on general principles for managing infections in transplant recipients and to decrease the risk of superinfection.

o Consider the risk of kidney injury in COVID-19 and monitor calcineurin inhibitor levels. o Adjustment of immunosuppressive medications must be individualized based on

severity of COVID-19 and risk of graft rejection. o An approach to managing liver transplant recipients with COVID-19 is shown in Figure 3.

• In patients with AIH on immunosuppression without COVID-19: o Do not make anticipatory adjustments to current immunosuppressive drugs or dosages.

• In patients with AIH on immunosuppression with COVID-19:

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 14

o Consider lowering the overall level of immunosuppression, particularly anti-metabolite dosages (e.g., azathioprine or mycophenolate) based on general principles for managing infections in immunosuppressed patients and to decrease the risk of superinfection.

o Adjustment of immunosuppressive medications must be individualized based on severity of COVID-19.

• Initiate immunosuppressive therapy in patients with liver disease with or without COVID-19 who have strong indications for treatment (e.g., AIH, graft rejection).

• In patients with COVID-19, use caution in initiating prednisone, prednisolone, or other immunosuppressive therapy where the potential benefit might be outweighed by the risks (e.g., alcohol-associated hepatitis).

Inpatients What we know

• Health care workers and other hospital staff are at risk for COVID-19.72 • Health care workers with SARS-CoV-2 may spread the virus to patients and to each other and

should remain away from in-person work until approved to return by local health authorities. • Minimizing interactions among health care workers and between health care workers and

patients is critical to reducing the spread of SARS-CoV-2. • Minimizing the transport of patients within and between health care facilities could reduce the

spread of SARS-CoV-2. Recommendations

• Consider cohorting of inpatients with COVID-19 from other non-infected patients in the hospital. • Consider equipping patient rooms with telemedicine equipment (e.g., tablet) to enable remote

consultation and monitoring. • Limit the number of team members who enter a patient’s room for patient examinations and

encounters. • Consider conducting virtual visits for updates not requiring direct examination. This will reduce

contact risks as well as unnecessary utilization of PPE thereby preserving hospital supplies for essential needs.

• Discourage in-person multidisciplinary rounds with dietary, pharmacy, social work, and care coordination staff.

o Consider the use of virtual conferencing to reduce direct staff interactions. • Depending on local prevalence of COVID-19, consider continuing to limit the presence of non-

essential team members in the hospital (e.g., students, observers, research staff) to minimize exposure risk and prioritize the use of PPE.

• Consider use of telephone or virtual language translation services as needed to reduce contact with patients.

• Patients and visitors (if permitted) should wear masks while in the hospital. Masks should be provided to those without and/or homemade cloth masks should be permitted to preserve PPE resources.

• Limit the number of visitors who may see inpatients. • Consider developing a policy for review and triage of hospital inpatient transfers. For example,

when ICU capacity is limited or when risk of nosocomial transmission is high, consider accepting for transfer only patients with acute liver failure or those in need of urgent liver transplant evaluation during their hospital stay.

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 15

o Depending on local prevalence of SARS-CoV-2, consider accepting for transfer only other liver patients with a unique need for inpatient interventions at the transplant center.

o Screen and test all patients for SARS-CoV-2 prior to transfer or upon arrival if testing is not available at the transferring facility.

o Avoid direct hospital admission for patients with fever and respiratory symptoms, particularly admission to a transplant unit.

• Consider evaluating patients with liver disease for COVID-19 if they develop new onset encephalopathy or another acute decompensation.

• Have a low threshold for aggressive airway management in COVID-19 patients with underlying pulmonary diseases such as hepatic hydrothorax, portopulmonary hypertension, or hepatopulmonary syndrome.

• Perform a needs assessment prior to patient discharge to determine whether the patient can have follow-up encounters by phone or telemedicine and encourage early monitoring by these means to reduce early postdischarge, in-person visits.

o Consider home health or visiting nurse services for frequent blood draws needed after posttransplant hospital discharge.

• Patients with active viral shedding on discharge should remain in isolation at home and appropriate precautions should be taken for caregivers or family members who live with the patient.

• Consider the capacity of local rehabilitation centers to accept complex patients as beds in those facilities may be limited during the COVID-19 pandemic.

o Patients should have a negative SARS-CoV-2 test prior to discharge to a rehabilitation or skilled nursing facility.

o Review the possibility of enhanced home services during the admission to expedite discharge.

Medication Management of Patients with COVID-19 and Potential Drug-Drug Interactions What we know

• Remdesivir is currently the only FDA-approved therapy for the treatment of COVID-19. o Remdesivir is a nucleotide analogue with demonstrated activity against SARS-CoV-2 in

human cell lines.73 o The FDA approved remdesivir on October 22, 2020 for use in adult and pediatric

patients >12 years of age and >40 kg with COVID-19 requiring hospitalization. o An Emergency Use Authorization for selected hospitalized pediatric patients <12 years

of age and <40 kg remains in effect. o Patients should receive 200 mg IV on day 1 and 100 mg/day for up to 5 consecutive

days. o Patients who are intubated or receiving ECMO may be treated for up to 10 days. o Liver biochemistries should be checked prior to starting remdesivir and during

treatment. o Clinicians should consider stopping remdesivir if ALT >10x ULN. o Remdesivir should be discontinued in patients with ALT elevation and signs or

symptoms of liver inflammation. o There are no studies of the pharmacokinetics of remdesivir in patients with hepatic

impairment or cirrhosis.

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 16

o Interim analysis of the NIH-sponsored Adaptive COVID-19 Treatment Trial (ACTT) showed that remdesivir significantly accelerates time to recovery to hospital discharge or return to normal activity level compared to placebo (mean of 11 days vs. 15 days, P<.001).74 Remdesivir may also have a survival benefit compared to placebo, but the

difference was not statistically significant (14-day mortality rate of 7.1% vs. 11.9%, HR 0.70, 95% CI 0.47-1.04).

o A Phase 3 trial of remdesivir showed similar efficacy between a 5-day course and a 10-day course in patients with severe COVID-19 who did not require mechanical ventilation at baseline.28 There was a trend toward better outcomes (discharge rates and death) in

patients treated with a 5-day course than in those treated for 10 days. This trend may be because the 10-day group included a higher percentage of patients who went on to require invasive mechanical ventilation and high-flow oxygen and a higher proportion of men.

Patients who progress to mechanical ventilation may benefit from 10 days of remdesivir.

2.5% (5-day group) and 3.6% (10-day group) discontinued treatment because of aminotransferase elevations.

o Elevated liver biochemistries have been commonly observed in the remdesivir clinical development program and in VigiBase, the World Health Organization’s safety reports database, rarely including elevations up to 10 times baseline values.75

o The total number of patients treated with remdesivir with elevated serum aminotransferases was 32/532 (6%) vs. 55/516 (10%) with placebo.

o The incidence of hyperbilirubinemia with remdesivir was 2/532 (0.4%), which was similar in patients treated with placebo, 1/516 (0.2%).

o Investigational or off-label therapeutics for COVID-19 are infrequently discontinued because of hepatoxicity (Table 2).

