Welcome to our talk. We're going to be focusing today on discussing the emerging special pathogens in the year 2023, but also looking back and understanding a little bit more about the different disease processes and managements and how we can prepare for them. And we wanted this course to be something for all providers, right? It shouldn't just focus on infectious disease doctors or pulmonary-clinical care doctors. We want to open up to everyone to really understand exactly what we've learned and how we can share that knowledge as well. So I'm joined by a wonderful cast of phenomenal colleagues here with Dr. Kelly Cockett, who's coming from Nebraska. She's going to be speaking on the challenges and opportunities in ICU preparedness for special pathogens. Dr. Gavin Harris is coming from Emory, and he's going to be speaking on the role of medical countermeasures in special pathogens. And I'm Roderick Pustelniku. I'm at NYU and at Bellevue Hospital in New York, and I'm going to be speaking about the current landscape of special pathogens in this year, and just giving an update of where we are and what the different disease processes that we're following are currently out there. So all three of us are actually part of NETEC, which is the National Emerging Special Pathogens Training and Education Center. So this is a program that was developed around 2014, whose mission is really to set forth the gold standard for special pathogens preparedness and response across the entire United States, and really our vision is to create a sustainable infrastructure and culture of readiness for managing any sort of suspected or confirmed special pathogens across the country. And we're comprised of 13 different areas where we have regional emerging special pathogen training centers, and those are the ones that we really work very, very closely with in updating them on guidance and processes and just communicating about any potential risks that may be down the pipeline, and really having a network across the entire United States to be ready for any potential special pathogens that may come back to the United States in the near future. And really it's an amazing group of incredibly talented people that are really at the forefront of preparedness for the entire country. So my talk is going to be on the current landscape of special pathogens. I have nothing really to disclose. And what I want to focus on this morning is really going over a few core topics. I want to discuss what special pathogens are, what that really means to us when we hear the term special pathogen, you have a little bit better understanding what we're defining. Talk about different modes of transmissions. I'm going to focus a little bit and give a little bit of background on viral hemorrhagic fevers, focusing on Ebola virus disease, on Cremerian Congo hemorrhagic fever, and Marburg. And then lastly I'll close it out and we'll focus on H5N1, which is the highly pathogenic avian influenza A, which is now becoming more common and we're going to have a little bit more to discuss probably over the next few years as well. So when we're trying to define a special pathogen, what we're trying to look at is we're trying to look at the characteristics of the pathogens. So they can be placed in three different groups. Are they hazardous? Right? So a disease which causes a high incidence of morbidity and mortality. Are they infectious or potentially transferable to new individuals? Or are they communicable? Right? Are they, to what degree can they actually be transferred between different individuals or how contagious can they really, really be? And Ebola in this case is really in the middle of, as an example, of an infectious, a communicable, and a hazardous disease process. But what are the real special pathogens? We've intentionally kept away from trying to generate a list because the evolving nature of this whole disease process and the definition, but conceptually what we're discussing is essentially these three, hazardous, infectious, or communicable. And those are really, if they all fit in and it fits right in the middle, to us that's going to be a special pathogen. That's something that we're going to be discussing. And in general, given sort of the significant nature of these special pathogens, they often should be managed in a biocontainment unit. And there's a few across the country. I'm not going to focus on management of biocontainment units at this time. But there's a few that really, these are the disease process that we really want to focus on and we really understand when we're discussing essentially special pathogens. Such as viral hemorrhagic fevers like Ebola, smallpox, Nipah. These are pathogens that really raise political and assurance concerns, are most likely to present as a single case and can lend themselves essentially to BCU level care and really need of special guidance and special processes in place. So when we're thinking about them, we have to understand what are really the modes of transmission for these special pathogens. There's very different ones, right? They can be contact, they can be due to droplets, maybe droplet nuclei. There's really a variety of potential transmission vectors and that's really what's important for us to really understand how can we be prepared from a PPE point of view, from a containment point of view. These are all really, really important to understand in order to really mitigate and reduce any further spread. Now looking back over the last several years, and I'm not going to focus on COVID, I think we've all learned enough about COVID, but there have been several outbreaks since 2005. We focus on, for example, MERS, which happens usually annually around the Hajj pilgrimage, which is the annual pilgrimage amongst Muslims, they go to Mecca. And usually there's always an uptick in cases around the fall when the Hajj actually takes place. There's Ebola in Africa, and we're going to focus a little bit more detail about the different cases of Ebola and exposures with Ebola as well. And the cases that actually transferred and came to Europe and the United States as well in 2014. And then more recently, we're going to focus on H5N1. So now this is becoming a much more concerning pathogen, one that we're following much, much closer. Initially, it was contained to China, and there's been a spread and movement across from China to Europe, to Africa, and now in the United States as well, and in Central and South America as well. And the reason why this is important as well, now a pathogen can transfer so incredibly easily. We're a connected world. Someone who may have early symptoms of a disease can get on a plane in one part of the world, transfer and fly to another part of the world, and then potentially spread the disease process there as well, which makes it incredibly difficult and incredibly concerning to really contain diseases that can spread very, very quickly, and ones that we define as special pathogens that are highly pathogenic as well. So for us, now given the connectivity that we really have, we really need to be aware and be prepared as well as we can. I'll start quickly talking about the viral hemorrhagic fevers. So what are they? Well, they're RNA viruses focusing specifically on Ebola, Marburg, Lassa. They're enveloped. They're in the lipoprotein outer layer. They really, they naturally exist in animal or insects, and they're really restrictive to geographic areas where the host species live. They don't transfer as easily. Unfortunately, they can transfer from animal or insect to human, and there's been some instances as well of human to human transmission, which are the incredibly concerning part for us. And usually, the outbreaks with VHFs, they're very difficult to prevent since they occur usually in sporadically, and they occur in