Bioterrorism: Alert and Response

Table of Contents

Definition of Bioterrorism
Modes of bioterrorist attacks
Bioterrorist Agents:

Anthrax

Plague

Smallpox

Botulism Toxin

International Biological Warfare Agreements
Challenges of Bioterrorism: Clues to a Biological Attack
Surveillance for Bioterrorism
Other Surveillance Systems: EWORS
Surveillance System: Washington, D.C

Readings

Definition of bioterrorism

Biowarfare and bioterrorism are the intentional or the alleged use of viruses, bacteria, fungi and toxins to produce death or disease in humans, animals or plants. The potential for disrupting our society, both in this country and globally, is tremendous for not only a bioterrorist event against humans, but also against animals and plants. In fact, because of the way our agriculture systems operate, just a small handful of cases can lead to a devastating economic ripple effect. For example, mad cow disease in England affected a relatively small number of cattle, but devastated the cattle industry.

Historically, bioterrorism is not a new thing. You can go back centuries and learn about plague ridden corpses being flung over the walls of cities, infecting people within those walls. Allegedly, the British during the French and Indian War, gave blankets that were contaminated with smallpox virus to the Indians. There is a very disturbing legacy in World War II where the Japanese experimented with bioterrorist agents against thousands of people in Manchuria.

Modes of bioterrorist attacks

Bioterrorist attacks can be, at least in theory, executed at several levels:

1. The strategic level, which can cover large populations or geographic areas. This may also be directed against crops and livestock resulting in famine or economic disruption.
2. The tactical level, which is a more directed attack. These are usually limited by the incubation times. They are most effective against a fixed position. An example is the intentional contamination of a salad bar at a restaurant in The Dalles, Oregon in 1982.
3. The terrorist approach, which doesn't have to make anybody ill. This may be easy to deliver and difficult to detect. For example, in Washington D.C. the downtown area was gridlocked because somebody sent a petrie dish labeled "anthrax," into rush hour traffic.

Why are bioterrorist agents attractive? They are cheap, at least in the view of the United Nations chemical and biological expert panel. If you wanted to produce casualties using conventional weapons such as artillery, or bombs from airplanes, and you wanted to take a civilian square kilometer and destroy it, it would cost you $2000. With nuclear weapons the cost would be $800, using chemical weapons $600, but with biological weapons only $1. So biological weapons are inexpensive and thus within the economic reach of terrorist groups or small nations that could not attack us using the more expensive approaches.

Biowarfare and bioterrorist agents may also be attractive because they are relatively easy to produce. To build a nuclear weapon, you need elaborate facilities costing millions and millions of dollars. To make a bioterrorist weapon all you need are some of the things that are sitting in the many microbreweries scattered around this country. The simple fermentation equipment that you would find in a microbrewery or in a pharmaceutical plant can easily be adapted to growing of large volumes of bioterrorist type agents. Because of the dual use of many of the pieces of equipment needed to manufacture bioterrorist agents, it is somewhat easy to conceal and very difficult to regulate.

What is particularly difficult about bioterrorist agents, is not making them, but delivering them. There are many people who know how to grow a culture of anthrax, but to figure out how to deliver it in a fashion that can affect large numbers of people is a real challenge. Usually these agents are delivered by an aerosol route, or at least that is the theory of how they would be delivered, and to deliver them effectively, they need to have a certain particle size: one to five microns. The other thing is that bacteria have a certain fragility, so if you put them on the head of a warhead or a bomb, the same way that a bomb can hurt people, a bomb can hurt the bacteria.

This [SLIDE] illustrates, hypothetically, the potential impact of these agents if they are properly disseminated. The same way that airplanes can spray crops, you can spray upwind from a community, laying down a line of agent, and affect that community.

The impact of biowarfare on the healthcare system would be numerous including:

1. Terror in the affected population and in the medical care system.
2. Overwhelming numbers of patients with ICU demands and special medication needs.
3. Need for personal protection in the medical facility, clinical lab support and autopsy suites.
4. Difficulty with handling the remains.

Bioterrorist Agents:

Anthrax

There are many agents that theoretically can be used, the most recurrent being anthrax. If you are upwind from a city about the size of Washington, half a million, and you lay down a two-kilometer line, you can be as far as 20 kilometers upwind and still end up with almost 20% of the people dead and another 125,000 incapacitated.

Bacillus anthracis is a gram-positive rod that clinically can manifest in three ways. Most cases that are naturally occurring are cutaneous anthrax, but you can also get gastrointestinal anthrax from eating undercooked meat, and inhalational anthrax from airborne dissemination. One reason to have some knowledge of all three manifestations is to recognize an unusual case when it presents itself, such as cutaneous anthrax in a city worker. It may be a tip off that they are doing something that may be a problem. [SLIDE] This is a picture of cutaneous anthrax where the anthrax spores can enter a scratch or a crack in the skin and lead to a carbuncle, which can progress to this very dark eschar or scab. That is the classic lesion of cutaneous anthrax.

