and I'm a Professor of Internal Medicine at the University of Michigan. And on behalf of my co-moderator, Dr. Bilal Hamid from UCSF, we'd like to welcome you today to our program entitled COVID-19 in 2021, Updates on Hepatic Outcomes, Clinical Practice and Vaccination. Now, needless to say, many of us know the impact of COVID-19 has had in all of our personal lives, as well as our medical practices. I think many of us were hopeful that as the third wave was coming in late 2020, that with the introduction of the mRNA and adenoviral vaccines, that we would see a reduction that would be sustained in the morbidity and mortality due to this highly infectious virus. But unfortunately, we all know that the more contagious and potentially more virulent Delta variant recently emerged in 2021 and has led to further havoc in our daily practices. So with this in mind, the ASLD has been attempting to help practitioners and scientists get a handle on the COVID-19 epidemic. As a member of the task force, we've been involved in two important documents that you may be interested in on the ASLD website. The first one about recommendations regarding the diagnosis and management of COVID-19 in patients with liver disease and post-transplant. And then in 2021, we published the first version of the vaccination document for patients with liver disease and liver transplant. And we recently updated that in August of 2021. Now, we clearly know that this field is rapidly moving. So that is why we're having the program today in November of 2021. I'm very pleased to share with you an excellent outline of speakers we've been able to have for you today. The first one will be looking at the big picture of how to track vaccine safety in the United States from Dr. Pedro Moro, who works at the CDC. And he'll tell us about the incidents in association with various adverse events and the three available vaccines. Then we will move on to Dr. Emily Bloomberg from Penn, who will tell us about the latest safety and efficacy data of using the COVID vaccines in patients with chronic liver disease and liver transplant patients. Following that, Dr. Mike Shilsky from Yale will tell us about the known long-term hepatic outcomes with COVID-19 infection, including the evolving cholangiopathy story. And lastly, we'll finish up with Dr. Marina Serper from Penn talking about the impact of COVID-19 on hepatology practice, both in the inpatient and outpatient setting in patients with liver disease and post-transplant. After that, we've left 20 minutes for a robust discussion of the panel, which will be live. And for those of you attending today, we would encourage you to submit your questions through the chat function at the bottom of the Zoom so that we can attempt to address them as the moderators at the end of the program. So thank you again for joining us this morning for the program, and we will now move to the beginning of the program with Dr. Pedro Moro from the CDC addressing us on tracking vaccine safety in the United States. Thank you. Well, good afternoon, and I'd like to thank the organizers of this conference for giving me the opportunity to come and do this presentation. So I'll be talking about the systems used to monitor the safety of the COVID vaccines in the United States. And these are the topics that I'll touch upon. I'll describe the systems we use at the Immunization Safety Office, the ones that you see in the slide. So this slide shows the vaccine life cycle, and I just want to point out that vaccine safety is an important component in the development of a vaccine. So in the initial phases of the development of a vaccine, safety is important, and also after the vaccine is licensed or authorized for use, a monetarization of the safety continues. So why is post-licensure safety monitoring important? Well, there are two important reasons. The first one is that the safety standards for vaccines are very high. Now, these are agents that are given to healthy people, and many of them are children, so we expect them to be very safe. Another important reason is the clinical trials, the clinical trials done to assess the efficacy and safety of the vaccine are small in size, and they are not really adequate to study very rare adverse events. So here in this slide, we see what are considered to be serious adverse events. This is based on the Code of Federal Regulations. This is the definition that FDA and CDC use. So I'll be describing the established vaccine safety systems, and so I'll be talking first about VAERS, the Vaccine Adverse Event Reporting System, and then the Vaccine Safety Data Link. I won't discuss CISA, which is a different project. I just want to point out that currently what we are witnessing is the most intensive vaccine safety monitoring effort in U.S. history. And so I started with VAERS. VAERS is, again, the Vaccine Adverse Event Reporting System. This is a national passive surveillance system that is co-administered by CDC and the FDA, and it was created in 1990. VAERS has a number of strengths and limitations. Perhaps an important strength is that it can rapidly detect potential safety problems, and it can also detect very rare adverse events, and that has been shown for the COVID-19 vaccines. Now, among the limitations, one important limitation is that VAERS is not designed to assess causality, and other important limitation is that VAERS has a number of — there are a number of potential biases that one has to take into account that can occur, over-reporting or under-reporting of an adverse event. So the objective of VAERS is signal detection, hypothesis generation. It detects new, unusual, or rare vaccine adverse events. Here, this slide shows what the VAERS form looks like and what the type of information that is collected. And nowadays, most of the reporting is done electronically, about 90 percent, but the purpose is just to show the information. It's a lot of demographic information, information about the vaccines administered, about the adverse event experience. And in this next slide, the VAERS follow-up is an important component of VAERS. VAERS follow-up means that VAERS staff are going to follow up the serious adverse events, and maybe certain pre-specified conditions. So medical records will be obtained for any serious adverse event, and medical officers at FDA and CDC will review medical records, and they will look to verify diagnosis or to gather additional information. So signal detection is done primarily through data-mining methods, that is to assess for disproportional reporting, and also through crude reporting rates, which are compared to background rates, published background rates. Now, for COVID vaccines, it's possible to calculate reporting rates because there's data on the number of doses of COVID-19 vaccines being administered. So you need that to be able to calculate rates. Normally, VAERS does not collect denominated data, so that can be a limitation. But for COVID vaccines, we can calculate some crude reporting rates. So here, we see a list, a preliminary list of various adverse events of special interest. Now, the priorities of some of these conditions have changed, and obviously, for example, myopericarditis and Janberg syndrome are being prioritized right now because they are signals. So another adverse event that is of great interest was anaphylaxis, especially at the beginning of the rollout of the vaccines. As you will recall, this was in the media, but anaphylaxis is a condition that, well, that can be associated with vaccines, and these are the rates. These are from a publication in JAMA, and what you see are the crude reporting rates, so the number of cases per million, 4.7 for Pfizer and 2.5 for Moderna, and these have remained very steady up to recently. Here in this other slide, we see another signal that was found for myopericarditis. It was found to be more frequent in males compared to females, and after the second dose of the messenger RNA vaccines, especially in the age group less than 30 years of age. And another signal was the Janberg syndrome after the Janssen vaccine. Here in this slide, this slide shows the reporting rate, which was eight times higher for Janssen compared to the messenger RNA vaccines. And the other system is the Vaccine Safety Datalink, which is a collaboration between CDC and nine participating health organizations, which cover a population of 12 million persons. You can see the locations in the map. So, BSD collects data, immunization data, hospital discharge diagnosis codes, and a variety of other information in a large linked database. And the Vaccine Safety Datalink is an active surveillance system, and it has a number of strengths. Perhaps I would say the main strength is that you can calculate the incidence or prevalence of an adverse event. You can assess risk of an adverse event, and among the limitations, the main one is that the sample size may be inadequate to study very rare adverse events at the start of a vaccination program, and that was the case for the COVID-19 vaccines. One type of analysis used to detect signals in BSD is the rapid cycle analysis, which is actually a very complex type of statistical analysis. I won't go into details, just to point out that when one looks at our pre-specified conditions, one doesn't look at all the adverse events. Only certain pre-specified conditions, and one looks to see if a certain statistical threshold is exceeded, and if