more remote areas across the regions of where their disease process is occurring. So it's not as easy to contain, and you really need to have an astute network ready to act immediately when one is identified. And there's significant unique challenges with VHFs. Most of the people in the world are at risk for VHF, but since the person-to-person transmission can occur so easily. So this is, again, why it's important. Once we have a confirmation of a VHF case, it can take time. It's not going to happen in a few days. It may take a week. It may take longer, especially depending on where this outbreak is occurring. And in that time process, that's when there's essentially more spread that can occur, especially if the factors are not mitigated immediately. And really, the availability of vaccines and treatments are limited. Dr. Harris is going to speak a little bit more to it this morning. But since we don't have a lot of countermeasures, the highly pathogenic nature of these disease processes is incredibly concerning. So we'll focus now on Ebola. Essentially, Ebola is a rare but severe and often fatal viral disease that affects humans and other primates. There's six species in the genus of Ebola virus, three of which, specifically Sudan and Zaire and Boudin-Buyo. They've previously caused large outbreaks. Ebola viruses are transmitted to people usually from wild animals such as fruit bats. They can be from porcupines and non-human primates. But they spread in the human population through direct contact with blood, through secretions, organs, or other bodily fluids, and they affect people within the surfaces or materials that they're touching as well. So the problem with that is that because it transfers so easily, it can become highly pathogenic. The mortality is about 50% that we've seen in reported cases. It can vary from 30% to about 70%, depending on where the patients of the Ebola are being treated. Obviously, in more resource-poor areas, the mortality is going to be much, much higher. Since 1977, when the first cases were identified, most outbreaks have occurred in Central Africa with one outbreak in South Africa, or at least where they originated. But in 2014 is where we had a widespread outbreak that occurred more in Central Africa and then transmission as well to Europe and the United States. This usually occurred in travelers or people that were working in the communities there, health care workers that went to help with the relief efforts, and they brought it back. And then in the United States as well, there's been some transmission within nurses in 2014 as well, taking care of patients with Ebola as well, which is concerning and speaks to the highly pathogenic nature of this disease. So looking back at 2014, this was a rural disease. We learned a lot from it. We learned about containment. We learned about how we can identify patients, isolate patients, and how to really try to mitigate outbreaks. And since then, we've modernized our approach significantly. And we've modernized our personal protective equipment, how we identify these patients, how we can contain the disease and prevent the spread further from the disease as well. In 2014, the reason we keep harping on this year is because this was the biggest outbreak and the one that really brought it to light to the rest of the world as well. And this outbreak at that point caused mainly, as I said, in Central Africa. But there was almost 28,000 cases that occurred around the world. In the US, as I said, there was a few cases, four cases. There was one death. There was a transmission from a nurse to a nurse as well in the United States. So those are all incredibly concerning because we are learning about preparedness and protection at that point as well. But we've learned so much in those times since then. The most recent outbreak occurred last year in Uganda from 2022 to early 2023. This was caused by the Sudan Ebola virus species. And the Sudan Ebola viruses are first detected in 1977. They cause Ebola that's clinically indistinguishable from the Ebola Zaire strain, but it's less transmissible than it is. But unlike Ebola Zaire, there are no countermeasures and no vaccines available, which make it incredibly dangerous. In Uganda, it was the first Sudan Ebola virus outbreak in over a decade. And there were 142 cases. There were 55 confirmed deaths. And there was 19 health care workers actually were affected. This picture is from some of the containment that occurred at that point. And you can see in the right side some of the bins where patients' personal belongings go or patient discarded material that was used for the patient care are placed and then isolated and left there and discarded appropriately. The personal PPE that the health care workers are using as well has advanced over the years. You can see sort of hot zones where patients can be contained, where health care workers are donning and darfing their personal equipment as well. So it's evolved significantly from the first outbreaks to now us understanding how we can protect not only ourselves, but the patients and the communities as well that are at risk. When we look at the clinical course of EVD, we see that it can go up to about 21 days or so. There's a latency from initial infection. And there's a prodromal phase, which is really interesting. It's very mild. It's usually in the first three days. There's fever, malaise, headaches, myalgias. But what's interesting is that at that point, there's very limited viral shedding. And the blood tests are initially negative. So the PCR tests are negative, which makes it difficult for diagnosis and containment as well. Because someone could be in this prodromal phase, then travel, and then develop the disease. And at that point, they can spread it further as well if they're not identified and isolated appropriately. In the middle, so from days 4 to about 12, is where we have more of the disease process developing. We have some vomiting and diarrhea. And this is what's really interesting, is that the significant amount of volume depletion that occurs in these patients and the electrolyte loss. Usually patients lose about 5 to 10 to 12 liters of volume a day. So they need significant support in this time period. There's metabolic alkalosis, and there's going to be some liver abnormalities as well that occur. And the critical illness usually occurs towards the end of the whole disease process. This is where the patients develop respiratory distress, respiratory failure. They can end up on renal failure, needing hemodialysis potentially. And they go in significant shock. And usually the shock is going to be due to volume depletion, but they can also have hemorrhagic shock as well. And this is where you need the appropriate resources in order to take these patients who are critically ill at this time. From all the patients that we evaluate for Ebola, we see that essentially across the board 100% of them end up having diarrhea. And this is where we're talking about the large volume losses of 5 to 10 liters a day. The mortality rate is so incredibly high because of the fact that in a lot of these treatment centers across the world, especially in rural communities, the supportive care is really not there. And you need a lot of supportive care in order to be able to have a successful outcome on these patients. And care is extremely resource intensive. So if you don't have the strategies in place to be able to take care of these patients, unfortunately the mortality is going to go higher as well. If the patients develop multi-organ failure, you need a real true multidisciplinary team to take care of these patients, which fortunately in more resource avid places like the United States or in Europe is much easier than in other countries around the world. And the one thing that's interesting