This chapter was adapted from an article that originally appeared in the December 2001 edition of The Cleveland Clinic Journal of Medicine.

Recent events have highlighted the need for clinicians to educate themselves and prepare for the threat of biologic terrorism. For many years, these attacks seemed unlikely. No more. The events of September 11, 2001, the cases of anthrax due to letters sent in the mail, and increasing intelligence revealing the existence of biologic agents available to governments and terrorist organizations have awakened health care providers to the need for preparation.

The ideal biologic weapon is one that can be quickly and easily disseminated to a large population, is highly contagious, causes high rates of morbidity and mortality, requires vast resources to combat, and causes mass panic, confusion, or social disruption.

Because panic and paranoia are undesirable, preparation is the best response to biologic terrorism. Governmental agencies, health departments, and the Centers for Disease Control and Prevention (CDC) have identified the most likely agents to be used in a biologic attack (Table 1), and they have plans in place to address such attacks.¹ These plans emphasize the important role of frontline medical providers in recognizing and reporting suspected biologic and chemical attacks.

Biologic weapons are likely to be used in covert rather than overt attacks. Symptoms and signs of disease would have a delayed presentation, depending on the incubation period of the organism and the clinical syndrome. Covert attacks will be detected only if health care providers are vigilant and trained to recognize infections with potential bioterror organisms. At the very least, any cases of rare, unusual, or unexplained diseases should raise the red flag of suspicion in the clinician's mind. Recognizing and reporting such cases is critical to mitigate the impact of an attack.

According to military intelligence and various government agencies, at least 10 countries have the capability of producing and disseminating biologic or chemical weapons.² It is either unknown or unpublished how many terrorist organizations have the capability to procure, manufacture, or effectively deploy these agents.

The fall of the Soviet Union and the investigations of Iraq by the United Nations have given us firsthand observations of biologic and chemical weapons programs. The current locations of former Soviet stockpiles and the scientists who developed them are largely a matter of speculation. Iraq produced approximately 8,000 L of anthrax solution, 20,000 L of botulinum toxin, 340 L of Clostridium perfringens, and 10 L of ricin. A 1997 report concluded that "it is prudent to assume that the Iraqis retain hidden stores of freeze-dried organisms from its former biological warfare program."³

Anthrax
Three varieties of anthrax occur in humans: inhalational, cutaneous, and gastrointestinal. Cutaneous anthrax is the most commonly encountered form, typically following exposure to anthrax-infected animals (Figure 1). Anthrax spores can enter wounds or broken skin, a route suspected in some of the recent cases of intentional anthrax exposure. Gastrointestinal anthrax is rare, yet can follow ingestion of undercooked contaminated meat. Inhalational anthrax, although rare, is the most fatal.

Until the recent bioterrorist events, only 18 cases had been reported in the United States in the last century. As of December 5, 2001, 11 additional cases of inhalational anthrax and 11 cases of confirmed and suspected cutaneous anthrax have been identified as a result of an apparent intentional release into the postal system.⁴ A 1993 report by the U.S. Congressional Office of Technology Assessment estimated that between 130,000 and 3 million deaths could occur as a result of the release of 100 kg of aerosolized anthrax spores over a heavily populated area.⁵

Information on human inhalational anthrax largely comes from an outbreak in Sverdlovsk (in the former Soviet Union) in 1979 and from the recently documented U.S. cases, although this information is evolving rapidly. The Sverdlovsk outbreak resulted from the accidental release of aerosolized anthrax spores from a military microbiology facility, causing at least 79 cases and 68 deaths.⁶

Bacillus anthracis is an aerobic, gram-positive, spore-forming, nonmotile bacterium. Spores form when environmental nutrients are exhausted, and they can exist for decades. When exposed to the appropriate nutrient-rich environment, the spores germinate and can potentially cause disease.

