[Dr. Stewart introduces Patterson]
Let me introduce Dr. Patterson. She will give the opening lecture.

[Dr. Patterson]
Thank you. What I'd like to share with you tonight from my perspective as an infectious disease clinician, are the signs and symptoms and what you can do about recognizing the top four potential bioterrorism pathogens.

Several weeks ago, most of the public didn't know what anthrax was and now it's become a very common household word. We'll talk specifically about the details about anthrax since it's the main issue of concern right now. But we'll also address smallpox, which you've also read some about in the media, as well as plague and other potential concerns and botulism.

There are some historical precedents for bioterrorism. The first that we know about was in the Dark Ages---the Tartar Siege of Caffa, when the used for their ammunition catapulting of plague victims over the wall of the city of Caffa. In the 1700s during the French and Indian Wars, there's was correspondence suggesting that the British used blankets with smallpox scabs from smallpox victims and gave them to Native Americans. In the 1920s, a Japanese doctor who began the biowarfare program in the country, laced some chocolate with anthrax and distributed them to Chinese children and distributed flea bombs over Chinese cities that were infected with plague and anthrax.

But surely by the late 1900s, we were too civilized for that. There was a biological weapons convention and treaty in 1972 that was negotiated by President Nixon and ratified by 140 nations. This officially terminated offensive biowarfare research and stockpiles were officially destroyed.

Since then, and until the present time, there have been some small incidents. In 1986 a cult in Oregon distributed salmonella in some restaurant salad bars in order to incapacitate voters and influence a local election. In 1995, a cult in Tokyo dispersed anthrax and botulism aerosols from roof tops in Tokyo at least eight times and were unsuccessful in causing disease. They did however, subsequently did the gas attack in the subway there. In 1995, a member of the Aryan nation in the United States was arrested for ordering a culture of plague from a culture collection in this country.

In 1979, there was a incident in Sverdlosk in the Soviet Union where there was an accidental release of anthrax aerosols from biowarfare plant. Of course this wasn't officially acknowledged because this was after the biological weapons treaty and this wasn't supposed to be a biowarfare plant. However, there were 79 cases, 68 deaths. At the time this was attributed to an outbreak of anthrax in contaminated meat. However, in 1992, Boris Yeltsin acknowledged Sverdlosk as what it was and promised to terminate the biowarfare program. Around this time there were some defectors from the Soviet biowarfare program who said that there were large stocks of smallpox vaccine and there's been some concern since that time that some of those stocks could have gone to nations that were interested in biowarfare. In the 1990s during the Persian Gulf War, Iraq was found to have 19,000 liters of botulinum toxin and 8,500 liters of anthrax.

Why would such horrible weapons be used? The cost of casualties per square meter is estimated to be for conventional weapons about $2,000, for nuclear weapons $800, chemical $600 and for biologic weapons $1. This is why many nations are thought to have biological weapons and you see of those listed here.

There are some constraints, however. This includes access and transport to these weapons. Certainly in this country, we no longer can order agents that can be potential biological weapons. Aerosol delivery has to be accomplished for some of these agents and a relatively large aerosol as you'll see for some of these agents. And the aerosol has to be the right size so it can get down into the bottom of the lungs to cause disease. Also some of these agents are very sensitive to these environmental conditions: Ultraviolet light as in sunlight. If the wind conditions are wrong, it may not blow the right direction. Also temperature and desiccation can inactivate some of these agents.

How might it happen? It could be a overt attack or threat. Or as we've seen very clearly in the past month, a covert attack where there is delay between exposure to the illness and patients may present to different doctors' offices and hospitals. In this instance the first responders will really be the medical care community. In fact, it was an astute clinician in Florida who recognized the first sentinel case in Florida as what it was.

Potential bioterrorism agents. Anthrax tops the list for reasons that we'll discuss. The name of this organism is bacillus anthracis. Plague is another potential bacterial organism, versinia pestus. And botullinum toxin-the toxin that's produced by the bacterium clostridium botulinum is another potential agent mentioned. As far as viral agents, the most dreaded one is smallpox and we'll discuss that in detail. Other mentioned viral hemorrhagic fevers such as ebola and lassa fever, but these are less communicable than smallpox. And even some fungal pathogens might be used. So there are a variety of biological organisms that could be used as biological weapons.

