Online Medical Reference

Biologic Weapons and the Primary Care Clinician

Thomas Tallman

Steven Gordon

Thomas P. Noeller

Published: August 2010

Definition

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, but no longer. The events of September 11, 2001, the cases of anthrax caused by 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 preparatory measures. Bioterrorism is the intentional use of a pathogen or biologic product to cause harm to humans and other living organisms, influence the conduct of government, or intimidate or coerce a civilian population.

Weapons of mass destruction include nuclear, biologic, and chemical weapons. Biologic weapons disseminate pathogenic microbes or biologic toxins to cause illness or death in human, animal, or plant populations. Potential living biologic warfare agents include bacteria, viruses, rickettsia, and fungi. Why use biologic agents as weapons? They are relatively easy to produce, can disseminate great distances from a target, result in effects ranging from incapacitation to death, and can be difficult to detect, and the threats alone can result in panic.

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. Bioterrorism release types include overt and covert release.

Government 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 (Box 1) and 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.

The United States had an offensive biologic weapons program in place from 1943 to 1969 that included lethal agents such as anthrax and botulinum toxins, incapacitating agents such as Brucella suis and Venezuelan equine encephalitis (VEE) virus, and anticrop agents such as wheat stem rust and rice blast. Today, 17 countries are suspected of including or developing biologic agents in their offensive weapons programs. Almost all these countries are signatories to the 1972 Biological Weapons Convention, yet they continued to maintain offensive programs.

Box 1 Most Likely Bioterrorism Agents
Bacillus anthracis (anthrax)
Variola major (smallpox)
Yersinia pestis (plague)
Clostridium botulinum toxin
Francisella tularensis (tularemia)
Viral hemmorhagic fever viruses

Adapted from Centers for Disease Control and Prevention: Biological and chemical terrorism: Strategic plan for preparedness and response. Recommendations of the CDC Strategic Planning Workgroup. MMWR Morb Mortal Wkly Rep 2000;49(RR-40):1-14.

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Pathophysiology

Anthrax

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.

Anthrax in nature is a zoonosis; humans become infected through contact or ingestion of contaminated animals or animal products. It is not transmitted via person-to-person contact, so no special isolation of suspected or proven cases is necessary.

Anthrax may cause an acute infectious disease in humans of three types: inhalational, cutaneous, and gastrointestinal. Cutaneous anthrax is the most commonly encountered form, typically following exposure to anthrax-infected animals (Fig. 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, but can follow ingestion of undercooked contaminated meat. Inhalational anthrax, although rare, is the most lethal.

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.2 The most recent case of anthrax in the United States occurred in a man in New York, in 2006, who had made a drum from infected animal skins.

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. The anthrax genome contains two plasmids, one of which codes for toxin-making genes. In Sverdlovsk, hemorrhagic thoracic lymphadenitis and hemorrhagic mediastinitis occurred in all patients, and hemorrhagic meningitis occurred in 50% of cases.3

Smallpox

Once one of the deadliest diseases known to humankind, with a mortality rate of 30%, smallpox is the only human disease that has been successfully eradicated, with the last natural case occurring in 1977. Immunization ceased in 1980 based on recommendations from the World Health Organization.4 Routine immunizations in the United States ceased in 1972. There is now a large U.S. population that would be very susceptible to this disease.

Caused by variola virus, smallpox is potentially the most devastating of the bioterrorism 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. The organism has a high potential to be used as a bioterrorism (BT) weapon, because it is endemic in many animals worldwide, is easy to grow and disseminate, has a high fatality rate, and can be spread from person to person.

Y. pestis is classically transmitted through the bites of infected fleas, resulting in several forms of the disease, including bubonic, pneumonic, and primary septicemia 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.5

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 septicemia plague. Primary pneumonic plague is rare in the United States (endemic in parts of the southwest), 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, producing paralysis in its victims. 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. Natural botulism occurs in three common forms, foodborne, wound, and intestinal.6 All forms result from toxin absorption through mucosal surfaces or wounds, because 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 could 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 can survive 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.7 Sporadic human cases occur following spread by ticks or biting flies, and occasionally from direct contact with infected animals. 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, make 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 bioterrorism exposure, would likely result in predominantly pulmonary disease, manifesting in hemorrhagic bronchial inflammation and progressing to pleuropneumonitis. Hilar lymphadenopathy is a common finding. Biologic attack with this agent would most likely occur via aerosolized bacteria, resulting in tularemia with or without pneumonia.