that occurs, further evaluation is needed, like, for example, review of medical records. So here is a preliminary list of BSD pre-specified outcomes for RCA, and again, for BSD, myopericarditis was also found to be a signal. It was more frequent. The rate were more frequent in males compared to females, and especially higher for those two. After those two, then those one were the messenger RNA vaccines. And for Janberis syndrome, the same rate was higher for Janssen compared to the messenger RNA vaccines. Now, this v-safe is a smartphone-based safety monitoring system that was created especially for COVID-19 vaccines, and you probably have the experience with v-safe or have received some of the text. But basically, once you enroll in v-safe, you receive these text messages that ask you about possible local or systemic reactions you may have experienced. They also ask you about whether the adverse event may have resulted in a... may have had a health impact, such as visiting a doctor or going to the ER or going to the hospital. If that happens, those cases will be followed up, and medical records will be obtained. Another question that women get if they are... it's women of reproductive age, is if they were pregnant at a time of vaccination. And if they were, they'll be contacted later on, and they will be invited to participate, to enroll in the v-safe pregnancy registry. This registry has been an important addition. It has been... It has allowed to study the maternal safety of the COVID vaccines. So, with v-safe, you can estimate the rates of local and systemic reactions. You can also estimate the rates of clinical important adverse events. With the v-safe pregnancy registry, you can calculate rates of pregnancy-specific conditions. This is a publication that came out in June that describes preliminary findings of the messenger RNA COVID-19 vaccine safety in pregnant persons using v-safe and VAERS. So, in summary, there are four systems that are being used to monitor the safety of the COVID-19 vaccines, VAERS, the Vaccine Safety Datalink, v-safe, and the v-safe pregnancy registry. These systems have together provided early post-authorization safety data for very rare and serious adverse events. And the information on these conditions has led to policy changes and also updates in the vaccine UA information statements. And these four systems, even though they are different and work a little bit differently, they have worked in a complementary way to provide vaccine safety monitoring data on the COVID-19 vaccines. And I believe that's my last slide. And I want to thank you for listening to my presentation. Hello. My name is Emily Blumberg. I'm the Director of Transplant Infectious Diseases and a professor of medicine at the University of Pennsylvania. Today, I'll be talking to you about the safety and efficacy of COVID-19 vaccines in patients with chronic liver disease and liver transplant recipients. These are my disclosures, none of which are relevant, but I will be discussing off-label use of COVID-19 vaccines. As of October 12, 2021, over 44.4 million cases of COVID-19 have been reported in the United States with over 714,000 deaths. Notably, among the most vulnerable are those individuals with chronic liver disease and those who've undergone transplantation. But we have an important tool to fight this infection, the COVID-19 vaccine. It's very important to note that those places where COVID-19 vaccines have been deployed most effectively have been those in places with the lowest rates of COVID-19 in the United States. And so we know that vaccinations are an important tool to move forward. Currently, there are three vaccines available in the United States. Two of these are mRNA vaccine, BNT162b2, otherwise known as the Pfizer vaccine, and mRNA1273, otherwise known as the Moderna vaccine. There's also a third vaccine, which is a replication-incompetent adenovirus-based vaccine called AD26COV2S, which is by Johnson & Johnson & Janssen. These vaccines have been FDA-approved in the case of Pfizer or otherwise authorized under emergency use in the case of the other two and in the Pfizer case for those 12 to 15 years old. All of the vaccines have been shown to be quite effective, with 94 to 95 percent efficacy in the initial studies with the two mRNA vaccines. The Johnson & Johnson vaccine was less effective in terms of actual prevention of disease, but very effective at preventing severe and critical COVID-19 infection. The vaccines do contain polyethylene glycol in the case of the mRNA vaccine and polysorbate in the case of the adenovirus vector vaccine. And for the rare individual who may have allergies, this information is important to know. There have been a lot of concern recently about the variants that have been circulating, especially the Delta virus variant. But it's important to note that the mRNA vaccines, especially, have remained effective at preventing severe infection with these variants. Now, there are some adverse effects that have been reported with these vaccines, and it's pretty common to have acute effects, such as injection site pain, fatigue, headache, myalgias, and chills following the mRNA vaccines or the J&J vaccine. But there have been additional, very rare, serious adverse events, which have been highly publicized, although quite uncommon. This includes anaphylaxis, delayed cutaneous responses, as shown in the photographs below, myocarditis, especially in younger men receiving mRNA vaccine, vaccine-induced thrombotic thrombocytopenia, especially in women ages 30 to 49 who've received adenovirus vector vaccines, and rare cases of neurologic side effects, including Guillain-Barre. Now, when we think about how well a vaccine works, we should remember that vaccine studies were initially geared to look at effectiveness. This means how well the vaccine did at preventing infection, symptomatic disease, significant infection requiring hospital admission, ICU admission, and death. And what's impressive is how well these vaccines have performed in this case. But many studies now are starting to look more and more at antibody as a measure of the immune response. And what we're starting to learn is, with time, antibody responses do wane, even in the normal host. Now, antibody responses are only part of the story, and I want to caution you about relying totally on them. Remember, there are over 50 FDA-approved tests for measuring antibody. But when we talk about vaccine responses, we're really only interested in antibodies to the receptor-binding domain of the spike protein. In other words, that portion of the virus that's actually incorporated into the vaccine itself. Now, typically, we're measuring binding antibody, but what we're really interested in is neutralizing antibody, and most tests do not measure this. The vaccines also the antibody tests also vary in terms of the platforms, the specificity, the sensitivity, the predictive value, the immunoglobulin isotype, and the antigens that have been targeted. Notably, the timing of testing can affect results. So if you actually measure antibody shortly after vaccine, you can expect lower results than if you measure it several weeks later. Importantly, there's no direct correlation of antibody with cellular responses. And in fact, there are almost no commercially available cellular responses. And the one that is available is specifically designed to actually look at response to infection, not to vaccination. We also know that these antibody tests do not have a specific correlate with protective levels because these have not been defined. So based on all of these factors, the FDA currently does not recommend antibody testing after vaccination to determine if a patient has responded. But despite this, that's mostly what we're looking at when we try to determine if patients respond in terms of vaccination. So what do we know? We know that the responses in chronic liver disease are actually pretty good. This is based on several different types of studies. The one by John and colleagues looks at a large cohort of both patients with chronic liver disease and match control in a VA system. Caleri and Wang are actually looking at small center-based studies. Now, in general, when these studies have been developed, they're actually looking at people with MELDs of eight in the VA study or 12 in the Italian study. These are typically mRNA-based vaccine studies, and you can see the efficacy rates are pretty high, especially the benefits for preventing hospitalization and death. The Wang study is a little bit different because we don't really know much about the patient's degree of liver disease. They included all patients with non-alcoholic fatty liver disease, and they used a completely different vaccine, one relying on an inactivated viral vector vaccine. But again, response rates were good. What about in liver transplant patients? Well, here you can see highly variable responses. All of the studies that I've listed here are based on mRNA vaccines, and you can see most of them are pretty small. We also know that vaccine antibody levels actually vary from 34.8 percent in the initial study by Mazzola to much higher rates in the Herrera study. Now, the Herrera study was unique in that it looked both at antibody and cellular responses and noticed that there was a difference between the two, and some patients only had cellular responses and a few only had antibody responses, but all