Agents of Bioterrorism
Michael Osterholm
Elizabeth Linner McClure
C. J. Peters
THE HISTORY OF BIOTERRORISM
The weaponization of biologic agents is as old as recorded history (1). Serpents, tossed onto enemy ships, were used in ancient times as weapons of warfare. The Tartar army, in 1346, used the bodies of plague victims as weapons of war, catapulting them into the city of Caffa. In 1763, the British army intentionally infected Delaware Indians by providing them with blankets used by smallpox victims. Various human and animal pathogens were used on a limited scale as biologic weapons in both World War I and World War II.
Both Twentieth Century World Wars stimulated research and development of biologic weapons. Although many countries, including the United States, Canada, the United Kingdom, and the Soviet Union, continued the development of biologic agents as weapons following World War II, most of these programs were abandoned in the late 1960s and early 1970s. In 1972, the Biologic Weapons Convention Treaty was ratified by >140 nations. This treaty prohibited the possession, stockpile, or use of biologic weapons, although no provisions for monitoring, inspection, or enforcement were made within that treaty.
In the mid-1990s, it became evident that the Soviet Union had secretly continued an aggressive program to weaponize biologic agents (2). Major aspects of that program included the production of large amounts of smallpox virus and research surrounding a means to weaponize it. Other biologic weapons were developed by the Soviets and included Bacillus anthracis spores and botulinum toxin (3).
The dissolution of the Soviet Union increased the vulnerability of the world to bioterrorism. Soviet scientists left the Soviet Union and have been actively recruited by rogue nations such as Iraq, Iran, Syria, and North Korea. Stockpiles of biologic agents from the Soviet program are also missing or inadequately contained (4).
After the Gulf War, there was concern that Iraq may be developing an extensive biologic weapons program predominately involving anthrax and botulism. There is also concern that both Iraq and North Korea may have obtained smallpox virus.
Today, there is little doubt that biologic weapons of mass destruction lie within the grasp of many nations and groups. The recent terrorist attack on the United States in 2001 with aerosolized anthrax is just one example of the reality of biologic agents as weapons. Several commissions have recently reviewed the threat of bioterrorism on the United States (United States Commission on National Security/21st Century, 2001; National Commission on Terrorism, 2000; Gilmore Commission, 2000). In November 2001, the Institute of Medicine convened a workshop on Biologic Threats and Terrorism: Assessing the Science and Response Capabilities. All these expert panels have uniformly concluded that the United States is highly vulnerable to another bioterrorist attack potentially much more massive in scale than the anthrax attacks of 2001.
BIOLOGIC AGENTS AS WEAPONS
What are the agents that would be employed as biologic weapons or instruments of terrorism? One way to analyze the problem is to narrow the problem according to the scenarios that are most damaging. The modes of dissemination of a biological agent are numerous, but the optimum way to infect large numbers of persons with a lethal agent is to use infectious aerosols. This conclusion allows us to narrow the spread of agents of concern to those that can be grown in large quantities and that are infectious in aerosols, a relatively small subset of the total number of microorganisms that a terrorist might employ. Contamination of the food supply is another possible route of infection that is of great concern, but probably not as potentially severe as an aerosol attack. Other means of infection could be imagined, but none seem to be so effective in producing mass casualties by direct infection. Smallpox is particularly concerning, however, because in addition to its direct aerosol transmission it can be spread from person to person in ever-widening circles and thus could be a highly effective terror weapon even if the initial number of persons infected were relatively small. The Centers for Disease Control and Prevention (CDC) published a list of biologic agents in 2000 selected for their needs for public health preparedness and their likely health and social impact (5). The list is divided into categories A, B, and C. Category A agents are characterized as being easily disseminated or transmitted from person to person. They are capable of causing high mortality, leading to public panic and government destabilization. They also require rapid public health response
and preparedness. Category B agents are moderately easy to disseminate. They cause lower morbidity and mortality and require important public health diagnostic capability and disease surveillance. Category C agents include emerging biologic agents that could be weaponized in the future due to their availability, ease of production and dissemination, and high morbidity and mortality (Table 103-1).
and preparedness. Category B agents are moderately easy to disseminate. They cause lower morbidity and mortality and require important public health diagnostic capability and disease surveillance. Category C agents include emerging biologic agents that could be weaponized in the future due to their availability, ease of production and dissemination, and high morbidity and mortality (Table 103-1).
