Hello, I'd like to thank the course directors for their invitation to speak during today's transplant surgery workshop about COVID-19 in the liver. My name is Oren Fix, and I'm the medical director of the liver transplant program at Swedish Medical Center in Seattle. I have no relevant financial disclosures. Today I'm going to be talking about the COVID-19 US timeline, just to set the stage for this workshop, followed by a little description of how AASLD responded. And then we'll go into some information about the effect of SARS-CoV-2 on the liver, how to evaluate patients with COVID-19 and elevated liver biochemistries, discuss chronic liver disease and HCC, and end with cirrhosis and COVID-19's effect on those patients. So first, the US timeline of COVID. January 20th was the first day that a case of COVID-19 was described in the United States, and that was fairly quickly followed by the first death in the United States on February 29th, both in the Seattle area. Soon after on March 11th, the World Health Organization declared a global pandemic, and then the United States declared a national emergency. At the time, we were aware of what was happening in Italy, the epicenter of the pandemic at the time, where we were hearing about healthcare workers becoming infected, ICUs at capacity, and scarcity of ventilators. And there was speculation that the United States was very close behind the experience in Italy, perhaps by about a week. With the first cases and death happening in Seattle, you can imagine how frightened I was as the director of the liver transplant program, and wondering how to respond to this pandemic that we knew was coming. Very quickly after that, the ASLD formed a working group, actually on March 16th, and within a week, we had a publication online called Clinical Insights for Epidemiology and Liver Transplant Providers During the COVID-19 Pandemic. Now, this has been updated multiple times since, has now been downloaded over 7,200 times and translated into other languages. We followed that with a webinar a few days later describing this document, and we've had 15 webinars since with a cumulative view of over 228,000 times. And then we published a paper online in hepatology of an expert panel consensus statement, again, trying to help support our hepatology colleagues in managing patients with liver disease and cirrhosis, not just in the effects of COVID-19 on liver disease, but also in managing clinic flow and liver transplantation and protecting healthcare workers. This document has been cited now over 80 times. And all of this is available on ASLD's COVID-19 website, located at asld.org slash COVID-19, where you can find download links for this document as well as views of all of our webinars. So a lot of my talk is going to be focused on some of the things in that document. First of all, what does COVID-19 have to do with the liver specifically? Well, we know that the ACE2 receptor is the receptor that SARS-CoV-2 uses to gain entry into cells, and it is present on cholangiocytes and to a lesser degree on hepatocytes. So the liver is a potential target for direct viral infection. And in fact, an American autopsy series showed nonspecific findings of macrosingular steatosis, mild acute hepatitis, and mild portal inflammation, but did show SARS-CoV-2 viral RNA. That was detectable by PCR and liver tissue samples. So we know that COVID-19 hepatitis is, in fact, an entity. In multiple studies, we find that elevations in liver biochemistries are commonly described in hospitalized patients with COVID-19, ranging anywhere from 14 to 83%, depending on your definition of abnormal in the study that's conducted. Usually, this is pretty mild AST and ALT elevations of one to two times the upper limit of normal, perhaps mildly elevated bilirubin, and it's usually self-limited without any need for a specific treatment. Liver injury tends to be more common in more severe cases of COVID-19 than mild cases, and there have been some rare cases of severe acute hepatitis. Usually, AST is higher than ALT, and this ratio and degree of AST elevation is associated with severe COVID-19 and with mortality. However, it's not clear that this is necessarily due to direct liver involvement and could be due to some other complications of COVID-19, including myositis and cardiac ischemia. So overall, the effect of SARS-CoV-2 on the liver is multifactorial. A patient that presents with COVID-19 and elevated liver tests could have a direct viral effect from the virus, could have a secondary inflammatory immune response, could have complications of COVID-19, such as myositis and cardiac ischemia, and also could have drug hepatotoxicity. So many of the therapeutics that are being used for COVID-19 have the potential for hepatotoxicity, including remdesivir and tocilizum. To evaluate a patient with COVID-19 and elevated liver biochemistries, I think the focus here is that you should not assume that the elevated liver biochemistries are because of COVID-19, and you should consider other etiologies, especially viral hepatitis A, B, and C. And we've developed a very simple algorithm shown here on the slide, starting with those etiologies, reviewing medications, trying to avoid imaging so that we're not exposing patients and healthcare workers unnecessarily to COVID-19. And usually the liver enzymes are going to improve spontaneously. If they don't, or if they get worse, then you need to look for other causes, such as myositis, especially when AST is greater than ALT, ischemia, cytokine release syndrome, drug-induced liver injury. Consider a biopsy, but generally this is not needed in these patients. There will be some cases where a biopsy is needed to establish a diagnosis. For example, with autoimmune hepatitis, we don't want to assume that a patient with elevated liver enzymes