Bioterrorism, once limited to military-directed biowarfare, has developed considerable prominence due to increasing world threats and the anthrax outbreak in the United States in 2001. Clinicians and public health officials have become more aware of these rare diseases as local, state, and national programs increase detection, therapeutic options, and responses to the causative agents.
Early recognition of bioterrorism agents can be difficult since the early prodromal phase of most agents is similar and often indistinguishable from other causes of febrile respiratory illnesses. Febrile respiratory illnesses and respiratory failure can signify a natural outbreak (e.g., severe acute respiratory syndrome, plague, tularemia, or a novel strain of influenza) or a bioterrorism event. Most cases of febrile respiratory illnesses admitted to intensive care units (ICUs) are caused by community-acquired pneumonia, and respiratory failure and acute respiratory distress syndrome (ARDS) subsequently develop in up to 11% of these community-acquired pneumonia cases. Although most cases of community-acquired pneumonia are recognizable, the rare and contagious causes (e.g., plague) can have a large impact on the health care and public health systems. Thus, early recognition of these infections becomes important for two reasons. First, early infection control and public health preparedness strategies must be implemented to reduce spread to health care workers and the public, particularly in the acute stages of disease when patients are most contagious and most likely to undergo aerosol-generating diagnostic procedures. Second, intentional release of these agents is a bioterrorism event, and public health and law enforcement authorities are now trained to provide immediate investigation and support. Therefore, early suspicion of a bioterrorism or outbreak event, along with early protective measures and public health contact, will reduce the likelihood of transmission to health care workers, visitors, patients, and the community.
Bioterrorism involves the deliberate release of viruses, bacteria, or their products (e.g., toxins) to cause morbidity and mortality in humans, animals, or plants. All bioterrorism agents are naturally occurring organisms or toxins that can cause sporadic disease under ordinary circumstances, but on occasion, an agent has been manipulated to increase resistance to antibiotics or increase organism virulence. This chapter provides an overview of the major agents of bioterrorism and highly lethal disease outbreaks along with clues for detection, steps for public health response, and infection control interventions.
Bioterrorism: A Historical Perspective
Bioterrorism has existed for centuries, from ancient Mesopotamia to current times. The initial goal was to incapacitate the enemy through death or stir panic in the population, leading to surrender. For example, in the 14th century, the Tartars catapulted plague-infected corpses into Kaffa, leading to disease spread and defeat of the city (also starting the second wave of the Black Death in Europe). In the New World, smallpox-contaminated blankets may have been distributed by early settlers to natives in an effort to overcome the siege of Fort Pitt. However, bioterrorism took form in the last 100 years with extensive biowarfare units in World War I and II. Notably, Unit 731 of the Japanese army in World War II used anthrax, plague, cholera, and typhoid on Chinese prisoners with high mortality, but the transition to the battlefield was less successful. The Cold War saw both the United States and the former Soviet Union develop bioweapon stockpiles that have since been dismantled. However, over the past 25 years, there has been an increase in individual-initiated bioterrorism, culminating in the anthrax outbreak in 2001 that used the postal service for distribution, causing 22 cases.
Basics of Bioterrorism
The route of transmission of bioterrorism agents can be by air (e.g., aerosol generation), food (e.g., botulism), or water (e.g., gastroenteritis agents). Delivery can mimic naturally occurring disease, especially if the food or water supply to the public has been targeted. However, with aerosol generation, rapid increases in new cases are seen in low-risk populations, as seen with the anthrax cases in 2001.
Because most bioterrorism agents are infectious diseases, presentation of disease is usually covert, with health care workers seeing the initial cases. Particularly with contagious diseases such as plague pneumonia, smallpox, and viral hemorrhagic fevers, secondary infections may propagate the event, allowing it to last weeks to months, stressing the capacity of the health care system. Chemical and explosive forms of terrorism, however, are often overt and immediately known, with first responders in the field evaluating the initial cases and subsequent cases rarely following the initial event. Therefore, epidemiologic evidence (e.g., an increase in pneumonia or a specific rash) may be the initial clue that there has been a bioterrorism event.
