key: cord-0966218-1ayrc5u3
authors: Boettler, Tobias; Marjot, Thomas; Newsome, Philip N.; Mondelli, Mario U.; Maticic, Mojca; Cordero, Elisa; Jalan, Rajiv; Moreau, Richard; Cornberg, Markus; Berg, Thomas
title: Impact of COVID-19 on the care of patients with liver disease: EASL-ESCMID position paper after 6 months of the pandemic
date: 2020-08-04
journal: JHEP Rep
DOI: 10.1016/j.jhepr.2020.100169
sha: 7a3dfd9c3abe46da203145eb42db70b8a9f7f354
doc_id: 966218
cord_uid: 1ayrc5u3

During the early stages of the coronavirus disease 2019 (COVID-19) pandemic, EASL and ESCMID published a position paper to provide guidance for physicians involved in the care of patients with chronic liver disease. While some healthcare systems are returning to a more normal routine, many countries and healthcare systems have been, or still are, overwhelmed by the pandemic, which is significantly impacting on the care of these patients. In addition, many studies have been published focusing on how COVID-19 may affect the liver and how pre-existing liver diseases might influence the clinical course of COVID-19. While many aspects remain poorly understood, it has become increasingly evident that pre-existing liver diseases and liver injury during the disease course must be kept in mind when caring for patients with COVID-19. This review should serve as an update on the previous position paper, summarising the evidence for liver disease involvement during COVID-19 and providing recommendations on how to return to routine care wherever possible.

Obesity represents a significant risk factor for a severe course of 4] with severe 26 pneumonia being particularly increased in obese men [3] . While the precise mechanisms driving 27 this association remain unclear, it has been postulated that adipose tissue may serve both as a 28 viral reservoir and also an immunological hub for the inflammatory response [5] . Similarly, other 29 metabolic syndrome elements such as hypertension and diabetes are commonly observed in 30 patients with severe COVID-19 [6] . As metabolic dysfunction-associated fatty liver disease 31 (MAFLD, previously known as non-alcoholic fatty liver disease, NAFLD) [7] and non-alcoholic 32 steatohepatitis (NASH) are closely associated with these metabolic comorbidities, it is of 33 relevance to identify whether presence of MAFLD specifically predisposes to a more severe 34 course of COVID-19. A retrospective cohort of 202 patients with COVID-19 demonstrated an 1 association between MAFLD and disease progression defined as deteriorating dyspnoea, 2 hypoxia or radiological findings whilst in hospital [8] . This additional risk has been observed 3 even in younger patients with MAFLD [9] and in the absence of type 2 diabetes [10] and 4 interestingly, patients with MAFLD also appear to have a longer duration of viral shedding [8] . 5

Within patients with MAFLD, non-invasive fibrosis scores appear to correlate with higher 6 likelihood of developing severe COVID-19 illness, irrespective of metabolic comorbidities [11] , 7 however, genetic polymorphisms implicated in the development and progression of NASH do 8 not appear to be associated with severe disease [12, 13] . In addition, transcriptional activity of 9 genes relevant for SARS-CoV-2-infection has not been found to be increased in liver-tissues of 10 MAFLD patients [14] . Larger analyses are needed to determine whether MAFLD is an 11 independent risk factors for a poor prognosis in COVID-19 or whether the reported effects are 12 due to the presence of confounding factors. 13

14 Chronic viral hepatitis 15 In contrast to metabolic liver disease, little or no evidence has emerged to suggest that the 16 presence of chronic viral hepatitis affects the COVID-19 disease course. Data from both an 17 international registry and from a multicenter cohort study in Italy on COVID-19 outcomes in 18 patients with chronic liver disease include patients with viral hepatitis (23%-37%). However, 19 despite both studies demonstrating associations between severity of liver disease and poor 20 outcome, it remains unknown whether the presence of chronic viral hepatitis influences 21 prognosis [15, 16] . 22 23 Autoimmune hepatitis 24

In the previous position paper, we advised against the withdrawal of established 25 immunosuppressive therapy in patients with autoimmune liver disease [17] and a panel of 26 experts on autoimmune liver disease have subsequently given similar recommendations [18] . 27

While there is still little evidence to demonstrate that immunosuppressive therapy per se 28 predisposes to SARS-CoV-2 infection, a handful of observational studies have suggested an 29 association between corticosteroid use and a more severe COVID-19 disease course [19] [20] [21] [22] [23] . 30