has an autoimmune hepatitis flare, and we also don't want to assume that it's because of COVID-19. So here a biopsy may be useful. Any children that have elevated liver biochemistry should be evaluated for underlying liver disease. They rarely present with elevated liver biochemistries from COVID-19 alone. And I think it's reasonable to monitor every patient who's hospitalized with COVID-19 by a liver test because of the common etiology or common incidence of COVID-19 and elevated liver biochemistries, especially if they're being treated with drugs such as remdesivir or tocilizumab. And I think abnormal liver biochemistry should not be a contraindication to using investigational or off-label therapeutics for COVID-19. Again, elevated liver biochemistries are common in these patients, and we don't want to restrict them from potentially life-saving therapies. For patients with chronic liver disease and hepatocellular carcinoma, we're seeing a lot of data emerging about COVID-19's effect on these patients. A large study called OpenSafely, which is still in preprint form, was a large cohort study of electronic health record data of over 17 million patients in the UK. This included over 114,000 patients with chronic liver disease. And in this study, chronic liver disease was a risk factor for in-hospital death from COVID-19 with a hazard ratio of 1.6. In a large U.S. study of almost 3,000 patients with COVID-19, chronic liver disease was associated with significantly higher mortality with a relative risk of 2.8, and that risk was even higher when looking at patients with cirrhosis with a relative risk of 4.6. Not surprisingly, NAFLD and NASH were the most common etiologies, but mortality risk was independent of BMI, hypertension, and diabetes. So of course we know that NASH and NAFLD have common comorbidities with those that predispose patients to high risk of severe COVID-19, obesity, diabetes, hypertension, cardiovascular disease. But it's not clear if patients with NAFLD and NASH have a higher risk of severe COVID-19 because of these comorbidities, or whether it's because of chronic inflammation of fibrosis or some other combination of factors. It's long been known that host immune response is the main driver for pulmonary injury due to COVID-19, and we speculated from the beginning of the pandemic that immunosuppression might be protective. Now we have data showing that several studies with a mortality benefit for corticosteroids in the treatment of critically ill patients with COVID-19 and now everybody knows that dexamethasone is a common treatment for moderate or severe COVID-19. So it seems reasonable that reducing or stopping immunosuppressants could be harmful, for example, by causing a flare of autoimmune hepatitis. And indeed the NIH recommends that any patient with oral corticosteroid therapy for an underlying cause that's unrelated to COVID-19 should not have those drugs stopped when COVID-19 is diagnosed. We recommend that any patient with hepatitis B or C who's already on treatment should continue treatment. There's really no reason to stop. We don't see any association with these treatments and adverse effect on COVID-19. In a patient without COVID-19 who has indications for therapy, it's reasonable to start therapy. In a patient with COVID-19, there's no contraindication to starting hepatitis B therapy, and this would be especially important in a patient where you suspect a flare of hepatitis B or a patient where immunosuppressants are about to be started. Initiating treatment of hepatitis C in a patient with COVID-19 is not routinely warranted, but not especially contraindicated. In patients with hepatocytic carcinoma, we don't want to exacerbate the pandemic by missing a diagnosis or missing surveillance or treatment of a hepatocytic carcinoma. We recommend continuing to monitor these patients who have a history of HCC or who are at risk of HCC, such as hepatitis B or cirrhosis, and liver cancer treatments should proceed. These are not elective procedures, and barring any logistical issues, which for the most part we are past by now, these patients should continue to get radiologic surveillance and treatment. And with cirrhosis, we have a lot of data emerging now about the significant mortality risk that cirrhosis presents to any patient who is diagnosed with COVID-19. We have data from a combined international registry, the Secure Cirrhosis and the COVID Hep Registries of the first 152 patients with COVID-19 and chronic liver disease, showing a high mortality of 40%. And then mortality strongly correlated with child turkopuse class, as you can see from the graph. Hepatic decompensation during COVID-19 was strongly associated with a risk of death, 63% in those who decompensated compared to 26% in those who did not. And 24% of the patients with hepatic decompensation had no respiratory symptoms at the time of their COVID-19 diagnosis. So we need to have a very high index of suspicion for COVID-19 in any patient with liver disease who presents with decompensation. In a retrospective Italian study of 50 patients with COVID-19 and cirrhosis, there was a high rate of hospitalization, 96%, and a high rate of death, 35% of those who were hospitalized. End-stage liver disease was the cause of death in 29%, as opposed to a primary pulmonary cause in the other patients. And patients with cirrhosis and COVID-19 had higher 30-day mortality at 34%, compared to those with cirrhosis and bacterial infection at 17%, or even those with COVID-19 who did not have cirrhosis at 18%. And finally, in a multi-center study of inpatients with cirrhosis and COVID-19 who were compared with age and gender match patients with COVID-19 alone and cirrhosis alone, cirrhosis and COVID-19, again, had a much higher risk of death compared to those with COVID-19 alone, 30% versus 13%. But