key: cord-0040455-un5xucwh
authors: Sandrock, Christian
title: Bioterrorism
date: 2015-04-03
journal: Murray and Nadel's Textbook of Respiratory Medicine
DOI: 10.1016/b978-1-4557-3383-5.00040-3
sha: 65f1a7d29db0f33353ce9c2bf906323532f268a8
doc_id: 40455
cord_uid: un5xucwh

nan

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. 1, 2 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. 3, 4 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. 2, 5 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 aerosolgenerating 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. 6, 7 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. 7 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 has existed for centuries, from ancient Mesopotamia to current times. 7, 8 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). 9 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. 7, 8 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. [7] [8] [9] 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. 7, 8, 10 

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. 11 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. 2, 7 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. 12 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. 7, 8, 13, 14 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) 7, 8, 13, 14 (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) . 7 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) . 14 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. 

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 sporecontaining soil through grazing. 15, 16 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. 10 Apart from this outbreak in 2001, anthrax remains rare in the United States, with most endemic and epizootic tis and necrosis, and then rapid progression to shock and death. 17 Mortality for cutaneous anthrax is low (<1% in treated patients; approximately 20% in untreated), while inhalational anthrax can carry a mortality of 89%. [15] [16] [17] The inhalational cases from 2001 in the United States had a lower mortality of 45%. 10

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. 18 From these observations, a scoring system was devised that had approximately 80% sensitivity and 80% specificity for distinguishing inhalation anthrax cases. 18 Diagnosis of anthrax is best performed by isolation of B. anthracis from cultures of blood, sputum, pleural fluid, cerebrospinal fluid, or skin 16, 19 (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. 16, 19 The radiographic imaging findings associated with anthrax include a widened mediastinum consistent with hemorrhagic mediastinitis, the hallmark of inhalation anthrax 15, 16 (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. 16 In each of these cases, a widened mediastinum was present on chest radiograph, with follow-up confirmation performed by computed tomography scan.

Treatment includes supportive therapy and antibiotics 17, 19 (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. 2 Antibacterial treatment includes ciprofloxacin, doxycycline, or if the isolate is susceptible, penicillin. 17, 19, 20 In 2001, rifampin, clindamycin, or vancomycin in combination with ciprofloxacin was used, because the isolate was resistant to penicillin. 17, 19, 20 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. 17 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 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. 16 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. 15, 16 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. 15, 16 

Three clinical disease syndromes are seen with anthrax: cutaneous, gastrointestinal, and inhalational. [15] [16] [17] 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. 15 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). 17 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 lymphadeni-ceased worldwide. 26 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). 27, 28 Smallpox exists in two forms, variola major and variola minor. 24, 25 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. 24, 25 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. 24, 25 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). 24, 25, 29 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; improved survival at 14 and 28 days. 21, 22 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. 23 Exposure to aerosolized spores requires prophylaxis with either ciprofloxacin or doxycycline in adults; amoxicillin is a second-line agent in children and pregnant women. 16, 19 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 7,16 (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. 24 Smallpox was eradicated worldwide in 1977, but now has regained interest because of its potential as a bioterrorism agent. 24, 25 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. 24, 25 After global eradication of smallpox was declared in 1977, routine vaccination for smallpox * 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. 24, 25 

Spread is through contact with infected lesions or respiratory secretions and thus full PPE, including respiratory protection, gown, gloves, and face shield, is required. 32 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 32 (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. 9 Plague is a zoonosis, primarily affecting rodents; humans and other animals (especially domestic cats) are accidental hosts. 33, 34 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. 33, 34 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. 33, 34 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. 35 

Three clinical syndromes are associated with plague: bubonic plague (80% to 90% of cases), septicemic plague (10% of cases), and pneumonic plague (very rare). 33, 34 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. 36 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. 33, 34 this type was common in vaccinated individuals. 24, 25, 29 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. 24, 25, 29 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 24, 30 (see Table 40 -5) . For laboratory diagnosis, variola-and orthopox-specific PCR assays are performed at the CDC or World Health Organization-sponsored laboratories. 24, 30 If a case of smallpox is suspected, information on diagnosis, infection control, and public health measures are available at http://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 24,31 (see Table 40 -6). Lobar opacities may be seen and are most often associated with secondary bacterial pneumonia.

Treatment is largely supportive, with some evidence that cidofovir, an antiviral with activity against cytomegalovirus, has activity in animal models 24,31,32 (see Table 40-7) . Aggressive ICU support, including volume resuscitation, vasopressor support, and low tidal volume ventilation should be used for severe cases. 1 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. 26 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. doxycycline; most are also susceptible to ciprofloxacin, although there is less clinical experience with this drug in plague. 38 Chloramphenicol is preferred for cases of meningitis due to its ability to cross the blood-brain barrier. Because most cases of primary pneumonia lead to multiorgan failure and acute lung injury, volume resuscitation, vasopressor support, and low tidal volume ventilation are indicated. 2 There is no evidence of benefit from corticosteroids. Postexposure prophylaxis includes ciprofloxacin and doxycycline orally, with trimethoprim-sulfamethoxazole (if the isolate from the index case is susceptible) or gentamicin for children and pregnant individuals. 38

Due to the high rate of transmission of plague via aerosols, all patients should be on strict airborne isolation until at least 48 hours of antibiotics have been given 34 (see Table  40 -8) . Infection control measures include airborne isolation, including negative-pressure ventilation. Appropriate PPE, including an N95 mask or powered air-purifying respirator, should be worn by all personnel in contact with a patient with suspected or confirmed pneumonic plague.

