 I heard about the plague outbreak in India a few years ago. I mean, is this the same plague that could be used as a VW agent? Absolutely, Doris. Plague is caused by the gram-negative rod, your sineapestis. It's an organism of great historical importance. It's an organism that has this bipolar safety pin staining. You can see that here on the slide. In fact, it has a long history as a biological weapon. Probably the first recorded biological weapon. In 1346, a group of Tatar invaders were besieging the city of Kafa, now known as Fyadosia in Ukrainian Crimea. And holed up within this city of Kafa were a bunch of Genoese merchants. Well, the plague struck the Tatar invaders outside the city. And in frustration, I guess, they hit upon the somewhat clever idea of catapulting the dead bodies of their fellow soldiers over the walls into the city of Kafa in an attempt to institute a plague epidemic within Kafa. And it worked. The Genoese merchants inside the city got the plague. They panicked. They fled the city, got on their boats, sailed back to Italy, took the plague with them. And from there, the rest is history. That's how the Black Death got its foothold in continental Europe. We now know that maybe this catapulting of bodies really wasn't the real reason for the plague epidemic within the city. We now know that plague is transmitted by fleas. The fleas are carried by rats. Fleas tend to leave a body as soon as it cools a degree or two. And so, in all likelihood, the bodies that were flung over the walls of Kafa probably weren't infectious. And the real reason people inside the city got the plague was the rats burrowed in and out of the city. In addition to this problem in Kafa, or this use in Kafa, we know that the Japanese in the years prior to World War II had a unit known as Battalion 731 or Unit 731. And they did experiments in occupied Manchuria with probably 20 different pathogens and included amongst those was plague. All right. Well, we now have Colonel Russ Byrne, Chief of Bacteriology at USAMRID with us today. He's going to assist us in discussing the plague. Welcome, Colonel Byrne. Thank you. Don't we have plague in this country too? Plague arrived in San Francisco in 1899 as part of the third pandemic. It kind of settled in the southwestern states of this country, northern New Mexico and Arizona and the Fort Florence area. This country averages about 10 cases of plague per year. There are much larger outbreaks in other areas of the world. I think the first two pandemics are worth mentioning too because they're interesting. The first pandemic of plague was known as the plague of Justinian. And again, this is an organism with historical features that are somewhat unprecedented and fascinating. The plague of Justinian was probably responsible for putting the final nail in the coffin of the Byzantine Empire back in the 500s. And then the second pandemic of plague was that great black death that swept through Europe that involved or that emanated from this incident in the coffin. And how long does the pandemic last? Well, a pandemic can last hundreds of years. And in fact, as Colonel Byrne alluded to, we're in the third global pandemic of plague right now. All right. Craig Levy, an epidemiologist with the Arizona Department of Public Health, has many years of experience with plague out there. So let's listen to him talk about the source of the bacteria in this country. What you tend to see in plague in nature is you have the plague cycling amongst rodent populations through flea bites. Rodents get plague. Many of the rodents die of plague. Fleas move on to other rodents. What you see here is a flea literally embedding his mouth parts and sucking blood from a potential victim. If that flea had taken a blood meal from an infected rodent, that flea would have a chance to have bacteria multiply in its gut and foregut and proven triculus. And in the process of feeding, can regurgitate literally thousands of bacteria into the bite wound. This is a flea here that has just taken a blood meal from a rodent. In that big red spot you see in the abdomen is the blood meal that he took in. When they do suck a blood meal, the abdomen tends to expand out like an accordion. And then over time, as this blood meal digests, if the food source was an infected rodent, you'll have plague bacteria multiplying within the gut of that flea and up in the esophagus in the foregut. This is a flea here that has digested much of the blood meal and you see a dark mass in the flea that consists of partly digested and bagulated blood as well as thousands of white pestice bacteria. Now this flea can become blocked, meaning that when it tries to feed that this bolus of bacteria and blood can prevent it from actually sucking blood, and this flea can become highly agitated and start biting frantically and in the process start regurgitating some of this material into the bite. This is a prairie dog which is one of the rodents that is a highly susceptible to plague infection, and generally when plague comes into a prairie dog colony it will wipe out these animals in a large scale. And one of the things that we do in plague surveillance is we monitor rodent colonies such as prairie dogs to look for any signs of potential disease in the animals. You have signs of a diop which may be in the form of just animals disappearing or rodent burrows that show spider webs and so forth in the entrance. That's a good time to collect fleas for the plague testing. Plague outbreaks in prairie dog colonies does occur as episodic so that most, if not all of the animals, will be killed in the outbreak. Pet cats are very susceptible to plague infection, much like people. And when a cat is exposed to the disease, either by flea bite or very commonly by eating infected rodents, they will develop symptoms to it including in many cases becoming infected with mnemonic plague. And at that point a cat can be infectious for humans. They will often have a swollen node or lymph node on the side of the face associated from an oral exposure to plague by eating a rodent. Oftentimes they'll have oral lesions and bloody nasal discharge. And almost virtually all of the human cases of plague where there was primary mnemonic transmission of the disease in the U.S. in recent years have been from cat to humans. During a plague outbreak in rodents, you can have pet cats starting to show up sick or disappearing in an area. And when we have cats dying, one of the things we will do is again collect some tissue such as liver and spleen, blood, sometimes even removing a lymph node for isolating the plague organism. Now that we know the cycle between animals and people, what does it do once it enters the body? Once the organism gets underneath the skin that's