I am Rohit Kohli, and I welcome you to a webinar co-hosted by NASPGAND, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition, along with the American Association for the Study of Liver Diseases, AASLD. This is a new worldwide enigma that we would like to understand a little bit better with our speakers today. There's been an increased reporting of cases of acute hepatitis in children, and together these two organizations would like us to better understand and communicate to the organizations that are helping gather data. If you have questions for our panelists, please use the Q&A box located in the bottom portion of your screen and tag the presenter you're addressing so that we can answer specific questions with specific panelists. You can use the chat window to engage with attendees as well and connect with AASLD staff for immediate assistance. With that, I'd like to introduce my two co-moderators, Dr. Estella Alonso from Lurie Children's Hospital at Northwestern University, who is the Vice Chair for the Department of Pediatrics and the Associate Chair for Clinical Services at the Department of Pediatrics. She's also the Sally Burnett Searle Professor of Pediatric Transplantation and a Professor of Pediatrics and Medical Social Sciences. Last but not least, Dr. Saul J. Carpin, MD, PhD, who is from the Emory University School of Medicine. He's a Pediatric Hepatologist and a Professor of Pediatrics at the Emory School. He's also the Raymond F. Shinatsi City Distinguished Medical Chair and Chief of the Division of Pediatric Gastroenterology, Hepatology, and Nutrition at Emory University School of Medicine, as well as Healthcare of Atlanta. With that, Dr. Carpin and Dr. Alonso. Well, welcome, everyone. We want to get underway pretty efficiently this morning. We have a series of 10-minute talks, which will then be followed by a 15-minute period of questions and answers. Dr. Coley had mentioned the different ways that you can register your questions, and I will also remind you to tag the person that you're directing your question towards. Our first report this morning will be with presenter Helena Gutierrez-Sanchez, who is Assistant Professor of Pediatrics and the Medical Director of Liver Transplantation at the University of Alabama, Birmingham. She really has a very important insight in being the clinician who cared for the nine patients that were reported in the Alabama outbreak. And so we will hand that off to you, Dr. Gutierrez-Sanchez. Although I see maybe we have the talk for Dr. Ward up. Yes, I was going to say, Dr. Alonso, we'll start with Dr. Ward and then transition to Gutierrez. Oh, I'm sorry. I must have had an old agenda. So Dr. Ward, the Director for the Coalition of Global Hepatitis Elimination and Task Force for Global Health. He's a professor of the Hubert Department of Global Health at the Rollins School of Public Health at Emory. I'm sorry for the confusion, Dr. Ward. Take it away. No problem. Thank you. Great to be part of this. I'm going to go off video in the interest of web band capacity, given that I'm coming to you from Luxor, Egypt. But I've been very interested in this outbreak as a former director of the Division of Borrel Hepatitis at CDC and have had multiple discussions with hepatologists about the etiologies of this. And I was asked to give some outline of the basic approaches to outbreak investigation because a number of people on the call today are clinicians and may be less familiar with this public health approach that I think you'll see as evident in the presentations to come regarding the investigations in the United States and globally. In short, the steps of an outbreak investigation, number one, some cases of concern are brought to the attention of public health authorities, typically by an astute clinician that recognizes that something appears unusual. And importantly, they know who the contact in public health to make an outbreak investigation possible, if that's considered to be appropriate. There also could be community sources, families, households, et cetera, but just for the purposes of this audience and as is evident in this investigation, an astute clinician contacting public health is key. And then it's up to public health to begin to assess what is this really constitute an outbreak, you know, what's known about it, how's that compared to other data that they're aware of, obviously verifying the diagnosis and getting in contact with experts relevant to that investigation. And I think that's why this type of webinar is so important to bring that expertise together with the public authorities conducting the investigation. Next slide, please. Thirdly, really, you know, the key element here, once you think an investigation is necessary, and you may not really even know you have an outbreak, but you think you have a cluster of cases that are grouped together in time that suggested something is unusual, or perhaps even a novel agent. So you want to begin to investigate it to see if indeed you do have an outbreak linked to a common source. So you develop a case definition so you can standardize your reporting with standardized criteria. Very early on, as you'll see here, you have a, you try to, you know, throw out a fairly broad net so that you have confirmed probable and possible cases so that you can see captured data to help you to find the extent of the problem, the populations at risk, and begin to generate some hypotheses about possible causes. And then as you gather data, as you, as the investigation moves forward, we may even come up with specific diagnostic tests and et cetera that help you revise your case findings to be more specific and really focus on more confirmed case definitions to really improve the precision of your outbreak investigation. Next slide, please. Next, you really begin to conduct case finding, and you can do that in a passive manner just by letting people sort of send out a notice of concern and communicating in a very general manner to possible reporters and more generally about that you're requesting cases and instructing them how to report cases, that's known as passive surveillance, and then you can have active surveillance where you're actively, you know, calling people up, promoting, encouraging, reporting, doing a lot of follow-up to keep that line of communication and line of reporting active, and, you know, and even conducting facility visits, et cetera. You may also encourage reporting from case patients, recognizing that there could be contact cases that meet the case definition, so that's another thing, another approach, and then you have the type of information, obviously demographic, geographic, clinical information, both symptoms, signs, laboratory data, that's the kind of information that will fit your, decide whether that case meets the case definition, and then you can begin to, as appropriate, put in data elements regarding exposures that can help you identify the cause of the cases being reported. Next slide, please. You then can move into a data analysis with a description of cases with initially collected data, sort of descriptive epidemiology that can provide some clues about etiology, the source of emotive transmission. It's really the first real evidence to identify risk populations and begin to help public health authorities decide what type of prevention recommendations are appropriate based on those, that early collected data. You know, a key feature of descriptive epidemiology for outbreak investigations is the epi curve, so you can look at the magnitude and temporal trends in the reporting to know if you're on the front end or the back end of an outbreak, and even the