Jeffrey R. Suchard
Biologic weapons are microorganisms or toxins derived from microorganisms that are intentionally used to cause death, disability, or damage to humans, animals, or plants. Although small-scale biologic warfare (BW) has been practiced since antiquity, it is only in the past several decades that such weapons could be mass-produced and have the potential to cause widespread casualties. Even limited releases of BW agents can have major public health impact, causing widespread fear and affecting far more than simply the medical disease, as with the 2001 outbreak from anthrax spore-contaminated mail (1). Biologic weapons may hold particular appeal to terrorists, because the investment is less than for other weapons of mass destruction, although the potential morbidity and mortality remain high.
BW agents fall into three general categories: (1) bacteria, (2) viruses, and (3) toxins. The first two categories are infectious agents, although these diseases are now rarely encountered in clinical medicine (e.g., anthrax, plague, Q fever, viral equine encephalitis) or no longer occur naturally (e.g., smallpox). Although most of the diseases caused by infectious BW agents cannot be contracted by interaction with the patient, some (e.g., pneumonic plague, smallpox, viral hemorrhagic fevers [VHFs]) are able to cause secondary casualties, necessitating careful precautions and patient isolation to prevent uncontrolled outbreaks. Toxins are not transmissible, because they cannot reproduce, effectively making them chemical weapons from a biologic source.
The most efficient method of producing mass casualties from BW agents is by aerosol inhalation. The ideal aerosol particle size to promote deposition in the respiratory tract is 1 to 5 μm, which corresponds to the size of individual bacteria or spores and would not be detectable by sight, smell, or taste. A likely scenario following BW-agent exposure would be an epidemic of persons with a nonspecific acute respiratory syndrome (i.e., fever and cough).
Although chemical weapons produce acute symptoms within minutes to hours, the effects from BW agents may take many hours, days, or sometimes weeks to manifest, depending on the incubation period of the agent. Thus, the epidemic curve of case incidence will be more difficult to detect than for chemical weapons, as patients will present less tightly clustered in time and location. An obvious ploy to avoid early detection would be to release an agent causing an endemic infection (or disease resembling an endemic infection) during its season of peak incidence. For example, in areas where bubonic plague is endemic, an intentional release of Yersinia pestis may elude detection until many more cases develop. Similarly, the early symptoms of inhalational anthrax could easily be missed during influenza season, and it might not be until an unusually high morbidity was evident that a biologic weapon’s attack was suspected. On the other hand, even a single case of smallpox or a VHF in a nonendemic area would immediately raise suspicion of a BW attack.
High-risk potential BW agents include smallpox, anthrax, plague, botulism, tularemia, and several hemorrhagic fever viruses. These agents are easily disseminated or transmitted from person to person, cause high mortality with the potential for major public health impact, and may cause panic and social disruption requiring special action for public health preparedness. Moderate-risk agents include Q fever, brucellosis, the equine encephalitis viruses, ricin, and staphylococcal enterotoxin B. Although other biologic agents could potentially be used as weapons, this chapter will focus on agents of greatest concern for causing mass casualties.
ANTHRAX
Bacillus anthracis is a spore-forming gram-positive rod. Anthrax spores are found in the soil in many parts of the world and mostly cause disease among grazing animals. Human anthrax generally occurs in farmers, ranchers, and among workers handling animal carcasses, hides, hair, and bones. Different clinical forms of anthrax occur depending on the route of exposure. (1) Cutaneous anthrax occurs from direct inoculation of spores into the skin via abrasions and accounts for approximately 95% of human cases. (2) Gastrointestinal anthrax follows the ingestion of insufficiently cooked meat of infected animals. (3) Inhalational anthrax occurs after exposure to aerosolized spores. The inhaled spores are taken into the lymphatic system, where they germinate, reproduce, and cause swelling of the mediastinal lymph nodes. Although this form of anthrax is very rare, it is closely associated with occupational exposures called woolsorter’s disease. Inhalational anthrax is the most likely form of a BW attack, because the spores would be most effectively disseminated by aerosol. In the 2001 anthrax attack in the United States, 11 cases were inhalational (all five fatalities were in this group), and 12 were cutaneous (2).