picked up and carried to the regional lymph nodes where the infection becomes much more aggressive and accelerates, the organism starts producing a capsule called the F1 that prevents phagocytosis. This produces the bubo in the lymph node, the enlarged, tender lymph node that's characteristic of that form of disease. Following this, the infection disseminates. It gets into the bloodstream and sets up secondary sites, particularly in the lungs. This is an inguinal bubo in a young girl with a plague. This probably occurred because of a flea bite somewhere on the leg. If the bite occurs on the arm, the axillary lymph nodes tend to be involved. Plague is a very serious form of disease. Untreated plague has a 60% mortality when it's of the bubonic type, septicemic and pneumonic plague have mortalities approaching 100% untreated. Antibiotic treatment changes that. If antibiotics that are effective are started in time, the mortality can be reduced to about 10%. The key is in time. What is in time? Too late comes up pretty quick when you're talking about plague. I don't have good data for bubonic plague, but it's fairly well established that effective treatment is not started within 24 hours of the onset of symptoms with pneumonic plague. The outcome is going to be very poor. How do people come in contact with the bacteria naturally? There's a couple of ways that one can contract plague. Exposure to infected fleas is the most likely route of exposure. A flea has fed on a plague-infested animal and then comes and feeds on you or tries to feed on you. That's a good way to get plague. To get plague is to be exposed to the respiratory droplets of an infected animal or of an infected person. Once exposure has occurred, there's an incubation period that's 2 to 10 days for bubonic plague, 2 to 3 days for pneumonic plague. The different forms of the disease are manifest by different signs and symptoms, bubonic plague being manifest mainly by the bubo. As I mentioned, they tend to occur in the area, draining the flea bite. This is an axillary lymph node that's become infected probably from a flea bite on the chest or abdomen or the arm. Are there systemic signs of symptoms occur, fever, chills, headache, overall prostration? All right. How is it... Is this how it would be disseminated as a B.W. agent by fleas? That's probably not as crazy as it sounds. That certainly probably wouldn't be the most efficient way of disseminating plague. Japanese, again, in Unit 731 in the years leading up to World War II, did attempt to disseminate plague this way. They dropped millions of infected fleas over occupied Manchuria and did start a bubonic plague outbreak in an area where it hadn't been seen before. Again, today, probably most terrorists or belligerent states out there are going to try to disseminate this via aerosol. That would cause the more deadly form of plague, the pneumonic form. Cough, chest pain, hemoptysis, and severe systemic symptoms. The chest x-ray would show a number of findings. It could show cavitation, apache, bronch, pneumonia, or franklobar consolidation. As we can see on the chest x-ray here, this is virtually opacified. Other laboratory data that would be observed, the white count is going to be elevated 20,000 or higher. The bands are going to be increased. The carbon degradation products may be identified indicating the patient may go into DIC. A liver function test, the AST and the ALT, may be elevated indicating that there's involvement of the liver. DIC, Ted, describe it. DIC Doris is disseminated in revascular coagulation. Basically, it's a clinical state where the clotting system has gone haywire. You start to develop microclots in the small blood vessels, typically in the fingers, the toes, et cetera. When you see this in plague, you start to see some of the hallmark findings that are associated with plague. And here you can see in this shot, necrosis of the tips of the fingers in an unfortunate gentleman who contracted the septicemic form of plague. And I think we have another shot that again highlights this devastation. You can see this gentleman's probably going to lose several fingers. Maybe the tip of his nose, maybe his lip, because of the disseminated in revascular coagulation associated with septicemic plague. Now besides clinically, how can you diagnose the plague? Well, diagnostic tests would include staining a gram stain or wastes and stain of fluid that ought to be sterile. There are ordinarily plenty of organisms there to see. A lymph node aspirant might reveal the organism. Sputum gram stain may indicate that it's there, the typical bipolar staining, gram-negative conchalbacilli. Obviously, gram stain, the spinal fluid that's positive for these organisms would be a serious concern. A gram stain of blood can even shell organisms. Patients can have tremendous back to reamings during the course of this disease. Once a gram stain has identified an organism, this can be confirmed with a direct fluorescent antibody test that's performed at the Samrit. A polymerase chain reaction can also identify the organism. The F1 antigen that I mentioned can be identified by an ELISA capture assay. What about cultures? Yosinia pestis grows up pretty well on most culture media. The problem is that it grows up a little slowly. It may take two or three days to complete its biochemicals. It wouldn't be surprising to be involved in a case of plague and not have the diagnosis absolutely confirmed until you're 48 or 72 hours into a course of treatment. Now, Ted, you mentioned before that people can get pneumonic plague from respiratory droplets from another person, but does this mean that plague is contagious? Yes, it does. In fact, that's a very important point that we need to understand concerning plague. Again, we said earlier in the broadcast that one of the few bits of good news about these biological agents is that they're not contagious person to person in many cases. But this is one of the exceptions. Plague and smallpox, pneumonic plague at least, and smallpox can be spread person to person. So proper precautions are necessary. And in the new terminology of the CDC, that would be droplet precautions that one would utilize. Plague has the potential for person to person spread, but it tends to be pretty close contact. And this contact can be limited by appropriate respiratory precautions and the disease can be controlled with prophylactic antibiotics. It's not nearly as contagious as some of the other organisms that we've talked about earlier today, or nearly as contagious as some of the common viral illnesses, such as influenza or measles, where you can acquire the illness from somebody you haven't even seen. Well, we have an interview with Dr. Dave Dennis from the CDC in Fort