shape of the epi curve can give you some idea about the type of exposures that are causing the outbreak, and then it can be spot mapped, so you can show the location of cases, because that can also be very informative to look at common exposures, and with that, you can generate hypotheses and to think about the source of imputative agent modes of transmission exposures. You may, that may spur collection of additional data, contact again the clinicians, experts in the field, collecting additional information from case patients, etc. Next slide, please. And then you can test your hypothesis. That can be done with, you know, comparing your collected data with established facts about different diseases and infections, toxins, environmental exposures, etc. Again, I think you'll see that done here. Then you can conduct analytic epidemiologic studies to quantify the relationships and assess, you know, the role, what seems to be associated with the cases versus a chance exposure, so you can either do retrospective cohort studies or case control studies that can give you more data to test hypotheses, and I think you'll see some of those mentioned in the investigations that will be described here in a moment, and then, you know, then you would like to move into actually, you know, implementing control and prevention measures based on your data, and, you know, you try to do that as early as possible, and then, you know, it can be more definitive, you know, as your data, strength of data grows with your investigation. Now, the last part, when you put into these classic approaches to investigation, it's like you communicate findings, but I think, you know, hopefully you can recognize communicating about the outbreak throughout this process is critically important to make people aware of the outbreak, stimulate reporting, begin to get feedback from clinical experts in that particular area. Epidemiology is a movable field of investigation that can be applied, you know, in multiple ways and to multiple, to more outbreaks as is here, but you really need that feedback of experts in the field, and again, that's why this type of webinar, strengthening those types of relationships is so important. You know, obviously, in this particular outbreak, we had, we had a great deal of help in communicating the outbreak, probably because the sensitization from over, you know, going on three years of reporting on the pandemic. The media is very sensitized to that. It'll be interesting to hear from these investigators, the strength and limitations of broad immediate media scrutiny on public health investigations. Hope that's helpful to set the stage for these descriptions of these investigations to come. Thank you very much. And thank you, Dr. Ward, for that excellent overview to help set the tone for how we should be approaching these investigations. Now we will move on to Dr. Gutierrez-Sanchez's talk, which is titled The First Reports of the Hepatitis Outbreak in the U.S. As I mentioned, she's from the University of Alabama at Birmingham and is the medical director of their liver transplant program and had first-hand experience as one of the treating clinicians for these cases. Thank you, Dr. Gutierrez. All right, thank you. I want to thank the organizers for including me as a presenter in this webinar. I will be discussing the clinical presentation and evaluation of our Alabama cohort. Next. I have no disclosures. Next. And I would like to start by giving some background information on pediatric acute hepatitis and acute liver failure. Next. Next, yeah. So acute hepatitis is defined as inflammation of the liver, regardless of etiology. It is basically an umbrella term. With hepatitis, you see elevation of liver enzymes, and this reflects damage to the liver. Once the damage is severe, you see abnormal albumin and INR, and this happens in the setting of impaired liver synthetic function or liver failure. Hepatitis has a wide range of presentation. It can present asymptomatically as a subclinical hepatitis. It can present with mild to moderate symptoms of hepatic damage. Here you likely appreciate jaundice, some abdominal pain and malaise. It can also present in the setting of chronic liver disease or even cirrhosis with ascites, coagulopathy, and gastrointestinal bleeding. And lastly, it can also present as an episode of acute liver failure or sometimes acute or chronic liver failure with compromised synthetic function, including hyperammonemia, coagulopathy, low albumin, and hepatic encephalopathy. Next. The diagnostic evaluation of a patient with acute hepatitis is driven by the history and clinical exam at presentation. The differential diagnosis in the pediatric population is broad, and it can be categorized as infectious versus non-infectious. Within the infectious possible etiologies, you have the hepatotrophic viruses from A to E. You also have non-hepatotrophic viruses that are named in this table, such as CNV, adenovirus, CNV, enterovirus, EBV, HSV, among others. And there are also non-viral infections, as you can appreciate in this slide. Next. As previously mentioned, there are also non-infectious etiologies, and these include autoimmune conditions, such as autoimmune hepatitis, but also systemic diseases, such as lupus or juvenile rheumatoid arthritis. There are also many metabolic conditions, anatomical abnormalities, toxic exposure, and hemodynamic instability or obstruction that could lead to hepatitis. Next. Pediatric acute liver failure is an acute onset of liver disease without evidence of chronic liver disease. Here you have coagulopathy that is not corrected by administration of vitamin K, and the definition of pediatric acute liver failure is met if the patient has a PT greater or equal to 15 and an INR greater or equal to 1.5 with evidence of hepatic encephalopathy or a PT greater than 20 and an INR greater than 2 with or without hepatic encephalopathy. The estimated frequency of adult and pediatric acute liver failure in the U.S. is approximately 17 cases per 100,000 population per year. The frequency in children is unknown. However, population white rates estimate this number at around 500 cases per year, and it is important to know that 30% of these cases are actually of indeterminate etiology. Furthermore, in 2020, there were close to 500 pediatric liver transplants in the United States, and approximately 20% of these 500 had a unknown diagnosis. So now I'll be switching gears to talk about the clinical presentation of our cohort. Next, we have a total of nine patients with an age range between 1.1 and 6.5 years. The majority were below the age of three. Seven out of nine were female. All patients were of white race, and six out of nine patients were Hispanic. All patients reside in Alabama, and there was no geographical linkage among them. Next. Symptoms during symptom duration prior to presentation was between a few days to two weeks. The most common symptoms were gastrointestinal indigestion with emesis and diarrhea, followed by fever, fatigue, and upper respiratory symptoms. Upon initial presentation, physical exam, the majority of these patients had sclericteria and jaundice, followed by hepatomegaly, and only a few had splenomegaly and hepatic encephalopathy. Next. Initial laboratory studies were concerning. Liver enzymes were significantly elevated. Bilirubin, INR, and ammonia levels were anywhere from normal to elevated. The median ALT at presentation was 1,724, with a range between 600 to 4,695. As a reference, normal ALT values are roughly between 14 and 20, so the initial median ALT value of our cohort was anywhere from 85 times the upper limit of normal, and those at the