Viral Hemorrhagic Fevers

Four main classes of viruses cause viral hemorrhagic fever (VHF): arenaviruses (Argentine, Bolivian, and Venezuelan hemorrhagic fevers, and Lassa fever), Filovirus (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. Human-to-human transmission can occur through direct contact with infected fluids and even through contaminated objects.8 A BT attack most likely would occur from an aerosolized virus. Case-fatality rates range from 0.5% for Omsk hemorrhagic fever to 90% for Ebola.

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Clinical Presentations, Syndromes, And Differential Diagnoses

Table 19 summarizes clinical presentations, syndromes, and differential diagnoses of select agents of bioterrorism.

Table 1 Clinical Presentations, Syndromes, and Differential Diagnoses of Select Bioterrorism Agents
If Patient Has: Consider: In Addition to:
Few days of nonspecific flulike symptoms, with nausea, emesis, cough ± chest discomfort, without coryza or rhinorrhea → abrupt onset of respiratory distress → shock → mental status changes, with chest x-ray abnormalities (wide mediastinum, infiltrates, pleural effusions) Inhalational anthrax Bacterial mediastinitis, tularemia, ruptured aortic aneurysm, SVC syndrome, histoplasmosis, coccidioidomycosis, Q fever, psittacosis, Legionnaires’ disease, influenza, sarcoidosis
Pruritic, painless papule → vesicle(s) → ulcer → edematous black eschar ± massive edema and regional adenopathy, ± fever, evolving over 3-7 days Cutaneous anthrax Recluse spider bite, atypicalLyme disease, staphylococcal lesion, orf, glanders, tularemia, rat bite fever, ecthyma gangrenosum, plague, rickettsialpox, atypical mycobacteria, diphtheria
Cough, fever, dyspnea, hemoptysis, lung consolidation ± shock Pneumonic plague Severe bacterial or viral pneumonia, inhalational anthrax, pulmonary infarct, pulmonary hemorrhage
Sepsis, disseminated intravascular coagulopathy, purpura, acral gangrene Primary septicemic plague Meningococcemia; gram-negative, streptococcal, pneumococcal, or staphylococcal bacteremia with shock; overwhelming postsplenectomy sepsis, acute leukemia
Synchronous, progressive papular → vesicular → pustular rash on face, extremities, trunk → generalization ± hemorrhagic component, with systemic toxicity Smallpox Atypical varicella, drug eruption, Stevens-Johnson syndrome, atypical measles, secondary syphilis, erythema multiforme, meningococcemia, monkeypox (with African travel history)
Acute febrile illness with pleuropneumonitis, bronchiolitis ± hilar lymphadenopathy, variable progression to respiratory failure Inhalational tularemia Inhalational anthrax, influenza, mycoplasma pneumonia, Legionnaires’ disease, Q fever, plague
Acute onset of afebrile, symmetrical, descending flaccid paralysis that begins in bulbar muscles, dilated pupils, dry mucous membranes, with normal mental status and absence of sensory changes Botulism Brainstem cerebrovascular accident, polio, myasthenia gravis, Guillain-Barré syndrome, tick paralysis, chemical intoxication

SVC, superior vena cava.

Adapted from the Infectious Disease Society of America website. Available at http://www.idsociety.org/WorkArea/showcontent.aspx?id=4284.

Anthrax

Cutaneous anthrax manifests as a “malignant” ulcer that initially occurs as a painless pruritic papule on the hands or face. The classic coal-appearing black eschar usually evolves over 3 to 7 days.

The clinical diagnosis of inhalational anthrax requires a high degree of suspicion. It generally manifests as a two-stage illness.10 First, a flulike 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%.