The potential implications of these observations are discussed below in more detail. Further 31 data are needed to determine whether the specific risk of COVID-19 is increased in patients 32 with autoimmune hepatitis and the influence of steroids and/or other immunosuppressive 33 medications on outcome (see also Box 1). 6 1 Cirrhosis 2

Patients with liver cirrhosis are at increased risk for infections and associated complications due 3 to cirrhosis-associated immune dysfunctions, which is particularly important for patients with 4 decompensated cirrhosis. A recent case-series from China reported that from 21 consecutive 5 patients with pre-existing cirrhosis, 5 did not survive SARS-CoV-2-infection [24] and specifically 6 patients with Child-Pugh class C cirrhosis were more likely to suffer a fatal course of COVID-19 7 [24, 25] . Another case series from Italy documented 50 patients with cirrhosis and COVID-19; 8 26% of these patients presented with MELD ≥15, increasing from 13% at the last documented 9 visit prior to SARS-Cov-2 infection. The 30 day mortality was 34%, with end-stage-liver disease 10 considered as the cause of death in only 5 patients (29%) whilst respiratory failure due to 11 COVID-19 accounted for death in 12 patients (71%) [15] . These data are in line with 12 pattern of liver injury with elevated serum aminotransferases (rarely > 5 x upper limit of normal) 20 although cholestatic or mixed patterns of liver injury have also been reported. Importantly, this 21 appears to occur to a similar degree in patients with and without pre-existing liver disease [26] 22 and has also been documented in pregnant women in association with increased levels of pro-23 inflammatory cytokines [42] . To what extent this liver injury is derived from the direct effect of 24 SARS-CoV-2, as opposed to a secondary phenomenon caused by the broader disease course In the aftermath of COVID-19 at its peak, there was an urgent need to anticipate and plan for 10 the wave of liver disease yet to come. This will be characterised by emergent hepatic 11 decompensation, increased dropouts from transplant waiting lists and a vast back-log of 12 deferred hospital visits and testing [51] . Clinicians and their institutions should therefore be 13 proactive in structuring their services to tackle these challenges and strive to resume standard-14 of-care for patients with liver disease wherever possible. Equally, it is important to embrace 15 innovative technologies and methods of practice developed during the pandemic which may 16 continue to be of benefit to patients (e.g. telemedicine use, remote monitoring) [52] . Combining 17 standard of care with novel ideas will help to mitigate against longer term consequences of the 18 pandemic including missed diagnosis, incomplete HCC screening, and progressive liver 19 disease. Furthermore, in light of accumulating evidence that baseline liver disease severity is 20 associated with poor outcomes from COVID-19 [15, 16] , treatment of underlying liver disease 21 may represent one of the most important strategies to protect patients from the adverse effects 22 of any future SARS-CoV-2 infection. This in turn will further reduce the burden on healthcare 23 systems and allow more rapid return towards gold standard hepatology practice (Fig 1) . The 24 epidemiology of COVID-19 has proven unpredictable, but the burden of disease is likely to 25 expand and shrink episodically within populations for some time to come. The approach to 26 patient care must therefore be personalised and flexible, balancing national dynamics of SARS-27

CoV-2 infection, the local resource availability, and the severity of each individual patient's 28 underlying liver disease. Lastly, with time, it will be important to resume clinical trial enrolment 29 wherever possible to allow the field to advance despite unprecedented global events. • Patients should be made aware of potential adverse metabolic and hepatic consequences of 2 social isolation including more sedentary lifestyles and increased consumption of processed 3 foods. 4

• Preventing liver disease progression through intensive lifestyle intervention, including 5 nutritional guidance, weight loss advice, and diabetes management may help prevent the 6 development of a severe disease course with future SARS-CoV-2 infection. 7

• Treatment of arterial hypertension should continue in accordance with existing guidelines. • In patients with COVID-19, initiation of treatment for HBV and HCV is usually not warranted 28 and should be deferred until recovery from COVID-19. 29

• In patients with COVID-19 in whom there is evidence of high disease activity (flare) or 30 clinical suspicion for severe acute HBV hepatitis, a decision to initiate antiviral therapy 31 should be made on a case-by-case basis in consultation with a specialist. 32

• In patients with chronic, occult or resolved HBV and COVID-19 receiving corticosteroids, 1 tocilizumab or other immunosuppressive agents, consider the use of antiviral therapy to 2 prevent viral flare or reactivation. 3

• Continue to work towards the WHO goal of eliminating viral hepatitis by 2030 by trying to 4 adapt the cascade-of-care to the new coronavirus situation and make modifications for safe 5 delivery of services according to the local requirements. 6 7 Alcohol associated liver disease 8

