My name is Bob Fontana from the University of Michigan, and on behalf of my co-moderator David Thomas from Johns Hopkins, we'd like to welcome all of you to this special symposium entitled COVID-19 in the liver. Needless to say, COVID-19 has had a profound impact on all of us in so many ways in everything that we do. From the impact on our clinical practices to the research that we're trying to continue to perform, as well as the patients that we're having to learn to care for. With all this in mind, the ASLD Governing Board commissioned a COVID-19 task force in March, and part of this was to develop outreach programs such as this. Therefore, we had the opportunity to pull together some of the leading speakers in the world on this rapidly evolving topic. Over the next 90 minutes, from 2 to 3.30 p.m., we will then cover for you the latest on diagnosis, treatment, and outcomes with COVID-19. To do this, we've assembled a really star-studded cast of speakers. Our first speaker really requires no introduction, and it is Dr. Anthony Fauci from the NIAID, who will be giving the overview talk on COVID and where we are at with vaccines, both in terms of efficacy and safety. Following that, we have Dr. Elizabeth Verna from Columbia University in New York City, who will give us an overview on the hepatic manifestations of COVID and what they mean. Following that, we have Dr. Mark Sulkowski from Johns Hopkins University, who will give us an overview on the current approach to treatment of the hospitalized patient with COVID-19 and the potential hepatotoxicity of various agents used. After that, we will have a combination talk between Dr. John Ward from the Global Health Alliance and Dr. Jungmi Ki from South Korea, who will give us the important information that I think we know the least about as hepatologists, which is the importance of non-medical or public health interventions in controlling the disease and containing it. Dr. Ji has particularly interesting perspective working at the NIH in South Korea and some of the successes that they've been able to achieve there through social distancing, contact tracing, and close epidemiologic follow-up. And then lastly, we have Dr. John Brothers from the University of Michigan, who will be highlighting the importance of health disparities in COVID-19 susceptibility as well as outcomes. Throughout the program, you can submit questions through the chat box and those will be addressed either live by one of the moderators or collectively together in a written response that will come after the conclusion of the meeting. In addition, we anticipate there will be a lot of questions and further dialogue that participants will want to engage in. Therefore, we have a series of three breakout sessions after the program is completed. One session will involve the panelists and speakers from today to go over various topics. Another session will involve our European colleagues from EASL with particular European perspective. And a third breakout session will be from our colleagues in Latin America and the issues that may be arising with COVID-19 in Latin America. So needless to say, I think we've got quite a great program for you here in the next 90 minutes. And without further ado, let me turn it over to Dr. Fauci. Greetings. My name is Tony Fauci and it is my great pleasure to speak to the American Association for the Study of Liver Diseases about COVID-19. I also thank you for all your good work, especially during these difficult times. As you can see from this first slide, I'm going to be discussing the public health as well as the scientific challenges associated with the historic COVID-19 pandemic. This slide shows the cover of JAMA from a viewpoint that my colleagues and I published in January of this year. And as you can see from the title, it says coronavirus infections more than just the common cold. I did not choose that to in any way be facetious, but I wanted to point out to the readers of the viewpoint, the fact that we have had experience with coronaviruses now for decades and decades. In fact, if you look at this phylogenetic tree of the coronaviruses, the human coronaviruses are indicated in red letters. There are bat and other intermediate hosts in which coronaviruses are important in that these animals are a very critical reservoir for these viruses. But pointing out on the slide, the four coronaviruses that are highlighted in yellow are the common cold coronaviruses that together account for about 15 to 30 percent of all of the common colds that we repetitively experience, usually throughout the winter months. And then in 2002, we had the first experience with a pandemic coronavirus with SARS. And then in 2012, we had the experience with MERS, another coronavirus. If you take a look at these two, the SARS coronavirus emerged from China in the Guangdong province from a bat to a civet cat to a human, leading to a global outbreak of 8,000 cases and almost 800 deaths. Although it transmitted readily from human to human, it did not have a high degree of efficiency. And so public health measures, including quarantine and contact tracing, essentially extinguished the outbreak without any other intervention. The Middle East Respiratory Syndrome, or MERS, began in 2012, again from a bat to a camel to a human. It had an outbreak that was mostly confined to the Middle East, but did have some global spread. And in fact, it is still occasionally re-emerging, usually in Saudi Arabia and other Middle East countries. Fast forward to today, we have now the third pandemic coronavirus, which appeared clinically in China in the Wuhan district in December of 2019 and was identified as a novel coronavirus by the Chinese in the first week of January of 2020. And getting back to the phylogenetic tree, you can see where it stands relative to the other viruses. Note that since it's phylogenetically proximal to the original SARS, the original SARS was given the name SARS-CoV-1 and the new virus SARS-CoV-2. And so for terminology's sake, the disease is COVID-19, which stands for coronavirus disease 2019 because of the December 2019 recognition. And as I mentioned a moment ago, the virus itself is referred to as SARS-CoV-2. So here we are now with a global pandemic of historic proportions, the likes of which we have not seen in the last 102 years since the now iconic outbreak of the pandemic of 1918. Currently, there are close to 50 million cases with 1.2 million deaths worldwide. In the United States, we have been hit the hardest of any other country with close to 10 million cases and over 230 million deaths. The heat map here showing the relative density of cases per 100,000 population. I want to take a moment to compare the response and the dynamics in the United States versus Europe. As shown here, the blue line where the European Union got hit earlier and peaked a little bit earlier than we did, but after the initial assault came back down to a very low baseline, where we in the United States, where our first big outbreak was dominated by the Northeastern corridor, particularly the metropolitan area of New York City, which went up to a high level, but never ever came down to a low baseline, even as New York sharply came down. Because at that point, other areas of our large country were beginning to have cases. Note that around June 19th, we had the beginning of a resurgence of cases due to the attempts to so-called reopen the economy or reopen the country, which was done variably with regard to adhering to the guidelines which came out. Different states did it differently and we had a resurgence back up to close to 70,000, went back down, stayed around 40,000 for a while, and now is going up to 86,000 with a mean, I say, an average of weekly somewhere around 80,000. Unfortunately, on November the 4th, we hit 100,000 cases in a single day. The European Union, as you see in the blue line, is doing really rather poorly also with the resurgence of cases, mostly related to the cooler weather of the fall and coming winter, driving people indoors with activities that would otherwise be done outdoors. Now, why the difference? If you go back to this slide, why did we in the United States not go back down to a low baseline after our initial peak? If you look at the degree to which we actually shut down or locked down, there was significant difference between the European Union and the United States. When you do GPSs to look at mobility over time in parks and outdoor spaces, note the United States does not go down nearly as much as Italy and Spain, which are representative of the European Union. When you look at going to workplaces, the same thing. The United States in the dark line does not go down nearly as much as Spain and Italy, and even more emphatically, when you look at visits to grocery and pharmacy stores, again the United States does not go down nearly as much as those other countries. That's the epidemiology. Let's take a quick look at the virology. As I mentioned, this is a beta coronavirus. It's an RNA virus. It has a large genome, multiple structural proteins, the most important of which is the S protein, which stands for the spike protein, giving its appearance of a corona or a crown when you look at it under electron microscopy. The receptor binding domain of this spike binds to the ACE2 cellular receptor, which is distributed widely in the upper and lower airways, as well as the GI tract, as well as other systems of the body, such as the