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 (chickenpox), 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 persons, occurs from the systemic inflammatory response and cardiovascular collapse.11,12

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 have a similar presentation, a productive cough, especially hemoptysis, preferentially suggests 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, symmetrical, flaccid muscle paralysis that first manifests in the bulbar muscles. Regardless of type of exposure to the toxin, acute bilateral cranial neuropathies will occur. Cranial nerve palsies result in diplopia, dysphagia, dysarthria, and ptosis. Other symptoms can include blurred vision, dry mouth, and mydriasis. Fever and sensory complaints or findings are absent. Hypotonia, paralysis of respiratory muscles, and loss of the gag reflex may result in the need for mechanical ventilation. Although the degree of hypotonia can 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 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 that of 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. Death rarely results 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.

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Diagnosis

Anthrax

In a previously healthy patient, an overwhelming febrile illness with a widened mediastinum on chest radiography should alert the clinician to the possibility of inhalational anthrax.

Definitive testing can be arranged through local and state health departments or the U.S. Army Medical Research Institute of Infectious Diseases. Rapid diagnostic tests such as the enzyme-linked immunosorbent assay (ELISA) or polymerase chain reaction (PCR) assay 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 staining of the blood may demonstrate the organism: gram-positive bacilli with bamboo rod appearance. Sputum culture and Gram staining are unlikely to be useful because the disease may not involve a pneumonic process. Postmortem examinations revealing hemorrhagic mediastinitis or hemorrhagic mediastinal lymphadenitis and hemorrhagic meningitis are essentially pathognomonic of inhalational anthrax.13 Nasal swabs are ineffective for ruling out anthrax and should not be used as a clinical test.

Smallpox

Smallpox virus is shed from the oropharynx and from 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 assay 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. The main diagnostic tool for smallpox is the history and physical examination. Public health authorities must be notified based on clinical suspicion alone, without waiting for diagnostic test results.

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.14 The laboratory needs to be notified of the suspicion of plague, because special culturing techniques may be needed. Gram staining may show characteristic safety pin bipolar staining. Chest x-rays reveal patchy infiltrates.

Botulinum Toxin

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. Suspected cases of botulism should be reported immediately to local health authorities to expedite epidemiologic investigation, provision of antitoxin when indicated, and prevention of further cases. The CDC is available 24 hours a day to consult with state authorities, facilitate provision of antitoxin when indicated, and provide botulism information.

The CDC emergency operations center can be reached at 770-488-7100 to request equine antitoxin release or consultation about suspected adult botulism cases. The California Infant Botulism Treatment and Prevention Program can be reached at 510-231-7600 for consultation on suspected infant botulism cases.

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 assay, and other methods are available in select reference laboratories.10 Laboratory personnel should be notified promptly whenever tularemia is suspected, because special safety precautions and diagnostic procedures are required.

Viral Hemorrhagic Fevers

Diagnosis of viral hemorrhagic fevers is suspected on clinical grounds, but confirmatory testing with ELISA, PCR assay, and virus isolation is available. Immunoglobulin M and immunoglobulin G titers can also be measured in specialized laboratories. Public health authorities should be notified promptly, even before the diagnosis is confirmed.

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Treatment and Outcomes

Anthrax

The following information on anthrax therapy and outcomes comes largely from CDC reports and guidelines.15,16 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 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 published antimicrobial recommendations (Table 2). For postexposure prophylaxis, ciprofloxacin or doxycycline is recommended and should be continued for 60 days. Evidence has shown that recently identified strains possess penicillinase and cephalosporinase activity. Concern for a beta-lactamase induction event in the presence of large numbers of organisms has prompted the recommendation that beta-lactams not be used for treatment of active disease.

Table 2 Centers for Disease Control and Prevention Recommendations for Antimicrobial Therapy Against Anthrax
Adults Children
Postexposure Prophylaxis Postexposure Prophylaxis
Ciprofloxacin, 500 mg PO bid
or
Doxycycline, 100 mg PO bid
Ciprofloxacin 10-15 mg/kg PO bid*
or
Doxycycline
>8 yr and >45 kg, 100 mg PO bid
>8 yr and ≤45 kg, 2.2 mg/kg PO bid
>8 yr and≤45 kg, 2.2 mg/kg PO bid
Cutaneous Anthrax
Ciprofloxacin, 500 mg PO bid
or
Doxycycline 100 mg PO bid
Ciprofloxacin, 10-15 mg/kg PO bid*
or
Doxycycline
>8 yr and >45 kg, 100 mg PO bid
>8 yr and ≤45 kg, 2.2 mg/kg PO bid
Inhalation Anthrax
Ciprofloxacin 400 mg IV bid
or
Doxycycline, 100 mg IV bid plus (for either drug)
One or two additional antibiotics (e.g., rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, clindamycin, clarithromycin)
Ciprofloxacin, 10-15 mg/kg IV bid*
or
Doxycycline
>8 yr and >45 kg, 100 mg IV bid
>8 yr and ≤45 kg, 2.2 mg/kg IV bid
≤8 yr, 2.2 mg/kg IV bid plus (for either drug)One or two additional antibiotics

*Ciprofloxacin dose in children not to exceed 1 g/day.