Once inhaled, spores are transported via lymphatics to mediastinal lymph nodes, where germination can occur up to 60 days or more after exposure. The disease progresses rapidly once germination occurs because replicating bacteria elaborate toxins that lead to hemorrhage, edema, and necrosis. In Sverdlovsk, hemorrhagic thoracic lymphadenitis and hemorrhagic mediastinitis occurred in all patients, and hemorrhagic meningitis occurred in one half.⁶

It was previously thought that anthrax does not cause a clinically evident pneumonic process, although postmortem examinations in Sverdlovsk patients showed a focal, necrotizing pneumonia in a substantial minority. Analysis of recent cases has revealed that anthrax can cause pulmonary infiltrates as well as pleural effusions. Anthrax is not transmitted person to person.

Smallpox
Smallpox was globally eradicated in 1977, and immunization ceased in 1980 based on recommendations from the World Health Organization.⁷ Routine immunizations in the United States ceased in 1972.

Caused by variola virus, smallpox is potentially the most devastating of the bioterror agents because it has a high infectivity rate, a fatality rate of up to 30%, and a high person-to-person transmission rate. Like anthrax, smallpox can be easily disseminated in aerosol form. Infection occurs after deposition of the virus particles on upper respiratory mucous membranes.

Plague
Plague is well known in history, having caused several pandemics and millions of deaths. Several countries, including the United States, have experimented with plague as a biologic weapon, using flea vectors in World War II and, more recently, an aerosolized form of the causative organism Yersinia pestis.

Y. pestis is classically transmitted through the bite of infected fleas, resulting in several forms of the disease, including bubonic, pneumonic, and primary septicemic plague. Bubonic plague is historically the most common manifestation, characterized by markedly tender and swollen lymph nodes, or buboes, resulting from local lymphangitic spread of the organism. Necrosis of the involved nodes is followed by endotoxemia, leading to cardiovascular and neurologic collapse.⁸

As a biologic weapon, plague would most likely manifest as the primary pneumonic form of the disease resulting from an aerosolized attack. Pneumonic plague is usually a secondary result of bubonic or primary septicemic plague. Primary pneumonic plague is rare in the United States, so such a case should raise the suspicion of a biologic attack.

Botulinum Toxin
As the most potent poison known, Clostridium botulinum toxin has been well documented as a biologic weapon. Aum Shinrikyo, the Japanese cult responsible for the sarin gas attack in Tokyo in 1995, has attempted to use it on at least three occasions. Iraq has admitted to producing 20,000 L of concentrated botulinum toxin, of which 12,000 L were loaded into weapons.^3,9

Botulinum toxin is a zinc endopeptidase that irreversibly blocks fusion of acetylcholine-containing vesicles with the terminal membrane of the motor neuron, resulting in flaccid paralysis. Naturally occurring botulism takes three common forms: food-borne, wound, and intestinal. All forms result from toxin absorption through mucosal surfaces or wounds, as botulinum toxin cannot penetrate intact skin. A botulinum toxin attack could take the form of a focused aerosol release in a populated area, or it may possibly be released into a food source.

Tularemia
Francisella tularensis, one of the most infectious pathogenic bacteria known, is the causative organism for tularemia. It is a nonmotile, aerobic, gram-negative, non-spore-forming coccobacillus that is capable of surviving for weeks at low temperatures in water, soil, hay, and decaying animal carcasses. Human infection can result from inoculation or inhalation of as few as 10 organisms.¹⁰ Although mortality from tularemia is relatively low and human-to-human transmission is not known to occur, its high infectivity rate and ease of dissemination coupled with its ability to inflict significant morbidity makes it a candidate for use as a biologic weapon.

Tularemia can assume many clinical forms, depending on the route of exposure. An aerosol release, the most likely route of terrorist exposure, would likely result in predominantly pulmonary disease, manifesting in hemorrhagic bronchial inflammation and progressing to pleuropneumonitis. Hilar lymphadenopathy is a common finding.