Tularemia is caused by the gram-negative bacterium Francisella tularensis and is a zoonotic disease; humans are accidental hosts. 39 F. tularensis is found throughout the Northern Hemisphere in a wide variety of wild and domesticated species and the organism persists in nature. Humans become infected by the bites from infected vectors (ticks and flies), the handling of infected animals, ingestion of improperly prepared animal meat, animal scratches and bites, the drinking of contaminated water, or inhalation of an aerosol of the organism from the environment or in a bioterrorism event. [39] [40] [41] Human-to-human transmission has not been described.

Six distinct clinical syndromes have been observed with tularemia: ulceroglandular, glandular, typhoidal, pneumonic, oropharyngeal, and oculoglandular. 42, 43 Ulceroglandular disease accounts for approximately 60% to 70% of cases. 42, 43 After an incubation period of 2 to 10 days, there is an abrupt onset of fevers, chills, headache, and malaise. Most patients have a single papuloulcerative lesion with a central eschar and associated tender lymphadenopathy (Fig. 40-5) . In glandular disease, lymph nodes enlarge without the characteristic lesion (about 15% of cases). 42, 43 Pneumonic tularemia results from primary inhalation or hematogenous spread from typhoidal tularemia, and this is expected to be the main clinical presentation in a bioterrorism event with tularemia. 40 The incubation period tends to be shorter in these cases, with the rapid onset of pneumonia. Respiratory failure and ARDS develop rapidly (see Table 40 -4).

Typhoidal tularemia is rare and is seen with or without pneumonia; patients present with a febrile illness followed by sepsis without the glandular disease. 43 Oropharyngeal tularemia results when undercooked infected meat or water 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.

In septicemic plague, acute fever is followed by sepsis without a bubo. 33, 34 Additional symptoms such as nausea, vomiting, and diarrhea also complicate septicemic plague. Sepsis, disseminated intravascular coagulation, and multiorgan failure develop quickly.

In pneumonic plague, most cases are secondary (hematogenous) from bubonic or septicemic plague, but primary pneumonic plague can also develop after exposure to infected humans, animals, or aerosols in an intentional bioterror attack. 33, 34 Initial cases in outbreaks of primary pneumonic plague have a very short incubation period of hours to a few days, followed by sudden onset of fever and cough, rapid onset of respiratory failure with ARDS, and death (see Table 40 -4).

The clinical diagnosis of plague can be difficult, but exposure to animals in an endemic area is an important clue to seek. 33, 34, 37 (see Table 40 -5) . During intentional dissemination, multiple cases of severe, rapidly progressive pneumonia may be the first sign of an attack. Laboratory diagnosis is primarily by culture of the sputum or blood because Y. pestis grows well on routine laboratory media. Serology and rapid diagnostic testing by ELISA or PCR is also available but is used primarily in field testing. 33, 34, 37 On chest radiographs, a sudden and diffuse alveolar filling process is seen consistent with acute lung injury 33, 34 (see Table 40 -6) . Additional mediastinal lymphadenopathy may be present, as may pleural effusion in later stages. Lobar opacities are less common.

The primary agent for antibacterial therapy of plague has long been considered streptomycin but, based on its limited availability, gentamicin or doxycycline is preferred 33, 34 (see Table 40 -7). Most isolates are susceptible to gentamicin and 

Clostridium botulinum, a gram-positive, spore-forming, obligate anaerobe, is the bacterium that produces and excretes botulinum toxin. 48, 49 This neurotoxin is responsible for the clinical disease known as botulism and is the only category A agent that is a toxin. Seven serotypes of botulinum toxin exist, A through G, and are produced by different strains of C. botulinum. All botulinum neurotoxins act as proteases that cleave proteins on synaptic vesicles or the presynaptic plasma membrane of the neuromuscular junction and cholinergic autonomic synapses. The resulting inability to release neurotransmitters and disruption of neurotransmission account for the clinical findings. Serotypes A, B, and E predominate in human disease, although any serotype can cause disease. 48, 49 Serotypes C and D are predominately found in animal populations. Botulinum toxin is extremely potent, with the median lethal oral dose estimated to be 1 ng/kg, although the lethal dose may be two to three times higher if exposure is by inhalation. 48, 49 Disease presents from four potential sources: food-borne, wound, infant, and intentional. 48, 49 Food-borne disease presents in outbreaks and is often associated with homecanned foods, such as fruits, vegetables, and fermented fish. Wound botulism has been associated with intravenous and subcutaneous injection of black tar heroin, mostly of Mexican origin. Infant botulism is seen sporadically in some western states, likely from spore acquisition from soil or raw honey, with toxin production in the gastrointestinal tract. Finally, intentional release during a bioterrorism event may lead to oral ingestion or inhalation of the toxin.