neurological system and the cardiovascular system. Transmission. Clearly, this is a respiratory-borne virus, and transmission is through exposure to respiratory droplets, the standard larger droplets that we know of that tend to fall within a few feet of being expelled from the infected person, but we're also realizing now that there is some degree, we don't know exactly what percentage, but some degree of aerosol spread, aerosol meaning smaller droplets that have the capability of remaining suspended in the air for longer periods of time and over various distances. The virus is found in other bodily fluids, stool, blood, semen, etc. Its role in transmission is not known, but likely not of considerable importance. The fundamentals to preventing the acquisition and the transmission of SARS-Coronavirus-2 are fivefold. One is the universal wearing of masks or cloth coverings. The other is maintaining physical distances, at least six feet, to avoid crowds in congregate settings, particularly indoor situations. Conduct activities outdoors much more preferentially than indoors, and frequently washing hands. If those five public health measures were adhered to universally and consistently over the country, it is clear from our previous experience with other nations and even regions in our own country, we would not be having the degree of surging of cases that we are currently seeing. The clinical manifestations are protean. If you look at the initial signs and symptoms, they resemble very much what we see in a typical flu-like syndrome, as shown by the indications on this slide. There is, however, a peculiar loss of smell and taste, which precedes the onset of respiratory symptoms in certain individuals. Individuals, about 80%, have mild to moderate symptoms, whereas about 15 to 20% have severe symptoms. It should also be pointed out that a considerable proportion, up to 40%, have no symptoms at all. The case fatality rate varies from a few percent under certain circumstances to about 20 to 25% in people who, in fact, require mechanical ventilation. People who are at increased risk for severe COVID disease include older individuals and people of any age with certain underlying conditions. If you look at the data related to age, it's striking. The parameter used here is the rate of hospitalizations per 100,000 populations, and take a look at the extraordinary disparity between hospitalizations in younger individuals on the left-hand part of the slide compared to the elderly between 75 and 85 plus on the right-hand part of the slide. In addition to the elderly, people literally of any age with certain underlying medical conditions. Under these conditions, there's an increased risk that's clearly associated with COVID illness, severe COVID illness. In other words, those individuals who would fall in the category that I showed you on the prior slide of having severe or critical illness. Paramount among this is obesity and chronic obstructive pulmonary disease, as well as other conditions such as chronic heart conditions and hypertension. Those conditions that may confer an increased risk for severe disease are shown here. Again, I point out a few that dominate. One is hypertension, and the other is overweight, not quite getting to the definition of obesity, but overweight being an important one. If you look at the manifestations of severe COVID-19, they are plentiful. I mentioned the cardiac ones, but there are also acute respiratory distress syndrome. There is kidney injury, neurological injury, a hypercoagulable state manifested by microthrombi in small vessels, and acute thrombotic phenomenon sometimes seen in otherwise well young individuals. There's also a curious multisystem inflammatory syndrome first described in children resembling Kawasaki syndrome. In addition, there is what we called a post-COVID-19 syndrome, which in variable percentages, and we're working out right now what percentage that is, of people who have symptomatic disease, be it symptoms that don't necessarily require hospitalization or symptoms that actually drive people to requiring hospitalizations. When they recover virologically, a certain percentage, sometimes as high as one-third, experience lingering symptoms for weeks to months, including profound fatigue, shortness of breath, muscle aches, occasional fever, dysautonomia, and what some describe as brain fog or inability to concentrate. Moving on to racial and ethnic disparities, this is really quite serious. In the United States, we are seeing a rather profound disparity, not only in the incidence of infections due to the jobs that people of a minority demographic group, namely African-American and Latinx have, that put them out in the community exposed to infection, but also an increased incidence of the comorbidities, which in fact allow for more severe COVID-19 disease. This is a striking slide. If you look at, again, the parameter of the rate of hospitalization per 100,000 population, look at the three top bars with Latinx, American Indian, Alaska Natives, and African-Americans going from 390 to 408 compared to white non-Hispanics at 94. Moving on to therapeutics, the NIH has established an expert treatment guidelines panel, which puts forth a living document online that is frequently updated in real time, providing for the medical community, the latest clinical data, both published as well as expert opinion to help and assist the clinicians dealing with this disease to use the most updated data in the care of their patients. This is easily accessible on covid19treatmentguidelines.nih.gov. That's covid19treatmentguidelines.nih.gov. If you don't remember that, just put NIH.gov and you could find it in the search instrument. Now, with regard to the therapeutics, there have been two that have been now recommended by the guidelines panel, remdesivir for hospitalized individuals who have lung involvement and dexamethasone for hospitalized individuals who have ventilatory requirements and or high flow oxygen requirements. In that study, which is a randomized controlled trial, placebo controlled, it was a clear-cut benefit in diminishing the 28-day mortality in the dexamethasone group. In addition, there are examples of other investigational therapies, direct antivirals, blood-derived products such as convalescent plasma, hyperimmune globulin, monoclonal antibody studies are being very actively pursued now, as well as immunomodulators. And finally, let's move on to vaccine. We at the NIH and in the federal government have adopted a strategic approach to covid19 vaccine research and development as articulated in this piece in science from May of this year. By a strategic approach, we mean harmonized protocols in which the six companies that are involved in operation warp speed that is being helped by, developed by, and supported by the federal government. When these six companies now adopt a common data and safety monitoring board, common primary and secondary endpoints, and common immunological parameters that would allow us to bridge one study to another. This is a list of the three separate platforms and the companies involved. As you can see, we have a nucleic acid platform, predominantly messenger RNA from both Pfizer and Moderna, viral vectors from AstraZeneca, Janssen, and Merck, including adenovirus vectors and VSV, and protein subunits together with an adjuvant from Novavax and Sanofi. We have six of these going, three of which are in phase three trial, two of which, Moderna and Pfizer, began in July 27th. Both of those are fully enrolled and as we have seen from the very exciting news just recently, Pfizer, when their data and safety monitoring board looked at the data in their 44,000 people in that clinical trial using a messenger RNA, showed a more than 90% efficacy. This is a very important advance. Moderna company is very close behind soon to be able to look at their data to determine if they have the same sort of results, and the other companies are also not far behind. We now look at this with cautious optimism that by the end of this calendar year and well into 2021, we will be administering doses first to the highest priority and then ultimately to virtually everybody in the United States as we get into several months into 2021. I'd like to close by putting this slide up. It is the Prevention Network to COVID-19. As you can see, you can access this online at www.preventcovid.org. That's www.preventcovid.org. For those who have any interest in enrolling in the still ongoing clinical prevention trials, please take a look at this. No obligation. You can just indicate your interest in participating. Thank you. Good afternoon, and thank you for this opportunity to present an update on hepatic manifestations of COVID-19. My name is Elizabeth Verna, and I'm from Columbia University in New York. Here are my disclosures. Since the very first published descriptions of the clinical manifestations of COVID-19 from China, there have been reports of liver enzyme elevation as a common phenomenon. The literature on this association between COVID-19 and elevated liver tests is now extensive, including several meta-analyses and systematic reviews. While the proportion of patients with evidence of liver injury varies by geographic location, the definition of the upper limit of normal, the disease severity in the cohort, and the timing of the liver enzyme measurement in the disease course, overall, elevation in liver tests have been reported in 14 to 