Welcome back. In this lesson we have another special presentation. This time from Doctor Bruce Ribner, professor of medicine in the division of infectious diseases at Emory University and the medical director of a serious communicable disease unit at Emory University Hospital, and the person who lead the team that successfully cared for Ebola patients here at Emory University Hospital. Doctor Ribner's talk entitled Treating Patients with Ebola Infection in the United States, Lessons Learned, was given as a department of medicine grand rounds here at Emory on January 27, 2015. >> December 26, 2013, and 18 month old boy who lived in Guinea developed an illness characterized by fever, black stools, and vomiting. He died two days later. By the second week in January, several members of his immediate family had developed a similar illness, followed by rapid death. The same was true for several midwives, traditional healers, and staff at a hospital, which cared for them. Although these unfortunate people and the health care workers who cared for them were not aware of it at the time, this was the start of the biggest Ebola Virus disease outbreak in the history of the world. This graphic shows you the involved area in West Africa where the outbreak is ongoing. The yellow circles are sized proportional to the number of cases in each locale, and you can readily appreciate the multiple epicenters that have occurred in this outbreak. This is a time line which shows you the basically all of the major outbreaks of the Ebola virus disease since the initial outbreak in 1976. Two things I would like to call your attention to. Number one, you will notice that there are a number of gaps where there are years where no activity was detected, and we'll get into the importance of that in a couple of moments. The other thing I would draw your attention to is that with the current outbreak in, even in the late summer as it surpassed 1000 cases, had already dwarfed any other prior outbreak which had been recorded up until that time. Now, to bring us to today, or, more correctly, to last week, because this is a rapidly moving target. You'll notice that the total number of cases identified by the World Health Organization, which is undoubtedly a gross underestimation, is that there were 21,797 cases identified of Ebola virus disease of approximately, approximately 8 to 9,000 of whom had died. What you can also appreciate from the curve which is shown on this slide is that while the slope of the curve in Guinea seems to be bending, as we pour more and more resources into this part of the world, and while the slope for Liberia seems to be bending, we're not sure we can be optimistic about what is happening in Sierra Leone. So still a, a tragic outbreak, which is ongoing. So just by way of background, Ebola virus belongs to the family Filo-viruses of which there are two genera, the Marburg viruses and the Ebola viruses, both of which cause a very similar clinical picture. They are enveloped, negative, single-stranded RNA viruses. Within the Ebola viruses there are five species. There's the Ebola, which is sometimes called Ebola Zaire, which was an, its original name. There's Sudan, Tai Forest, Bundibugyo and Reston. The first four of these cause clinical illness in humans. The last one, Reston, named for an outbreak in a primate colony in Virginia, causes primarily illness in nonhuman primates. Both of these classes or genera of organisms are transmitted by contaminated blood and body fluids. And historically mortality from Ebola virus outbreaks has been on the order of 40 to 88%. Now as I noted on the timeline there are periods of multiple years during which there is no identified human disease occurring. And whenever we see a pattern that looks like that, we think about an animal reservoir. And in the case of Ebola disease, it is, it is currently felt that the natural reservoir for this infection is the fruit bat. The fruit bat is infected, but does not develop disease, but does transmit the virus to other mammals, including non-human primates, and occasionally humans. And once there is acquisition in humans, there is then the potential for person to person transmission. Going back to our unfortunate 18 month old child. When field epidemiologists visited his village, they found that the area where the child had been playing included a hollow tree which was heavily infested with bats. They further noted that in that region of the country there had been approximately an 80% deforestation due to mining and timber operations, which as deforestation undoubtedly does, brought animals, including the bats, into close proximity with humans. Looking a bit at the clinical disease associated with Ebola virus, there is a latency period of two to 21 days, most typically it is eight to ten, this is where the magic 21 day quarantines and all of the other interesting measures that have been taken in the United States come from. After the, end of the incubation period is a one to three day prodromal period, which is characterized by fever, malaise, fatigue, headache, and myalgias. Clinically indistinguishable from malaria, Lassa fever, Typhoid fever and many other infectious diseases which are endemic in this part of the world. For those patients who do have blood testing done, they are leukopenia, leukopenic especially, lymphopenic, and they have thrombocytopenia. Fortunately, during