 Well, let's move on now to our next two guests. Joining us today is Dr. Mark Poli, a research scientist in the toxinology division at USAMRAID. And Dr. David Frantz, who is vice president and responsible for the chemical and biological defense division of Southern Research Institute. And Dr. Frantz was also the previous commander of USAMRAID. So if I call him Colonel, you understand. Thank you both for joining us again this year. And let's talk about toxin. Ted, define a toxin. Well, there's toxins are interesting. They're not living replicating agents like the viruses and bacteria. And so people would ask, why are we talking about them in a biological warfare course? Some people, in fact, in the old Soviet Union, they often classified toxin-mediated diseases as chemical warfare. But the distinction we make in the United States is that these toxins, these chemicals came from or were derived from living organisms. And that's why we classify them as biological agents. Since I don't come in contact with these particular agents too often, and since I suspect that most clinicians in the United States really don't deal much with toxin-mediated diseases, I want to turn that discussion over pretty much to Dr. Frantz. Dr. Frantz, what's the difference, or what are the differences between toxins and chemical agents? Well, as you mentioned, Ted, toxins like chemicals are not living. They're not like bacteria or viruses in that they replicate in our bodies. So what you get is what you've got if you're exposed. Toxins are really chemicals that are made by nature. They're made by animals, by plants, or by microorganisms. And there are, however, some very important physical differences, and this is the key. Toxins are neither volatile nor are they dermally active. And so if you think about the Aum Shinrikyo scenario, for example, in the Tokyo subway, even though botulinum toxin is maybe 10,000 times more toxic than the sarin that was used in that attack, botulinum toxin would not have worked because they used a very primitive sort of a weapon system in that they had sarin in plastic bags and then punctured the bag and the toxin came out because of its high vapor pressure. It vaporized and came out and either made you sick or killed you. That wouldn't happen with botulinum because it is not volatile. And that's an important consideration for a proliferator who might be interested in developing a weapon. All right. What type of toxins would work as a biological warfare agent? Well, there are actually hundreds of toxins, of biological toxins. But whether you're planning to use a develop a biological agent for a battlefield or for a street corner as a terrorist, you have to think about three factors. You have to think about the toxicity, the stability of the toxin and the ease of production. And toxins that might be useful as weapons have to score pretty high in all of those three areas. We're going to talk today about botulinum toxin, which is one of the most toxic of toxins. We're also going to talk about ricin, which is one that fits the ease of production scenario. Although there are hundreds of toxins that might be used, it's a very few actually that would be useful as weapons agents. Well, are there toxins that wouldn't make good weapons? Well, yes. Actually, we need to remember that although many toxins won't work on a large-scale battlefield, one that covers tens or hundreds of square kilometers, there may be toxins that are perfectly legitimate weapons in a smaller-scale area, in a room, in a sports arena. They make excellent terrorist weapons and they'll make good weapons of assassination. Yeah, I just want to review that actually. We talked about this a little bit on the first day of this course. We divided these weapons into strategic, terrorist, and tactical contexts. And I think we said that really toxins would never make good strategic weapons or at least I can't envision them making good strategic weapons because they don't have the stability in the atmosphere in general. And they lack some of the other characteristics that would allow them to be disseminated over big areas. You might say they could make a good tactical weapon and I think we said that on the first day of the course. But on the other hand, some people would argue that biological warfare in general doesn't really make good tactical sense because, again, they have incubation periods. So if I'm a battlefield commander and I'm tasked with capturing that hill over there, what I really don't want to do is throw a weapon on that hill and sit around for several days and twiddle my thumbs and wait for it to have its effect. So in that sense, they perhaps don't make great tactical weapons as well. But I agree fully with Dr. Polly. I could certainly envision a terrorist use for them and they certainly, some of them have brand name recognition as terrorist weapons. And state-sponsored militaries can use them. You may have read recently in the past couple of years about the Iraqi production of aflatoxins. Aflatoxins are fungal metabolites that are most closely associated with grain or peanuts. And we feel that they were produced by the Iraqis for the purpose of biological warfare. Now, we believe they weren't used, but the fact that they were produced is very puzzling to us. You know, I've received some questions about this aflatoxin. I've never really known what their purpose was in using them. Like Colonel France, I know you've been an unscombed inspector. You've led inspection teams to Iraq. What do you think about this? Why would the Iraqis have weaponized aflatoxin? Ted, I don't think anyone really knows exactly why they did it. But I have a hypothesis that I sort of developed during my time over there working with Dr. Taha and the other key players in their program. I think they have political pressures and they live in a bureaucracy in Iraq. And I would suspect that possibly Dr. Taha's team was under great pressure to produce a biological weapon. Someone probably understood how to grow large quantities of aflatoxin and decided that they would weaponize it. Just because they did that, they did it. And just because they did doesn't necessarily mean, as Mark mentioned, that it is a good tactical or strategic weapon. It might have had a terror component. There may have been a psychological component that would have been useful as a weapon. But with regard to causing acute illness, it wouldn't be effective. Now for the first toxin that even I have heard about. Don't you get botulism from eating contaminated food? Well, yes, Doris, you do. In fact, that's the usual route of acquisition in peacetime. Botulism is acquired typically by ingesting one of seven related neurotoxins. And all seven of those are formed by various strains of the bacterium Clostridium botulinum. This bacterium is closely related to the bacterium that causes tetanus, Clostridium tetanide. And as such, and like tetanus, it's readily found in soil virtually everywhere in the world. The interesting thing about this bacteria is that it typically doesn't harm you. Ingesting my new quantities of the toxin will, but consuming the bacteria does not. And again, I think you all know we all consume little bits of dirt every day. You get dirt on your fingernails, you pick your teeth. You're constantly ingesting minute amounts of Clostridium botulinum organisms, and yet your stomach acid is able to deal with those. But it's consuming the toxin, that's the problem. Dr. Paul, what does the toxin do once you ingest it? Well, it binds to presynaptic nerve terminals. Now in a normal cell, the electrical impulse traveling up the nerve triggers the chemical release of neurotransmitter into the synaptic cleft. In the case of botulinum toxin, I think we've got, right, here's a video clip that will depict that. Okay, well, let's look at this. Normal neurotransmission, you've got electrical impulse, you've got the release of neurotransmitter across the synaptic cleft. Estheal choline. Estheal choline in this case. In the case of botulism now, botulinum toxin binds to the presynaptic nerve terminal and interrupts the cellular mechanism that's involved in the chemical release of the neurotransmitter into the synaptic cleft. This results in a lack of neurotransmitter in the cleft. Okay, and this lack of acetylcholine, Doris, would result in the exact opposite effect that you would see with a nerve agent, where in the case of nerve agent, there's too much acetylcholine because the enzyme acetylcholine esterase has been inhibited, and that's the enzyme that would normally break down that neurotransmitter. So with nerve agent intoxication, you get overexcited nerves, you get muscle fasciculations, and you get maybe a spastic paralysis, but with bot intoxication, you see a gradual and more flaxid paralysis. We'll go into that in quite a bit of depth later on. Okay, let's get back to ingesting the toxin. That is the way you usually get it. Well, that is the way you usually get it. There are other ways of getting it. They're not as common. And I think Dr. Franz, Dr. Franz can probably describe for us how bot tox is formed. And then with that knowledge, I can probably better explain how we can become intoxicated with that toxin. Well, as you mentioned, Ted, bot is produced by a commonly found soil pathogen. And historically, at least from a public health standpoint, the most common mechanism of intoxication has been individuals canning either vegetables or meat, as we see in this slide. What happens during the canning process is