with this virus as well is that it's really immune and it stays in the body for a prolonged period. So in amniotic fluid, in the eye, in CNS, and even in semen for prolonged cases. And we're still truly trying to understand how long the pathogenesis is actually available while it's there. Shifting gears a little, we'll focus on Marburg briefly. So Marburg is a phylovirus, essentially it's a cousin of the Ebola viruses. It causes a hemorrhagic fever that's very, very similar to that of Ebola. Like Ebola, it can be transmitted from person to person, typically through close contact with people who are very sick, or commonly also for those that are at funerals. And that's where usually a lot of transmission occurs. The funerals in a lot of areas throughout Africa as well are very communal. A lot of the family members and the community gathers. They stay with the body, they hover over the body, they help clean the body. And at that point, that's when transmission can actually occur. Especially early on in a disease outbreak where it's unclear if there's another Ebola virus strain going around. At that point, the pathogenesis is so high that then it can spread to an entire community in that area. Marburg, interestingly, was actually detected in 1967, and it was diagnosed actually by an outbreak that occurred, actually diagnosed by a physician from Marburg, Germany, and then also in Belgrade and Serbia as well. And actually got his name from Marburg, Germany, and that's why it's stuck since then. Hopefully it'll change at some point, but it's interesting how the history of that comes together. There's no real treatment that we have right now for Marburg, and really the case fatality rate is from 23 to 90%, again, in resource-poor settings, the mortality rate is going to be much, much higher. And in 2023, there have been two outbreaks so far, one in Tanzania and one in Equatorial Guinea. In Tanzania, there are eight cases, five of which confirmed deaths, and then in Guinea, there are 16 confirmed cases, 12 of which were dead as well. Next up, just briefly, Cremian-Congo hemorrhagic fever, or CCHF. It's caused by infection of a virus that carries by a tick. Its transmission pathways to humans are from direct bites from an infected tick or from an infected animal blood, bodily fluids, or tissues. The human-to-human infection occurs, again, similarly to the other VHS as well, from human blood or bodily fluids. It's endemic in Africa, the Balkans, the Middle East, and Asia, and has actually what's very interesting, a geographic limitation below the 50-degree north latitude. So most of the cases have occurred really just below that. Above that, the tick is unable to survive, so the transmission is not occurring. Obviously, human-to-human transmission can potentially occur in those situations, but those are much more limited. And countries in the regions that are below the 50th, they're the ones that really have reported those high case numbers. Since January 2023, there have been some outbreaks in Iraq and Afghanistan and Guinea, Georgia, and the Republic of North Macedonia. They've been in Iraq and Afghanistan, there have been 250 cases in Iraq and 1,115 cases in Afghanistan. And again, the mortality rate in those areas have been about 40 to 50 percent during this time period. There's a potential, again, for continued outbreaks, and the lack of specific antiviral treatment for this disease process makes it really difficult, makes preparedness so incredibly important as surveillance as well. And lastly, I want to close out by talking about H5N1, and I think this is where we're going to spend a little bit of time discussing sort of what we understand now as far as pathogenesis occurs, how it's occurring, how it can spread as well, and how it can evolve. And we've learned, obviously, a lot in the last few years with COVID and those transmissions, but H5N1 is something that's on our landscape right now that we're following very, very closely. So H5N1 is essentially a very highly pathogenic avian influenza. It's first identified in humans in 97, and there were sporadic cases of avian to human transmission. Human to human transmission hasn't occurred as significantly, but there's been an uptick in the last few years of human to human transmission, which is very concerning for us. Usually, again, it's been sort of direct exposure to specifically infected poultry, but most recently there's been outbreaks in mink as well throughout Europe, which is concerning that they're showing that there's this pathogenesis now and that the virus has been able to transmit from a different vector to another one now. There's a wide range of disease severity, but what's interesting is that since 97, since we've been following, most of the cases have occurred in young patients, and not as much elderly or middle-aged, but it's probably due to the fact that they're the ones that are working directly with infected poultry or with the mink, and that's where the pathogenesis is occurring. There have been 870 human cases, 460 deaths, with a fatality rate of about 50%, which is incredibly high. This is across 22 countries, and in 2023, we've had some cases in the United States, China, Cambodia, Chile, and Ecuador. There have actually been two new cases in Cambodia this week alone, one in a child and one in a farmer that's in his early 20s, but like I said, most of the cases are in young adults. Looking back at the history of it, what's interesting is that the first human, as I said, was identified in 1997. So in 1997 is when we had the first infection that we've been recording. Since then, there was a lull, but it's probably due to testing and following until 2003 and 2004 and 2005, where there's outbreaks further in China, and so most of it had stayed in China at that point, and then we had transmission that passed on from China to the Middle East and Europe and Africa, until most recently we have the cases that have come in the United States and Central and South Americas here towards the end of 2022 and 2023 as well. What's interesting, this big spike over here sort of shows how preparedness and understanding of disease is really, really critical. So this occurred in Egypt. At that point, there was an outbreak that was in poultry farms from 2014, late 2014, and the Egyptian government had decided that they wanted to pursue vaccination strategy, controlling of the infected parent flocks, and sort of zoning and limited movement across the country. Unfortunately, no one really followed those protocols and those guidelines and just focused on vaccination alone, and transmission from poultry to humans was incredibly high at this point and really just shows how important it is to have a real good preparedness strategy and follow through on especially everything that is decided and not just focus on limited just vaccination alone. You need more input and more follow through. You need to have zoning, you need to have culling of the infected animals, and you need to have more coordination at the government level as well. And when we look at H5N1, so initially how it transmitted, the pattern emerges that there's this shaded area right here in central China. And this was the hypothetical epicenter of the emergence of H5N1, the different clades and subclades that occurred at that point, so it's H5N1 initially at the end. And the virus were being perpetuated in domestic birds of that region, and despite the use of universal vaccination, a lot of the poultry had to be culled, and this is some of the culling that they did as well, where millions upon millions of different animals had to be culled in order to mitigate the transmission of the disease process. For about 15 years or so, one of the key questions that really stood out for us at that point was, especially in pandemic preparedness, is