upper range had an ALT near 200 times the upper limit of normal. Similarly, the median AST was also significantly elevated at near 2,000, and this is close to 100 times the upper limit of normal. The median total bilirubin was 7, direct bilirubin was 5.5, median INR was 1.2, and median ammonia was 73. Next. Diagnostic workup was clinician-driven, so based on assessment of individual patients, and therefore was not fully standardized. All of our patients tested positive for adenovirus per whole blood qPCR. The median viral load at presentation was 11,000 copies per ml. Six out of nine patients were positive for EBV per whole blood qPCR, with a median viral load of 1,680. Five out of these six patients had serologies, and they were all negative for EBV-IgM, and four out of five were EBNA positive. All nine patients tested negative for COVID by nucleic acid amplification testing. All nine patients tested negative for viral hepatitis A, B, and C. Multiple viruses were detected on respiratory PCR panels, and this was done in eight patients, and four out of eight were positive for enterovirus, rhinovirus, and one out of eight for either metonymovirus, RSV, or seasonal coronavirus. Only one patient had adenovirus positive via these respiratory PCR, and one out of three patients that had stool tested for adenovirus was positive. Next. As part of the workup, we looked into the possibility of autoimmune hepatitis. Five out of nine patients had elevated IgG, and four out of nine patients had one positive autoantibody, either ANA or SMA, in the low range, so anywhere from 140 to 180. Taking this into consideration, along with the liver biopsy findings and clinical course, non-met criteria for autoimmune hepatitis. We also looked into the possibility of an underlying metabolic condition. Serum amino acids were checked in five patients, and the results were either non-specific, which can be seen in the study of severe illness or normal. Similarly, urine organic acids were checked in five patients, and again, results were reassuring, and we also obtained acylcarnitine profile in four patients, and we found one patient to have nonspecific abnormalities and three patients to have normal results. We looked for alpha-1 antitrypsin deficiency, and all of the patients who had this done, which were five of them, had normal phenotypes. We looked for the possibility of Wilson disease, which typically does not present this early, but we did obtain seroloplasmin, and levels were within normal. Acetaminophen level was checked in seven patients, and none of them had abnormal levels, and not in this slide, but all of our patients also had liver ultrasounds that did not show any anatomical or vascular abnormalities. Next. Six out of nine patients had a liver biopsy. All biopsies had variable degrees of acute inflammation from lobular to interphase and portal. Some had canalicular cholestasis, unspotted hepatocyte necrosis. Fibrosis was either minimal to not present. None of the biopsies demonstrated the confluent necrosis, which is typically seen in adenovirus hepatitis. Additionally, adenovirus was not seen in immunohistochemistry, neither was identified as viral inclusions in electromicroscopy. EBER in cytohabitation was negative on all patients, providing us with lack of evidence towards possible EBV-driven hepatitis. On adenovirus PCR, it was positive in liver tissue in two out of three patients. However, it is unclear if this is secondary to the adenovirus in the liver tissue or contamination from blood at the time of the liver biopsy. Next. The clinical course of our patients can be divided into groups, so those who had severe hepatitis and those who had acute liver failure. So six patients did not progress to acute liver failure and only had severe acute hepatitis. These cohort had statistically lower liver enzymes at presentation with a median ALT of 911 and a median AST of 1,626 versus 3,854 and 4,000 in the acute of liver failure, respectively. The median viral load was also significantly lower. It was 9,262 versus 55,340 copies per ml. All of these patients recovered with their native livers. A clinic follow-up with a median of about 38 days, three out of five patients were still viremic with adenovirus with a median of 2,000 copies per ml. The second group of patients either presented with acute liver failure or progressed into liver failure. The median INR, the peak was 8.8 and the peak of ammonia was 169. One patient recovered spontaneously and is doing well with the native liver. However, two patients who presented with acute hepatitis progressed into acute liver failure. These two patients had a significantly higher median viral load of adenovirus at presentation. It was 63,000 versus 7,465 when compared to those who recovered spontaneously. Both patients received Zadafivir despite treatment and their median peak of adenovirus was 100,000 copies. Both of them developed hepatic encephalopathy and ascites. One patient required continuous renal replacement therapy. One patient required total plasma exchange. One patient met criteria for HLH and was subsequently started on etoposide and dexamethasone. Both patients were transferred to another coronary hospital for possible extracorporeal liver support in the setting of ongoing adenovirus viremia. They ultimately did need a transplant and both of them are currently doing well. Thanks. Thank you so much for that very detailed description of that cohort. Keep these in mind as we move on in our presentations. Our next presentation will be Dr. Hannah Kirking from the CDC National Center for Immunization and Respiratory Diseases, the viral hepatitis branch at the CDC. Her title is the CDC Report of Cases of Acute Hepatitis in Children. Thank you very much Dr. Kirking for being with us here this morning. Sure. Thanks for the introduction and it's good to be here kind of working across our organizations to try to better understand this. It was a nice introduction by Dr. Ward first to what we're going to talk about in terms of giving us the framework for how CDC is approaching this as well as I'll say one of the classic first steps to kind of where we all started with with this was an early phone call from Dr. Gutierrez as well on the Alabama cases. She indeed is the astute clinician that tells the story in an epidemiologic way. Next slide please. So kind of as Dr. Gutierrez just mentioned, in November essentially this all started when we received a phone call from our Alabama Department of Public Health colleagues as well as Dr. Gutierrez and her team. It was because they had noticed four or five cases of acute hepatitis in children who came in and also all seemed to test positive for adenovirus without a lot of other explanatory etiologies identified and so we continued to work with them and ultimately got to the nine cases that you just heard about. Alabama as a state did put out a statewide notice in February of 2022 looking for additional cases to see if this was part of a larger outbreak and at least from a statewide outreach did not identify additional cases. And so it wasn't a broader, we didn't put out broader notification at that point in time until in April essentially the UK Security Health Agency reached out to us here and specifically reached out to our colleagues in the Division of Viral Hepatitis because they had noticed an increase in cases of acute pediatric hepatitis of unknown etiology there. And so after we had a call in mid-April and exchanged information based on what they were seeing as well as what we were working on with colleagues in Alabama, identified what could be a larger issue and that's kind of where we are now. Just