• Chronic alcohol consumption may increase susceptibility of acute respiratory distress 9 syndrome (ARDS) secondary to SARS-CoV-2 infection [56] . 10

• Social isolation can lead to new or increased alcohol consumption [57] and an increase in 11 alcohol related admissions including new hepatic decompensation should be anticipated 12 during and after periods of physical distancing. 13 • Clinicians and institutions should therefore implement pre-emptive strategies such as patient 14 outreach and telephone alcohol liaison and cessation services. • There remains a paucity of data to make specific recommendations for patients with primary 7 biliary cholangitis, primary sclerosing cholangitis and IgG4-related disease. 8

• All patients should receive vaccination for Streptococcus pneumoniae and influenza 9 10 Cirrhosis 11

• Patients with cirrhosis are particularly vulnerable to both the consequences of SARS-CoV-2 12 infection and to the adverse effects of delayed or altered standard of care during the 13 COVID-19 pandemic. 14 • Every effort should be made to resume the best standard of care for patients with cirrhosis 15 according to guidelines [62] wherever possible. 16

• Patients with cirrhosis who are infected with SARS-CoV-2 are at high risk of new or 17 worsening hepatic decompensation, severe COVID-19 and death [15, 16] . 18

• All patients with new or worsening hepatic decompensation or acute-on-chronic liver failure 19 (ACLF) should be prioritised for SARS-CoV-2 testing even in the absence of respiratory 20 symptoms [16] . 21

• In those with cirrhosis who are admitted for reasons other than COVID-19, particular effort 22

should be made to manage these patients in a designated non-COVID-19 ward, preferably 23 in a side-room, in order to reduce the risk of nosocomial SARS-CoV-2 infection. 24

• Guidelines on prophylaxis of spontaneous bacterial peritonitis, gastrointestinal 25

haemorrhage, and hepatic encephalopathy should be closely followed to prevent 26 decompensation and avoid admission [62] . 27

• Early admission should be considered for all patients with cirrhosis who become infected 28 with SARS-CoV-2. 29

• Because of the potential of circulatory dysfunction, in particular in the pulmonary circulation 30 associated with COVID-19 [63] , the use of vasoconstrictor therapy, which is known to 31 increase pulmonary pressure and decrease cardiac output, should be considered with great 32 caution among critically ill patients with cirrhosis and COVID-19. 33

• Rapid clinical deterioration in patients with advanced liver disease and COVID-19 should 1 prompt consideration of a symptoms-based approach using palliative care guidelines [64] . 2

• All patients should receive vaccination for Streptococcus pneumoniae and influenza. 3 4 Liver transplant (LT) candidates 5

• Patients on the LT waiting list with decompensated cirrhosis are at high risk of severe 6 COVID-19 and death following SARS-CoV-2 infection. 7

• We therefore recommend LT centers aim to restore transplantation services following the 8 peak of the COVID-19 epidemic wherever possible. 9

• In centers with ongoing resource limitations, LT should be prioritized for patients with poor 10 short-term prognosis including those with acute/acute-on-chronic liver failure (ALF/ACLF), 11

high model for end-stage liver disease (MELD) score (including exceptional MELDs) and 12 HCC at the upper limits of the Milan criteria. 13 • The risk of SARS-CoV-2 transmission via liver transplantation remains unknown [65] and 14 therefore we currently recommend to test all donors for SARS-CoV-2 infection by RT-PCR 15 and recommend against using livers from SARS-CoV-2 infected donors [66]. 16

• We encourage LT centres to develop and improve local and global risk stratification 17 pathways for LT donors and recipients incorporating a combination of clinical history, chest 18 radiology, and SARS-CoV-2 testing [67] and ethical considerations regarding transplantation 19 activities and allocation [68] . 20

• Measures should be taken to reduce the risk of SARS-CoV-2 infection in the peri-21 transplantation period. In areas of high disease burden, a COVID-19 free pathway through 22 transplantation should be implemented including strict social isolation for waiting list 23 patients, telephone screening for symptoms and exposures before admission, and 24 perioperative management in a designated clean ICU and post-LT ward [69] . 25

• Consent for diagnostic and therapeutic procedures related to transplantation should include 26 the potential risk of nosocomial COVID-19. 27

• LT candidates should be made aware that infection with SARS-CoV-2 in patients 28 undergoing major surgery is associated with an increased risk of severe COVID-19 and 29 death [70]. 30

