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  Unlike other mass casualty events, mass exposure to a biological agent is unlikely to be realized until cases start presenting and a high degree of suspicion is needed to realize this.

  
  
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  Specific knowledge of the various types of agents is required to help in the diagnosis and management.

  
  
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  Victims of class A agents such as plague, anthrax, botulinum toxin, smallpox, and viral hemorrhagic fever are likely to be critically ill and in need of the expertise of intensivists.

  
  
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  Preparedness for a mass casualty event is key in dealing with effective care of patients in the hospital setting, containment of spread of particularly virulent organisms, and controlling public hysteria.

Since the terrorist attacks of September 11, 2001, and the distribution of mail containing anthrax spores that led to seven deaths in the United States, the threat of a large-scale bioterrorist attack has become very real.¹ A recent report by the Monterey Institute for International Studies found a total of 121 biocrimes were committed since 1960, with a reported sharp rise since 1995.^2,3 Reports of biological agent stockpiles and their weaponization by Iraq and the former Soviet Union, as well as the use of various biological agents by cult organizations such as the Rajneesh cult, Aum Shinrikyo, and Minnesota Patriots, make the possibility of their use by a rogue nation or nonmilitary organization a very real one.

Attack of a civilian target would cause a large number of casualties, panic, and civil disruption. There would be a rapid overwhelming of public health facilities and capabilities.^4,5 It is highly likely that many if not the majority of patients would need some degree of critical care such as a ventilator or hemodynamic support. Thus the critical care physician’s role could be a central one that depends on specific knowledge of the various agents, and preattack preparedness, the two cornerstones in dealing with such a catastrophe. The main objectives of this chapter are to provide a concise review of individual agents likely to be used in a bioterrorist attack, and focus on key issues related to the intensivist in preparing to deal with such an event.

The Centers for Disease Control and Prevention’s strategic planning workgroup categorizes biological warfare agents into groups A, B, and C, based on capability to cause illness or death, stability of the agent, ease of delivery, ease of mass production, person-to-person transmissibility, potential for creating public fear and civil disruption, and the ability of the public health systems to deal with such an attack.⁶ Category A agents would have the greatest impact on public health and its infrastructure. Category B agents would have less impact on the public health and its infrastructure. Category C agents are least likely to impact on the public health and include various emerging infectious agents.⁷ This list is not definitive and serves only as a guideline for preparation for a bioterrorist attack (Table 81-1).

Recognition of a bioterrorist attack would require prompt identification based on typical clinical syndromes, since awaiting laboratory confirmation of these otherwise rare illnesses might be delayed. Certain epidemiologic features peculiar to a bioterrorist attack help distinguish it from a natural outbreak of disease as outlined in Table 81-2.^8,9

Because of the greater absorption surface area of the alveolar bed, a biological weapon is more likely to be delivered via an aerosol spray or a cloud. This would require an agent to be aerosolized into droplets or particle sizes of 1 to 5µm in diameter in order to reach and be absorbed via the alveolar bed. Particles >5 to 10µm would be filtered out by or deposited into the upper respiratory tract. However, many viruses like influenza, viral hemorrhagic fevers, and smallpox can be infective at these sites. Aerosol delivery of an agent would also give rise to unusual presentations of diseases such as inhalational anthrax and pneumonic plague.¹⁰

A bioterrorist attack through the contamination of food and water is less likely for several reasons. Most category A agents are not transmitted via food and water, while category B agents that can be transmitted by these routes usually cause short-term vomiting and diarrhea with a relatively quick recovery. Current water treatment methods effectively kill many biological agents and contaminating a water or food supply effectively would require large amounts of toxin and bacteria in order to overcome any dilution factor. Furthermore, boiling water and cooking food destroys most agents. A recent study warns of the United States’ vulnerability to such an attack based on very centralized food processing methods and distribution of the foods over large areas. Likely agents are botulinum toxin, Salmonella, Shigella, Escherichia coli, and Vibrio cholera.¹¹

Contact with intact skin with any of these agents is unlikely to result in disease. However, if the skin integrity is compromised, the potential for disease exists. Current studies suggest that thorough washing with soap and water is sufficient to overcome even this threat.

