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INFECTIOUS DISEASES
Bioterrorism: Introduction and Major Agents
Charles Kemp, FNP

Dedicated: To the Working Group on Civilian Biodefensewho may have saved many lives with their seminal and comprehensive work. It is not if, but where and when. In light of the September 11 World Trade Center and Pentagon attacks, biological terrorist acts in the United States seem more likely than ever before. We know there are people willing to die to kill Americans and we know that nations with a history of supporting terrorism have biological warfare (BW) capability. Some of the states capable of BW include Iraq, Libya, Syria, and Iranall of which have close ties to transnational terrorist groups such as Al-Qaeda, Armed Islamic Group of Algeria, and Al-Jihad of Egypt (Davis, 1999; McGovern, Christopher, & Eitzen, 1999; Sanger, & Kahn, 2001). The threat is not limited to these nations or groups, but all do present a clear danger. According to the U.S. Central Intelligence Agency, operatives of Al-Qaeda (the Osama bin Laden group) have trained to conduct attacks with toxic chemicals or biological toxins (Broad, & Peterson, 2001).

NATIONAL PLANNING AND RESPONSE Most planning for response to biological attack is at local levels and preparedness is poor (Moser, White, LewisYounger, & Garrett, 2001; Wetter, Daniell, & Treser, 2001). In most locales, civilian resources to meet BW attacks are limited to resources currently in use (i.e., hospitals, emergency medical response systems, law enforcement, and private providers), which, in the case of a significant attack, are likely to be quickly overwhelmed (Broad, & Peterson, 2001; Garrett, Magruder, & Molgard, 2000; Terriff, & Tee, 2001; Wetter, Daniell, & Treser, 2001). The Centers for Disease Control (CDC) has developed strategic plans for domestic BW. These plans are focused primarily on planning, detection and surveillance, laboratory analysis, emergency response, and communications (CDC, 2000). To contact the CDC directly, call the Duty Officer of the day at 404-639-2807 (8:00am to 4:00pm) or 404-639-7100 (after hours). The federal government has begun establishing stockpiles of pharmaceuticals essential to treat victims of BW; however, these are unlikely to be adequate to the
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task if there is a large attack (Khan, Morse, & Lillibridge, 2000). The military is better prepared than other government entities to meet domestic BW attacks, but a harsh reality is that in a widespread attack, military resources might not be diverted to civilian interests except to prevent civilian encroachment on military facilities. Biological warfare presents a unique problem in warning and response: In many cases, if the attack proceeds as planned, the people under attack would not be aware that the attack occurred until hours or days later, depending on the agent and its incubation period. Thus, emergency departments and primary care providers are likely to be the earliest warning source, as well as among the first to be secondarily exposed. Response, of course, is hindered by already busy resources overwhelmed by enormous numbers of extraordinarily sick and contaminated victims, by inadequate facilities and medications, supplies, and in many cases, by inadequate planning and training (Broad, & Peterson, 2001; Henry, 2001; Mabee, 2001; Macintyre et al., 2000; Siegelson, 2000). The inability to respond to a significant BW attack would most likely

lead to massive social and political disorder (Bardi, 1999). While there are a variety of means of delivery of BW agents, the most likely in a domestic context is aerosol (Burrows, & Renner, 1999). This is because the most lethal weaponized agents (anthrax, plague, smallpox, tularemia, and botulinum toxin) are efficiently delivered by aerosol methods and because other means either do not work or are inefficient. Contamination of a large-scale water supply is difficult for several reasons: (a) the volumes of water in large-scale supplies would necessitate very large volumes of the agent, (b) not all weaponized agents are waterborne threats (including the most lethal agents), and (c) the existence of more efficient and common means of delivery (Burrows, & Renner, 1999). Person-to-person (secondary aerosol) transmission will occur with some agents, especially plague and smallpox. On a smaller scale, it is possible that attempts may be made to contaminate food with agents such as botulinum, staphylococcus enterotoxin B, and cholera. It is possible that more than one means of delivery and several agents may be used simultaneously in an attack (Davis, 1999).

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ANTHRAX (Bacillus anthracis)