• The RECOVERY trial of dexamethasone 6 mg oral or IV daily for up to 10 days demonstrated a significant mortality benefit in the dexamethasone arm (RR 0.83, 95% CI 0.74-0.92, P<.001).65

o Dexamethasone reduced deaths by 35% in patients receiving invasive mechanical ventilation (RR 0.65, 95% CI 0.51-0.82, P<.001) and by 20% in patients receiving oxygen without invasive mechanical ventilation (RR 0.80, 95% CI 0.70-0.92, P=.002).

o There was no benefit (and possible harm) from dexamethasone in patients who did not require respiratory support (RR 1.22, 95% CI 0.93-1.61, P=.14).

• In a prospective meta-analysis of 7 randomized trials that included 1703 patients, 28-day all-cause mortality was lower among patients who received corticosteroids (dexamethasone, hydrocortisone, or methylprednisolone) compared with those who received usual care or placebo (summary odds ratio 0.66).66

• In a retrospective study from China of 20 patients with COVID-19 and untreated chronic hepatitis B, 3 patients who received corticosteroids or interferon alpha-1b experienced hepatitis B reactivation.76

• The NIH recommends dexamethasone (or alternative corticosteroids) for the treatment of COVID-19 in patients who are mechanically ventilated and in patients who require supplemental oxygen.71

• The Infectious Diseases Society of America (IDSA) recommends dexamethasone for hospitalized critically ill patients with COVID-19 or patients with severe, non-critical COVID-19.77

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 17

• Drugs that target the IL-6 receptor (e.g., tocilizumab) are being tested only in hospitalized patients with moderate to severe COVID-19.

o The IDSA and NIH recommend using tocilizumab only in the context of a clinical trial.78 o A recently completed double-blind, placebo-controlled trial of a single dose of

tocilizumab in 243 patients with severe COVID-19 failed to demonstrate any clinical or survival benefit.79

o Sarulimab was not more effective than placebo in a recent randomized controlled trial and associated with more frequent AST and ALT elevations and is no longer under consideration for treatment of COVID-19.80

o In the Phase 3 COVACTA trial, no differences in any primary or secondary outcomes were noted in 450 patients with severe COVID-19 who were randomized to tocilizumab vs. placebo.

• Cocktails of monoclonal antibodies targeting the receptor binding domain of the spike protein and viral binding to the ACE2 receptor are being developed to treat COVID-19.81

o Preliminary results from an ongoing study in 799 treated patients demonstrated improvement in viral loads with different doses of the cocktail compared to placebo, particularly when given early to seronegative outpatients.

• Hydroxychloroquine (an analogue of chloroquine with a better safety profile) has been shown to have anti-SARS-CoV-2 activity in vitro.82

o The FDA revoked the Emergency Use Authorization for chloroquine and hydroxychloroquine after determining they are unlikely to be effective in treating COVID-19 and risks of cardiac adverse effects may outweigh potential benefits.83

o The NIH recommends against the use of hydroxychloroquine plus azithromycin except in the context of a clinical trial because of the risk of QT prolongation.71

o The CDC issued a warning about the danger of using nonpharmaceutical chloroquine phosphate, a commercially available chemical for aquarium use, to treat or prevent COVID-19. One individual died after using nonpharmaceutical chloroquine and another became critically ill with gastrointestinal symptoms and cardiac conduction abnormalities.

• Convalescent plasma transfusion was approved by the FDA under Emergency Use Authorization on August 23, 2020 for treating hospitalized patients with COVID-19.84–86

o Antibody levels in currently available COVID-19 convalescent plasma are highly variable and assays to measure them remain limited.

o PLACID was an open-label, randomized controlled trial of convalescent plasma vs. standard of care that demonstrated no difference in progression to severe disease or survival.87

o Currently, the NIH and IDSA recommend that convalescent plasma should not be considered standard of care treatment for COVID-19 and that additional prospective, well-controlled, randomized trials are needed.

• The NIH recommends against the use of lopinavir-ritonavir for the treatment of COVID-19, except in the context of a clinical trial.71

o An open-label, randomized, controlled trial of lopinavir-ritonavir vs. standard of care in adults hospitalized with severe COVID-19 showed no clinical benefit.88 Treatment was stopped early in some patients taking lopinavir-ritonavir because of adverse events.

o Lopinavir-ritonavir combined with ribavirin and interferon-beta-1b showed more rapid viral clearance by nasopharyngeal swab compared to lopinavir-ritonavir alone in a phase 2, open-label, randomized trial.89

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 18

o Ritonavir is a potent inhibitor of CYP3A4, which is involved in the metabolism of calcineurin inhibitors, sirolimus, and everolimus.

o The use of ritonavir requires a reduction in the tacrolimus dosage to 1/20-1/50 of baseline because of this drug-drug interaction.

• Treatment with ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) results in upregulation of ACE2, the target for SARS-CoV-2 entry into cells.90

o Increased ACE2 expression theoretically facilitates infection with SARS-CoV-2. o Animal studies suggest that ACEIs and ARBs may protect against serious lung

complications from SARS-Co-V, but to date there are no data in SARS-CoV-2 or in humans.91

o There is no evidence that ACEIs or ARBs are harmful in the setting of COVID-19.71,92,93 Recommendations

• Monitor studies of antiviral and immunomodulatory approaches to COVID-19 at NIH’s clinicaltrials.gov.

• Remdesivir is recommended for the treatment of adult and pediatric patients >12 years of age who weigh >40 kg with COVID-19 requiring hospitalization.

o Liver biochemistries should be checked in all patients prior to starting remdesivir and daily while receiving remdesivir.

o Remdesivir should not be initiated in patients with ALT ≥5x ULN at baseline or in patients with an estimated glomerular filtration rate <30 mL/min.

o Remdesivir should be discontinued in patients who develop ALT ≥10x ULN during treatment or ALT elevation accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR.

o Remdesivir may be restarted when ALT is <5x ULN. • On the basis of the preliminary report from the RECOVERY Trial, the NIH and IDSA recommend

using dexamethasone 6 mg po or IV daily for 10 days in patients with moderate-to-severe COVID-19 requiring mechanical ventilation or supplemental oxygen.

o If dexamethasone is not available, the NIH recommends using equivalent daily doses of prednisone (40 mg), methylprednisolone (32 mg), or hydrocortisone (160 mg).

o Prolonged use of systemic corticosteroids may increase the risk of hepatitis B reactivation and other latent infections including herpesviruses, strongyloides, and tuberculosis, and therefore appropriate screening and monitoring should be undertaken.

o Dexamethasone is a moderate CYP3A4 inducer and potential impact on other CYP3A4 substrates such as calcineurin inhibitors should be considered.

• The available evidence does not currently support the use of drugs targeting the IL-6 pathway outside of clinical trials.79,80

• The available evidence does not currently support the use of lopinavir-ritonavir for the treatment of COVID-19.71,88

• Hydroxychloroquine with or without azithromycin is not routinely recommended and may be associated with serious adverse events such as prolongation of the QT interval.

• Patients receiving ACEIs and ARBs should remain on them even in the setting of COVID-19. • Acetaminophen at a daily dosage of ≤2 g/d is the preferred analgesic and anti-pyretic for

patients with known or suspected COVID-19. • NSAIDS may also be used or continued as needed. • Consult the University of Liverpool Drug Interactions Group COVID-19 Drug Interaction Checker.