told, 93 percent of the individuals had at least some result. Notably, the time from transplant was quite variable, and this probably impacted on the responses that we see so that those individuals who were more remote from transplant had better responses. What else was affected with poor vaccine responses? Well, clearly, immunosuppression made a difference. Patients who were on more immunosuppression, for example, with triple immunotherapies, antimetabolites, high-dose steroids, had received depleting antibodies, or in the rare occasion, belatacept, were much less likely to respond. I mentioned time from transplant being especially important, but other factors included hypogamic lobulinemia, older age, typically over 60 or 65, and worse renal function. How do liver transplant patients compare to other solid organ transplants? Well, they actually do quite a bit better, probably because they're on less immunosuppression. What about how do they do compared to those individuals who have chronic liver disease? Well, those with chronic liver disease clearly seem to do better than those who have actually been transplanted. What does this mean in real time? Well, it turns out that we're starting to see breakthrough infections in all people, regardless of immunosuppression, but the numbers still are quite low, even in the vaccinated solid organ transplant patient. Notably, although low, those SOT breakthroughs are still higher than that of the general population. It's hard to get at exact numbers because the studies include people who've not been fully vaccinated, who've been fully vaccinated but have a short time from the last dose of vaccine, and there's a lot of uncertainty about both numerators and denominators, and also probably some differences based on variants. There's also been quite variable disease reported from asymptomatic to very severe disease and death, and it's pretty clear that when compared with non-transplant, non-sorotic patients, SOT patients, and sorotics both have a higher risk of death. Early monoclonal antibody may impact treatment, and it's also notable that the transmission risk is likely highest with household contacts. In this large UK transplant registry study, it does show that deaths are clearly less in those individuals who are fully vaccinated, in this case, primarily with an adenovirus vector vaccine. So, based on that, there's been a lot of interest in giving third doses to patients who are at high risk for breakthrough infections. What we see here, and I caution you that these studies have very few liver transplant patients, is that overall, solid organ transplant patients who receive third doses do experience boosting in some cases in terms of response to mRNA vaccines. Now, we know that that's true in the case of the Camar study on the left, primarily a kidney transplant population, that about two-thirds of the patients by the end of the study had some evidence of antibody response. In the study by Hall and colleagues from Toronto, what we saw was also there was some improvement in terms of cellular responses in addition to humoral responses. So, where does that leave us? Well, there's still a lot we don't know. We don't know if these immune responses are going to translate to effectiveness. We also don't know if they might be even better if we tried to think about how to best change the immune suppression, and studies about that are ongoing. We also don't know if it's better to mix and match vaccine types, change the dose, change the administration site, or alter the time between doses. So, where does that leave us? Well, based on all of these findings, the ASLD has come up with the following guidelines, and I'm synopsizing just some of the important take-home points. For chronic liver disease, vaccination is recommended for all, regardless of disease, and should only be delayed for a recent febrile illness. Booster doses are appropriate 28 days or later after the second dose in mRNA vaccines, as per CDC guidance, and especially applied to those with hepatocellular cancer and immune suppression. Currently, immune suppression is not suggested to be altered in anticipation of vaccination. For all solid organ transplant patients, including liver transplants, a three-dose series with a third dose is recommended after 28 days after the second dose. There should be a delay if there's active rejection going on and that's being treated, and it's notable that if LFTs rise after vaccination and stay elevated, a biopsy should be considered, although, thus far, there's not really compelling evidence that rejection is a significant risk. It's important not to delay transplant to complete the vaccine series, and so far, we don't think you should reduce your immune suppression in anticipation of vaccination, but more to come about that soon. Ultimately, it will be very important to keep the ring of people around the patient safe, and so that means vaccinating all eligible household and close contacts, and that everyone should continue with other safeguarding measures, including masking and social distancing. I'll be happy to take any questions, and thanks again to all of you for your attention and to the organizers for the invitation to speak. Hi, my name is Mike Shilsky, and I'm here today to discuss the long-term outcomes for COVID-19 in patients with liver disease. These are my disclosures, and the topics for discussion today include the impact of COVID-19 on the liver, the impact of liver disease on the outcomes of COVID-19, the impact of COVID-19 on candidates for liver transplant, and the impact of COVID-19 on our patients with liver disease independent of their liver disease. This is a cartoon that shows the hepatocytes on the right and the cholangiocytes on the left, and it was taken from a nice review that was published recently, and you can see that there in the boxes many different areas that highlight how the liver and the bile ducts may be injured during COVID-19. Since there are few ACE2 receptors on the hepatocytes, it would be rare to have a virus go directly in and be cytopathic for liver cells. By contrast, the cholangiocytes do have ACE2 receptors and may take up the liver cells. However, it may not indeed be the virus itself that may injure the cholangiocytes during infection, but at times the hypoxemia, cytokine storms that may occur during severe infection, and indeed for the liver cells, other impacts include drug-induced liver injury as well. Now, with respect to impact on the liver, we see in patients who have COVID-19, not infrequently, elevations in ALT and AST with a pattern of AST greater than ALT. You may see alkaline phosphatase and GGT elevated, and these almost always resolve after the infection. There are also elevations in liver tests that occur more frequently in patients with severe disease, and that's been seen in some but not all studies that have looked at this. Now, we have noted that acute liver injury and acute liver failure due to COVID-19 alone is extremely rare. The other impacts of COVID-19 may be a little direct, and that may be from problems that arise in delays in care, and that is impacting on both HCC surveillance of treatment, antiviral therapy, and many effects on our transplant candidates as well. And interestingly, there may be a post-COVID syndrome known as cholangiopathy, and in these individuals, this tends to occur after recovery. We'll discuss that later in the talk. This is taken from a study which reviewed a number of different hospitalizations in China as well as in the United States, and those different studies are shown on the left. On the x-axis are the percent of patients with elevations in ASD and then ALT as well. The line vertical that's dark shows approximately 20 to 25 percent. So, you can see that in the majority of these reports, they're from hospitalized patients, whether it was in China or the United States, about a quarter of patients or more had elevations in the transaminases, whether it's ASD or both. Now, importantly, there is an increased frequency of hepatic decompensation and organ failure in patients with more advancing liver disease and is in direct proportion to that. And this was from a wonderful study that was derived from registries in the United States and the United Kingdom. In the United States, it was part of the Secure Cirrhosis Registry, and in the UK, it was the COVID HEPNET. And you can see on the left that the proportion with decompensation increases as you have increased liver disease severity. With chronic liver disease alone, there's almost no impact. And the case fatality rate similarly rises when you go from chronic liver disease alone to multi-organ failure that may accompany the hospitalization for patients with liver disease. Now, also, COVID-19 mortality is certainly higher in patients. And from that same registry study, we can see that, again, once you go from child A to child B to child C, you make significant increases in mortality to reaching almost 40% in patients with child C. Now, impact of cirrhosis on immune function may be the reason that we're seeing these changes, and the impact is likely in proportion to the severity of the liver disease. And some of these impacts are local to the liver, and some are systemic. There may be macrophage dysfunction, reduced protein synthesis, inflammation, and immunodeficiency. And each of these has different impacts on the host response and the ability to