to flag this, a kind of high-level overview of the Alabama cases that Dr. Gutierrez just described was published in early May and there's a reference here and the slides should be available to you just to take a peek at that. So in general right now where we sit here at CDC and kind of across the U.S. and quite frankly world as we'll hear more about shortly is that we're trying to address these specific questions. First of all to what extent are we seeing an increase in pediatric hepatitis of unknown etiology and is this focal or nationwide or global frankly? What is the etiologic role of adenovirus and potentially specifically adenovirus 41? Are there other pathogens or co-factors playing a role in explaining why we're seeing this now? If this is primarily due to adenovirus why is it happening now? Do we have a large adenovirus type 41 season or circulation ongoing? Do we have a new strain? Did pandemic lockdown contribute to this somehow? You know all of those questions. And then last as we kind of get additional answers to the first set of questions what can we do for prevention and control? All right next slide. So on April 21st here at CDC we put out a health alert network health advisory and essentially this advisory had three main points. It had recommendations for adenovirus testing based on what we'd already seen in Alabama as well as what we'd heard from colleagues in UK as well as it asked for a reporting of additional cases that could be coming from other jurisdictions. Next slide please. So ultimately in this notification the recommendations included the following. First of all it asks clinicians to consider adenovirus testing in pediatric patients with hepatitis of unknown etiology and specifically PCR testing or nucleic acid amplification is preferred and can be done in respiratory specimens stool or rectal swabs and blood. Additionally we had some early evidence from Alabama that whole blood testing by PCR may be more sensitive than testing plasma or serum and so this was also included in the recommendations to consider whole blood testing if possible preferentially in these patients. Next slide. So the second part of that that health advisory was essentially asking for more cases to be reported to us. You know right now because we're still sorting through what the etiology is behind these patients hepatitis we're not calling them cases per se and instead we're using the language patients under investigation and so right now the patients under investigation that we're asking for additional reports include children less than 10 years of age with elevated AST or ALT above 500 who have an unknown etiology for their hepatitis and our call for additional cases goes back to October 1st 2021 and extends to where we are today. Next slide please. So essentially if you have patients that you've cared for please do and who meet this definition please report them to your state or local health department as well as CDC and I went ahead and put the email inbox here that you can send us notification. Next slide. I also included a couple links to websites here that have additional clinical guidance for any clinicians that may be on this call as well as there's additional instructions for antivirus diagnostic testing typing and submission of additional specimens. Next slide please. So as part of this call for additional cases what that really represents is that we're starting to launch a nationwide epidemiologic investigation to get a better handle on what might be behind all of these patients or at least some of what we're seeing right now. So what will happen is that each of the patients under investigation will have additional information that we're asking to kind of collect in a standardized way. In short we have a case report form that largely is a medical chart abstraction for these children and then we also have an exposures case report form that's designed to have the health department work to complete with parents. And so again if you've had patients that meet this criteria your state or local health department can share these forms back with you when you report your patients and then you can sort out usually with your state or local health department how to complete the medical chart abstraction as quickly and completely as possible. Next slide please. In addition as part of this nationwide investigation we are trying to obtain lab test information. Some of that will be collected through the medical chart abstraction and just by data report that we receive but then there also is some additional specimen collection and testing that we are hoping to to be able to do. And so through the medical chart abstraction we're hoping to get clinical history of lab testing and workup for autoimmune hepatitis, infectious, metabolic, and toxicology and that's all determined by clinicians on the front line. But additionally we're hoping to do additional adenovirus genomic sequencing and or typing for those that test positive for adenovirus and because we're still kind of casting a broad net as we approach this we are requesting residual specimens be shipped for whether it's additional tissue pathology testing, metagenomics, looking more broadly at all different pathogens, etc. So again if you're a clinical site or a clinician on the front lines and you have patients that meet the criteria please save any residual specimens that you have and your state or local health department will be able to share additional instructions on specimen handling and shipping so that we can include them in the larger investigation. So just wanted to transition a little bit to give a status update of where we are here in the U.S. Right now we've had I think 38 states that have reported patients under investigation as part of this and this is as of May 25th. From those 38 states we've received reports of 216 patients and I just included some preliminary characteristics here. In general right now the patients are not necessarily concentrated in time. We're receiving retrospective reports back to October through May. There are more that have happened more recently but again it's hard to know if that's a true epidemiologic pattern that we're seeing or if it's kind of recall bias or selective recall to more recent cases. 89% of the cases have been hospitalized, 6% required liver transplant, and we have seven deaths under investigation. Of note about 45% of the patients had a blood specimen tested for adenovirus and this could have been whole blood or plasma or serum and about 48% of those tested positive. Next slide. And so one important question that Dr. Ward nicely highlighted is one that we're asking ourselves and that is associated with what we're seeing and getting with case reports is there actually an increase in hepatitis and or adenovirus cases here in the U.S. in children? And so one of the things that I think we're all realizing as we've tried to understand this better is that our surveillance for acute hepatitis is not set up in a way that gives us easy answers to that question and then similarly our adenovirus surveillance is a bit passive and it's not particularly active and that's largely driven by the fact that adenovirus doesn't have compulsory reporting here in the U.S. And so we're relying largely on syndromic surveillance data which is data that we can pull from emergency rooms and hospitals on syndromes or presenting complaints as well as ICD codes. We're also looking at pediatric liver transplant data that is available as well as virologic surveillance for adenovirus and again, with some kind of lens of wondering about enteric versus respiratory adenovirus because there are different types