Bacillus anthracis is a gram-positive spore-forming bacterium. It is an encapsulated, nonmotile, and nonhemolytic organism, and usually grows within 6 to 24 hours on conventional culture media. The vegetative form is incapable of surviving outside of a warm-blooded host, and colony counts are undetectable in water after 24 hours. As a biological weapon it is likely to be delivered as an aerosol. Clinically this would produce inhalational anthrax, the deadliest and rarest form of the disease. The cutaneous form is not considered lethal with current antibiotic regimens, and the gastrointestinal form is exceedingly rare with essentially no cases having been reported in the United States.^12,13

Inhalational anthrax occurs after spores are ingested by alveolar macrophages and transported via regional lymphatics to mediastinal lymph nodes. Germination takes place in 2 to 5 days, but can be delayed as much as 60 days, after which disease rapidly occurs.¹³ The major virulence factors are the antiphagocytic capsule and three toxin components (lethal factor, edema factor, and protective antigen). The three toxins cause edema, hemorrhage, and necrosis, producing a thoracic lymphadenitis and hemorrhagic mediastinitis. Death can occur despite antibiotic administration if toxin levels have reached a critical threshold.¹³

Clinically anthrax presents as a biphasic illness. The first stage is characterized by nonspecific symptoms of fever, chills, weakness, headache, vomiting, abdominal pain, dyspnea, cough, and chest pain, lasting for hours up to a few days. This may be followed by a short period of apparent recovery. The second stage is characterized by sudden resurgence of fever, shortness of breath, profound sweating that drenches the patient, and shock. Hypocalcemia, hypoglycemia, hyperkalemia, depression of the respiratory centers, and terminal acidosis are some of the biochemical and physiologic signs that develop in severe infections.¹⁴ Delirium, meningismus, obtundation, seizures, and coma secondary to hemorrhagic meningitis occur in up to 50% of cases.¹⁵ Involvement of the gut is also a common feature of advanced disease and thought to be secondary to hematogenous spread (different from primary gastrointestinal anthrax) presenting as abdominal pain (33%), and can lead to necrotizing enteritis of the bowel.¹⁶ The lag period between the initial exposure and the onset of symptoms seems to be inversely proportional to mortality.¹⁷

Diagnosis of inhalational anthrax clinically requires a high degree of suspicion given that the symptoms on initial presentation can easily be confused with a seasonal viral syndrome. Presenting symptoms and routine laboratory tests are nonspecific, and the only clue prior to development of fulminant disease may be a widened mediastinum on chest x-ray.^18,19 The recent series of cases in the United States suggest a parenchymal process is likely to be more common than previously thought. Small pleural effusions that rapidly progress to a large size appears to be a consistent finding and may correlate with the progression of the disease. Thoracentesis yields a hemorrhagic fluid with relatively few white blood cells (WBCs), and is positive for the bacteria by Gram stain and culture. Noncontrast computed tomography (CT) scan of the chest is extremely helpful in determining the extent of mediastinal adenopathy and edema.^20-22

Meningeal signs develop in 50% of cases, with contrast CT scan of the brain revealing diffuse leptomeningeal enhancement, with intracerebral and subarachnoid hemorrhages.²³ Cerebrospinal fluid (CSF) is usually bloody and gram-positive. Gram stains of sputum are typically negative, while those of blood and pleural fluid are more likely to be positive. Blood cultures are almost always positive within 24 hours; however, laboratories may presumptively assume a contamination of specimens with Bacillus cereus.²⁴ Thus microbiology labs need to be notified of the suspicion, so they may use selective media to isolate anthrax. Confirmatory testing such as growth on special nutrient agars, susceptibility to lysis by gamma phage, direct fluorescence antibody staining, nucleic acid signatures, and enzyme-linked immunosorbent assay (ELISA) for protective and capsule antigens are performed at level B and C laboratories of the Laboratory Response Network (LRN) for Bioterrorism, CDC, or the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID).¹³ Serological testing of acute and convalescent serum is useful only retrospectively.

Postexposure prophylaxis for adults (including pregnant women and the immunosuppressed) is initially with ciprofloxacin 500 mg orally every 12 hours or doxycycline 100 mg every 12 hours. If the strain is susceptible, then amoxicillin 500 mg orally every 8 hours or the above dose of doxycycline can be taken. These regimens should be taken for 60 days owing to the unpredictable latency of inhalational anthrax.¹³ An aluminum hydroxide adsorbed, licensed vaccine made of noninfectious sterile culture filtrate from attenuated B anthracis is available in highly limited supply, and only currently provided to the military; evidence shows it to protect against aerosol challenge. However, currently it is not recommended for postexposure prophylaxis in either health care workers or the public.³²