Botulism begins with the acute onset of bilateral cranial neuropathies with rapidly descending weakness (see Table  40 -4) . No fever is present and mental status is not affected. 48, 49 The cranial neuropathies are usually symmetrical and often begin with oculomotor dysfunction. However, asymmetrical cranial nerve dysfunction has been reported. 50 Diplopia, dysphagia, ptosis, and facial weakness are the most common early complaints. 48, 49 In food-borne exposure, there may also be gastrointestinal symptoms, including nausea and vomiting. In infant botulism, poor feeding and lethargy may be the only symptoms. Food-borne botulism usually has an onset of symptoms 12 to 36 hours after exposure; symptoms rapidly progress over the next 12 hours. If botulism is not suspected and treatment is not started rapidly, weakness and paralysis of respiratory muscles ensues, requiring mechanical ventilatory support. 50 Once the muscles of respiration are involved, mechanical support may be required from 1 to 3 months. 50 Since the toxin-mediated blockade of neuromuscular transmission is reversible, full recovery can be expected although recovery may be prolonged.

Early and prompt diagnosis is essential because respiratory support is often required and early treatment may alter the extent of progression of weakness. Thus the clinical findings of cranial nerve palsies, particularly in the appropriate clinical setting (e.g., heroin use, or ingestion of the same is ingested and is associated with fever, pharyngitis, and cervical lymphadenopathy. 43 Oculoglandular tularemia results from direct inoculation from contaminated fingers or accidental exposure. Conjunctival swelling and erythema, and regional lymphadenopathy may be present.

Culturing F. tularensis is suboptimal in a few respects: specific culture media (with cysteine) is required, growth is slow, and cultures are hazardous to laboratory personnel 44, 45 (see Table 40 -5 and Chapter 17, Table 17 -5). PCR detection of F. tularensis is rapid, is not hazardous, and has a reported sensitivity of approximately 75% and high specificity (see Table 17 -5). PCR-positive fresh samples should be submitted to a reference or public health laboratory for confirmation.

Radiographic imaging studies show patchy opacities bilaterally, lobar disease, and hilar adenopathy 46 (see Table  40 -6). There can also be pleural effusions and a miliary pattern, and hilar and mediastinal adenopathy.

Similar to the treatment for plague, gentamicin is the treatment of choice for tularemia 45, 47 (see Table 40 -7); doxycycline or ciprofloxacin may be used as second-line therapy. For meningitis, chloramphenicol is preferred. Postexposure prophylaxis with doxycycline or ciprofloxacin may be efficacious, with trimethoprim-sulfamethoxazole or amoxicillin for children and pregnant patients. 45 ,47 ICU management of tularemia includes supportive care and low tidal volume ventilation for ARDS. The overall mortality for tularemia is around 4%, but is thought to be higher in aerosolized disease that causes pneumonia or typhoidal tularemia. 42, 43 

Tularemia is not spread by human-to-human contact, so once the diagnosis is confirmed, respiratory isolation can be discontinued 43, 47 (see Table 40 -8) . Rules about reporting tularemia to public health officials varies across North America but pneumonic or typhoidal cases, particularly if thought to be secondary to a bioterrorism event, must be reported. viruses causing Bolivian (Machupo virus) and Argentine (Junin virus) hemorrhagic fever are in the family Arenaviridae. The Crimean-Congo and Rift Valley fever viruses belong to the Bunyaviridae family. Only the Filoviridae (Ebola and Marburg viruses) and Arenaviridae are listed as category A agents. The Filoviridae family serves as a classic template for viral hemorrhagic fevers and is largely discussed here. 54 Marburg virus has a single species, while Ebola virus has five different species that vary in virulence in humans. 55, 56 Transmission appears to be through contact with blood or secretions of nonhuman primates and infected individuals. People have become infected after handling primate products, after consuming nonhuman primate meat, or after exposure to symptomatic patients, including in hospitals. Several cases have presented due to exposure in laboratories. The use of hemorrhagic fever viruses as bioterrorism agents has also been postulated, largely based on their high contagiousness in aerosolized primate models. 55, 56 The animal reservoir for these viruses was initially thought to be wild primates, but has recently been tentatively identified to be bats, which transmit the infection to nonhuman primates in the wild.