whether the H5N1 virus might acquire the ability to transmit from aerosols to respiratory droplets. And especially what's interesting with that is that we've seen now that in the last five years or so, there have been significant changes in the sequences of the H5N1 at that point, in the clades and subclades of H5N1. And at that point, we've also had this transmission from poultry now to mink, and mink to mink transmission, which shows you that the virus is evolving, and it puts it at really high risk that if it evolves even further and continues to go down this pathway, well, what does that mean when we have mink to human transmission and potentially human to human transmission as it continues to evolve? If it becomes much more easy for this human to human transmission to occur, we're going to be at another situation where a pandemic could potentially occur as well. So this is obviously a very significant concern for us and something we're following very, very closely. The way H5N1 presents, and these are some x-rays shared with a colleague from the CDC, and unfortunately, they're not great quality. These are a picture of a picture of an old film x-ray, but in general, again, it looks like a pneumonia pattern. It's going to be a diffuse process, and most of these patients end up in respiratory failure or ARDS. It depends on the resource support that is in that environment where the patients are living. There's a patient earlier this year in Chile that was placed on ECMO. Unfortunately, they didn't survive, but in general, it's going to be a significant pneumonia ARDS picture with shock as well, TIC and AKI, that's sort of concurrent as well. But we don't have any effective therapies for these patients at this time, and there's no vaccination, so really, it's going to be supportive measures, and again, it comes back to the situation where you need to have enough support in the environment to take care of these patients. So a resource-limited setting is going to have worse outcomes than a very resource-avid setting like in the United States or Europe or even in Central America and South America or certain countries. So in summary, we've talked about many different recent outbreaks that have occurred. There's been an increasing prevalence. We've focused on Ebola. We haven't had any significantly in the last year, but in 2022, we had one. We talked about Marburg, CCHF, and recently H5N1, the one that we're following very, very closely. We know that the modes of transmission are really important. The human-to-human transmission, the vectors are incredibly important for us to understand, and really, unfortunately at this point, and Dr. Harris is going to speak a little bit more about it, how can we actually treat these different processes? Are there any countermeasures? We're evolving. We're understanding a bit more, but for the most part, it's a lot of supportive care for this disease process, so you need to be in an environment where you can really support these patients. And with that, I thank you, and don't forget to evaluate the session after that. Thank you, everyone. Good morning, everyone. No, Dr. Polson-Niccio and I did not coordinate our outfits this morning, but you missed the memo, yes. Dr. Calkin missed the memo. In any case, I'm Gavin Harris here on behalf of NETEC, for which I do receive funding. It's nice to see some great familiar faces in the audience, so hopefully people will keep me honest here. I have some objectives here. We're going to go through some possibilities for medical countermeasures for some of the pathogens that was just mentioned. We'll talk about some prevention, detection, therapeutic approaches, and then also some opportunities perhaps in the future. But first, I just wanted to do an old-fashioned audience response question here, so just for a show of hands, based on the pathogens that was just discussed, how many people feel that at their home institution, if someone presented with a special pathogen, they would feel completely prepared? Okay, we have a few. Okay. It sounds like we have some work to do. How about who would feel somewhat prepared, but a few things left to do? Some more hands. Okay, great. How about, you know, we haven't really acted on much, but we've thought about this in the future? Some more hands, too. How about people would feel perhaps, unfortunately, completely unprepared? We have some hands there as well. Okay. So we're pretty widespread. Good. So hopefully you can take home some, you know, messages here, and we can help with some of that, too. So, you know, when we talk about special pathogens, we talk about biopreparedness. The traditional approaches have been those of what we call the big three Bs, biosafety, biocontainment, and biosecurity. These all form what is known as biorisk management. But as the human and animal interface has changed, as humans have come more in contact with these zoonotic diseases, these approaches may not completely work as well as they should. And so we add to that our biodefense approaches. And this can really consist of three pillars, that of prevention, detection, and then therapeutics, of which I'm going to focus my talks on, or my talk on, excuse me, today. So we already introduced this paradigm or this framework of how we think about these diseases. I would actually argue as well that when we talk about where to treat some of these patients, whether that is in a biocontainment unit or not, we think about whether we have effective medical countermeasures for these patients. And that would be the fourth criteria in my mind. You could argue, as we'll see, that perhaps some species of Ebola don't need to be treated in a biocontainment unit from a physiologic perspective, but perhaps from a socioeconomic and political perspective, we would argue that it's best that they do. So some challenges with special pathogens, right? We know that an ever-growing amount of population in the world is at risk for these special pathogens. As was already mentioned too, confirmation can sometimes take a lot of time. And our landscape for treating is pretty limited. I'm going to add to this slide that we showed here. This is one of my most favorite slides of all time. This is from 2017, so pre-pandemic era traveling. And when we think about what can we do as intensivists in regular ICUs, I want you to think about these next two slides. I'm going to superimpose shipping lanes. You can see there's a lot of traffic around the coast, Pacific areas of the Pacific Rim, the eastern seaboard of the United States. And then we're going to superimpose that with migratory bird routes. And you can see all of our continents are encompassed by this. So at any time, at any point, we can have some of these pathogens present, and it is important to know how we can treat them. Now, the WHO does give us a list of pathogens they are concerned about called the list of nine. But when we think about a list-based approach, as these diseases evolve and as with most of disaster preparedness, our treatments are very reactionary, and we have to start being proactive. Can we identify specific traits? Can we identify specific common themes and perhaps even common therapeutic approaches that can treat not just what's on this list, but perhaps what is coming? I also bring this up because it's important to note that almost half of people who might present to a hospital or to a facility, to an institution, with signs and symptoms concerning for special pathogens do not, in fact, have these special pathogens. So when we think about medical countermeasures, we can't lose sight of the forest for the trees. We have to think about, we have to make sure these patients don't have routine bacterial sepsis, things like malaria. Common things being common, they are part of our medical countermeasures approach. And it's