normally it's heated under pressure to a point that the bacteria are killed. If the process is not complete and not and the bacteria are not all killed. After the canning process, these bacteria wake up in an environment that's perfect for the production of the toxin, low in oxygen in a sealed can nutrients available. And so the bacteria produce the toxin. Then we open a can of green beans and think we'll just taste one before we heat it to see whether how they taste. And one green bean can kill you. Because the toxin is so extremely toxic and is found has been produced after the canning process. Well, suppose you want to heat what you can, if you want to heat it up, I mean, what happens that typically if you heat botulinum toxin to boiling temperatures, you can destroy the toxin. Okay, but I think you've ruined your product. Okay, Dr. Sorgal of the CDC is in charge of the botulinum program. Let's hear what he has to say about the epidemiology of botulism. At the beginning of the century, cases of botulism increased largely due to the increased popularity of home preservation of foods, home canned foods. However, the numbers of cases decreased after educational efforts were disseminated to improve canning procedures. There was more availability of refrigeration. There were improved preservation techniques and their cases actually came down. Since the 1960s, we've had an increased number of cases. This is largely due to new vehicles that we hadn't suspected before. Foods that do not have preservatives that are kept under anaerobic conditions such as garlic under oil, even baked potatoes wrapped in foil. We've also had an increased number of restaurant associated outbreaks. And we've also had problems with centralized production of foods. So if a single product becomes contaminated, then that can be widely distributed and it can cause a lot of people to become ill. There have been changes in the way foods are produced, which sometimes can take a safe product and make it an unsafe product. For example, salsa made from tomatoes was basically a safe product and been made for centuries. However, people like tomatoes that don't have as much acidity in them, they're sweeter tasting. But what has happened is that when you start using those tomatoes to make salsa, you've changed the pH and the acidity of the salsa. And that has caused outbreaks because that salsa is not acid enough to prevent toxin production. So simple changes in food production can potentially cause food items that were safe to become dangerous. Another example is in the United Kingdom, they had a yogurt that was made with a hazelnut paste and it was widely distributed. They changed the hazelnut paste from being made with sugar to being made with a sugar substitute. That simple change changed the water activity of that product and would now allow botulism spores to germinate and toxin to be produced. And that caused a widespread outbreak in the United Kingdom. So simple changes in food production can potentially make safe products unsafe now. You know, Doris, another way of getting exposed to botulism toxin is through a wound that hasn't been properly cleansed. And I think you can understand maybe how you could get that. You get a wound that gets sealed off somehow and anaerobic conditions ensue and the bacterium is able to proliferate under those conditions. It's similar to what you would see in tetanus, but a very, very rare way of contracting botulism. A third method of contracting botulism is familiar to probably most pediatricians in the audience. And that's infant botulism. And here's an infant who is under a year of age. And basically I told you that eating clostridium botulinum spores is by and large harmless because our stomach acid destroys those spores. Infants, however, often don't have the same degree of stomach acidity that adults have. And it is rare, but not unheard of, that infants can get botulism from eating the whole bacterial cells. Honey is a food stuff that is typically has a high content of botulinum spores. And pediatricians used to tell parents who had constipated young infants give your infant a spoon of honey and it'll relieve constipation. The problem is in rare cases, right, it led to botulism. So pediatricians don't recommend that anymore. And the infant would basically ingest the clostridium botulinum spore. It would proliferate in the gut and start cranking out toxin. And so the syndrome you would see would be identical to that seen in foodborne disease, but a little bit different mechanism of pathophysiology. Okay. Can it be transmitted by aerosol? Well, not normally. It isn't contagious at all. None of the toxins, in fact, are. And really the only way for it to be transmitted by aerosol would be someone working with it in a laboratory who somehow got it in their face or in an intentional release by a terrorist or belligerent. That's, in fact, in a biological warfare scenario, exactly what we would envision it being used. And speaking of distances, will it go along? No, it will travel a long distance. It's not very stable in the natural environment. And in fact, computer scenarios that I've played with suggested, even under optimal conditions, it won't travel more than a few hundred meters. However, that doesn't mean it's not a good terrorist weapon. In the closed space, it would be a perfectly viable weapon. And of course, you can also use it to target food or water supply. Right, right. And that gets back to what we're saying earlier. Certainly wouldn't make a good strategic weapon, but on a smaller scale, perhaps a viable weapon. Okay, so it's not as effective over long distances as anthrax would be. But if you're in the aerosol cloud, does it cause the same disease as when you ingest it? Yes, Doris. Actually, the mechanism of cellular mechanism of action that Mark described earlier is the same mechanism that occurs after an aerosol challenge. There are some differences, however. We have found in animal models that botulinum toxin inhaled appears to be, depending on the serotype, appears to be 20 to 80 times less potent. And this is probably because of absorption mechanisms and binding in the lung and things like that. So there may be a delay and onset of the signs and symptoms, but they will be identical to those that are seen after either oral ingestion or injection of the toxin. Okay, now we know how it causes disease, but what happens to the patient, Ted? Well, Doris, first of course, there's an incubation period. I don't know if incubation period is the right term in terms of toxins, but there's a latent period after an inhaled dose of botulism. And then the clinical disease starts after approximately 24 to 36 hours in most cases, sometimes as late as several days. Lower doses, of course, would take longer incubation periods and higher doses would probably present more quickly. Bulbar palsies, bulbar paralysis, would be what you would see early on with eye symptoms such as blurry vision due to the medriasis, the diplopia, the ptosis, and the photophobia that would go along with the case of botulism. Those are evident, I believe, in a slide we have here. As a pediatrician, I can tell you all teenagers look like this to a degree, but this is an unfortunate teenager who contracted botulism. And what you notice about this youngster is he's unable to move his facial muscles. So he's unable to smile, he's even unable to lift his eyelids. You also get dysarthria and dysphonia and dysphagia, so he can't swallow, he can't swallow his secretions. You get extreme dryness of the mouth and throat and you're supposed to notice here that the tongue is quite dry. But what kills you is that this paralysis progresses distally to involve all skeletal muscles, particularly the skeletal muscles that control respiration, the intercostal muscles in the diaphragm. It presents clinically as a symmetrical, descending, progressive weakness, and again abruptly culminates in respiratory failure. It can progress rather quickly. In fact, with some cases of foodborne botulism, you go from the first signs of botulism first symptoms as far as death in as little as 24 hours. And again, you saw that in that teenager. He was put on artificial ventilation and fortunately lived happily ever after. I want to stress to the clinicians out there that with everything in medicine there's a differential diagnosis and that certainly applies to botulism as well. If you were out there on the battlefield and you saw a single case of this flexed paralysis, you would have to entertain diagnoses such as Myasthenia Gravis, the Eaton-Lambere syndrome, maybe poliomyelitis, even though that's basically gone in the Western Hemisphere, the Guillain-Barre syndrome, things like that, maybe even nerve agent intoxication on the battlefield. If you saw 20 cases, there's no way that 20 cases of Myasthenia Gravis are going to come into the same treatment facility clustered in space and time. So a very easy diagnosis or at least it should be a very easy diagnosis to make on the battlefield. And again, the real differential in the battlefield is going to be botulism versus nerve agent intoxication. And we're going to talk at length later in the show about how to make that distinction. Okay, so that's what you'll see in the patient. Right. Alright. Right. Hopefully not the death part. Right. You should see them when they present initially. Probably all they're going to have is a little bit of weakness. They're probably not going to have a fever. They're probably still going to be alert