PLAGUE
Y. pestis is the gram-negative bacillus that causes plague. Like anthrax, plague occurs in different clinical forms. (1) Bubonic plague is the most common naturally occurring form of the disease, transmitted from the bites of infected fleas. (2) Pneumonic plague may be secondary to septicemia during cutaneous plague seeding the lungs, or it may occur primarily from the inhalation of infected respiratory droplets or an intentionally disseminated BW aerosol. Primary pneumonic plague would be the expected form of the disease from an aerosol BW agent release and should occur in the absence of bubonic plague (3).
TULAREMIA
Francisella tularensis is a small, aerobic, gram-negative coccobacillus. Tularemia may occur in (1) ulceroglandular or (2) typhoidal forms, depending on the route of exposure. Ulceroglandular tularemia is more common, occurring after skin or mucous membrane exposure to infected animal blood or tissues. Exposure to aerosolized bacteria may result in typhoidal tularemia with prominent respiratory symptoms (4).
SMALLPOX
Variola, the virus that causes smallpox, is a large DNA-bearing orthopoxvirus with a host range limited to humans. Naturally occurring smallpox was eradicated by a global vaccination campaign in the 1960s and 1970s, yet stocks of the virus still remain in labs in the United States, Russia, and possibly elsewhere. Smallpox remains a significant potential BW threat, because a large portion of the current population has not been immunized and the degree of immunity conferred by remote vaccination is not clear. Transmission occurs through inhalation of droplets or aerosols but may also occur through contaminated fomites (5).
VIRAL HEMORRHAGIC FEVERS
Several diverse RNA viruses produce VHF, an acute febrile illness with increased vascular permeability that cause bleeding manifestations in the more severely affected. The VHF agents of greatest concern are those that may be intentionally disseminated by an aerosol route; these include the Marburg, Ebola, and Hanta viruses and those causing Lassa fever, yellow fever, Rift Valley fever, and Crimean-Congo hemorrhagic fever (6).
BOTULISM
Botulinum toxin would most likely be disseminated through food contamination or by aerosol. Either method would result in the clinical syndrome of botulism (see Chapter 352) (7). Rarely, inhalation botulism from laboratory accidents has occurred.
Several clinical syndromes may occur from exposure to BW agents. Because inhalation of an aerosol is a likely method of exposure, development of an acute respiratory syndrome is common to many agents. Other syndromes include influenza-like illnesses, cutaneous lesions or ulcerations, fever with lymphadenopathy or arthralgias, acute neurologic syndromes (with or without fever), and hemorrhagic diathesis. An individual case of illness from BW agent exposure may be very difficult to detect, because many commonly occurring diseases also fit into such clinical syndromes. It is quite likely that a BW agent attack will be detected by the presence of an unusual epidemiologic curve, when a cluster of patients with unusual findings or with a fulminant clinical course present within a short period of time.
CLINICAL PRESENTATION
The clinical presentation of patients exposed to BW agents will obviously vary depending on the agent.
Cutaneous anthrax results in a black eschar with significant surrounding edema at the site of skin entry. Most lesions will heal spontaneously, although 10% to 20% of untreated cases progress to septicemia and death. Cutaneous anthrax fatalities are rare with antibiotic therapy. Gastrointestinal anthrax causes nausea, vomiting, fever, abdominal pain, and mucosal ulcers, which can cause hemorrhage, perforation, and sepsis; mortality is high (2).
Inhalational anthrax has an incubation period of one to six days. Patients then develop fever, malaise, fatigue, nonproductive cough, and mild chest discomfort. Symptoms may abruptly progress to severe respiratory distress with dyspnea, diaphoresis, stridor, and cyanosis. Bacteremia, shock, metastatic infection (meningitis occurs in approximately 50% of cases), and death follow within 24 to 36 hours. Inhalational anthrax is a mediastinitis, rather than a pneumonia. Chest radiography and computed tomography typically show mediastinal widening and pleural effusions, although pneumonic infiltrates are also reported (2).