Collins, Colorado, discussing some outbreaks of pneumonic plague and risk factors for them. Let's take a look at the video. The history of pneumonic plague outbreaks with the third pandemic since the beginning of this century is interesting. There were huge outbreaks involving tens of thousands of persons, of person to person pneumonic plague, primary pneumonic plague, that occurred in Manchuria in 1910 and 1911, and again 1920, 21 and so. And that was peculiar circumstances where there were people, large numbers of people, crowded into very small spaces into railroad cars, into small shacks. Plague had been brought into these populations by people who were hunting infected marmots for their skin. I think marmot skin hats was, something was popular at that time. Not only were the pelts infected, but people skinning it got infection through cuts in their skin and developed the plague and then the plague became pneumonic plague and then it rapidly spread person to person. The circumstances that we think that were favorable to it, rather than just crowding, was that it was very cold and very humid and the plague organism is very susceptible to dryness and to heat. And so in normal circumstances, the plague dies very quickly when in the ambient temperature and environment. But in those cold, human circumstances in Manchuria during the winter time, and those crowded conditions spread very quickly and with extraordinary high fatality amongst this group. We don't know everything that we would like about the dynamics of its spread. In some circumstances it seems to be able to spread quite easily and others it isn't. But we do know that plague pneumonia is so severe and so dramatic that patients are seen early and once they're hospitalized and put under isolation with respiratory precautions the transmission stops quite quickly because the organism does not aerosolize such as measles, virus, smallpox virus or tuberculosis bacteria. And it is only spread by those respiratory droplets. So it spreads to persons who are in close contact with someone who is coughing generally the organism in the early stages of the disease. It's a manated person to put under isolation with respiratory precautions. The way to prevent the spread obviously is have good surveillance to detect cases in the early stages to put them quickly in isolation under respiratory precautions to identify all contacts and those that had close contact put them under antibiotic post-exposure prophylaxis with all antibiotics, cycling, chloramphenicol for all antibiotics. Sometimes the person who is allergic to medications cannot take them because of age and whoever can be treated with prognathoprine so from the boxes all as they prevent it. Yes, and of course early treatment of the cases themselves can't continue to spread the organism. I would think that treatment of the case brings about interruption of transmission within 24 hours in most cases that perhaps even shorter than that. Well Russ, Dr. Dennis mentioned several antibiotics actually that were useful in the prophylaxis of plague. What would you recommend? Doxycycline, 100 milligrams twice a day for seven days or as long as the exposure lasts. Now I assume the treatment of the sick patients is also important in decreasing the spread. Well that's right, Doris. Treatment of sick patients certainly is important and the recommended drugs in this case would be streptomycin. Streptomycin would be administered in a dosage of 30 milligrams per kilogram per day. It would be given infromoscularly in two divided doses and you'd probably want to continue that for at least 10 days. Streptomycin is obviously difficult to procure in this day and age. Acceptable alternatives to streptomycin would include doxycycline. You could give that at a dosage of 200 milligrams initially and then 100 milligrams Q12 hours again for 10 to 14 days. In those 6% of plague cases that would be expected to develop meningitis you would want to use chloramphenicol since that's the only drug that reliably treats your cine infections in the central nervous system. It's important to remember to start treatment very early. It needs to be started within 18 to 24 hours after the onset of symptoms if you stand a decent chance of salvaging the patient. Colonel Byrne, maybe you can enlighten us as to whether there are new treatments that one could consider besides the drugs I've already reviewed. Well, considering the limited availability of streptomycin, genomycin is usually used initially and that's not a new drug obviously. There's evidence to suggest that the chronolones would be effective. There's in vitro evidence and there's evidence in lavatory animals. There's evidence of any human data to support them. There's evidence to indicate that the penicillins and the cephalosporins are not effective and I believe that they're actually contraindicated in the treatment of plague based on certain animal studies that have been done. What if people were exposed and they don't have symptoms yet? Well Doris, in that case I'd use the same treatment that we discussed for healthcare workers namely doxycycline prophylaxis. Is there a vaccine for plague? It's licensed in this country. Three shots are administered over a three to six month period. It has an acceptable side effect profile. It's not the easiest vaccine that we have to get but it's not the worst. The majority of the patients have some local symptoms and perhaps 10% will experience systemic side effects. You know, I think it's... I'd like to point out here at least. We've heard a lot about anthrax vaccine and we hear a lot about anthrax vaccine being the first anti-biological warfare vaccine. And yet there's this plague vaccine that's been around for a long time and again we've used it in Vietnam etc. So the question is, what's up? Well, I think the answer to that question is we've never thought of the plague vaccine as an anti-biological warfare vaccine. In fact, when we administered that vaccine in Vietnam it was to protect against endemic bubonic plague not against biological warfare, pneumonic plague. The vaccine really as far as animal studies revealed to us doesn't seem to work against pneumonic plague, against aerosol plague. And I wonder if Russ, you had any more comments about the vaccine, its availability, and issues like that. Well, outside of the military the plague vaccine is a very limited market in this country. There's only a single manufacturer of plague vaccine and the existing stocks of vaccine become outdated before the end of this year. Currently there are efforts underway to get the new lots of the vaccine licensed. Since this organism is contagious are there any additional decontamination methods that you need to use? Well, Russ, besides strict