key: cord-0777083-wbykvxg2 authors: Cho, Ju-Yeon; Lee, Young-Sun; Kim, Soon Sun; Song, Do Seon; Lee, Jeong-Hoon; Kim, Ji Hoon title: Update on liver disease management during the pandemic of coronavirus disease 2019 (COVID-19): 2021 KASL guideline date: 2021-09-17 journal: Clin Mol Hepatol DOI: 10.3350/cmh.2021.0293 sha: 3b266cdf1c722560c150d29dbd490e6739597347 doc_id: 777083 cord_uid: wbykvxg2 nan This document has been accredited by the Korean Association for the Study of the Liver (KASL). This guideline is an update of the previous KASL guideline published in 2020. 1 The update is based on recently accumulated data with particular focus on the treatment and vaccination section. The purpose of this guideline is to assist medical practitioners in the treatment of liver disease patients during the pandemic of coronavirus disease 2019 (COV-ID- 19) . The original guideline could be referred for an overall recommendation. As the knowledge regarding COVID-19 is continuously evolving, this document has not been thoroughly reviewed for its role as a medical standard of care or practice guideline. Liv-er disease management should be customized to accommodate specific medical situations and regional characteristics. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and the liver 1) Cellular entry of SARS-CoV-2 is enabled by binding its spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor and is primed by transmembrane protease serine subtype 2 (TMPRSS2). As a result, hepatocytes and bile duct epithelial cells with increased expression of ACE2 and TMPRSS2 become target cells for viral infection. 2 SARS-CoV-2 has been detected in the hepatocyte cytoplasm with histological characteristic of viral infections. 3 2) Abnormalities of liver function test (LFT) a. Incidence rate: 14-83% [4] [5] [6] [7] b. Chronic liver disease can be affected by SARS-CoV-2 due to the primary toxicity of the virus to the liver, reactivation of antecedent chronic hepatitis virus, and damage caused by SARS-CoV-2 treatment. Remdesivir and tocilizumab, treatments for COVID-19, may lead to liver injury; however, this potential side effect rarely results in the cessation of the drugs. 6 c. Antithrombotic treatment in hospitalized COVID-19 patients may result in improved outcomes due to the increased risk of thromboembolic events in SARS-CoV-2 infection. 8 were no significant differences in respiratory symptoms and clinical outcomes between COVID-19 patients who had underlying liver disease and those who did not. 19 2) A US nationwide study reported that the number of cirrhosis hospitalizations decreased during the COVID-19 pandemic. Model for end-stage liver disease score at admission was lower during the early stages of the pandemic than the later period. 20 The hospital admission of cirrhotic patients may have been deferred by the pandemic due to the lack of medical resources. The indirect effects of COVID-19 regarding cirrhotic patients should be considered. 1) According to existing studies, the innate immune response to SARS-CoV-2 exacerbates pulmonary injury and immunosuppression might have a protective role. 5 National Institutes of Health (NIH) recommends the use of remdesivir in patients with increased oxygen demand. 30, 31 d. Remdesivir is administered intravenously 200 mg on day 1 of treatment, followed by a daily dose of 100 mg for 5 days. 30,31 e. As the final reports of ACTT said no benefit was observed in patients on mechanical ventilation or ECMO, these patients are excluded from remdesivir treatment in Korea. 32 f. Adverse effects of remdesivir include nausea, vomiting, and increase in liver function. Regular follow-up of LFTs during treatment is recommended. 30,33 g. There are currently no existing research on the pharmacological differences of remdesivir in patients with chronic liver disease, including cirrhosis. The US FDA recommends discontinuing remdesivir treatment in case of more than 10-fold increase of ALT or acute hepatitis accompanied by the elevation of ALT. 30 2) Monoclonal antibodies targeting the SARS-CoV-2 spike protein, bamlanivimab alone or casirivimab+imdevimab, have been approved for emergency use authorization by the US FDA in mild to moderate COVID-19 patients with a high risk for progression to severe COVID-19. 34 3) Dexamethasone is recommended in COVID-19 patients with increased oxygen demand, as decreased mortality rates were reported with its use. a. The RECOVERY trial reported a significantly increased survival rate in patients receiving 6 mg of dexamethasone daily by oral or intravenous methods for up to 10 days (RR, 0.83; 95% CI, 0.74-0.92; P<0.001). 25 4) Tocilizumab, an interleukin-6 (IL-6) inhibitor, did not improve the clinical course or survival rate in a double-blind, randomized controlled trial. 35 Also, phase 3 COVACTA trial did not show significant improvement in the clinical course or the survival rates. 36 However, studies with positive clinical results using IL-6 inhibitors have recently been reported. 37 showed no benefit compared to standard care, and the treatment was halted prematurely in 13 patients (13.8%) due to adverse events. 