Historically, the mortality rate from inhalational anthrax was nearly 100% once symptoms develop, even with antibiotics. Experience from the 2001 outbreak in the United States shows that over half of the patients with inhalational anthrax survived with aggressive supportive care and antibiotic therapy. Earlier hospitalization appeared to correlate with improved outcome (1).
Bubonic plague has an incubation period of 2 to 10 days preceding the onset of fever, malaise, and painful, enlarged regional lymph nodes (buboes). Septicemia may occur and can be accompanied by disseminated intravascular coagulation (DIC) and acral gangrene. Necrosis of the digits and nose seen with septicemic plague is a likely origin of the term “black death” (3).
Pneumonic plague has an incubation period of two to three days. The onset of disease is acute and often fulminant. Patients develop fever, malaise, and cough productive of bloody sputum, rapidly progressing to dyspnea, stridor, cyanosis, and cardiorespiratory collapse. Plague pneumonia is almost always fatal unless treatment is begun within 24 hours of symptom onset.
Ulceroglandular tularemia is characterized by local skin ulceration and associated lymphadenopathy, fever, chills, headache, and malaise. Typhoidal tularemia presents with fever, prostration, and weight loss without adenopathy. Exposure to aerosolized bacteria should result in typhoidal tularemia with prominent respiratory symptoms like a nonproductive cough and substernal chest discomfort. Chest radiographs may show infiltrates, mediastinal lymphadenopathy, or pleural effusions. A temporarily incapacitating infection is most likely (4), but fatalities may occur.
Smallpox has a 12- to 14-day incubation period. Initial symptoms include fever, malaise, and prostration with headache and backache. Oropharyngeal lesions appear first, shedding virus into the saliva. Two to three days after the onset of fever, a papular rash develops on the face and spreads to the extremities. The fever continues as the rash becomes vesicular and then pustular. The pustules scab over and eventually separate, leaving pitted and hypopigmented scars. The mortality rate of smallpox can be as high as 30%, with death most commonly occurring during the second week of the illness (5).
VHF is characterized by fever, malaise, prostration, and hemorrhagic rash. Clinical features, such as the extent of renal, hepatic, and hematologic involvement, vary according to the agent involved. Mortality rates also vary, from <1% for Rift Valley fever up to 50% to 90% for the ebola virus (6).
Botulism results in multiple bulbar nerve palsies and a symmetric descending paralysis, with death occurring from respiratory failure (see Chapter 352). Onset of symptoms can occur within 24 to 36 hours or take several days (7).
DIFFERENTIAL DIAGNOSIS
Familiarity with the expected clinical syndromes produced by BW agents will aid in the differential diagnosis. An acute respiratory syndrome with fever may occur with inhalational anthrax, pneumonic plague, Q fever, hantavirus, and exposure to several other bacterial, viral, and fungal agents, as well as several common, endemic respiratory tract infections (e.g., influenza, the common cold, bronchitis, and community-acquired pneumonia). Patients with inhalational anthrax are more likely to have nausea or vomiting, tachycardia, elevated transaminases, low sodium levels, high hematocrit, low albumin levels, and normal white blood cell counts than those with influenza-like illnesses and community-acquired pneumonia, and patients with an influenza-like illness are more likely to have myalgias, headache, and nasal symptoms (8). The presence of pulmonary infiltrates on chest radiographs does not rule out inhalational anthrax, although anthrax patients are likely to also have an enlarged mediastinum and pleural effusions.
Agents producing cutaneous lesions include anthrax, plague, smallpox, tularemia, and many of the VHFs. Experience from the 2001 outbreak shows that cases of cutaneous anthrax may occur amidst other cases of inhalational anthrax. Small pustules or skin lesions may be found at the site of flea bites in cases of plague, whereas petechial rashes are common with VHFs. The individual lesions of smallpox closely resemble those from herpesvirus infections like chickenpox. Smallpox lesions will all be at the same stage of development, and they are found mostly in a centrifugal distribution (i.e., hand, feet, and face), in distinction from the typical centripetal pattern (chest and abdomen predominance) of chickenpox with patches of lesions at various stages of development.