the prodromal, the patient does not usually have viremia, which means the blood PCR is going to be negative. It also means that there is very limited potential for transmission person to person. Regardless of some of the measures we've seen for control which have been taken in the United States and elsewhere. Starting on day three to four and lasting for about the next week, is what we call the fever and gastroenteritis hepatitis stage during which there is vomiting and diarrhea with substantial volume depletion and electrolyte loss. This is occasionally referred to as the wet period of Ebola virus disease because of the enormous amount of secretions and excretions the patients are putting out and the implications for transmission during that period of time. Patients have a metabolic acidosis, they have a fairly pronounced hepatitis with the AST greater than the ALT, but minimum elevations in bilirubin and usually only slight elevations. In the alkaline phosphate phase. [COUGH] During the second week of illness is when the patients become critically ill with respiratory distress and failure and renal failure present in a high proportion of the population. But also encephalopathy, encephalitis, shock. And rarely, but occasionally, severe hemorrhage. Now most of these observations have been made over the last 40 years by our colleagues treating patients in West Africa. Unfortunately, they do not have the sort of infrastructure that we are blessed with in this country. And so, as more patients have been treated in developed countries, we have made a number of observations, which they were not able to make. It is striking that in most of these patients that are treated in developed countries, we see simultaneous hypovolemia while the patients are gaining 10 to 20 kilos of fluid. And this is secondary to the fact that as the patients have hypoalbuminemia and vascular damage, they develop enormous third spacing. Now this is an observation which is not traditionally made in third world countries, because pragmatically speaking in most Ebola treatment centers in Africa, they are unable to keep up with the 5 to 10 liters a day of body fluid that these patients are losing. And so they do not develop the third spacing, but they certainly develop profound hypovolemia. There are also marked electrolyte abnormalities and nutritional deficiencies really regardless of when the patients are seen or the severity of illness. Hypokalemia, hypocalcemia, hyponatremia to varying degrees. We have seen this causing cardiac arrhythmias in several of our patients. And the patients frequently are so hypokalemic that we certainly replace them intravenously, but frequently have to also look at oral supplementation as well. The key to survival of patients with Ebola virus disease is high-level critical care and this primarily descends down to excellent nursing care and supportive care in the patient treatment units. Most of our patients are extremely nursing intense we actually have two nurses to each patient frequently during about a week of the period of ill, their illness when they're most critically ill. And this gives us the luxury of being able to rapidly respond to various metabolic and other changes that occur in our patients during this extremely dynamic period of time. Emotional support, it's difficult to emphasize how important that was. We had at least one of our patients say to us, you know, I've treated patients with Ebola virus disease. I thought you were bringing me back here, so I would die on American soil. And so, it was critically important to address the emotional needs of some critically ill patients and also because of the configuration of our unit, we were able to deve, deliver good family support even during their most critical phases. So, aggressive supportive care, nothing very exotic, nothing that we don't do on a daily basis in our ICUs. Maintenance of intravascular volume, correction of electrolyte and metabolic abnormalities, correction of coagulopathies. We tend to use a higher threshold for tran, platelet transfusion, because of some recent data suggesting that higher platelet counts are associated with better survival and replacement of coagulation factors with fresh frozen plasma on nutritional support service under Dr. Ziegler was critically important. Not only because these patients are catabolic, as are most of our critically ill patients in this facility, but also because there are good data that as the gastrointestinal tract is ravaged by this virus, appropriate replenishment of various nutritional elements speeds the recovery of the gut mucosa. Uveitis has been observed in prior outbreaks, but during the current outbreak, it has been striking that amongst survivors, 15 to 20% suffer uveitis. Which frequently leads to permanent damage and even blindness, which you can only imagine how catastrophic that must be in this part of the world. The interesting thing is that while there is a mild uveitis during the critical phase of the patient, the most noticeable components are actually seen weeks to months after the patient has controlled the viremia. And in fact, cleared it and after they are, otherwise, clinically quite stable. And this has lead us to speculate whether in fact, this is an immunologic response or whether it's a ju, just a delayed infection in an immune privileged body site. A lot's been written about experimental