The clinical manifestations of both Marburg and Ebola viruses are similar in presentation and pathophysiology. 56, 57 The incubation period after exposure to either virus is usually 5 to 10 days, but may be as long as 19 days. Clinical disease begins with the abrupt onset of fever, chills, malaise, severe headache, nausea, vomiting, diarrhea, and abdominal pain. 56, 57 Over the next few days, symptoms worsen to include prostration, stupor, and hypotension. In some patients, coagulation becomes impaired with the appearance of increased conjunctival and soft tissue bleeding. In some of the reported outbreaks, hemorrhage can be massive in the gastrointestinal and urinary tracts and, in rare instances, the lung. 56, 57 In the outbreak of Ebola virus disease centered in Guinea, Liberia, and Sierra Leone in 2014, hemorrhage was not prominent; instead, the clinical picture was dominated by voluminous diarrhea. 57a,57b The onset of maculopapular rash on the arms and trunk may be a very distinctive sign (Fig. 40-6 ). Along with volume depletion and hypotension, multiorgan failure can develop and often leads to death (see Table 40 -4). Outbreaks and cases have largely been described in developing countries where critical care resources are limited, thus experience with mechanical ventilation and the development of ARDS is not well documented. Case-fatality rates have ranged from 40% to 90%. 54,56,57,57b,58 

It is important to suspect the diagnosis of a viral hemorrhagic fever in order to initiate supportive care before the onset of shock, to involve the public health department, and to implement infection control measures. Viral hemorrhagic fevers should be suspected in cases of an exposed laboratory worker or an acutely ill traveler from an endemic area (i.e., central or west Africa), or in the presence of characteristic clinical findings in the context of other cases in the community, suggesting a bioterrorism attack. 56 The presence of high temperature, malaise and joint pain, conjunctival bleeding and bruising, vomiting and diarrhea, food as another person with botulism) should prompt consideration of botulism (see Table 40 -5) . Laboratory diagnosis is by toxin detection or organism isolation. 45 Detection of toxin in blood or stool is most reliable. 51 The growth of C. botulinum from a stool or wound sample with the corresponding clinical findings can also confirm the diagnosis. Electromyography will also support the diagnosis if toxin and organism isolation is unsuccessful. There are no specific radiologic changes seen with botulism. Low lung volumes on chest radiographs may be seen but are not specific (see Table 40-6) .

Supportive care is the cornerstone of management of botulism. Monitoring for impending respiratory failure and providing mechanical ventilation when needed are the highest priorities. An equine trivalent antitoxin (against serotypes A, B, and E) is available from state public health departments and the CDC, and is directed at neutralization of toxin that has not yet entered cells. Botulinum antitoxin cannot reverse botulinum intoxication 48, 49, 52 (see Table  40 -7). While the antitoxin is widely used in cases of botulism, its efficacy has only been inferred and, since the available antitoxin is derived from immunized horses, anaphylaxis and/or serum sickness can develop in 9% to 20% of recipients. A human-derived antitoxin is available but only for infant botulism. Human monoclonal antibodies have been prepared that neutralize multiple types of botulinum toxins, and these provide the potential for use in adults with a lower risk of adverse effects than the equine antiserum. 53 In wound botulism, after wound drainage, antibiotic administration is useful; penicillin or clindamycin are the drugs of choice. 48, 49 In food-borne and inhalation botulism, because the disease results from exposure to the toxin and not from infection, antibiotics are not efficacious. In all cases of botulism, routine monitoring of forced vital capacity is recommended, with early intubation if the vital capacity falls below 10 mL/kg (approximately 30% predicted). There is no direct prophylaxis for exposure, but in the setting of high-risk threats, a vaccine directed against serotypes A and E is available and has been largely used in the military. 52 Patients die of botulism due to respiratory failure without ventilatory support or from complications during critical care.

Because botulism is a toxin-based disease, no specific infection control measures are required 48 (see Table 40 -8) . An exposure to spores or toxin should be followed by decontamination, although secondary infections or intoxication in medical personnel have not been reported.

The hemorrhagic fever viruses include multiple geographically distributed viruses, including Ebola and Marburg viruses, and the viruses causing Rift Valley fever, Bolivian, Argentine, and Crimean-Congo hemorrhagic fevers, Lassa fever, yellow fever, and dengue fever. [54] [55] [56] Ebola and Marburg viruses are in the family Filoviridae; Lassa virus and the patients mandate stringent precautions to protect personnel. Placement of the patient in an isolation room with strict procedures for handling waste is essential to protect healthcare and other personnel [55] [56] [57] (see Table 40 -8) . Equipment should be dedicated to that individual, and all higher risk procedures must be done with full PPE. Any suspected case of viral hemorrhagic fever should immediately involve the public health officials and infection control department, because public health interventions and outbreak investigation are essential to reduce spread of disease within the community and to investigate any potential bioterrorism attack.

Glanders is caused by the gram-negative bacterium Burkholderia mallei. 63 It is primarily a disease of horses; humans become infected through broken skin or droplet inhalation. Naturally occurring human infection is rare, but occupational cases (principally in horse veterinarians) are seen sporadically. In bioterrorism, aerosolization is the anticipated method of exposure. Glanders can present as an acute or chronic skin infection, but with aerosolization, rapid pneumonia and/or sepsis can result. 63 Diagnosis is by culture, but B. mallei can be misclassified by some automated systems as a Pseudomonas species. Treatment includes supportive care as well as systemic antibiotics such as a third-generation cephalosporin, imipenem, or ciprofloxacin. 63 Human-to-human transmission has not been detected, but universal precautions with droplet isolation for respiratory cases are recommended. Any suspect case should prompt immediate notification of the public health department.