Critical Biological Agents: Category A Note: Category A agents pose a risk to national security because they can be easily disseminated or transmitted from person to person; cause high mortality, with potential for major public health impact; might cause public panic and social disruption; and require special action for public health preparedness (CDC, 2000, p. 5). Anthrax (Bacillus anthracis) Smallpox (variola major) Plague (Yersinia pestis) Botulism (Clostridium botulinum toxin) Tularemia (Francisella tularenis) Ebola and Marburg hemorrhagic fevers (filoviruses) Lassa, Junin, and related arenaviruses In this article only the first five agents are discussed, because they are the most likely biological agents to be used in a domestic BW attack. Of these five, four are known to have been extensively studied by the Soviet Union/Russia where the capacity to produce these as weaponized agents was measured in hundreds of tons. Iraq also developed and likely still has capability to produce and deliver several Class A agents as well as Class B and chemical agents (Davis, 1999; Kortepeter, & Parker, 1999). Agent: (Bacillus anthracis) is a very hardy Gram-positive spore-forming aerobic rod that causes cutaneous or pulmonary infection. Anthrax is the greatest known BW threat and has been weaponized by several countries, including Iraq, which tested it extensively on humans (Cieslak, & Eitzen, 1999; Shoham, 2000). It has been estimated that release of 100 kilograms of anthrax spores upwind of Washington D.C. would result in up to 3 million deaths (U.S. Congress, 1993). Routes of Infection: Endemic or naturally occurring (cutaneous) anthrax accounts for more than 95% of cases and is contracted primarily through direct inoculation of a break in the skin in contact with an infected animal. Cutaneous anthrax is not an issue in a BW context. As a biological weapon, anthrax is delivered in an aerosol dust and is contracted via inhalation. Delivery systems range from bombs to disguised cigarette lighters. Person-toperson transmission is not known to occur. It is not known how long anthrax spores remain viable in the environment, but experience with accidents in Russia indicates a maximum of 45 days (Inglesby et al., 1999: Shoham, 2000). Incubation: The incubation period is usually 1-7 days but can be up to 60 days (Chin, 2000). CLINICAL FINDINGS & TREATMENT Signs & Symptoms: Inhaled spores are carried by pulmonary macrophages to tracheobronchial or mediastinal lymph nodes where the B. anthracis multiplies and produces at least three proteins: edema factor (or toxin; EF), lethal factor (LF), and protective antigen (PA), the latter of which is a carrier molecule for EF and LF. These toxins (EF + PA and LF + PA) cause lymphatic tissue necrosis, which releases large numbers of B. anthracis that cause overwhelming septicemia and death. Inhalation anthrax is usually biphasic in presentation, beginning with a prodrome of nonspecific febrile flu-like illness with low-grade fever, malaise, headache, nonproductive cough, precordial discomfort or pressure, and myalgia. After 1-4 days there is sometimes a brief period of slight improvement, followed by rapid deterioration marked by fever

Empiric Therapy Although there is not widespread acceptance (or rejection) of the idea, the battlefield concept of empiric therapy may be indicated when large numbers of people present with undifferentiated febrile illness with similar time of onset and under credible threat of biological attack. Under such circumstances, and when medical facilities are not readily available, empiric therapy is ciprofloxacin 500 mg po (or IV) every 12 hours or doxycycline 200 mg po (or IV) initially and then 100 mg every 12 hours until danger has passed, been dismissed, or specific therapy initiated (Cieslak et al., 2000). Note that the authors are writing about battlefield conditionswhich we may see in the homeland.
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and respiratory distress, including some or all of the following: dyspnea, stridor, cyanosis, increased chest pain, diaphoresis, and sometimes subcutaneous edema of neck and chest. Meningitis, usually hemorrhagic, occurs in about 50% of cases. Pneumonia is usually not present, but pleural effusions may be present. Chest radiographs show a widened mediastnum as early as the second day after exposure. This second phase of respiratory distress is followed by shock and nearly always, death. Without treatment, the death rate is essentially 100%; a treatment delay of more than 48 hours after symptoms appear results in a death rate of approximately 95% (Cieslak, & Eitzen, 1999; Friedlander, 2000; Henry, 2001; Inglesby et al., 1999; Shafazand, Doyle, Ruoss, Weinacker, & Raffin, 1999). Diagnosis: In an attack, the first patients at the first stage would likely be misdiagnosed as having viral upper respiratory infections and many people would simply self-medicate with over-the-counter cold and flu medicines. Some would seek care; the influx of large numbers of otherwise healthy people with the above first stage symptomatology should arouse suspicion. With large numbers of patients presenting in the second stage of illness, it would be clear that a disaster (either anthrax or pneumonic plague) is unfolding as otherwise healthy people present in a toxic febrile condition with severe respiratory distress and cyanosis without clinical evidence of pneumonia. The widened mediastinum on chest radiograph (CXR) is pathognomonic of advanced inhalation anthrax. Grams stain of cerebrospinal fluid or pleural fluid shows typical grampositive bacilli and diagnosis is confirmed by culturing B. anthracis from blood or on autopsy (Cieslak, & Eitzen, 1999; Friedlander, 2000; Inglesby et al., 1999; Shafazand et al., 1999). Differential Diagnosis: Initially, the differential includes any flu-like upper respiratory infection unless very large numbers of patients seek care, in which case, anthrax might be suspected. At the second stage the differential is pneumonic plague. Treatment: Early treatment is essential if
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there is to be any hope of recovery. Naturally occurring strains can be successfully treated with penicillin, but in a BW attack, penicillin resistance is possible. All treatment is for a total of 60 days of therapy (or when sufficient vaccine has been received) due to the possibility of delayed spore germination. Mass casualties or post-exposure: Adults: Ciprofloxacin 500 mg po every 12 hours. If the strain of B. anthracis is shown to be susceptible, adults and children over 20 kg can be given amoxicillin 500 mg po every 8 hours OR doxycycline 100 mg po every 12 hours. Children: Ciprofloxacin 20-30 mg/kg/24 hours po every 12 hours (not exceeding 1 g/24 hours). If the strain of B. anthracis is shown to be susceptible, children weighing 20 kg or more can be given amoxicillin 500 mg po every 8 hours. Children weighing less than 20 kg can be given amoxicillin 40 mg/kg/24 hours divided into 3 doses taken every 8 hours. Immunization should be used if available but this is unlikely for civilian populations (CDC, 1999; Friedlander, 2000; Inglesby et al., 1999). Contained casualties (All are treated for 60 days): Adults: The ideal treatment for clinically evident anthrax is ciprofloxacin 400 mg IV every 12 hours until the patients condition improves, at which time oral ciprofloxacin is given. Other fluoroquinolones can likely be substituted for adults, but are not recommended by the CDC for children. If the strain of B. anthracis is shown to be susceptible, adults and children over 45 kg can be given penicillin G 4 million units IV every 4 hours OR doxycycline 100 mg IV every 12 hours. Children: IV Ciprofloxacin 20-30 mg/kg/24 hours every 12 hours (not to exceed one g/24 hours), and therapy is continued as above. Other fluoroquinolones are not recommended for children by the CDC. If the strain of B. anthracis is shown to be susceptible, children over 12 years can be given penicillin G 4 million units IV every 4 hours OR doxycycline 100 mg IV every 12 hours. Children less than 12 years receive penicillin G 50,000 u/kg IV every 6 hours.
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Doxycycline can also be used: children over 45 kg receive the adult dose and children 45 kg or less receive 2.5 mg/kg IV every 12 hours. Protection: Post-exposure prophylaxis is discussed above. Person-to-person transmission is not known to occur; hence standard precautions with hospitalized patients are sufficient. Environmental surfaces can be cleaned with standard hospital disinfectants. It is essential that bodies (human and animal) be disposed of quickly. Embalming is risky and cremation is the ideal means of body disposal. Although anthrax spores can remain in the environment for years, based on experience with accidents in the Soviet Union and in animal processing plants, the risk of infection after the primary aerosolization becomes very small or even non-existent beyond a maximum of 45 days post aerosolization (Inglesby et al., 1999).