therapeutics, but I think as of today, it's fair to say that there is no vexing, no antiviral, no antibody preparation, which has been shown to improve the outcome of patients with the Ebola virus disease. One has to appreciate as you're reading about these various agents most of them have little to no safety data. They certainly have no or limited efficacy data. They will also be extremely challenging to use in part of the worlds where this infection is endemic. you need a cold chain to make sure the preparation doesn't denature during transport. And you frequently need careful intravenous administration, which is a luxury that many of these centers don't have. But it's important to emphasize as much as we criticize federal agencies, that the CDC and the FDA were enormously helpful. And helping us work through each of our patients and evaluate which experimental agents might be most appropriate for them. We also had an enormous amount of support from industry and medical and scientific colleagues around the world. We actually had one scenario where some industry representatives actually drove the agent to Atlanta to make sure we would get it in as timely a fashion as possible. Again, the literature tells us that patients with Ebola virus disease have a lot of virus in all of their body secretions and we were able to follow that very closely in our unit. We found viral RNA on the skin, in the blood, in the urine, in the semen, in the endotracheal suctioning, the vomit and the stool of our patients and there was no surprise there. What did surprise us a bit, because it's not really well emphasized in the literature is the level of viremia that we saw in our patients. And these were frequently log orders higher. Then what we see with HIV, or even Hepatitis C infection. And so, it helped us to better reinforce the idea of why there is so much health care infection, and why there is, during the later stages of disease, so much of a propensity towards transmission to family members who may be caring for individuals who don't make it to healthcare facilities. Even a small exposure to one of these body fluids will subject the individual to logs higher virus than we see with any of the other infections which were spread by the same blood and body fluid modality. We found prolonged viral presence what are nominally called immune, immune privileged sites. Such as semen, such as intraocular contents, and there was a recent report by the World Health Organization out of Guinea, documenting two women who where pregnant. Who successfully survived Ebola virus infection. Unfortunately their fetuses did not and when the women were induced several weeks later, there were high titers of virus in the amniotic fluid. So, immune privileged sites remain a concern that we have tried to address in terms of infection control protocols. Fortunately, for the patients who required dialysis, we did not find any viral RNA in the dialysate. And, several of our members did extensive sampling of the room, including the bathroom and the high touch areas when the patients were discharged. But before we did our terminal cleaning, and high level disinfection. And we found no evidence of viral RNA in the room, i.e., substantiating or reinforcing that are infection control protocols were appropriate and did create an environment safe for our health care workers. One of the other factors that we've seen over the last six months is what I'm going to call a very substantial change in the clinical paradigm of managing patients with Ebola virus disease. Before we treated our first two patients in August of this year, it was fairly well established that if a patient developed renal failure, that if a patient developed respiratory failure, there was no point in doing dialysis, there was no point in ventilatory support because the patient wasn't going to survive anyways. So, why bother subjecting them to all of this and endangering your staff. We and others in the developed world, we are now up to 24 patients who have been treated between the US and Europe. Have shown this is definitely not the case. And we have had patients who have been on ventilators and on dialysis for weeks. And yet have completely clinically recovered from their illness. And so, now, there is this substantial change in terms of what individuals are prepared to do during the aggressive supportive care of these patients, and we are now in the process of discussing with our surgical and with our, obstetrical colleagues, whether there is a role to play, in pregnant and, patients with surgical emergencies who also happen to have the Ebola virus disease. Now, it's critical, as it is to deliver aggressive, supportive care. There is nothing more demoralizing than to have a healthcare worker become ill during the care, during the process of delivering that care, and we've all seen at least one unfortunate episode of that in the United States. And that's why we've always stressed, good infection control protocols. As I've said, this disease is spread exactly the same way as HIV and Hep C. Blood, body fluids, respiratory droplets. During the initial phase, the prodrome where it's so difficult to make the diagnosis, it is fortunate that there is usually not viremia and body fluids are not contagious. Unfortunately, as the patient becomes more ill and the log titers of virus reach the kind of levels we've, been talking