Current CDC recommendations for empiric treatment of inhalational anthrax in adults (including pregnant women and immunosuppressed) are ciprofloxacin 400 mg intravenously every 12 hours or doxycycline 100 mg intravenously every 12 hours. These should be given with another one or two additional antibiotics that have in vitro activity against anthrax (rifampin, penicillin, ampicillin, vancomycin, imipenem, clindamycin, chloramphenicol, or clarithromycin). If the strain of the organism is susceptible, then 4 million units of penicillin G intravenously every 4 hours can be used. High-dose intravenous penicillin may provide better CNS penetration in cases associated with meningitis. Recent survivors of inhalational anthrax were treated with a combination of ciprofloxacin (based on official recommendations), rifampin (for increased gram-positive coverage and for its intracellular mechanism of action), and clindamycin (for its ability to prevent expression of toxin). It is important to note that B anthracis isolates produce cephalosporinase, making treatment with cephalosporins such as ceftriaxone useless.²⁵

As person-to-person transmission does not occur, patients can be cared for under standard precautions. However, it should be remembered that in an act of suspected bioterrorism one would not immediately know whether patients are affected with anthrax or a more transmissible agent such as plague, which warrants respiratory isolation precautions as well (Table 81-3). Patients with cutaneous anthrax should be cared for under contact isolation. Specimens should be handled under Biosafety Level (BSL) 2 precautions. Decontamination of individuals exposed to the initial aerosol attack is not necessary, and washing with soap and water is sufficient to eliminate any secondary aerosolization. For contaminated hospital areas, bleach solutions and 0.5% hypochlorite solution are adequate for decontamination.²⁶

Yesinia pestis is a nonmotile, gram-negative bipolar coccobacillus that is the causative agent of plague. Recently, the organism has been used as the hypothetical biological weapon in the TOPOFF scenario, theoretically causing thousands of casualties and widespread disruption of the public health system.²⁷ The most likely route of delivery during an attack would be via aerosol.²⁸

Human plague occurs worldwide and is endemic to the southwestern United States, with an average of 10 cases reported each year. Its natural reservoirs are urban and rural rodents. The transmission vector is the oriental rat flea (Xenopsylla cheopis). Humans become accidental hosts after being infected by an infected flea’s bite. Humans very rarely are responsible for its propagation, except when they have the pneumonic form of the disease.²⁹

Humans contract plague from the bite of an infected flea, inhalation of respiratory secretions of animals or humans with pneumonic forms of plague, or direct handling of infected animal tissues. The former is the most common route, while the latter two are very rare in nature and usually give rise to the pneumonic form of disease. In the United States, there were 390 cases of plague reported between 1947 and 1996. Of these 84% were bubonic, 13% bacteremic, and 2% pneumonic. Fatality rates were 14%, 22%, and 57%, respectively.^29,30

Yesinia pestis has a number of virulence factors including V and W antigens, lipopolysaccharide endotoxin, capsular envelope (antiphagocytic fraction I antigen), coagulase, and fibrinolysin. Bacteria inoculated into the skin by an infected flea become phagocytosed by mononuclear cells. They multiply intracellularly, eventually lysing the cells, after which they become resistant to further phagocytosis. Bacteria are transported via lymphatics to the regional lymph nodes causing inflammation and hemorrhagic necrosis, and subsequently give rise to the typical bubo.³¹

The incubation period for bubonic plague is 2 to 8 days. It presents with sudden onset of fever, chills, weakness, and headache. Within a few hours to a day patients notice the bubo, which is characterized by its sudden onset, absence of overlying skin lesions, marked surrounding edema, and extreme pain that limits the motion of the region. Buboes can occur in the inguinal, axillary, or cervical nodes, and can present as an 1 to 10cm firm, extremely tender, nonfluctuant mass.³¹ Subsequently, patients deteriorate rapidly over 2 to 4 days, having high fever, tachycardia, malaise, headache, vomiting, chills, alterations in mental status, prostration, and chest pain, eventually progressing to vasodilation and septic shock. During this time patients may have signs of disseminated intravascular coagulation (DIC), with acral purpura that may progress to gangrene. Hematogenous spread can give rise to complications such as plague pneumonia (5%-15%), meningitis, hepatic and splenic abscesses, and endophthalmitis. Patients ultimately manifest signs of multiorgan failure and acute respiratory distress syndrome (ARDS). A minority present with the bacteremic phase of disease (primary bacteremic plague without bubo formation).