Gastrointestinal anthrax results from eating raw or inadequately cooked meat and it can lead to a more gastrointestinal syndrome with gastroenteritis, vomiting, and diarrhea. The mortality, even with aggressive treatment, is 50 to 100%. [SLIDE] Here is a picture of the bowel. The black lesions are the eschars of gastrointestinal anthrax.

What we really worry about with bioterrorism is inhalational anthrax. Many of these bioterrorist agents, including anthrax, present with flu-like symptoms after an incubation period of 1-6 days. Inhalational anthrax kills you as a result of hemorrhagic mediastenitis. [SLIDE] Here is the classic picture of a widened mediastinum that you see with anthrax. Usually the lung fields are relatively clear. In 1979 in Sverdlosk, USSR where Russia was manufacturing tons of anthrax, they changed some filters and forgot to replace a filter and put a sizable amount of anthrax into the environment of the city. They started seeing cases up to 43 days later, both human and animal cases. For some strange reason, no children were affected.

The current treatment for anthrax is antibiotics such as doxycycline or ciprofloxacin and supportive care. Despite this treatment, the mortality rate is significantly high. For this reason the anthrax vaccine is used in high-risk situations. This vaccine is a licensed vaccine. It has been licensed since the early 1970's and in animal models appears to be reasonably effective in preventing inhalational anthrax. The side effects associated with it are not significantly different from what you see with many other vaccines. The problem with this vaccine is that it is very cumbersome to use. You need to give it at 0 weeks, 2 weeks, 4 weeks, and then again at 6, 12, 18 months, so the primary regimen involves six doses with yearly boosters. An alternative is to use post exposure prophylaxis with either ciprofloxacin or doxycycline. You could provide outstanding care for a first responder, who went to an anthrax scare and thought he or she was exposed, by putting them immediately on post-exposure antibiotics and only then immunizing them.

Plague

Yersinia pestis is a gram negative coccobacilli and is the cause of plague. Plague can manifest itself in several ways. Bubonic plague is probably the most common, and results from being bitten by fleas that are infected with the plague bacillus. In a bioterrorism application, what you are really worried about is pneumonic plague, which, unlike anthrax, can be transmitted from person to person. This is a picture of the pneumonia that is associated with pneumonic plague. [SLIDE]

Pneumonic plague can be primary or secondary; that is, it could be secondary to bubonic plague, where the condition advances from primarily being a bubonic form focused in the lymphatics, to the respiratory system. This is highly fatal if you are not treated, though treatment can be highly effective. In contrast to anthrax, plague is highly contagious if it is in the pneumonic form. In World War II when the Japanese did their experiments in Manchuria, one experiment resulted from taking infected fleas and dropping them in the city. Rather than taking the actual bacteria and aerosolizing it over the city, they took live, infected fleas and let them loose in the city. Normally, these fleas live on a variety of animals and rodents.

Let me give you an example of how even a naturally occurring plague episode can move beyond being a natural occurrence and raise the concern of bioterrorism. In 1994, there were a relatively small number of plague cases in Surat, India. As a result of this, hundreds of thousands of refugees fled from this part of India, Surat, to some of the biggest population centers in India. Because of the fear associated with this emerging infection, several countries close to India closed their borders to trade and travel. The stock exchange plunged, imports were restricted, and the Indian army was called in to control the population. Then the CDC did not recognize the strain of plague as being something that they had seen before, and when that was reported to the Indian government, the Indian government, for one reason or another, thought that they might have been victims of a bioterrorist attack from some ultra-rebels. At that point the investigation was transferred from public health authorities to the Indian Ministry of Defense. Who knows where it could have gone from there, because if they perceived that they were under attack, it is unclear what retaliatory actions might have been taken. I use this as an illustration that even a small, naturally occurring episode in the era of bioterrorism can potentially spin out of control.

Smallpox

Smallpox has been eradicated since 1977, and is probably one of the most inspiring public health accomplishments in history. Sadly, it has not been eradicated from arsenals around the world. It is a virus that is transmitted by person to person. The clinical syndrome of smallpox begins with a flu-like prodrome with fever, chills, headache, vomiting and malaise, followed by a typical smallpox rash [SLIDE - facial rash, SLIDE - rash close-up]. Approximately 30% of exposed, susceptible persons actually develop disease, so you would not necessarily have to infect a large number of people to cause a huge problem.