53% of inpatients with COVID-19. And general themes that have emerged include that AST is the most commonly elevated value. In this particular meta-analysis, largely of reports from China, elevated AST was found to have a pooled prevalence of 21%. This is followed by ALT, here with a pooled prevalence of 18%, and then followed by elevations in bilirubin or alkaline phosphatase, which are less common. In data from our own center, when comparing the first about 2,200 patients with confirmed COVID-19 to 1,100 patients who were tested negative for COVID-19, but hospitalized in the same period as a control group, the overall initial and peak AST and ALT were elevated among patients with COVID-19 compared to controls, but these elevations were generally mild, with the peak ALT over the upper limit of normal in 45%, but over five times the upper limit of normal in only 6%. It is also important when reviewing this literature to consider the trajectory of the COVID-19 disease course. Liver enzyme elevation may not be present at initial presentation and may be a later manifestation of the disease following progressive pulmonary and kidney manifestations. And each individual assay in the liver function panel may have a different trajectory, with ALT perhaps being the most reflective of the clinical association between the virus and liver injury. Predictors of liver injury have been evaluated in many cohorts with variable results overall. In our cohort, there was not a clear association between liver enzyme elevation defined by ALT over five times the upper limit of normal and some of the traditional risk factors for severe COVID-19, including advanced age and elevated BMI. Rather, there was a clear association with other inflammatory markers, including IL-6 and ferritin, even controlling for these traditional risk factors, perhaps implicating at least in part the host immune response in the pathogenesis of elevated ALT in this case. While liver enzyme elevation is generally mild and does not require specific intervention, it may be an important prognostic marker, even at lower levels of elevation. While the literature on this has not universally demonstrated an association between elevated liver enzymes and disease severity or death, meta-analyses such as this one have shown a significant association between AST and ALT elevation and critical illness related to COVID-19. Again, in our own data, we did find that peak ALT was highly predictive of death or discharge to hospice, controlling for advanced age, comorbidities that have been associated with COVID-19, and importantly, controlling for markers of critical illness, including the need for intubation or renal replacement therapy. So what is causing this liver enzyme elevation? It is likely multifactorial in many cases. Certainly underlying liver disease may play a role in a certain portion of our patients. For those that require ICU-level care, sepsis, ischemia, and congestion are important considerations. Non-hepatic sources are also important to consider, in particular when AST is elevated out of proportion to the other markers. Drug-induced liver injury is probably quite common, and importantly, both the host immune response and also direct virally-mediated liver injury are also likely playing a role. It is now known that the ACE2 receptor is expressed in the liver itself, and this has been shown in a number of different studies with different methodologies, including here single-cell expression of the ACE2 receptor. Probably cholangiocytes have the highest level of expression, but there is also documented expression in hepatocytes themselves. And there is now a growing literature on the histological changes that are seen in these patients, predominantly from post-mortem studies. And these findings do include findings typical of a virally-mediated process. So in the first 40 autopsies reviewed at our center for patients that died of COVID-19, about half of patients had lobular necroinflammation and or portal interface hepatitis. In addition, we also found high rates of steatosis has been reported by other groups as well, with 75% of patients overall having steatosis, many without traditional risk factors for this, and about 30% with moderate or severe steatosis. We also found interesting vascular findings, including plebris sclerosis, endothelial injury, and sinusoidal thrombosis, as well as thrombotic bodies that are thought to be aggregations of platelets. Finally, we looked for the virus in these tissues. Among 20 specimens that were interrogated with PCR testing for the virus itself, 55% were positive, though with a wide range of copy numbers detected. Interestingly, although the numbers are small, there was no correlation between a positive PCR in the liver tissue and the time from diagnosis to death or any of the individual lab test results, although those with a positive PCR had a trend towards higher AST and ALT. Other investigators have reported similar findings on postmortem exams. This group, for example, looked with EM and other techniques to find what they believe is ultra-structural and histological evidence of typical viral infection and perhaps even the COVID virus itself. An additional important consideration is a high likelihood of drug-induced liver injury in many patients with COVID-19, especially those who are hospitalized. And this may be due to many different classes of drugs that are commonly used in these patients, including acetaminophen, antivirals, antibiotics, immunomodulators, and corticosteroids. You'll hear more about antiviral treatment in the upcoming lecture, but in particular, due to reports of hepatotoxicity, the current emergency use authorization for remdesivir recommends against its use in patients with AST or ALT above five times the upper limit of normal, which clearly means that we don't have all the therapeutic options we would like in this cohort of patients that may be at risk for severe disease. So what do we do as hepatologists when consulted on these patients? Luckily, as liver enzyme abnormalities are often mild and resolve on their own, really minimal initial workup is currently recommended, including testing for viral hepatitis, such as hepatitis A, B, and C. Additional workup, including imaging and other studies, is probably most likely reserved for patients with progressive or severe liver enzyme elevation or in patients with more of a cholestatic pattern, which would be less typical of COVID-19-related liver injury. So what about patients with chronic liver disease and liver transplant recipients? Overall, there does not appear to be an overrepresentation of chronic liver disease in the largest cohorts reported so far of patients with COVID-19. In this recent Nature paper with over 17 million adults and over 10,000 COVID-19-related deaths, patients with chronic liver disease made up less than 1% of the cohort. Other large cohorts have reported 1 to 11% with chronic liver disease overall. And while this may be underreported, it does not appear that patients with chronic liver disease are overrepresented. However, it is possible that chronic liver disease does increase the risk of severe outcomes, including hospitalization and death. And you can see here again in this very large cohort that chronic liver disease was associated with a hazard ratio of 1.75 for death. Other reports have found similar findings. This is one of the initial papers to look at chronic liver disease, where they looked at almost 3,000 patients with COVID-19 across multiple healthcare systems and found that in a propensity-matched analysis that patients with chronic liver disease of all etiologies had an increased risk of hospitalization and mortality. Other studies, including multicenter cohorts and also large single-center studies, have not necessarily shown the same association between chronic liver disease and, in particular, non-sorotic chronic liver disease and adverse outcomes. And it is perhaps important to consider that not every type of chronic liver disease is going to have the same associated risk of outcomes. In particular, metabolic-associated fatty liver disease or non-alcoholic-associated fatty liver disease is emerging as a possible risk factor for severe outcomes. Clearly, this disease is associated with other diseases that are associated with poor outcomes, including diabetes, hypertension, obesity, and cardiovascular disease. And when we look at non-alcoholic fatty liver disease in large cohorts, either with imaging evidence of steatosis or with nondirect markers, there has been variable reports of an association with severe outcomes. However, when these are grouped in meta-analyses, such as this one, it appears that there may be an increased risk for severe disease. But perhaps the patients at highest risk of adverse outcomes among those with COVID-19 are those with advanced liver disease, both with cirrhosis and also decompensated cirrhosis. In this large international registry study that was recently reported, compared to patients with chronic liver disease without cirrhosis, those with child's A cirrhosis and then B and C cirrhosis had a stepwise increase in the rates of major adverse outcomes, including death, with each liver disease stage. Interestingly, it appears that the cause of death in these patients was often associated with COVID-19 itself, meaning it was related to lung disease rather than liver-specific or liver-related outcomes. And when this group looked for