The Centers for Disease Control and Prevention (CDC) has separated bioterrorism agents into three broad categories (A, B, and C) based on ease of spread and severity of illness. Category A agents are considered the highest risk to the public and national security for the following reasons: (1) easy person-to-person spread; (2) high mortality; (3) major public health impact causing panic and social disruption; (4) requirement for specific and specialized public health emergency response (e.g., public prophylaxis or protective equipment) ( Table 40-1 ). Category B agents are moderately easy to spread and result in moderate morbidity but low mortality in those affected. Fewer specific public health responses are required ( Table 40-2 ). Category C agents are considered future or potential threats because they are easily available and can have a high mortality, but they have not been documented or engineered successfully ( Table 40-3 ). Although all of these agents can potentially cause serious disease, the category A agents, along with select category B agents, would be seen by clinicians and have the greatest impact on the public and health care system. These agents present initially with a nonspecific prodromal phase but with epidemiologic clues that may separate them from other less threatening causes of a febrile respiratory illness. Tables 40-4 to 40-8 list the unique features associated with category A agents: clinical syndromes, preferred diagnostic methods, radiologic features, treatment, and infection control and respiratory protection.
|Definition: Category A agents have the potential to be easily disseminated, have higher contagiousness, have high morbidity and mortality, and require increased public health preparedness|
|Anthrax ( Bacillus anthracis )|
|Smallpox (variola major)|
|Plague ( Yersinia pestis )|
|Tularemia ( Francisella tularensis )|
|Botulism ( Clostridium botulinum toxin)|
|Viral hemorrhagic fevers (filoviruses [e.g., Ebola, Marburg] and arenaviruses [e.g., Lassa, Machupo])|
|Definition: Category B agents are moderately easy to disseminate, carry a high morbidity but low mortality, and require public health laboratory and surveillance enhancements|
|Glanders ( Burkholderia mallei )|
|Melioidosis ( Burkholderia pseudomallei )|
|Psittacosis ( Chlamydophila psittaci )|
|Q fever ( Coxiella burnetii )|
|Ricin toxin from Ricinus communis (castor beans)|
|Brucellosis ( Brucella species)|
|Epsilon toxin of Clostridium perfringens|
|Food safety threats (e.g., Salmonella species, Escherichia coli O157: H7, Shigella )|
|Staphylococcal enterotoxin B|
|Definition: Category C agents have the future potential for engineering for easy dissemination or high mortality|
|Influenza (novel strain)|
|Typhus disease ( Rickettsia prowazekii )|
|Viral encephalitis (alphaviruses [e.g., Venezuelan equine encephalitis, eastern equine encephalitis, western equine encephalitis])|
|Water safety threats (e.g., Vibrio cholerae, Cryptosporidium parvum )|
|Agent||Unique Clinical Finding/Syndrome|
|Smallpox||Poxlike rash with systemic inflammatory response syndrome leading to septic shock|
|Plague||Sudden acute respiratory failure and sepsis|
|Tularemia||Patchy alveolar pneumonia with sepsis|
|Botulism||Descending flaccid paralysis|
|Viral hemorrhagic fevers (e.g., Ebola)||Sepsis with bleeding diathesis, massive fluid loss from diarrhea and vomiting|
|Agent||Laboratory Diagnostic Method|
|Anthrax||Culture of organism from blood or body fluid. Serology for uncultured cases. BSL 3 required at state and regional public health laboratory.|
|Smallpox *||PCR of pox lesion. EM confirmation, viral isolation from skin/fluid in BSL 4 laboratory (CDC only).|
|Plague||Culture of organism from blood or sputum. Serology for uncultured cases. BSL 3+ at state or regional public health laboratory.|
|Tularemia||PCR. Difficult to culture. Performed at local, state, and regional public health laboratories.|
|Botulism||Detection of toxin in blood or stool. Toxin identification (A-E) performed at state or regional public health laboratories.|