and oriented. Maybe they'll have some postural hypotension initially. And again, they're going to complain initially of weakness and maybe the Bulbar symptomatology associated with that weakness, the blurry vision. You might notice dilated pupils if you do a thorough exam on neurologic exam. They may have some degree of muscle weakness. And here's our teenager demonstrating the medriasis. If you pursue your physical exam as you should, you'll notice an absent gag reflex. Deep tendon reflexes may be present, may be absent. Okay. Well, let's listen to Dr. David Swirlow outline the differential diagnosis between botulism and other diseases. If you have a patient with a suspect case of botulism, a patient with cranial nerve dysfunction, descending symmetrical motor paralysis with sensory nervous system preserved, then the first thing you need to do is rule out a couple of other common syndromes. Some of those other syndromes include myocenia gravis, Guillain-Barre syndrome, stroke syndrome, and toxin ingestions. That can be done with a scan of the head in MR or a CAT scan to rule out stroke syndrome, lumbar puncture to rule out Guillain-Barre. Although early on in Guillain-Barre, you may not have an elevated protein which is characteristic of Guillain-Barre. So you need to be suspicious that a patient could still have Guillain-Barre even with a normal protein. A Tensilon test can rule out myocenia gravis. The other thing you can do if you have a suspect case of botulism is perform an EMG. And this needs to be a specialized EMG with rapid repetitive stimulation. It needs to be done by someone who knows that they're looking for botulism and does this special rapid repetitive stimulation to look for an augmented response that can be typical of botulism. If you have a suspect case of botulism, you should call the State Health Department who can then contact CDC 24 hours a day. CDC provides clinical consultation and can help decide whether appropriate confirmatory testing should be done and whether antitoxin should be administered. It should be kept in mind that you really can't wait for the confirmatory tests in order to act on a possible case of botulism. The earlier you administer antitoxin the better and thus we do not wait for a confirmatory test in order to administer the antitoxin. In addition, any case of foodborne botulism is an emergency because we need to be sure that there isn't other food products out there that can make other people sick. So contact the State Health Department is very important to be able to begin any investigation to prevent anyone else from becoming ill. Okay Doris, I think the point that the clinician out there should remember is again if you see a cluster of paralytic disease out there on the battlefield there's not a whole lot that can be other than botulism. I think you need to think of a large point source outbreak and that could be foodborne or possibly the result of an aerosol delivery of botoxin. Okay, now Dr. Swargo mentioned antitoxin for treatment so how do you treat the disease? Well it's important to note Doris that prior to 1950 botulism had a mortality rate as high as 60% with modern medical care now and ventilatory assistance and intensive care, supportive care, we've been able to decrease that mortality rate to less than 5% but it becomes much much more difficult to provide that supportive care once your casualty numbers start to increase. I think it's safe to say that no military medical unit has enough ventilators to treat all their soldiers. The average battalion aid station doesn't carry a thousand ventilators and it's go to war stock. The good news is though that we have something besides supportive care to rely on and to help us take care of these patients. I think Dr. France would be best suited to tell us about the antitoxins available. Yes Ted, there are actually three antitoxins available. The first is a despesiated heptavalent equine antitoxin. It's called heptavalent because it contains antibodies against A through G, serotypes A through G. It's called despesiated because the antibodies are produced by immunizing horses and the antibodies are taken out of horses by plasma freezes. This is actually a photograph of first flight, one of the most famous horses that was used to produce some of this heptavalent antitoxin. Still living at Fort Detrick by the way. Despesiated because when they take the antibody out, they take out the IgG and if you know what an IgG molecule looks like, it has an FC portion down on the bottom. That's the part that looks like a horse if it was produced in a horse. So you cut that off with an enzymatic process leaving just the business end of the antibiotic. That's called a Fab II and that makes it despesiated. That was produced by the Army. There's also a human pentavalent shown here which was produced by the Army as well. It has, it's called a bot immune globule and this was done by immunizing humans then taking their antibodies out and they can be used for treatment. In that case you don't need to despesiate them of course. So it's the whole IgG. Dr. Steve Arnaugh, a pediatrician in California, also produced some of this material and did a recent clinical study in which he demonstrated efficacy in infants with infant bot. The third product is one that's available through the CDC produced by Canot Laboratories a number of years ago and it contains antibodies against A, B and E. So it's called a trivalent. Antibodies are produced in equine in horses but in that case they did not remove the FC portion so it's not a despesiated product. I should point out that all of these products are available in rather short supply. I think we may have a film clip that will show us exactly the mechanism of action of some of these antitoxins and if we could roll that film clip maybe you could narrate for us what's going on here. This is very similar to what we saw in the one that Mark described earlier here. The pink balls are the toxin which would in the previous film clip blocked the action of the release of acetylcholine. In this case the yellow balls came in, blocked the toxin so that they could not bind to the presynaptic receptors and acetylcholine that through. Great, great. I want to point out that because of the serum sickness question involved in these equine antitoxins before anyone administers the antitoxin they should first test their patient for horse serum sensitivity and this is done by injecting a one-tenth of an ML dose of a one to ten dilution of the antitoxin interdermally much in the same way you would do a PPD test for tuberculosis and then monitoring that patient for 20 minutes and if the injection site then becomes erythematous or the patient develops fever chills hypotension or any other signs of a reaction respiratory distress nausea vomiting generalized itching then the skin test would be considered positive and before you would proceed then to give antitoxin it would be incumbent on you to desensitize that patient first if the test is negative then the intravenous antitoxin dose can be given and that would be 10 milliliters given again intravenously over 20 minutes and you'd observe the patient of course for improvement. Okay now would you actually do that Ted if you had a thousand patients exposed? Well this I think you would and the reason I say I realize fully that doing this on a thousand patients seems cumbersome and seems to be a triage issue and in a sense it is so you would take into account your resources but I want to tell you you're going to give this antitoxin intravenously anyway so these patients are going to be in a facility of sorts they're going to be occupying a bed of sorts however primitive that bed space may be they're going to need to have an IV line started and so I don't think it's much more of a hoop to jump through to put that skin test on. Okay what about animal studies Dr. Frantz? During the Gulf War actually we did animal studies in monkeys challenging them with serotype A of botulinum toxin by inhalation and then either pre treating them or treating them at a prophylaxin them or pre treating them with either the human B.I.G. the bot immune globulin or the equine in despesiated product and found that it was very efficacious if you can get this material into the patient into the rhesus monkey in my case before the onset of clinical signs you just don't see clinical signs and a little antibody goes a long way but the key is getting it in before the onset of clinical signs because after signs have occurred there is obviously toxin in some isolated compartment within the body that the antibody can't get to and so it will still mop up what's out there in the circulation but the antibody probably doesn't get to what's in there at the pre synaptic neuron. Okay so Dr. Poli since this is a toxin and you can diagnose at the same way can you diagnose at the same was a bacteria and viruses? Yes and no in the case of a toxin what you do is you look for the toxin directly in this case botulinum toxin is such an exquisitely toxic compound but it's very difficult to find it in the bloodstream or anywhere else because it's there in such tiny amounts however you may be able to find maybe able to detect it in nasal exudates if you get that within a few hours after exposure and by the same token even afterwards even convalescent there's because there's such a tiny amount of toxin there people typically don't have an immune response so you can't even check for antibodies like you could for a virus or a bacteria. You know even