predictors of death among this population, they found that advanced age, advanced liver disease, and in particular alcohol-related liver disease were the strongest predictors of death. Similar findings were also recently reported in a U.S. multi-center cohort with patients from 21 institutions. Almost 900 patients were included in this analysis. And again, they also found that alcohol-related liver disease, decompensated cirrhosis, and hepatocellular carcinoma were the strongest predictors of COVID-19-related death. And finally, I'm going to close with just a few slides about liver transplant and liver transplant recipients. Certainly, COVID-19 has impacted really all aspects of liver transplantation. And you can see here data from UNOS regarding the decline in transplant volumes that occurred at the peak of COVID-19 transmission in the spring. However, when we look at outcomes in liver transplant recipients, interestingly, it does not appear that liver transplant recipients are more likely to have severe outcomes or to die compared to non-transplant recipients. And this is, again, a report from the large international multi-center cohort where 151 patients, liver transplant recipients, were compared to 627 non-transplant controls. And this is a very large number. So, and they found that in propensity score-matched analysis where they adjusted for age, sex, kidney function, obesity, hypertension, diabetes, and ethnicity, that liver transplantation was not associated with an increased risk of death. And among liver transplant recipients, the strongest predictors of death included sort of traditional risk factors for poor outcomes in COVID-19, including age, serum creatinine, and non-liver cancer. Similar results were also recently reported from the COLD Consortium, a multi-center study in the United States of liver transplant recipients, where among 112 liver transplant recipients, 22% died. And the predictors of mortality that they found to be most significant included diabetes, but interestingly, also the occurrence of liver injury during the course of disease. And among these patients, risk factors for liver injury included advanced age, race, ethnicity, the presence of metabolic syndrome, the use of antibiotics and vasopressors. Again, getting at the idea that probably liver enzyme elevation in these patients is multifactorial, but importantly, liver injury in these patients was strongly associated with negative outcomes, including death. So to summarize, liver enzyme elevations are common among patients with COVID-19. Although they're often mild, they may limit our therapeutic options, and it is associated with disease severity and death. There's increasing evidence of a component of direct virally mediated liver injury in these patients, and certainly we still have more work to do to understand the pathophysiology of this process. Patients with chronic liver disease may be at increased risk of severe COVID-19. However, the greatest impact seems to be among patients with decompensated cirrhosis. And finally, liver transplant recipients do not seem to be at higher risk of mortality compared to non-transplant populations. However, the impact of the type and intensity of immunosuppression remains to be fully described. Thank you very much for your attention. Hello. I'd like to thank the organizers for the opportunity to present in this important session. My task today is to cover current therapies and hepatic issues. I'm Dr. Mark Solkowski, professor of medicine at the Johns Hopkins University School of Medicine. More recently, I've served as the director of the COVID-19 Clinical Research Center. My disclosures are outlined here. Before we get into specific treatments, I want to first look at what we think of as the natural history of SARS-CoV-2 infection. In general, we can think of this as an early stage. These are patients with a viral response. That is, the virus is taking hold and there's a multi-immune response. Many patients will recover. Some will progress to develop a pulmonary phase characterized by infiltrates as well as hypoxia, and in some patients, transaminitis. In a subset of these patients, there's a further progression to a hyper-inflammation phase. This is characterized by severe ARDS and elevated inflammatory markers such as IL-6 and ferritin. As we think about interventions, we think in broad terms as antivirals being more appropriate early in the course of the disease and host modifiers later in the course of disease. We'll come back to this framework. I've outlined my discussion of treatments following the NIH COVID-19 treatment guidelines. In this guideline, they have recommended therapies. There are some for which there is insufficient use to recommend for or against. There are some treatments for which there is a recommendation against the use, particularly outside of clinical trials. And finally, I want to touch on this area of non-hospitalized patients for which there are no specific antiviral or immunomodulatory therapies recommended. Now, I'm going to first look at the recommended use of dexamethasone and the now FDA-approved antiviral remdesivir. Let's start with dexamethasone. The study I want to emphasize is the RECOVERY trial. This study enrolled more than 11,500 patients at more than 176 hospitals in the UK. They randomized people to standard of care, no additional treatment, and then several interventions, which included lopinavir, ritonavir, dexamethasone, the study that will focus on 2,104 patients, hydroxychloroquine, or azithromycin. There was subsequent randomizations to tocilizumab and also an investigation of convalescent plasma, but here we'll talk about dexamethasone. The primary outcome was all-cause mortality within 28 days. The patient population was older at 67. Median days of symptoms were 8. You can see that 15% at the time of entry into recovery were on mechanical ventilation and 61% were receiving oxygen. The intervention was dexamethasone, 6 milligrams by mouth or IV for 10 days, plus usual care. And you can see that in patients receiving oxygen, and particularly those with invasive mechanical ventilation, there was a benefit with respect to 28-day mortality. In contrast, those with no oxygen requirement, there was no benefit of dexamethasone. This suggests it's better in people with more advanced disease. There was a subsequent meta-analysis published in JAMA from the WHO. This looked at seven randomized controlled trials of corticosteroids. These included dexamethasone, but also hydroxy cortisone and methylprednisolone. The bottom line that the summary odds ratio was 0.66, confirming a benefit of corticosteroids, particularly in patients with more advanced disease. Now let's turn to look at remdesivir. I don't have time to cover all the studies, but I want to emphasize the adaptive COVID-19 treatment trial, so-called ACT-1. In this study, hospitalized patients were randomized to remdesivir IV for 10 days versus placebo. The primary outcome was recovery time. And you can see in the table that remdesivir patients had a recovery time that was significantly faster than those on placebo, 10 versus 15 days. The study was not designed to look at mortality. There was a trend towards lower mortality with remdesivir, but this was not significant. If we then dig down in the types of patients that benefited from remdesivir, if we look at the baseline ordinal score, those receiving oxygen, the largest group, had the greatest benefit with a recovery rate ratio of 1.45. And those with more severe disease, those receiving high flow oxygen or mechanical ventilation or ECMO, appear to have little benefit. So if we think about where this may help, the antiviral remdesivir may be better in patients with earlier infection. Now there is another study that has not yet been published in a peer-reviewed journal, but I feel like I need to cover it here because of its potential impact. The WHO solidarity trial was similar to recovery in that it was a study done comparing usual care to a number of interventions. This study enrolled more than 11,260 adults in 30 different countries. They were all hospitalized with COVID-19. You can see that most were less than 70, the majority male. They received the intervention at day zero or one of hospitalization in most cases. They studied a no study intervention group, which was 4,088. They studied remdesivir in 2,750, as well as hydroxychloroquine, lopinavir, ritonavir, and interferon beta. I won't emphasize those here, but I do want to emphasize remdesivir. In both ventilated and non-ventilated patients, there was no significant benefit with respect to 2018 mortality, which was the primary endpoint of the study. I'll also point out that corticosteroids were used in about 47% of both control remdesivir, so no mortality benefit. This pre-print also included a meta-analysis of four randomized control trials where remdesivir is compared to a control group. And if we look at the bottom line, in more advanced disease patients, those with ventilation, there was no benefit. There was a trend towards mortality benefit in lower risk groups, those with no mechanical ventilation. So we wait for their analysis of this paper and its publication. Now, if we look at remdesivir and liver injury, the FDA-approved prescribing information indicates remdesivir is approved for adults and pediatric patients 12 or older. They do note that transaminase elevations were seen in healthy volunteers as well as patients. If