this was actually not significantly higher than patients who had cirrhosis alone at 20%. So the groups differed in the reasons for admission and complications, but those with cirrhosis and COVID-19 had similar mortality to those with cirrhosis alone. And it seemed that those with cirrhosis and COVID-19 presented with respiratory symptoms and had a course very similar to COVID-19 alone, whereas those with cirrhosis alone had many more complications of cirrhosis and died of liver-related issues. So I think the key takeaways of my talk are that elevated liver biochemistries are common in hospitalized patients with COVID-19, and the causes are multifactorial. So don't assume that elevated liver biochemistries are because of COVID-19. We know that corticosteroids are protective in critically ill patients with COVID-19, and stopping corticosteroids in those patients who are already on it may be harmful. Chronic liver disease and cirrhosis are risk factors for death from COVID-19, and mortality correlates with child turkopu class. Hepatic decompensation is strongly associated with death in COVID-19, and the risk of death in COVID-19 and cirrhosis is similar to the risk of death from cirrhosis alone. I'd like to thank the ASLD COVID-19 Clinical Oversight Subcommittee, whose work has been instrumental in putting together updates of this clinical insights document and putting together these webinars, and I encourage you to go to our website to learn more. Thank you very much for your attention. Hi, everybody. Welcome to our next session entitled Treatment Options for COVID-19 from Hydroxychloroquine to Vaccination. What have we learned? My name is Laina Beam, and I would like to thank the organizers for the invitation for this talk. Over the next 15 minutes, we will review some aspects of management of COVID-19, and note that I will be discussing off-label and investigation-use products for management of COVID-19, such as Redemsevir and convalescent plasma. COVID-19 pandemic came with many challenges to the U.S. and world health infrastructure. From a cluster of reported pneumonia cases at the end of 2019 in Wuhan, to declaration of pandemic by the WHO in March of 2020. The challenges we faced included those of limitations in testing capacity, the public health response, and understanding transmission of the virus, as well as what are the available and best-utilized treatment options for this novel organism. Multiple states and countries elected to shut down in an effort to flatten the curve and decrease pressure on the health care systems. Where are we now? As of October 12th of 2020, United States has had more than 7.7 million cases, with 214,000 total deaths reported due to this infection. As we think about what management options there are for COVID-19 and the organism SARS-CoV-2, we'll review a bit about the pathogenesis. Early on, it was noted that many patients, many days after onset of symptoms, required hospitalization, at which time their illness turned to a critical illness with laboratory evaluation suggesting significantly elevated inflammatory markers. This presentation made us realize that the virus was acting in two phases. The first presented a viremic phase, responsible for the viral symptoms the patients reported. The second phase of the illness was an inflammatory phase. This is where a critical illness set in, ARDS-like picture, and almost resembling a cytokine release storm picture presentation in our patients who required mechanical ventilation. So as we think about the therapeutics that have been investigated, it is helpful to think through these two phases. Some of the tested agents are direct antivirals or have a direct antiviral effect, while others focus on the second phase, the inflammatory phase, and have an anti-inflammatory response that we're looking for. Let's start with the direct antivirals first. Early in the pandemic, hydroxychloroquine and chloroquine were amongst the drugs that were looked at for management of COVID-19 because they were available for other indications and on the market. There was hope as there was some in vitro antiviral activity noted for both hydroxychloroquine and chloroquine. Unfortunately, this activity did not replicate itself in clinical studies. Multicenter studies, such as the one in Recovery Collaborative Group, noted no effect on mortality or change in mortality for those who received hydroxychloroquine as opposed to usual care. And unfortunately, there was a signal for possible increase in cardiac events. In addition to investigations in terms of treating COVID-19 with hydroxychloroquine, studies have also shown no effect when it is used as a prophylactic agent. In a large, randomized trial of hydroxychloroquine as post-exposure prophylaxis for moderate and high-risk exposure for household and occupational contacts, no benefit was noted when the drug was given within four days. Because of this, in June of 2020, the United States FDA revoked its emergency use authorization for these agents. Another drug already available and on the market were some of our HIV antiretrovirals. Lopinavir and ritonavir underwent evaluation for management of COVID-19 as well. And again, in a large, randomized, controlled, open-label trial, no difference in mortality, duration of hospital stay, or risk of progression to mechanical ventilation and death was noted. And the use of these agents is not recommended. Finally, there was some hope. Remdesivir is a direct antiviral. It works on inhibiting the RNA-dependent RNA polymerase. Should be noted that there are some issues in terms of hepatotoxicity and nephrotoxicity that we need to consider for this drug. The drug is not recommended for those who have an elevated alanine aminotransferase greater than 5 times the upper limit of normal. And this drug should be discontinued