Chapter 61. Biowarfare Agents

• 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.
• Specific knowledge of the various types of agents is required to help in the diagnosis and management.
• 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.
• 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 U.S., 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 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.3–5 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.6,7 This list is not definitive and serves only as a guideline for preparation for a bioterrorist attack (Table 61-1).

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 61-2.8,9

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 5 μm in diameter in order to reach and be absorbed via the alveolar bed. Particles >5 to 10 μm 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.10–12 Aerosol delivery of an agent would also give rise to unusual presentations of diseases such as inhalational anthrax and pneumonic plague.

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 cholerae.13

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.14 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 U.S.15,16

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.1,16,17 The major virulence factors are the antiphagocytic capsule and three toxin components (lethal factor, edema factor, and protective antigen).18 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.

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.1,16,19 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.20,21 Delirium, meningismus, obtundation, seizures, and coma secondary to hemorrhagic meningitis occur in up to 50% of cases.14,22,23 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.1,22,100 In a series of 11 cases in the U.S., there was a 33% incidence of supraventricular arrhythmias and one case that had fatal pericardial effusion.1 Severe infection leads to hypotension and cyanosis progressing rapidly to death.1,19,24,25 The lag period between initial exposure and the onset of symptoms seems to be inversely proportional to mortality.16

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-ray25,27,100 (Fig. 61-1). Autopsies of victims from the Sverdlovsk incident failed to reveal any diffuse bronchopneumonic process; however, 11 of the 42 autopsies did show a necrotizing lung lesion similar to a Ghon complex.22 The recent series of cases in the U.S. suggest a parenchymal process is likely to be more common than previously thought.1 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 WBC, and is positive for the bacteria by Gram stain and culture.1 Noncontrast computed tomography (CT) scan of the chest is extremely helpful in determining the extent of mediastinal adenopathy and edema25 (Fig. 61-2). Given the rapidity at which death can occur, a delay in administration of antibiotics greatly decreases chances of survival.1,25,27,28

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 grampositive. Gram stains of sputum are typically negative, while those of blood and pleural fluid are more likely to be positive (Fig. 61-3). Blood cultures are almost always positive within 24 hours; however, laboratories may presumptively assume a contamination of specimens with Bacillus cereus.29 Thus microbiology labs need to be notified of the suspicion, so they may use selective media to isolate anthrax.30 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 United States Army Medical Research Institute of Infectious Diseases (USAMRIID).14,32 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.14,33 An aluminum hydroxide adsorbed, licensed vaccine made of noninfectious sterile culture filtrate from attenuated B. anthracis is available, and 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. However should it become available, it would be used at 0, 2, and 4 weeks postexposure.32

Treatment of patients with inhalational anthrax that has progressed to its fulminant stage warrants close observation in a monitored setting. Surveillance of serum chemistries, oxygen saturation, and EKG are all warranted. Chest tube placement for moderately large pleural effusions is necessary as they can increase rapidly and worsen respiratory distress.1 Patients with meningeal involvement may require steroids, phenytoin, and benzodiazepines to control edema and seizures. They may also need mechanical ventilation for airway protection. The additional support of mechanical ventilation and vasopressors are ominous signs.

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).33,34 If the strain of the organism is susceptible, then 4 million units of penicillin G intravenously every 4 hours can be used.14,33 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).25 It is important to note that B. anthracis isolates produce cephalosporinase, making treatment with cephalosporins such as ceftriaxone useless.

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 61-3). Patients with cutaneous anthrax should be cared for under contact isolation. Specimens should be handled under Biosafety Level (BSL) 2 precautions.31 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.14,31

Of the 77 cases of anthrax in the Sverdlovsk incident, only 11 patients survived. There was a reported hospital stay of 1 to 2 days for those who died and 3 weeks for those who survived. There are no details of the medical therapy that they had received but some of the survivors did need mechanical ventilation.16 Prior to 1978, inhalational anthrax in the U.S. had a mortality of 80% to 90%.19 However, the more recent experience in the U.S. showed a 40% mortality, and this may

be due to early recognition, better antibiotics, and modern intensive care units.1

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,4 theoretically causing thousands of casualties and widespread disruption of the public health system.14,35 The most likely route of delivery during an attack would be via aerosol.

Human plague occurs worldwide and is endemic to the southwestern U.S., with an average of 10 cases reported each year.36 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.37

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.37 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 U.S. there were 390 cases of plague reported between 1947 and 1996. Of these 84% was bubonic, 13% septicemic, and 2% pneumonic. Fatality rates were 14%, 22%, and 57% respectively.38

Y. 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.37,39

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 10 cm firm, extremely tender, nonfluctuant mass.35,37,40,41 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% to 15%), meningitis, hepatic and splenic abscesses, and endophthalmitis. Patients ultimately manifest signs of multiorgan failure and acute respiratory distress syndrome (ARDS).37,39,41–45 A minority present with the septicemic phase of disease (primary septicemic plague without bubo formation). A distinguishing clinical feature is severe abdominal pain. Patients in this group present earlier, are more likely to be elderly, are more toxic in appearance, and are hospitalized sooner than patients with bubonic plague. Despite this they have a higher mortality, likely related to the delay in the diagnosis.45

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.46 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.38,47 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 61-3). Death usually occurs within 18 to 24 hours after the onset of symptoms. Pulmonary complications include localized necrosis, cavitation, pleural effusion, and ARDS.16,18,32,41 In addition the course is complicated by endotoxemia and septic shock.