we then look at safety of remdesivir versus control, I've selected a couple of studies. The ACT-1 study that I talked about and Spinner et al. that compared 10 or 5 days remdesivir to standard care. We can see that grade 3, 4 adverse events in SAEs were similar in the control versus remdesivir. If we look specifically at AST and ALT elevations, they were observed, but in general, they were lower or similar to the placebo patients. So we didn't get a strong signal of drug-induced liver injury in this patient population. So if we then look at the NIH COVID-19 treatment guidelines panel recommendations, we can see that they've broken these down as I talked about the natural history in disease severity. As I mentioned earlier, no specific recommended treatments for non-hospitalized patients. In particular, if the patient is not receiving a supplemental oxygen, they recommend against the use of dexamethasone. For those who are hospitalized requiring supplemental oxygen, there's a strong recommendation for remdesivir for five days or until hospital discharge or the use of remdesivir plus dexamethasone. As we move to the more advanced patients, hospitalized requiring high flow oxygen or non-invasive ventilation or invasive mechanical ventilation or ECMO, this group, the emphasis really is on administration of dexamethasone and the opportunity to give dexamethasone plus remdesivir with less certainty about that recommendation. So we do have recommended therapies for COVID-19. Now I'm going to turn to talk about the statements regarding convalescent plasma for which there is insufficient data to recommend for or against the use. Now I'm going to first focus on the expanded access program conducted through the Mayo Clinic. I've selected the seven-day adjusted mortality by time from diagnosis and antibody titer, about 3,000 patients. If we look at less than or equal to three days from diagnosis and high antibody titer, we can see lower evidence of mortality. In fact, when the FDA issued an emergency use authorization, they noted there were more than 85,000 patients treated in the Expanded Access Program. And they looked at a subgroup of patients less than 80, not intubated, and treated within three days of diagnosis. And here, the seven-day mortality for high titer plasma was 6.3, and for low titer plasma, 11.3, suggesting a significant impact. But I'll point out this was not a randomized controlled trial. I'll highlight one RCT done in India called PLACIT. In this study, 446 adults with moderate COVID-19 were randomized to standard care versus two units of plasma. They saw no difference in progression of disease or death. But it should be noted that only 67 patients received high titer plasma. So it's not entirely clear that we can adapt this to our use of plasma. So at this point, the NIH Guidelines panel says there's insufficient data and recommends RCTs. They do note, however, that plasma has been safe with rare serious adverse events. Let's move to a couple of treatments that are not recommended for use, certainly not outside of clinical trials. Now, there are a number of different studies, but in the interest of time, I'll highlight the recovery trial. This was the study done in the United Kingdom of more than 11,500 patients. If we look first at the left panel, this is hydroxychloroquine. In the recovery study, the 28-day mortality compared to standard care was similar for hydroxychloroquine versus usual care. The NIH panel says do not use hydroxychloroquine in hospitalized patients, a strong recommendation. Now, if we look at the right side of the panel, this is lopinavir or ritonavir. Again, no difference in 28-day mortality. And the NIH panel says don't use this anti-HIV regimen outside of clinical trials. But not significant data to support its use. Now, there are several other therapies that fall in this category of not currently recommended outside of clinical trials. The most prominent is perhaps IL-6 or interleukin-6 inhibitors. I'm going to emphasize tocilizumab, but there are other agents that have been studied. There have been cohort studies of tocilizumab, the largest by Gupta et al., published in JAMA Internal Medicine. Here, there was the suggestion of less death than those who received tocilizumab. If we then look at RCTs, I've listed a number of randomized controlled trials, some published, and the phase 3 trials not yet published at the time of this presentation. In general, we don't see a difference in progression to death with tocilizumab. One study, the IMPACTUS study, suggested less progression of mechanical ventilation. We await publication of that. If we then look at interferons, I'm going to emphasize interferon beta-1a. This has been looked at in a couple of studies. The WHO Solidarity trial that I mentioned earlier had more than 2,000 patients randomized to receive interferon beta. And suffice to say, without getting into the details, it was not associated with decreased mortality in hospitalized patients. I'll go on to say that in the ACT-III study, remdesivir with placebo or interferon beta-1a is being evaluated in a randomized controlled trial. We await the outcome of the ACT-III study. I'll also point out that JNS-associated kinase inhibitors are being studied, potentially to blunt the immune response. ACT-II looked at remdesivir plus placebo or baricitinib. And in this preliminary report, not yet published, there was a reduction in time to hospitalization and fewer deaths numerically observed. We'll await the publication of these data. But some suggestion that baricitinib as a JAK inhibitor may be beneficial. Now, I'm finally going to talk about the non-hospitalized patients. I think it's critically important that we develop treatments that can be used to prevent and treat people with early infection. So I'm going to talk about the publication of a neutralizing monoclonal antibody, which targets the spike protein receptor binding domain. Now, this was the BLASE-1 trial of banlanivimab. This is a interim analysis of a randomized double-blind placebo-controlled study. The study enrolled outpatients. Most had mild, but some had moderate disease. These patients were randomized to a single IV infusion. It was dosed at a median four days of symptoms. I'll highlight the safety that there were no serious adverse events. The table highlights the primary outcome. There was no difference in the change in SARS-CoV-2 viral load at day 11. But if we look at day 3 and the pooled analysis of three doses of the monoclonal antibody, there was a reduction of about 0.5 log when using the monoclonal antibody. The outcome that's gotten a lot of attention is the secondary outcome of hospitalization or emergency department visit by day 29. It was lower in those who received the monoclonal antibody, 1.6 versus slightly over 6% placebo. I'll point out that this monoclonal is being studied as prevention in long-term care facilities. And there is the notation that among hospitalized patients, more advanced disease, the ACTIV-3 study was stopped because of no clinical benefit. Now, there are several other investigational antivirals for non-hospitalized patients. The monoclonal antibodies are also being looked at from a couple of different companies. There is the Regeneron monoclonal antibodies, which is a combination of two that target the spike protein. We do not yet have a publication. But there has been two press releases, totaling nearly 800 patients. There is a report of a suggestion of benefit, both antiviral benefit and clinical benefit, particularly among those with high viral loads and no detectable antibodies. We await the publication of these important studies. I'll mention peganinferon lambda, which was studied for hep C, hep B, and now for hepatitis D. There was a study from Toronto in which those who received a single injection of peganinferon lambda had more rapid clearance. But it was limited to those with a high viral load. And lastly, I'll talk about a nucleoside analog called molnupiravir. This is being developed as an investigational agent. Its mechanism of action is thought to be a mutagenesis. It increases the viral mutation rate. It's an oral drug administered twice daily. And it's being investigated in multiple RCTs of both outpatients and early hospitalized patients. So we await data regarding these treatments. So my key takeaways, randomized controlled trials are essential to identify evidence-based treatments. The NIH Guidelines Panel has used evidence to recommend for the use of dexamethasone and remdesivir in specific patient populations. They've also used evidence to recommend against the use of hydroxychloroquine and lopinavirotonavir. And we clearly need more data. Fortunately, there are now a number of investigational agents being studied in robust clinical trials and research networks. And finally, I'll comment that drug-induced liver injury must always be considered, particularly in patients with advanced COVID-19. Thank you. Good day, everyone. I'm Dr. John Ward, Director of the Coalition for Global Hepatitis Elimination at the Task Force for Global Health and also with the Rollins School of Public Health at Emory University. I've been asked to give you a brief overview of the non-pharmacologic interventions that prevent transmission of SARS-CoV-2 infection, the cause of COVID-19. I'll be reviewing with you some of the viral characteristics that have a role in transmission, the transmission of this virus by fomites, aerosols, and