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 19

Procedures What we know

• There is potential for fecal-oral SARS-CoV-2 transmission,5,27,94,95 and the virus is detected in saliva.5,27,42,96

• The decision to reopen endoscopic facilities ultimately rests with state and local authorities based upon criteria in the White House guidance document.

• The American Society of Gastrointestinal Endoscopy (ASGE) provides guidance for practices in endoscopy centers.97

• Endoscopic procedures should be considered aerosol-generating.98 • To limit disease transmission, the Joint Gastroenterology Societies and the American

Gastroenterological Association recommend health care workers involved with endoscopy wear a full set of PPE, including N95 masks and double gloves.99

Recommendations

• Consult state guidelines and local regulatory authorities to determine if hospitals and endoscopy centers can schedule elective procedures.

• The ASGE guidance document should be consulted for areas that allow elective/non-urgent procedures.97

• Consider, in the interim, primary prophylaxis with beta blocker therapy instead of screening endoscopy in patients with clinically significant portal hypertension or high risk of decompensation.

• Some procedures should continue to be performed in areas that are limiting elective/non-urgent procedures, e.g., liver biopsy to rule out rejection or diagnose AIH, therapeutic paracentesis, transjugular intrahepatic portosystemic shunt and/or endoscopy for variceal bleeding, follow-up band ligation in those with recent variceal bleeding, urgent biliary procedures for symptomatic disease such as cholangitis and sepsis (interventional radiology or endoscopic).

• Follow ASGE recommendations for patient and staff screening procedures and PPE use in the endoscopy suite.97

• Regularly monitor state and local regulations and society guidance documents as the pandemic evolves.

• Follow CDC recommendations for cleaning and disinfecting rooms or areas visited by individuals with suspected or confirmed COVID-19.

Research What we know

• Because of quarantine-related travel restrictions and potential supply chain interruptions, the FDA and NIH have posted guidance documents for the conduct of clinical trials during the COVID-19 pandemic.

• As the FDA states, protocol deviations may be necessary and will depend on many context-dependent factors related to the nature of the study, the patient population, and environmental circumstances.

• Patient safety is of utmost importance and should be used to guide decisions impacting the trial, including recruitment, continuation decisions, patient monitoring, delayed assessments, and investigational product dispensing.

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 20

• Evaluation of alternative visits, including virtual, phone, or remote contact, may be warranted if safety of the patient can be assured with the alternative approach.

• Protocol changes that reduce immediate danger or protect the well-being of the research participants may be implemented before Institutional Review Board (IRB) approval but must be subsequently reported.

• The NIH encourages grant recipients to discuss changes that prioritize patient and staff safety, including limiting study visits or conducting them virtually, suspending unnecessary travel, and increasing flexibility for laboratory testing and imaging with both the institution and the IRB.

• In an effort to ensure patient safety and maintain trial integrity, sponsors, investigators, and IRBs should document all such contingency measures and reasons for protocol deviations.

Recommendations

• Resume suspended or delayed clinical trials as able based on local SARS-CoV-2 prevalence and local/institutional policies.

• The study physician – in consultation with the study team, the patient’s physician, the patient, and the patient’s family – should continue to carefully assess the necessity and risks of in-person study visits.

• Research staff should continue efforts to use alternative methods to conduct research visits or perform testing such as check-ins with participants by phone and/or performing research-related lab testing at lab testing centers if feasible.

• Research staff should continue to work remotely while following site/institutional guidance for working on site when necessary and allowed. Presence on site is necessary for certain study-related procedures such as collection of liver biopsies, and specimen processing and shipping to central laboratories.

• Discuss options for conducting telehealth study visits with clinical research organizations and study sponsors.100

• Arrange for research medications to be sent to subjects by the study sponsor if the research pharmacy is unavailable.100 Dispensing Investigational Product on site can be gradually scaled up based on allowed visits to sites by research patients.

• Institutional policies on clinical research may be more restrictive and should supersede the recommendations contained here.

• Laboratory/basic science research may also be restricted based on local policies. Trainees What we know

• Although residents and fellows have much to learn from the diagnosis and management of COVID-19, the risks of exposing trainees to SARS-CoV-2 may outweigh the benefits in areas with ongoing SARS-CoV-2 community spread.

• Our improved understanding of the epidemiology, pathogenesis, and transmission of SARS-CoV-2 allows us to continue to involve trainees in patient care with appropriate PPE and other safety considerations.

• In a Letter to the Community, the Accreditation Council for Graduate Medical Education (ACGME) announced it has suspended some activities during the COVID-19 pandemic, including self-studies, accreditation site visits, Clinical Learning Environment Review (CLER) program site visits, and resident/fellow/faculty surveys

• The ACGME issued new requirements to allow residents/fellows to participate in telemedicine.

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 21

• The ACGME requirements for adequate resources and training, adequate supervision, and work hour limitations have not changed.

• The ACGME has clarified the local circumstances in which fellows may function within their core specialty (i.e., act as attending physicians).

• See ACGME’s response to the pandemic crisis for more details. Recommendations

• Ensure adequate resources including PPE appropriate to the clinical setting for all trainees. • Resume patient care and educational activities as appropriate based on local SARS-CoV-2

prevalence, PPE supplies, and training requirements. o Consider a phased approach to returning fellowship training to pre-pandemic

practices.101 • Assign fellows only to participating sites that ensure the safety of patients and fellows. • Ensure appropriate supervision of trainees if they are conducting remote patient care activities

(telephone/telemedicine visits). • Continue to hold virtual educational conferences as appropriate based on local SARS-CoV-2

prevalence. • Consider assigning fellows and other trainees to indirect patient care activities and/or

telemedicine visits. • Consider remote supervision of trainees by concurrently monitoring patient care through

appropriate telecommunication technology. • Consider conducting fellowship recruitment and interviews virtually.

Telemedicine What we know

• Telemedicine can mitigate the exposure of patients and health care workers to COVID-19 and has potential to change health care delivery now and after the COVID-19 pandemic.102–105

• Emergency funding legislation HB 6074 waived many of the long-standing restrictions to the use of telehealth for Medicare recipients, including: rural area requirements for originating sites (i.e., patient location); allowing a patient’s home to be an eligible originating site; allowing phones with two-way, real-time interactive audio and visual capabilities to be used; and allowing the provider to conduct a telemedicine encounter from their home.106

• The Department of Health and Human Services Office of Civil Rights announced that it would not impose penalties for the good faith provision of telemedicine during the COVID-19 public health emergency, even if remote communication technologies used for such services may not fully comply with the requirements of the Health Insurance Portability and Accountability Act (HIPAA) Rules.

• Medicare currently reimburses telephone and telemedicine visits for both new and established patients.

• Telemedicine limitations include patient access to the electronic health record patient portal; access to a computer, phone, or tablet with video/audio capabilities; and ability to manage the technology.

• See the Joint Gastroenterology Societies' message about telehealth. Recommendations

• Consider phone visits or telemedicine as appropriate and available to replace in-person visits.

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 22

• Consider ways to mitigate disparities in access to care delivered through telemedicine (e.g., rural populations, older adults, racial/ethnic minorities, low socioeconomic status, limited health literacy, limited English proficiency).107

• Conduct patient education and social work, dietitian, and financial consultations by video conference, telemedicine or telephone for liver transplant evaluations.