if you can't do specialized tests though if you suspect this and or if you suspect any of these bio warfare diseases we're talking about in in this context today I would urge the clinician out there to obtain whatever samples they think are appropriate and stockpile those away for later use whatever that use may be. All right let's review the key points about botulism the incubation period is one to five days the symptoms terminate in a paralysis that causes respiratory failure and only very specialized laboratory tests exist to kind of help you out so you need to think about it clinically. Absolutely. Dr. France what what about prevention measures. Well there is an IND pentavalent ABCDE toxoid this is a formal and treated toxin which makes a toxoid much like tetanus toxoid that has been tested in primates extensively is very protective in the case of primates and it's been used in our laboratory workers for many years to provide them protection in working with the agent. The beauty of botulinum is that in this case we have an excellent surrogate marker if you have antibody which you get as a result of being immunized with the toxoid you're protected based on our animal studies there's also a new recombinant product that was developed at USAMRA over the last six or eight years it's a piece of the the toxin about a third of the toxin that's expressed for in another system it's going to be the next generation vaccine it's going to be cheaper it's going to be cleaner it may not be more efficacious because the old toxoid is very very efficacious as well but on the other hand it might be better because there's no formal one involved in this one so there's no cross-linking of key epitopes on that piece of protein so that's coming up in the future. Now wasn't this vaccine used in the Gulf War? Yes we immunized about 8,000 service personnel during the Gulf War most of those were special operating forces and others that were believed to be at high risk. Ted were there any side effects to the vaccine? Well Doris there weren't any long-term side effects certainly there were some minor local reactions redness edema enduration and those seem to increase somewhat with each successive dose severe reactions though such as extensive edema extensive enduration are very very rare. Systemic reactions with fever, malaise, headache and myalgia were reported in roughly 3% of recipients. Okay now Ted was able to give some instruction when he was down at Port Bragg with the 28th Combat Support Hospital so we're going to go back to the 28th and we're going to listen to a case presentation. Okay today we're going to discuss the case of specialist Kern where are you from Kern? New Jersey sir? Great before we do the actual patient discussion though let me set the stage here scenario is this it's 1998 and we're at war with the Soviet Union the nations the former Soviet Union have decided they really weren't doing very well on their own they reformed the new and improved Soviet Union and now they're not messing around they're not taking any chances they've launched a freeze full scale assault over the pole through Canada and a plunge deep into the heartland of the United States and right now the front lines of the battle are raging in and around that critical government think tank at Fort Leavenworth, Kansas. You though are here with 28th Cash at Sleepy Fort Bragg a thousand miles from the front nothing going on here at all very quiet day at the 28th when in Staggers specialist Kern and his story goes something like this three days ago he was pulling guard duty some kind of alarm went off he really wasn't sure what this alarm meant but all his buddies started to get their mop gear he figured he better get his mop gear too but he didn't have his mop gear with him so he runs back to his tent try to get his mop gear trips on the way hurts his leg ends up taking them 10 minutes to get in his mop gear but 30 minutes later the all clear sounds gets out of his mop gear and other than a sore ankle he feels fine for the next two days he goes about his duties no problem feels fine now in the morning of day 3 he staggers into your sleepy a post here at the 28th cash and he says you know doc got help me having a hard time can't catch my breath feel real weak we guys think going on with current here blue blue good where you from for Georgia Georgia good blue absolutely influenza very common disease occurs in wartime just as well as in peacetime and in a scenario like this especially a scenario a thousand miles from the front line it's far more likely you're going to be thinking garden variety types of diseases like the flu maybe he's got the flu maybe he's got mono maybe he's just scared that he's going to be sent to the front maybe he's worried about his mama back in New Jersey maybe he's worried about his girlfriend back in New Jersey a lot of other things could be going on with current and probably playing the odds those things are far more likely than anything real sinister like chemical or biological warfare cave in a chem bio warfare context what could this be nerve agent nerve agent really good good so this could be nerve agent at least nerve agent would give you some of the features of currents condition here now when you start to approach this on the battlefield I tend to find that students get real confused that there's a dozen different chemical agents dozen different biological agents going through their mind and it gets real difficult trying to sort those out so what I like to ask students to do is envision this two by two table we're looking at is this a pulmonary syndrome versus a neuromuscular syndrome and then we're looking at does this present in delayed fashion or does this present in immediate fashion so the first question is is this a pulmonary syndrome or is a neuromuscular syndrome and how would you differentiate those two while you take a stethoscope here and you could listen to his chest so if I take a stethoscope here I'm gonna listen to this guy's chest and if this were primarily a pulmonary syndrome I might hear Rawls, Ronkai, a lot of congestion in his chest but I don't hear that here so this doesn't seem to be primarily a pulmonary syndrome this seems to be a case of Kern's not able to breathe or he's having trouble breathing but it's not because there's anything wrong with his lungs it's because the muscles that operate the lungs don't work properly and in fact if I examine other muscles if I were to lift up his arm for example then I would find the same thing so I'm going to pick his arm up and you notice it just drops right back down to the gurney so he seems to have a neuromuscular syndrome rather than a pulmonary syndrome you guys are exactly correct when you say that nerve agent intoxication can produce a neuromuscular syndrome okay now how would you differentiate nerve agent intoxication from something else this might be and again nerve agent intoxication is a chemical effect what about biological weapons any biological weapon that could cause this anybody botanism botulism Jackson good so this could be botulism or it could be nerve agent intoxication and to the army truck driver those two might be confusing but to a bunch of highly trained medics there are some very simple ways of differentiating nerve agent intoxication from botulism and how would you tell the difference between between those two entities secretions good so what would you expect the nerve agent casually to look like secretion wise wet wet absolutely so the nerve agent casualty looks a lot like you looked last time you staggered out of the gas chamber they're drooling their slobbering snot pouring out their nose tears running out their eyes what would you expect the bot casualty to look like right dry absolutely main or good so the bot casualty they may have a little bit of drool because their muscles of swallowing are so weak but in general you'd expect their tongue and their lips and their gums to be very dry so secretions excellent what else can you use to differentiate pupils good so the pupils in a nerve agent casualty would be what constricted or dilated it's restricted constricted constricted how about a bot victim dilated so if you look at Kern's pupils his pupils would be very dilated so you can use the presence or absence of secretions you can use the size of the pupils and then finally we talked about the neuromuscular paralysis of nerve agent intoxication and of botulism and the type of nerve neuromuscular paralysis with those two entities is very different and you notice that when we lifted Kern's arm up it just flopped right back down to the Garni so he has a flaxet paralysis and botulism would give you a very flaxet paralysis what would the chemical agent the nerve agent casualty look like it could end up being flaxet but first there's hyperactivity hyperactivity so the nerve agent casualty generally starts out the very spastic paralysis he's twitching he's spasming he may even be seizing so very easy to tell the difference between nerve agent intoxication and botulism based on size of the pupils based on the type of paralysis based on the presence or absence of secretions but there's an even easier way and a more important way to tell the difference when would botulism present you saw he presented three days after this alarm went off and if you really believe that that alarm was occurred around the time of the exposure then this took him several days to present when would a nerve agent casualty present immediately immediately and the point I