also important, too, because the diagnosis of these special pathogens, as you've already seen, overlap. It's very challenging on a clinical basis to figure out what diseases, in fact, patients may have, especially if we are in settings when access to testing and things like that might be limited. To talk specifically about medical countermeasures that we have, this is what we have right now. It's not a lot, okay? So, you know, for the six species of Ebola, we have one species of which we have licensed preventative vaccines. For Sudan virus, they are in phase one clinical testing. We were hoping to deploy them, as we'll see, in the Sudan outbreak last year, but that outbreak fortunately ended. But unfortunately, from an academic sense, we were not able to engage in proper research to figure out how well they worked. But for the other four species of Ebola virus disease, we do not have any preventative vaccines. As you can see, for Marburg, Lhasa, Crimean Congo, Nipah, Hendra, we also have these vaccines that are in development, very early clinical testing. We also have a non-human primate models. And then for the South American hemorrhagic fever viruses, of which there are quite many, for a few we have licensed vaccines, but only in countries such as Argentina and Bolivia. We do not have licensed vaccines for resource-rich settings. This is a viral hemorrhagic fevers list. I did also just want to mention that for H5N1, as was mentioned before, we do have a vaccine that is not licensed. It has never been used before, and we do not anticipate that at this time. If we did have a significant outbreak of H5N1, we would have the ability to deploy it on a rapid scale. It was originally developed for the U.S. Army. And it remains in our national strategic stockpile. Ebola virus vaccines, we have the most data. And these are the vaccines that we have approved. So Evrebo and Zabdeno, as you can see, their vectors are quite different. The first one uses a reticulobacillus stomatitis vaccine as a vector to deliver the vaccine. And then we have an adenovirus vector for the remaining vaccines. Now, the European Medicine Agency, which approved the second vaccine, it's a two-dose regimen. And that's important to think about, because in the setting of an acute outbreak, a prime and boost model may not be the most effective approach when we're thinking about post-exposure prophylaxis. For Sudan virus, as you can see, 24 platforms are currently under development. Three have reached the clinical testing phase. So a lot of vaccine candidates here. Also utilizing adenovirus, chimpanzee adenovirus vectors, as well as DNA vaccines or recombinant viruses, which may have some potential if we think about targeting multiple different viruses, filoviruses here in particular. What's also interesting is that, well, let me get to that in a second here, too, just to round this off, to think about some of the other hemorrhagic fevers. Again, similar vaccine candidates that we have in phase one and phase two clinical testing have never been deployed on a large scale. Now, mRNA technology has the potential to really change this landscape. And that is actively being worked on at this point. And if you think about it, also has the potential to have rapid escalation of the development of some of these vaccines. How do we utilize these vaccines? Well, we use what's called a ring vaccination approach. And this was the approach taken to eradicate smallpox. When someone is infected, we contact trace. And then we vaccinate those contacts. And then those contacts of those contacts. So we have multiple different tiers or rings. This was the strategy that was quite effective in taking with the Ebola vaccine when it was deployed at the end of the 2014 outbreak, and then also the approach that would have been taken when we looked at the Sudan virus vaccinations. Now, you'll hear more about this in the next talk. But I did also want to mention that aside from our vaccines as preventative measures or preventative countermeasures, personal protective equipment here is super important. And we've all learned this during COVID, during the past several years. But it is something that we can't get in the habit of thinking this is routine. That we know how to treat these viruses. We know how to approach this. Because as you can see, the precautions for each type of these viruses is very different. And it can be really dependent upon what we think is going on. Now, PPE, as I mentioned, is a form of prevention. It straddles all of bio-risk management. It helps us to contain this virus. It helps us to ensure that we don't have misuse of these viruses. And it can also help protect our staff. So much of medical countermeasures involves infection prevention and control. So much of it. Basics, hand hygiene, education of civilians in safe food and animal handling. We heard about the issues with burial practices and funereal practices. As well as sanitation. So it's important to really keep in mind. And there are tons of open resource areas on the internet. This is an image from our NETEC at netec.org. But also the CDC and the WHO have some fantastic graphics about utilization of PPE. All right. I'm just going to shift gears a little bit to our next pillar of medical countermeasures, which involves detection. Okay. So, you know, Ebola virus disease could take weeks when it was first discovered. The diagnosis, confirmation of it. Here, just as of last year, it can take minutes to hours, depending on the rapid diagnostic tests that we use. And next generation sequencing has really revolutionized how we think about these diseases. How we detect them. How we determine where the vectors or the reservoirs might be. Our rapid diagnostic tests in the field is really critical to respond to these rare and re-emerging diseases. And we have different modalities to do this. We have immunohistochemistry, reverse transcriptase, PCR. Viral culture can certainly take a bit longer. And it has to be done under the proper conditions, of which, of course, not every area in the world has the ability to do this. And what's important, and when we're thinking about detection, is that decentralization collaboration amongst the private and public sector is very important here. In the United States, it's very complex. But each state has the ability to run specific tests with confirmation coming from the CDC in Atlanta. In the United States, we do have a network to try to detect some of these diseases. The GeoSentinel Global Surveillance Network, which was established in 1995. This was founded by the CDC in conjunction with other organizations. This serves as a provider-based global emerging infection sentinel network, mostly for travel-based infections. So fevers and the returning traveler. And also communicates and assists with the global health public response. It's essential for how we track typhoid fever, leishmaniasis, Zika virus, dengue fever, chikungunya. We also have the Laboratory Response Network, which was established in 1999. And this purpose is to really have a network of labs that can respond to biological and chemical threats and mass casualty events. It includes state, local public health reference laboratories, veterinary labs, military labs, as well as international labs as well. Here in the United States, the CDC leads this. We also have the U.S. Army Medical Research Institute in Fort Detrick, Maryland. The National Medical Reference Laboratory. And there's about 130 or so additional reference labs and sentinel labs throughout the country. From a military standpoint, we have the Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense, which is part of the Department of Defense. And then with BioFire, developed a film array and warrior panel. This is how we detect specific diseases that can be used for a variety