Viral Hemorrhagic Fevers
Four main classes of viruses cause viral hemorrhagic fever (VHF): arenaviruses (Argentine, Bolivian, and Venezuelan hemorrhagic fevers, and Lassa fever), filoviruses (Ebola and Marburg), bunyaviruses (Hantavirus, Congo-Crimean hemorrhagic fever, Rift Valley fever), and flaviviruses (dengue and yellow fever). All are zoonotic, RNA (ribonucleic acid) viruses that cause infection naturally in humans by contact with infected animals, most often rodents or arthropods, or through bites or contact with contaminated meat or carcasses. Some animal vectors are unknown, such as in the case of Ebola and Marburg viruses. Human-to-human transmission can occur through direct contact with infected fluids and even through contaminated objects.¹¹

No confirmed weaponized forms of these viruses exist, but they are often considered as possible bioterror agents because of their lethality and their ability for aerosolization. In general, the VHF agents exert their pathophysiologic effect by causing microvascular damage and changes in vascular permeability.¹²

Anthrax
The clinical diagnosis of inhalational anthrax requires a high degree of suspicion. It generally presents as a two-stage illness. First, a flu-like syndrome begins with nonspecific symptoms of fever, dyspnea, cough, headache, vomiting, rigors, generalized weakness, and abdominal and chest pain. This stage can last from a few hours to a few days.

The second, fulminant stage can follow immediately or after a brief period of improvement. The second stage tends to develop abruptly with fever, dyspnea, diaphoresis, and shock. Stridor can result from upper airway obstruction caused by mediastinal lymphadenopathy and hemorrhage. Chest radiography may demonstrate pulmonary infiltrates, pleural effusions, and a widened mediastinum. The development of hemorrhagic meningitis may be heralded by meningismus, delirium, and obtundation.

Death occurs rapidly, and the mortality rate may approach 50%, based on analysis of recent cases.¹³

Smallpox
Early features of smallpox, which generally begin 12 to 14 days after exposure, include malaise, fever, rigors, vomiting, myalgias, delirium, and rash. Over the next few days, the patient develops mucous membrane lesions and a rash, which progresses from macules to papules to pustules.

Smallpox can be easily confused with varicella (chicken pox), but there are differences. The pustules in smallpox tend to be round, tense, deep dermal lesions that are all in the same stage of development; in contrast, the pustules of varicella tend to be in various stages of development. In addition, varicella lesions tend to predominate on the trunk, whereas smallpox lesions tend to occur more commonly on the face and extremities, including the palms and soles. Death, which may occur in up to 30% of infected individuals, occurs from the systemic inflammatory response and cardiovascular collapse.^14,15

Plague
The onset of plague symptoms follows exposure by 2 to 4 days. Plague is characterized by fever, cough, and dyspnea and may include prominent gastrointestinal symptoms, such as abdominal pain, nausea, vomiting, and diarrhea. The cough may be productive of watery, bloody, or purulent sputum.

Although both inhalational anthrax and pneumonic plague initially present similarly, a productive cough, especially hemoptysis, would preferentially suggest plague. Radiographic findings also differ. Plague results in a pneumonic process whereas anthrax produces a prominent mediastinum in addition to pulmonary infiltrates and pleural effusions.

Botulinum Toxin
Botulism is characterized by descending, symmetric, flaccid muscle paralysis that first manifests in the bulbar muscles. Cranial nerve palsies result in diplopia, dysphagia, dysarthria, and ptosis. Other symptoms may include blurred vision, dry mouth, and mydriasis. Fever and sensory complaints or findings are absent. Presentations may be variable, but hypotonia, paralysis of respiratory muscles, and loss of the gag reflex may result in the need for mechanical ventilation. Although the degree of hypotonia may make the patient appear obtunded, the sensorium is preserved, so the clinician must understand that the patient is aware of his or her surroundings.