TABLE 103-1 Critical Biologic Agents for Use in Bioterrorism | |||||
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This chapter will focus on CDC category A agents including B. anthracis, Clostridium botulinum toxin, Yersinia pestis, Francisella tularensis, variola major virus (smallpox), and the viral hemorrhagic fever (VHF) viruses. Major clinical, microbiologic, and epidemiologic factors will be addressed, particularly within the context of the suitability of each agent as a potential biologic weapon. This list is by no means comprehensive. There are many other known biologic agents suitable for weaponization, which could become the source of a bioterrorist attack in the future. The Soviet Union alone is known to have weaponized at least 30 biologic agents, some of which focus on vaccine or drug resistance (4).
ROUTES OF DISSEMINATION
Many different bioterrorist attack scenarios are possible. As noted above, two important modes of transmission include aerosol and foodborne attacks. Aerosols are an efficient mode of transport to a wide geographic area. The inhalation of small particles (1-5 µm) causes deposition deep in lung tissue, and some agents are capable of very efficiently setting up a systemic infection from that site. There are basically two mechanisms for developing these aerosols. One involves the generation of particles from liquids energized by passage of air over a nozzle, and the other is the production of fine powders that are treated to be electrically neutral and readily propelled into the air by small energy input and to continue to be carried by the air currents. Potentially available means for wide-scale dissemination of aerosolized particles could include the use of crop-dusting planes, small aerosolizing generators in closed spaces such as shopping mall or subways, the dissemination of particles through the ventilation systems of large buildings, and the contamination of items in the environment by fine powders as was the case with the recent anthrax attacks on the United States in 2001.
Foodborne bioterrorism, which could encompass a variety of biologic agents, is also a real threat. These agents are relatively easy to obtain and some agents can cause mortality at very low doses. They are also readily available in the environment and may in fact be the easiest bioterrorism agents to disseminate. Contamination of water sources is much less likely to be effective as the dilutional effect would be too great and most agents are vulnerable to chlorine, a standard additive to potable water.
AGENTS
Anthrax
B. anthracis is a large gram-positive bacillus. It forms long chains in vitro but exists in single cells or short chains in vivo. It is a nonmotile, catalase-positive aerobe or facultative anaerobe. Colonies are fast growing and exhibit a ground glass appearance. B. anthracis also exists as a spore. These spores germinate, forming vegetative cells in nutrient-rich environments. Anthrax bacilli are vulnerable and readily inactivated outside mammalian hosts and will sporulate when nutrients in their environment are exhausted. These spores are highly stable, existing in the environment for years at a time. Spores have been shown to survive in the environment >40 years (6). These spores germinate, forming vegetative cells in nutrient-rich environments.
Laboratory diagnostic procedures beyond culture are not well-standardized. Blood cultures are usually positive in serious cases, but automated systems may reject the early-growing Bacillus as a contaminant. Late in infection, direct smears of peripheral blood or cerebrospinal fluid usually show the microorganism directly. Autopsy findings are pathognomonic and tissue Gram stains positive. Polymerase chain reaction (PCR) of tissues and direct tests for toxin in the blood are promising experimental approaches to microbiological diagnosis. Convalescent patients usually develop antibodies to anthrax toxins such as protective antigen.
Modes of Transmission Anthrax is primarily a disease of livestock or other herbivores. Infection is acquired through consumption of soil or feed containing B. anthracis spores. Illness in humans most often occurs following exposure to infected animals. Exposure to infected animals occurs from contact with contaminated tissue; the consumption of undercooked, contaminated meat; or the vigorous handling of tainted wool, hides, or other animal by-products during processing. Person-to-person transmission has occurred rarely with cutaneous anthrax, but not gastrointestinal (GI) or
inhalational disease (7,8). Cutaneous disease from laboratory inoculation with B. anthracis has also been recognized (9).
inhalational disease (7,8). Cutaneous disease from laboratory inoculation with B. anthracis has also been recognized (9).
Clinical Syndromes Naturally occurring anthrax infection in humans can present as cutaneous anthrax, inhalational anthrax, or GI anthrax. The cutaneous manifestation is the most common presentation. Inhalational anthrax is the disease associated with aerosol dissemination in a bioterrorist attack, although cutaneous disease might result from environmental contamination.