of tissues, such as cerebral spinal fluid, wounds, blood, et cetera. This was a partnership with 16 high-priority domestic laboratory reference facilities. And now with the Administration for Strategic Preparedness and Response, as well as all of the NETEC sites that we saw on the map earlier. And then lastly, we also have the CDC Division of High-Consequence Pathogens and Pathology, which also includes the Viral Special Pathogens Branch, which has really been responsible for the medical management of some of these special pathogens. So we have a lot of different levels, and it is very complex. And it varies, of course, between geographies and also depending on socioeconomic availabilities. So that's prevention. A little bit about detection. Let's talk about therapeutics now. This is also the landscape of what we have. It's not much, as you can see. So for Marburg virus, preclinical testing for specific monoclonal antibodies for Sudan virus, phase one clinical testing as well for MBP134. Now we used to use ZMAP, which was utilized in the first Ebola outbreak. That is no longer in use because it was found to be less inferior, more inferior, excuse me, than the two licensed monoclonal antibodies that you can see on the screen that we have for Ebola virus disease. There's also a monoclonal antibody in development for our Hendra viruses, so, excuse me, our Hennepa viruses, so Nipah virus and Hendra virus. I'm going to skip over remdesivir for the moment. Ribavirin we use for a wide variety of viral hemorrhagic fevers as well as some other viruses too. It inhibits RNA metabolism. So it may play a role in a wide variety of conditions. It's very toxic, as we know, and it's very challenging to give. Similarly, favipiravir has a broad antiviral activity in interfering, excuse me, also with RNA metabolism and may play a role here in certain viral hemorrhagic fevers, specifically those in South American hemorrhagic fevers. I'm not sure we've truly found a home for remdesivir yet. We certainly try very hard, and we have continued to try. It was originally developed to combat Ebola years ago, and we've employed it in just about any viral outbreak that we've had since with mixed results. So perhaps it plays a role. That's really much it at the moment. If we just take a think about the type of therapeutics that we're dealing with here. So there's only three antivirals I really have on this screen here. The rest are monoclonal antibodies, and that's on purpose because we really have potential, I think, in this sphere to utilize monoclonal antibody development to attack and to target these specific viral hemorrhagic fevers and likely special pathogens on a much broader scale. One thing I haven't put on here as well is to think about any therapeutic medical countermeasures for our respiratory viruses, such as MERS, other coronaviruses, and highly pathogenic avian influenza. As was mentioned, we really don't. We assume that Tamiflu would work for something like H5N1, given that it is an influenza A virus, but it's never really been deployed or utilized in human cases to good effect. So it may have some mixed results there as well. But I do think that monoclonal antibodies hold the most promise. When do we think about how do we put this all together, right, in terms of medical countermeasures? So to use an example of Crimean-Congo hemorrhagic fever virus outbreak events to think about this. So the virus itself circulates in wild animals. So it will circulate, and it will vary depending on the varied weather patterns for multiple years. It will increase in ticks and rabbits and other vectors as well. At some point, there will be a spillover event, though. And that spillover event may occur into wild animals that are additional to the original vectors of ticks, or it may occur into domestic animals, in which case there will be amplification, given the living conditions. And at a certain point, there may be a spillover event into humans, those who come in close contact with these animals, in which you will have amplification and you will have an outbreak. We need to take a One Health approach when we think about how do we utilize medical countermeasures. So if we put all of this together, our detection strategies really need to be very early on. Ideally, when this virus is circulating in wild animals, which may be, of course, be quite challenging, we want to detect these events before they happen, or perhaps at the very instant in which they happen, right at that point of when there is a spillover event. And we also want to think about when do we deploy vaccines. You can see that syringe with that dotted red line. Well, do we want to vaccinate just our human populations, in which case we won't be preventing a spillover event? Do we also want to start to think about vaccinating domestic populations? Do we want to think about can we really vaccinate wild animals to prevent those spillover events? And I would argue that we want to think about taking perhaps a three-pronged approach to flatten that curve of the amplification events in domestic animals, and also to flatten the curve of the amplification in humans. This is what we call vector control. Once we have the surveillance, we detect an event, we detect an alert, well, then we have to respond to it. And this is the control phase, so the number three that's in there in green, because we want to ensure that we can provide the best benefit to our domesticated populations of animals, as well as humans, too. This is where we deploy our therapeutic medical countermeasures. And so all these different approaches contribute to how we control outbreaks. It needs to be in a multi-tiered, one-health approach, meaning encompass all areas of wildlife, of the environment, and also human populations to have the most benefit. In turn, this will protect global health security. So when we think about what can we as intensivists do, we are all part of the response team. Everything that we do, from surveillance to testing based on our level of suspicion, based on the history that we can take for these patients to determine their travel history. We can think about our proper infection prevention and control practices, which you may hear more about. The actual clinical management of these patients. We can assist with outbreak analytics. The last two on the right side of the screen may perhaps be the most important. Because the community in which we work may not always agree with the work that we do, but it's important that our messaging is clear as to why we do it, how we are protecting folks. And so communication with our team, with the community is extremely important to engage people to really understand that when we attack these viruses, when we utilize all of our medical countermeasures, we are really ensuring global health security. Because we may not always have access to the appropriate clinical testing, the appropriate medical countermeasures, but we certainly all can play a role in helping. And that leads me to perhaps the most important medical countermeasure, and I think we talked about this a little bit already, is that early and aggressive, good critical care supportive therapy is perhaps most important in these patients. That is perhaps the most important medical countermeasure that we have. Evidence has shown that while they have significant fluid losses, treatment in ICU level care, especially for these viral hemorrhagic fevers, is extremely effective. And we had vast differences in mortality rates from those who were treated perhaps in resource-rich settings, such as the United States, Canada, and Europe, versus those who unfortunately were not able to be treated then. Survival rates are upwards of 85% of those who were treated in resource-rich settings. And if you, you know, if we think about, well, what if we don't