|Viral hemorrhagic fevers (e.g., Ebola) *||Nucleic acid detection by RT-PCR. Viral culture from blood/body fluid only performed under BSL 4 containment.|
|Agent||Radiologic Pulmonary Findings|
|Anthrax||Widening of mediastinum (rapid enlargement on serial imaging), unilateral or bilateral hilar node enlargement. Peribronchovascular thickening and pleural effusion. May also have patchy alveolar opacities, but extensive consolidation uncommon. CT may show hyperattenuating lymphadenopathy|
|Smallpox||Patchy alveolar opacities|
|Plague||Patchy, potentially nodular bilateral opacities that may coalesce to more diffuse alveolar disease resembling ARDS. Cavitation uncommon. Lymph node enlargement possible, but inconsistent|
|Tularemia||Multifocal bronchopneumonia that may cavitate, or lobar pneumonia. Pleural effusion and lymphadenopathy not uncommon|
|Botulism||Normal to lower lung volumes|
|Viral hemorrhagic fevers (e.g., Ebola)||Few available data. Chest radiography may be normal. Diffuse alveolar opacities with areas of dense consolidation; widened mediastinum, pleural effusions also reported. American hantavirus-pulmonary edema pattern with interlobular septal thickening despite hypovolemia; may progress to bilateral air space opacities|
|Agent||Primary Treatment||Secondary Treatment|
|Anthrax||Ciprofloxacin 15 mg/kg IV twice daily |
Raxibacumab 40 mg/kg IV, one dose
|Clindamycin 900 mg IV three times daily|
|Plague||Gentamicin 5 mg/kg IV/IM daily |
Streptomycin 1 g IM daily
|Ciprofloxacin 15 mg/kg IV twice daily |
Chloramphenicol 15 mg/kg IV four times daily
|Smallpox||Supportive care |
Vaccinia Immune Globulin (unproven in smallpox; approved for use in vaccine recipients with progressive vaccinia infection)
|Tularemia||Gentamicin 5 mg/kg IV/IM daily |
Streptomycin 1 g IM daily
|Doxycycline 100 mg IV twice daily |
Ciprofloxacin 15 mg/kg IV twice daily
Chloramphenicol 15 mg/kg IV four times daily
|Viral hemorrhagic fevers||Supportive care |
Ribavirin for Lassa fever
|Investigational agents: Monoclonal antibodies, convalescent serum, antiviral agents|
|Botulism||Trivalent antitoxin (A, B, E) |
* Obtained through the CDC only (see www.bt.cdc.gov/agent/smallpox/vaccination/vig.asp ).
|Agent||Isolation||Baseline Protection||Protection in Higher Risk Procedures|
|Viral hemorrhagic fever||Contact||N95 mask with full face shield or PAPR; full skin coverage with fluid-resistant or impermeable gown or coveralls||Current CDC guidelines available at www.cdc.gov/vhf/ebola/hcp/procedures-for-ppe.html|
|Smallpox||Airborne and contact||N95 mask||N95 mask or PAPR|
|Plague *||Droplet and contact||N95 mask||N95 mask or PAPR|
CDC Category A Agents
Anthrax is caused by Bacillus anthracis, a spore-forming gram-positive rod . B. anthracis is a normal soil inhabitant; the organism can multiply if soil conditions are favorable. Otherwise, B. anthracis persists for long periods in a spore form, resistant to decontamination and environmental extremes. From the soil, B. anthracis spreads to herbivores, such as cattle, as they come into contact with spore-containing soil through grazing.
Human anthrax largely arises through contact with animal products, such as animal skins, where B. anthracis persists as spores. In 2001 in the United States, 22 cases of anthrax were due to an act of bioterrorism through the postal system, placing anthrax on the forefront of bioterrorism. Apart from this outbreak in 2001, anthrax remains rare in the United States, with most endemic and epizootic cases seen in the Middle East. Most cases in the United States arise through the handling of animal products, such as the 2006 cases associated with animal hide drum skins imported from Africa.
Disease begins when B. anthracis spores are introduced subcutaneously or via ingestion or inhalation. After introduction to oxygen and a protein-rich environment, the spores convert to the vegetative (bacillus) form and initiate replication. Exotoxin secretion leads to local spread, edema, hemorrhage, and tissue necrosis. The anthrax capsule, edema factor toxin, and lethal factor toxin act in concert to drive disease.