Melioidosis is caused by the gram-negative bacterium Burkholderia pseudomallei. 63, 64 Unlike B. mallei, this bacterium has a natural reservoir in the soil and contaminated water and is spread through direct contact or inhalation. Thus disease predominates during the rainy season. In bioterrorism, aerosolization would lead to a clinical picture of pneumonia or melioidosis sepsis. 63, 64 With melioidosis, the incubation period can be highly variable, with some cases presenting acutely, some having extended incubation periods, and others remaining asymptomatic. [63] [64] [65] Sepsis with multiple metastatic foci develops in most symptomatic cases, eventually progressing to multiorgan failure. Diagnosis is by culture using routine methods. Treatment involves imipenem or a third-generation cephalosporin, followed by a 20-week treatment with doxycycline and trimethoprimsulfamethoxazole for eradication of metastatic foci. 63, 64 

Psittacosis is caused by Chlamydophila psittaci, an intracellular bacterium routinely associated with birds such as parrots, cockatiels, and canaries. Psittacosis presents confusion, and progression to shock and multiorgan failure should raise suspicion of a viral hemorrhagic fever. Laboratory diagnosis consists of viral nucleic acid detection by PCR 56 (see Table 40 -5) .

Radiologic changes include a diffuse alveolar process consistent with acute lung injury 56,57 (see Table 40 -6). As the disease progresses, the alveolar process can become dense as alveolar hemorrhage develops. Pleural effusions may also be present.

Current patient management includes supportive care, including agressive volume resuscitation, and a lungprotective strategy with low tidal volume ventilation if ARDS is part of the disease course 55-57 (see Table 40-7) . Recent experiments in nonhuman primates have established therapeutic efficacy of a combination of three monoclonal antibodies to the Ebola glycoprotein. 59 This provides proof of principle that specific treatment of Ebola infection is possible, and the humanized monoclonal antibodies may progress to availability for human use. With the arenavirus group (Lassa, Junin, and Machupo viruses) and the Bunyaviridae (Crimean-Congo hemorrhagic fever and Rift Valley fever viruses), ribavirin is recommended. [55] [56] [57] The recent finding that Ebola replication requires the Abelson tyrosine kinase (C-abl), and that C-abl kinase inhibitors (currently used for treatment of chronic myelogenous leukemia and certain other malignancies) block Ebola replication in vitro suggests an additional potential treatment approach. 60 If a health care worker is exposed, there is no approved postexposure prophylaxis; infection control and occupational health personnel should be involved immediately. Two distinct vaccines protect nonhuman primates against Ebola challenge and are entering initial trials in humans. 61, 62 

Transmission is by the droplet route, and the very high viral loads found in blood, diarrhea, and secretions in Ebola 

Brucellosis is caused by a number of species within the genus Brucella. Disease is common in livestock workers, particularly in areas of poor sanitation, where Brucella is found in domesticated animals. 71 Brucella is a category B agent due to its low mortality and prolonged incubation period. 72 After exposure through ingestion of contaminated food or intentional aerosolization, symptoms develop after a few weeks to months. Initially fevers persist irregularly over weeks to months, followed by arthralgias, gastrointestinal symptoms, and possibly endocarditis. 71 Diagnosis is suspected with a plausible history of exposure, with isolation of the organism by blood culture. However, growth is slow, so all cultures should be kept for 4 weeks if the diagnosis is suspected. Treatment is with doxycycline for up to 6 weeks, for children, treatment is with trimethoprimsulfamethoxazole for children. 71

The Clostridium species produce multiple toxins; epsilon toxin is produced by Clostridium perfringens types B and D. 73 The toxin acts on host cell membranes, producing pores that cause nonselective permeability. Clostridium perfringens uses the toxin to gain access into the bloodstream from the gut. However, in bioterrorism, intentional release via ingestion or inhalation of the toxin alone is most likely. 74 Based on data from animals, rapid ingestion or inhalation would cause diffuse tissue edema and be manifested as central nervous system dysfunction (weakness, ataxia, confusion), pulmonary edema (shortness of breath, cough, bronchospasm, respiratory failure), nausea, vomiting, tachycardia, and hypotension. 73 Diagnosis requires clinical suspicion consistent with a bioterrorism attack; the toxin can be detected by ELISA. Treatment is supportive, with penicillin if C. perfringens is present in addition to the toxin. 73 Food Safety Threats (e.g., Salmonella Species, Escherichia coli O157:H7, Shigella)