if that occurs on treatment. There is some theoretical nephrotoxicity concerns as the drug is utilizing a cyclodextrin carrier. For this reason, it is not recommended to use this drug if an AGFR is noted to be less than 30. The first trial for efficacy that we will review for remdesivir is the ACTT1 trial. This is a randomized placebo-controlled trial that included 60 sites. And the major endpoint that was evaluated here was the time to recovery. It was noted that those who were randomized to receive remdesivir as opposed to placebo had a faster median time to recovery of 10 as opposed to 15 days. The most benefit was noted in those who were requiring low-flow oxygen. And that is how remdesivir is currently used in most hospitals. Second trial we'll review looked at remdesivir and duration of treatment. It compared five-day course as opposed to a 10-day course. Note that this was a randomization of duration that occurred for patients who were hypoxic on remer or receiving non-invasive oxygen supplementation. And here, the endpoint at 14 days showed no significant difference for 5 versus 10 days with higher numerical values for clinical improvement and discharge for the five-day course. Again, I would say this was applicable to our patients who are hypoxic on remer or are non-invasive oxygen supplementation and is not extended to those who require mechanical ventilation. Next, let's review what options we have as we focus on the inflammatory phase of the disease. Some of our go-to anti-inflammatories, dexamethasone and other glucocorticoids, were first to be evaluated. And we have evidence now that supports the use of dexamethasone in hospitalized patients with COVID-19, requiring low-flow oxygen. We have to be mindful of potential adverse effects of steroids, which includes other infections, hyperglycemia, a potential for prolonged viral shedding. In areas that are endemic with chondroloides, this may need to be treated preemptively. Dexamethasone efficacy has been reviewed, and we'll review one of the trials here. In a large 176-site trial with a total participants of 6,425 patients, dexamethasone was given as opposed to standard of care for up to 10 days. The endpoint of this study was all-cause mortality, with benefit notable to those who received dexamethasone. When the trial evaluated the subgroups in terms of what kind of support they needed, those with invasive mechanical ventilation and oxygen requirement were noted to have significant improvement in mortality outcomes. As opposed to those who did not require oxygen, statistical significance was not achieved there. There are further agents that are now under investigation. Among these is convalescent plasma. There is a large open-label expanded access program with over 35,000 patients transfused with convalescent plasma. We do not yet have peer-reviewed evidence of how convalescent plasma works in large trials. However, some pre-publication material notes potential improvement in mortality in those groups that received high antibody titers convalescent plasma. More to come. Additional COVID-19 treatments that are now under investigation include antiviral effects with monoclonal antibody trials, VAP revere, as well as anti-GMTSF monoclonal antibody and other anti-inflammatory type of agents, including terminal complement inhibitors. There are also studies underway that evaluate combination therapy of an antiviral plus an anti-inflammatory, like an IL-6 inhibitor or a JAK inhibitor. There are multiple guidelines now available for management of COVID-19 that really emphasize evidence-based medicine in management of COVID-19 and governing bodies that have publications on this topic. Vaccine, in terms of COVID-19, is the next goal. We all know prevention is better than cure, and there are numerous types of vaccine studies under investigation, including nucleic acid-based vaccines, viral vector vaccines, and inactivated and recombinant protein vaccines. As of October 12th of 2020, there were 21 registered trials that were phase 1, early safety trials, 14 as phase 2, later safety trials. And some of these may overlap with each other. And there were 11 trials that were in phase 3, or direct efficacy trials. There are a number of vaccines that have achieved a limited approval in some countries where this approval occurred before availability of phase 3 trial data. And we have FDA guidance on vaccine development for companies to follow that is published as well. The vaccine trials are underway, yet we are still learning about implications of immunity in terms of natural immunity, vaccine immunity, and concern for reinfection and what reinfection would look like down the line. That is not yet determined. Some key takeaways from the talk today. We have some promising data, including faster time to recovery with use of Redemsevir in patients with COVID-19 who are hospitalized and on low flow oxygen. Another promising data comes from dexamethasone, where improvement in mortality is noted for those who are hospitalized with oxygen requirement. Further study is needed in other treatment mortalities. And we now know that there are some drugs that are not effective for COVID-19, like hydroxychloroquine or lopinavir, ritonavir. COVID vaccine studies are underway. We look forward to see what kind of immune response, as well as clinical protection they provide. Thank you for your time and attention for this talk. Good morning. It's an honor for me to present at this virtual liver meeting on COVID-19 and liver transplantation, the European experience. I will present on behalf of all my colleagues the different European countries. These are my disclosures. As you all know, transplant activity was strongly hit by COVID-19 outbreak everywhere in the world. This is a figure showing the trends of solid organ transplantation activity