Data from Centers for Disease Control and Prevention: Update: Investigation of anthrax associated with intentional exposure and interim public health guidelines, October 2001. MMWR 2001;50:889-893; and Centers for Disease Control and Prevention: Update: Investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy, October 2001. MMWR 2001;50:909-919.

For treatment of active disease, ciprofloxacin or doxycycline is recommended, given IV 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.15-17

The anthrax strains from the postal attack 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 the treatment of anthrax. The CDC suggests combination therapy with two or more antibiotics until susceptibility testing is performed. IV antibiotics can be switched to oral equivalents when clinically appropriate and continued for 60 days.

If a patient goes to an emergency department or physician’s office after being exposed to a suspicious substance, the clinician should isolate the patient and 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 U.S. military for several years. The government is stockpiling vaccines against anthrax (75 million doses) and research is under way for an improved anthrax vaccine.

Smallpox

Patients with suspected smallpox should be quarantined, and appropriate respiratory isolation precautions should be taken. Any person known to have been exposed to the virus may be placed in respiratory isolation and observed for signs of the disease until after the standard 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.11 Smallpox vaccine (vaccinia) can be obtained through the CDC, and approximately 35,000 civilian first responders have received booster vaccinations. The federal supply of smallpox vaccine has increased to more than 300 million full doses from an initial stockpile of about 15 million doses. Research is under way to develop a more effective smallpox vaccine for use in immunocompromised persons. Routine vaccination in the United States stopped in 1972, and it is unlikely that people immunized before this time would still have protective immunity.12 Vaccination up to 4 days after exposure may prevent or attenuate the illness.13 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 empirical 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.14 In a large-scale attack, when hospital supplies of IV drugs might be limited, doxycycline is recommended as an alternative for patients suitable for oral therapy. Fluoroquinolones have not been adequately studied in controlled human trials, but have demonstrated clinical efficacy comparable with that of doxycycline in the treatment of pneumonic plague in animal models.19-21

Postexposure prophylaxis in the form of IV 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.22

Person-to-person transmission of plague can occur via respiratory droplets, prompting the recommendation that infected patients 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 sensitive to environmental conditions and is only infective for up to 1 hour after aerosolization.23

Botulism

Early recognition of botulism, treatment in an intensive care unit, provision of mechanical ventilation when indicated, and rapid administration of antitoxin (optimally within 12 hours of presentation) are the cornerstones of treatment. An antitoxin available through the CDC and health departments is a trivalent compound active against the three most common types of botulinum toxin. The U.S. Army has an investigational heptavalent antitoxin that may be available during an outbreak. Antitoxin should be given to patients with neurologic signs of botulism at the time of diagnosis unless the patient is already improving.6 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.24 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 through person-to-person contact, so isolation is unnecessary. Based on risk versus benefit, antitoxin prophylaxis is not recommended for 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 case of an outbreak, health agencies would work to identify the source of the toxin and perform decontamination procedures, which may be necessary because it could take days for the toxin to degrade naturally.25

Tularemia

In addition to 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 first-line drugs for the management of tularemia. Alternate choices are doxycycline or chloramphenicol (14-21 days) or ciprofloxacin (10 days).10

Viral Hemorrhagic Fevers

Treatment for VHF is mostly supportive. Ribavirin and passive antibody therapy have proved effective in some arenavirus and bunyavirus infections,9 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.9

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National Guidelines

Biologic defense is a layered defense system, consisting of accurate threat intelligence, physical countermeasures (e.g., detection, personal protection, decontamination procedures), medical countermeasures (e.g., vaccines, oral chemoprophylaxis, diagnostics, therapeutics), and education and training. 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. In the event of a bioterrorism threat, the CDC should be contacted (telephone 1-800-CDC-INFO, or e-mail cdcinfo@cdc.gov). Many resources provide information on chemical and biologic terrorism; however, only reliable sources be contacted because, unfortunately, times like these spawn a few who seek to spread fear and panic through misinformation. For more information, refer to the CDC website at www.cdc.gov, the World Health Organization at www.who.int, and the U.S. Army Medical Research Institute of Infectious Diseases at www.usamriid.army.mil.