An acute neurologic syndrome with fever suggests disease from a viral equine encephalitis, although other viral and bacterial BW agents (Q fever, smallpox, typhus) may also have prominent headache, photophobia, and myalgias. A neurologic syndrome without fever from BW agents is likely to be as a result of botulism or other preformed toxins such as domoic acid, saxitoxin, or tetrodotoxin.
Botulism may resemble several other neurologic diseases, including myasthenia gravis, Guillain–Barré syndrome, tick paralysis, poliomyelitis, and organophosphate poisoning. Individual cases of such diseases occur but are rare so the simultaneous presentation of multiple patients with progressive paralysis should immediately suggest an environmental exposure, either to botulinum toxin or an organophosphate chemical warfare agent.
ED EVALUATION
It is likely that the first few cases will be missed but the best defense for detecting an abnormal pattern is an alert and curious clinician. Historical data to collect that might help the investigation include documentation of the time and place of BW agent exposure and if any other persons were potentially exposed and whether they are symptomatic. The time of onset, nature, progression, and severity of symptoms should be noted. The presence of any visualized suspect material (e.g., an unidentified white powder) should be determined, so that samples may later be taken by the proper authorities. Public health authorities may have to help and determine the exposure pattern and epidemiology. Respiratory precautions should be used by all clinicians when BW is in the differential diagnosis.
Physical examination should focus first on the vital signs and assessment of the patient’s cardiopulmonary function and neuromuscular status to determine if emergent resuscitative efforts are necessary. Ideally, all patients should have continuous cardiac and oxygen saturation monitoring, although this may not be possible in a mass-casualty setting. Physical examination should be performed with particular attention to detecting pulmonary rales, diminished breath sounds, the presence and characteristics of any rash, lymphadenopathy, meningismus, and any neurologic deficits.
Patients with pulmonary symptoms should have a chest radiograph, looking for pulmonary infiltrates, mediastinal widening, and pleural effusions. Chest computed tomography was also used in several patients with inhalational anthrax in 2001 (1). Arterial blood gas analysis should also be considered.
Ill patients should have a broad panel of other laboratory tests, which may include a complete blood count, comprehensive metabolic panel, DIC screening, serologies, blood cultures, and Gram staining, depending on the suspected agent and clinical status of the patient. Laboratory personnel should be informed of the suspected pathogen(s). Antibiotic-susceptibility testing should be performed on all bacterial isolates, as strains may be deliberately modified by terrorists to enhance antibiotic resistance. Patients with suspected smallpox should have vesicle fluid from lesions cultured, and scrapings should be sent for electron microscopic analysis. Spirometry and arterial blood gas analysis should be performed on patients with suspected botulism to establish their ventilatory capacity.
Plague can be diagnosed by various staining techniques, immunologic studies, or culturing the organism from blood, sputum, or lymph node aspirate. Y. pestis appears as a “safety-pin” bipolar coccobacillus. Chest radiographs in pneumonic plague show patchy or consolidated bronchopneumonia. Leukocytosis with bandemia is common, as are markers of low-grade DIC and elevations of bilirubin and the hepatic transaminases. Diagnosing tularemia is often difficult, as the organism is hard to isolate by culture and the symptoms are nonspecific.
KEY TESTING
• Will vary depending on presenting clinical syndrome, but typically includes:
• Chest x-ray, if pulmonary symptoms
• CBC
• CMP
• Cultures: blood, sputum, lesion
• Pulmonary function tests (FVC, NIF) if patient has neuromuscular weakness
ED MANAGEMENT
Advanced life-support measures are instituted as necessary for patients requiring resuscitation. Unlike with chemical weapons, patient decontamination is rarely an issue with biologic weapons. Most BW agents, with the notable exception of anthrax spores, are degraded by sunlight and desiccation and do not survive well in the environment for more than 1 to 2 days. In the scenario of a covert BW agent release, by the time patients present for medical care several days after exposure, decontamination is futile and will only delay care. Even with an acute, efficiently dispersed release of a biologic weapon via aerosol (including anthrax spores), little surface contamination is produced. Clothing removal and a soap-and-water shower will remove 99.99% of any remaining organisms on the skin (9), and this may occur in the patients’ home to reduce the strain on medical resources. Any grossly visible contamination with a BW agent, if present, should be removed by water irrigation, washing the skin with a sporicidal/bactericidal solution (e.g., 0.5% sodium hypochlorite, a 1:10 dilution of household bleach), and a final water rinse (9). If patient decontamination is performed at a healthcare facility, patients should remove their clothing and place it into sealed and labeled plastic bags, wash their hands, and shower thoroughly with soap and water.