So we'll discuss anthrax first, bacillus anthracis, in detail. Under the electron microscope which is the picture you see on the left, these organism form rods. And a special stain that we use commonly in clinical medicine called the gram stain is shown on the right and it's gram positive or blue staining with this stain. In a clinical specimen or a culture of this organism the gram stain would look like this. This is called a box car appearance where these organisms appear to form a train and they individually look like box cars of the train. It was distinctive appearance that tipped off the clinician in Florida when he examined spinal fluid from Robert Stevens, the first patient found to have anthrax. It was this gram stain that clued him off that this could be anthrax.

This is the lifecycle of anthrax. The reservoir for it in nature is herd animals. So this could be cow, goat, sheep, horses and they ingest in from the soil, from grazing, grousing, or drinking. They may inhalate from spore-latent dust. The organism from the soil is stored in spores. The spores form a very hard coat around the bacterium and it's a very stable form of the bacterium and it can last years. When the animal becomes infected with anthrax, they actually become sick as well and die. And from discharge from that animal, the anthrax goes back into the soil in a vegetative form and on exposure to oxygen forms the spores again. Humans are an incidental host and infection can occur three different ways. The most common way, and 95 percent of natural cases are cutaneous or skin anthrax. And this occurs from inoculation of the spores through the skin through a cut or break in the skin. The other way which is much less common is gastrointestinal anthrax which occurs from eating meat which is infected with anthrax. And finally, the pulmonary or inhalation anthrax where spore-latent dust is inhaled.

To go into a little bit more detail about these three different types of infections. With the inhaled anthrax, the spores are drawn into the lungs and cause hemorrhage, bleeding and breakdown of blood vessels and death could follow very quickly if it's not recognized and treat early. For the skin infection, which again is the most common natural kind of infection, the spores enter through the skin through cuts or breaks in the skin and it causes a local ulcer that very characteristic and can be readily recognized and treated. If not treated, there are some cases, 10 percent or so, that can develop into blood stream infection or septicemia and can become quite serious, but this is uncommon because antibiotic treatment is usually given and recognized for the skin infection. And finally, if it's ingested through contaminated meats it infects through the intestinal tract and can be fatal again if not recognized.

This is the cutaneous form of anthrax and this was an infection that was acquired occupationally from carrying an animal hide on this man's shoulder. The lesion initially looks like a red bump, then blisters develop and swelling around these blisters. Then the very characteristic black center and then some blisters around the edge-called a ring of pearls. This black center lesion of very characteristic of cutaneous anthrax and in fact the name, anthrax for anthracis, comes from the meaning of the word coal. That's how it got it's name-anthrax. So this is a very characteristic lesion, it can be readily recognized and treated with antibiotics.

I might mention also that we still do see some anthrax in Texas. There are some animals in the Southwestern part of Texas where it still occurs. And there was a case, a natural case, where cutaneous reported this summer in a rancher who had skinned a buffalo. A horse that died later at the ranch was found to have anthrax. This individual had a characteristic lesion and was treated successfully.

Now to talk a little bit more in detail about the inhalation anthrax, remember that spores have to be inhaled and its estimated that between 8,000 and 11,000 spores have to be inhaled to cause an infection. If inhaled the larger particles lodge in the upper respiratory tract where they're less dangerous. But particles are one to five microns in size-a micron is about a 1,000th of a millimeter in size-so they're very, very small particles. If those are air sliced and inhaled, and if enough of them are inhaled, they can penetrate the avelea, which are the tiny sacs in the lower part of the lung. The immune system responds and destroys some spores, but go to the lymph nodes or glands in the chest. The spores under the right conditions can germinate and multiply. They affect the chest tissues and organs. This is where the disease really takes off. The patient may have chest pain at this point of time. As they infect the tissues in the chest, the bacteria produces toxins and its really the toxins that can be fatal in this disease not the bacteria itself because the toxins cause adema and bleeding and organ destruction. In the lungs and in the chest these toxins cause bleeding and tissue decay.