SMALLPOX (Variola Major) Agent: Variola major is a DNA virus, which is a member of the orthopoxvirus family. As a result of a worldwide eradication campaign, the last endemic case of smallpox was reported in 1977. Russia and the U.S. are the last two known repositories of smallpox virus; Russia has the virus stored at several sites. Plans to destroy the virus by 1999 were delayed and it is not known when or if the stores will be destroyed. There is reason to believe that the Soviet Union, and later Russia, produced large amounts of smallpox virus and attempted to develop more virulent and contagious recombinant strains of the virus (Henderson et al., 1999). The smallpox virus is specific for humans and non-pathogenic in animals. Smallpox is one of the two most dangerous BW agents (the other being anthrax) because of its high case-fatality rate (>30%), ready person-to-person transmission, lack of population immunity (possibly including persons immunized 25+ years ago), and lack of treatment (Henderson et al., 1999; Kortepeter, & Parker, 1999). Routes of Infection: Weaponized smallpox can be spread by aerosol and can be delivered directly (e.g., sprayed or

released in enclosed spaces) or by bombs or missiles. The virus is stable and the infectious dose is small (Johns Hopkins University, 2000). Once introduced into a population, smallpox would spread from person to person via respiratory secretions inhaled and implanted in oropharyngeal or respiratory mucosa, with many second-generation cases infected by first-generation cases. Clothing and related items are also infectious. People with smallpox are most infectious from the time of the onset of the rash (i.e., pox), by which time the patient is very ill and often prostrated, to the time of scab formation (though the scabs contain viable virus; Bardi, 1999; Henderson et al., 1999). It is estimated that smallpox virus released in an attack would remain viable in the environment for up to 24 hours and perhaps longer under ideal conditions (cool temperatures and low humidity). In hot humid weather, the virus would likely persist in the environment for about six hours (Henderson et al., 1999). Incubation: The average incubation period is 12-14 days, with a range of 7-17 days (Henderson et al., 1999; Johns Hopkins University, 2000). CLINICAL FINDINGS & TREATMENT Signs & Symptoms: In most cases, smallpox is initially characterized by high fever, malaise, and prostration with severe headache and backache. Severe abdominal pain and delirium may also be present. This initial presentation is followed by a centrifugal maculopapular rash on the oral mucosa, face, and forearms, spreading to the trunk and legs. It is at this point that the illness becomes most contagious. The rash becomes vesicular and then pustular. Pustules are round, firm, and imbedded in the dermis. The lesions are densest on the face and extremities and in the various regions (e.g., face, arms, trunk) are usually at the same stage of development. Lesions of the oral mucosa and pharynx are the first to ulcerate. After about a week, the pustules begin to scab and later separate from the skin, leaving pitted scars. Scabbing marks decreased infectiousness. Other organ involvement and secondary bacter-