and different types have different tropism for tissues. And so right now, current review of our surveillance data shows that there may be a recent increase in hepatitis and adenovirus compared to levels during the pandemic, but these levels are not necessarily higher than pre-pandemic levels for this age group. And so the other thing that is definitely interesting and challenging is that we're seeing this pattern at a point in time when we've seen changes in a lot of our surveillance data because of COVID-19. So right now, our limited surveillance data does not indicate a marked increase in pediatric hepatitis or transplants. But again, there's some challenges to that given the pandemic as well as some reporting delays. We're continuing to gather data on the patients under investigation and this is incredibly important. So for any of you who have already notified us or shared data, we appreciate it. And for those of you working on it and, or as you see future cases, please do realize this is greatly appreciated and will help us answer questions sooner. And then we'll eventually describe these patients as we get more of the data in. And specifically, we want to examine the link between adenovirus and other co-factors, probably through analytics epi studies, which largely right now is we're talking about setting up case control studies. And specifically matching controls. I think that's all I have. And so I'll stop there and pass it off to our next speakers. Great, well, thank you so much, Dr. Kirking. It's really my deep pleasure to introduce our next speaker, Dr. Philippa Easterbrook, who is a senior scientist, global hepatitis program, global HIV, hepatitis programs at the World Health Organization in Geneva. Dr. Easterbrook has led development of normative guides for HIV and hep B and hep C. We are extremely lucky to have her as part of our webinar because she is really the pillar lead for the WHO headquarters global response to this particular severe acute hepatitis outbreak in young children. Dr. Easterbrook. Thank you very much for that introduction. And thank you to ASLD and Nesbogan for being the drivers behind this important webinar. Next slide. So I'm gonna briefly cover the global situation as of the 26th of May. The response from WHO and partners. Touch on the case definitions and the different case definitions. And then on the working hypothesis and the ongoing investigations and what we know so far and the next steps. Next slide. So as of 24th of May, at least 650 probable cases have been reported from 33 countries with 99 additional cases pending classification. The majority of the reporting countries are in the European region, but also reports from four other WHO regions, particularly from the Americas driven by the United States. There are 14 of the 33 countries that are reporting more than five probable cases. And you can see listed here in particular, the UK, the US, Spain, Italy, Japan, Belgium, the Netherlands, Israel. 38 children, 6% required liver transplantation and at least nine deaths have been reported. And then based largely on data from the WHO, largely on data from the European region, around 75% of all the cases are in children less than five years. And again, based on the Euro ECDC data, the majority have been hospitalized and intensive care required in about 15%. Next slide. And just keep pressing the tabs so that we display all the timelines of events. So this is a summary, a timeline summary of the key actions and activities of WHO and partners. And starting really on the 5th of April with the initial notification, sorry, back to the previous slide, the initial notification through the UK international health regulations focal point on the 10 cases, which rapidly was then 74 cases. And on the 10th of April, WHO communicated the event confidentially to the member states through the standard EIS or event information system. And then followed this with the publication of the disease outbreak, new so-called DONs. You need to get used to these many acronyms here, which is the public face of the communication from WHO. And this then led to the establishment in the headquarters of the incident management support team and a similar structure in the European region, which is the standardized approach to the management by WHO of an emergency response. There were then subsequent briefings across all the regions and the establishment of the first data collection system with the European protocol being entered through the TESI system. And we recently established a pediatric hepatitis working group that met to really help support the development of the case report form and some of the diagnostic workup and management protocols. And then beneath and then highlighted really in the black boxes are the similar responses from other organizations, the European Centers for Disease Control, ECDC alerting its network. And of course, CDC, similarly, reports being issued from these organizations. And the UK, which has led many of the investigations and has the largest number of cases has now issued three technical reports. Next slide. So this summarizes the case definitions, the evolution of the case definitions. And then I've highlighted in orange the main working definition that's being used by the WHO and the ECDC. And all the definitions share in common, the determination of an acute hepatitis based on serum transaminases greater than 500 IU per mil. And that the differences largely are in relation to the time. So that the UK HSA is focusing on cases since January, 2022. The WHO one focusing since October in keeping with the US CDC so that we ensured that the US cases were captured. And the main other differences relate to whether or not there's some specification of other than non-hepatitis A to E, the exclusion of other metabolic or inherited or genetic causes. Next slide. But inevitably it's important to recognize that some of these differences in the case definitions will inevitably reflect in the etiology as we go forward. So the working hypothesis and what we know so far, I think it's fair to say that much of this has been driven by what we have learned from the UK HSA investigations and of course from US CDC. And that the common viruses A to E have not been detected. There appears to be no clear link to a particular geographic area or common exposure to specific foods, medications, toxins. And importantly, no clear evidence of a link to the COVID vaccination as the majority, 85% were unvaccinated and none of those less than five years who account for the majority of the cases. So the working hypotheses on the previous slide that have been identified and highlighted by the other speakers are the adenovirus either through abnormal susceptibility, co-infection or a dysregulated immune response and a possible link to prior or current COVID infections. But there may well indeed be several factors underlying causes for the identified cases. Next slide. So this summarizes some of the findings from the 14 countries reporting more than five cases with the last three columns just summarizing some of the data that is available on the COVID PCR results and the adeno detection also. I think the purpose of the slide is really to illustrate that much of the data is being driven by just a couple of countries and we still have sparse data in terms of more comprehensive investigation from other countries. Next slide. So focusing now on the UK where really much of the kind of comprehensive and systematic pathogen and other investigations has been undertaken. The chart on the right really shows a listing of all the pathogen investigations with green indicating the positive