Inhalational Anthrax Inhaled B. anthracis spores are deposited deep in the lung. Endospores are then phagocytosed by macrophages and transported to regional lymph nodes. Within the lymph nodes, spores germinate into vegetative cells, multiply, and enter the bloodstream. Bacteremia leads to septic shock and toxemia. Hemorrhagic mediastinitis and massive pleural effusions frequently occur. Secondary meningitis or involvement of other lymph nodes can be seen. The chest X-ray is a critical part of the diagnostic workup because of the typical widened mediastinum from regional lymph involvement (10). It has become apparent that the use of thoracic computed tomography scans is a more sensitive way to detect and quantify the pathognomic node involvement as well as the effusions.
Illness may be biphasic, with an initial prodrome of fever and malaise. If left untreated, a second phase follows characterized by a sudden increase in fever and rapidonset respiratory distress and cardiovascular collapse. Case-fatality rates decrease with prompt and aggressive antibiotic therapy.
The ID50 for inhalational anthrax has been estimated at 8,000 to 50,000 spores (11), although the minimum infective dose may be considerably less. Extrapolation of doseresponse curves from cynomolgus monkeys predict that the LD10 in humans may be as low as 50 to 98 spores, and the LD1 may be only a single spore (12). Host factors may affect susceptibility, as well.
Cutaneous Anthrax Cutaneous anthrax is largely a localized infection caused by the introduction of endospores into a break in the skin. Germination at the site of entry causes localized infection, which appears as a papule with localized edema. Ulceration occurs after 1 to 2 days followed by the formation of a black eschar over the ulcerated lesion. These lesions heal without scarring in 80% to 90% of patients. Rarely, a more generalized lymphadenitis can occur; patients with multiple bullae deteriorate secondary to severe edema and shock. The overall case-fatality rate is extremely low with proper antibiotic therapy. Before the era of antibiotics, the case-fatality rate approached 20%. The infective dose for cutaneous anthrax is not known (13).
Gastrointestinal Anthrax GI anthrax is rare and its etiology is poorly understood. Unlike the other forms of anthrax in which the endospore is the infecting agent, GI anthrax is thought to be secondary to the ingestion of vegetative cells from undercooked meat taken from ruminants dying of anthrax (13). Patients infected with anthrax via the GI tract may exhibit symptoms ranging from oropharyngeal involvement to widespread edema, ascites, hemorrhage, and shock. The overall case fatality is between 25% and 60%. The impact of early antibiotic therapy is not known.
Epidemiology B. anthracis can be found in the soil of many areas around the world, particularly those that experience episodic periods of heavy rainfall followed by drought. It is a disease of animals primarily and is endemic in most areas of the Middle East, equatorial Africa, Mexico, Central and South America, and some Asian countries (14). Globally, several thousand cases of anthrax are reported each year (15). These are mostly cutaneous; inhalational and GI anthrax occur at much lower rates.
In the United States, naturally occurring anthrax is relatively rare in humans. Approximately 10 cases of human disease were reported in the United States each year since the late 1960s; a number that has declined from over 100 cases per year in the early 1900s. Since 1990, only two cases of naturally occurring anthrax were reported: one in 1990 and one in 2000. Both were cases of cutaneous anthrax (16). Livestock and wild ruminant disease is common, particularly in the western states.
Anthrax as a Biologic Weapon B. anthracis is an ideal biologic agent for weaponization. It is stable in spore form, making it easy to store, transport, and aerosolize (13). It is readily available in nature and has a long history of development as a weapon of mass destruction since the early 1940s. The impact of a massive aerosolized anthrax release attack is not known, but several agencies have conducted hypothetical scenarios that predict extremely large casualties. The Office of Technology Assessment in 1993, for example, concluded that deaths of over 3 million could occur following a 100-kg aerosol release dissemination of B. anthracis.
Although aerosolization release of anthrax spores is the most likely mechanism for its use as a biologic weapon, deliberate contamination of food is also a possibility. During World War II, the Japanese reportedly impregnated chocolate with anthrax to kill Chinese children. The apartheid government of South Africa also experimented with anthrax in chocolate (17).