For patients who present with symptomatic illness after a covert attack, decontamination is unlikely to be helpful, but healthcare provider protection is critical. Standard infection-control measures (gloves, gown, mask with eye shield) provide adequate protection from most agents. However, unless the offending BW agent is already known, it must be assumed that the patients have a potentially transmissible disease such as smallpox, pneumonic plague, or a VHF, which require airborne, contact, and droplet precautions. Patients with respiratory symptoms or a rash should be placed in a private negative-pressure room, and medical personnel caring for the patient should wear well-fitting N95 high-efficiency particulate air-filter masks until the results of a more complete evaluation can guide treatment (9). If multiple casualties present at the same time, space limitations may require that patient isolation occurs in groups rather than individually.
Current treatment recommendations for anthrax rely primarily on ciprofloxacin and doxycycline (2) and are shown in Table 349.1. The currently recommended duration of therapy after bioterrorist exposure to anthrax is 60 days, to protect against the delayed development of inhalational anthrax which might occur.
TABLE 349.1
Antibiotic Treatment of Anthrax, Plague, and Tularemiaa,b
Effective vaccines against anthrax are available (10). Anthrax vaccine adsorbed (AVA) is used in the United States, which consists of a sterilized filtrate of an avirulent bacterial strain. As with any vaccine, local reactions to AVA occur in a minority of recipients (up to 20% with mild, local reactions), and self-limited systemic reactions occur even more rarely (<1.5%); serious adverse events are very rare. The dosage schedule for AVA is 0.5 mL subcutaneously at 0, 2, and 4 weeks and 6, 12, and 18 months, with yearly boosters. For emergency use after confirmed exposure, the vaccine is given as soon as possible and again at 2 and 4 weeks, along with prophylactic antibiotics.
Respiratory droplet precautions are necessary in pneumonic plague until the patient has received antibiotics for at least 48 hours and shows clinical improvement. Antibiotic choices are similar to anthrax, with a high reliance on ciprofloxacin and doxycycline (Table 349.1). Antibiotics must be initiated early after exposure, because waiting for symptoms will result in extremely high mortality (3). Antibiotic treatment for tularemia is virtually the same as for plague (4).
The treatment of smallpox is largely supportive. Persons exposed to smallpox but without clinical disease should also be isolated and observed for the development of fever and rash for 17 days; this observation period may occur at home. The antiviral drug cidofovir may be beneficial in preventing smallpox, if administered early after exposure, but is probably no better than postexposure vaccination (5).
Vaccination before smallpox exposure or within 4 days after exposure significantly ameliorates subsequent illness. Vaccination against smallpox carries some risk for adverse reactions. The two most serious reactions are postvaccinal encephalitis and progressive vaccinia. Postvaccinal encephalitis occurs in about three cases per million primary vaccinees. Forty percent of cases are fatal, and some survivors are left with permanent neurologic sequelae. Progressive vaccinia can occur in immunosuppressed individuals and is treated with vaccinia immune globulin.
Most VHF agents carry the risk of secondary infection through droplet aerosols, and careful patient isolation is critical. Ribavirin has been used for some VHFs, but supportive care is the mainstay of therapy (6).
The mainstay of botulism therapy is supportive care, with ventilation if necessary. An equine antitoxin for passive immunization is available in the United States from the Centers for Disease Control and Prevention (CDC) through contact with local and state health departments. The antitoxin prevents worsening of disease caused by the toxin serotypes responsible for foodborne illness (A, B, and E) but does not reverse established effects. An investigational heptavalent antitoxin against serotypes A through G has been developed (7).