about, there is substantial risk. And in fact, in many of the centers in West Africa, 25% of the individuals who are infected have been health care workers. Just a brief word about the setting in which we treat our patients, we established a patient biocontainment unit at Emory in 2001. Not because we were anticipating Ebola Virus Disease, but because we were anticipating there would be serious communicable diseases of unknown fashion. Presenting needing our attention, needing us to treat patients with these diseases. Again to emphasize, this level of isolation is not required for Ebola Virus Disease because its major difference from our standard. Contact precautions is the special air handling that we have in the urine unit. And again, Ebola Virus Disease is not transmitted by the air. The initial patient bio containment unit in the United States was developed at an army facility in the Washington D.C. area. We established the first civilian fa, facility in 2001 and subsequent that, to that there have been a unit established at the University of Nebraska in Omaha and the NIH hospital in Bethesda. This is a brief graphic of it. You have a five-minute guided tour of our unit which points out all of the capabilities that we have there. Okay, so, this is the entrance to our unit and the room behind here is called the anteroom. As you'll notice on the wall we have a pressure monitor. The air in the anteroom is supposed to be in designed to be negative with relation to the hallway, so, that the air movement goes into the room and when the door is opened, air goes from the hallway into the anti-room and does not come back out. This pressure monitor is on all the time, so that we're sure it actually fulfills that need. [SOUND] This is the anteroom which is, where all the preparations for going into the patient room occurs. Things you might notice, we have a, light activated sink so, that people don't have to touch handles. We also have a, an intercom system, so, that visitors can look through the glass and talk to the patient without going into the patient room. You will also notice that there is a red square on the floor, actually rectangle on the floor. And that red rectangle is, part of our process for take, taking off personal protective equipment, because we strongly believe that most healthcare workers get infected by contaminating themselves as they take off personal protective equipment. Here, you will notice the shells, that are for the hoods that we wear when patients are, generating a lot of droplets which may be contagious. They basically, fit like bicycle helmets like so and then we have a hood that covers it and covers the shoulders. Again, just another measure to protect our health care workers. As long as we're in that corner, we have a biological safety hood. This is where we do certain specimen preparation under high containment situations. For example, if we're collecting specimens to go the Centers for Disease Control, we would prepare them in that hood. Coming off this room, we have the locker, as you can see, everybody's got their shoes here. They wear special shoes when they go into the patient room. And, we also have a shower. The shower is designed in case, people get a large splash or exposure, they can come immediately into this shower room, and, decontaminate themselves. Now, we have two patient rooms coming off of this anteroom. Both of them are identical. Once again, you will notice there's a monitor. And, this monitor again assures us that all of the air in the patient room stays in the patient room. The pressure in that patient room is negative with regard to this anteroom. So, that when the door is opened all of the air goes into the patient room, and none of it comes out of the patient room. So again, we have, now, two levels of protection in terms of airborne transmission. Air goes from the hallway into this anteroom, and then it goes from this anteroom into the patient room. So, two levels of protection to make sure that no airborne particles in the patient room go into the patient, sorry, into the general hallway. The patient room, itself, has been designed as an intensive care unit. The head wall that we have over there is identical to the head wall in one of our intensive care units. It has all of the oxygen, electrical and suctioning connections that we would require to take care of a patient with any degree of illness. The other thing that characterizes this room is the very special air handling. So, all of the air comes in through the ceiling supply, and goes in a directional fashion, down to the air return. That ensures that there's no turbulence, or mixing, and all of the air goes directly out. Once, once the air goes into this supply, it is HEPA filtered, and then 100% exhausted to the outside. Once again, I call your attention to two squares on the floor, actually two rectangles on the floor. And, once again, these rectangles are designed to be different stations in the process of removing personal protective equipment. Getting back to the air changes, there are 20 air changes per hour in these rooms. So, roughly every three minutes, the air in this room is changed. The only additional thing we have, is each room has its own contained bathroom. And again, this has been designed so that, patient waste can be disinfected before it's entered into the sanitary sewers. So, that no live pathogens are released.