do this? Well, there are significant costs with this, and we learned this in 2014 here in the United States. A patient walked into an emergency room in Texas and was misidentified as having a regular viral hemorrhagic, excuse me, a regular viral illness and was sent home when in fact that patient had Ebola. And that patient came back and it led to two nosocomial cases of Ebola virus disease and one death. Other countries, just from, you know, thinking about SARS-CoV-1 outbreak in Canada, we want to think about economics here. There was over $1 billion in tourism costs, and excuse me, in tourism profits that was considered lost because of this. So it significantly impacted the domestic economy. Of course, we can think about what SARS-CoV-2 did if we think, if we want to, you know, consider the last three years as well. So significant infection prevention practices failures can really be harmful to patients and can prevent us from delivering the best medical countermeasures that we have. Some additional challenges, well, I mentioned this. We focused on list-based approaches in the past. That probably is not going to be a sustainable approach moving forward because it fails to account for unknown pathogens and also those without historical precedence. We have to think about developing and maintaining flexibility with the deployment of testing, with the deployment of therapeutics, and also with the deployment of preventative medical countermeasures as well. And I just, let me pause there. I'll leave it with that because the rest, Dr. Colcott is going to take us home. So thank you. All right. Well, thank you so much. And it's fantastic to have all of this really great education about kind of the global perspectives, the countermeasures coming into my talk because my intention really here is to give you a little bit of the nitty-gritty of, for all of you who didn't feel 100% confident that your organization is ready for a special pathogen. What can you take away with all of this education? And what are some actionable things that you can bring with you to try and help be prepared and help prepare your organization should a special pathogen arise? So I think this is really incredibly important when we think about all of these outbreaks that we've heard over time being represented to you in all this education, which is that history repeats itself. And it has to because we never listen. We never learn enough to be good enough to not have all of the failures and the errors and a system that is cohesive and strong enough to withstand a pandemic. And this is incredibly important because when you look at the history of pandemics over time, you will see a transition into viral pandemics. Now, this is not including Ebola and some of the other things where there were outbreaks or epidemics. There are innumerable of those in addition to what's on this chart. But what we know is that the probability that another pandemic likely as a virus has a two to three-fold increase in frequency that we should anticipate it. And so if we know it's coming, we need to actually be prepared for it to show up because we never know when that is going to happen because of all those maps you've seen of the travel and the exposure and the changes in viruses. So you've seen a few variations of lists like this. This is not comprehensive by any stretch compared to some of the others. But any of these could show up at your front door of your organization. They could walk into your ED, they could be in your ICU. And the question is, if it is, then what? And then you have your disease X idea. What might we see? Something that doesn't have a name yet, just like we saw with our COVID-19 pandemic, right? A new pathogen arising. And these are constant threats to human health that we may see that jump from animal to human of a novel virus again. It can present anywhere in the world. And all of these things that you've heard about with climate change, travel, urbanization are all hugely impactful for this. And it is an issue, especially when you think of those three circles you've seen, right? We don't know when there is a new emerging pathogen what the infectivity really looks like. We don't know how communicable it is right away. We don't know what the hazard may be in full. So we have to be prepared and err on the side of higher level infection control, higher level awareness, and a really good clinical history and clinical care in order to be prepared for these and prevent continued transmission and risk to ourselves, our colleagues, our communities should a special pathogen arise. So that early recognition is incredibly important. And some things to think about, what might it look like if something shows up on your doorstep? You might have some unusual disease presentations or patterns that give you pause. You might not. It might look like pneumonia. But other things might be slightly different or the history might be a little different. You might have a small outbreak of patients presenting pretty close in time with a very similar syndrome. But it's not really identifying out the right way. And you need to have that awareness of possible travel-related exposures. So I believe all of our organizations ask every patient more times than they could ever want when they show up. Where have you been? Where have you traveled to in the last so many days? What kind of symptoms do you have as you come in? Because we're always screening to see, is there a chance that you are importing something to our facility that could be a special pathogen? And what should you be doing? So if you're worried about it, you really have a person under investigation, right? The PUI, that's the language you're going to hear. And it includes two major components. The clinical syndrome of what are they presenting with, what are their labs and images looking like, and then the epidemiologic history. And this is where you all need to harness your best ID doctor self and ask those questions. So what are you going to do? Harness your best ID doctor self and ask those questions. Have they had exposures to an infected person? Have they been traveling to somewhere where there is known widespread transmission of cases of a special pathogen? Or are they coming from a place where there has been an outbreak and now they've traveled back, but you don't have more details on that? Or they think there was an outbreak of something, but you don't know? But asking a lot of really good questions is really important. And why do I say that is important? Because if you think you have a case like this scenario, three patients come in from the ED and they're admitted to the ICU with fever, cough, and shortness of breath with impending respiratory failure. Because you all asked your great ID questions, you find out that they traveled in a group of five to Saudi Arabia with travel in rural and urban areas, including travel with camels, and returned three days ago. They did note that the guide who was also caring for the camels became sick on the last two days of their trip with a cough. So if you think about this, this should automatically raise a little bit of a red flag, right? An area where there's been MERS outbreaks that have been documented regularly, a respiratory syndrome, a lack of clarity, and a group of people all sick with the same thing. Now it could be a variety of other things, but this story should make you pause and say, what am I going to do? Who am I going to call now? Because I do not want you to walk away from this lecture thinking that you should not be getting help because we all need help with these cases, and it's a multidisciplinary impact. And it may mean that you extend outside of your physical borders of your organization for that assistance. So the first thing you do is not call someone. If you've identified the