adherence to droplet precautions for the pneumonic form of plague you would want to administer antibiotics, obviously, as indicated, and for the first 48 hours of that antibiotic treatment you would continue these droplet precautions. If you then subsequently confirmed that in fact you were dealing with plague you would continue those droplet precautions until sputum cultures were negative. You have to remember that if someone has recently been exposed and they're not yet, and the person they were exposed to is not yet coughing, is not yet generating secondary aerosols, then they're probably at very little risk and just soap and water or dilute bleach for decon, et cetera, would be effective. So I think you have to take that into account. Okay, well I think most people remember an outbreak of plague in India a few years ago and as an example of some of the fear of this disease and to emphasize some of the epidemiology information we covered earlier, let's go back to Dr. Dennis and hear about his experiences investigating that outbreak. We were first made aware of an unusual situation in India in September of 1994 when we had requests for large, lots of reagents for the diagnosis of plague and when we queried the WHO office in India about this, they got information from the Ministry of Health that there was a suspected outbreak of plague occurring in West Central India. It was the worst case scenario from a public health standpoint in Surat. It was the city of about 2 million people, many living on the edge of the poverty, many people who were transient coming in from the rural areas to find work and living in slum areas, shantytowns and extraordinarily poor sanitary and hygienic measures in place. The garbage was littering the streets so the rat population undoubtedly exceeded the human population and when the word got out that plague was occurring the government was putting into place plague control measures and they were very efficient at plague control measures. They could mobilize large numbers of people to go in to identify people who had fever and hospitalized them to treat people with antibiotics to provide antibiotics for prophylaxis to put up free suppression measures. They were quite good at that but anyway when the word went out that they suspected plague people still had a memory of the outbreak of plague that occurred in the 30s and the 40s in the early 50s terrorized the population and of course they wanted the exodus and tens of thousands of people anyway and in the press it was reported hundreds of thousands of people left the city of Surat and spread themselves out in other areas of India. The panic was so great that physicians and nurses and other healthcare workers deserted their posts and so that further decreased the confidence in the public that the government was able to manage the situation. Fortunately we have no evidence that there was spread of plague to other large cities or other areas in which there was inhuman to human transmission. We did identify one person in Delhi with a confirmed human plague from a laboratory standpoint who had been living in rural Maharashtra and had traveled to Delhi at the time he was incubating the disease but there was no secondary spread of course in this person that was the chronic plague. I don't think there was any way to really determine quickly what the evolution of the outbreak was and it certainly could have been an unnatural event as far as we know especially the situation in Surat where there was an amount of plague cases what happened was there was an explosion over a period of a few days of about 100 cases of severe pneumonia with respiratory insufficiency, homoptices and rapid death and the high fatality in persons who weren't treated quickly in fact there was about 40 deaths of 100 cases that occurred in the first few days. The thing that was unusual about it was there had been no antecedent plague in Surat for decades. There was no known cycling of plague in the rodents and their fleas in the city. There had been no reports of rat die off in Surat in that city. There were no bubonic cases which you would expect to be very much greater numbers than the mnemonic plague cases than the perceived mnemonic cases. That was not in place. So I mean in actuality it makes a very good scenario for an accidental or a determined event. We still don't know really what happened but the best conjecture at that time was that someone had come in from the area where they had reported the outbreak of bubonic plague in the countryside in Surat at the time that they're incubating the disease developed secondary mnemonic plague and then there was a burst of cases arising from exposures to that and secondary cases accounting for those mnemonic plague cases and deaths that occurred in the city and then it quickly died out and without evidence of there being rat plague or bubonic plague cases occurring there what is needed to respond to a plague case or plague cluster of cases or an outbreak is a multidisciplinary team in effect a SWAT team and that really is what was needed in India. They needed a team of epidemiologists who understood plague including clinicians who could determine whether or not the clinical signs and symptoms really were compatible with plague they needed a microbiologist that had a mobile laboratory at least to have the reagents and to have the materials to do a presumptive diagnosis of plague and they needed to have the entomologist and the zoologist the utologist that understood the natural cycle of plague and how it could have spread to the human population and if they'd had a team of those people they could have gone in and made sense out of that outbreak in Surat in 24, 36, 48 hours but they missed the boat. Now as I recall there was a lot of international fear that this plague could have spread around the world. Conor Byrne? Well the severe form of nature of the disease requires effective focused containment measures there's panic associated with it and justified it so international regulations allow a quarantine of up to six days of individuals suspected of having a significant exposure to mnemonic plague and that was the justification behind the cancellation of flights and holding planes on the runway and stuff like that. The key point is significant exposure that requires household contact or possibly workplace contact or face to face contact like you and me right now. Certainly a lot of these issues that we're talking about here call into mind the importance of epidemiology and of conducting a good epidemiologic investigation as we talked about earlier on the show. Alright, why don't we move on to another bacterial agent the one that causes tularemia? Okay, tularemia doris is a disease that's primarily