Three clinical disease syndromes are seen with anthrax: cutaneous, gastrointestinal, and inhalational. Cutaneous anthrax is the most common form worldwide and has an incubation period of 7 to 14 days after inoculation of spores into the subcutaneous space. This is followed by a small, painless papule that can be pruritic. The papule enlarges and develops a central vesicle, followed by erosion into a painless black eschar ( Fig. 40-1 ). Marked edema (mediated by anthrax edema toxin) characteristically surrounds the lesions, and there may be regional lymphadenopathy, with systemic symptoms of fever and malaise. The hands, arms, face, and neck are the areas most commonly affected.
With inhalational anthrax, spores that reach the distal airways are transported by inflammatory monocytes or dendritic cells to the mediastinal lymph nodes, with replication followed by onset of disease. The incubation period averages 1 to 7 days, followed by clinical symptoms of a nonspecific febrile illness, often mimicking influenza. However, within 24 hours, disease rapidly progresses with the development of respiratory failure, hemorrhagic mediastinitis, necrotizing pneumonia, shock, multiorgan failure, and death (see Table 40-4 ). Shock and multiorgan failure can develop rapidly, and along with hemorrhagic mediastinitis ( Fig. 40-2 ), are the clinical hallmark of anthrax.
Gastrointestinal anthrax is rare and is usually seen in family clusters following the consumption of undercooked meats of infected animals. The disease begins with development of bowel edema, followed by mesenteric lymphadenitis and necrosis, and then rapid progression to shock and death.
Mortality for cutaneous anthrax is low (<1% in treated patients; approximately 20% in untreated), while inhalational anthrax can carry a mortality of 89%. The inhalational cases from 2001 in the United States had a lower mortality of 45%.
Although the initial symptoms of inhalational anthrax are nonspecific, some early findings distinguish inhalational anthrax from influenza-like illness or community-acquired pneumonia. Compared with patients who presented with community-acquired pneumonia in a retrospective study, patients with inhalational anthrax were more likely to have nausea or vomiting, tachycardia, elevated transaminases, hyponatremia, and normal white blood cell counts. From these observations, a scoring system was devised that had approximately 80% sensitivity and 80% specificity for distinguishing inhalation anthrax cases.
Diagnosis of anthrax is best performed by isolation of B. anthracis from cultures of blood, sputum, pleural fluid, cerebrospinal fluid, or skin (see Table 40-5 ). Clinicians should notify the laboratory of suspected anthrax, because spores can form during culture, leading to spread to laboratory workers if not properly handled. Additionally, any suspect case of anthrax should involve the public health laboratories for confirmation and strain typing. Polymerase chain reaction (PCR) and rapid enzyme-linked immunosorbent assays (ELISAs) are available and have good sensitivity and specificity.
The radiographic imaging findings associated with anthrax include a widened mediastinum consistent with hemorrhagic mediastinitis, the hallmark of inhalation anthrax (see Fig. 40-2 ) (see Table 40-6 ). However, during the 2001 outbreak, other findings, including patchy alveolar opacities, lobar consolidation, and pleural effusions, were also reported. In each of these cases, a widened mediastinum was present on chest radiograph, with follow-up confirmation performed by computed tomography scan.
Treatment, Prophylaxis, and Prognosis
Treatment includes supportive therapy and antibiotics (see Table 40-7 ). Intensive care management with early and appropriate volume resuscitation and lung-protective low tidal volume ventilation should be used if indicated. Antibacterial treatment includes ciprofloxacin, doxycycline, or if the isolate is susceptible, penicillin. In 2001, rifampin, clindamycin, or vancomycin in combination with ciprofloxacin was used, because the isolate was resistant to penicillin. Pleural drainage or a central nervous ventriculoperitoneal shunt may also be used in individual cases. Corticosteroids are widely used to reduce edema and hemorrhage, especially when cutaneous anthrax affects the head and neck, threatening airway integrity, but there are very limited data on their efficacy.