• Consider telemedicine alternatives in place of outreach clinics. • Minimize in-person visits for posttransplant patients by maximizing use of telemedicine.

Reentry and Return to a Pre-Pandemic State What we know

• The necessary prioritization of the acute care of patients with COVID-19 and implementation of strategies to minimize risk of disease transmission has resulted in a delay of elective procedures, routine care, and clinical research.

• It has been suggested that a backlog of routine procedures and clinic visits could result in an increase in hepatic decompensating events and morbidity in patients with liver disease.108

• Patient perspectives and comfort level about in-person clinic visits, hospital-based procedures, laboratory testing, and imaging studies may influence their willingness to comply with standard recommendations and impact their quality of care.

Recommendations

• Develop policies and processes for reentry to gradually ramp up clinical operations and clinical research with pathways for minimizing SARS-CoV-2 transmission and for care of patients who develop COVID-19.

• Consult CMS for general guidelines pertaining to reentry. • Consult CDC guidelines for a reentry framework based on potential for patient harm and degree

of community transmission. • Continue to prioritize patients who need to be seen in person, such as those with

decompensated cirrhosis with high MELD scores. • Schedule patients with sufficient time to minimize patient and staff interactions and screen for

fever or COVID-19 symptoms before clinic visits. • Avoid patients congregating in the waiting area. • Providers, patients, and caregivers (if caregivers are permitted) should wear a mask in the clinic

area. • Remain aware of SARS-CoV-2 prevalence, incidence, and diagnostic testing availability in your

community.109 • Establish criteria for reentering the mitigation phase if necessary based on increases in the local

prevalence of SARS-CoV-2.109 • Continue to develop a telemedicine program to reduce contact between patients and health

care workers. • Consider the role of telemedicine in patient care during local changes in SARS-CoV-2 prevalence

and beyond the COVID-19 pandemic.108

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 23

AASLD COVID-19 Clinical Oversight Subcommittee Oren K. Fix, MD, MSc, FAASLD (Co-chair) Swedish Medical Center, Seattle, WA Elizabeth C. Verna, MD, MS (Co-chair) Columbia University, New York, NY Kimberly A. Brown, MD, FAASLD Henry Ford Health System, Detroit, MI Jaime Chu, MD Icahn School of Medicine at Mt Sinai, NY, NY Bilal Hameed, MD University of California, San Francisco, CA Laura M. Kulik, MD Northwestern Medicine, Chicago, IL Ryan M. Kwok, MD Uniformed Services University, Bethesda, MD Brendan M. McGuire, MD University of Alabama, Birmingham, AL

Daniel S. Pratt, MD, FAASLD Massachusetts General Hospital, Boston, MA Jennifer C. Price, MD, PhD University of California, San Francisco, CA Nancy S. Reau, MD, FAASLD Rush University, Chicago, IL Mark W. Russo, MD, MPH, FAASLD Carolinas Medical Center, Charlotte, NC Michael L. Schilsky, MD, FAASLD Yale University, New Haven, CT Norah A. Terrault, MD, MPH, FAASLD Keck Medicine of USC, Los Angeles, CA Andrew Reynolds (Patient Advocate)

COVID-19 Working Group Members who have contributed to the development of this document Jorge A. Bezerra, MD, FAASLD Cincinnati Children’s Hospital, Cincinnati, OH Raymond T. Chung, MD, FAASLD Massachusetts General Hospital, Boston, MA Robert J. Fontana, MD, FAASLD University of Michigan, Ann Arbor, MI

David C. Mulligan, MD, FAASLD Yale University, New Haven, CT K. Rajender Reddy, MD, FAASLD University of Pennsylvania, Philadelphia, PA

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 24

COVID-19 Liver Disease and Transplant Registries • SECURE-Cirrhosis (COVID-19 in patients with cirrhosis and liver transplant recipients, “PHI-free”,

North or South America, China/Japan/Korea) • COVID-Hep (COVID-19 in patients with cirrhosis and liver transplant recipients, “PHI-free”, for

cases outside North or South America, China/Japan/Korea) • University of Washington (COVID-19 in solid organ transplant recipients, “PHI-free”) • COVID-LT Consortium (COVID-19 in patients with cirrhosis and liver transplant recipients) • NASPGHAN and SPLIT-TTS- COVID -19 Pediatric Registry (pre- and post-liver and intestine

patients, 0-21 years, “PHI-free”)

Helpful Resources • AASLD Patient Flyers can be found on the AASLD COVID-19 and the Liver website • Asian Pacific Association for the Study of the Liver (APASL) • American Society of Transplantation (AST) COVID-19 Information for Transplant Community • European Association for the Study of the Liver (EASL) • Centers for Disease Control and Prevention, COVID-19 Website

o CDC recommendations for cleaning and disinfecting rooms or areas visited by individuals with suspected or confirmed COVID-19

• The Transplantation Society Guidance on Coronavirus Disease 2019 (COVID-19) for Transplant Clinicians

• Association of Organ Procurement Organizations COVID-19 Bulletin • FDA Guidance on Conduct of Clinical Trials of Medical Products During COVID-19 Pandemic • Guidance for NIH-funded Clinical Trials and Human Subjects Studies Affected By COVID-19 • Medicare Telemedicine Health Care Provider Fact Sheet • CMS Flexibilities to Fight COVID-19 • ACGME’s Response to the Coronavirus (COVID-19) • Joint GI Society Message for Gastroenterologists and Gastroenterology Care Providers • ASGE guidance for resuming GI endoscopy and practice operations after the COVID-19 pandemic • Joint GI Society Message about Telehealth • University of Liverpool Drug Interactions Group COVID-19 Drug Interaction Checker

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 25

Tables Table 1. Diagnostic Methods for SARS-CoV-2 Detection

Test (method)

Turn around

(hrs) Sensitivity Comments

Rout

ine

Bloo

dwor

k an

d Im

agin

g

CBC with differential & platelets

<1 NA Lymphopenia frequently identified at presentation and associated with poor prognosis Elevated WBC and thrombocytopenia indicate poor prognosis

Comprehensive metabolic panel

<1 NA Abnormal aminotransferases are common but usually 1-2x ULN Alkaline phosphatase usually normal Acute kidney injury indicates poor prognosis

LDH, D-dimer, CRP, INR, CPK, ferritin

<1 NA Elevated inflammatory markers associated with poorer outcomes

Chest CT <1 80%-90% Bilateral ground glass opacities (lower lobe and peripheral) seen in >90% of hospitalized cases confirmed by RT-PCR Specificity only 25%

Com

mer

cial

ly A

vaila

ble

Diag

nost

ics

Nasopharyngeal swab (RT-PCR)

2-48 40%-80% Peak shedding 12-14 days after infection; Nasopharyngeal higher yield than oropharyngeal Requires frozen transport media if >24 hours False negative common in early in disease

Qualitative nasopharyngeal swab (non-PCR)

<1 80%-90% Point of care qualitative test using isothermal detection methods Results in 15 minutes

Saliva (RT-PCR) 2-48 80% FDA emergency approval for simplified tests with self-collection

Sputum (RT-PCR) 2-48 60%-80% Should be spontaneous expectorant Do not induce

Bronchoalveolar lavage (RT-PCR)

2-48 95% Recommended only for intubated patients with negative nasopharyngeal swab

Plasma serology (IgG, IgM, IgA)