droplets, some of the circumstances that increase the risk of transmission, the recommended prevention interventions and their effectiveness. Regarding fomite transmission or the contamination by contact with an object that's been contaminated with the virus and then the transmission of that via manual contact with mucosal membranes. It's been shown that the virus can apparently survive on a variety of different types of surfaces, but the length of that survivability varies by the type of surface as shown here. And then there has been studies to look to see if you can find evidence of viral contamination on various objects that are in close proximity to people with COVID-19, showing that the closer that proximity is, the greater the likelihood of that contamination, not surprisingly. Again, on a variety of different objects, again, as shown on this slide. So this certainly makes fomite transmission plausible as a mode of transmission. Unfortunately, SARS-CoV-2 is readily deactivated by a variety of different means, by heat and by a variety of chemicals of which there's a long list provided by the EPA. It has been shown in household studies that households using these disinfectants have a lower risk of transmission. So therefore it certainly, again, increases the plausibility of fomite transmission, even though I've been unable to find a documented case of fomite transmission, suggesting that this is a minor route of transmission of SARS-CoV-2. And respiratory transmission is the major mode through two different channels, contact with respiratory droplets, which are fairly large in diameter, but typically fall to the surface within about six feet of the infected person. And then aerosol droplets, which are smaller in diameter and can remain in the air for a longer period of up to 16 hours in some studies. And then that concentration within the environment goes up the poor the ventilation is, as shown by the line graph to the right on this slide. So again, these droplets are released into the environment through talking, sneezing, coughing, the amplification of the voice increases the aerosolization of SARS-CoV-2. So that needs to be kept in mind as a risk factor. It's hard in epidemiologic studies to differentiate the relative attributable fraction of transmission from respiratory or aerosolized droplets, but the prevention measures are the same to reduce transmission through both of these channels. Some of the virology needs to be kept in mind when looking at risk of transmission. The viral load appears to be highest right before the onset of symptoms. And then rapidly declines in that first week of infection and then has a very long tail where you can find evidence of PCR positivity for longer than four weeks after the onset of symptoms. It's important to note that a large number of transmissions appear to occur before that individual becomes symptomatic. Regarding PCR positivity after the onset of symptoms, it doesn't align perfectly with infectiousness. And indeed, it looks like that infectiousness is very rare about eight days after the onset of symptoms. And that's the evidence supporting the recommendations from both WHO and the US CDC that persons who are symptomatic should self-quarantine for up to 10 days to get over that highly infectious period. Also in regard to the transmission dynamics of SARS-CoV-2, it appears that it has an RO of about two to three with two to three infections for every one infected person. But it has this model of over-dispersion where not every infected person has an equal likelihood of transmission. And indeed, in several studies of new studies, and indeed in several studies of which I've given you two examples on this slide, it appears that a minority of infected persons are responsible for the great majority of transmissions. And so you have this concept of super spreader events of which I've given you some examples of in the table that tend to occur in congregated settings that happen indoors, typically in poorly ventilated areas where people are brought together for a long period of time where there may be exposures because of singing or talking such as in sermons at religious ceremonies that increase the chances of aerosolization of the virus. And household settings look to be the highest risk setting because of that prolonged exposures in indoor settings with close contact that really set up opportunities for these super spreader events. And multiple studies have shown that outdoor settings are the lowest risk settings for transmission. Looking at the various non-pharmacologic interventions recommended to prevent transmission, this one meta-analysis shows that they're highly effective. Social distancing greatly decreases the risk of transmission and obviously the greater the distance, the better. Face masks similarly also have a large protective effect with larger, if it's an N95 mask, again, not surprisingly but also a cotton mask, surgical mask also show high levels of protection as to the addition of eye protection. It's also been looking at several natural studies. I found this to be an interesting study looking at a city in Germany that implemented compulsory wearing of mask in public about 20 days before it was adopted more broadly by other cities and then eventually nationally for the whole country. Then they were able to develop a comparative set of cities to evaluate versus this city that implemented the compulsory mask wearing first. And they showed that there was about a 60% decrease in the daily infection growth rate and about a 23% decrease in total COVID-19 cases over just a 20 day period really providing some effectiveness data regarding the benefits of broad adoption of mask wearing. So that really leads us to the recommendations from WHO and CDC. A good hygiene to reduce that risk of fomite transmission, social distancing of at least six feet to reduce that contact of respiratory droplets and aerosols. Mask wearing to reduce the likelihood that you might become infected and then expose others and decrease your risk of exposure to others. And then being alert for symptoms so that you can self quarantine during that period of time when you might be the most infectious. Of interesting at this point in time, we're doing an open survey of clinicians to look at the impact of the COVID-19 response on their practice. And this is from clinicians from the Americas, Europe and Africa, showing a broad adoption of a variety of strategies of patient screening, where asking patients to wear masks and then personal protective equipment for staff. So clinicians, at least in this convenience sample appear to be taking a variety of measures to reduce the risk of transmission. So in summary, fomites have a minor role in SARS-CoV-2 transmission. However, good hygiene makes sense and it can readily eliminate this risk. Respiratory, whether by droplets or aerosols is the major mode of transmission. And that risk of transmission can vary by the timing of exposure to that index case, the duration of that exposure and the setting, particularly in congregated indoor settings with poor ventilation. Multiple studies show that non-pharmacologic interventions dramatically reduce risk. So we should all be following the recommendations for non-pharmacologic interventions that are appropriate for our area. Thank you very much. First of all, I want to thank the organizers of this symposium and Dr. John Ward for inviting me to this symposium to share Korea's public health responses to COVID-19 outbreak. So what are the key factors of COVID-19 outbreak response in Korea? Basically, there was no lockdown and we only had minimum travel restrictions and voluntary social distancing from an early stage of the outbreak. This was possible because of emergency use authorization of the diagnostic kits in early February after the meeting with pharmaceutical companies on January 27, when we had only four cases in Korea. And all important actions were taken before WHO declared public health emergency on January 30th. And we had lessons learned from MERS outbreak in 2015. So government changed governance, testing and tracing system after this outbreak. And another important factor will be easy access to medical services for everyone. So everyone is covered by the health insurance and we also have a nationwide public health centers which played quite important role in the response. And also private hospitals, which represent about 95% of hospitals operate still within national health insurance. And we also have high hospital bed number and government provided free testing and treatment for both Korean and foreign nationals from the beginning of the outbreak. And also we have to emphasize strong whole of government and society approach, including public private partnership and transparency in risk communications with public and media, which led to full community engagement. And we kept the society open through so-called four T's and test, trace, treat and transparency. Government prioritized early detection through preemptive diagnostic screening and rigorous epidemiological investigation. So in terms of testing government enhanced testing capacity by rapidly expanding testing labs, including public and private sectors by early February and turnaround time to receive the result with is always within 24 hours. Testing capacity can be easily scalable by involving private sectors. And positivity rate among tested is around 1% and WHO recommend less than 