zoonotic in nature. It's a disease of rabbits, hares, ground squirrels, muskrats, beavers and the like. As a disease of rabbits it's often known as rabbit fever. It's transmitted from animal to animal or from animal to person sometimes by the bite of various vectors. The deer fly, for example, and in that sense it's often referred to as deer fly fever. The disease tularemia is caused by infection with the gram-negative cacobacillary organism, Francisella tularensis. Tularemia is interesting in that it's found naturally only in the northern hemisphere. Alright, what are the ways people are infected? Well, there are several ways that one could be infected. One is through inoculation of the skin or of the mucous membranes by the blood and tissue fluids of infected animals. So if I skinned muskrats as a hobby or for a living, that would be a good way to contract tularemia. Another way is, again as I stated earlier by the bite of an infected deer fly infected mosquito and infected tick. Rabbit hunters are at particular risk. So if you want to get tularemia that's a good way to do it, be a rabbit hunter. Less commonly infections can occur by inhaling the contaminated dusts of areas where animals have frequented by ingesting contaminated food or water and the like. The organism is rather stable. It can remain viable for weeks in water, in soil or in the carcasses of those animals that we've discussed. Does the stability make it a good BW candidate? I'll let Colonel Byrne answer that. The stability makes it a good BW candidate along with the fact that it forms aerosols naturally and then it only takes one to ten organisms to initiate infection. The Japanese studied French cellularensis in Unit 731 and the United States weaponized this organism in the late 1950s and early 1960s. Is the disease fatal? Well, Doris, we used to consider tularemia a lethal agent back when we had an offensive biological warfare program. I think nowadays with modern medicine, modern standards of care, good antibiotics most of us would consider tularemia an incapacitating agent. Most naturally acquired cases in the 1990s have a fatality rate of only 5-10% actually without treatment. If you were doing biological warfare, you may be able to select out a more virulent strain and it may be a little higher than that especially given that what you're going to see in biological warfare or terrorism would be primarily the septicemic form of the disease. But with appropriate antibiotic treatment basically the case fatality rate should be 0. Okay, so but if a patient is exposed, what do they experience? Colonel Bernardo, you could probably answer they may have seen more tularemia than I have. Well, it's an incubation period that can range from 1 to 14 days. It's usually 3 to 5 days. Then the clinical presentation depends on how the infection was initiated. The most common form is the ulceral glandular form and that produces an ulcer at the site of inoculation. Now also associated with this are regional lymph adenopathy and systemic symptoms such as fever, malays, chills, so on. I think we have a case here that we can show you, give you a feel for what this looks like. In this case there was a woman who was treated by my partner George Christopher at Scott Air Force Base. This woman was apparently bitten by a tick and she came in complaining of a two-day history of fever and debilitating malaise. You can see the ulcer that has formed at the site of a tick bite on her scalp. She was treated, she did fine, she lived happily ever after. If the ulcer was not present then you would basically have a syndrome that we call glandular tularemia. There's also a syndrome known as pharyngeal tularemia and there's an ocular glandular tularemia and basically the only difference is that there the conjunctiva is the portal of infection. All of these syndromes can progress to a disease which we often refer to as typhoidal tularemia. That can also result directly after the ingestion or the inhalation of Francislla tularensis. Okay, so which is the most likely form in a BW attack? Well, assuming a biological warfare attack would probably be that the bad guy out there would aerosolize this stuff. We would inhale it and the form of the disease we would get would primarily be typhoidal tularemia. Typhoidal tularemia presents with fever, you may have respiratory involvement with some sub-sternal discomfort and a non-productive cough. The pneumonic involvement is not always present though, even after an inhalational exposure. Here is an example of a good pneumonic tularemia case and you can see the infiltrates on chest x-ray. Respiratory symptoms sometimes may be the predominant manifestation of illness though. Okay, Colonel Burr, are there any other ways to diagnose tularemia? Unlike plague there are usually not a lot of organisms to see on stains. Staining sputum or lymph nodes is usually not very helpful. The organism can be cultured but it's difficult because it has specific growth requirements and it's also a little bit dangerous to work with. There have been a lot of laboratory outbreaks of tularemia in people who work with this organism. The laboratory ought to be notified if you suspect tularemia so they can institute appropriate BL3 containment measures. This is usually established by acute convalescent to antibody determination in serum. Ordinarily these are agglutination tests. There's also an ELISA available. Lumerous chain reaction has also been used. If organisms are identified in tissue there's an indirect fluorescent antibody that's used at UCM-RID that can confirm the diagnosis of tularemia. Alright, well since it's not usually fatal, do you really need to treat the disease? Well do as you do. First of all it can be fatal and again belligerence out there could pick an especially virulent strain that can be fatal up to 30% of the time. And even if it's not fatal it certainly is not a pleasant disease. People can get pretty sick from tularemia. We usually consider it an incapacitating agent but again not a pleasant disease if you get it. Both streptomycin and genomycin are effective in treatment so we have good relatively inexpensive therapy and certainly I would use that if I had a case of tularemia. As you can see here the recommended therapeutic regimen would be streptomycin 1 gram every 12 hours given intramuscularly over a 10 to 14 day period and alternatively one could use genomycin that would be given 3 to 5 milligrams per kilogram per day intravenously again for a 10 to 14 day period. Tetracycline and chloramphenicol can be effective but they're associated probably with a higher relapse rate than the immunoglyphosine. What about contagion with this agent? Do healthcare providers really need to worry? Although laboratory infections