1-2 70%-90% Indicative of prior exposure False negative early in disease False positive because of lack of SARS-CoV-2 specificity IgA/IgM positive at 3-6 days after symptom onset May be useful in health care workers, close contacts, and epidemiological studies

Inve

stig

atio

nal

Diag

nost

ics

Nasopharyngeal swab (CRISPR)

1-2 NA Colorimetric dipstick in development

Blood (RT-PCR) 24 15% May be present in more severe cases Stool (RT-PCR) 24 30% May be detectable throughout disease phase Cell culture >24

(days) NA For research purposes only

Requires high level safety lab Used for vaccine and antiviral testing

CBC, complete blood count; CPK, creatine phosphokinase; CRISPR, clusters of regularly interspaced short palindromic repeats; CRP, C-reactive protein; CT, computed tomography; INR, international normalized ratio; LDH, lactate dehydrogenase; RT-PCR, real-time polymerase chain reaction; ULN, upper limit of normal

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 26

Table 2. Investigational Treatments for COVID-19 Agent

(route/mechanism) Target

population Safety issues Issues related to

liver disease Approval status

Antiv

iral A

gent

s

Remdesivir (IV/nucleotide analogue)

Moderate-severe

Nausea/vomiting Drug vehicle accumulation in acute kidney injury Exclusions: GFR <30 mL/min AST or ALT >5x ULN

Incidence of AST, ALT, bilirubin elevations similar to placebo Consider stopping drug if ALT >10x ULN Stop drug if symptoms of hepatitis

FDA approved for patients >12 years and >40 kg EUA for patients <12 years or <40 kg

Favipiravir (oral/RNA polymerase inhibitor)

Early to mild disease

Investigational Approved for influenza in Asia Tested with interferon-α aerosol x 14 days

Lopinavir-ritonavir (oral/HIV protease inhibitor)

Moderate-severe

CYP3A4 substrate Severe DDI with CNI 13% early discontinuation because of side effects

Use with caution in patients with hepatic impairment

FDA-approved for HIV No survival benefit in RCT vs standard of care x 14 days Shorter time to viral clearance when combined with ribavirin and interferon-beta-1b in a phase 2, open-label, randomized trial89

Nitazoxanide (oral/host proteins)

Moderate-severe

Similar to placebo in influenza trials

FDA-approved for Cryptosporidium/Giardia In vitro activity against coronaviruses

Hydroxychloroquine (oral/host proteins)

Moderate- severe

QTc prolongation Nausea and vomiting Exclusions: QTc >415 ms Cardiomyopathy G6PD deficiency

FDA revoked EUA after determining it is unlikely to be effective in treating COVID-19 FDA-approved for lupus/rheumatoid arthritis/malaria

Chloroquine (oral/host proteins)

Moderate-severe

QTc prolongation Nausea and vomiting Exclusions: QTc >415 ms Cardiomyopathy G6PD deficiency

FDA revoked EUA after determining it is unlikely to be effective in treating COVID-19 FDA-approved for malaria Reduced progression of disease and symptom duration in China

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 27

Azithromycin (oral/host proteins)

Moderate-severe

CYP3A4 substrate Moderate DDI with CNI Rare cholestatic hepatitis Exclusion: QTc >415 ms

Can rarely cause cholestatic hepatitis

FDA-approved for bacterial infections Should only be combined with hydroxychloroquine in clinical trials because of risk of QT prolongation

Famotidine (oral or IV/protease inhibitor)

All None significant

FDA-approved for other indications A retrospective study demonstrated famotidine was associated with lower in-hospital mortality (OR 0.37, 95% CI 0.16-0.86)110 In a propensity score-matched analysis, famotidine was associated with a reduced risk of death or intubation (adjusted HR 0.42, 95% CI 0.21-0.85)111

Imm

unom

odul

ator

y Ag

ents

Combination monoclonal antibodies (IV/target SARS-CoV-2 proteins)

All Half-life of 18-21 days Placebo studies ongoing

Submitted to FDA for EUA on 10/8/2020

Tocilizumab (IV/monoclonal IL-6 receptor antagonist)

Severe (high IL-6 levels)

Grade 1-2 ALT 20%-40% Grade 3+ ALT 1%-2%. Acute liver failure <1% Neutropenia 3% Thrombocytopenia 2% Opportunistic infections Exclusions: ANC <2,000/m3 Platelets <100,000/m3 ALT >5 xULN

Incidence of AST and ALT elevations similar to placebo

Only recommended for COVID-19 in a clinical trial RCT in 243 patients showed no clinical benefit compared to placebo FDA-approved for RA 8 mg/kg dose

Siltuximab (IV/monoclonal antibody)

Severe (high IL-6)

Grade 1-2 ALT Rash 30% Thrombocytopenia 9% Exclusions: ALT >5x ULN

No published data in COVID-19 yet available

FDA-approved in Castleman’s disease Only recommended for COVID-19 in clinical trial

Convalescent plasma (IV/neutralizing antibodies)

Severe or life-

Potential TRALI/ anaphylaxis ICU monitoring needed

Available in US under FDA EUAInvestigational

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 28

threatening pneumonia

Must screen donor for other transmissible pathogens

Recommended only for intubated patients or those needing supplemental oxygen Finding donors with neutralizing IgG activity not well established Reserved for severe/life threatening cases

Dexamethasone (oral or IV/anti-inflammatory)

Moderate-severe

Potential for hyperglycemia and reactivation of latent hepatitis B, tuberculosis, herpes

Hepatitis B reactivation may occur within 1 week of hospitalization

FDA-approved for multiple indications Recommended by NIH as 6 mg every 6 hours for up to 10 days in hospitalized patients with moderate-to-severe infection

ACE2, angiotensin converting enzyme 2; ANC, absolute neutrophil count; CNI, calcineurin inhibitor; DDI, drug-drug interaction; EUA, Emergency Use Authorization; G6PD, glucose-6-phosphate dehydrogenase; GFR, glomerular filtration rate; HIV, human immunodeficiency virus; ICU, intensive care unit; IV, intravenous; RA, rheumatoid arthritis; RCT, randomized controlled trial; SC, subcutaneous; TRALI, transfusion-related acute lung injury; ULN, upper limit of normal

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 29

Figures Figure 1. Approach to the Patient with COVID-19 and Elevated Serum Liver Biochemistries

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 30

Figure 2. Approach to Liver Transplant Organ Offers

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 31

Figure 3. Approach to the Liver Transplant Recipient with COVID-19

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 32

References 1. Lan J, Ge J, Yu J, Shan S, Zhou H, Fan S, et al. Structure of the SARS-CoV-2 spike receptor-binding

domain bound to the ACE2 receptor. Nature 2020 May;581:215–220.

2. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003 November 27;426:450–454.

3. Qi F, Qian S, Zhang S, Zhang Z. Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses. Biochem Biophys Res Commun 2020 May 21;526:135–140.

4. Wang Y, Liu S, Liu H, Li W, Lin F, Jiang L, et al. SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19. J Hepatol 2020;73:807–816.

5. Guan W-J, Ni Z-Y, Hu Y, Liang W-H, Ou C-Q, He J-X, et al. Clinical characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020 April 30;382:1708–1720.

6. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020 15;395:507–513.