Enteropathogenic gram-negative bacteria, such as Escherichia coli, Salmonella, and Shigella, constitute a large group of agents that make up food supply threats. 75 Public health officials are familiar with these bacteria from numerous episodes of food contamination that lead to localized outbreaks and large product recalls. In an intentional release, these agents would produce widespread gastrointestinal symptoms leading to significant morbidity but with low mortality. After an incubation period of 3 to 7 days, there would be abdominal cramping, nausea, vomiting, and diarrhea. The diarrhea may be voluminous and bloody. 75 Diagnosis is by stool culture of the agents. An aggressive public health investigation usually yields the initial agent, because bioterrorism resembles a point-source outbreak. 76 Treatment is intravenous hydration as needed and, with some agents (Salmonella, Shigella), antibacterial therapy with ciprofloxacin. 76 nonspecifically, and most cases go undiagnosed. 66, 67 As a category B bioterrorism agent, C. psittaci can cause morbidity with low mortality. Intentional aerosolization would lead to multiple cases of nonspecific "atypical pneumonia" with cough, fever, and headache. 66, 67 Diagnosis has historically been difficult, but sensitive PCR techniques offer the potential for rapid, specific diagnosis (see Chapter 17; Table  17 -1). Treatment is with doxycycline, a macrolide, or ciprofloxacin. Mortality is low at 1% in treated cases. 66, 67 Universal precautions are required for patient care, although an N95 mask and coveralls are recommended for environmental decontamination.

Q fever is a zoonotic disease caused by Coxiella burnetii. Cattle, sheep, and goats are the primary reservoirs of C. burnetii; this disease is found worldwide. 68 Coxiella burnetii usually does not cause clinical disease in animals, but organisms are found in milk, urine, feces, amniotic fluids, and placenta. The organisms are resistant to heat and drying, and can cause infection by inhalation of environmental dust contaminated with dried placental material, birth fluids, and excrement. The incubation time is 1 to 2 weeks, after which clinical illness develops in approximately 50% of infected persons. 68 Q fever is characterized by high temperatures (often greater than 40°C/104°F), severe headache, myalgia, sore throat, nonproductive cough, nausea, vomiting, diarrhea, abdominal pain, and chest pain. 68, 69 Pneumonia develops in 30% to 50% of patients with symptomatic infection.

One percent to 2% of people with acute Q fever die of the disease. 68, 69 In a small percentage of those infected, chronic Q fever (infection that persists for more than 6 months), including endocarditis, develops; up to 65% of persons with chronic Q fever die of the disease. Diagnosis of Q fever depends on serologic testing, most commonly using the indirect immunofluorescence assay (see Chapter 17; Table  17-5) . 68, 69 The antibiotic treatment of choice for acute Q fever is doxycycline 100 mg twice daily for 15 to 21 days. 68, 69 Fluoroquinolones may be effective alternatives.

Ricin is a potent biologic toxin (toxic protein) derived from castor beans (Ricinus communis) during manufacture of castor oil. 70 Ricin acts as a toxin by the inhibition of protein synthesis; 0.2 mg (1/5000th of a gram) is thought to be the lethal dose. Symptoms begin within 4 to 12 hours after exposure. Systemic effects of ricin poisoning depend on route of exposure and exposure dosage. Signs and symptoms from oral ingestions include vomiting and profuse diarrhea; in addition, there may be fever, myalgia and arthralgia, hallucinations, and seizures. 70 Hypovolemic shock and multiorgan failure may intervene, and represent the likely cause of death. 70 Based on animal experiments, after an inhalational exposure, symptoms in humans are expected to include cough, respiratory distress, and bronchoconstriction. Influenza-like symptoms (fever, myalgia, and arthralgia) may be seen, as can hypotension, respiratory failure, and multiorgan failure. 70 Few symptoms and signs exist to separate ricin intoxication from other causes of respiratory failure, although excessive diaphoresis has been reported and would be unusual in other causes. No present with nonspecific symptoms. 86 Figure 40 -7 outlines an approach to early isolation, testing, and involvement of institutional infection control and public health officials in cases of acute febrile illness. Upon admission, cases of acute febrile illness and respiratory failure should undergo initial diagnostic testing, including pretreatment Gram stain, respiratory culture, and urine antigen testing for Legionella. If an etiologic agent is identified on initial screening and clinical findings (i.e., gram-positive diplococci with a lobar pneumonia on radiograph), targeted treatment should be initiated, with appropriate isolation precautions based on the pathogen. However, if an agent is not easily identified, patients should be placed in isolation and further diagnostic testing should be performed. If multiple cases with similar symptoms or a case with an uncommon epidemiologic link is determined, patients should be isolated and public health officials should be contacted. If specific clinical features subsequently arise, then directed diagnostic testing should be performed. If no clear etiology is detected, further evaluation is warranted with invasive and expanded testing.

Staphylococcal enterotoxin B is a toxin produced by Staphylococcus aureus commonly associated with food poisoning. Symptoms of food poisoning include vomiting and diarrhea several hours after ingesting food. 77 Naturally occurring, it is rarely lethal. The clinical presentation would depend on the route of administration. Oral administration (poisoning of food or water supplies) would present as vomiting and diarrhea. 77 If inhaled, respiratory failure with neurotoxic effects may be seen. 77

In 2009-2010, a new variant of H1N1 influenza A virus emerged and caused a global influenza pandemic. 78 Treatment strategies and interventions used in this H1N1 pandemic have impacted the planning for responses to highly infectious agents, including agents of potential bioterrorism. The administration of antivirals, particularly oseltamivir, reduced hospitalizations and death when administered within 48 hours of symptom onset. [79] [80] [81] [82] In critically ill patients with pandemic H1N1 influenza, oseltamivir was associated with increased survival compared with no treatment (75% versus 58%) with a median time of treatment initiation 4 days from symptom onset. 79 However, treatment initiated within 5 days after symptom onset was still associated with increased survival compared with no therapy. 80, 81 Similar findings were seen in children and other at-risk individuals, including immunocompromised and pregnant women. 82 Therefore the importance of early distribution and administration of therapy, including the rapid dissemination of therapy guidelines for practitioners, must be a cornerstone of any bioterrorism response.