are a real problem, human transmission is very unusual and standard precautions with respect to secrecy are all that is necessary to prevent transmission in the healthcare setting. Okay now if you've been exposed is there anything you can take to prevent infection? Well Doris antibiotics are very effective in preventing disease after aerosol exposure. We know that from a lot of animal data. Two week course of tetracycline or doxycycline is what we would recommend and you can see here the recommended regimen with respect to doxycycline would be 100 milligrams orally every 12 hours for a two week period. Is there a vaccine? A live attenuated vaccine is available as an IND product. It works quite well in preventing laboratory infections and in preventing infection by aerosolization and human volunteers in old studies. As with most vaccines all vaccines that I know of the detection can be overwhelmed by very high inoculum of organisms. At present the vaccine is only used in laboratory workers. The vaccine is an interesting history as you're aware. Right, the vaccine actually was given to us in 1955 at the very height of the Cold War by the Soviet Union. It came from their Gamelia Research Institute and we refer to it as the Gamelia Strain. We're using that at the exact height of the Cold War we would get this from the Soviets. Exactly. Well, tell what, let's start on our last disease of the day, brucellosis. And before we get started I'd like to welcome our last guest expert for today, Colonel David Hoover. Colonel Hoover is the scientific coordinator for the Brucello vaccine program at the Walter Reed Army Institute of Research. Hoover, can you describe to us some of the background of Brucellosis? Brucellosis actually has a long history associated with the military. It was first described in 1861 by Marston in British troops who were stationed on the island of Malta. And then studies in the late 1800s by Bruce and Hughes define the clinical spectrum. It's actually quite prevalent in the developing world, but there are less than 100 cases per year in the United States. It's an important cause of abortion in large animals, especially large food animals, and it's naturally acquired by contact with infected animals or their products. There are actually six recognized species of Brucello. Four of these are pathogenic for humans. Brucello melotensis infects sheep and goats and is the most virulent for humans. Followed very closely by Brucello suis, which is a pathogen of swine. Brucello abortus is the primary cause of infection in cattle and Brucella canus in dogs. You know, there are some pretty interesting ways in which one can become infected with the Brucella. As Colonel Hoover stated, these are common pathogens of certain farm animals, and so if one were a rancher or worked in the animal husbandry industry, for example, that would be a good way to contract Brucello suis. Brucello suis is essentially a venereal disease of animals. It's present in the gynecologic tract of cattle, of sheep, and of goats, and so if you were a rancher assisting in the delivery, for example, of a pregnant cow and you weren't wearing gloves or you had a tear in your glove, you had a tear in your skin, that would be a good way to inoculate oneself with Brucello suis. It's present in the milk of many of these animals, as well Brucello suis is, and so, for example, on the Mexican border, goat's milk cheese is a common delicacy and it's often unpasteurized. So to go down to the Mexican border in south Texas, for example, and sample the unpasteurized goat's milk cheese, a good way to get Brucella melotensis infection. In south Texas they're fond of hunting havalina, these wild boars that are found in far south Texas and those are good animals to transmit Brucella suis infection. And finally, in Saudi Arabia where Brucello suis is very common, there's a very interesting habit, shepherds in Saudi Arabia, as part of their payment when they deliver their sheep to market, the sheep are slaughtered and they're given hot right out of the animal the caudate lobe of the liver and it's customary and it's considered a delicacy to eat that raw caudate lobe of the liver. And a lot of Brucellosis cases emanate from that very interesting practice. So this is a disease that's highly infectious by aerosol but it's got a long and variable incubation period. So the fact that it's highly infectious makes it somewhat attractive as a biological weapon, but the fact that its incubation period is so long and so variable to track somewhat from that Doctor Hoover, tell us what a typical case of Brucellosis looks like. It's a little hard to define a typical case because of this variability in presentation, but Brucella can either present as an acute febrile illness with fever and sweats, headache, arthralgias and general malaise, and these kinds of symptoms can go on for weeks or months until the disease is diagnosed or it actually can present as a more insidious illness with anorexia, weight loss, difficulty concentrating and depression. About a third of patients develop spread to the bones and joints. And younger people, sacroiliitis is the most common joint infection and this is typically a non-destructive infection. But in older patients, as seen in this photo here, you can get vertebral osteomyelitis and here the disease starts in the intervertebral disc and spreads to the adjacent vertebrae. In addition, you can get chronic genital urinary tract infection, particularly epididymitis. And you can also get meningitis or endocarditis, which are the main causes of fatality, although fortunately these are very rare. I've actually seen a case of Brucellosis. Before I joined the army, I worked for a while with the public health service in Barrow, Alaska, this remote Eskimo village and we had a gentleman come in and was ultimately diagnosed as having Brucellosis and he had hunted a polar bear and had eaten raw polar bear meat. We presumed that that was the source of his Brucellosis although that's not the most typical animal to harbor that disease. But I can tell you from experience, a very difficult disease to diagnose. It took us several weeks before we finally came up with the proper diagnosis of Brucellosis in that case. Those patients who have respiratory symptomatology often have normal chest x-rays. Some patients have a paddle splenomegaly, some patients don't. So you can see it's tough to diagnose. For those patients who do have joint involvement, CAT scans, MRI scans, plane radiographs, bone scans may be helpful, but again very tough disease sometimes to diagnose. So how do you confirm that it's Brucella causing all the symptoms? Well, culture is actually the most reliable test of either culture of blood or suspected infected body