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ial infections are uncommon. Death usually occurs in the second week after onset of illness and is likely due to toxemia from circulating immune complexes and variola antigens (Henderson et al., 1999; Johns Hopkins University, 2000). There are two less common known forms of smallpox: hemorrhagic and malignant. Assuming Soviet/Russian success in developing more virulent forms of smallpox, close attention should be paid to these (and other) less common presentations. Hemorrhagic smallpox is characterized by a slightly shorter incubation period and more profound prostration period as described above. The rash is dusky and erythematous and is followed by petechial hemorrhage into skin and mucous membranes. Fatality approaches 100% and usually occurs in less than a week after the onset of the rash (Henderson et al., 1999). Malignant smallpox is characterized by abrupt onset and constitutional symptoms similar to the above. The rash is confluent and lesions are soft and velvety, more macular than papular, and do not become pustular. The skin is finegrained, reddish, and in some cases, there are hemorrhages under the skin. The malignant form is frequently fatal (Henderson et al., 1999). Complications: Encephalitis occasionally develops. Diagnosis: In the event of an outbreak, laboratory confirmation would occur at a high-containment BL-4 facility with assistance from the CDC. Collection of a specimen requires vaccination of the person doing the collecting, and transportation of the specimen requires safeguards as designated by the government. After confirmation, subsequent cases that are clinically similar would not require confirmation (Henderson et al., 1999). Differential Diagnosis: Varicella is distinguished by more superficial lesions at varying stages of development that, in contradistinction to smallpox, are seldom found on the palms or soles. Hemorrhagic smallpox may resemble meningococcemia or acute leukemia. Malignant smallpox has sometimes been mistaken for hemorrhagic chickenpox or surgical abdomen. Monkeypox is a differVOLUME 13, ISSUE 11, NOVEMBER 2001

ential in endemic areas and the disease may also resemble bullous erythema multiforma. Treatment: There are no known antiviral agents effective in the treatment of smallpox; hence treatment is supportive, except for antibiotics to treat secondary bacterial infections. Smallpox vaccine is active only if administered in the first four days post-exposure (note that the incubation period is 7-17 days). Vaccination after exposure has an effect ranging from preventing illness to decreasing fatality, with earlier vaccination producing the best results. There are 6,000,000 to 7,000,000 vaccination doses (manufactured in the 1970s, hence viability is unknown) available in the U.S. and no nation or health organization has any surplus. Vaccine is being produced in the U.S., and the first 40 million doses are scheduled for delivery in 2004. Persons who are immunocompromised may not be able to tolerate the vaccine (Henderson et al., 1999; Henderson, 1999; Johns Hopkins University, 2000; Kortepeter, & Parker, 1999). Protection: In the event of a contagion, health and other public safety personnel should be vaccinated, as should all hospital employees and patients in facilities where a patient has been diagnosed with smallpox. Laundry personnel are at very high risk. All persons suspected of having smallpox should be isolated in their homes and not in a hospital. Persons living with the patient or who have had face-to-face contact after the onset of fever should be vaccinated and placed under surveillance (the disease is not contagious until the rash begins). Exposed persons should have their temperature checked daily (evening is best); a fever of >101oF/38oC anytime within 17 days post-exposure may indicate smallpox and requires immediate isolation. Hospitalized patients should be kept in rooms with negative pressure and particulate air filtration, and staff should use standard precautions (gloves, gown, and mask). In the event of contagion, it is likely that one or more hospitals in a given area would be designated for smallpox patients only. Bedding, clothing,

other personal items, as well as protection gear, should be autoclaved or washed in hot water with bleach added. Contaminated surfaces should be cleaned with disinfectants such as hypochlorite and quaternary ammonia. Corpses should be cremated and mortuary personnel should be vaccinated (Henderson et al., 1999; Johns Hopkins University, 2000).

PLAGUE (Yersinia pestis)

Agent: Plague is an acute febrile zoonotic disease caused by Yersinia pestis, a nonmotile microaerophilic bacillus (sometimes coccobacillus) of the family Enterobacteriaceae. There are three common forms of plague: bubonic (most common), pneumonic (most rapid and most frequently fatal), and septicemic. The latter two are either primary or secondary to metastatic spread. A BW attack using plague would produce primarily pneumonic plague. Plague has a high mortality rate (>50%, with pneumonic having a higher rate) and over history has caused approximately 200 million deaths in pandemics in various parts of the world. The most recent pandemic was in the late 19th and early 20th centuries and resulted in estimated 12,000,000 deaths. In recent years (1970s-1990s), most cases have been reported in Africa, Asia, and the Americas (Chin, 2000; Heddurshetti, Pumpradit, & Lutwick, 2001; Inglesby et al., 2000). Routes of Infection: In a BW context, Y. pestis would be delivered in an aerosol, and the inhaled organisms would cause primary pneumonic plague, with significant numbers of septicemic cases. Secondary pneumonic cases would occur from contact with patients with pneumonic plague. The bacillus may remain viable for as long as an hour after an attack (Heddurshetti et al., 2001; Inglesby et al., 2000). As a naturally occurring zoonosis, plague is endemic among more than 200 rodents; it is spread among them and transmitted to humans primarily by fleabite (resulting in bubonic plague). Direct inoculation through handling infected mammal carcasses or person-toperson via the respiratory route via infected droplets from a patient with pneu486