If it were used in a bioterrorist scenario, it would be spread by aerosol. Officially there are two known arsenals of live smallpox virus, in the United States and in the former Soviet Union. The former Soviet Union produced tons of smallpox virus during the "Cold War" years. If you are younger than 30 years old, you probably were never immunized against smallpox.

The vaccine against smallpox is highly effective, but there are not many doses of vaccine available to use to respond to a bioterrorist attack with this virus. Even though the vaccine is very effective against smallpox, it has not been in use since eradication because of the increased risk of vaccine reactions today. Also, we do not have enough vaccine to immunize the 270 million people in the United States if we needed it in an emergency. I think it would be the height of immorality if anybody ever attempted to use smallpox virus, considering what it would do to the world, how it would spread, and how it would turn back public health for years. The value of keeping smallpox stores is controversial and has led to much discussion. And still the discussion continues.

Botulism Toxin

Botulism is one of the most powerful toxins that exists in the world. Naturally occurring botulism can be food-borne (infants can acquire it through eating things that are contaminated) or acquired by contaminated wounds. Clinically you get a syndrome of neuromuscular paralysis and a symmetrical descending flaccid paralysis, starting with the cranial nerves and resulting in double vision and droopy eyelids. Thereafter the bulbar nerves, the extremities and respiratory muscles are affected, leading to death by respiratory failure. If it were used as a bioterrorism agent it would most likely be used as an aerosol. The downwind hazard would be less than with anthrax, but it would still overwhelm medical resources. If people are exposed to botulism, there are some methods of post-exposure prophylaxis. There is an antitoxin, supplied by the Centers for Disease Control and Prevention (CDC), that can be used. If given before the onset of symptoms, animal studies have shown it to be effective. Epidemiologic data with humans show decreased length of hospital stay and decrease in morbidity and mortality. It must be given as soon as possible after exposure.

International Biological Warfare Agreements

From a national security and public health perspective we have been interested in trying to ban biological weaponry globally since 1925. The Geneva Protocol of 1925 was not very persuasive. Most of the more highly developed countries still pursued biological weapons programs. Since 1969, the United States has completely dismantled its offensive bioweapons program. In 1972 the Biological Weapons Convention was ratified, and the parties agreed to never develop, produce, stockpile, acquire or retain any biological agent for other than peaceful purposes. Unfortunately, because it is so easy to produce biowarfare agents, it is very hard to enforce this convention. Some people feel that the best form of enforcement is openness. That is why, in our Department of Defense facilities that are involved with defense against these agents, we have many visiting scientists and we publish extensively in the open literature. That tends to lead to confidence.

Challenges of Bioterrorism: Clues to a Biological Attack

One challenge with bioterrorism is detecting who is making it. Another challenge is detecting who is using it. You can think back to The Dalles article I asked you to read. Those outbreaks associated with the salad bars were actually trial runs for the coup de grâce that was going to occur around Election Day. The challenge is that you may not be able to tell the difference between a natural epidemic and a bioterrorist episode if it is not a huge event.

What are the epidemiological clues to a biological attack?

1. Large unexplained epidemic with similarly acute patients with an unusual epidemic curve.
2. More severe case of disease than usual with higher mortality, refractory to treatment and usually with respiratory manifestations.
3. Multiple diseases in the same patient.
4. Unusual geographic, seasonal, or patient distribution.
5. Suspicious transmission pattern.
6. Unusual genetic or molecular patterns.
7. Multiple simultaneous epidemics.
8. Unusual clinical presentation.
9. Unexplained animal deaths.
10. Direct evidence of biowarfare munitions.
11. Claims by aggressors and/or prior intelligence.

Surveillance for Bioterrorism

If you are going to see that you have an unusually severe outbreak or that it has a transmission pattern that is unusual, you need to have a reference point. The definition of public health surveillance system is the ongoing, systematic, collection, analysis, and interpretation of health data essential to the planning, implementation, and evaluation of public health practice closely integrated with the timely dissemination of these data to those who need to know.