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Summary

  • Biologic warfare and terrorism are real threats and mass casualties could result.
  • The U.S. public health system and primary health care providers must be prepared to address various biologic agents, including pathogens that are rarely seen in the United States.
  • High-priority agents include organisms that pose a risk to national security because they can be easily disseminated and transmitted from person to person, result in high mortality, might cause public panic and social disruption, and require special action for public health preparedness.
  • Such high-priority or category A agents include anthrax, smallpox, plague, botulinum toxin, tularemia, and viral hemorrhagic fevers.
  • Medical defenses are available against several threat agents.
  • Work needs to be done in many areas before it can be said that we are adequately prepared to respond to an actual biologic weapon attack.

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Suggested Readings

  • Abramova FA, Grinberg LM, Yampolskaya OV, Walker DH: Pathology of inhalation anthrax in 42 cases from the Sverdlovsk outbreak of 1979. Proc Natl Acad Sci USA 1993;90:2291-2294.
  • Brachman PS: Inhalation anthrax. Ann NY Acad Sci 1980;353:83-93.
  • Centers for Disease Control and Prevention: Biological and chemical terrorism: Strategic plan for preparedness and response. Recommendations of the CDC Strategic Planning Workgroup. MMWR Morb Mortal Wkly Rep 2000;49(RR–40):1-14.
  • Dennis DT, Inglesby TV, Henderson DA, et al: Tularemia as a biological weapon: Medical and public health management. JAMA 2001;285:2763-2773.
  • Franz DR, Jahrling PB, Friedlander AM, et al: Clinical recognition and management of patients exposed to biological warfare agents. JAMA 1997;278:399-411.
  • Inglesby TV, Dennis DT, Henderson DA, et al: Plague as a biological weapon: Medical and public health management. JAMA 2000;283:2281-2290.
  • Inglesby TV, Henderson DA, Bartlett JG, et al: Anthrax as a biological weapon: Medical and public health management. JAMA 1999;281:1735-1745.

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References

  1. Centers for Disease Control and Prevention: Biological and chemical terrorism: Strategic plan for preparedness and response. Recommendations of the CDC Strategic Planning Workgroup. MMWR Morb Mortal Wkly Rep 2000;49(RR-40):1-14.
  2. Centers for Disease Control and Prevention: Update: Investigation of bioterrorism-related anthrax—Connecticut, 2001. MMWR Morb Mortal Wkly Rep 2001;50:1077-1079.
  3. Meselson M, Guillemin J, Hugh-Jones M, et al: The Sverdlovsk anthrax outbreak of 1979. Science 1994;266:1202-1208.
  4. World Health Organization: The global elimination of smallpox. Final Report of the Global Commission for the Certification of Smallpox Eradication, Geneva, 1979. Geneva, World Health Organization, 1980.
  5. Butler T: Yersinia species (including plague). In Mandel GL, Bennett JE, Dolin R, (eds): Principles and Practice of Infectious Diseases, 4th ed. New York, Churchill Livingston, 1995, pp 2070-2078.
  6. Shapiro RL, Hathaway C, Swerdlow DL: Botulism in the United States: A clinical and epidemiologic review. Ann Intern Med 1998;129:221-228.
  7. Dennis DT, Inglesby TV, Henderson DA, et al: Tularemia as a biological weapon: Medical and public health management. JAMA 2001;285:2763-2773.
  8. Centers for Disease Control and Prevention: Emergency Preparedness and Response: Viral Hemorrhagic Fevers. Available at http://www.bt.cdc.gov/agent/vhf/ (accessed March 9, 2009).
  9. Franz DR, Jahrling PB, Friedlander AM, et al: Clinical recognition and management of patients exposed to biological warfare agents. JAMA 1997;278:399-411.
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