monic plague also occurs (Chin, 2000). Incubation: The incubation period (with aerosolized Y. pestis) is usually 2-4 days with a range of 1-6 days. CLINICAL FINDINGS & TREATMENT Signs & Symptoms: An old nursery rhyme is said to characterize the symptoms and course of plague: Ring around the rosy (rose-colored purpuric lesions) Pocket full of posies (flowers carried to prevent the disease and cover the stench) Ashes, ashes (death) or in an alternate version, Achoo, achoo (sneezing in pneumonic plague) We all fall down (we all die) Patients with pneumonic plague following an attack would present with acute fulminate pneumonia with high fever, malaise, dyspnea, and cough (sometimes productive of watery bloodtinged sputum and less commonly purulent sputum). Cutaneous manifestations (terminal stage) include livid cyanosis and large ecchymosis. Acral (digits, nose) necrosis may also occur. Gastrointestinal symptoms might occur, including abdominal pain, nausea, vomiting, and diarrhea. Buboes (an imflammatory swelling of lymph nodes) would seldom be present, in contrast to bubonic or secondary pneumonic plague, in which buboes are common. Sepsis would develop rapidly, with signs of progression including dyspnea, stridor, cyanosis, shock, and respiratory failure (see septicemic plague below). Common radiographic finding would be bilateral alveolar infiltrates and consolidation (Heddurshetti et al., 2001; Inglesby et al., 2000; McGovern et al., 1999). Naturally occurring plague is manifested by abrupt onset of high fever, severe headache, severe myalgias, prostration, and in some cases, delirium. The
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incubation period is 2-10 days. An ulcer may develop at the inoculation site. Lymphadenitis is followed by a painful, draining bubo (or buboes). Hematogenous spread or septicemic plague is characterized by rapid decline, disseminated intravascular coagulation, purpura, and coma (Chin, 2000; Titball, & Leary, 1998). Diagnosis: Delayed diagnosis virtually guarantees death. A presumptive diagnosis can be made on the basis of acute fulminating pneumonia with Gram-negative bacilli or coccobacilli and bipolar safety-pin staining organisms in sputum, peripheral blood, lymph node needle aspirate, or other specimens. The sudden appearance of large numbers of otherwise healthy individuals with severe pneumonia and sepsis indicates either plague or anthrax. Differential Diagnosis: Large numbers of patients with severe pneumonia and sepsis indicates either plague or anthrax; if hemoptysis is present, plague is the more likely diagnosis. A single case might be one of several pneumonias. Diagnosis is confirmed by culture, antigen detection, IgM enzyme, immunostaining, and polymerase chain reaction (Heddurshetti et al., 2001; Inglesby et al., 2000). Treatment: Treatment must begin within 24 hours of the onset of symptoms and preferably before. There is a lack of experience in treating (especially primary pneumonic) plague in humans, hence some therapies discussed below have not been adequately studied and are not FDA approved. Mass casualties and post-exposure (treat at least seven days): Adults: Recommended treatment is Ciprofloxacin 500 mg po every 12 hours OR doxycycline 100 mg (po or IV) every 12 hours. An alternative for adults is chloramphenicol 25 mg/kg po four times daily. All are given for at least seven days. Children: Doxycycline is the preferred choice; if weight is 45 kg or more, give adult dose and if less than 45 kg, give 2.2 mg/kg po every 12 hours (maximum 200 mg/24 hours) OR ciprofloxacin 20 mg/kg po every 12 hours (up to adult dose). An alternative for children more than two years old is chloramphenicol 25 mg/kg po four times daily. All are given for at least seven days.