results, blue the negative and then either pending or not done for the orange and the yellow. And the main message is that as of the 170 tested, 68% were positive for adeno in the blood, 38 cases subtype 27.41F and for the SARS-CoV-2 it was detected in 15%. But the serologic testing in terms of past infection is still ongoing. And if you look at in terms of the other pathogens they were detected in a low proportion of cases but of uncertain significance. Next slide. So I think a further prompt to the interest in the adeno cases that were detected and this is a working hypothesis was the building on the opportunity of the routine surveillance of pathogens in public health laboratories in the NHS in the UK, monitoring for changes in trends and statistical exceedances. And since the end of 2021, there had been a reported increase in new diagnosis and statistical exceedances for adenovirus, enterovirus, rhino and norovirus in those less than 10 years. What you see is the chart on the right with the time series chart for the adeno in both respiratory fecal and blood according to different age groups. And whereas at pre-pandemic period, there were only 50 to 150 cases being reported per week. That was right down to less than 50 between the period March, 2020 to May, 2021. And then a marked increase to 20 to 300 cases reported per week. So clearly evidence of enhanced community transmission. Next slide. So the UK HSA has really developed a very comprehensive series of further investigations. And these fall into several categories, both the analytic epidemiology, so a very important case control study for which we're awaiting the results of comparing the rates of adenodetection in children with the presentation of acute hepatitis as compared with other hospitalized children. I think also important pathogen investigations to the whole genome sequencing, the metagenomics and in terms of the host characterization, really looking at the host genetic characterization and the immunological characterization. Is it something about the nature of the host response that's generating this severe disease course? Next slide. And I just wanted to touch on, because I know this will come up in the discussion, that critical question of whether or not the cases now being reported represent a clear increase above the background rate of what we know are rare, but regularly reported cases of acute hepatitis of unknown etiology and also with acute liver failure in children. Two surveys that were done in the European region. The first one that was done very rapidly over a period of just a few days to really identify what was the background reporting in the previous five years compared to this year. Responses received from 54 hospitals and overall in 15 out of 18 European countries, one out of nine non-European compared to previous years, there's a report of a probable increase. Similar survey undertaken in 34 participating liver centers across Europe, 12 reporting a suspected increase, but no rise in numbers. So a variable result in terms of whether or not there is a clear signal, perhaps in some, but not all countries. Next slide. And so following on from this, and just to conclude, is WHO is now planning a global survey to extend this work across multiple regions and multiple countries, but with still some work to be done on honing the precise questions. But this is a survey that we hope in collaboration with many other partner organizations to launch in the next week. Next slide. Similarly, we are now just finalizing a global case reporting form that builds on the excellent foundation from CDC and the ECDC reporting tool that is a comprehensive data collection from admission during admission to hospital discharge. Next slide. So finally, in terms of the ongoing WHO response priorities that we are liaising closely with those partners who have really driven many of these preliminary studies to establish really what the priority projects would be going forward to extend across multiple countries. That baseline survey of the incidence of acute hepatitis of unknown etiology across multiple countries, the case report form, the clinical management guidelines that we're working with a number of partners to finalize, diagnostic algorithm and interim lab guidance. And we plan to have a technical brief that brings together all the data we have to date on the global situation. And next slide. And just to highlight some of the discussion points, the challenges that we face at the moment with a relatively nonspecific case definition that there is the non-standardized approach to work up these cases in many countries, that the likely mix of cases and therefore etiologies in some of the reported cases and the challenge that many low and middle income countries really have limited capacity for comprehensive diagnostic workup and the limited data capture on some of the specific clinical management interventions. And with thanks to the many members, excellent members of the incident management team at WHO headquarters. Thank you. Great, thank you so much, Dr. Easterbrook. And certainly last but not least, we have Dr. Saeed Mohammed, who's an associate professor of pediatrics at Vanderbilt University in Nashville. Dr. Mohammed is the director of the Pediatric Solid Organ Transplant Center and his role here is he's the NASPICN chair of the Hepatology Committee. Dr. Mohammed. Thank you, Saul. I wanna thank the organizers too for inviting me to this webinar. And I'm here to talk about our planned survey. So we have designed a red cap survey along with the ASLC and members of NASPICN. It's designed to minimize our data entry burden while trying to... Institutions. Similar to what others have been talking about, the case definitions. We've maintained the case definition to AST and ALT over 500, but have expanded the inclusion criteria to under 18 years of age. So some of the variables that we're collecting are general demographics, presenting symptoms, peak lab values and testing. So we're asking about respiratory panels and serum and blood viral PCRs. We're also asking about treatment patterns, asking if anybody has given antivirals or if people are giving steroids, especially in cases of indeterminate acute liver failure. We have a section for biopsy findings that will be free text. And obviously we're gonna be asking about final outcomes, whether they be complete resolution, death or transplant. So this survey, like all, will have a number of limitations. We think that children's hospitals and transplant centers may be overrepresented. We're hoping through the broad reach of NASPIN and the ASLD that we will be able to reach gastroenterologists and pediatricians from all over the country. There's obviously a limited amount of data that's going to be collected to try to encourage people to report the cases without putting undue burden on them, and it's reliant on self-report. I'd like to just acknowledge the Dr. Anita Pai and Katie Black, who helped to create the survey, and then obviously the moderators here, Dr. Ben Gold and Margaret Stahl-Stollings from NASPGN. Thank you. Thank you so much for a very seamless and engrossing, I will say. I was the one forwarding the slides, but I got lost once in a while just listening. So thank you to all the speakers. And back to you, Dr. Karpen and Dr. Alonzo for the Q&A. Thank you so much, Dr. Coley. I'm gonna lead off the Q&A, but this is certainly not in order of importance, but I think that there are some common themes. I will call out a couple of our panelists. Maybe we can have those show up on camera if possible, so we can call on them. And a number of questions came through Q&A, but