during COVID-19 outbreak in Europe and in the US. And I will focus on European countries, such as Spain, shown in blue, Italy, shown in green, and France, shown in yellow. There was an abrupt and significant reduction in transplant activity, reaching numbers almost close to zero during the months of March, late March, and April, with a subsequent return to pre-outbreak activity in more recent months. During this time, we have learned that it is essential to screen both the donor and the recipient. And while this is not specifically directed to European countries, I do believe it is important to remember these strategies. We need to test the transplant candidate. And if the transplant candidate tests positive, we should not proceed with liver transplantation or call for a backup recipient. In terms of the donor, we need, again, to test the donor. And if the donor tests positive, on the left side of the slide, again, we need to discard the organ or delay liver transplantation by at least 28 days in live donor liver transplantation. And if the test is negative in the donor or the test isn't available, we should base our decisions on epidemiological and clinical screening that need to take place in all cases. If both epidemiological and clinical screening and PCR test is negative, this is the green on the bottom, we can continue with liver transplantation. If these screening procedures are positive, regardless of the negative PCR, and particularly in areas of high transmission of the virus, shown in red, we do not proceed with liver transplantation or delay liver transplantation in cases of live donor liver transplantation. If any of these screening procedures are positive and the other one is negative, we shall proceed on a case-by-case basis. And so what is the issue with the immunosuppressed patient? The problem really relies on immunosuppression, which has been described as a double-edged sword. And indeed, broad immunosuppression may inhibit antiviral immunity, and in doing so, delay viral clearance and perpetuate illness-prolonging hyperinflammation and poor outcome. But at the same time, we know that broad immunosuppression may lessen or reduce hyperinflammation, which we all know is associated with poor outcome in the general population. So what is the data? And particularly, what is the data that has been generated in Europe? This is a table, an initial table published in July 2020 with initial cases, very few cases, where there was a great disparity in time from transplantation, immunosuppressive agents, age, and so forth. And in fact, based on these initial studies, it was very difficult to assess baseline immunosuppressive therapy, and particularly, the appropriateness of modifications of immunosuppression or risk factors for poor outcome. And this was related to multiple reasons. The large variation in SARS and immunosuppressive management, the very limited data on risk factors for poor outcome, and specific data on immunosuppression, such as doses or target trough concentrations, large variations in transplant and clinical characteristics, particularly in time from transplantation, which is an indirect measure of the intensity of baseline immunosuppression, but also on additional confounding factors, such as investigational agents used to treat COVID or to treat complications related to COVID. And finally, and importantly, really insufficient data on some key outcome variables, such as graft function. What is the data that has been generated more recently? Well, the data mostly come from multicenter studies in the different countries. We will start first with the incidence of COVID in the liver transplant population, and whether it is enhanced by this immunosuppressed status. And this is a very important paper from Spain, a multicenter study where 111 liver transplant patients were infected with COVID at a mean of 105 months from transplantation. And the first important conclusion that was that the standardized incidence ratio was increased in liver transplant patients compared to the general population, adjusting for additional co-variables, particularly age and sex. However, the same has not been confirmed in all European countries. This is an ELITA ELTR registry where data from different countries in Europe was just published in this study. 301 COVID-19 positive patients, including 244 recipients and 57 candidates. And in this study, indeed, where they show the incidence of COVID in the general population in blue, in liver transplant recipients in red, and in liver transplant candidates in yellow, you can observe how overall the incidence was similar in the liver transplant population, 0.34%, compared to the general population, 0.33%. And this was, in fact, related to the heterogeneity of results in the different countries, with countries such as Spain, as I mentioned before, where the incidence was higher in liver transplant patients. The same in France, the same in Belgium, but then other countries where the incidence in liver transplant patients was extremely reduced compared to the general population, such as the UK or Germany. What about the outcome of COVID-19 in liver transplant patients? Again, a different registry. This is the ELITA ERTR registry. And I will focus on the 244 recipients infected with COVID. And in this registry, the author showed, and again, liver transplant recipients in red, general population in blue. The authors found a significantly increased mortality in the liver transplant recipient, as well as the liver transplant candidates, compared to the general population. Of note, though, this was not standardized data, and this was not adjusted for different factors, particularly age and sex. In the Spanish multicenter study, where the data was adjusted for other factors, the author showed that, in fact, the standardized