• Living-donor transplantations should be considered on a case-by-case basis and include 31 careful risk stratification of donor and recipient incorporating a combination of clinical history, 32 chest radiology, and SARS-CoV-2 testing. 33 34 13 LT recipients 1

• We advise against reduction of immunosuppressive therapy to prevent SARS-CoV-2 2 infection. Reduction should only be considered under special circumstances (e.g. 3 medication-induced lymphopenia, or bacterial/fungal superinfection in case of severe 4 COVID-19) after consultation with a specialist. 5

• Clinicians must be aware of the high reported rates of fear and anxiety regarding COVID-19 6 in LT recipients and the barrier this may pose to compliance with immunosuppressive 7 medication and attendance at scheduled medical visits [71]. 8

• Drug levels of calcineurin inhibitors and mechanistic Target of Rapamycin (mTOR) inhibitors 9

should be closely monitored when they are administered together with drugs such as 10 hydroxychloroquine, protease inhibitors or alongside new trial drugs for COVID-19 as they 11 emerge. 12

• Early admission should be considered for all LT recipients who develop COVID-19 13

• Risk factors for a severe course of COVID-19 in LT recipients may include underlying 14 malignancy, sarcopenia, graft dysfunction and metabolic comorbidities. However, the 15 individual contributions of these factors require further clarification. 16

• All patients should receive vaccination for Streptococcus pneumoniae and influenza. In patients with COVID-19, liver biopsy may be performed based on the individual indication for 26 histological assessment. It has to be considered that treatment/care for COVID-19 may 27 outweigh the diagnosis of co-existing liver disease and that systemic inflammation associated 28 with COVID-19 is likely to obscure aetiology-specific histologic characteristics. As discussed 1 above, liver function test abnormalities are common in patients with COVID-19 particularly with 2 more severe disease and routine liver biopsy in this context is not required. 3 4 6. Liver specific considerations in the pharmacological management of COVID-19 5

The targeted management of COVID-19 is a rapidly evolving field with a plethora of new or 6 repurposed medications constantly shifting in and out of favour. In Europe alone there are 7 currently over 200 registered COVID-19 specific drug trials [73] . This number will no doubt 8 continue to increase as we learn more about the pathophysiology of the disease. It is beyond 9 the scope of this updated position paper to comprehensively review the potential therapeutic 10 options for COVID-19. While some interventions, such as infusion of convalescent plasma or 11 favipiravir (recently approved in India) show encouraging signals of efficacy, little is known with 12 regards to liver-specific side effects or contraindications. However, for some therapeutic agents 13 there are liver-specific considerations which we will discuss. Hepatologists must be mindful of 14 the secondary effects these drugs may have on the liver and continually evaluate the specific 15 risks and benefits conferred to their patients with underlying liver disease. 16 17 

Remdesivir is an adenosine-analogue that induces RNA chain termination and was initially 19 developed as an antiviral agent against Ebola. It has emerged as a promising treatment 20 candidate against COVID-19 being shown to reduce the duration of symptoms when used early 21 in the disease course [74, 75] Interleukin-6 (IL-6) appears to be a key driver of the "cytokine storm" leading to significant lung 5 and other organ damage in cases of severe COVID-19. Tocilizumab, a humanized monoclonal 6 antibody targeting IL-6 has therefore been postulated to counter this dysregulated inflammation 7 and has shown promise in retrospective series of COVID-19 by reducing the need and duration Patients with advanced liver disease are at increased risk of venous thromboembolism [82] . 3

Similarly, coagulopathy is a common abnormality in patients with COVID-19 and has emerged 4 as a major driver of morbidity and mortality, particularly in patients with severe disease. 5

Hospitalised patients with COVID-19 have alarmingly high rates of venous thromboembolic 6 disease with an observed incidence of 20% at day 7, and 42% at day 21 despite 7 thromboprophylaxis [83] . As well as macro-thrombotic events, COVID-19 is also associated with 8 widespread micro-thrombosis and endothelial dysfunction contributing to multiorgan failure in 9 the terminal phase of the disease [84, 85] . The role of anticoagulation in patients with COVID-19 10 has therefore been extensively investigated and has been shown to improve outcomes in 

• Risk factors for increased mortality in patients after liver transplantation 31

• Role of pre-existing immune activation (e.g. in cirrhosis or MAFLD/obesity) in exacerbating 32

• Identification of central hubs for SARS-CoV-2 dissemination within the GI-tract and fat 1 tissues 2