Contained casualties (treat 10 days): Adults: Streptomycin 1 gram IM twice daily OR gentamicin 5mg/kg IM or IV once daily (gentamicin is the choice for pregnant women). Alternatives are doxycycline 100 mg IV twice daily OR doxycycline 200 mg IV once daily OR ciprofloxacin 400 mg IV twice daily OR chloramphenicol 25 mg/kg IV 4 times daily. Children: Streptomycin 15 mg/kg IM twice daily (maximum dose 2 grams) OR gentamicin 2.5mg/kg IM or IV 3 times daily. Alternatives include doxycycline: if 45 kg or greater, give adult dose and if less than 45 kg, give 2.2 mg/kg IV twice daily (maximum 200 mg/24 hours) OR ciprofloxacin 15 mg/kg IV twice daily OR chloramphenicol 25 mg/kg IV 4 times daily if two years or older. There is not currently a plague vaccine available in the U.S. (Heddurshetti et al., 2001; Inglesby et al., 2000). Protection: Patients should be isolated for the first 48 hours of antibiotic treatment and until there is improvement; unnecessary contact with others should be avoided. Close contacts should receive prophylactic treatment. Isolation of close contacts who refuse prophylaxis is not recommended. However, such persons should be closely monitored for fever or cough for the first seven days after exposure and treatment started if either occurs. Patients and others in contact should wear disposable surgical masks. Rooms of patients with pneumonic plague should be terminally cleaned and contaminated linens disinfected according to hospital protocol. Plague aerosol would likely be infectious for as long as one hour after release, hence later environmental danger is minimal (Inglesby et al., 2000).

BOTULISM (Clostridium botulinum

toxin) Agent: Botulism is caused by the neurotoxin produced by the bacillus Clostridium botulinum, a spore-forming obligate anaerobe widely found in soil; it may be caused by other Clostridium species. Botulinum toxin is the most lethal known natural poison. There are seven different Botulinum toxins, designated A-G. Significantly, botulinum anti-

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toxins are specific to type, i.e., type A anti-toxin does not neutralize type B, and so on (see treatment below). As a naturally occurring disease, botulism appears as a severe food poisoning resulting from ingesting the neurotoxin, wound infection with the toxin, and intestinal (formerly infant botulism). Botulism as a BW weapon is discussed below (Arnon et al., 2001; Chin, 2000; Schecter, & Arnon, 2000). Routes of Infection: As a bioterror weapon, botulism can be dispersed in aerosol form or dispensed in food. The aerosol (inhalation) form would create more casualties, but the food method would also be disruptive, as patients with botulism require lengthy critical care and ventilator support. Indeed, even a single case of botulism, especially if there is no obvious source, raises the possibility of deliberate use. By two days following an attack, aerosolized botulinum would likely be degraded to a level of little danger (recalling that botulinum is widely found in soil; Arnon et al., 2001; Chin, 2000). Incubation: The usual incubation period is 12-36 hours and ranges from 2 hours up to 8 days, depending upon several factors (especially the amount of toxin absorbed), with the shorter period associated with more severe disease (Chin, 2000). CLINICAL FINDINGS & TREATMENT Signs & Symptoms: Regardless of route of ingestion, all forms of botulism produce similar neurological signs; gastrointestinal (GI) distress may occur from naturally occurring food-borne botulism. The severity of symptoms varies significantly. Initial presentation includes cranial nerve involvement, with bulbar palsies, ptosis, diplopia, blurred vision, photophobia, and decreased visual accommodation. The mouth may be dry with pharyngeal injection. Symptoms progress to dysarthria, dysphonia, and dysphagia with loss of gag reflex. Further progression includes a descending symmetric flaccid paralysis with loss of head control, hypotonia, generalized weakness, and diaphragmatic and respiratory muscle paralysis. Death results from airway obstruction and inadequate tidal volume. Sensorium remains intact and, unless
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there is a secondary or unrelated infection, patients are afebrile (Arnon et al., 2001; Cieslak, & Eitzen, 2000). The classic triad of botulism (Arnon et al.) is symmetric, descending flaccid paralysis with bulbar palsies, afebrile, and clear sensorium. Diagnosis: Initial diagnosis is on clinical grounds and workup may include electromyogram. Confirmation is through laboratory testing at CDC or one of about 20 other laboratories; the CDC furnishes instructions for obtaining samples. Differential Diagnosis: A cluster of patients with the classic triad of botulism is highly suspicious. Major differentials include Guillain-Barre syndrome, myasthenia gravis, depressant intoxication, and other central nervous system disorders. Treatment: Treatment includes passive immunization and supportive care. If botulinism is identified early, botulinum antitoxin decreases the progressive nerve damage and disease severity but does not reverse extant damage; thus, speed is essential. The trivalent antitoxin available from state and local health departments has antibodies effective against botulinum types A, B, and E. Iraq is known to have produced and likely still possess weaponized types A, B, E, and F (several strains of A and E; Shoham, 2000). The military has a heptavalent antitoxin effective against types A-G. The antitoxins are equine, hence a test dose is required (see insert for updates) and desensitization necessary in a small percentage of patients. Supportive care is focused primarily on respiratory support. For isolated severe cases, critical care includes mechanical ventilation, enteral or parenteral feeding, and prevention and treatment of secondary infections. With decreasing respiratory function, anticipatory intubation is indicated. Ventilation may be necessary for several months. If secondary respiratory infections develop, aminoglycosides and clindamycin are contraindicated due to exacerbation of neuromuscular blockade. Obviously there are insufficient critical care beds, ventilators, or trained staff for a major attack. In the absence of ade-

quate support, positioning at reverse Trendelenburg at 20-25 degrees is recommended over Fowlers or supine positions. Food should be given in small amounts; it should be soft, non-abrasive, moist, and semi-solid or finely chopped ; liquids may be better tolerated through a straw (Arnon et al., 2001; Chin, 2000; Cieslak, & Eitzen, 2000). Protection: The botulinum toxin cannot be absorbed through intact skin; therefore, covering the mouth, nose, and eyes provides some protection in the event of known presence of the toxin. Aerosolized toxin is significantly degraded after two days. Effective, post-exposure prophylaxis is a problem because of a lack of sufficient doses of antitoxin and the risk of reaction to the antitoxin. The toxin is destroyed by heat (85o C for at least five minutes). Clothing and skin can be cleansed with soap and water and contaminated surfaces with hypochlorite bleach. Person-to-person transmission is not a danger.