also a lot of questions and comments have come through the chat. We'll try to collect these as best as possible. I'm gonna really start questioning first Dr. Gutierrez. And that is several people asked us some clinical questions about these, one with sort of the diagnostic workup about how deep an immunological or even a genetic workup that you may have done. Maybe start with that. Yeah, so the two patients that presented with hepatitis and then develop acular failure did have a more detailed immunologic workup. I know we're all thinking at least we thought about immune dysregulation playing a role in all of this. And both of them had IL-2 receptor levels that were high. Lymphocyte markers were normal in both of them. And as you know, one had HLH and the criteria for that. I believe some of the X-plant will undergo further testing to see if markers of immune dysregulation or T-cell driven injury shows up in these liver tissues. So we'll have to just wait for further details about that. Great, thank you. And a second clinical follow-up that was by some people was about the Cydophobia and sort of your experience with it and even post-transplant experience with Cydophobia. Yeah, so I can only speak pre-transplant because I was not involved, right? Like perioperatively. I know that we here initiated Cydophobia in the patients who were not getting better. So the two that went into acute liver failure were not showing signs of improvement. So two of them, and they continue it briefly at the other facility, but I cannot speak any further because I was not involved in their clinical management. So do you have any information about the X-plants that provide some input or something? Was there a great cytopathic effect? Was there a lot of immune? What did we see? Any mitochondrial issues was a question in the chat as well. Yeah, so from the mitochondria from our patients that had electromicroscopy, they were all normal. I believe a few had to morphic changes that really, we know it doesn't really represent anything specifically, but there were not specific findings for that. Regarding the X-plants, again, I don't have data that I can disclose. All right, great. Well, maybe I'll ask a couple more questions. I'm gonna hand it off to my co-moderator, Dr. Alonzo, for the rest of the questions. We definitely have 15 minutes, which is great. So please, we'll do the best to gather the current questions. But if there are some that were missing, please do not feel shy about reposting them in the Q&A. So this is kind of a general question really to Dr. Kirking and Dr. Easterbrook that has come up with some of the comments is, how real is this? So both of you have addressed this. As a field, we've never collected these cases. So when you start from a ground of zero, and then of course the numbers are gonna increase day by day with more collecting, how do you slice this between cluster versus outbreak versus just random? Maybe we start with Dr. Kirking and ask Dr. Easterbrook to chime in. Thanks, Dr. Karpen. I think it's a great question. And in many ways, it's a million dollar question. I think, yeah, I think a couple of things might be going on and Dr. Easterbrook can probably speak to this as well. I think the UK is confident in that they are seeing an increase in acute hepatitis in kids as well as higher rates of adenovirus. And their answer to that question is fairly clear. I think there's other countries in Europe that have kind of the same as UK and that they feel like both are elevated. And then they have some that are showing a little bit more line to what we're seeing here in the US where rates might be higher than they were during the pandemic, but not necessarily higher than they were before the pandemic. And so I think the question of trying to understand are we above baseline or are we at baseline is a little bit more nuanced given the last three years of all of our lives. I think the other question that we keep asking ourselves is do we have an uptick or are we identifying an issue that's always been there and we just haven't been looking at it and haven't been putting a spotlight on it. My gut sense is it might be a little bit of each, but I think we're still working to get data to support that. We've had some strong and high quality conversations with kind of broad collaborators here at CDC, but we regularly rely on our clinical colleagues or partnerships. And it has been interesting because we're looking at surveillance data on our end, but when you talk with some clinicians too, we hear aggressively, this is definitely more than it was before. And so trying to both listen to our astute clinicians as well as use our data is kind of what we're trying to do moving forward. So short answer I think is it's a mixed bag and I think we're still working through imperfect data to be confident in kind of where we land on that question. Sure, so maybe this is a good point for Dr. Easterbrook because for those of us, if you don't have a case, you don't report that you don't have a case. So perhaps we're getting more input from the UK methodologists and Dr. Easterbrook. Thanks, no, well, I'd very much agree with Dr. Kirkland's comments. I think what we are seeing in terms of the increased case numbers, we're getting both current as well as historic cases reported. And we haven't fully sort of teased out and some countries are reporting many historic and others, both historic and current. So we need to drill down a bit more into that data. I think it's also clear that the picture is mixed by the nature of this active case finding, asking countries to report cases back to October, 2021. We are going to flush out some of those regular, albeit rare, recognized cases of acute hepatitis of unknown etiology. And so that is why I suppose, we are starting to see those settings, perhaps the US is included in that as well as the UK, where the adenose story seems to be more compelling, although we still need to, this needs to be taken right to the end in terms of that etiological investigation at case control study to really nail down, is this a bystander infection or is this a sort of true pathogen or co-pathogen? I think, I do think your comment about this also being an opportunity to finally get to the bottom of what has been a longstanding conundrum over these cases of acute hepatitis of unknown etiology. And so I think we need to use this intense investigation period as an opportunity to bring clarity, not just to this current episode, but perhaps what's gone before. So I think it will pay dividend. And I think it's interesting that every event outbreak generates new questions. And I think with monkeypox, it was more straightforward. There's an etiologic agent, there's a defined clinical presentation. And really the interesting part there is this seemingly sort of appearing in populations you wouldn't expect. So it's nailing down the transmission and communicating ways of protecting. But we are faced with the etiology. And so it's an altogether a different conundrum. Thank you. Picking up on some of that theme, this would be directed to Dr. Easterbrook and Dr. Kirking. There were multiple questions about the role of SARS-CoV-2 in this outbreak. Realizing that the majority of children were not immunized because of their age, and that in some of the countries, Israel and Scotland being good examples, this outbreak was superimposed on a time when the general population had a high prevalence of active COVID infection because of the Delta outbreak. But what do we know yet at the CDC or through the WHO about history of prior COVID infection? So perhaps the child was not co-infected with COVID at the time