7. Fan Z, Chen L, Li J, Xin C, Yang J, Tian C, et al. Clinical features of COVID-19-related liver functional abnormality. Clin Gastroenterol Hepatol 2020 June;18:1561–1566.

8. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020 February 15;395:497–506.

9. Xu L, Liu J, Lu M, Yang D, Zheng X. Liver injury during highly pathogenic human coronavirus infections. Liver Int 2020 May;40:998–1004.

10. Zhang C, Shi L, Wang F-S. Liver injury in COVID-19: management and challenges. Lancet Gastroenterol Hepatol 2020 May 1;5:428–430.

11. Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA 2020 April 22;323:2052–2059.

12. Phipps MM, Barraza LH, LaSota ED, Sobieszczyk ME, Pereira MR, Zheng EX, et al. Acute liver injury in COVID-19: Prevalence and association with clinical outcomes in a large US cohort. Hepatology 2020 May 30. doi: 10.1002/hep.31404. [Online ahead of print]

13. Ferm S, Fisher C, Pakala T, Tong M, Shah D, Schwarzbaum D, et al. Analysis of gastrointestinal and hepatic manifestations of SARS-CoV-2 infection in 892 patients in Queens, NY. Clin Gastroenterol Hepatol 2020 September;18:2378–2379.

14. Hundt MA, Deng Y, Ciarleglio MM, Nathanson MH, Lim JK. Abnormal liver tests in COVID-19: A retrospective observational cohort study of 1827 patients in a major U.S. hospital network. Hepatology 2020 July 29. doi: 10.1002/hep.31487. [Online ahead of print]

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 33

15. Redd WD, Zhou JC, Hathorn KE, McCarty TR, Bazarbashi AN, Thompson CC, et al. Prevalence and characteristics of gastrointestinal symptoms in patients with SARS-CoC-2 infection in the United States: a multicenter cohort study. Gastroenterology 2020 August;159:765–767.

16. Lei F, Liu Y-M, Zhou F, Qin J-J, Zhang P, Zhu L, et al. Longitudinal association between markers of liver injury and mortality in COVID-19 in China. Hepatology 2020 August;72:389–398.

17. Wander P, Epstein M, Bernstein D. COVID-19 presenting as acute hepatitis. Am J Gastroenterol 2020 June;115:941–942.

18. Liu W, Tao Z-W, Lei W, Ming-Li Y, Kui L, Ling Z, et al. Analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease. Chin Med J 2020 May 5;133:1032–1038.

19. Pereira MR, Mohan S, Cohen DJ, Husain SA, Dube GK, Ratner LE, et al. COVID-19 in solid organ transplant recipients: initial report from the US epicenter. Am J Transplant 2020 July;20:1800–1808.

20. Iavarone M, D’Ambrosio R, Soria A, Triolo M, Pugliese N, Del Poggio P, et al. High rates of 30-day mortality in patients with cirrhosis and COVID-19. J Hepatol 2020 November;73:1063–1071.

21. Lu X, Zhang L, Du H, Zhang J, Li YY, Qu J, et al. SARS-CoV-2 infection in children. N Engl J Med 2020 April 23;382:1663–1665.

22. D’Antiga L. Coronaviruses and immunosuppressed patients. The facts during the third epidemic. Liver Transpl 2020 June;26:832–834.

23. Feldstein LR, Rose EB, Horwitz SM, Collins JP, Newhams MM, Son MBF, et al. Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med 2020 July 23;383:334–346.

24. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020 April;8:420–422.

25. Yao XH, Li TY, He ZC, Ping YF, Liu HW, Yu SC, et al. [A pathological report of three COVID-19 cases by minimally invasive autopsies]. Zhonghua Bing Li Xue Za Zhi 2020 May 8;49:411–417.

26. Lagana SM, Kudose S, Iuga AC, Lee MJ, Fazlollahi L, Remotti HE, et al. Hepatic pathology in patients dying of COVID-19: a series of 40 cases including clinical, histologic, and virologic data. Mod Pathol 2020 November;33:2147–2155.

27. Gu J, Han B, Wang J. COVID-19: gastrointestinal manifestations and potential fecal-oral transmission. Gastroenterology 2020 May;158:1518–1519.

28. Goldman JD, Lye DCB, Hui DS, Marks KM, Bruno R, Montejano R, et al. Remdesivir for 5 or 10 days in patients with severe Covid-19. N Engl J Med 2020 May 27. doi: 10.1056/NEJMoa2015301. [Online ahead of print]

29. Muhović D, Bojović J, Bulatović A, Vukčević B, Ratković M, Lazović R, et al. First case of drug-induced liver injury associated with the use of tocilizumab in a patient with COVID-19. Liver Int 2020 August;40:1901–1905.

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 34

30. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for the treatment of Covid-19 - final report. N Engl J Med 2020 October 8. doi: 10.1056/NEJMoa2007764. [Online ahead of print]

31. Sciascia S, Aprà F, Baffa A, Baldovino S, Boaro D, Boero R, et al. Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19. Clin Exp Rheumatol 2020 June;38:529–532.

32. Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, et al. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol 2020 June 16;75:2950–2973.

33. Paranjpe I, Fuster V, Lala A, Russak A, Glicksberg BS, Levin MA, et al. Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. J Am Coll Cardiol 2020 July 7;76:122–124.

34. Ji D, Qin E, Xu J, Zhang D, Cheng G, Wang Y, et al. Non-alcoholic fatty liver diseases in patients with COVID-19: a retrospective study. J Hepatol 2020 August;73:451–453.

35. Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19): Groups at higher risk for severe illness. Published April 2, 2020. https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/groups-at-higher-risk.html. Accessed November 2020.

36. Fang Y, Zhang H, Xie J, Lin M, Ying L, Pang P, et al. Sensitivity of chest CT for COVID-19: Comparison to RT-PCR. Radiology 2020 August;296:E115–E117.

37. Salehi S, Abedi A, Balakrishnan S, Gholamrezanezhad A. Coronavirus Disease 2019 (COVID-19): a systematic review of imaging findings in 919 patients. AJR Am J Roentgenol 2020 July;215:87–93.

38. Ai T, Yang Z, Hou H, Zhan C, Chen C, Lv W, et al. Correlation of chest CT and RT-PCR testing in Coronavirus Disease 2019 (COVID-19) in China: a report of 1014 cases. Radiology 2020 August;296:E32–E40.

39. American College of Radiology. ACR recommendations for the use of chest radiography and computed tomography (CT) for suspected COVID-19 infection. Published March 22, 2020. https://www.acr.org/Advocacy-and-Economics/ACR-Position-Statements/Recommendations-for-Chest-Radiography-and-CT-for-Suspected-COVID19-Infection. Accessed November 2020.

40. Loeffelholz MJ, Tang Y-W. Laboratory diagnosis of emerging human coronavirus infections — the state of the art. Emerging Microbes & Infections 2020 December;9:747–756.

41. Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA 2020 March 11;323:1843–1844.

42. Wyllie AL, Fournier J, Casanovas-Massana A, Campbell M, Tokuyama M, Vijayakumar P, et al. Saliva or nasopharyngeal swab specimens for detection of SARS-CoV-2. N Engl J Med 2020 September 24;383:1283–1286.