fight the infection or co-infection that may occur in some of these individuals. Importantly, liver disease patients really suffer the same slings and arrows as non-liver disease patients with respect to increased risk for COVID-19 disease if they are older, if they are obese, if they have diabetes, if they have chronic lung disease, or if they have renal failure. Now, the consequence is that a number of our patients, once they're hospitalized and released, suffer readmissions, not infrequently. And within two months of discharge, about 9% to 15% are readmitted. And if you wait up to six months, it's almost 30%, fairly high proportion. And there are many different reasons for this. And the underlying risk factors are similar, as we've seen before. But they also may include a very short stay where patients may be released sooner and still have ongoing symptoms and need hospitalization again. Or they may have problems in relation to thrombosis, and they might not have been adequately integrated during that time of hospital stay. Now, there's also an impact on the patient independent of liver disease. And these sort of fall under this sort of category umbrella term, as coined by the CDC, of post-COVID conditions. And it's a term for the wide range of physical mental health consequences experienced by some patients present four or more weeks after their infection. And it includes patients who had even mild or asymptomatic acute infection. And therefore, it's important when we see these patients after their infection and recovery, and they come back to us in the clinic, we follow up on their renal function. We look for any evidence of critical myopathy or polymyopathy, especially those who are in the ICU. We look for any problems in cardiac function or in dysrhythmia. We may look for how their pulmonary function has been impacted. They may experience psychiatric sequelae, including post-traumatic stress syndrome, especially in those who have been in the ICU on ventilators. And they may have neurologic sequelae, including brain fog or postural tachycardia syndrome, which may be dysautonomia. Now, the area that probably is common to all these people that have these post-COVID syndrome, and some have called that long-crawler, is probably inflammation and vasculitis. And the incidence of this has been estimated as high as even 10% of infected patients from one number that came from the UK. And there are a number of different factors which may determine whether this prolonged disease occurs. But again, the common element seems to be inflammation and vasculitis. Now, one in particular we need to focus on with respect to our liver patients, and that is if they have prolonged colostasis, because the bile ducts may be affected in a way that mimics secondary sclerosine cholangitis. And this really occurs in the critically ill patients. And it really is, again, ischemia, ischemia, ischemia, whether it's due to thrombosis, hypertension, or hypoxemia. And it also may be affected, again, by cytokine storm as well. And the presentation of these patients is after recovery. And again, in a number of these patients, it may be so severe that liver transplant is required. In one series from a large institution in New York, where they reviewed thousands of charts, they found 12 patients, mostly men that were the mean age of 58 years, that had developed this cholangiopathy typically after almost four months after their hospitalization. The peak transaminase of ALT was at 660. And the peak median alpha phosphatase was 1855, certainly recognizable. And we wouldn't miss those. And these patients had marked elevations in inflammatory markers, subgrades, ERP, D-dimers, and had abnormal findings on their imaging of their bowel ducts, whether it was beading of the intrapathic ducts, thickening of the wall, or the high signal on the peritoneal area. And a number of these were referred and have required transplantation. Now, there's clearly other impacts overall of COVID-19, and that is, again, a general pandemic effect, one essential reducing the access and willingness of patients to come for essential testing and treatment. And with respect to the liver disease, we've seen that in particular as it relates to parasitic carcinoma, as well as standard diagnostics where patients have delayed either imaging or biopsy. And there's disruption in treatment and detection of viral hepatitis. Now, transplant candidates may also be affected. Patients may not be referred as easily, and a number of centers may not accept all referrals, especially if they're on transfer for when their hospitals are being overwhelmed. There may be inactivations of patients on the list. And then the important question is, when are they safe to move forward again? And have they suffered any damage, which may keep them from being as good a candidate as they were before? And then also, as I mentioned, the chronic COVID syndrome as well. Now, in understanding how to detect and deal with these patients who have had sort of presence of the virus still detected by PCR, further out from their infection, we know that it occurs more often in patients who are on immune suppression, whether it's patients who have autoimmune hepatitis or post-transplant. And then we can see the difference instead of the short curve that's shown on the bottom, we see the stretching of the curve to the right, where we can see the presence of the virus, even on lower cycle threshold. And on this slide, introducing a little bit more of the concept of the cycle threshold. So remember, PCR is an amplification process. If you find something with a low number, that means you need less amplification to detect it. So shown on the left side on the y-axis are the amplification cycles, and low is on top, high is on the bottom. And you can see in a number of patients here, these were not hospitalized patients that had COVID detected, and they're showing you the cycle threshold and the timing from the time that they had symptom onset. And you can see with time, as it goes further out, the only way you can detect the virus still is by going to a high cycle threshold. And at that point, these are not symptomatic, nor necessarily infected patients, especially when the cycle threshold reaches above 35. And similarly, in our post-transplant patients, again, on the knee suppression, you see that sort of shift to the right. And you may see these prolonged presence of the virus particles, and yet that may not necessarily mean that these people are infected. So it's more important for us to know and get the cycle threshold to understand in terms of infection control, do these people still need to be isolated from our other patients, or can they proceed on to transplant? And in summary, we've discussed the impact on the liver, elevated liver tests being common with multiple causes for that, rare acute liver injury and acute liver failure. We've seen the liver disease itself does impact the outcome with respect to organ failure and mortality. We've seen that liver transplant candidates may have delays in evaluation of treatment, listing and delay in their transplantation. And we've seen impact of COVID-19 on patients independent of their liver disease, as well on systems other than the liver, and also including phalangeopathy, and introduced the concept of cycle threshold as well, which is more helpful for us for our infection control purposes than indeed for most else. Finally, I want to thank our committee members and efforts from the beginning for the task force. And in particular, we've produced two wonderful documents, the best practice advice, as well as the vaccine consensus statement. And all of these are available on the COVID area for resources. And also would like to thank our ASLB staff that's been with us from the beginning, helping our task force, being able to bring the information to you. So thank you, everybody, for your attention. And I look forward to our discussion. Thank you so much for the opportunity to present to you on hepatology clinical practice in the COVID era. My name is Marina Serper. I'm a transplant hepatologist at the University of Pennsylvania. I'm a health services researcher who studies care quality and care delivery in liver disease. And here are my disclosures. So this talk is going to be really in two parts. First, I'm going to discuss changes to clinical care and hepatology that occurred either as a result of or during the COVID-19 pandemic. We will discuss a major pivot to telehealth services, how some of that impacted access and quality of care, and we'll talk about what has happened to liver transplantation. The second part of my talk will describe how hepatology clinicians perceive the impact of COVID-19 on their practice. We will discuss the prevalence and factors associated with burnout among hepatologists and then discuss ways that practicing clinicians can be supported through the pandemic and beyond. First, let's talk about innovation and a shift to care that really was born out of necessity. Obviously, we're in a new world over the past 18 months, and unfortunately, the world has majorly changed and the COVID-19 pandemic has really impacted the way we deliver care. Let's talk about what has happened first to telemedicine use as a first result of shelter-in-place orders and then that really was brought on by necessity. Before the COVID-19 pandemic, telehealth services were growing slowly and