they presented, but do we believe that many of these children had COVID as a prior infection that could have potentially primed their immune system? There were at least five or six questions revolving around that scenario. Do you want to start, Dr. Kirking, perhaps? Sure, I can definitely do that. First of all, I think it's a great question. I think as we, you know, not surprising, this is happening at this point in time, and that's making it more challenging to figure out whether or not COVID's related or a bystander, as someone asked in their question in the chat. I think as we're approaching it from the CDC side, and my guess is my colleagues also agree, the CDC side, and my guess is my colleagues will say the same across in Europe and elsewhere in the world, but I think there's three questions we're asking with how COVID might be implicated. There's the direct question of whether a current COVID infection is related and or driving hepatitis. I think that's less likely based on what we're seeing in that, you know, most of the children are still getting universally screened for COVID upon admission, and most of them have tested negative. And so it seems less likely that it's a direct infection cause. Number two, it could be some kind of indirect immunologic thing that, you know, after a SARS-CoV-2 infection, kids are then getting some kind of immune response that is targeting the liver specifically. I saw there were some questions in the chat about MIS-C, and is there overlap? And, you know, I think that all kind of fits in that same bucket of how we're approaching this epidemiologically. And so largely what we're trying to do is see how can we best identify if kids have had past infection. We're doing that at CDC by asking in our forms whether or not they've had past infection, asking if they've been tested in the past. We can look in surveillance data to see if they were reported as a case, but we all know the kids have mild symptoms. And so there's probably a significant number of kind of silent infections, which is why everyone's asking about antibody testing. So I think what I can say on the CDC side is we are coming out with new lab guidance that will probably more strongly recommend serologic testing for SARS-CoV-2 in these children. And if you're not having access to consider sending a specimen so that we can help do the testing, that'll be coming in the near future, and or we'll ask for results to be reported if they're done at the clinical site, which usually is the quickest way. The one challenge to that, though, that I will temper and that we've spent time talking about is that after the Omicron wave, over winter here in the United States, we know that children in this age group have pretty high levels of antibodies for SARS-CoV-2. And so interpreting results might be challenging in that from our seroprevalence data, we know that probably seroprevalence is probably 70% in this age group. So we'll work with that kind of as we get results. The third thing that, and someone else's comment in the chat alludes to this, the third thing we're considering is did the lack of exposure to whether adenovirus or other common childhood viruses during the pandemic lockdown somehow increase a signal that kids get a viral infection and some small proportion of them do have an extreme hepatitis. Maybe before we didn't see that because we only had one age cohort that was having their first infection, whatever it might be. And now we have a two or three times the size of the cohort of kids at risk because they were not exposed the last two or three years. That's the third thing that we're looking at as well. And so some higher end laboratory testing which includes pathology and immunologic testing, I think is going to target some of that to see if we can get data behind it. Thank you. Dr. Easterbrook, do you have anything to add to that? Yes, I mean, I think just to say that, I think early on there was a sort of focus on adeno and I think there was an initial sense that the pickup of the PCR positivity for COVID was quite low, sort of 12%. But it was important to recognize there was also variation, that there were some countries that were actually reporting a higher proportion that were PCR positive, but there's still limited data from across the countries. But then very importantly, the next step was to really look at the serology. But with all the caveats and the challenges that Dr. Kirklings mentioned, we know that the antibody positivity rate would be extremely high in those children. So the interpretation. But I think doing the serologic testing now and going back and trying to get a bit more information on that, particularly from other countries which didn't have this very high, perhaps had a lower prevalence of antibody positivity is a really important sort of now line of inquiry. And we are also capturing in our new case reporting form, all the information on previous COVID testing, both the serologic as well as the PCR. And I think just to say that the scientific community is obviously forever inventive in responding to the sort of evolution of the data. And so some very interesting mechanistic hypotheses have been proposed, and I'm sure you may have read the letter in Lancet Hepatogastroenterology, which was on this super antigen mediated immune activation. So COVID infection in the past, sometimes perhaps some time ago, residing in the gut, and then an adeno infection or perhaps some other infection really sparking off this intense immune activation and the well may be a genetic mediated response to that host and the host genetic studies will help. Yes, that was really a very interesting speculation. We have time for one final question. Rohit, do you think we have time for one final question? I was gonna address this to Dr. Mohammed. I think that maybe you could comment on how the collection of data for the REDCap survey will integrate with what our centers are already reporting to the CDC through our local health authorities and making sure that the REDCap survey isn't redundant, but only complimentary to that reporting so that maybe it, how is that gonna integrate? Yeah, thanks for that question. I think there are going to be some sort of obvious redundancies. I know what we're reporting to the Department of Health of Tennessee, and I'm sure everyone else is reporting up doing all the same. So we are collecting, I think a lot of our data are similar to the WHO case form where we are asking for some SARS-CoV-2 data, not actual serologies, but just data on vaccinations and whether they've had it recently. We're asking things like the ALT and AST levels, INR, which I don't think are on all the CDC forms for the peak lab values. So we're still, we've created, but have been tweaking it and have been looking at the different sort of case forms that have come out and are gonna try to make it sort of as easy as possible to enter the data and to get as many people to do it as we can. Thank you. And thank you to the moderators, Dr. Parpin, Dr. Alonzo, and to all the speakers, Dr. Kirking, Dr. Easterbrook, Dr. Gutierrez-Sanchez, Dr. Muhammad, and to ASLD and NASP again for allowing us to co-host, co-sponsor this event. To that point, to Dr. Muhammad, ongoing efforts, NASP again will continue this discussion on Twitter this Thursday. We have yet another opportunity for people to ask questions. And once the REDCap survey is launched by NASP again, ASLD, we hope to have participation from all and potential every site. Thank you so much. Thank you.

webinar

acute hepatitis

children

reporting

investigations

cause

clinical presentation

evaluation

global situation

outbreak

survey