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 35

43. US Food and Drug Administration. Qualitative detection of nucleic acid from the SARS-CoV-2 virus in direct nasal, nasopharyngeal or throat swabs and nasal, nasopharyngeal or throat swabs eluted in viral transport media from individuals who are suspected of COVID-19 by their healthcare provider. Published September 17, 2020. https://www.fda.gov/media/136522/download. Accessed November 2020.

44. Walker M. First antibody test for COVID-19 gets FDA authorization - Emergency use OK’d to diagnose infection. Published April 2, 2020. https://www.medpagetoday.com/infectiousdisease/covid19/85772. Accessed November 2020.

45. Food and Drug Administration Office of the Commissioner. Coronavirus (COVID-19) update: FDA authorizes first antigen test to help in the rapid detection of the virus that causes COVID-19 in patients. Published May 9, 2020. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-antigen-test-help-rapid-detection-virus-causes. Accessed November 2020.

46. Infectious Diseases Society of America. IDSA COVID-19 antibody testing primer. Published May 4, 2020. https://www.idsociety.org/globalassets/idsa/public-health/covid-19/idsa-covid-19-antibody-testing-primer.pdf. Accessed November 2020.

47. To KK-W, Hung IF-N, Ip JD, Chu AW-H, Chan W-M, Tam AR, et al. Coronavirus disease 2019 (COVID-19) re-infection by a phylogenetically distinct Severe Acute Respiratory Syndrome Coronavirus 2 strain confirmed by whole genome sequencing. Clin Infect Dis 2020 August 25. doi: 10.1093/cid/ciaa1275. [Online ahead of print]

48. Centers for Disease Control and Prevention. Ten clinical tips on COVID-19 for healthcare providers involved in patient care. Published April 30, 2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-tips-for-healthcare-providers.html. Accessed November 2020.

49. Bai Y, Yao L, Wei T, Tian F, Jin D-Y, Chen L, et al. Presumed asymptomatic carrier transmission of COVID-19. JAMA 2020 February 21;323:1406–1407.

50. Centers for Disease Control and Prevention. Preliminary estimates of the prevalence of selected underlying health conditions among patients with Coronavirus Disease 2019 - United States, February 12–March 28, 2020. MMWR Morb Mortal Wkly Rep 2020 April 3;69:382–386.

51. Williamson EJ, Walker AJ, Bhaskaran K, Bacon S, Bates C, Morton CE, et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature 2020;584:430–436.

52. Singh S, Khan A. Clinical characteristics and outcomes of COVID-19 among patients with pre-existing liver disease in United States: a multi-center research network study. Gastroenterology 2020 August;159:768–771.

53. Portincasa P, Krawczyk M, Smyk W, Lammert F, Di Ciaula A. COVID-19 and non-alcoholic fatty liver disease: Two intersecting pandemics. Eur J Clin Invest 2020 October;50:e13338.

54. Lens S, Miquel M, Mateos-Muñoz B, García-Samaniego J, Forns X. SARS-CoV-2 in patients on antiviral HBV and HCV therapy in Spain. J Hepatol 2020 November;73:1262–1263.

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 36

55. Liang W, Guan W, Chen R, Wang W, Li J, Xu K, et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol 2020 March;21:335–337.

56. Rich NE, John BV, Parikh ND, Rowe I, Mehta N, Khatri G, et al. Hepatocellular carcinoma demonstrates heterogeneous growth patterns in a multi-center cohort of patients with cirrhosis. Hepatology 2020 February 4. doi: 10.1002/hep.31159. [Online ahead of print]

57. Yan CH, Faraji F, Prajapati DP, Boone CE, DeConde AS. Association of chemosensory dysfunction and Covid-19 in patients presenting with influenza-like symptoms. Int Forum Allergy Rhinol 2020 July;10:806–813.

58. Moon AM, Webb GJ, Aloman C, Armstrong MJ, Cargill T, Dhanasekaran R, et al. High mortality rates for SARS-CoV-2 infection in patients with pre-existing chronic liver disease and cirrhosis: preliminary results from an international registry. J Hepatol 2020 September;73:705–708.

59. Bajaj JS, Garcia-Tsao G, Biggins SW, Kamath PS, Wong F, McGeorge S, et al. Comparison of mortality risk in patients with cirrhosis and COVID-19 compared with patients with cirrhosis alone and COVID-19 alone: multicentre matched cohort. Gut 2020 July 13. doi: 10.1136/gutjnl-2020-322118. [Online ahead of print]

60. Agopian V, Verna E, Goldberg D. Changes in liver transplant center practice in response to COVID-19: unmasking dramatic center-level variability. Liver Transpl 2020 August;26:1052–1055.

61. American Society of Transplantation. 2019-nCoV (Coronavirus): FAQs for organ donation and transplantation. Published March 20, 2020. https://www.myast.org/sites/default/files/COVID19%20FAQ%20Tx%20Centers%2003.20.2020-FINAL.pdf. Accessed November 2020.

62. Gerussi A, Rigamonti C, Elia C, Cazzagon N, Floreani A, Pozzi R, et al. Coronavirus Disease 2019 (COVID-19) in autoimmune hepatitis: a lesson from immunosuppressed patients. Hepatology Communications 2020 June 9;4:1257–1262.

63. Chopra V, Toner E, Waldhorn R, Washer L. How should U.S. hospitals prepare for Coronavirus Disease 2019 (COVID-19)? Ann Intern Med 2020 May 5;172:621–622.

64. Bhoori S, Rossi RE, Citterio D, Mazzaferro V. COVID-19 in long-term liver transplant patients: preliminary experience from an Italian transplant centre in Lombardy. Lancet Gastroenterol Hepatol 2020 June 1;5:P532-533.

65. RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in hospitalized patients with Covid-19 - preliminary report. N Engl J Med 2020 July 17. doi: 10.1056/NEJMoa2021436. [Online ahead of print]

66. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JAC, Murthy S, Diaz JV, Slutsky AS, Villar J, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA 2020 September 2;324:1–13.

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 37

67. Colmenero J, Rodríguez-Perálvarez M, Salcedo M, Arias-Milla A, Muñoz-Serrano A, Graus J, et al. Epidemiological pattern, incidence and outcomes of COVID-19 in liver transplant patients. J Hepatol 2020 August 1. doi: 10.1016/j.jhep.2020.07.040. [Online ahead of print]

68. Webb GJ, Marjot T, Cook JA, Aloman C, Armstrong MJ, Brenner EJ, et al. Outcomes following SARS-CoV-2 infection in liver transplant recipients: An international registry study. Lancet Gastroenterol Hepatol 2020 August 28. doi: 10.1016/S2468-1253(20)30271-5. [Online ahead of print]

69. Belli LS, Duvoux C, Karam V, Adam R, Cuervas-Mons V, Pasulo L, et al. COVID-19 in liver transplant recipients: preliminary data from the ELITA/ELTR registry. Lancet Gastroenterol Hepatol 2020 August;5:724–725.

70. Rabiee A, Sadowski B, Adeniji N, Perumalswami P, Nguyen V, Moghe A, et al. Liver injury in liver transplant recipients with Coronavirus Disease 2019 (COVIE-19): US multicenter experience. Hepatology 2020 September 22. doi: 10.1002/hep.31574. [Online ahead of print]

71. National Institutes of Health. Coronavirus Disease 2019 (COVID-19) treatment guidelines. Published November 3, 2020. https://www.covid19treatmentguidelines.nih.gov. Accessed November 2020.