Additional adjunctive therapies during the H1N1 pandemic also became a cornerstone of response, including the use of extracorporeal membrane oxygenation, which was used in some patients with ARDS (predominately single organ failure) resulting from pandemic H1N1 influenza. Small observational studies suggested a mortality benefit in patients who received extracorporeal membrane oxygenation. 83, 84 However, extracorporeal membrane oxygenation is only performed at specialized centers and is resource intensive, thus requiring regional and statewide coordination in order to ensure success. Additional therapies, such as corticosteroids, inhaled nitric oxide, N-acetyl cysteine, and proning were also administered without established benefit. 85

The recognition of a case of a disease related to a bioterrorism event relies on a high index of suspicion by the clinician. However, recognition may be difficult in the early stages of disease, in that many of the category A agents casualties with an immediate critical area response. In contrast, because some of the category A agents are spread by contact and respiratory transmission, new cases will be seen after the initial outbreak. As these cases progress, the cumulative number of cases with severe respiratory illness will increase, potentially stressing the critical care system and leading to a sustained need for emergency mass critical care (EMCC) for weeks to months. Sustained EMCC can lead to depletion of critical care resources, such as mechanical ventilators, specially trained staff, antibiotics and antivirals, and ICU beds. 5 Thus, the unique issues associated with sustained EMCC have led to improved planning for a response to a bioterrorism or emerging infectious diseases outbreak. 89, 90 Recent consensus statements have recommended special critical care preparedness to include ICU capacity expansion, critical care resource storage, and the coordination of critical care across communities to a regional and statewide level. 89, 90 Capacity for critical care should be approximately three times normal ICU capacity, with all critically ill patients to be located in acute care hospitals (less severely ill patients will be diverted to alternative sites within the community). Each hospital should have enough supplies for 10 days for each critically ill patient along with plans to have expanded care by noncritical care specialists in the case of a shortage. 91 ICU admission should be limited to the most severely ill. Most importantly, establishment of a triage mechanism is required for the allocation of scarce resources in sustained EMCC, with the most identified critical resource being mechanical ventilation and medical oxygen. 92 This triage mechanism shifts the focus of critical care from optimal care of the individual to optimal care for the population and would identify critically ill patients who may not get specific scarce resources during a period of limited supply in an outbreak. It would include inclusion and exclusion criteria for ICU admission along with a triage scoring mechanism for patient assessment. The Sequential Organ Failure Assessment score is valuable, due to its value in sequential assessments and its ease of use given its lower reliance on laboratory data. Additional triage scoring systems may be warranted in future outbreaks as disease and outbreak conditions change.

Although bronchoscopy generates aerosols that increase the risk of transmission, bronchoscopy should be performed with appropriate protection of personnel in these cases, because identification of the etiology of illness is an essential component of an appropriate public health response. The public health authorities and the institutional infection control should be contacted as early as possible when clinical suspicion of bioterrorism arises or when diagnostic tests do not yield results.

Once a bioterrorism agent is suspected, the diagnosis is confirmed by specialized public health laboratories. Initial cases must meet a case definition for the suspected agent (see http://emergency.cdc.gov/bioterrorism/casedef.asp) before there is further evaluation. In order to meet the case definition, at least one critical distinguishing feature must be met along with other clinical and laboratory features.

Involvement of institutional infection control, microbiology, and public health experts must be initiated as early as possible. They should be notified when there is one of four conditions: (1) a clinical or epidemiologic feature suggestive of bioterrorism (see Table 40 -4), (2) an unexpected clinical link or increase in number of cases (e.g., pneumonia with respiratory failure), (3) an extensive workup of a febrile respiratory illness fails to reveal an organism and an infectious disease is suspected, or (4) transmission of disease to health care workers. Hospital infection control will assist in isolation and health care worker protection, and the hospital microbiology laboratory should be notified of suspected pathogens, allowing for worker protection and targeted testing of samples. 1, 87 Finally, public health involvement allows a broader diagnostic testing, including subtyping and resistance testing. If the agent is a novel or emerging pathogen, as seen with severe acute respiratory syndrome or avian influenza, early public health involvement allows for rapid laboratory testing, epidemiologic investigation, case definition, and community prevention.