incrementally. However, because of shelter-in-place orders in the United States and because of loosening of interstate licensure requirements and on-par reimbursement during the public health emergency, telehealth claims grew 78 times early in the pandemic and then had later stabilized still at very high volumes at 38 times. We saw an impact of this nationally on hepatology practice. These are early data generated by Nadeem Mahmood and our team. As you can see here on the left panel in red, is an increase in telemedicine visits in the VA healthcare system, which is the largest provider of liver disease care in the US, and a major drop in in-person services. You can also see an increase in telehealth as shown by the dark blue on the right throughout the COVID-19 pandemic. Now, I will tell you that access to care was not completely compensated for by telehealth. Now, let's look at how telehealth actually impacted quality of care. Again, these are data generated within the VA healthcare system, so national data by Nadeem Mahmood. We looked at the impact of COVID-19 on screening imaging for HCC among a patient of cohort with cirrhosis. What you will see here, if you look at the top panel A, compared to 2019, which is shown to you in blue, if you look at the red dots, there's a profound drop in imaging early in the COVID-19 pandemic. As you can see in panel B, as shown to you by the blue pre-pandemic and red early pandemic bars, there has been a slight and slow increase back up to baseline pre-pandemic levels, but at least early on in the pandemic within the first six months or so, we did not catch up in terms of HCC surveillance. This had a profound impact on practice and care quality. Now, if we look at factors associated with HCC surveillance during COVID-19 in the VA, we saw that patients who were older, patients who were due for imaging studies later in the pandemic, were associated with higher surveillance. Surveillance was also higher in academic centers, which may not surprise you. Among those patients who had a recent appointment and patients who accessed any care, by primary care or gastroenterology and hepatology. Unfortunately, HCC surveillance was lower in some geographic regions, particularly the South. In unadjusted analyses that you see on the left, black race was associated with lower HCC surveillance. In terms of access to care, those patients who saw specialists, GI and hepatologists in person, were the most likely to receive HCC surveillance. However, again, important to recognize that any appointment with primary care or with hepatology or GI in-person or telemedicine, were all associated with more surveillance versus no visit at all. What about the impact of COVID on liver transplantation? Well, this slide can probably be summarized very briefly, but I'll go into some of the details. In summary, during the COVID-19 pandemic, we have seen an increase in alcohol-associated hepatitis, wait-listing, and transplantation, as well as chronic alcohol-associated liver disease. My colleagues, Tess Bitterman, Nadeem Mahmood, and Peter App, looked at wait-list registration and transplantation for alcohol-associated hepatitis early in the COVID pandemic through February 2021, so really the first year of the pandemic and compared to previous trends prior to the pandemic. In February 2021, listings for alcohol-associated hepatitis increased by more than 100 percent and transplantation increased by 400 percent. Now, though the relative increases were large, the actual magnitude was still modest. This amounted to about 13 patients being wait-listed per month, or rather 18 patients being wait-listed and 13 patients being transplanted. Now, the study that I'm showing on the right, done by Chalankaril and colleagues, looked at chronic alcohol-associated liver disease and wait-listing for alcohol-associated liver disease went up early in the COVID pandemic by seven percent and transplantation went up by 11 percent. Important to recognize that alcohol liver disease accounted for 40 percent of wait-listing, which was greater than hepatitis C and NASH combined. We also need to recognize though, that these changes in transplantation are not necessarily just due to COVID-19. We have to account for the fact that in February 2020, OPTN came out with what we now call the acuity circle policy, which of course enhances and improves access to transplantation for patients with high MELD, but also incentivizes transplant centers to transplant and wait-list those patients with high MELD due to alcohol-associated hepatitis. We also need to pay attention to the fact that hazardous drinking has gone up among young individuals. This was prior to the pandemic, but accelerated even more so during the pandemic. We as a transplant community in the United States have had a greater acceptance of transplantation for alcohol-associated hepatitis and of course, the ever-dropping hepatitis C prevalence in the background. So not all of this can be attributed to the pandemic. And now we're going to shift gears and talk about the impact of COVID-19 on hepatology clinicians. So I want to share data with you that we conducted as part of a national survey and work conducted by the COVID-19 task force in the ASLD. We conducted a national survey of ASLD members from February to March, 2021, and asked them 26 questions on clinical practice and emotional wellbeing with 230 ASLD respondents. Here are our demographics. 40% of our respondents were adult transplant hepatologists, 20% were advanced practice providers, 25% were general hepatologists or gastroenterologists who practice primarily taking care of liver disease patients, 5% were pediatric hepatologists, 78% of respondents were from a transplant program with wide national representation. We had 46% females, 69% were white, 20% were Asian, 5% were Hispanic or Latinx, and 2% of respondents were black. Here's how hepatology clinicians responded in terms of how has the pandemic affected their practice. 54% said that they switched primarily to telemedicine early in the pandemic, which are data that I showed you. 40% said they had to reduce staff, 30% experienced a reduction in compensation, 11% moved to new employment, 9% closed their practice, and 5% switched from patient care to non-patient care roles. 27% of clinicians reported burnout, and only 29% met criteria for job fulfillment. Here, I'm showing you factors associated with burnout among hepatology clinicians, and I would like you to actually look at the data that are univariable, so the top part of the forest plot. So burnout was associated, so being early in your career was associated with higher burnout, being late in your career was lower burnout. Burnout was also higher among females and advanced practice providers, and was lower among Asian compared to all other races, and transplant hepatologists compared to non-transplant hepatologists. And here, I'm showing you data for work fulfillment among hepatology clinicians stratified by sex, because we did see some sex-based differences in burnout. So these are quite fulfillment questions, so questions like, I feel happy at work, I feel worthwhile at work, my work is satisfying to me, I feel in control, I feel like I'm contributing professionally in the way that I value most. It's important to notice that about a quarter to a third of hepatology clinicians did not feel fulfilled in their work, and there were important differences in terms of saying that felt worthwhile, so females were less likely to report that they felt worthwhile at work, so certainly some concerning data. And here is another important table. We asked hepatology clinicians about their attitudes towards their employers and stratified this by burnout, yes versus no. This will probably surprise no one, but these are important data to bring to the forefront. So clinicians who reported burnout did not feel as strongly that their employer took appropriate steps to protect them. At work, prepared them for the duties they were asked to perform with COVID-19, listened and understood their concerns, provided timely information, provided tangible support for childcare and other needs, provided emotional support. I thought that this was quite a striking difference, 26% versus 64%, and honored their dedication and sacrifice in a meaningful way. So these are all the ways that employers can support the clinicians, and we see very strong associations with burnout here. Well, what's interesting is that some of the burnout questions actually were not necessarily probably due to the COVID-19 pandemic, or at least the answers. There was a survey conducted by Dr. Michael Chris from Colorado and colleagues that looked at early career hepatologists in 2019. 