mortality ratio was similar in the liver transplant patients compared to the general population. And this has also been shown in other studies, also from Italy. What are the risk factors that have been highlighted in these European studies? Well, I believe the most important one is age, as it happens also in the general population. In the European liver study, liver transplant registry study, mortality was observed only in patients aged 60 years or older. In fact, in the Spanish multicenter study, again, mortality was only reduced to the patients who were 60 years or older. In the UK experience, recently published, assessing the outcome in solid organ transplant recipients overall and by organ, the only variable independently associated with death in these organ transplant recipients was age. In the international registry, where many European countries participated, with a total of 151 liver transplant recipients assessed, age was the strongest factor associated with outcome, similarly to what we see in the non-liver transplant population, shown in blue, and the liver transplant population in the graph, shown in red, with the highest death rates in patients older than 60 years of age. The second risk factor associated with poor outcome in COVID liver transplant patients, and this has been highlighted, although it has not reached statistical significance, is time from transplant. In this first Italian study, mortality related to COVID occurred only in long-term liver transplant recipients who were more than 10 years from transplantation. Patients who were under minimal immunosuppression, and yet, these patients were enriched with comorbidities that have been shown to be associated with worse outcome in the general population, such as diabetes, arterial hypertension, history of cardiovascular event, and chronic kidney disease or underlying cancer. And the same has been also shown by the ELITA registry, where although not statistically significant, more patients who were transplanted at least two years previously died than did those who received their transplant within the past two years. What about immunosuppression? Well, in fact, most of the studies in Europe do not show an association between immunosuppressive agents and outcome, except this Spanish multicenter study that showed an association between the use of mycophenolate and poor outcome with a worse survival in those using immunosuppression, using mycophenolate, as opposed to those not using mycophenolate. And in fact, in this study, there was a dose-dependent effect, such that patients using more than 1,000 milligrams per day of mycophenolate had a worse survival compared to those using less lower doses of daily mycophenolate. So in conclusion, I think based on this data, these are the recommendations from the different societies, and I will focus on the European societies that currently advise against reduction of immunosuppressive therapy. Reduction should only be considered under special circumstances, particularly medication-induced lymphopenia or bacterial fungal superinfection in case of severe COVID-19, and always after consultation of a specialist. I would like to finish highlighting the importance of drug-drug interaction. And again, this is not particular to European studies, but I think it's very, very important, as some of the mortalities may have been related to this interaction between immunosuppressive agents and the different drugs that we use to treat COVID-19 or to treat the complications related to the infection by the COVID-19 infection. So in summary, transmission from donor to recipient and healthcare workers occurs, and this is particularly true in areas of high transmission of the virus. Outcome of infection does not seem to differ from the outcome we see in the non-immunosuppressed individuals in the general population. The risk factors that have been associated with poor outcome are similar to the ones that have been described in the general population and include particularly age and time from transplant as an indirect marker of the role of comorbidities. And finally, although we need more studies, immunosuppression seems to play a reduced role in disease outcome. So clinical and virological screening of donors and recipients is strongly recommended. Abrupt and large modifications of immunosuppressive agents are not recommended, and we need studies with longer follow-up, multivariable analysis and data to assess the impact of COVID. Thank you very much. Thank you for the invitation to present today on SARS-CoV-2 infection in children with liver transplant and disease of the native liver, results from an international registry study. This work was completed with my colleagues Mohit Kihar, Vicky Ng, Steve Labrido and Mercedes Martinez and was an important collaboration between two major pediatric societies, the Society of Pediatric Liver Transplantation called SPLIT and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition called NASPGM. My name is Noelle Ebel. I'm an assistant professor at Stanford where I'm the director of the Allergial Syndrome Program and associate program director of the Transplant Hepatology Fellowship. My research interests lie at the intersection between the heart and the liver and also in improving long-term outcomes after pediatric liver transplant. My advocacy interests relate to disparities and access to transplant and equitable post-transplant outcomes for all children. My email address and Twitter handle are listed here. I have nothing to disclose. I want to acknowledge the many individuals and centers that contributed to the COVID registry and provided critical review of the manuscript. Thank you to the SPLIT Quality Improvement and Clinical Care Committee and the NASPGM Hepatology Committee for their help in the development of the SPLIT and