Tularemia
Naturally occurring forms of tularemia include ulceroglandular, glandular, oculoglandular, oropharyngeal, pneumonic, typhoidal, and septic. Aerosol release of tularemia in a populated area would result in a cluster of people with an acute onset of fever, rigors, headache, coryza, cough, and respiratory distress. Without antibiotic treatment, mortality can reach 30% to 60% for the pulmonic forms, but this figure drops to 2% with appropriate recognition and antibiotic therapy.

Viral Hemorrhagic Fevers
The syndromes caused by each of the VHF viruses are slightly different, but those that cause the most severe disease have certain characteristics in common. Initially, the clinical syndrome may mimic any other viral illness, with fever, generalized malaise, myalgias, dizziness, weakness, and fatigue. Following this nonspecific prodrome, patients may display dermal ecchymosis and bleed from the mouth, eyes, ears, and even internal organs, with predictable presentations and sequelae. Rarely does death result directly from blood loss. Rather, end-stage disease is manifest by shock; central nervous system disturbances such as delirium, coma, and seizures; and multisystem organ failure.

Anthrax
Clinicians who have a high degree of suspicion for anthrax should immediately notify their local or state health department. In a previously healthy patient, an overwhelming febrile illness with a widened mediastinum on chest radiography should alert the clinician to the possibility of anthrax.

Definitive testing can be arranged through local and state health departments or the US Army Medical Research Institute of Infectious Diseases. Rapid diagnostic tests such as enzyme-linked immunosorbent assay (ELISA) or polymerase chain reaction (PCR) are generally available only at reference laboratories. Standard blood cultures and serologic tests are likely the most useful diagnostic tests, but the clinician should alert the laboratory to the possibility of anthrax when the culture is sent. Direct gram stains of the blood may demonstrate the organism. Sputum culture and gram stains are unlikely to be useful because the disease may not involve a pneumonic process. Postmortem examinations revealing hemorrhagic mediastinitis or hemorrhagic mediastinal lymphadenitis are essentially pathognomonic of inhalational anthrax.¹⁶

Smallpox
Smallpox virus is shed from the oropharynx and from the skin lesions until they are completely healed. The preliminary diagnosis may be made by electron microscopy. Diagnostic confirmation is done through virus isolation, ELISA, and PCR from skin scrapings and oropharyngeal swabs in a facility equipped to manage this organism. Once an outbreak has occurred, diagnosis can be made on clinical grounds.

Plague
Confirmatory tests for plague are generally available only through health departments, which should be notified immediately if plague is strongly suspected. Cultures of blood, sputum, or lymph node aspirate would be useful.¹⁷

Botulism
Botulism is diagnosed clinically. Specialized laboratory testing may take days to confirm the diagnosis, although electromyography may aid in the differential diagnosis. Possible misdiagnoses include Guillain-Barré syndrome, myasthenia gravis, Lambert-Eaton syndrome, tick paralysis, and stroke. Laboratory testing is available only through the CDC and certain health departments, and suspected cases should be reported immediately to the local health department.

Tularemia
Diagnosis of tularemia is suspected on clinical grounds when a cluster of patients presents with acute pneumonia, pleuritis, and hilar lymphadenopathy. Routine microbiologic procedures may miss the organism for days or weeks. When tularemia is suspected, direct immunohistochemical or fluorescent antibody stains of fluids or tissue specimens may yield the diagnosis. Growth in culture is the definitive means of diagnosis, but ELISA, PCR, and other methods are available in select reference laboratories.¹⁰

Viral Hemorrhagic Fevers
Diagnosis of viral hemorrhagic fevers is suspected on clinical grounds, but confirmatory testing with ELISA, PCR, and virus isolation is available. Immunoglobulin M and immunoglobulin G titers can also be measured in specialized laboratories.

THERAPY AND OUTCOMES

Anthrax
The following information on anthrax therapy and outcomes comes largely from CDC reports and guidelines.^18,19 Antibiotic prophylaxis is indicated based on exposure to known or suspected anthrax spores, not on laboratory testing. Nasal swabs are to be used for epidemiologic but not for diagnostic purposes because they can rule in but not rule out exposure.