Weaponized anthrax has been the cause of disease outbreaks twice in history. In 1979, an accidental release of weaponized anthrax from a laboratory weapons factory in the Soviet Union caused 75 cases of inhalational anthrax and 2 cases of cutaneous anthrax. The overall case-fatality rate was 86% (18). The release dose amount of anthrax was estimated by investigators to be as low as a few milligrams.
The United States, in 2001, experienced an outbreak of anthrax involving the intentional contamination of mail with anthrax spores. Four letters containing up to 2 g of powder, with over 500 billion spores per gram were mailed from Trenton, NJ, over a 3-week period. Twenty-two cases of anthrax (11 inhalational and 11 cutaneous) were reported. All cases involved the Ames strain of B. anthracis and shared identical molecular subtyping. The case-fatality rate for inhalational anthrax was 45% (19,20).
Following recognition of anthrax in postal workers, the U.S. Postal Service initiated a pilot program called the Biohazard Detection System in July 2003, which involves placing anthrax detection systems at selected mail-processing centers around the country.
Therapeutic Countermeasures for Weaponized Anthrax Release
Vaccine Currently, BioPort Corporation manufactures a cell-free anthrax vaccine called AVA (Biothrax) (21). Seroconversion following three doses of the vaccine is reported (in one study) to be 95% (22); however, the correlation between antibody titer and protection against infection has not been defined. The duration of vaccine efficacy is also unknown, but thought to be approximately 1 to 2 years.
Randomized controlled trials on the clinical effectiveness, immunogenicity, and safety of anthrax vaccines were recently reviewed. The authors concluded that vaccines based on anthrax antigens are immunogenic in most vaccines with few adverse events, but data were limited (22A). A recent review of anthrax vaccine-related VAERS (Vaccine Adverse Event Reporting System) reports from 1990 to 2007 showed no unusual pattern or high frequency of adverse events reported (22B).
Preexposure: Biothrax is not available to the general public. Persons who should receive a preexposure vaccination series include the following: members of the military (or other select populations with a risk of exposure to weaponized anthrax), laboratory workers engaged in production of B. anthracis cultures, veterinarians or other high-risk persons handling potentially contaminated meat or animal products, and workers who may be making repeated entries into a B. anthracis contaminated site after a bioterrorist attack (23,24,24A). Anthrax vaccine is not currently recommended for postexposure use, so it must be given under an investigational new drug application with the Food and Drug Administration (FDA).
Postexposure: Recent Advisory Committee on Immunization Practices guidelines recommend the use of anthrax vaccine in combination with antibiotics following an inhalational exposure to B. anthracis (24A). Exposed persons should receive a three-dose regimen of Biothrax and a 30-day course of antibiotic therapy (25). Anthrax vaccine is not currently licensed for postexposure use, so it must be given under an investigational new drug application with the FDA.
Research into new anthrax vaccines is ongoing. Most vaccines under investigation utilize either recombinant technology or employ novel adjuvant to increase the immune response. Combination vaccines, such as the one against both anthrax and plague, may represent an evolution in vaccine development against agents of bioterrorism (25A).
Antibiotics The FDA has approved doxycycline, ciprofloxacin, and penicillin G procaine for use in postexposure prophylaxis against aerosolized anthrax. Prophylactic antibiotic therapy is recommended for persons exposed to an airspace contaminated with a suspicious material that may contain anthrax spores or those exposed to an airspace with known anthrax release. This includes unvaccinated laboratory workers exposed to suspected aerosolized B. anthracis in culture. Antibiotic prophylaxis is not recommended for autopsy personnel, for medical personnel caring for anthrax victims, or for the prevention of cutaneous anthrax (25).
In the event of a massive aerosolized release of anthrax spores, rapid delivery of prophylactic antibiotics would be crucial in preventing large casualties (26). States can request antibiotic and medical supplies from the Strategic National Stockpile through the CDC. State and local health departments should activate their bioterrorism preparedness plans to distribute antibiotics rapidly.