124 hepatologists responded, 78% said they were satisfied with their job, but 35% had met criteria for burnout, similar to our survey. And factors associated with lower burnout among early career hepatologists will also probably surprise no one. This was salary support outside of the division, non-clinical time, adequate clinical support were all associated with lower burnout. So how can we mitigate burnout? It's easier to say than probably to do. A lot of this is actually out of our hands. In our survey, we asked, how can ASLD help? And the respondents said, well, expanding mentoring and networking through virtual platforms could be helpful. Enabling group discussions to address the challenges in clinical practice could also be helpful for members just to feel like they're supported, that there's a community to which they can talk to. However, I would say that the responsibility for burnout really rests with the individual clinical practices and institutions. So really the ways to decrease burnout are to decrease clinical burden, to improve administrative support, to provide clinical intangible support, whether it's in the form of emergency childcare or transportation or other needs, to improve the physical working environment and to improve the workplace culture. And these are factors that will serve us well beyond the COVID-19 pandemic. So the key takeaways from my talk are that COVID-19 resulted in major care disruptions, a major pivot to telehealth services that of course mitigated some of the access issues but did not fully make up for them. So in-person visits still were associated with higher access and quality of care, at least in HCC surveillance. We saw increased wait-listing and transplantation for alcohol-associated liver disease and alcohol hepatitis, trends that had already been growing but probably were accelerated given increased alcohol consumption and changes in transplant policy. We also saw that hepatology clinicians reported significant burnout. This was associated with being early career, female sex and advanced practice providers who are very important collaborators in how we take care of our patients increasingly have become instrumental in transplant centers, unfortunately reported a lot more burnout. And so there are important initiatives that we have to undertake to make sure that they continue to be able to practice in a way that reduces burnout and improves job satisfaction. And given the lessons learned, there are multiple opportunities for policymakers and health systems to optimize care delivery for our patients and support the hepatology clinician workforce. And I thank you for your attention. Great. Well, welcome everyone. My name's Bob Fontana from the University of Michigan and on behalf of myself and Bilal Amid from UCSF, we'd like to welcome you now to the fun part of our session for live Q&A. We've already gotten a series of questions through the chat box and we encourage all of you to submit further questions through that as well. So Dr. Morrow, there are a couple of questions I think directed to you that maybe you could help clarify for some of the audience members. There was a little bit of confusion about, do patients, the data that you publish on Guillain-Barre and other adverse events, is that patient self-reported or is this verified through the CDC and FDA? Several people had a few questions about that. You're referring to, we are probably referring to the cases of GBS after the Johnson. So those are reports that have been submitted to VAERS and those reports come, well, anyone can report to VAERS, but many of those reports may have come from providers, from the physician. And what I can say, I haven't reviewed the reports themselves, but a number, although have been verified, we use the Brighton definition system to actually verify the diagnosis of GBS. Some of them have been verified, but I cannot really give you a number in terms of how many have been verified as cases of GBS. Some of them may have been just reports submitted by the healthcare provider or by the patient himself or herself and without verification, without review of medical records. So, but I don't have the, I haven't worked with GBS specifically, that's why I don't answer the question. And then there were other than another question about the recent approval of the pediatric Pfizer vaccine for the five to 11 year olds. Can you or Dr. Chu kind of comment on the safety profile of what we know about the vaccine, what the dose is and what you, we can expect or what we already know about safety amongst younger children? Well, what I can say, I mean, I cannot, in the clinical trials, my understanding is I'm not, I don't know in detail the adverse events, but I know that most of the adverse events were local and systemic reactions in children and very young children. What I can say is that for the post-authorization safety monitoring that will take place, we're going to look at, through B-SAFE, we're going to look at reactogenicity, you know, the local and systemic reactions, see if there is a, if there are any, anything of concern or if they are consistent with what has been observed in the clinical trials. And of course, one area of interest, and we are going to monitor that very carefully is cases of myopericarditis. So that's another, and perhaps the other pre-specified conditions, but I would say that that's an important one that will, I will probably, I should add also that CDC will be providing an update on the, to ACIP, to the Advisory Committee on Immunization Practices. I would suspect not very long from now because there is a lot of interest in knowing the safety of these vaccines in children. So maybe I can just add to that. So the CDC has approved or recommended primary vaccine series for children greater than five. And so the dose from five to 11-year-olds now is actually a third of the dose of the dose that's greater than 12-year-olds. So it's 10 micrograms versus 30 micrograms. You know, the side effect profile was very similar to that that we've seen with the older children and adults. There, in terms of the myocarditis risk, we get a lot of that from our patients in terms of those questions and hesitations. But I think ultimately, given the rare incidence of that, we really believe that the incidence of myocarditis following vaccination is much less than the incidence of myocarditis following COVID disease or infection. So if you were to take, you know, 100,000 males, ages 16 to 29, about five of them would get myocarditis after vaccination, but 59 of them would get myocarditis after primary COVID infection. So the benefits really outweigh the risks for vaccination. So we are routinely recommending that from our liver, pediatric liver patients as well. And there were no incidents of myocarditis seen in the vaccine trials, but the numbers as Emily had, yes, they weren't powered to look for that. So we hadn't seen any, but that doesn't, you know, we're still, it's ongoing. So Dr. Morrow, another series of questions towards you were about the liver safety. And, you know, several of us have seen an autoimmune-like hepatitis, and we've been kind of searching around with our colleagues in other major centers. And do you have any data on the liver safety of the mRNA and the adenoviral vaccines in the United States? Yeah, we've, yes, we've looked at, I actually looked at their system, the Vaccine Adversary Reporting System, to see if, how many reports of autoimmune hepatitis have been reported. And actually, we haven't really seen any increased reporting of autoimmune, for autoimmune hepatitis. I mean, I can tell you that as of, I actually did a search probably a month ago, and there were 35 reports of autoimmune hepatitis submitted to VAERS after any COVID vaccine. That compares to 10 reports for non-COVID vaccines and, but this number is actually quite small. I mean, we would expect a higher number. And what we look at is for disproportional reporting. And we haven't seen that. We also have looked at other adverse events. In VAERS, we use MedDRA, which is a code for an adverse event. If, for example, I looked for some transplant codes, and we haven't seen any increased reporting. Actually, the numbers are quite small. And also for the code is cirrhosis, or decompensated cirrhosis. And we haven't seen anything of concern. That's the way we would search the reverse system. And I think Dr. Morrow and or actually Dr. Blumberg or Dr. Shulsky about the one question that's coming up is the risk of rejection after the COVID-19. Is there any data, have you seen anything about it? I can start that and then maybe Mike can add to this. You know, it's very hard to actually attribute rejection to vaccination in these patients because there, you know, if somebody rejects it's hard to know that that's what it's from. But in general, there have been in the Hopkins, the initial Hopkins report, a single report of a heart transplant recipient who rejected of the 30 who they reported on but it's not clear whether that was related or not. And I think while there's a lot of concern because certainly other vaccines have been associated with potential upregulation of HLA, for example, there has been no concrete evidence that there is rejection associated with these vaccines. Now, I will caution you that if people start to modulate their immune suppression in anticipation of vaccine, we may start to see other things happen. And that's why I'm glad that at least there's one clinical trial that will look at this very carefully. That's a multi-center perspective NIH sponsored trial. And I think that will be very helpful for us to learn really is there a rejection signal, especially as we think about how best to address immune suppression. So, Bala, thank you for asking as well. I agree totally with Emily that we've really not seen this as a clinical entity and I had shared the same fears, especially as she was showing the data on the patients who were on anti-metabolites and the less effective production of antibody and perhaps immune response in those individuals. I know from my own personal practice, a number of my patients, once they learned of