72. Remuzzi A, Remuzzi G. COVID-19 and Italy: What next? Lancet 2020 April 11;395:P1225-1228.

73. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020 March;30:269–271.

74. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for the treatment of Covid-19 - preliminary report. N Engl J Med 2020 May 22. doi: 10.1056/NEJMoa2007764. [Online ahead of print]

75. Montastruc F, Thuriot S, Durrieu G. Hepatic disorders with the use of remdesivir for coronavirus 2019. Clin Gastroenterol Hepatol 2020 November;18:2835–2836.

76. Liu J, Wang T, Cai Q, Sun L, Huang D, Zhou G, et al. Longitudinal changes of liver function and hepatitis B reactivation in COVID-19 patients with pre-existing chronic hepatitis B virus infection. Hepatol Res 2020 August 6. doi: 10.1111/hepr.13553. [Online ahead of print]

77. Infectious Diseases Society of America. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19. Published September 25, 2020. https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management. Accessed November 2020.

78. Bhimraj A, Morgan RL, Shumaker AH, Lavergne V, Baden L, Cheng VC-C, et al. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19. Clin Infect Dis 2020 April 27. doi: 10.1093/cid/ciaa478. [Online ahead of print]

79. Stone JH, Frigault MJ, Serling-Boyd NJ, Fernandes AD, Harvey L, Foulkes AS, et al. Efficacy of tocilizumab in patients hospitalized with COVID-19. N Engl J Med 2020 21. doi: 10.1056/NEJMoa2028836. [Online ahead of print]

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 38

80. Sanofi. Sanofi and Regeneron provide update on Kevzara® (sarilumab) Phase 3 U.S. trial in COVID-19 patients. Published July 2, 2020. https://www.sanofi.com/media-room/press-releases/2020/2020-07-02 22-30-00 2057183. Accessed November 2020.

81. Hansen J, Baum A, Pascal KE, Russo V, Giordano S, Wloga E, et al. Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail. Science 2020 21;369:1010–1014.

82. Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020 July 28;71:732–739.

83. US Food and Drug Administration. Coronavirus (COVID-19) update: FDA revokes emergency use authorization for chloroquine and hydroxychloroquine. Published June 15, 2020. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-chloroquine-and. Accessed November 2020.

84. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA 2020 March 27;323:1582–1589.

85. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci USA 2020 April 28;117:9490–9496.

86. Joyner MJ, Bruno KA, Klassen SA, Kunze KL, Johnson PW, Lesser ER, et al. Safety update: COVID-19 convalescent plasma in 20,000 hospitalized patients. Mayo Clin Proc 2020;95:1888–1897.

87. Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T, Malhotra P, et al. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ 2020 22;371:m3939.

88. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 2020 May 7;382:1787–1799.

89. Hung IF-N, Lung K-C, Tso EY-K, Liu R, Chung TW-H, Chu M-Y, et al. Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. The Lancet 2020 May 30;395:P1695-1704.

90. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med 2020 April;8:e21.

91. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med 2005 August;11:875–879.

92. Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin–Angiotensin–Aldosterone system inhibitors in patients with Covid-19. N Engl J Med 2020 April 23;382:1653–1659.

93. Fosbøl EL, Butt JH, Østergaard L, Andersson C, Selmer C, Kragholm K, et al. Association of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with COVID-19 diagnosis and mortality. JAMA 2020 July 14;324:168–177.

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 39

94. Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020 March 5;382:929–936.

95. Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology 2020 May;158:1831-1833.e3.

96. To KK-W, Tsang OT-Y, Chik-Yan Yip C, Chan K-H, Wu T-C, Chan JMC, et al. Consistent detection of 2019 novel coronavirus in saliva. Clin Infect Dis 2020 July 28;71:841–843.

97. Hennessy B, Vicari J, Bernstein B, Chapman F, Khaykis I, Littenberg G, et al. Guidance for resuming GI endoscopy and practice operations after the COVID-19 pandemic. Gastrointest Endosc 2020 September;92:743–747.

98. Soetikno R, Teoh AYB, Kaltenbach T, Lau JYW, Asokkumar R, Cabral-Prodigalidad P, et al. Considerations in performing endoscopy during the COVID-19 pandemic. Gastrointest Endosc 2020 July;92:176–183.

99. Sultan S, Lim J, Altayar O, Davitkov P, Feuerstein J, Siddique S, et al. AGA Institute rapid recommendations for gastrointestinal procedures during the COVID-19 pandemic. Gastroenterology 2020 August;159:739–758.

100. Verna EC, Serper M, Chu J, Corey K, Fix OK, Hoyt K, et al. Clinical research in hepatology in the COVID-19 pandemic and post-pandemic era: Challenges and the need for innovation. Hepatology 2020 November;72:1819–1837.

101. Palchaudhuri S, Gabre J, Prenner S, Solga S. COVID-2019.2 reboot: Returning a GI fellowship to pre-pandemic practices. Dig Dis Sci 2020;65:2461–2465.

102. Terry K. Telehealth seen as a key tool to help fight COVID-19. The Hospitalist. Published March 6, 2020. https://www.the-hospitalist.org/hospitalist/article/218574/coronavirus-updates/telehealth-seen-key-tool-help-fight-covid-19. Accessed November 2020.

103. Keesara S, Jonas A, Schulman K. Covid-19 and health care’s digital revolution. N Engl J Med 2020 June 4;382:e82.

104. Serper M, Cubell AW, Deleener ME, Casher TK, Rosenberg DJ, Whitebloom D, et al. Telemedicine in liver disease and beyond: can the COVID-19 crisis lead to action? Hepatology 2020 August;72:723–728.

105. Fix OK, Serper M. Telemedicine and telehepatology during the COVID-19 pandemic. Clinical Liver Disease 2020;15:187–190.

106. Lowey NM. H.R.6074 - 116th Congress (2019-2020): Coronavirus Preparedness and Response Supplemental Appropriations Act. Published March 6, 2020. https://www.congress.gov/bill/116th-congress/house-bill/6074. Accessed November 2020.

107. Nouri S, Khoong EC, Lyles CR, Karliner L. Addressing equity in telemedicine for chronic disease management during the COVID-19 pandemic. NEJM Catalyst 2020 May 4. doi: 10.1056/CAT.20.0123. [Online ahead of print]

© 2020 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG | Released November 9, 2020 40

108. Tapper EB, Asrani SK. COVID-19 pandemic will have a long-lasting impact on the quality of cirrhosis care. J Hepatol 2020 August;73:441–445.

109. American College of Surgeons. Local resumption of elective surgery guidance. Published April 17, 2020. https://www.facs.org/covid-19/clinical-guidance/resuming-elective-surgery. Accessed November 2020.

110. Mather JF, Seip RL, McKay RG. Impact of famotidine use on clinical outcomes of hospitalized patients with COVID-19. Am J Gastroenterol 2020;115:1617–1623.

111. Freedberg DE, Conigliaro J, Wang TC, Tracey KJ, Callahan MV, Abrams JA, et al. Famotidine use is associated with improved clinical outcomes in hospitalized COVID-19 patients: A propensity score matched retrospective cohort study. Gastroenterology 2020;159:1129-1131.e3.