38 a. The US NIH currently does not recommend lopinavir/ritonavir or human immunodeficiency virus (HIV) protease inhibitors as COVID-19 treatments. 38 been demonstrated in vitro, 39 ineffective or harmful results in the clinical studies have led to NIH recommendations against its use. 38 7) The US FDA has issued an emergency use authorization to al-low convalescent plasma transfusion for severe COVID-19 treatment based on reports of potential benefit with its use. 40,41 8) Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor inhibitors (ARBs) promote SARS-CoV-2 infection as they increase ACE2 expression, the target for the virus to enter cells. 42 Nevertheless, existing studies have reported that ACEI/ARB have cardio-pulmonary protective effects, and increased ACE2 expression can reduce acute lung injury. Therefore, there is not enough evidence to limit ACEI/ARB treatment in COVID-19 patients. 43, 44 [Recommendations] 1. Remdesivir is administered intravenously 200 mg on the first day of treatment, followed by a daily dose of 100 mg for 5 days in patients with increased oxygen demand. 2. Remdesivir treatment should be halted if more than a 10fold increase of alanine aminotransferase (ALT) is present or if liver inflammation is present with the elevation of ALT. 3. Dexamethasone 6 mg daily by oral or intravenous methods for up to 10 days is recommended in severe COVID-19 patients with increased oxygen demand or those on mechanical ventilation. 4. Recommendations against the use of lopinavir/ritonavir or HIV protease inhibitors as COVID-19 treatments are ensued based on current research. 5. Hydroxychloroquine treatment with or without azithromycin may bring about serious side effects; therefore, its use is not recommended. 6. Treatment with tocilizumab, an IL-6 inhibitor, warrants caution as controversial studies are being reported. 7. Patients with ACEI/ARB medication are recommended to continue treatment. vaccine. 50, 51 a. Although the exact pathogenesis has not been confirmed, the leakage of DNA from the adenovirus infected cells binding to platelet factor 4 seem to trigger the production of auto-antibodies. 50 increased dose of the COVID-19 vaccine, and doubling the dose or frequency is not recommended in cirrhotic patients. 58, 59 8) The safety and efficacy of the COVID-19 vaccine in chronic liver disease patients have not been fully elucidated. However, the European Association for the Study of the Liver (EASL) recommends vaccination early as possible in chronic liver disease patients, as there is a greater risk of severe COVID-19. 60 The American Association for the Study of Liver Diseases (AASLD) recommends the administration of mRNA vaccines in chronic liver disease patients. 61 Additional research should be conducted regarding the safety and vaccine efficacy of vaccines in chronic liver diseases, including decompensated liver cirrhosis, and the risk and benefit of vaccination must be further evaluated. 9) Research regarding the superiority of adenovirus-vector vaccine or mRNA-based vaccine in chronic liver disease patients has yet to be conducted. Clinical trials of the COVID-19 vaccines included only a small proportion of chronic liver disease patients (0.5-0.6%), and sub-group analyses have not been reported. 48, 49, 62 Although studies have found that adenovirus-vector vaccines in chronic hepatitis C patients are safe, there are concerns regarding the use of adenovirus-vector vaccines in immune-compromised patients, including chronic liver disease patients, and further research is required. 63,64 10) Data regarding the safety and effectiveness of the COVID- 19 vaccines in liver transplant patients is limited. Although it is not recommended to vaccinate transplant patients with live vaccines, as the adenovirus-vector or the mRNA vaccines cannot replicate, the EASL, the AASLD, and the Korean Society for Transplantation recommend the administration of COV-ID-19 vaccines in this population. 60, 65, 66 The AASLD recommends vaccination at least 3 months after transplantation when immunosuppression is lower and the patient is stable. However, vaccination can be undertaken as early as 6 weeks post-transplant if there is a greater risk for other comorbidities during a pandemic. 11) Continuous research regarding the safety and efficacy of the COVID-19 vaccine should be conducted in patients with chronic liver disease. [Recommendations] 1. COVID-19 vaccination should be prioritized for chronic liver disease and liver transplant patients. The patients should be monitored for any development of adverse events. such as fever, should be vaccinated after achieving medical stability. 5. All chronic liver disease and liver transplant patients, including vaccinated recipients, should continue to adhere to infection prevention and control guidelines and also practice social distancing. 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All authors revised and approved the final version of the manuscript. The authors have no conflicts to disclose.