5%, which means epidemic outbreak is under control. And we also introduced the need-based free testing of asymptomatic people in Seoul. In terms of tracking, government introduced a smart tracking system and this system significantly reduced time for the epidemiological investigation. In terms of treatment, government designated the infectious disease hospitals for the patient and also community treatment centers for mild cases. And these centers are repurposed corporate and public training facilities. And these mild cases are still monitored by healthcare staff at least twice a day. In terms of transparency, government provided press briefing twice a day since the first day of the case confirmation. Next slide shows the smart tracking system for contact tracing. So various sources are used to collect the epidemiological data and those data collected by Korea CDC and Ministry of Health and Welfare will be shared with local government or health related agencies and also with the public based on legal mandate for disclosure. Anonymized information is provided to the public to encourage testing of the people who may have crossed the path with confirmed cases. Government also introduced special entry procedures and these procedures were expanded to all incoming travelers from March 19th for both Korean and foreign nationals. And also began testing of all incoming travelers, including asymptomatic people. And even if the testing results are negative, all travelers must go into 14 days of self-quarantine or government quarantine from April 1st, and this still continues. And government also adopted the social distancing measures of level 1, 2, level 3, depending on number of daily new cases for last two weeks. So if number is less than 50, it will be level 1. Between 50 to 100, it will be level 2. And over 100 to 200 will be level 3. So measures for the gathering, meeting, and sports event, and religious service, or schools, kindergarten, and institution and company will operate depending on which level. I also want to show one good example of impact of wearing mask. There was an outbreak in Paju, and at least 56 cases were linked to one Starbucks cafe in Paju. And 27 people were directly infected from one guest who stayed for 2.5 hours without wearing mask, and another 29 people were infected by secondary or tertiary spread. And customers were not wearing face mask, and there was a lack of poor ventilation inside the store. And none of the employees were infected because all were wearing mask during their shift. Government also announced code of conduct for the public to avoid three Cs, crowded places, close contact settings, and confined and closed spaces. And to make sure to wear mask indoors, including public transportation and all buildings, and keeping on outside even if we are not able to keep a two meter distance. Also plans to enhance infection prevention and control measures were announced for distancing level 2, and government banned on gathering of 50 or more indoors and 100 or more for outside. And also designated 12 types of high risk facilities, including clubs, singing rooms, buffet restaurants, and PC cafes. Only exceptions among those high risk facilities are distribution and logistics centers because they are essential industrial facilities. And you can see the breakdown of cluster of outbreaks. As you can see, Shincheonji related cases is over 21% among whole cases. And this Shincheonji special religious group, which actually initiated the first peak during late February and March. And there are some other outbreak clusters related to some other churches and also call centers. And we had around 15% related to imported or import related cases. And as of October 15, we have around 25,000 cases with 1.76% mortality rate. So what are the next steps? We still have a long way to go to achieve herd immunity at the national level. And two seroprevalence studies showed extremely low positivity rate. And first one showing a 1.03% and second 1.07%. And it is quite obvious we can only achieve herd immunity by vaccination. So although we have done quite well so far, we still need to invest further in medical resources, infrastructure, and human resources. And we will have to publish our accumulated data and share with global community to enable data-driven strategies and scale of R&D. And we will have to strengthen partnership with global health partners. And government is securing vaccine doses for 60 to 70% of whole population by participating in COVAX facility and beyond. And how to adjust face social distancing in various settings to balance public health and economic and societal impact until herd immunity can be achieved by vaccination will be the key factor. Thank you very much. Hello, my name is John Carruthers, and thank you for having me today. I'm going to tell you a little bit about the impact of health disparities in the treatment and outcomes of patients with COVID-19. I have no disclosures. My outline is shown here. I'm going to tell you a little bit about racial and ethnic disparities with COVID-19, some changes to treatment and outcomes, and then close with some take-home points. So we know that COVID-19 is a new, severe, principally pulmonary, but also vascular disease caused by the SARS-CoV-2 virus. The SARS-CoV-2 virus utilizes ACE2 receptors to infect cells and gain entry, triggering pneumonitis and potentially severe cytokine storm for severe disease in a person. The disparity for COVID-19 deaths is predominantly for Black and Latinx patients, as well as Native American patients, which aren't shown on this slide. I highlight the mortality data for Michigan, my state, which shows a standardized mortality ratio of 7.45 for Blacks as compared to Whites. And you notice that the Latina X was to the left of the standardized line for the state of Michigan. So the disparity seems to be widely large for Black patients, but also large for Latinx patients. A preprint study highlights social and epidemiological risk factors for COVID-19 death. People with medical disability, poor grocery mobility, think food deserts, and poverty, irrespective of race, are at the highest risk factor for COVID-19 death. People who are insured, irrespective of race, or live near parks have the lowest risk for COVID-19 death. I note again that African Americans and Latinx people have the highest COVID-19 infection and death rates and are the hardest hit economically before as well as after COVID-19. Hispanics and African Americans are more likely to lose their job or have pay cuts and less likely to have savings to counter economic loss during this pandemic. African Americans in particular carry more health medical conditions, making them more susceptible to COVID-19. With a higher vulnerability index in middle and older ages and a higher number of comorbid risk factors, shown here with three close risk factors from age 45 to 64 and 65 plus compared to non-Hispanic whites and Indians. It is largely in large U.S. metropolitan areas where there are higher proportions of African Americans hospitalized. Reviewing the experience in New Orleans, African Americans were more likely to be hospitalized, indicating severe COVID-19 infection, but once hospitalized, had the same rates of death as non-Hispanic whites and Indians. African Americans were more likely to be hospitalized, indicating severe COVID-19 infection, but once hospitalized, had the same rates of death as Caucasians. Age, lower socioeconomic class, and comorbidities remain COVID-19 risk factors, whereas female gender was a low risk factor for both hospitalization and death from COVID-19. I do point out that the data here is from larger academic centers, not small centers, so there may be different rates of deaths in smaller centers. I also point out that this shows comparable data between African Americans in the United States and people of color and blacks in the UK as well. So, in my estimation and in my collation of the data, the risk for COVID-19 starts with socioeconomic inequalities. That puts someone at a lower socioeconomic status, generally forces them to have lower levels of education because of affordability, and may have difficult access to healthcare. This has downstream consequences. People reside in lower-income neighborhoods, hold lower-paying jobs because they're less educated. They may work several jobs to make ends meet, including jobs that are determined essential. They may live in grocery store deserts, poor access and affordability of healthcare, maybe eat high-fat, high-caloric, low-fiber diets because of the grocery store deserts. They're more apt to use tobacco and alcohol, living near party stores, and may have lower physical activity because they don't live near parks and use lower levels of preventive medicine. That, over time, over one's lifetime, has physiologic consequences. They will alter their gut and their pulmonary microbiome. They will have increased localized inflammation because of the types of diets they're on, and eventually, with obesity and other things, can have compromised immunity. That puts one at higher risk for cancer and obesity and diabetes, metabolic syndrome, asthma, hypertension, kidney and cardiovascular disease. And over time, over one's lifetime, as one ages, those risk factors increase. These are the exact risk factors for high risk for COVID-19 severity. So, by my estimation, these roots start out with socioeconomic inequalities, the way our structures are done