Here is the clinical progession in the case of inhalation anthrax. The incubation period, that is the time from exposure to the illness until the time of development of systems can range anywhere from one to 60 days. More usually, it's a range from 3-5 to 3-7 days. The first symptoms that may be noted by maybe the third day includes fever, fatigue, muscle aches and generally feeling unwell, not wanting to get out of bed. If you've ever had influenza, this is kind of the same symptoms as influenza-flu-like symptoms. A couple of days later-a severe shortness of breath can occur and this can be progressive from a more mild shortness of breath to a severe shortness of breath. And then swelling in the chest and neck-at this point in time the patient may have chest pains from the swelling. A complication that can occur and was noted particularly in the Spherlox case wehre there was thought to be a large amount of aerosol inhaled and also in the Mr. Stevens case in Florida is meningitis. This is an infection of the lining of the brain and this is a severe complication of this disease. So at this stage meningitis can occur so can respiratory failure, shock and death.

How can it be diagnosed? Well, it's easy to grow in cultures, so it's relatively easy to diagnose, but the laboratory culture itself is not a rapid diagnosis. You have to wait a day or to before you see it growing. So a gram stain of the blood, or in Mr. Steven's case the spinal fluid, can be very helpful in getting an early diagnosis. That's because of its characteristic appearance under the microscope. As for controlling the infection as you heard there's no person-to-person transmission. In the hospital we would use only our standard precautions as we use for any patient or control.

For treatment it's most effective in the initial stages of this disease because as I mentioned in the later stages it's the toxic production that's the problem. Right now the current recommendations are Ciprofloxacin therapy while awaiting susceptibility. This is primarily because there's been concern that agent, an anthrax bacteria used for biological warfare might have been genetically manipulated to be resistant to penicillin which has been a treatment for anthrax in the past. However, the strains that susceptibility testing have been performed on have been susceptible to all of these antibiotics including penicillin. Other approved treatments include doxycycline and penicillin and in fact if a patient has meningitis one might use high dose penicillin because this goes well into the meningis. Prevention after exposure-and this is really where cipro is being used most for and it is the only one of the antibiotics that has the indication for the prevention after exposure. There's three antibiotics that have indication for treatment and in combination to the vaccine, which the general public really doesn't have access to right now, ciprofloxacin or doxycycline can be used for 30 days, plus three doses of the vaccine. Or antibiotics alone can be given for 60 days. And this is what's being done in the cases that have bee prophylaxed right now.

So let's move on to another disease that we haven't seen in the United State since 1949 and it hasn't been seen the word since 1978 and its smallpox. Smallpox is not a bacteria it's a viral infection and this picture shows some characteristic things about the distribution of the rash of smallpox that's distinctive and differentiates itself from other infections where these blisters can occur. In smallpox the blisters occur in the peripheral parts of the body-the face, the arms, the legs and the chest and the back, as you can see I this picture are relatively spared. Also, all of the blisters and pustules progress at the same time, as where in a disease like chicken pox all of the skin lesions progress at different times-you may have some red bumps, you may have some blisters, you may have some scabs-all different phases.

Now the reason that natural cases of smallpox have been eradicated from the world is vaccination. The principal of vaccination actually was first done in Asia, many years before Edward Jenner, who's depicted here, he actually popularized vaccination. In Asia, patients who had a mild form of smallpox and inocculant was taken from them and given to other people in hopes they would have a milder form and not a fatal form. And sometimes that worked and sometimes it didn't. The practice went from Asia to Europe. But it wasn't really popularized until 1796 when Eward Jenner applied the scientific method for some of this. There was a popular folk notion at the time that milk maids didn't get smallpox because they got cow pox. That cows had a disease similar to smallpox where they would get pox in their udders and the maids would get a similar disease and become immune to smallpox and never got it. And so when he heard about this notice he decided to take some fluid from a pustule from a milk maid with cow pox and inoculate it into an 8-year-old boy, James Phipps, and then several weeks later he inoculated the same boy with smallpox and he didn't get smallpox. It was after that that vaccination took off. The term vaccination comes from the Latin word Vaca, meaning cow. So Edward Jenner gets credit for popularizing vaccination, but really it had gone on before his time.