The basic infection control requirements are outlined in Table 40 -8. Anthrax and botulism are the only category A agents that are not contagious and do not require respiratory protection for caregivers. If the number of cases exceeds the health care capacity for isolation, patient cohorting and accessory isolation measures can be used. Finally, higher risk procedures should be limited in these cases (Table 40-9) . Aerosol-generating procedures are most common in ICU patients, and reducing unnecessary risky procedures reduces patient and health care worker risk. However, these procedures should be performed if needed. Appropriate PPE should be worn by health care workers at all times and, if worn properly, reduces the risk of disease transmission. 88

Acts of conventional terrorism, such as with explosive devices or chemical attacks, result in a single point of mass 

■ Bioterrorism and emerging infectious diseases present unique and different diagnostic and treatment challenges. ■ 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; and (4) requirement for specific and specialized public health emergency response (e.g., public prophylaxis or protective equipment). Diseases caused by these agents initially present with a nonspecific prodrome that develops into severe disease with specific epidemiologic hallmarks. ■ Category A agents are anthrax, smallpox, plague, tularemia, botulism, and viral hemorrhagic fevers (e.g. Ebola, Lassa). ■ Category B agents are diverse but carry lower morbidity and mortality, with some having few to no pulmonary manifestations. ■ Category C agents have the potential for future use as bioterrorism agents. ■ Early recognition relies on the astute clinician, with early involvement of public health and institutional infection control personnel to reduce spread to health care workers and the community. ■ Aggressive supportive care is the mainstay for all critically ill patients infected with a bioterrorism agent. Targeted therapy is under development. ■ For inhalational anthrax, raxibacumab, a human IgG1 monoclonal antibody directed against B. anthracis protective antigen, has been approved for use and should be used in combination with antibiotics when

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Severe febrile respiratory illnesses as a cause of mass critical care

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Open lung biopsy in early-stage acute respiratory distress syndrome

Pathogenesis and sepsis caused by organisms potentially utilized as biologic weapons: opportunities for targeted intervention

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Plague: a review of its history and potential as a biological weapon

Update: investigation of bioterrorism-related anthrax

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Detection and early identification in bioterrorism events

Pulmonary disease from biological agents: anthrax, plague, Q fever, and tularemia

Category C potential bioterrorism agents and emerging pathogens

Anthrax: from antiquity and obscurity to a front-runner in bioterrorism

Anthrax-associated shock

Clinical features that discriminate inhalational anthrax from other acute respiratory illnesses

Recognition and management of anthrax-an update

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How to reduce the impact of "low-risk patients" following a bioterrorist incident: lessons from SARS, anthrax, and pneumonic plague

Raxibacumab for the treatment of inhalational anthrax

Anthrax vaccines

Smallpox: clinical and epidemiologic features

Vaccines for preventing smallpox

Smallpox as a bioterrorist weapon: myth or menace?

The looming threat of bioterrorism

Smallpox: the basics

Development and experience with an algorithm to evaluate suspected smallpox cases in the United States

Smallpox as a biological weapon: medical and public health management. Working Group on Civilian Biodefense

Plague as a biological weapon: medical and public health management. Working Group on Civilian Biodefense

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The Yersinia virulence effector YopM binds caspase-1 to arrest inflammasome assembly and processing

Plague gives surprises in the first decade of the 21st century in the United States and worldwide

Resistance of Yersinia pestis to antimicrobial agents

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Subversion of host recognition and defense systems by Francisella spp

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Tularemia: history, epidemiology, pathogen physiology, and clinical manifestations

Tularemia: current diagnosis and treatment options

New approaches to diagnosis and therapy of tularemia

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Tularemia as a biological weapon: medical and public health management

Botulism: cause, effects, diagnosis, clinical and laboratory identification, and treatment modalities

Clinical predictors of respiratory failure and long-term outcome in black tar heroin-associated wound botulism

Botulism diagnostics: from clinical symptoms to in vitro assays

Botulism: the many faces of botulinum toxin and its potential for bioterrorism

Neutralizing human monoclonal antibodies binding multiple serotypes of botulinum neurotoxin

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Hemorrhagic fever viruses as biological weapons: medical and public health management

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Ebolavirus and other filoviruses

Doing Ttoday's work superbly well-treating ebola with current tools

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Productive replication of Ebola virus is regulated by the c-Abl1 tyrosine kinase

Chimpanzee adenovirus vaccine generates acute and durable protective immunity against ebolavirus challenge

Antibodies are necessary for rVSV/ZEBOV-GP-mediated protection against lethal Ebola virus challenge in nonhuman primates

Burkholderia mallei and Burkholderia pseudomallei: the causative micro-organisms of glanders and melioidosis. Recent Patents Anti-Infect Drug Disc

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The atypical pneumonias: clinical diagnosis and importance

Psittacosis: a flu like syndrome

Q fever: epidemiology, diagnosis, and treatment

Clinical manifestations of Q fever in adults and children

Ricin poisoning: a comprehensive review

Human brucellosis

Brucella as a biological weapon

The enteric toxins of Clostridium perfringens

When biotoxins are tools of terror: early recognition of intentional poisoning can attenuate effects

Precautions against biological and chemical terrorism directed at food and water supplies

New issues in infectious diarrhea

Toxins: bacterial and marine toxins

Update: novel influenza A (H1N1) virus infections-worldwide

Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09

Critically Ill patients with 2009 influenza A(H1N1) in Mexico

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Definitive care for the critically ill during a disaster: medical resources for surge capacity

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