in our society. Now, the SARS-CoV-2 virus relies on two main human cell factors for infection. The ACE2, to which it binds, and TMPRSS2, a serine protease that primes the spike S protein of the virus. Both ACE2 and TMPRSS2 are androgen responsive for expression, so I won't go into full detail on this, but they're androgen responsive for expression. And, in particular, the TMPRSS2 promoter has an androgen response element that is activated by testosterone to increase expression. The virus has its principal tropism for the lungs. However, the virus can infect any cell that may express ACE2, including the liver, kidney, gut, and heart. Vascular endothelialitis appears to be more severe with COVID-19 as compared to, for instance, influenza or nonspecific interstitial pneumonia, creating a unique difference in driving this particular disease. I will also note here that many patients shown here also have several comorbidities in this purple area that may affect viral infection. Now, why is that important? So, one explanation why health comorbidities are a risk factor for severe COVID-19 is that some of these conditions increase the expression of ACE2 and TMPRSS2 in the lung and perhaps other organs. For instance, here, shown on the left, among asthma patients, males, if you're African American, and those with diabetes mellitus, all had increased ACE2 and or TMPRSS2 expression from collected sputum cells. This puts these people at higher risk for COVID-19. On the right, showing data from bioinformatics, several other groups show that there is increased ACE2 expression among people with lung disease, for instance, lung cancer patients, those with a history of smoking and COPD, and those with pulmonary arterial hypertension as compared to controls. I also will note that some of this data takes back data going back as far as 2004, showing that this expression has nothing to do with our studies currently for COVID-19. So, because of that data, I think there's two intersecting vulnerability cycles for COVID-19, particularly for those generating disparities. So, in one cycle, shown here by the purple arrows, you start out with socioeconomic inequalities and vulnerable populations, and as you age, you'll get health comorbidities, as I showed you in the other slide, and get severe illness. And even the severe illness, even if you survive from that, it can exacerbate your socioeconomic inequalities and reduce your income or ability to work. In the other intersecting circle shown in the black arrows, you develop health comorbidities, you increase ACE2 and TMPRSS2 expression, which increases your susceptibility for COVID-19 and can give you severe illness. And if you survive from that, you may still continue with health comorbidities because we do not know some of the long-term consequences of COVID-19. So, I'm going to go into the next point of my outline, which is COVID-19 changes for treatment and outcomes. So, first, the delay of acute care. This is data during the COVID-19 pandemic surge in the spring, showing the number of out-of-hospital, that's out-of-hospital cardiac arrests, is about 30% lower than the previous year, here shown for data from Italy. On data from California on the right, it shows that about a third less patients were hospitalized for acute MI. So, there could be theoretically two reasons for this observation. There's less stress leading to less MIs, perhaps because there's less in hospital, but there's more out-of-hospital cardiac arrests. Or, as the way this data points, is there is more avoidance of hospitals, largely because of COVID fear. I will note that this data has not been examined to date on race and ethnicity. Here's data showing the number of stroke evaluations, which may be seen in patients with uncontrolled hypertension, which are more prevalent amongst African Americans. This dropped during the COVID surge shown here in the blue area, but began to return to baseline after the surge. This might suggest, along with the reduced out-of-hospital, excuse me, reduced hospital cardiac arrests, that avoidance of care rather than a reduction in strokes, as implied with the myocardial data, is the driving force. Here's data from Italy showing a marked reduced or stopped outpatient evaluations in care for several patients with liver disease. You see the reductions range from 5% to, you know, stopping is close to 30% of care for these patients in the outpatient setting. Additionally, liver transplant evaluations and liver transplant surgeries were greatly reduced and are stopped as a result of COVID-19. Again, I will point out this data has not been evaluated based on race and ethnicity. Now, why is that important? Well, here's data modeling, this is modeling data, which examines the number of additional cases of advanced liver disease and a number of increased hepatitis C related deaths as a result of treatment delays for COVID-19. The data indicates that with longer treatment delays, shown here on the x-axis by months, the number of severe liver disease and hepatitis C deaths rise. Again, this has not specifically been examined in those who are medically underserved. So my summation of this is that COVID-19 may potentially exacerbate and worsen access to acute care for minorities and medically unserved patients, although the data is not there yet that fully examines this. What about delay of preventative care? Well, the rates of influenza vaccination, for example, for people of color is already lower compared to whites and Asians. This disparity will likely be exacerbated with COVID-19. This shows that all cancer patients and new patient encounters drop dramatically with the cessation of elective procedures with the COVID-19 surge. In particular, preventative screening services for cancer, for breast and colorectal cancer drop 85 to 90% from normal trajectories. This is a graphic that I put together that projects three medical and community responses to the drop in cancer prevention. And this could be additionally ported to other areas of health care. So Scenario A indicates a rapid recovery that under one year with fairly rapid clearance of any backlog of screening. Scenario B depicts a delayed return to historical screening trends over one to three years with a much longer clearance of backlog over several years. And Scenario C depicts a situation in which we never get back to historical trends, creating a public health crisis. Delays in returning to baseline or higher levels of screening with reverse gains causing additional preventive deaths from cancer. So this is dramatic. COVID-19 will likely exacerbate and worsen rates of preventive care for minorities and medically unserved. And that's largely because those groups already have lower uptake for these types of screening. And this is just an estimate. This may set us back 10 years of slow gains on closing the disparity gaps with things like navigation and other use of things to slow that gap. Some other things have come up. Food insecurity. The poorest households spend up to 70% of their income on food just to eat. There's also decline in labor-intensive food production with the pandemic. There's supply chain interruption. Think meat packing plants, for instance. And since many of these people with low income work in these industries, there's loss of income with decline in the world economy. And on top of that, this affects people going to public schools and principally because of school interruption and many vulnerable kids get their meals at school. So I'm going to summarize with take-home points. I didn't cover everything on this particular table and slide, but this table depicts the COVID-19 risk factor, the attribute for risk, and the driver for risk. For age, older age, we know that more infections are in younger people, but most of the deaths are in older people. And that is a manifestation of either the age or the presence of age-related comorbidities. Comorbidities, such as diabetes and hypertension and obesity, really drive the risk for COVID-19. And there's evidence that those comorbidities can induce increase in ACE2 and tempers-2 expression to increase the risk for COVID-19. What about race and ethnicity? We know that those of African ancestry, Native American, and Latinx have three to four times the rate of deaths from COVID-19 compared to white Americans. And that probably has its origins in structural, systemic, socioeconomic disadvantages, and in the overall development and presence of comorbidities that drive ACE2 and tempers-2 expression. And I didn't talk about gender, where males have 1.7 times the deaths of females, but I did mention that androgen can drive the expression, both of ACE2 and tempers-2 expression. And finally, there's potential exacerbation of disparities with disruption in access for acute medical care, and there could be long-term consequences with disruption of preventive care and food insecurity. And some additional issues, use of video versus phone for telehealth, as some households don't have the technology to do telehealth. And there's worsening enrollment and outreach for underrepresented minorities to participate in clinical trials, which has been a longstanding issue, but will probably be exacerbated in the presence of COVID-19. Thank you very much.

COVID-19

liver

clinical practices

patient care

diagnosis

treatment

outcomes

hepatic manifestations

liver enzyme elevation

dexamethasone

remdesivir

mortality reduction

healthcare disparities