Raxibacumab, a human IgG1 monoclonal antibody directed against B. anthracis protective antigen (whose role is to bind host cells and deliver anthrax edema factor and lethal factor to the host cell cytoplasm), has been effective for the treatment of anthrax in animal models, with improved survival at 14 and 28 days. In 2012, raxibacumab was approved by the U.S. Food and Drug Administration (FDA) for the treatment of inhalation anthrax and, as such, should be used in combination with antibiotics and initiated when the diagnosis of inhalation anthrax is suspected or confirmed. An anthrax vaccine, prepared from the culture filtrate of an attenuated strain of B. anthracis, is approved for humans by the FDA, but its use has been limited, due to the need for multiple doses, local side effects, and efficacy concerns, and it is currently reserved for military personnel. Exposure to aerosolized spores requires prophylaxis with either ciprofloxacin or doxycycline in adults; amoxicillin is a second-line agent in children and pregnant women. The recommended duration of postexposure prophylaxis is 60 days, because none of the antibiotics eradicate spores, which may germinate weeks after exposure.
Anthrax is not transmitted from an infected person, because B. anthracis is in the vegetative form during clinical infection, and only spores are transmissible (see Table 40-8 ). Contact with infected animal carcasses and animal products (especially hides) can result in infection; wearing appropriate personal protective equipment (PPE) is indicated when handling these materials or when exposed to other suspected contaminated objects.
Variola virus is the causative agent of smallpox and is a member of the Poxviridae family. Smallpox was eradicated worldwide in 1977, but now has regained interest because of its potential as a bioterrorism agent. Smallpox was widely endemic and at one point accounted for more than 10% of all deaths worldwide. Smallpox is very contagious; approximately half of all unvaccinated household contacts contract disease. After global eradication of smallpox was declared in 1977, routine vaccination for smallpox ceased worldwide. Due to an increasing unvaccinated population, along with its contagiousness and ability to be transmitted by aerosol, smallpox is a CDC category A bioterrorism agent. Only two stockpiles of the virus are known to remain (at the CDC and the Russian State Research Center).
Smallpox exists in two forms, variola major and variola minor. Variola major is the most common form of smallpox, has more severe disease with an extensive rash and fever, and carries a higher mortality (around 20% in the unvaccinated). Variola minor is less common and less severe, with mortality estimated at less than 1%. Variola minor has a genetic sequence very similar to that of variola major; quantitative differences in gene expression are thought to account for the variable mortality between the major and minor forms.
Smallpox infection begins when the virus enters the respiratory tract, replicates locally, and is transported to regional lymph nodes. Viremia follows with spread to lymphoid organs, followed by further viral replication and progressive symptoms. Variola major presents in five major clinical categories: ordinary, modified, flat, hemorrhagic, and variola sine eruptione.
Ordinary type infection accounted for more than 70% of cases when smallpox was endemic. After an incubation period of 10 to 14 days, disease (pre-eruptive phase) manifests with high temperature, severe headache, and malaise. The pre-eruptive phase can last 2 to 4 days and is followed by the eruptive phase, which is characterized by rash. The lesions first appear as small erythematous macules on the mucous membranes, tongue, and face (herald spots). The lesions spread in a centrifugal fashion, with macules evolving into papules, then vesicles, and finally the classic pustules (pox) ( Fig. 40-3 ) by day 5 to 7 of the rash (see Table 40-4 ). Fever usually resolves during the eruptive phase but may persist after the pustules develop. Crusting and healing begin by day 14 of the rash.
The modified type of variola major is similar to the ordinary type except that the rash is more rapid but less severe; this type was common in vaccinated individuals. The flat type had pustules that remained flat and confluent and often was seen in children.
The hemorrhagic type was rare but severe, with the lesions and mucous membranes becoming hemorrhagic. This type was more common in pregnant women and led to multiorgan failure within a few days.
The variola sine eruptione type is associated with fever but no rash; this type was often seen in previously vaccinated individuals.