New Therapeutic Approaches In addition to antibiotic treatment protocols, several new therapeutic approaches are being researched; most involve the use of monoclonal antibodies (26A,26B and 26C). The Department of Health and Human Services is working with Human Genome Sciences, Inc. to develop a human monoclonal antibody called ABthrax or raxibacumab (26D). Another therapeutic approach under investigation is the use of human hyperimmune plasma and immune globulin from previously vaccinated persons undergoing serial plasmapheresis. Hyperimmune plasma and immune globulin isolated in this way could potentially serve as a basis for a new anthrax treatment (26E).
Implications for Healthcare Workers Standard Precautions are considered adequate for patients with inhalational, GI, and oropharyngeal anthrax since personto-person transmission for these forms of the disease has not been reported (13). Although people with inhalational anthrax may have residual contamination of hair and clothing from their exposure event on presentation to a medical facility, this does not appear to be a transmission concern to healthcare workers. Standard Precautions are also recommended by most sources for cutaneous anthrax; however, because person-to-person transmission has occurred rarely for this type of anthrax, Contact Precautions have also been recommended (7,27).
Complete information regarding the use of personal protective equipment for first responders and other healthcare workers can be found in the following documents (see Refs. 25 and 28):
CDC: Protecting investigators performing environmental sampling for B. anthracis: personal protective equipment
OSHA: Anthrax in the workplace
OSHA: Fact sheet and references on worker health and safety for anthrax exposure
Botulinum Toxin
Botulinum toxins are the most lethal human toxins known. They are colorless, odorless, and tasteless at concentrations that are lethal. The toxins are produced by vegetative cells following the germination of C. botulinum spores and released by cell lysis. In the case of wound botulism or infant botulism the microorganisms may be present in the wound or the bowel, but in foodborne disease or bioterrorist events the toxin is released from the microorganism prior to the intoxication. Several distinct antigenic toxin types are produced by C. botulinum and other Clostridium species. Types A, B, E, and F cause natural disease in humans; toxin type F accounts for <1% of naturally occurring disease. Other antigenic subtypes, including toxin types C, D, and G, can cause disease in other mammals and birds. Botulinum toxin is inactivated by heating it to 85°C for 5 minutes (29). It is important to note that in the event of an intentional dissemination of botulinum toxin, the causative (vegetative) microorganisms may not be present.
Diagnostic procedures usually rely on the toxicity for mice confirmed by neutralization of the toxin by antiserum.
Toxin can be detected in food, gastric contents, or serum. Antibodies do not usually develop in convalescence because of the very small lethal dose.
Toxin can be detected in food, gastric contents, or serum. Antibodies do not usually develop in convalescence because of the very small lethal dose.
Clostridium botulinum C. botulinum is a gram-positive spore-forming bacillus. It is “sluggishly” motile and anaerobic and can be found in soil and aquatic sediments. There are several strains of C. botulinum; subtyping is based on metabolic characteristics of the microorganism. Groups I and II are responsible for the toxin production, which is lethal to humans.
C. botulinum spores are resilient, resisting destruction with prolonged boiling at high temperatures and desiccation. They have been shown to survive in a dry state for over 30 years. The spores are susceptible to chlorine in dilute concentrations (as in chlorinated water). They undergo germination most readily by exposure to heat (“heat shocking”) of 80°C for 10 to 20 minutes (30).
Botulism Pathophysiology and Clinical Presentation Botulinum toxin can enter the body via ingestion or inhalation. Exposure can also occur through local production in the GI tract or necrotic tissue at the site of a wound. Botulinum toxin is activated by proteolytic cleavage; the activated structure contains a heavy and light polypeptide chain. The toxin is carried through the bloodstream to the neuromuscular junction where the heavy chain binds to presynaptic receptors causing permanent inhibition of acetylcholine release. After several months, muscle function is regained based largely on the production of new synapses at the neuromuscular junction.
Clinically, patients present with neuromuscular weakness, ranging from mild cranial nerve dysfunction to complete flaccid paralysis. The severity of disease corresponds to the toxin dose and the toxin subtype; type A creates a more severe clinical presentation than type B or E. The major differential diagnoses include Guillain-Barré syndrome, Eaton-Lambert syndrome, and polyneuropathies such as the recently recognized West Nile syndrome. Botulism is characteristically distinguished by initiation of involvement with the cranial nerves and descending in the neuraxis as it progresses.