Natural cases were eradicated from the world in the 1970s. Routine vaccination in the United States stopped in 1972 because we hadn't seen a case in the U.S. since 1949. The last natural case in the world was in Somalia in 1977. There was an unfortunate laboratory-acquired case in 1978. And that was the last case of smallpox on earth. The last acknowledged stocks of smallpox are in the U.S. in Atlanta and the Center for Virology in Russia. These are now well guarded. As I mentioned, there was some concern that during the 1980s that some of the stocks of smallpox might have gotten into the hands of other countries that might use this agent as a biological weapon. One of the problems with smallpox is that it is contagious by the airborne route and also by contact with these skin lesions. And in one in three people who get smallpox will die. Those who survive can have complications of blindness and disfiguring scars.

The way smallpox might present, the time from exposure to illness is about two weeks. It can range from one to three weeks. The initial symptoms may just be fever, malaise, severe headaches, then this progresses to a rash. As I mentioned it's concentrated on the peripheral parts of the body-the face, the arms, and the legs. It initially would look like red bumps and then develop into blisters and then pustules over one- to two-week period. One thing that's characteristic about smallpox is that all of the lesions progress at the same time-called a synchronous progression. This is in contrast to chickenpox or varicella in which the lesions are all different sizes and types and are more concentrated to the back and the chest.

Again here is smallpox, which is on the leg in this case. All of the lesions look the same.

Right now there's not a specific treatment for smallpox. It's supportive treatment. There are some antivirals that may have some activity that look like an animal model, but these haven't been well studied. Prophylaxis we all know is a smallpox vaccine is given quickly after exposure and prevent infection. The smallpox vaccine is a live vaccine and it shouldn't be given to immuno-compromise persons or pregnant women. So the opten for them might be the vaccinia immune globulin. The problem is we have limited supplies available of both of these especially the vaccinia immune globulin. Vaccinia is simply the virus in the vaccine. The infection control measures for smallpox would be different because it is contagious by the airborne route so we would use both airborne and contact precautions to control this and a special handling of laboratory specimens.

Ok, going on to plague. The plague was epidemic in Europe in the Dark Ages and this is reminiscent of robe and mask that doctors would use as they saw plague victims. In the beak of this mask were spices bought to filter the humors that were thought to transmit plague.

However, plague for the most part is not transmissible by the airborne route. The problem was vectors and specifically fleas were the vectors and it was really the rodent population that made it the problem. The rodents provided a way for the fleas to get around to other rodents and to man. The Bubonic plague was the most common type and caused swelling of the lymph glands which were called bubois, hence the name, bubonic plague. The Pneumonic plague was actually quite rare. We can still see some cases of plague in the United States because it is endemic and found in animals in the Southwestern United States and found in squirrels and prairie dogs. So we occasionally do see a case of plague in humans in the United States. Pneumonic plague is very rare, so in the right context we might consider whether an aerosol exposure has occurred in a biowarfare type setting, particularly if it were outside the geographic area where plague can occur in the United States or if there were a cluster of cases. In the incubation period is one to three days and it would present as a very severe pneumonia. The patient might have watery, bloody sputum or phlegm. There is a high mortality rate unless early treatment is given. It's not as contagious as smallpox, it's not really airborne from long distances, but can spread by droplets from person to person by direct contact with respiratory droplets.

There is a characteristic appearance of plague under the microscope. You can see some of these dark-staining organisms have bipolar staining or a safety pin appearance and this is suggestive of plague on a gram stain. Pneumonic plague is treatable. The antibiotics used to treat it are gentamicin or streptomycin, ciprofloxacin or doxycycline can also be used. And there are regiments for prevention after exposure-doxycycline or ciprofloxacin or one of the other fluoroquinolones as in the same class as cipro.