• Involvement of liver endothelium in promoting SARS-CoV-2 dissemination 3

• Identification of direct and indirect effects of SARS-CoV-2 on hepatocytes/cholangiocytes 4

• COVID-19 as a trigger for ACLF and decompensation in cirrhotic patients 5

• COVID-19 induced thrombophilia as a contributor to progressive liver disease 6 7

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[12] Valenti L, Jamialahmadi O, Romeo S. Lack of genetic evidence that fatty liver disease 32 predisposes to COVID-19. J Hepatol 2020. 33 [13] Ellinghaus D, Degenhardt F, Bujanda L, Buti M, Albillos A, Invernizzi P, et al. 34

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• Patients should be made aware of potential adverse metabolic and hepatic consequences of social isolation including more sedentary lifestyles and increased consumption of processed foods. 

• LT recipients with underlying malignancy are a particular risk of mortality if infected with COVID-19 and need to be recognised as a group at high risk. • We advise against reduction of immunosuppressive therapy. Reduction should only be considered under special circumstances (e.g. medication-induced lymphopenia, or bacterial/fungal superinfection in case of severe COVID-19) after consultation with a specialist. • Clinicians must be aware of the high reported rates of fear and anxiety regarding COVID-19 in LT recipients and the barrier this may pose to compliance with immunosuppressive medication and attendance at scheduled medical visits. • Drug levels of calcineurin inhibitors and mechanistic Target of Rapamycin (mTOR) inhibitors should be closely monitored when they are administered together with antiviral drugs. • Early admission should be considered for all LT recipients who develop COVID-19 • All patients should receive vaccination for Streptococcus pneumoniae and influenza.

• Patients with cirrhosis are particularly vulnerable to both the consequences of SARS-CoV-2 infection and to the adverse effects of delayed or altered standard of care during the COVID-19 pandemic. • Every effort should be made to resume the best standard of care for patients with cirrhosis according to guidelines wherever possible. • Patients with cirrhosis who are infected with SARS-CoV-2 are at high risk of new or worsening hepatic decompensation, severe COVID-19 and death. • All patients with new or worsening hepatic decompensation or acute-on-chronic liver failure (ACLF) should be prioritised for SARS-CoV-2 testing even in the absence of respiratory symptoms. • In those with cirrhosis who are admitted for reasons other than COVID-19, particular effort should be made to manage these patients in a designated non-COVID-19 ward. • Guidelines on prophylaxis of spontaneous bacterial peritonitis, gastrointestinal haemorrhage, and hepatic encephalopathy should be closely followed to prevent decompensation and avoid admission. • Early admission should be considered for all patients with cirrhosis who become infected with SARS-CoV-2. • Because of the potential of circulatory dysfunction, the use of vasoconstrictor therapy, which is known to increase pulmonary pressure and decrease cardiac output, should be considered with great caution among critically ill patients with cirrhosis and COVID-19. • Rapid clinical deterioration in patients with advanced liver disease and COVID-19 should prompt consideration of a symptoms-based approach using palliative care guidelines. • All patients should receive vaccination for Streptococcus pneumoniae and influenza

• Patients on the LT waiting list with decompensated cirrhosis are at high risk of severe COVID-19 and death following SARS-CoV-2 infection. We therefore recommend LT centers aim to restore transplantation services following the peak of the COVID-19 epidemic wherever possible. • In centers with ongoing resource limitations, LT should be prioritized for patients with poor short-term prognosis including those with acute liver failure, ACLF, high MELD score (including exceptional MELDs) and HCC at the upper limits of the Milan criteria. • The risk of SARS-CoV-2 transmission via liver transplantation remains unknown and therefore we currently recommend against using livers from SARS-CoV-2 infected deceased donors. • We encourage LT centres to develop and improve local and global risk stratification pathways for LT donors and recipients incorporating a combination of clinical history, chest radiology, and SARS-CoV-2 testing and ethical considerations regarding transplantation activities and allocation. • Measures should be taken to reduce the risk of SARS-CoV-2 infection in the peritransplantation period. In areas of high disease burden, a COVID-19 free pathway through transplantation should be implemented including strict social isolation for waiting list patients, telephone screening before admission, and perioperative management in a designated clean ICU • Consent for procedures related to transplantation should include the potential risk of nosocomial COVID-19 and LT candidates should be made aware that infection with SARS-CoV-2 in patients undergoing major surgery is associated with an increased risk of severe COVID-19. • Living-donor transplantation should be considered on a case-by-case basis and include careful risk stratification of donor and recipient. Figure 2 

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