Loss of respiratory and pharyngeal muscle function can require a prolonged period of mechanical ventilation. Death often results from complications of prolonged ventilatory support. Prior to mechanical ventilation, death rates approached 50% (31). Case-fatality rates are now lower due to the advent of adequate supportive care including advanced respiratory support capabilities. The current overall case-fatality rate is 5% to 10% for foodborne disease and somewhat higher for wound botulism (31,32).
Modes of Transmission/Epidemiology
Foodborne Botulism Botulinum toxin can be produced in food items that are contaminated with C. botulinum spores. Conditions including an anaerobic environment, acidic pH, minimum temperature of 10°C, and availability of a water source must exist to facilitate germination of spores and production of botulinum toxin (33). Food containing the neurotoxin that is not sufficiently reheated to at least 85°C for 5 minutes becomes a potent toxin delivery source for humans (29).
A single case of foodborne botulism is considered an outbreak and declared a public health emergency. All cases of botulism must be reported to the CDC immediately. In the United States, an average of nine outbreaks per year was seen in the late 1990s, with approximately two to three cases per outbreak (33). Improperly home-canned vegetables are the most common source of foodborne botulism; however, over the past 20 years, a variety of commercially produced, preservative-free foods have caused outbreaks. Garlic in oil, baked potatoes in foil, jarred peanuts, and commercially processed cheese sauce have been associated with outbreaks (34,35,36,37 and 38).
Botulinum toxin is rapidly inactivated by the chlorine, which is a standard additive to potable water. For this reason, cases of botulism have not been associated with contaminated water (39,40).
Wound Botulism C. botulinum infection is usually associated with traumatic injuries of the extremities, especially those that involve contact with soil or another natural C. botulinum source. Although seen more rarely, cases of botulism following a postoperative infection, the use of intravenous or intranasal illicit drugs, or dental abscess have also been reported. Wound botulism is a rare event; only 78 cases were reported to the CDC for the period of 1986 to 1996 (33).
Inhalational Botulism Inhalational botulism is caused by inhalation of aerosolized preformed botulinum toxin into the lungs and, subsequently, the circulation. It is a very rare exposure event, occurring only once in a veterinary laboratory setting in Germany in 1962 (39). Inhalational disease has also been produced experimentally in primates. Results of this study showed disease onset occurring 12 to 80 hours after exposure (41).
Botulinum Toxin as a Biologic Weapon Botulinum toxin has been manufactured as a potential biologic weapon since World War II. The United States produced the toxin during that time period, but abandoned production after signing the BWTC in 1972 renouncing use, stockpiling, or production of biological weapons in 1968. The Soviet Union, however, continued production into the early 1990s. At the time of the Gulf War, Iraq had produced over 19,000 L of botulinum toxin, some of which was weaponized (42). On three occasions between 1990 and 1995, the Japanese cult Aum Shinrikyo attempted to use aerosolized botulinum toxin in Japanese cities, but was not successful.
Botulinum toxin could be disseminated via the deliberate contamination of food or beverages, or as an aerosol. Experts believe that the foodborne route represents the most likely bioterrorist scenario. Deliberate contamination of a large source of commercially available and distributed food or beverage product, particularly one in which adequate heating would be unlikely, could cause massive extensive casualties across the country. The widespread nature of the attack would also create significant panic, economic loss, and social disruption.
The dispersal of aerosolized toxin is also possible and could result in extremely large numbers of casualties, in this instance, concentrated in a single urban setting. One gram of aerosolized botulinum toxin could theoretically
kill 1.5 million people (43); however, it is likely that for practical considerations, the effects of a botulinum toxin attack would be relatively limited compared to one of the infectious agents.
kill 1.5 million people (43); however, it is likely that for practical considerations, the effects of a botulinum toxin attack would be relatively limited compared to one of the infectious agents.
Contamination of a water source is unlikely because of dilution as well as the vulnerability of the toxin to chlorine, a standard additive to potable water.
Therapeutic Countermeasures for Weaponized Botulinum Toxin
Botulinum Antitoxin Supportive care is the mainstay for treatment of botulism; prolonged intensive care, mechanical ventilation, and parenteral nutrition may be required. Botulinum antitoxin can be administered to treat forms of botulism (other than infant botulism) and is most effective when given early in the course of illness. It cannot reverse existing paralysis, but can prevent additional nerve damage if given before all the circulating toxin binds to the neuromuscular junction.