TULAREMIA (Francisella tularensis)

Agent: As a naturally occurring plaguelike disease (rabbit fever) of temperate areas of North America and Eurasia, tularemia is a bacterial zoonosis (disease transmitted from animals to humans) caused by the Gram-negative coccobacillus, Francisella tularensis. F. tularensis is highly infectious, requiring an inoculum of 10 or fewer organisms, and remains viable in the environment for weeks in cool weather (Cieslak, & Eitzen, 2000; Johns Hopkins University, 2000). There are two strains of F. tularensis, with type A being the most virulent and likely to be weaponized. It is probable that the Soviet Union produced strains that are resistant to antibiotics and vaccines and there is no reason to think that these remain only in Russian laboratories (Dennis et al., 2001). The release of 50 kilograms of F. tularensis as an aerosol under ideal conditions over a city of five million people would result in an estimated 250,000 incapacitating casualties, including 19,000 deaths (World Health Organization [WHO], 1970). Routes of Infection: Weaponized tularemia can be delivered by aerosol, and infection may be through inhalation of
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the aerosol or exposure (skin, mucous membranes, respiratory tract, or gastrointestinal tract) to contaminated soil, water, food, or animals. Laboratory personnel are at risk if handling dishes or containers with specimens of F. tularensis. Transmission from person-to-person is not known to occur. Incubation: The usual incubation period is 3-5 days with a range of 1-14 days depending on virulence of the infecting strain, size of inoculum, and site of inoculum (Chin, 2000; Dennis et al., 2001). CLINICAL FINDINGS & TREATMENT Signs & Symptoms: Presentation of tularemia is related to the route of introduction and the virulence of the agent. Inhalation is the most likely initial route in BW, but with a major epidemic, other routes would emerge over time. Initial presentation with inhalation is usually the abrupt onset of an acute febrile illness progressing most significantly to pneumonia, but also to pharyngitis, bronchiolitis, pneumonitis, pleural effusion, and hilar lymphadenopathy. Inhalation also commonly produces a primary septicemic syndrome without significant respiratory signs or symptoms and with a high case fatality rate (Chin, 2000; Dennis et al., 2001, Dennis, 2000). Constitutional symptoms of tularemia include abrupt onset of fever, headache, chills, rigors, rhinitis, sore throat, generalized body aches, and low back pain. A dry cough, substernal pain, and chest tightness are common. There may or may not be common signs of pneumonia, such as purulent sputum, hemoptysis, dyspnea, pleuritic pain, or tachypnea. Gastrointestinal disturbances such as nausea, vomiting, and/or diarrhea may occur. If untreated, constitutional symptoms progress and include malaise, anorexia, weight loss, and debility (Dennis et al., 2001). The most likely clinical presentations of BW tularemia are summarized below (1-3), followed by presentation of naturally occurring tularemia (4-6): 1. Typhoidal tularemia is a systemic illness without signs of inoculation or organ localization, presenting with fever, nausea, vomiting, abdominal pain, and
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diarrhea. 2. Septic tularemia is a systemic illness initially presenting similarly to typhoidal, characterized by fever and a systemic inflammatory response, which may include disseminated intravascular coagulation with bleeding, acute respiratory distress syndrome, multi-organ failure, confusion, coma, and shock. 3. Pneumonic tularemia may occur from inhalation or hematogenous spread from a primary site. Manifestations include pharyngitis, bronchiolitis, pneumonitis, pleural effusion, hilar lymphadenopathy, and systemic illness. As previously noted, inhalation also commonly causes systemic illness without signs of respiratory illness. Radiographic evidence may be absent in the early stages of pneumonic constitutional illness; some patients will have minimal or no evidence at any stage. Positive findings include peribronchial infiltrates, bronchopneumonia, pleural effusion, and hilar lymphadenopathy. Pneumonia may become severe leading to respiratory failure and death. 4. Oropharyngeal tularemia results from ingesting contaminated food or water and is characterized by exudative pharyngitis, tonsillitis, and sometimes ulceration of the oropharynx and cervical or retropharyngeal lymphadenopathy. 5. Ulceroglandular tularemia results from direct inoculation (e.g., vector bite or handling infected material) and is characterized by constitutional symptoms followed by a papule at the inoculation site. The papule becomes pustular and ulcerates and is associated with regional lymphadenitis. Oculoglandular tularemia occurs when the eye is contaminated. 6. Glandular tularemia usually is a result of an infected insect bite and is similar to ulceroglandular except there is not a skin ulcer. Diagnosis: Suspicion of attack with tularemia should be aroused by an outbreak of clustered acute undifferentiated febrile illness with atypical pneumonia, pleuritis, and hilar lymphadenopathy. The development of similar illness among laboratory personnel should arouse strong suspicion. Definitive diagnosis is confounded by a lack of widely available means of rapid testing.