like to make is made by asking you who decides whether current lives or dies out there on the battlefield who just determines whether he's going to do well or not do well you guys do right absolutely you're the medics if you do the right thing current might pull through if you don't do the right thing current might not pull through on the other hand who decides whether the chemical casualty lives or dies the casualty absolutely he's out there on the battlefield to get exposed to nerve agent he starts having symptoms immediately he gives himself a mark one he may pull through if his buddy gives him a mark one he may pull through but if they don't give him the mark one out there on the battlefield chances are he's not going to make it to the 28 cash for you to have a chance at salvaging him so this guy that he presented immediately or in delayed fashion he presented in delayed fashion so it's much more likely what chemical or biological biological right so you've got a delayed casualty with a neuromuscular syndrome not much else that can be other than botulism so you see how with a couple of minutes of training you guys can readily differentiate pulmonary versus neuromuscular syndrome immediately immediate versus delayed presentation this is a delayed presentation of a neuromuscular syndrome must be botulism not much else it can be out there on the battlefield so great job again in two minutes worth of training you guys have shown that you can readily manage these types of patients on the battlefield tough part is going to be sorting this guy out from everybody with the blue and mono and malingering and all that kind of stuff where should that guy have been? that guy that patient that guy seems like where are you from? I thought Ted there was one point about that scenario that was a little bit unrealistic in that Kern the patient based on my experience with monkeys would have probably been on a ventilator had he had that degree of peripheral paralysis I think you're right sir I think you're right that's where he should have been that's where he should have been on the ventilator I just want to translate who for the Air Force people out there that would translate as aim high all right I've been hearing that a lot all right why don't we go on now to the next toxin agent Staffa Cockle interoxin interotoxin I practice that to be or SEB now you may recognize the name staff toxin as a common cause of food poisoning that's right as a naturally occurring disease SEB disease or Staffa interoxin B disease is a very common cause of food poisoning outbreaks it's a relatively quick acting toxin it causes vomiting maybe some diarrhea usually no fever again that's the thing the intoxications have in common is generally they don't produce fever whereas infections do it generally resolves pretty quickly it's an incapacitating agent so basically you feel you feel great you feel fine one minute then the next minute you wish you were dead you may wish you were dead for 24 hours or so and then you feel fine okay so this is what a terrorist would want to cause with this particular agent then well Dr. France I don't know what would a terrorist want to want to do with SEB well Doris if you've ever experienced the abdominal cramps that follow ingestion of these toxins you probably know it can clearly be incapacitating the same kinds of effect but much more targeted on the airways occur after inhalation of the agents you get a severe pneumonia you get high fever and a lot of distress you'll be down in bed following following this this kind of an exposure you know Karl France I want to ask you a question that I asked in an analogous fashion yesterday we talked about Venezuelan equine encephalitis yesterday I asked why VEE why not EE why not WEE same thing with this we hear a lot about SEB as a weapon why not staff enterotoxin A why not staff enterotoxin C for example why do we focus on staff enterotoxin B as a weapon I think it may be analogous to the situation that occurred in Iraq talking to Bill Patrick and some of the old-timers from the our US offensive biological warfare program that began in the late 40s actually almost 50 years ago they looked at all the enterotoxins initially and they found that they were able to grow this this SEB to higher concentrations more effectively and more easily than any of the others so they selected it all right what this be a lethal agent then certainly it can be an lethal agent it was originally selected as an incapacitant during our old program then when they did some animal studies and other studies with this this agent they found that it was probably a little more likely to be a lethal agent than they had originally anticipated I think what you would see with an exposure is a lot of sick people but you'd also see some deaths in untreated populations okay how does it work well these agents are called super antigens and as such they bind to the major histocompatibility complex on immune cells this results in T cell proliferation and the massive release of cytokines and lymphokines which accounts for the symptomatology you know clinically this mechanism of action would result in a sudden onset of fever headaches chills muscle aches a non-productive cop some of the more severe cases would then progress to respiratory difficulty retrosteronal chest pain the fever that one sees with SEB inhalational disease which you don't see with ingested SEB can last as long as five days and can range as high as 103 to 106 degrees if people inadvertently swallow the toxin and I think you could see how that would happen if you're overwhelmed by an aerosol dose obviously some of it's going to get on your lips and tongues and gum you may ingest some of that and if you do then you will see the gastrointestinal symptomatology as well the nausea the vomiting and the diarrhea there's a good chance that the patient who is attacked with SEB may not be able to return to duty for as long as two to four weeks alright is there any way to diagnose SEB well as it sounds it's a rather non-specific disease in appearance so it is very tough to diagnose definitively in more severe cases one can see pulmonary edema that may tip you off but again even that's pretty non-specific the chest x-ray in these cases is generally normal even in some of the patients with a significant amount of respiratory symptomatology at electasis and pulmonary edema and ARDS though can be seen on some chest x-rays what about laboratory findings Mark any laboratory findings that would help us for SEB it's we're able to detect it immunologically in the urine believe it or not and also with a little bit more trouble in the serum so a physician or an age station personnel who suspects SEB I would ask them to take nasal swabs once again and also both acute and convalescent serum in urine samples okay Dr. France is there any treatment or prevention for this toxin unfortunately Doris there's no specific treatment for the toxin it would be a case of treating symptomatically treating the symptoms most patients would actually do quite well if there is underlying disease however it it could be a very invasive intoxication and this could go on for two to three weeks with regard to prophylaxis there is no licensed or IND vaccine for use in humans at this time however we have some very promising again recombinant candidates in the in the tech base not only for SEB but for the other Staphylococcal endotoxins they have not been tested in humans but they are a very effective in animal models in inhalation animal models in non-human primates all right well let's move along to the next toxin which is ricin and I know that this toxin comes from castor beans that's so right Doris ricin is derived from a common plant the castor bean I was supposed to show some castor bean seeds here your ex-husband stopped me in the hallway and I gave him you can buy those commercially and you can use them to grow the plant that you see here the ricin is communist plant this plant is grown worldwide because of the castor bean that it produces and those castor beans are used in the production of castor oil and here you can see a very beautiful beans often used to make necklaces as well this is a castor bean production plant in Thailand and again this stuff is used all over the world for a variety of of indication you know my mother used to use this stuff on me the delivery system was a spoon and I was sure she was trying to kill me it's a biological weapon right it's still it's still out there and still being produced however it used to be more of an intestinal lubricant now we use it more as an industrial lubricant as my mother said exactly it's grown worldwide in in tropical climates over a million tons of beans are pressed annually for the for the oil the protein cake as such is three to five percent ricin by weight okay so you know that it's out there you know ricin was used and I think we mentioned this earlier in the show was used as an assassin assassination weapon the georgie markov story that the Bulgarian gentleman who was assassinated in 1978 at a London bus stop he was injected with that ricin containing pellet so we know it can make people sick we know it can in fact kill people and we know it's something that obviously a terrorists have been able to get their hands on it I think Dr. France that probably can share us share with us some more anecdotes of how terrorists might have employed this there have been a couple of interesting cases actually in the 90s there were two tax protesters in the