similar data as it made it out in the news, we're asking, should we reduce our immune suppression? So I know it must be out there. We have seen a couple of patients with transient elevations in their liver tests after the immunization, which gave us a little bit of concern, but they were all very transient, went back down within a week or two and we didn't have to invest to get them further with biopsy or such, but we were ready to do so. So the answer I think is it's very safe for what we've seen now. Yeah, I'd like to reiterate that. I do have to say though, we probably are gonna have a few events and as Dr. Murrow said, is this just sporadic liver injury that happens after the vaccine or related? But certainly in other venues I've been involved in this meeting, several people have reached out to me with my drug hepatotoxicity hat on with the research I do there. And certainly I would encourage anyone who thinks they may have someone with a COVID vaccine hepatitis that I'd be happy to talk with them. And we have a prospective study to enroll them into the Dillon Network where we can do GWAS and HLA typing because it's an important question and it may be such a low rate that we just aren't seeing it yet, but I think we all would benefit from trying to gather those cases together. So one other important thing I think a lot of people are talking about or discussing about mandating vaccination for all liver transplant candidates. What is the panel? I think Emily, I'm gonna start with you with your expertise and we can open up the discussion. This is one of the hardest questions I think we address as transplant professionals. You know, we mandate a lot of things for our patients and there's been a tremendous groundswell of support for mandating COVID vaccines because we know that people who are vaccinated are less likely to have severe consequences, die on the list, come to be transplanted and then find that they have COVID and then you're not able to transplant them when they arrive. And so there's a lot of interest in mandating this, but there's also a lot of concerns about mandating it because there is some data that suggests that there's still an issue of healthcare disparities related to vaccine distribution. And it may be that these mandates will really disproportionately affect certain populations. And so I think from my standpoint, I'd like to see us be able to vaccinate as many and hopefully all of our patients, but I'm not quite sure that we're at a mandate yet. And especially as we look at the pediatric population, I think it's gonna be especially challenging now. And Jamie can probably comment on getting children vaccinated now. Yes, it's authorized for ages five and up, but there's still a lot of distribution issues. And so I'm sort of moving in that direction, but I'm not totally there yet, but I think it would be great to really push this. The one other thing I wanna say about mandates is remember we send our patients back to a community and just vaccinating them will never be sufficient. We wanna make sure their home environments are safe too. And we've really been trying to push, and I know Marina is aware of this, trying to create safe environments for our patients by looking at what's happening in their family situation. And I think we really have to be cognizant of pushing vaccines for family members as a way to protect their loved ones. Yeah, this was the topic of the Friday night debate. If some of you were able to tune into that, it was a very lively discussion. And I believe it was the USC team who got the shorter stick of trying to defend not mandating it. One of the points they made, which I thought was very important, and we can all have a part in this, is that they cited some data that I can't remember if it was from the VA or where it was, but coming into the clinic, there were something like 70% of people who had not gotten the vaccine. And after talking with their doctor, who then kind of dispelled what their issues were, concern of getting the infection from the vaccine and so on, the vaccination rate went from 70% up to 95 after just an encounter with their provider. And I think that speaks a lot because a lot of these conversations I've had with my patients, it's frequently misunderstood and they can't keep track of the constant blur of information out there. So I don't know if others have the same experience that when you actually talk to your individual patients, you've been hesitant that they come around. But Bilal, what's been the experience in San Francisco? I would just have Dr. Serber start with that. I think she has some. Thank you. Wanted to raise my hand. So a couple of things. So of course it depends where we are in the pandemic. So actually our group did a couple of studies. Right as the first vaccine was approved, Pfizer, I guess it was December now, 2019, 2020, excuse me. I'm getting all my years messed up. We did a very quick survey of our patients in terms of vaccine beliefs. And this was before, this was right before the EUA and this was right before people knew really about safety and side effects. And patients, these were cirrhosis patients, those who had a liver transplant and inflammatory bowel disease patients. They very strongly told us that they actually trust their subspecialists, those who manage their complex chronic diseases and they trust their advice beyond others. And they trust their primary care physicians, but mostly they trust their subspecialty physicians. So that was one. This was before we even knew a lot of information. The other thing that we did, we actually did a very quick pragmatic pilot. This was, I guess, oh my goodness. This would have been over the summer where a medical student, his name is Peter Liu, he presented an oral at this meeting. We just did a very pragmatic study where we called 100 liver and kidney transplant recipients. And we said, we had a list of who didn't get the vaccine. And that list was about 50% accurate because the EHR is not able to capture outside vaccines that well. But once we got a hold of 100 people who were liver and kidney transplant recipients who were not vaccinated, about 20 to 30% of them were willing and subsequently were vaccinated. We actually had higher success for whatever reason with liver rather than kidney recipients. We had higher success with patients who were black and Hispanic than white. And actually what we've seen nationally, this is kind of paralleled what's happening. It's become now less about access and more about beliefs, kind of in the later phases as we're vaccinating more and more people. So I don't know that I believe in mandates. I do think we as trusted clinicians can make a difference. But I think as we're getting later and later in this whole process, it's hard to move people's beliefs. But we did try techniques like motivational interviewing rather than saying everybody should get the vaccine, the vaccine is safe and being judgmental. We would say, well, what are your concerns? Can we address your concerns? And can we also give you examples of the way that it could work? And could we also schedule the vaccine for you right then and there? And so we were able to get 20 to 30% based on the population, but it still had a pretty good effect and it was pretty feasible and easy to implement in clinical practice. I think with the interest, I think there, Dr. Shulsky, there's a lot of questions about post-COVID cholangiopathy and the questions include the treatment. When do you refer these patients for liver transplantation and is anything else that you need to do for the management of these patients? Thanks, Bilal. I saw that there was a question about particularly about ursodiol. And again, none of these things are evidence-based, but I think we should do as we do for our other patients with secondary cholangitis and especially those that have potential super infection and use those same measures. So I think ursodiol is a very reasonable attempt at trying to keep those patients from having more stasis and more rapid progression. I have seen more so in my own personal experience, the acceleration of disease in patients by the cholangiopathy in people who already had advanced disease. We've seen that in one patient with NASH and another with Wilson disease that pushed them from probably compensated into the decompensated state towards transplant. And in those patients, they behaved like all other patients did. And once they entered the compensated phase, it was very clear that the direction was not for medical management. Of the series that was recorded in New York, I think it was just very early on. So of their six patients, there was one that went to transplant, five others they were observing. And it would be interesting to know what their later progressive course is. I kind of view these patients probably in that same mode as stuck as many of our patients with BCD cholangiopathy. And they're probably gonna be chronic and caught up in potentially some of them with symptomatic disease, especially if their bile acid levels rise. And that leads to the second possibility of treatment of thinking of things like polystyrene or other bile acid binding agents for those who do have colitis. Otherwise, I don't think that impacts on the progression of disease. There was one other question about whether there's an autoimmune component to that. And I certainly think, certainly with injury, you can uncover