F. tularensis grows slowly (14 days) in the laboratory where clinical diagnosis is confirmed by culture. Rapid diagnostic procedures are available through the National Public Health Laboratory Network. Some research or reference laboratories are able to perform antigen detection assays, polymerase chain reaction, immunoblotting, and other specialized techniques (Chin, 2000; Dennis et al., 2001). Differential Diagnosis: The primary differentials in an outbreak are plague, anthrax, legionellosis, Q fever, typhoid, and brucellosis. Numerous differentials exist for individual cases (Dennis, 2000). Treatment: Duration of treatment varies as shown below. Mass casualties or post-exposure (All regimens are for 14 days): Adults: Doxycycline 100 mg po every 12 hours OR ciprofloxacin 500 mg po every 12 hours (the latter is not USDA approved). Children: If 45 kg or larger, give doxycycline 100 mg po every 12 hours and if less than 45 kg, give doxycycline 2.2 mg/kg po every 12 hours OR ciprofloxacin 15 mg/kg po every 12 hours (no more than one gm/24 hours). Human-to-human transmission is unknown; therefore, exposure to an infected person does not warrant treatment. Contained casualties: Adults: Streptomycin 1g IM every 12 hours for 10 days. Gentamicin is an alternative and is given 5 mg/kg/24 hours IM or IV once daily for 10 days. Children: Streptomycin 15 mg/kg IM every 12 hours (up to 2 g/24 hours) or gentamicin 2.5 mg/kg IM or IV every 8 hours (not USDA approved) for 10 days. Other choices are IV doxycycline, IV chloramphenicol, or IV ciprofloxacin for 14-21 days (Dennis et al., 2001). In an outbreak, testing for antimicrobial susceptibility should begin immediately in a biological safety level (BSL) 3 laboratory (state health department) to determine if drug-resistant strains of tularemia are being used. Protection: Isolation of persons with tularemia is not necessary. Standard precautions should be used by hospital and other personnel in contact with patients. Laboratory procedures should be con-

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Table 1. Summary of Selected Class A Biological Warfare Agents Disease & Agent Type Probable BW Route Incubation (days) Signs & Symptoms (incomplete) Febrile flu-like; then severe respiratory distress High fever, prostration; then rash & pustules Fulminate pneumonia; then sepsis Bulbar nerve palsies; descending flaccid paralysis Febrile, flu-like; respiratory; sepsis Treatment of mass casualties Prophylaxis Vaccine

Anthrax: Spore-forming bacteria Smallpox: Virus

Aerosol; no person-toperson Aerosol; then person-toperson

1-7 (or more)

Doxycycline or Ciprofloxacin

Doxycycline or Ciprofloxacin

Available, but short supply

7-17 days

Supportive only

None

Available but short supply

Plague: Bacteria

Aerosol; then person-toperson Aerosol; no person-toperson

1-6 days

Doxycycline or Ciprofloxacin

Doxycycline or Ciprofloxacin

Not now available

Botulism: Toxin from bacteria

2 hours to 8 days

Passive immunization (antitoxin); supportive care Doxycycline or Ciprofloxacin

Passive immunization (antitoxin); supportive care Doxycycline or Ciprofloxacin

Antitoxin in short supply

Tularemia: Bacteria

Aerosol; no person-toperson

1-14 days

Not widely available & gives incomplete protection

ducted in BSL 2 conditions. Bodies should be handled using standard precautions. Contaminated clothing or linens should be disinfected using standard procedures (Dennis et al., 2001). REFERENCES
(Readers are especially referred to the JAMA series on biological weapons, which this writer has consulted heavily. The JAMA articles and other critical articles are *starred below. The JAMA articles are available in their entirety at the Johns Hopkins BioDefense site: http://www.hopkins-biodefense. org/ and the CDC site: http://www.bt.cdc.gov/. Updated information in this article is available at Http://www.baylor.edu/~Charles_Kemp/Infectious _Disease.htm) *Arnon, S.S., Schecter, R., Inglesby, T.V., Henderson, D.A., Bartlett, J.G., Ascher, M.S., Eitzen, E., Fine, A.D., Hauer, J., Layton, M., Lillibridge, S., Osterholm, M.T., OToole, T., Parker, G., Perl, T.M., Russell, P.K., Swerdlow, D.L., & Tonat, K. (2001). Botulinum toxin as a biological weapon: Medical and public health
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