CRITICAL INTERVENTIONS
• Wear gloves, gown, eye shield, and an N95 high-efficiency particulate air-filter mask when evaluating and treating patients with possible exposure to transmissible BW agents.
• If possible, place patients with respiratory symptoms or a rash in a private negative-pressure room.
• Contact appropriate local public health and law enforcement authorities in cases of suspected BW agent exposure.
DISPOSITION
All cases of suspected exposure to BW agents should be reported to local public health and law enforcement authorities. Unless the patient contracted their illness through unintentional exposure in a research laboratory, each case is potential evidence of a criminal bioterrorist act, requiring contact also with law enforcement agencies such as the local Federal Bureau of Investigation field office. Consultation with a local physician resource familiar with BW agents, such as an infectious disease specialist, military physician, toxicologist, poison control center, or the CDC (770-488-7100) is recommended.
Patients with known or suspected acute exposures to infectious BW agents are likely to be asymptomatic and require no emergent interventions. Such patients require initiation of appropriate postexposure prophylactic antibiotics and/or vaccinations, depending on the agent involved. Asymptomatic patients acutely exposed to anthrax or plague may be discharged home with antibiotic prescriptions, if adequate follow-up can be arranged through the local public health agency or their private physicians.
Patients exposed to smallpox may require quarantine, which should be coordinated with the assistance of public health and law enforcement agencies. Patients acutely exposed to toxin weapons might be asymptomatic at presentation but still require admission for a period of observation depending on the agent involved. Botulinum toxin exposure, for example, mandates admission to monitor for development of respiratory failure.
Unless part of a mass-casualty incident, all patients known or suspected to have illness from BW agent exposure should be admitted, with the level of care dependent on clinical severity. Outpatient management of cutaneous anthrax may be considered for patients without systemic toxicity, who can tolerate oral antibiotics, and in whom outpatient follow-up can be assured. Isolation precaution will be necessary for patients with pneumonic plague, smallpox, and many of the VHFs. In mass-casualty situations, admission may need to be more selective and reserved for patients who cannot tolerate outpatient therapy but who are not moribund.
Common Pitfalls
• Lack of familiarity with likely BW agents and the clinical syndromes they produce.
• Failure to appreciate that some BW agents are transmissible and others are not and that isolation requirements will vary.
• Failure to institute appropriate postexposure prophylaxis among patients with plausible exposure scenarios.
• Failure to have a plan with established contacts to hospital, local public health, infectious disease and other experts.
REFERENCES
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2. Inglesby TV, O’Toole T, Henderson DA, et al. Anthrax as a biological weapon 2002: Updated recommendations for management. JAMA. 2002;287:2236–2252.
3. Inglesby TV, Dennis ST, Henderson DA, et al. Plague as a biological weapon: Medical and public health management. JAMA. 2000;283:2281–2290.
4. Dennis DT, Inglesby TV, Henderson DA, et al. Tularemia as a biological weapon: Medical and public health management. JAMA. 2001;285:2763–2773.
5. Henderson DA, Inglesby TV, Barlett JG, et al. Smallpox as a biological weapon: Medical and public health management. JAMA. 1999;281:2127–2137.
6. Borio L, Inglesby T, Peters CJ, et al. Hemorrhagic fever viruses as biological weapons: Medical and public health management. JAMA. 2002;287:2391–2405.
7. Arnon SS, Schechter R, Inglesby TV, et al. Botulinum toxin as a biological weapon: Medical and public health management. JAMA. 2001;285:1059–1070.
8. Kuehnert MJ, Doyle TJ, Hill HA, et al. Clinical features that discriminate inhalational anthrax from other acute respiratory illnesses. Clin Infect Dis. 2003;36:328–336.
9. Keim M, Kaufmann AF. Principles for emergency response to bioterrorism. Ann Emerg Med. 1999;34:177–182.
10. Friedlander AM, Pittman PR, Parker GW. Anthrax vaccine: Evidence for safety and efficacy against inhalational anthrax. JAMA. 1999;282:2104–2106.