Midwest that were attempting to intoxicate some some public servants in some way they were arrested in 1995 and charged under the anti-terrorism act in fact it was the the first case of use of the anti-terrorism act for possession of biological weapons there was another case of a worker from the trans-alaska pipeline but first brought some beans back with him moved to Arkansas was arrested again under the the anti-terrorism act and subsequently hung himself in his jail cell this happened just a couple of years ago I think this demonstrates the popularity of of ricin and as I mentioned earlier it's toxicity ease of production and stability that a proliferator or a terrorist might look at and in this case ricin scores very highly in ease of production and availability and I think also the popularization by the press has probably advertised this to some degree the Georgi Markov case for example now I remember we mentioned that ricin wouldn't be good on the battlefield well that's that's really correct even though ricin is stable and quite toxic by aerosol because it's not quite as toxic as some things such as Botox and it really would require a ton quantities on the battlefield however as as I mentioned before there's million tons of castor beans are pressed every year ton quantities really can be available and for that reason we still worry about it you know American physicians were never able to study Georgi Markov to learn from his case have there been any cases that we can maybe learn the signs and symptoms of ricin intoxication from well Ted there's a famous review paper that that was published in 1985 that reviewed all the cases of ingestion of ricin either beans or toxin that had occurred in the U.S. to that point it was some more than 700 cases I was surprised when I first read that to see that only 14 of those patients had actually died and in the following ingestion at least either in the serious or fatal cases we see very similar signs and those are rapid by rapid I mean within a few hours on set of severe GI signs nausea vomiting abdominal pain and then bloody diarrhea and cramps and for those who died eventually a shock like syndrome I'm not aware of any cases of inhalation of the toxin in humans and the resultant disease however in and around the the castor bean plants castor oil plants that Mark mentioned we see cases of inhalation of proteins that come from the beans these are typically allergic kinds of responses with wheezing tightness of the chest and so on and they respond to the normal therapies for for that kind of a syndrome so then after inhalation exposure then you would see mostly lung injury almost entirely if you give the toxin either IV or IP or sub-Q you see one kind of a syndrome if you give the toxin by inhalation you see almost entirely a pulmonary syndrome and this is a severe pneumonia and necrotizing pneumonia in which the airways and the alveoli become necrotic this is a gross slide from an animal model that was was challenged in this way you can see the hemorrhage in this slide and you also see eventually alveolar flooding this is likely the cause of death in inhalation intoxication for the clinician out there that would translate obviously into bilateral infiltrates on chest x-ray but I think you all realize that's a pretty non specific finding by now anything else mark that might help us diagnostically yes our reason is one toxin that we can detect immunologically in the serum and also because reason is such a highly immunogenic toxin in the convalescent serum several days or a week or two out we can often detect antibodies against rice in which can can help and make that diagnosis I would again hope that the physicians seeing the patients would take both acute and convalescent serum samples right how would you treat it well Doris as with many of these diseases it's non-specific treatment I don't know if Colonel France has anything more to add to that it would be simply symptomatic care non there there is no specific therapy for rice and intoxication you need to remember to keep up the with the fluids keep up with the intravenous hydration that would certainly be a key component of supportive care those with inhalational exposure would need appropriate treatment for pulmonary edema and respiratory support the same type of support you would provide for any patient with severe ARDS or like symptoms okay are there any protective measures there's no vaccine available yet although we do have one in the pipeline the best way to protect yourself against rice and is actually wearing a protective mask a protective master very effective in filtering out the toxin and it's not normally active so you don't have to worry about that route okay let's start now on our last agent of the entire three-day course the T2 mycotoxins now if I remember correctly we talked about these last year and are they but they're not really common knowledge they're not really widely known these are fungal metabolites there's a whole range of them there's over 40 of them they're usually associated with grains and nuts there are significant human health and agricultural problem in underdeveloped and developing nations many people while haven't heard much about these particular toxins you may have heard of yellow rain yeah well it sounds familiar but what happened with it I might comment on that Doris there are some this is a very controversial issue that occurred in the late 70s and early 80s there were reports of a yellow material yellow sticky material that was delivered from aircraft in remote areas of Laos Campuchia and Afghanistan there were reports of thousands of human and animal deaths investigators were sent in in an attempt to to collect samples they did collect samples from of leaves of some tree bark and soil and rocks brought them back to the U.S. and in a small number of cases did a small percentage of the samples were positive for a toxin called a trichothesine toxin called T2 and I think it was controversial because of the remoteness of the area the difficulty in obtaining good information about human cases and the fact that it was a relatively small percentage of the samples that were actually positive okay well other than that are there any naturally occurring diseases with mycotoxins many as I said this has been a huge agricultural and public health problem for forever aflatoxins are some of the most potent natural carcinogens we know they're very potent liver carcinogens a T2 toxin even when taken internally has been known to cause something called toxic elementary toxic alukia okra toxin another fungal metabolites from moldy grain is the source of bulk and endemic nephropathy and the list goes on and on there's many you know for the American clinician I think these have been very very obscure syndromes and I personally never really had a good clinical correlate to associate this with until fairly recently and I think many American clinicians are familiar with the fact that a while back a short while back in Cleveland Ohio 18 infants became ill and unfortunately three of those infants actually died and this epidemic was worked up and traced to something called stachyboitreous toxin and stachyboitreous is a black mold that was apparently growing to high tighter in the walls and dry dry wall of some of these houses in poor areas of Cleveland and it was postulated that inhaling the stachypoitreous led to pulmonary hemorrhage in these young infants so this is the first time I've really had a clinical correlate to some of these toxin diseases okay now these agents sound very different than the others is one of these the one that can be absorbed through the skin yes the one agent that's germally active and we've alluded to that several times during this course is the T2 mycotoxin the trichlothesine mycotoxins it could also be ingested after a terrorist attack and produce disease that way mark how does it cause disease this is a potent inhibitor of protein synthesis secondary to protein synthesis inhibition you often find nucleic acid synthesis inhibition because of this they act on rapidly proliferating tissues such as the skin the GI tract and the erythro portic system okay does it require any kind of special decontamination well it's a good question that you bring up we've stressed that for most of the biological agents decon is usually not necessary especially if it's been a day or more after exposure which because of the incubation period it's often going to be even if you know though that someone's just been exposed really all you need to do in most cases for most biological agents that we're discussing this course is the prudent use of bleach or soap and water and that works fine for almost everything out there this agent again is the one that's a little bit of an exception it works more immediately than many of the other diseases if someone's having skin symptoms this is one agent where you may need to do decon fairly quickly and you would probably want to add sodium hydroxide to the bleach that you're using to decon okay what about the symptoms after exposure to the toxin well the early symptoms that one would expect would include eye pain tearing redness blurry vision I think we've got actually an animation that will depict this better than I can describe it here you see some soldiers in a field aircraft flies by and drops T2 mycotoxin and then those toxin particles impinge on the skin they impinge on the conjunctiva as well they can lead to reddening of the eyes reddening of the conjunctiva as the