cryptogangogens and perhaps generate the development of an autoimmune cholangiopathy, but I am unaware of IgG4 or other changes in these individuals as yet. Maybe either you or Bob, or someone else can comment on that if they've seen it. Yeah, I have- Do you recommend biopsies in these patients, Bob? Are they drug-induced? Sorry. Well, I was just gonna say the MRCP is very helpful in these individuals, but I'll leave it next to Bob if he wants the biopsy as well. Yeah, no, that's a good question. So we've only seen, I think, one or two total patients here with this cholangiopathy, which I agree with Mike, a non-invasive approach with an MRCP would be the way to go. But if you will, extrapolating from other drugs that can cause a secondary sclerosing cholangitis, which is rare, but we've seen them in the Dillon Network. We published on that. I would certainly be hesitant to use any kind of immunosuppressant without a biopsy showing active inflammation, because my sense is that the histopathology here, Mike, is that they're going into sort of a progressive intrahepatic duct loss, as well as extrahepatic duct disease. And we know that immunosuppressants in general, like steroids, do not work well for run-of-the-mill PSC. So I'd be very reluctant without a biopsy to consider any kind of treatment beyond ERSA or cholestyramine for this entity. I think the good news is that it is so rare, and perhaps, and maybe Emily, you could comment on this, that I think we're doing better overall with real COVID infection in terms of the medical management. And perhaps are we seeing less of the sort of serious long-term sequelae, do you think? Or it's too early to tell? I think there's some data that suggests people who are vaccinated have fewer long-term sequelae. Okay. So that, definitely. But I think that early intervention, and now probably one of the most effective tools for early intervention in immunosuppressed or people with comorbidities like liver disease would be the use of monoclonal antibody within a couple of days of actual onset of illness. I think some centers are very challenged with delivering that because as the rates of COVID have risen, there's a lot of competition for the doses that are available in the space in which to give it. But monoclonal antibodies have made a difference. We are looking in the near future at the availability of antivirals. And while we still have a lot to learn about how these are going to be provided and who's gonna be the right candidate for it, I think that will help too. So I suspect we will see fewer of the longer term complications as we continue to improve in terms of our management strategies. And Emily, can I also ask you, we were talking earlier about the utility of monoclonal infusion for a vaccine poor responder to provide them six to nine months of coverage. I was very impressed with, I think it was a press release from Regeneron suggesting that they could prevent infection for nine months with a single dose. Do you wanna comment on that? Yeah, and in fact, there is an authorization for prevention after you've been exposed. So there's an emergency use authorization for post-exposure prophylaxis. Regeneron's currently sponsoring a clinical trial looking specifically at prophylactic strategies in these immune suppressed people, particularly the emphasis will be on people who'd never developed antibodies. So it'll be not just patients with transplants or liver disease, but people, a lot of people with cancer chemotherapy, other immunosuppressive conditions, which have really been largely impacting on their ability to develop antibodies. So B cell depletion, things of that sort. And I think the jury's still out how best to do this, but I think that there's no question that monoclonal antibodies may be part of the tools we can employ down the road for actually prevention of disease in certain at-risk people who will not be good vaccine candidates. So yeah, more to come on that. It's been really impressive how quickly we're gathering information and learning how best to help our patients along and how far we've moved away from some of these unproven therapies into a world where we actually have some proven therapies that can be beneficial. Maybe to Mike and Bilal, and then maybe Emily can correct us, but if you have a COVID positive liver patient who's wait-listed, and Mike said, look at the cycle threshold. And so you say, all right, I'll wait three or four weeks. They quarantine at home, they wait. Is there any value of repeating a PCR at three or four weeks? You know, if it's negative, I guess you feel better. If it's still positive, do you kind of tell your program, hey, that patient's fine, just go ahead. What's the thinking on that from a clinic? I think that's exactly where you ask them when you order it to get the cycle threshold, because if they're viral particles that may not be infected, still present, you're going to pick it up because of the sensitivity of the PCR assay. And so part of the problem is when people, they just get the test and they may not ask their laboratory to do the right test, in which case your colleagues can interpret that properly. I think I agree with Mike. I have, I think there's a question just came out from the audience and I think Dr. Blumberg or anyone can answer about, I would say that what would be the timing post-transplant that they were recommending the vaccine? And similar to that, the patient already received the first shot of either Pfizer or Moderna, how long to wait for the second shot post-transplantation? Okay, I'm happy to address those. I do want to say one thing about cycle threshold. I agree that we're all really starting to rely on this to try to help us stage the level of illness that may be going on. But remember cycle thresholds are a lot about the vaccine, about the platform being used and how this collection is done. And so if you're not consistent with getting your samples, you may have cycle thresholds that are not really that helpful to stage where you are. So I think what Mike said was completely true about understanding what the numbers mean and how amplification cycles are sort of helping you understand how much is there. But remember if you just sort of gently swap the nose once, you're gonna have a cycle threshold that's gonna look better than you might expect. That's a great point. And also where not to keep mixing and matching laboratories because the platforms may change quite a bit. Yeah, I totally agree with that. In terms of vaccination, nobody knows when is the right time. You certainly would like to ideally vaccinate people when their immune suppression has declined to a point that you think will allow them to respond. But the problem is we're in the middle of a pandemic. And so we have said that you can vaccinate as early as one month post-transplant. And if you had your first dose of vaccine that you can redo the second dose as early as a month post-transplant. Now, I think we're starting to look at vaccination and this actually is sort of evolving over time but in the immunosuppressed host, especially in the transplant patient that it's not a two dose series anymore. Probably the original vaccine series in adults and this is actually not been defined for children less than 12. So I'm gonna just say that this is for the older ages is that the vaccine series is actually three doses. And so once they're transplanted and probably a lot of immunosuppressed liver patients pre-transplant, you really need to be thinking about giving them a third dose as the primary series. So when we vaccinate them, we wanna, if we gave one dose pre-transplant or we're just starting it after transplant you'll do the standard two dose series for mRNA but then remember to be following that up with the third dose, which is your primary series. That's not actually their booster. That's part of their original vaccine series. And hopefully we'll learn more about what to do with the kids less than 12. And I don't know, Jamie, if you're sort of grappling with that now what do you do with a young child? I'm not sure that we have adequate guidance. Yeah, I think we go with the fact that there's no EUA for that just yet. So it's a little bit out of our hands but those decisions are surely coming for sure. So we are getting to the time. So thank you again for joining us today in this lively discussion. I want to thank all the presenters again for participating this year and for the incredible presentations. Before we conclude, I want to share a few additional notes. If we did not get a chance to answer every questions today the digital meeting, the liver meeting offers a unique opportunity to connect with presenters through the platform. You can navigate to the engage and play tab on the platform and select networking. Here you can search for a presenter by name. You may add them to the list of connections or request to schedule a meeting. If you did not have a chance to view the presentations or miss some of this live question and answer session all the content will be available on the digital meeting on demand until February, 2022. We hope you enjoyed the session and rest of the liver meeting digital experience. Thank you everyone.

COVID-19

hepatology

Delta variant

vaccination

hepatic outcomes

clinical practice

monitoring systems

booster doses

telehealth services

liver transplantation

mental health

burnout

alcohol-associated liver disease