concern based on those two criteria, you move to isolate that patient immediately. A private room, minimizing exposure to others, PPE, with at least that fluid and permeable gown, double gloves, surgical mask, and face shield kind of eye protection. You want to minimize the risk to any healthcare workers entering that room to the best of your ability until you know more. You dedicate patient equipment. You isolate anyone else with that patient. And then you step to inform. And the first call is usually to your infection control team. What do I do with this? Help me. And then you often are simultaneously being on a phone call with infection control and state or local health departments to figure out how do I get appropriate testing? Does this match really a true PUI case that we need to be testing for? And how do I do that safely without exposing lab personnel, anyone else? What do I do in this scenario? And it's really important because although we rely on this isolation and PPE, the other thing that when we think about challenges as you move someone to the ICU is PPE is like the bottom of the barrel of protective status. So you need it. It is critical. And it is the foundation of a flipped up pyramid. It is what we need to do. But we need to think about what other controls we can have in place. And I'll provide a few different examples of this in a moment. But it's really important. And I'll provide a few different examples of this as we go through a little bit later on. But how can you control to minimize spread with how your organization is engineered? How do you move through that process safely? And it's really key to think about this all the way through as far as how you can remove the hazards, how you can adjust to decrease the risk, what controls you can put in place as physical barriers, changes of ventilation, other components of that. And how you can continue to protect healthcare workers. The problem with this with an emerging pathogen is that we know this dogma of medicine that to err is human. But so is to fear in a special pathogen. And the problem with fear with any of these special pathogens arriving at a front door is that we know if your healthcare system or you as a clinician are driven by fear, you decide to move beyond the normal protocols. We tend in states of fear and uncertainty to say, that infection control plan really isn't as good as I want it to be, so I'm going to add extra things that I think are best. I think it's safer. And in actuality when you look at the research, what happens is when you make those extra steps yourself, you actually end up having more failures of infection control procedures and policies when you deviate from standards of care. And so it's really important that when this happens there's an immediate discussion and ask for help to minimize the fear and the errors that can happen in these scenarios. And as you've heard already in both of these lectures, early care is both safe from an infection control standpoint and also supportive. And that includes critical care, supportive care being your main say of treatment. Yes, you may have additional countermeasures to deploy, but you really want expert care in those scenarios with really talking to experts in infectious diseases, biocontainment, special pathogens care, to find out whether you have access to medications, safety to medications, and frankly whether your patient needs to be triaged up to another level of care in which a unit is more prepared for biocontainment and high level lab safety. So where do you start? You start local. You start with your infection control calls, your infectious diseases team and your health department. If you don't have a protocol at knowing who to call and where to call, you need to have that for your teams. You need to know what the next steps are and who takes those first calls. But you also need to know, oh no, I lost my slides. All right, well, in the interim, you should know that there are still, as were mentioned, with NETEC and many of the other organizations available both in the U.S. but also globally, you have resources to call for help, for consultation and preparedness to get access to that expert care if you don't have access to an infectious disease physician, if you don't have access to an infection control physician. And those pieces are all, oh, here we go, really important to have some awareness to on that who are you going to call standpoint, you should be calling. Sorry, guys, it makes it a little more awkward, doesn't it, when I can't see any of the slides and they disappeared from that perspective. So I know we're coming to the end of this scenario here. But there are a few other things that are really important to take home and hopefully we can figure out how to either make the slides available or touch on those after. But outside of that identify, isolate and inform, some of the next things you need to understand is there are some phases of incident management that become really important as an aftercare when you think you've identified a patient and you're moving through that field of care. And that really comes down to a really good debriefment of what happened, how did they present, what did we do, what mistakes did we make, what is our current status, do we need to mitigate anything if you have a patient or multiple patients still present, because it's kind of like a quality improvement cycle with PDSA. And then you have that end point of how do we kind of resume and recover back to normal. But I would argue you should never go back to normal. You should always be better than you were the first time. And if you're not cycling to be better, there's an issue. And then finally in that last piece of what do you take home with you is the thought of, sure, maybe it was only three patients, but what if it had been 30? Are you prepared in your ICU for the appropriate surge capacity? Do you have the appropriate space for patients or how you would make space? Some examples of that in the pandemic were transitions to negative air pressure rooms. You have the idea of staffing. How do you triage your staffing? Are you going to use some of the staffing paradigms that use different extending patterns if you needed to do that? Do you have a good plan still in place for that? Do you have a good plan for your stuff, for all that PPE and how to make sure you have enough this time so that you don't run out like you did before? And do you need different PPE or different types of ways to deploy that PPE to make it faster and more accessible to provide adequate patient care? And so you have your staffing stuff, space, and then you finally have systems. And did your system actually work? Is the system in place prepared for this? And if not, again, reassessing all of those very specifically to the ICU and the emergency room on how you execute that level of care. So with that, please just remember, these emerging pathogens can show up anywhere at any time. They can be in your organization. You want to identify them early. You want to take that really good history and recognize it quickly. You want to identify it, isolate the patients, and then inform as you ask for help, will you continue to provide that high-level supportive care for these patients until further expert guidance is available? And then make sure you go back after the fact and make sure that you review the entire scenario so that you are better prepared for the next scenario because it will happen again. That is what we are learning with history. It will repeat, and we cannot fail to listen to the lessons learned from all of these other outbreaks, epidemics, and pandemics. Thank you.

emerging special pathogens

Ebola

Marburg

CCHF

H5N1 avian influenza

NETEC program

biocontainment units

transmission modes

outbreak prevention

remote areas