So let's talk about the fourth potential pathogen and this would present in this way. A previously healthy person with two days of blurred vision, dry mouth, one day difficulty speaking, bilateral upper extremity or arm weakness, no fever, normal blood pressure, alert, oriented, anxious. And on physical exam, the eyelids would be drooping, the pupils dilating, they would be having difficulties with speech, absent upper extremity or arm reflex, but there sense of touch would be normal.

This is botulism and it's caused by the very potent neurotoxin of spore-forming clostridium botulinum. As you know this toxin is being used to treatment for good uses as for treatment for migraine headaches and even some applications for some cosmetics by getting rid of the worry lines by injecting right between the eyebrows. The key clinical feature of us presenting this disease would be that is would be a descending paralysis and it starts with palsies of the nerves and the face. It's not contagious. The main thing is to get the patient on a ventilator for respiratory support because the cause of death is paralysis of the respiratory muscles. And the antidote is botulinum antitoxin that can be obtained from public health departments. We occasionally do see cases of clusters or outbreaks of botulism in the Univd States and in fact there was one in Texas, in just the last few months, in Fort Worth, from a brand of chili. There were about 12 cases of botulism reported.

So what can we do as a society collectively? The panel will address this, but I'll just briefly mention. Obviously security, we have to be as aware as to who are in our workplaces, as well as our homes. We need to know who's there and what they're doing there. And intervention, the health care provider is important because they're going to be important in recognizing these diseases early on and reporting them to the Public Health department. Dr. Guerra will talk about the public health surveillance, laboratory confirmation, they're well in doing that and they're important role in epidemiologic investigation. And of course because these are criminal acts law enforcement and criminal investigation is very important.

There are some online resources, and you may have already referred to some of these Web sites that talk about bioterrorism. The CDC Web site has been widely used. The Texas Department of Health Web site and the Infectious Disease Society of America Web site. The Journal of the American Medical Association in 1998 had a very extensive issue on biological terrorism which is a good reference.

What can we as individuals do? There will be others on the panel discussing this in detail. But I think we can be informed and reassured as possible. We must, specifically with regard to the infectious aspects, we must be exposed to anthrax to get sick. Spores must be inhaled, touched or swallowed. It can be treated if detected early and it's not contagious. Large scale cipro prophylaxis is not recommended. And there are several reasons for this. One is other bacteria in our body can become resistant very quickly. This drug and other drugs in its class could be used normally for community-acquired pneumonia, urinary tract infections and other important infections. And if the bacteria in our body become resistant, they won't be helpful for those type of infections anymore. Also while cipro is relatively well tolerated particularly for a short period of time, if we have large numbers of people taking long courses of cipro, we will see some of the less common but important side effects. It can cause a very severe skin rash of sensitivity to the sun, and even tendon rupture in some people. Even though that these are rare side effects, if many people are taking this for long periods of time, we'll see some of these complications. Also it's difficult for the elderly to take some of these drugs sometimes. Many of them do not tolerate them because of mental status changes, irritability they're especially sensitive to. And this drug can interact with other drugs. It can raise the levels of certain medicines such as medicines used to treat lung disease and it can even raise caffeine levels and we're all jittery enough already. Influenza vaccine-I don't know of a better year for us to get our influenza vaccine. The less cases of influenza we have, the less time it will run in our mind and in our head and our health care providers' mind could this be something worse. And finally since this is a war that is really on our homeland, we are called to be soldiers, so we must be fit mentally as Dr. Wartman mentioned. We need to focus on our work and our families and go about our business. Physical fitness helps us with mental focus and also with resistance to disease including infection. And there's no better time to look at our spiritual values and turn to our faith and places of worship. So in the year 2001, everything old is new again and you can see that the garb that was used for in the Dark Ages is similar to the garb that was used on the last two to decontaminate the site in Florida and even to the gas mask many people feel like the ought to buy at this point in time. And these diseases which we thought we had conquered and eradicated this time have come back to haunt us not because of natural forces but because of man's inhumanity to man. However, since September 11 we have witnessed many kindnesses and much goodness in our fellow man. We have seen ordinary people to extraordinary things. And we are finding out how determined at resourceful we are to prepare for future incidents. And as some of what the rest of the panel will be discussing to you. Thanks for your attention.