NASPGM COVID registry and to the SPLIT Executive and the Transplantation Society for their support and involvement in this study. While the SARS-CoV-2 pandemic continues to produce staggering disease incidence, children account for two to seven percent of reported SARS-CoV-2 cases with death rarely reported at less than 0.1 percent. In a multi-centered cohort study of solid organ transplant recipients, age greater than 65 years and obesity were associated with mortality but immunosuppressive medication intensity was not. Webb et al. similarly reported that liver transplant status in adults was not independently associated with death. In our multi-center retrospective cohort study, we aim to evaluate the prevalence, clinical course, and outcomes of SARS-CoV-2 infection in this population and highlight the differences between patients with liver transplant and native liver disease. We additionally summarize treatment practices and evaluate risk factors for morbidity and mortality. We included patients less than 21 years old with liver transplant or native liver disease with lab-confirmed SARS-CoV-2 infection by nasopharyngeal PCR or by IgM-IgG antibodies. Recipients of multivisceral, isolated intestine, and multi-organ transplants were excluded. 28 centers from six countries contributed data with 85 percent of cases from North America. MIS-C was defined by CDC criteria. We defined severe SARS-CoV-2 infection as at least one of the following, death, pediatric ICU level of care, mechanical ventilation, vasopressor support, and or renal replacement therapy. There were 91 patients in our total cohort. 53 percent were male with a median age of 10. 44 had disease of the native liver with the most common diagnosis being NAFLD at 23 percent, biliary atresia at 23 percent, and autoimmune hepatitis at 18 percent. 47 patients were liver transplant recipients with the most common indication for transplant being biliary atresia at 43 percent, acute liver failure at 15 percent, and metabolic liver disease at 13 percent. The median time from liver transplant to SARS-CoV-2 infection was about 3.4 years with a range of four days to nine years. The majority of liver transplant recipients on the right were white at 43 percent. 38 percent of children were Hispanic, 5 percent were black, 6 percent were Asian, and 6 percent were other race or ethnicity. 28 percent of liver transplant recipients were asymptomatic. Respiratory symptoms were the most common presentation in 36 percent, followed by fever in 34 percent. Co-infections occurred in 18 percent of liver transplant recipients, including adenovirus, a nasopharyngeal PCR, and EBV viremia. All the patients in this table who presented with acute liver failure and or MSC had disease of the native liver. Pediatric acute liver failure, or PALF, was reported in four patients with concurrent MSC in 50 percent. Two patients had MSC alone, of which one patient died. No patients presenting with PALF or MSC had a prior history of liver transplantation, autoimmune hepatitis, or current immunosuppression exposure. All patients with PALF recovered spontaneously and did not require liver transplant. Of the liver transplant recipients with reported labs, 30 percent had an elevated ALT during their SARS-CoV-2 infection, with numbers ranging from 113 to 1,215, which was a significant increase from their baseline. The interquartile ranges are shown here. Of the native liver patients Of the native liver patients who reported labs, 52 percent reported elevated ALT with a range of 102 to 11,112. Additional lab values are reported in this table with patients with disease of the native liver having significantly lower nadir albumin, higher baseline ALT, higher peak ALT, and higher peak INR. This table shows baseline immunosuppression for patients with liver transplant only. 17 patients were on a single agent, 17 patients were on double immunosuppression, 11 on triple immunosuppression, one patient was on quadruple immunosuppression, and one patient was off all immunosuppressive medications. The column to the right reflects immunosuppression changes made in the setting of SARS-CoV-2 infection. Amongst liver transplant recipients, changes included reduction in immunosuppression in 28 percent and or discontinuation of a second agent in 15 percent. 68 percent of transplant recipients had no adjustments to their immunosuppression. For patients with disease of the native liver, two of seven patients with autoimmune hepatitis reduced their immunosuppression dose. Here we reflect the highest level of care by baseline immunosuppression for liver transplant recipients. The furthest to the left and darkest bar reflects the lowest acuity of remaining outpatient. The middle bar is inpatient and the right bar represents a PICU requirement. Interestingly, higher baseline immunosuppression in liver transplant recipients did not predict a need for higher level of care. 79 percent of the total cohort received no SARS-CoV-2 directed medical therapies. Treatment approaches reported to the registry varied widely over time. For example, the use of hydroxychloroquine occurred early in the pandemic. This variation precluded meaningful assessment of the reported agent's safety or efficacy. The darkest bars here represent patients with disease of the native liver and the light bars are those with liver transplants. Patients with native liver disease were less likely to be managed as an outpatient, 30 percent versus 57 percent with liver transplant with a p-value of 0.007. Patients with native liver disease were more likely to require PICU management, 32 percent versus 4 percent with liver transplant with a p-value of 0.001. Patients in the native liver cohort were more likely to have respiratory compromise requiring mechanical ventilation, 16 percent versus 0 percent with liver