The benefits of infectious disease surveillance are as follows:

• To detect trend in disease occurrence
• Detect epidemics
• Provide estimates of morbidity and mortality
• Stimulate epidemiologic research
• Identify risk factor for disease
• Assess the effectiveness of disease controls
• Improve clinical practice
• Improve resource allocation

How do you develop surveillance systems that are sensitive enough to pick up a problem within a day or so of when it begins? There are a few approaches that one can take for bioterrorism surveillance. You can do syndromic surveillance based on emergency medical system calls. Syndromic surveillance is not something that the public health community has traditionally done. Usually, when you report an illness to the state health department they want a confirmed diagnosis. Most of the bioterrorism agents are rather rare, so it is unusual to make an immediate diagnosis. The first moment that an inhalational anthrax patient walks into your emergency room, you are not likely to say, this is a patient with anthrax. You may well say that this is a patient with a flu-like syndrome that presents with flu-like cough, fever, malaise and headache.Our approaches have been to try to identify ways of capturing syndromes, rather than specific, laboratory confirmed diagnoses. One of the first surveillance systems that I have seen put into place that seems to hold a lot of promise is in New York City (NYC). The Public Health Department of NYC came up with a system based on emergency medical system calls. What they showed was that calls for respiratory complaints correlated with influenza outbreaks. They tend to also see a peaking in emergency medical system calls for respiratory complaints. This is one of several systems that New York City is using to identify an increase in syndromes that might be suggestive of a bioterrorist attack.

Other Surveillance Systems: EWORS

You do not have to be high tech and do not necessarily have to depend on emergency medical systems. I am going to show you two Department of Defense surveillance systems. One is a simpler system that we use in Indonesia, and the other that we are building for Washington D.C. The Indonesia system is called the Early Warning Outbreak Recognition System (EWORS). It has been in place for about one year now. It is a joint project of our laboratory in Jakarta, the WHO, and the Ministry of Health in Indonesia. Based on its early success, the WHO funded a meeting in July where we brought together people from Ministries of Health throughout Southeast Asia to try to expand this system. [SLIDE] This is also a syndromic surveillance system that currently captures clinical data from five sites around the Indonesian archipelago and downloads them every 24 hours to Jakarta. [SLIDE] It begins with the nurses who see patients at these sentinel sites, collecting typical data on symptoms of the patients and enter this information into a database. [SLIDE] Every 24 hours from all over Indonesia, this is downloaded to Jakarta where you can check off certain signs and symptoms to make a syndrome complex and then plot it graphically to see whether you are having an increase. [SLIDE] We have detected a number of enteric illness outbreaks already in Indonesia with this system. In addition, we can automatically plot it geographically so that you can see whether these are clustered in communities in a fashion suggestive of a problem. [SLIDE] So that is the type of system that one could put into place in a lesser-developed country.

Surveillance System: Washington, D.C.

We are developing a system in Washington, D.C. called ESSENCE, which stands for the Electronic Surveillance System for Early Notification of Community-based Epidemics. The focal point is military medical treatment facilities around the Washington D.C. area. We take outpatient diagnoses data and group them into 8 syndrome categories. Every day we get an electronic download from all these clinics around the Washington area and compare the incidence that day with what is expected geographically and seasonally. We are working with modelers who are experts in neural analysis to develop methods of forecasting what the clinical burden of a particular syndrome should be on a given day. [SLIDE] This is a map of the Washington D.C. Area and military treatment facilities around the Washington D.C. Area It shows the hospitals, clinics, and where patients live. We can use this GIS (geographic information system) to analyze any clustering of diseases that brought people into a specific clinic. [SLIDE] These are the syndrome groups that diagnoses get collapsed into. [SLIDE] This slide shows a one-year period from October of 1997 to July of 1999 of lower respiratory syndromes in Washington, D.C. It peaks during the week and tends to drop on the weekends. You can see how one can quickly see what the workload is for a particular healthcare system. Our plan is to expand this to include civilian hospital and health maintenance organizations (HMO). We need to increase the denominator we have under surveillance to be as sensitive as possible.

Some of the other approaches to bioterrorism surveillance include tracking unusual or increased laboratory examinations, over the counter pharmaceutical sales, and prescription drug rates. You can also track increased use of intensive care units and machines such as ventilators. Finally, tracking unexplained deaths is part of enhanced surveillance.

Those are the main things I wanted to share with you. Our challenge now is to try and institutionalize these programs so that they are in place all the time and can function well in a bioterrorist situation.

Readings:

Pavlin JA. "Epidemiology of bioterrorism." Emerg Infect Dis, 1999 Jul-Aug; 5(4): 528-30.

Danzig R, Berkowsky PB. "Why should we be concerned about biological warfare?" JAMA, 1997; 278(5): 431-432.

Torok TJ, Tauxe RV, Wise RP, Livengood JR, Sokolow R, Mauvais S, Birkness KA, Skeels MR, Horan JM, Foster LR. "A large community outbreak of salmonellosis caused by intentional contamination of restaurant salad bars." JAMA, 1997, 278(5): 389-395.

Holloway HC, Norwood AE, Fullerton CS, Engel CC Jr, Ursano RJ. "The threat of biological weapons: prophylaxis and mitigation of psychological and social consequences." JAMA, 1997; 278(5): 425-427. (Optional)

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