eye becomes more affected the vision can get blurry and that can of course be a big problem on the battlefield not only again does this impinge on the eye but it impinges on all the skin surfaces and it can produce a significant amount of elethema of the skin fairly rapidly blistering then ensues and in severe cases the skin can actually become necrotic and turn black and start to slough off and I think all that's pretty well depicted here you can also see irritation and bleeding of mucous membranes and these can occur actually much quicker than with most than the symptoms would occur with most biological agents sometimes in a matter of minutes okay what happens after ingestion of the toxin well after ingestion there's a broad range of symptoms that occur that include as you might expect initially anorexia nausea vomiting diarrhea than a bloody watery diarrhea and eventually multiple organ failure and I think mark mentioned the fact that it is a protein synthesis inhibitor so it's not surprising that you would see multiple organ organ failure no matter what the root of of challenge okay is there any way to determine if exposure has occurred well yes there are immunological tests for a few of the mycotoxins however because there's a lack of cross reactivity from toxin to toxin in test-to-test unless you know exactly what you're dealing with that's often not a good route the best route is LCMS or liquid chromatography coupled to mass spectrometry this is a very sensitive method we can detect it in the serum and animal studies we've been able to detect metabolites out as latest 28 days you know like so many of these other toxins that were discussing with the exception of Bacillus of course there's really no specific treatment other than the supportive therapy that we've been advocating and unfortunately in the case of these mycotoxins there's no currently available vaccine we obviously don't have time to put on any mop gear anything to protect yourself I mean is there some kind of cream or something you can put on actually Dr. Bob Wanamaker you Sam read did the studies six or eight years ago that demonstrated that the chemical protective creams do work in the case of the mycotoxins and they protect the skin just like they do from the chemical the topical skin protective yes yes all right well many toxins could be used theoretically you heard Dr. Poli tell us that there were dozens and dozens of toxins we've only had time obviously to cover a very few in this course but now we're going to test you with a short scenarios you are the chief nurse assigned to the 167th airlift wing of the West Virginia Air National Guard the 167th has been called to active duty in support of the ongoing mission in a Caribbean country for the past two weeks the unit has been ferrying supplies to a remote staging base and from there onward to the capital city recently the situation there has destabilized in multiple briefings joint staff intelligence has outlined evidence that enemy special operations forces have engaged in a campaign to discredit US peacekeeping forces there intelligence feels that the enemy is trying to make us efforts appear incompetent while portraying themselves as supporters of these Caribbean people apparently some in the enemy government feel this will sway world opinion towards condemnation of the US boycott of their country following a successful two-week stint in the Caribbean the 167th prepares to return to Martinsburg West Virginia on the final day of their deployment they are treated to a big luncheon in their honor the luncheon features large quantities of fresh traditional Caribbean seafood delicacies like conch welk grouper and amberjack beans rice and potato salad are also served you and the medical crew directors stay behind to begin preparing the aircraft for your return flight two hours after the luncheon ends you're securing equipment inside the aircraft when a number of personnel from your unit start to feel sick to their stomachs what's wrong I'm sick my stomach I'm cramping really bad I have tangling around my mouth you're not having chest pain are you no okay short of breath a little bit on my feet stomach it's mainly my stomach and my toes and my fingers everything's getting now to my finger you feel sick to my fingers you know what what's wrong stomach is kind of painful and just kind of have problems catching my breath Camunas? Yes. Sergeant Curry is here having trouble catching his breath? Oh Sergeant Curry having a lot of problems here what's the matter? Well, stomach hurts a little. Do you need I feel you? I haven't vomited. You have vomited? No I haven't. Okay. I got a little cramping but not much. It's also kind of having difficulty breathing. Catching my breath. Um, you think you'll be able to if I walk you back to the litter you'll be able to walk back and maybe I'll put you down. Oh yeah. I want you to do the strap here. Okay. You gonna be okay? Okay. Um, we'll put that oxygen mask on your face. Okay. You should just breathe normal. It hurts. Okay use the bag if you start feeling sick. Sergeant Tarnson you want to keep an eye on and keep the oxygen. Ma'am? Ma'am my stomach. My stomach's bad. I'm feeling sick on your stomach. I feel like I have to vomit. I'm all right. Look, did you just eat or did you eat at that banquet earlier today or? I was there. Okay. Sergeant Tarnson, um, did you eat at the banquet by chance? Yes ma'am I did. Oh, that's... Are you also having stomach cramps? Yeah. Still feeling sick to your stomach. Excuse me. Excuse me. Captain Fletcher. How's it going back here? Do you have anyone that's not sick? I'm having...I have some individuals that are having the same symptoms but I do have a couple individuals here that aren't experiencing any symptoms at all. They actually feel quite well. You guys could help me. Yeah. I had everything to eat like everyone else except for allergic to shrimp and oysters. I didn't have those. Did all of you guys eat at the banquet earlier today? Yes. Yeah. We ate shellfish. We ate shellfish. I ate everything. You ate everything? Yeah. A little bit of everything. I ate kind of everything but that slimy stuff. I'm not crazy about anything that, you know, has a sheen to it so I didn't eat that. And I had everything, a little bit of everything too but I don't feel good. You didn't eat any uncooked meats or fruits or vegetables? I think everything was cooked. Yeah. Yeah. Yeah. Okay. Well, we're back here with our studio audience and we will test them and see what they think of this scenario. So the first question that I'd like to pose to the studio audience is what's going on here? What would explain the symptoms that these airmen exhibited? Dr. Nidson. We're thinking of Revatoxin or maybe Saxotoxin as sodium channel blockers because of the symptomology and the fact that they've been eating these exotic shellfish since the Saxotoxin is produced by or the Revatoxin produced by dinoflagellate and the shellfish are filter feeders that could concentrate in the shellfish and that would explain the symptoms. You see these guys picked up on the fact that this was likely a toxin because it followed the toxin part of the video telegraph. Well, at least we know they want to sleep. Why, could it be anything infectious? I know we're talking toxins and those are certainly good thoughts, but are there any infectious diseases that explain this? Dr. Lee. The time course being such rapid onset points to a toxin rather than an infectious which requires an incubation period. Okay, good, good. So very few infections would have. But what about the symptomatology would lead you to believe a toxin and not a bacterial food poisoning for instance? The numbing, the vomiting, we're also thinking that maybe Dorototoxin if they've been puffer fish. Okay, so there certainly were implicated foods that would produce bacterial types of food poisoning. For example, there was potato salad at the banquet, that's a common cause of staph and Ratoxin B mediated food poisoning. I believe there was rice, did they say? There was rice. There was serious food poisoning. But there was also grouper, a large carnivore. And siglatoxin would fall into that category which is also a marine dinoflagellate produced toxin. I was sort of curious as to why you stayed away from the siglatoxin as a differential diagnosis? We didn't. You thought I'd say, okay. The first row has siglatoxin and they're different. Okay, good. Good. Okay, so people are thinking toxin and I assume the reason you're thinking toxin other than the fact we just finished talking about toxins is the incubation period here, two hours, I believe, the first people had symptoms, is shorter than one would expect with an infectious, if this were viral gastroenteritis or a bacterial gastroenteritis or something like that. I heard somebody mention the numbness and tingling of the lips. That doesn't ring a bell as far as I'm concerned for any bacterial or viral disease. And I think you're absolutely right. That would point me in the direction of a toxin. Now, the next question is, is this endemic or is this sinister? Is this naturally occurring disease just happened to occur in Ladobo here or did somebody do something intentional? And how are you going to decide that? It doesn't seem like it would necessarily be intentional, especially since everybody appeared to have these symptoms shortly after eating this banquet. The banquet could have been contaminated, but one would have to look at what was served and then try to trace that back as to