Botulinum antitoxin is of equine origin and has traditionally been developed for use against subtypes A, B, and E. The CDC formulary currently includes a botulinum antitoxin bivalent for types A and B (licensed by the FDA) and botulinum antitoxin equine type E (an investigational product). In the past, the CDC released a trivalent ABE antitoxin, but this product is not currently available. The CDC maintains an active surveillance program for cases of botulism and is responsible through state health departments for the distribution of antitoxin in suspected cases (39,41).
Antitoxin (supplied by the CDC) is maintained at quarantine stations in various metropolitan airports and, once requested, can generally be delivered within 12 hours (43A).
In the event of a bioterrorist attack with botulinum toxin, it is possible that other subtypes will be weaponized. The U.S. Army has developed an equine heptavalent botulinum antitoxin effective against all botulinum toxin types, but its efficacy in humans is not clear. Additionally, as for the licensed product, it carries with it the potential for serious allergic reaction. Additional research into heptavalent botulinum antitoxin has occurred through a U.S. Department of Health and Human Services development contract (Cangene Corp).
The dose of antitoxin required to reduce the effects of the neurotoxin varies with the inoculating dose. In the event of a mass release of weaponized botulinum toxin, the scarcity of antitoxin would be highly likely (39).
Botulinum Toxoid Vaccine Vaccination with botulinum toxoid is currently recommended for laboratory personnel who work with C. botulinum and military personnel at risk for exposure to weaponized botulinum toxin (44). The vaccine is not considered a viable countermeasure against a bioterrorist attack. It is not effective against all subtypes; it is painful to receive and requires a yearly booster; it also disallows the recipient from receiving botulinum antitoxin therapy for life.
Emergency Response to a Mass Exposure A single case of botulism is considered a public health emergency (45). In the event of a suspected botulism outbreak, public health officials will assist with appropriate laboratory testing to confirm diagnosis, authorize use of antitoxin, and conduct aggressive surveillance investigations to identify the source of an outbreak to determine if there is evidence to suggest a bioterrorism-related event.
In the event of a mass exposure, such as a widespread aerosol release of botulinum toxin, the rapid administration of antitoxin to ill persons would be indicated. Although antitoxin does not reverse existing paralysis, it binds remaining circulating toxin, mitigating progression of the disease. Rapid mobilization of mechanical ventilators and other ancillary supportive care tools would be critical to successful management of any mass-exposure botulism outbreak.
Implications for Healthcare Workers In the hospital setting, Standard Precautions are adequate for patients with botulism since person-to-person transmission does not occur. In the laboratory setting, C. botulinum toxin detection should only be performed by trained individuals at level C or higher Laboratory Response Network laboratories (46). The FDA also released biosafety recommendations for laboratories that test for C. botulinum. A partial list includes the following: placement of biohazard signage; the use of appropriate laboratory safety apparel including coats and safety glasses; restriction of solo work shifts; immediate autoclaving of all toxic material; and ready access to information on the location of an antitoxin source (47).
Plague
Y. pestis is the causative agent of plague. It is a pleomorphic gram-negative bacillus, existing as single cells or short chains in direct smears. It is a nonmotile, nonsporulating facultative anaerobe, slow growing in culture. At 48 to 72 hours of incubation on solid media, colonies have a raised, “fried egg” appearance. Data banks for many commercial laboratory identification systems do not include Y. pestis (48).
Y. pestis is thought to have evolved from Y. pseudotuberculosis 1,500 to 20,000 years ago (49). Recent data suggest the continued evolution of the bacillus through the emergence of several new genotypes (50).
Modes of Transmission Humans are an incidental hosts for Y. pestis and are not part of its natural life cycle. Many different animal species (mostly wild rodents) are natural reservoirs for the bacillus (51). Like humans, other nonrodent mammalian species serve as incidental hosts for Y. pestis. These animals, however, can serve as sources of human exposure. Disease occurrence in humans is dependent on the frequency of infection in local rodent populations. Human outbreaks are usually preceded by epizootics with increased deaths in susceptible animal hosts (52,53).
The vector for Y. pestis is the flea. Over 1,500 species of flea exist; approximately 30 are known to be vectors for Y. pestis (53).