In suspected cases of active disease, early antibiotic treatment is essential; the clinician should not delay treatment while waiting for disease confirmation. On the basis of past experience and susceptibility testing of recently isolated anthrax strains, the CDC has issued a new set of antimicrobial recommendations (Table 2). For postexposure prophylaxis, ciprofloxacin or doxycycline are recommended and should be continued for 60 days. Evidence shows that recently identified strains possess penicillinase and cephalosporinase activity. Concern for a beta-lactamase induction event in the presence of large numbers of organisms prompted the recommendation that beta-lactams not be used for treatment of active disease.

For treatment of active disease, ciprofloxacin or doxycycline is recommended, given intravenously for inhalational anthrax and orally for the cutaneous form. This applies even to children and pregnant women, in whom these antibiotics have been generally contraindicated, given the relative risks and benefits.^18-20

The recently identified anthrax strains also have demonstrated susceptibility to rifampin, clindamycin, vancomycin, and chloramphenicol, although clinical experience with these antibiotics is limited. Erythromycin, azithromycin, trimethoprim/sulfamethoxazole, and cephalosporins should not be used for treatment of anthrax. The CDC suggests combination therapy with two or more antibiotics until susceptibility testing is performed. Intravenous antibiotics can be switched to oral equivalents when clinically appropriate and continued for 60 days.

Patients should be advised not to take or stock up on antibiotics simply because of a potential threat of an anthrax attack. State and local health departments and the CDC have stockpiles of antibiotics and plans in place to address large-scale and small-scale events.

Anthrax scares are becoming increasingly common. White powder has been found in various locations, including US government offices, media outlets, mail facilities airplanes and shopping centers. Some samples have been positively identified as anthrax spores, but most are hoaxes. If a suspicious substance is found, local health authorities should be notified. If the threat is deemed credible, persons in contact with the substance should be decontaminated using HazMat protocols, and samples of the suspicious substance sent to the appropriate testing facility (usually the state or local health department). If anthrax spores are positively identified, antibiotic prophylaxis would be provided by the health authorities.

If a patient goes to an emergency department or doctor's office after being exposed to a suspicious substance, the clinician should isolate the patient and the substance while notifying the local health department. Biohazard precautions should be maintained to seal the substance and the patient's clothes in a plastic container, ensuring that the powder is not aerosolized. If the emergency department has decontamination facilities, the patient should shower before entering the clinical care area. The local health department will assist in testing the substance and instituting appropriate infection-control measures.

An inactivated, acellular vaccine has been used by the US military for several years. Because the supply is limited and large-scale anthrax exposure is relatively unlikely, the vaccine has not been given to the population at large. If a large-scale attack does occur, postexposure vaccination would possibly be made available.

Smallpox
Patients with suspected smallpox should be quarantined, and appropriate respiratory isolation precautions should be taken. Any individual known to have been exposed to the virus may be placed in respiratory isolation and observed for signs of the disease until after the typical incubation period, although doing so is considered controversial.

If possible, patients with smallpox should be treated in facilities separate from the usual hospital setting in an effort to minimize the spread of the disease. Even a single case of smallpox would be considered a significant international health event.

There is no specific treatment for smallpox, although cidofovir is effective in vitro.¹⁴ Smallpox vaccine (vaccinia) can be obtained through the CDC, but only a limited supply is currently available. In the event of a terrorist attack, the vaccine would likely be given to patients with smallpox and to their close contacts. Routine vaccination in the United States stopped in 1972, and it is unlikely that people immunized before this time would still have protective immunity.¹⁵ Vaccination up to 4 days after exposure may prevent or attenuate the illness.²¹ Vaccinia immune globulin should be given to patients with severe cutaneous reactions to the vaccine and to those with contraindications to vaccination. Secondary bacterial infections are rare, and antibiotic treatment would only be warranted as specific rather than empiric therapy.