fluids. And although it's considered a slow-growing organism, 95% of those cultures that will become positive become positive in seven days. It's still recommended to hold cultures for up to two months if you really suspect the disease. And culture of bone marrow can increase the yield substantially over blood culture alone. You should warn the laboratory, however, not to subculture the bacterium unless they have BL3 capability, since this is actually one of the most common causes of laboratory infections. Most cases are actually diagnosed by serology. The gold standard is a tubal glutenation test. You have to worry about cross-reactions with Francis L. Tullarensis and patients who have cholera or vaccinated with cholera. PCR is actually useful for speciation, but it's not very useful clinically at this point. Well, it sounds as if this could be a very prolonged illness. I mean, can it be treated? Well, of course, it's actually not too difficult to treat. There's some good news and there's some bad news attendant with treatment. The good news is that the treatment regimen is the standard regimen. There are actually several regimens one could use, but the most commonly recommended regimen is doxycycline plus rifampin. And the good news here is that both of those can be given orally, and both of those can be given once a day. So I can give you one pill a day of doxycycline 200 milligrams, one dose a day of rifampin 600 to 900 milligrams. And again, pretty easy to administer that therapy. The bad news is that you need to continue therapy for six weeks. And the literature is full of cases of relapsing brucellosis where the clinician didn't treat the patient for a long enough period of time or where the patient stopped taking the antibiotics. What do you do for severe disease? Well, you might want to add an aminoglycoside like genomycin. And for endocarditis you should certainly consider valve replacement early in the infection. You have to remember that you don't really need to isolate these patients since it's not transmitted person to person. Is there a vaccine available? Well, Doris, there's a great veterinary vaccine. In fact, there are a couple of great veterinary vaccines available and those vaccines have greatly decreased the number of cases in animals. And that's led to a decrease in the cases of human brucellosis. It's still important to emphasize though that you need to avoid the consumption of unpasteurized milk and cheese, the goat's milk scenario that I alluded to earlier. And it's important to know or to realize out there that there is no human vaccine currently available. But studies are going on? Yes, we do have some publishing animal studies going on, but vaccine is a few years away for sure. All right. Well, that about covers the bacterial agents and I guess it's time for our local activity number two. A recent vote of no confidence has led to parliamentary elections in Krasnovia. Control now lies in the hands of the hardliners who immediately after assuming power signed a mutual defense pact with Saracen and withdrew support for UN peacekeeping forces. Elite Krasnovian special forces plus three parachute infantry regiments have been deployed to Saracen despite vigorous U.S. and U.N. protests. In response the United States has moved the 18th airborne corps to staging facilities in Europe. You are a medic serving with the 28th Combat Support Hospital. The 28th currently occupies the old U.S. air base at Zweibrucken, Germany. In addition to the heavy workload and anxiety associated with site preparation, you are burdened by an unusually high number of sick call patients from your own unit presenting during the past 48 hours. Most of these patients have complained of fever, headache, fatigue and cough. Yesterday your partner wrote 43 azithromycin prescriptions for what he assumed to be walking pneumonia. As you come on duty you are surprised to see that half of those patients are back and that many new ones have arrived. What is going on? Hey Sergeant Walker, Sergeant Walker, who are the soldiers? Hey sir, it's been like this all night long. We've had about 20-30 patients all night not including these ones we got here. We're all complaining of the same thing. Headache, fatigue, tightness in the chest and a little bit of nausea. I don't know what else we can do with it. We've got vital signs. Alright, alright, who sick is? Well, he's sick, but we can start over here trying to get some vital signs. We've got a temperature on her. It's about 101. What's bothering you? I'm really hot. My chest hurts. Okay, great. Let me take a listen to you. Take a real deep breath. Okay, deep breath. Deep breath. You guys get x-rays in any of these? I tried to get some x-rays late last night, but the x-ray machine was down. Alright. She doesn't sound very bad. I don't hear any wheezing or anything. Who's next? This guy here. Same thing, tightness in the chest and coughing. What's bothering you? It's hard all the time. Let me take a listen to you. Take a deep breath. Deep breath. Just breathing normal now. I don't hear any rails or wheezing. You got somebody else? Well, this one over here he's been pretty sick. What's bothering you? What's bothering you? Are these folks in the same unit? Same unit, sir. Let me listen to you. You sit up a little bit. Take a deep breath. Sergeant Walker, you need to send somebody down to X-ray. You got to go right now. Yes, you do it. You need to go down to X-ray right now and get that portable down here ASAP. Okay. Let's go to CBC. All sides of some of these soldiers. A few hours later, an hysterical soldier runs in screaming that he just found his buddy dead in his bunk. Come on, soldier! One, two, three, one, two, three, five, I found him in his bunk and he's dead! You got to come! The X-rays you requested that morning finally arrive. Specialists, I need to check these 558s. There's too many similarities here. Have you noticed the vital signs? Everybody's got over a hundred and one temperature, a hundred and two temperature. They're all complaining about chest. Something must be going on. Whoa, whoa, whoa! This is the MT-1. What are you guys doing here? I'm listening to Colonel Messon from the 257th Company. Yeah, I'm Colonel Messon from the same company. We're dead, so we just arrived here. We're looking around and we wanted to see what was going on. Well, you're busy here. I'm not quite sure what it is yet. Well, we noticed a lot of spraying going on outside. It's truck driving around spraying something in. We're thinking ticks here. We're thinking maybe we need some tick-borne and civilized vaccine. Well, I don't know anything about that. My whole EMT is loaded with patients. I've got some serious problems here, okay? And you guys may have walked into