transplant with a p-value of 0.005, and need for ventilatory support, 16 percent versus 0 percent with liver transplant with a p-value of 0.005. Complications in the native liver cohort included first episode of variceal bleeding in two patients. One has subsequently been transplanted and the other is currently listed for transplant. Eight patients had new onset ascites and one reported bacterial infection. Two liver transplant patients developed biopsy proven rejection in the setting of immunosuppression withdrawal. One patient was in the immediate post-transplant period, the other patient was greater than 10 years out from transplant. Both episodes of acute cellular rejection resolved with targeted treatment with no reported graft loss. The only two reported deaths, 2.2 percent of the total cohort, were from the native liver cohort. One patient was a 17-year-old male who was morbidly obese with NAFLD, who developed a peak ALT of 2,600, INR of 2.6, total bilirubin of 34, and ferritin of greater than 16,000. His course was complicated by thrombotic microangiopathy. He required mechanical ventilation renal replacement therapy, and vasopressor support. He received eight COVID-directed medical therapies and died on day 35 of hospitalization in the setting of multi-organ failure. The second patient was an 18-year-old female with an underlying history of bone marrow transplant 13 years prior for Fanconi anemia with chronic hepatic GVHD, oocerosis, and bacterial syndrome. She met diagnostic criteria for MIS-C with a peak ALT of 900, INR 1.7, total bilirubin of 40, and ferritin of 1,500. Her course was complicated by encephalopathy and ascites, and she required mechanical ventilation and vasopressor support. She received two COVID-directed therapies and died on day 34 of hospitalization in the setting of acute on chronic liver failure and respiratory failure. 20 patients in the total cohort had severe SARS-CoV-2 infection, again defined as one of the following, death, pediatric ICU level of care, mechanical ventilation, vasopressor support, and or renal replacement therapy. Of the 20 patients with severe SARS-CoV-2 infection, 17 had native liver disease, and three were liver transplant recipients. Highlighted in orange, severe SARS-CoV-2 infection was significantly more likely in children with native liver disease than liver transplant, 85% versus 15%, with a p-value of less than 0.001. Severe SARS-CoV-2 infection was significantly more likely in patients with obesity, 40% versus non-obese patients at 13%, with a p-value of 0.001. In the total cohort, 17 had severe SARS-CoV-2 infection, and severe SARS-CoV-2 infection was significantly more likely in patients with NAFLD at 35% versus non-NAFLD at 4%, with a p-value of 0.001. Highlighted in yellow, patients with severe SARS-CoV-2 infection also had higher peak INR, peak ALT, peak ferritin, and lower nadir albumin compared to patients with non-severe SARS-CoV-2 infection. Both univariable and bivariable analyses show that patients with NAFLD with an odds ratio of 5.6, with a p-value of 0.02 versus non-NAFLD, and patients with native liver disease with an odds ratio of 6.1 and a p-value of 0.01 versus liver transplant recipients were both significantly associated with severe SARS-CoV-2 infection. In summary, here we report our findings from an international multi-center cohort study with the largest reported experience of lab-confirmed SARS-CoV-2 infection in children with liver transplant and native liver disease. As my key takeaway points, first, NAFLD predicted a nearly six-fold increased risk of severe SARS-CoV-2 infection. Second, despite immunosuppression burden, liver transplant recipients were significantly less likely to require ICU-level care, mechanical ventilation, or die compared to patients with native liver disease. Our findings mirror that of adult solid organ transplant recipients in whom immunosuppression intensity was also not associated with poorer outcomes or increased mortality. Third, all patients with pediatric acute liver failure recovered without liver transplantation. For potential next steps and targets, primary preventative measures and counseling are critical. There are excellent examples from split institutions that are providing education at the patient and family level that is also translated into Spanish. A link to the Pediatric Infectious Diseases Society Solid Organ Transplantation Return to School Guidelines are copied here. Second, obesity is a public health crisis for children in the setting of a public health emergency of COVID. One of the two deaths reported occurred in a morbidly obese teenager with NAFLD. It is imperative that we as clinicians aggressively target weight loss now in obese patients to potentially mitigate their risk of poor outcomes from SARS-CoV-2 infection. Third, in our study, 8% of children reported to the registry were Black and 34% were Hispanic. Both SARS-CoV-2 related deaths occurred in Hispanic children. Racial disparities in SARS-CoV-2 infection are widely reported, including a higher prevalence and mortality in Black and Hispanic compared to White individuals. As advocates for children, our mandate is to divest from racial health inequities by implementing meaningful changes to address structural racism and ensure equitable outcomes. And fourth, and finally, further data collection is required to permit the large-scale analyses essential to inform optimal immunosuppression management and disease-specific treatments for pediatric liver transplant recipients and those with disease of the native liver. And we encourage you to continue to submit cases to the registry, and the link is provided here. Thank you for your time and attention.

COVID-19

liver transplant patients

children

native liver disease

ICU

mechanical ventilation

risk factors

obesity

NAFLD