Primary pneumonic plague occurs by inhalation of aerosolized bacteria from patients who have lung involvement secondary to fulminant bubonic plague, or animals (cats) with secondary plague pneumonia.³² This is the most fatal form of the disease and its incubation time is 1 to 3 days. It manifests suddenly with fever, chills, headache, body pains, weakness, and chest discomfort. As the disease progresses there is an increase in cough and sputum production, as well as increasing chest pain, hemoptysis, and hypoxia, progressing rapidly to frank respiratory failure. The presence of hemoptysis should alert the clinician to the possibility of primary pneumonic plague, since it is less likely to present in inhalational anthrax (see Table 81-3). Death usually occurs within 18 to 24 hours after the onset of symptoms. Pulmonary complications include localized necrosis, cavitation, pleural effusion, and ARDS. In addition, the course is complicated by endotoxemia and septic shock.³³

Patients with primary pneumonic plague have an infectious pneumonitis at the onset of the disease. These patients are capable of a vigorous and highly infectious cough, and are not usually debilitated like patients with bubonic disease. Secondary plague pneumonia, on the other hand, is usually a result of hematogenous spread of the disease to the lungs. Usually the patient is ill for several days, debilitated, and unable to cough vigorously, making them less infectious. However, pneumonic plague (primary or secondary) should always be considered extremely infectious.^29,31,33

Routine blood tests are nonspecific. Bacteremia initially is transient, and single blood cultures at presentation are only 27% positive. Blood, sputum, bubo aspirates, and CSF Gram stains can reveal gram-negative bipolar coccobacilli, while the Wayson stain shows light blue bacilli with dark blue polar bodies on a pink background. Automated culture detection systems may present a delay or even misidentify the organism. Thus a high level clinical suspicion of the disease should prompt immediate notification of the lab. State level B or national level C (CDC or USAMRIID) laboratories should be notified through the LRN. Direct fluorescence staining for fraction 1 (F1) envelope antigen, phage lyses of cultures, or polymerase chain reaction (PCR) assay should confirm identification. Acute and convalescent serum titers for antibody to F1 antigen are retrospectively diagnostic. Chest radiographs in cases of bubonic plague may show small transient unilateral infiltrates. However, the presence of nodular or bilateral alveolar infiltrates in these patients is strongly associated with a more fulminant and fatal course. Primary pneumonic forms of plague are associated with bilateral alveolar and nodular infiltrates, with over half of them having pleural effusions. Cavitary lesions have also been noted to occur.^29,31,33

Treatment requires the prompt administration of antibiotics, especially in the bacteremic and pneumonic forms. As the bacteria is capable of inducing an endotoxemia leading to DIC, septic shock, ARDS, and multiorgan failure, close observation of the patient and early resuscitative measures are warranted at the earliest sign of progression toward a more fulminant course. These patients require aggressive volume resuscitation, and may need mechanical ventilation as well as vasopressor support.^29,31,33

Based on the Working Group on Civilian Biodefense’s recommendations for pneumonic plague, first-line therapy is with streptomycin 1 g IV or IM twice a day, or gentamicin 0.5 mg/kg IM or IV twice daily. Alternate therapies are doxycycline 100 mg IV twice daily, ciprofloxacin 400 mg IV twice daily, or chloramphenicol 25 mg/kg IV four times daily. Therapy should be implemented in anyone exposed with a temperature >38.5°C or a new cough.²⁸

In the setting of mass casualties where public health facilities may be overwhelmed, first-line therapy recommendations for postexposure prophylaxis in adults include doxycycline 100 mg orally twice daily, or ciprofloxacin 400 mg orally twice daily. Alternatively, chloramphenicol 25 mg/kg can be used. Currently no recommendations exist for vaccination of public or health care providers in the postexposure setting.^29,31,33

Patients with pneumonic forms of plague should be kept under respiratory droplet isolation protocols until they have received at least 48 hours of appropriate antibiotic therapy or shown improvement. Persons who have been exposed who refuse to take antibiotic prophylaxis but are not symptomatic do not require isolation, but need to be watched and treated at the first sign of cough or fever. The use of standard disposable surgical masks is recommended. Microbiology lab personnel should be aware of the potential of getting infected from handling samples during high-risk lab procedures, and BSL 3 precautions should be observed during such times.^29,31,33

Tularemia is caused by a gram-negative, facultative intracellular bacterium, Francisella tularensis. It is a zoonotic disease of small mammals and is transmitted by arthropod vectors (primarily ticks). There are two biovars of F tularensis. Biovar tularensis or type A is more common in the south-central and western United States, and is highly virulent to rabbits and humans. Biovar palearctica

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