something that we may have to call a quarantine. As a matter of fact, you're quarantined right now. Well, we can't do that. We can't do that. I've got radios. I've got landlines. We've got a real mess on our hands. I've got one medical doctor. I've got 20 patients out here. Why don't you guys give me a hand and a dentist? We have to be quarantined. You're sure we have to be quarantined? Well, I think so until we get to the bottom of this. Why don't you guys just give me a hand and you take these half over here and Doc, you take those half. Well, we have to. Sure. I've got medics working with them and they'll give you a heads up as to what they're seeing, but I think what you're going to see is you're going to see a lot of high fever here, 100 and 102. There's a lot of respiratory distress or at least they're complaining about tightness in their chest. Nobody's come back. I've listened to a couple of tests myself. I haven't really heard much activity. They just feel loud. Okay. Well, pretty frightening scenario, I think you'll all agree. What I want to do is very quickly review some of these questions and then we'll take it back to Doris and we'll take some more questions from the studio audience. First question. You saw that the physician who had been on the day before had started a lot of people on azithromycin therapy thinking that initially these may have been cases of walking pneumonia. What do you think about that? Would you continue the azithromycin at this point? Well, I'd certainly reconsider the antibiotic choice based on the fact that I've got so many troops coming back who are sicker on the therapy and I'd be rethinking my initial diagnosis. Good, good. And that's an important piece of epidemiology that you allude to. You need to take into account what's going on here. If it doesn't fit what you expect, these patients are starting to get sicker than you would expect the average case of walking pneumonia to be. I think you need to reconsider your diagnosis. So initially I don't have any problem with this diagnosis but now that patients are coming in sicker, I think you can see that you've got to rethink your diagnosis. Any tests you would want to do? Is it important to do any test? Of course it is. What kind of tests would you want to do in some of these patients? Well, again, at this stage of the game you're rethinking the diagnosis and gathering more data including initial vital signs. They already mentioned chest x-ray and these patients who are having significant respiratory symptoms, getting to include culture, maybe a gram stain if you have facilities to do that and some CBCs, things of that nature. Good, I agree with all of those. Now, in the case of blood culture it's going to take a couple days to get useful information out of blood culture but a chest x-ray ought to give you some useful information right up front. And I painted a pretty realistic scenario here, the x-ray machine's down, et cetera, et cetera, but I think it's very incumbent upon you to press for that diagnostic information that you need. So you eventually got that chest x-ray and what did you see on that chest x-ray? There's a widening of the mediastinum which clearly indicates that it's probably anthrax. Absolutely, so widened mediastinum almost has to be anthrax and the teaching point here is there isn't too much in the world of human medicine that produces a widened mediastinum like that. There's not too much that causes hemorrhagic mediastinitis and in fact the only battlefield relevant injury I can think of other than anthrax is a bullet hole through the mediastinum. So if I have patients with chest x-rays like that and I turn them over and there's no bullet hole there, they must have inhalational anthrax. So pretty easy diagnosis to confirm in this particular patient. I think you all realize this guy's probably not going to do very well but your job as clinicians is not necessarily to save that index case but rather to very rapidly learn from that index case and use that knowledge to hopefully save a lot of other people. Now the issue came up about quarantine for these two dentists who entered the picture. Anyone agree with that? Disagree with that? Do you quarantine these dentists, sir? That was, I think, overreacting since the diagnosis was made of anthrax then since there's not person-to-person transmission you wouldn't need to do that. Good, good. And if this were an unknown, you might approach it differently. For example, if pneumonic plague was still high in the differential diagnosis, I might think a little bit differently although even with that, these guys just stumbled in, they really haven't had time to be coughed on. Chances are that even with pneumonic plague they probably wouldn't need to be quarantined. But with anthrax, which doesn't have the possibility of person-to-person transmission, certainly those people don't need to be quarantined. Good. Okay. What do you want to do for these ill patients? These patients who are starting to clutter up your treatment facility who are coughing, who are febrile, who are ill? Anybody have any advice regarding therapy? Kent Lee? Well, if you have enough antibiotics you could try to start them all on antibiotics and then if you have a vaccine that you would also want to start them on the vaccine to pick up any of the latent spores that might still be in any of the individuals. Good. Good. So this is a triage issue and we've said throughout this course already that if you wait until patients are symptomatic to treat them, chances are they're not going to do well. So many of these people under certain circumstances might be categorized or triaged as expectant. But on the other hand, if your resources permit it would certainly be reasonable to try to treat those people with antibiotics. Now what about those people who are not yet ill? Patients who may not yet have shown up at your treatment facility but who were in the same geographic area as these sick patients? Dr. Bellin. You would still want to start them on antibiotic treatment and if they haven't been vaccinated to start them on the vaccination. Excellent. Excellent. So in this case the antibiotics could be oral and you would be given them as prophylaxis rather than as treatment. We discussed the dosages, etc. throughout the course and for those of you students out there in television land if you need the dosages, they're in your little blue books. In fact, that's why military BDUs have these hip pockets there to hold our little blue books. So you would look that up. And again, good prophylactic regimens are available and certainly they would need to be coupled ultimately with vaccination. Well, you guys have done great and I think there's again no sense trying to test you any further.