Diagnosis is largely clinical, with the acute onset of fever followed by the characteristic rash of deep-seated vesicles or pustules (see Table 40-5 ). For laboratory diagnosis, variola- and orthopox-specific PCR assays are performed at the CDC or World Health Organization–sponsored laboratories. If a case of smallpox is suspected, information on diagnosis, infection control, and public health measures are available at emergency.cdc.gov/agent/smallpox/response-plan/index.asp .
Radiographic imaging findings in smallpox are limited largely to diffuse alveolar opacities from an inflammatory response associated with the primary infection (see Table 40-6 ). Lobar opacities may be seen and are most often associated with secondary bacterial pneumonia.
Treatment, Prophylaxis, and Prognosis
Treatment is largely supportive, with some evidence that cidofovir, an antiviral with activity against cytomegalovirus, has activity in animal models (see Table 40-7 ). Aggressive ICU support, including volume resuscitation, vasopressor support, and low tidal volume ventilation should be used for severe cases. Vaccination as soon as possible after exposure may reduce the severity of illness and is the mainstay for reducing spread and controlling disease in the community. Vaccination administered within 4 days of exposure can still provide protection. Passive immunization with vaccinia immune globulin is FDA approved for patients suffering progressive vaccinia infection after vaccination; whether it has efficacy in treating smallpox has not been determined.
Mortality varies with the clinical category. The ordinary type carries a mortality from multiorgan failure and hypotension of around 20%, with the flat and hemorrhagic types carrying a higher mortality and the modified and sine eruptione types carrying a much lower mortality. Complications include secondary bacterial skin infections and pneumonia, along with encephalitis, orchitis, and extensive scarring of the skin and corneas.
Spread is through contact with infected lesions or respiratory secretions and thus full PPE, including respiratory protection, gown, gloves, and face shield, is required. CDC guidelines recommend airborne isolation with use of an N95 particulate respirator or a powered air-purifying respirator for respiratory protection, and all health care workers involved in care of a smallpox patient must be vaccinated against smallpox (see Table 40-8 ). If smallpox is suspected, public health officials must be contacted immediately.
Yersinia pestis is the etiologic agent of plague and has caused multiple pandemics, despite being a recently evolved pathogen. Plague is a zoonosis, primarily affecting rodents; humans and other animals (especially domestic cats) are accidental hosts. The natural ecosystem of Y. pestis depends largely on the flea-rodent interaction, with seasonal variation based on environmental conditions that favor large rodent populations. Infected fleas bite their rodent hosts, inoculating the rodent. Mortality in these animals is lower than in nonrodent mammals, and disease is passed from infected rodent to flea and the life cycle continues. Y. pestis is transmitted to humans by bites from rodent-infected fleas, scratches or bites from infected animals, exposure to infected humans, or bioterrorism. Bites by infected fleas are the most common mode of transmission; squirrels, rabbits, domestic and wild cats, and prairie dogs are the most common sources of infected fleas. Large rodent or other animal die-offs, particularly in more susceptible species, may herald a large epidemic in nature. Plague is found worldwide; in the United States endemic disease is concentrated in the western states; most likely because of introduction of Y. pestis– infected rats through the ports of San Francisco, Los Angeles, and Seattle in the late 19th century.
Three clinical syndromes are associated with plague: bubonic plague (80% to 90% of cases), septicemic plague (10% of cases), and pneumonic plague (very rare). After an incubation period of 2 to 7 days, symptoms usually arise, which differ depending on the clinical syndrome. The incubation period is prolonged and asymptomatic, due to multiple mechanisms used by Y. pestis to minimize early innate immune responses and inflammation, including specific inhibition of inflammasome activation.
In bubonic plague, a sudden onset of fevers, chills, and headache is followed by pain and swelling in the regional lymph nodes proximal to the site of the bite or scratch. This lymph node (bubo) is characterized by intense tenderness with erythema and edema but without fluctuation ( Fig. 40-4 ). Without treatment, disease disseminates, leading to pneumonia, meningitis, sepsis, and multiorgan failure. The development of secondary plague pneumonia is important to detect, because such patients are highly contagious.