Plague
Treatment recommendations for pneumonic plague resulting from a biologic weapons attack are based on limited scientific evidence. The plague vaccine was discontinued in 1999 and is no longer available.

The antibiotic most often recommended and used for the treatment of plague is streptomycin sulfate. Because the availability of streptomycin is now limited, gentamicin is recommended as an alternative.¹⁷ In a large-scale attack, when hospital supplies of intravenous drugs might be limited, doxycycline is recommended as an alternative in patients suitable for oral therapy. Fluoroquinolones have not been adequately studied in controlled human trials, but they have demonstrated clinical efficacy comparable to doxycycline in the treatment of pneumonic plague in animal models.^22-24

Postexposure prophylaxis in the form of intravenous antibiotics should be given to anyone in an area of a plague outbreak who has a fever. Tachypnea would be considered a sufficient indication in infants. Persons without symptoms who are in close contact with infected patients should receive oral antibiotic prophylaxis with doxycycline for 7 days.²⁵

Person-to-person transmission of plague can occur via respiratory droplets, prompting the recommendation that infected individuals and asymptomatic close contacts of an infected patient, whether confirmed or suspected, observe strict respiratory isolation precautions until after 48 hours of adequate antibiotic treatment or prophylaxis. Environmental decontamination of plague is not necessary because the organism is very sensitive to environmental conditions and is only infective for up to 1 hour after aerosolization.²⁶

Botulism
Treatment for botulism is largely supportive. An antitoxin available through the CDC and health departments is a trivalent compound active against the three most common types of botulinum toxin. The US Army has an investigational heptavalent antitoxin that may be available in an outbreak. Antitoxin should be given to patients with neurologic signs of botulism at the time of diagnosis unless the patient is already improving.⁹ As with any antitoxin, rare adverse reactions may occur, including anaphylaxis and serum sickness. A small test dose should be given before administering the full dose, and appropriate supportive resources should be immediately available.

With improvements in supportive and critical care in the past few decades, mortality from botulism has declined from 25% in the 1950s to 6% in the 1990s.²⁷ Because botulinum toxin binding is irreversible, patients may remain in critical care units on mechanical ventilation for months while motor neuron fibers regenerate.

Botulism is not transmissible person to person, so isolation is not necessary. Based on risk versus benefit, antitoxin prophylaxis is not recommended in people without symptoms who may have been exposed to the toxin; however, they should remain under close supervision and be treated promptly should symptoms occur. In the event of an outbreak, health agencies would work to identify the source of the toxin and perform any decontamination procedures, which may be necessary because it may take days for the toxin to degrade naturally.²⁸

Tularemia
Aside from supportive care, including appropriate respiratory support and fluid management, antibiotics can significantly decrease the severity of disease and overall mortality. Streptomycin is considered the drug of choice, but because of its limited availability, other aminoglycosides and fluoroquinolones are the first-line drugs in the management of tularemia. These agents should be taken for 10 days. Macrolides and beta-lactam antibiotics have been tried but are not recommended because they have been associated with treatment failure.¹⁰

Viral Hemorrhagic Fevers
Treatment for VHF is mostly supportive. Ribavirin and passive antibody therapy have proved effective in some arenavirus and bunyavirus infections,¹² but no specific therapy has proved useful for filovirus or flavivirus infections. Vaccines are available for yellow fever virus, Rift Valley fever virus, and some of the arenaviruses.¹²

Although it is not known whether or when a biologic or chemical attack will take place, clinicians can improve the medical community's readiness for such a situation by disseminating reliable information to others. Many resources provide information on chemical and biologic terrorism; however, one would want to focus on reliable sources because, unfortunately, times like these spawn a few who seek to spread fear and panic through misinformation. For more information, readers are referred to the CDC web site at www.cdc.gov, the World Health Organization at www.who.int, and the United States Army Medical Research Institute of Infectious Diseases at www.usamriid.army.mil.

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