Humans can become infected with Y. pestis via the bite of an infected flea, a bite or scratch from an infected incidental host mammal such as a cat, or direct contact with infected animal carcasses or products. Inhalation of respiratory droplets from infected animals or humans can also cause infection (54).
Pathogenesis/Clinical Syndromes The classic forms of plague are bubonic plague, pneumonic plague, and septicemic plague. Rarely, plague can be manifested as meningitis,
pharyngitis, or pestis minor, a milder form of bubonic plague.
pharyngitis, or pestis minor, a milder form of bubonic plague.
Bubonic Plague Bubonic plague is transmitted to humans via the bite of an infected flea, a bite or scratch from an infected animal or direct contact with infected animal carcasses. Between 25,000 and 100,000 Y. pestis microorganisms are inoculated into the skin after a bite from an infected flea (55). The microorganisms migrate through the cutaneous lymphatics to regional lymph nodes. Once in the lymph nodes they are phagocytized by polymorphonuclear leukocytes (PMNs) and mononuclear phagocytes. Microorganisms phagocytized by PMNs are largely destroyed, whereas those phagocytized by mononuclear cells proliferate intracellularly and are released when cell lysis occurs (53). Initially, affected nodes contain a thick exudate composed of plague bacilli, PMNs, and lymphocytes. This pattern gives way to hemorrhagic necrosis, which creates the clinical picture of swollen, painful buboes that are characteristic of bubonic plague. Microorganisms also enter the bloodstream causing hemorrhagic lesions in other lymph nodes and organs throughout the body. Eventually septicemia disseminated intravascular coagulation (DIC) and shock ensues. Without prompt antibiotic therapy, death usually results from overwhelming septicemia.
Pneumonic Plague Y. pestis can enter the lungs directly through direct inhalation (primary pneumonic plague) or via hematogenous spread of bubonic plague (secondary pneumonic plague). Primary pneumonic plague is acquired by inhalation of approximately 100 to 500 microorganisms (13). Clinically, patients present with fulminant lobar or multilobular pneumonia. Marked edema and congestion of the lungs are also common. Death from overwhelming sepsis, DIC, and multiorgan failure occurs rapidly without prompt antibiotic therapy; untreated mortality approaches 100% (53).
Septicemic Plague Primary septicemic plague is defined as systemic toxicity caused by Y. pestis infection without apparent lymph node involvement. Secondary septicemic plague occurs commonly as part of bubonic or pneumonic plague. Septicemia is the syndrome that leads to multiorgan failure, DIC, and death. In the late stages of the disease, high-density bacteremia often occurs, with ready identification of microorganisms on peripheral blood smears or buffy coat preparations (52).
Epidemiology
Historical Perspective Three plague pandemics have occurred during recorded history, causing an estimated 200 million deaths (56). The first recorded pandemic began in Egypt in 542 AD, spread throughout Europe, Central and Southern Asia, and Africa, killing over 100 million people. The second pandemic, widely known as the Black Death, began in Italy in 1347 and spread rapidly across Europe killing one third of the population. The most recent pandemic began in China in 1894 and spread throughout the world over a 10-year period, presumably facilitated by ship travel. This pandemic was responsible for an estimated 12 million deaths, most occurring in India.
Naturally Occurring Plague in the United States Plague was first introduced to the United States in 1900 as part of the third pandemic and created an epidemic in the early 1900s in San Francisco (57).
It was sporadically epidemic largely in urban settings secondary to infected rat populations (58). After 1926, plague became endemic in wild animal populations in the Western United States. Cases have also been associated with infected domestic cats (54).
Today, plague remains endemic in the United States. It is usually seasonal, with a higher case incidence during summer months (57,58). From 1947 through 1996, 390 cases of plague were reported to the CDC with an overall case-fatality rate of 15.4% (59). Bubonic plague accounted for 83.9% of those reported cases. An average of 8.9 cases per year were reported to the CDC from 1990 to 1999 (60,61). Many of these cases developed secondary pneumonia, but no transmission to contacts has been seen. The disjunct between the pneumonic transmission that occurred during the Manchurian epidemics early in the century and the uncommon documentation of pneumonic spread in other settings may reflect the crowding and lack of basic hygiene during earlier epidemics.
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