exactly where it came from. Was it fresh? Was it under observation? Did they get it from some street vendor off the back of his truck? That's an excellent point. However, there's a couple of things you need to think of. One, of course, Brevetoxin, Siglatoxin, both endemic to that region. Saxotoxin, one of your other choices, is not endemic to that region. That's a more northerly disease in Northern California, Alaska, Canada. It doesn't occur down there. It does occur in the tropics in Northern California, but not around Haiti. So that might help you in your diagnosis. One thing that you might also want to figure out is to see whether or not any of your hosts got sick. Because if they got sick, then it's probably the food. If they did not, then you might suspect terrorism. Also an excellent point. You need to go out and look into the indigenous population. If this is a local seafood problem, then civilians out there should also be getting sick. If nobody is sick except the people at your banquet, then that raises a whole host of other questions. That's right. In fact, I'm going to jump ahead a little bit. That kind of gets us to question four in the student activity. Question four says the commander wants to know if this is intentional. He's got his finger on the pulse of the National Command Authority. He needs to report back to his boss. He needs to advise his boss what to do about this. So he has a very vested interest in deciding whether this is intentional or sinister. We've already talked about some of the ways you're going to help to make that decision. Let me just review. The information that you're going to get is whether this is, in fact, whether these diseases, Brevetoxin, Saxotoxin, Sigwitoxin, are endemic to Ladovo or not. That's one question. Whether the local populace has been affected. In other words, we know people at the banquet were infected, the soldiers or airmen rather, the local dignitaries. But how about the local Ladovans who are out there? Have they been affected? And what would that tell you? If they were affected, what would that tell you? Well, it suggests that it's a naturally occurring event, perhaps. More likely it's naturally occurring if the local population is seeing that disease as well. And I don't think we've mentioned it yet, but there's this phenomenon of red tides. And I believe we have a still shot in our bank here that will show us red or red tide looks like. And in the case of Brevetoxin and Saxotoxin-mediated disease, that would be an important part of history. Have any red tides been noticed in the local area? Because Saxotoxin and Brevetoxin mediated diseases are associated with these blooms. Ed Eitzen, who was on the show on the first day and who will be on the show later today, is an Auburn grad. And he tells me these crimson tides are comprised of very, very primitive life forms. But that would be a crimson tide. We have also another shot that I think shows another sort of crimson tide. And, Mark, I wonder if you could maybe comment on this. This is an artificial red tide that occurred around one of the islands in Biscayne Bay a few years ago. No human health effects were noted from this. Isn't that the same artist who puts buildings in chocolate and that kind of thing? Oh, yeah. And long strings of laundry across the Southwest. Okay. Okay. Okay. So you got some information that was subsequently provided to you that says that there have been no red tides seen lately anywhere near Lidovo, but there was a red tide reported off of the American keys, the Florida keys. There have been no civilians in the populace affected by similar toxin-mediated diseases. What are you thinking now? Well, I wonder where the fish was caught. I mean, if the fish came from where the red tide had been noticed, that may... So it probably wasn't local. You're not seeing anybody affected. We need to step back one step here, because at the time of the outbreak, you're not going to be able to tell the difference initially between neurotoxic shellfish poisoning or brevetoxin intoxication and ciguatera poisoning. Many of the symptoms are identical. In this case, we have another clue. Did anybody pick up on the clue that differentiates the brevetoxin intoxication from ciguatera? Because ciguatera is endemic to Haiti, and it could very well have been the grouper or the yellowtail or the king mackerel that was served at the banquet. Sir, didn't they bring up that several of the members who did not become sick did not eat the oysters in the shrimp? Very good. You were paying attention. Yes, exactly. The people who didn't eat shellfish didn't get sick, and ciguatera is never caused by shellfish. It's only caused by large reef-blowing carnivores. So the fact that you can pin it on the shellfish now makes brevetoxin the primary culprit. I think they gave a history also of these two airmen who had CQ duty. They were back men in the telephones at the shop. They were brought their platters later, and they were out of conch and welk. So those two airmen didn't get any of the conch and welk, and they did not get sick, so that would implicate conch and welk. And I think this just all highlights the importance of epidemiology in general. Again, I've been harping on you for three days now about the importance of being an amateur epidemiologist, and I realize I'm certainly not going to make you all professional board-certified, preventive medicine officers. But epidemiology is still important. You need to know how to do a garden variety, gum shoe, quick and dirty epidemiologic assessment, and you can see here the value of that. And I think you're all thinking, oh, this isn't fair. We talked about foretoxins. We didn't talk about brevatoxin, and in fact, in that sense, it's not fair. And we picked brevatoxin just for grins, but this could easily have been saxatoxin or sigwatoxin or tetrodatoxin or fugu poisoning or any one of a zillion other marine or bacterial or reptilian toxins. And the importance here is not necessarily the identity of the toxin. Dr. Poli, I'm sure, would love for you to correctly identify this as brevatoxin, and he can do that in his laboratory. And if you can do that clinically, that's great. You get a merit badge and an extra credit and maybe even an army achievement medal. But the important point is can you figure out whether this is normal or abnormal? Can you figure out whether an epidemic is really even occurring in the first place? And can you figure out whether this is sinister or whether this is endemic disease? Let me ask you one last set of questions. What would you do for these affected individuals? I think activated charcoal would be warranted in gastric lavage if it's done immediately. Okay. Excellent point. But the key qualifier here is if it's done immediately. And these people who are already symptomatic, it's too late. If you had a situation where everybody ate at the banquet, they all got sick, but there were some people who didn't get to eat because they were working and somebody put a platter in the refrigerator for them and they came along later and started eating and you caught them. They had started eating but they weren't yet eating. So I think that those people would be great candidates for charcoal gut decontamination. But these people who are already symptomatic, unfortunately it's too late. Excellent point. Your window of opportunity for charcoal is probably under 12 hours. Okay. It may not be too late at the very onset of symptoms, but certainly 8 to 12 hours maximum is about all your window of opportunity is and if you don't get it by then, the charcoal is really not going to help. What about decon? Do these patients need deconning? No. Patients don't need deconning. This stuff is not contagious. The food needs deconning. So I've decon the food down the garbage. What I'd probably do is send the food to Dr. Fletcher. You collect it, you put my name on it and you send it back to you, Samrid. That's right. In addition to some serious specimens? Yes. However, at this point in time, we cannot detect, we don't know that we can detect Brevetoxin in serum after about somewhere in the first 24 hours. However, working on it, I can detect it in urine out at least 24 to 48 hours. So urine samples would be nice. Time urine samples over at least 24 to 48 to 72 hours if you can get them. That would help us determine the pharmacology and the pharmacokinetics of absorption and excretion. All of that is nice from a scientific standpoint. For you, I can help diagnose the problem, but I would like serum and urine collections. Okay. Any questions from you? I think there are a couple of other things that we need to consider with regard to this. One is that we have a military unit that's out of commission and somebody needs to receive that report. And the second thing is we have a breakdown in the food procurement preparation chain. And I think someone has to go back and ask who inspected the food items, who procured them and who gave the OK for this event. Excellent. Excellent point. And just highlights the military need in general to pass information up the chain of command and down the chain of command. Except there's an important point here is that if this were siglatoxin, it is bravatoxin. These food stuffs are perfectly fresh, perfectly healthy other than the toxin. You can't catch these by inspection. You'll never see it. They smell right. They look right. They're fresh. This is not an inspection issue. Okay. Well, that about wraps it up and you guys have done as usual a great job.