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.40,43

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 (Fig. 61-4). 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.31,35,37,39 Chest radiographs in cases of bubonic plague may show small transient unilateral infiltrates. However, 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.42,43,44,46

Treatment requires the prompt administration of antibiotics, especially in the septicemic 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.47,48

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.35

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. The reader is referred to the CDC article for dosing in children and pregnant women.35 Currently no recommendations exist for vaccination of public or health care providers in the postexposure setting.35,40,49

Patients with pneumonic forms of plague should be kept under respiratory droplet isolation protocols (Table 61-4) 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.31,35,39

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 U.S., and is highly virulent to rabbits and humans. Biovar palearctica or type B is more common in Eurasia and less virulent to humans. The bacteria can survive for long periods in soil, water, and animal carcasses. Organisms infect humans by direct contact with mucous membranes, broken skin, ingestion, or inhalation.50 Hunters, animal handlers, and laboratory personnel working with the bacteria are at greater risk for developing disease. Only 10 to 50 organisms are needed to cause infection in humans, via contact, inoculation, or inhalation.51 Theoretically, a biological attack with tularemia would be with an aerosolized form. From the site of entry, bacteria are ingested by macrophages and transported to regional lymph nodes where they multiply and disseminate. At the site of the entry, a predominantly cell-mediated inflammatory reaction causes necrosis and granuloma formation. Granulomas are also formed at other target organs after dissemination.50,52

The incubation period is 3 to 5 days. Patients present with abrupt onset of fever, chills, headache, coryza, malaise, and weakness. A temperature-pulse deficit is noted in 42% of patients. Patients may complain of cough and chest discomfort without having signs of pneumonia. Patients may have varying degrees of sore throat, abdominal pain, arthralgias, and myalgias. If untreated, anorexia, continued weight loss, and debility occur over a period of weeks to months.50,51,53 Clinically the disease may present as either ulceroglandular (which includes glandular, oculoglandular, and pharyngeal), or pneumonic (typhoidal) forms.

Ulceroglandular tularemia accounts for about 85% of natural cases, presenting as a cutaneous ulcer at the inoculation site within a few days of the onset of symptoms. The tender ulcer usually measures 0.4 to 3 cm in diameter, has raised edges, and is associated with regional lymphadenopathy. Affected lymph nodes are also tender, and can become fluctuant and suppurate. A minority present with the glandular form and no signs of skin involvement.50,52,54 The oculoglandular and pharyngeal forms refer to the primary sites of inoculation, and are associated with intense inflammation, edema, hemorrhage, and granulomatous disease of the inoculation site, as well as regional lymphadenopathy. Of interest is that the pharyngeal form of the disease is frequently associated with pneumonia.53

Typhoidal tularemia refers to illness without lymphadenopathy or signs of a portal of entry. It occurs in 15% of natural cases. It is likely that this is actually a primary pneumonic form of the disease, acquired by inhalation of the organism. Onset is more abrupt, and patients are more toxic, with pronounced gastrointestinal symptoms such as abdominal pain, prostration, and watery diarrhea. Respiratory complaints and pneumonia are associated with 80% of cases. Pharyngitis, pleuritic chest pain, cough with minimal sputum production, and bronchiolitis are common, while hemoptysis is uncommon.50,53–55 However, unlike both primary pneumonic plague and inhalational anthrax, the disease does not usually rapidly deteriorate to respiratory failure and death (see Table 61-3).

Both forms of tularemia are capable of causing pneumonia, ARDS, and septic shock, with the need for mechanical ventilation and vasopressor support, although only a handful of such cases exist in the postantibiotic literature.56 Interestingly, those that did had ulceroglandular forms of the disease. Mortality is 35% in pneumonic forms of the disease without therapy. With appropriate antibiotics fatalities would be <5%. However, potential for widespread disability would be great.24,57

Initial laboratory tests are nonspecific. Moderate leukocytosis, elevations in lactate dehydrogenase, serum transaminases, and alkaline phosphatase are common. CSF may show a small elevation in protein, low glucose, and minimal increases in white blood cells (WBCs).50,53 Typically blood cultures are negative, owing to poor growth on standard media and a low index of suspicion, and historically there is usually a delay of several days before identification. However, organisms have been recovered from blood, ulcers, conjunctival exudates, sputum, gastric washings, and pharyngeal exudates.53,58,61 Direct microscopic examination using fluorescent labeled antibodies provides a means of rapid diagnosis.50 Antigen detection, PCR, and ELISA are also used, and these methods are available at state and national reference labs through the LRN. Manipulation of cultures is a well-known hazard to laboratory personnel, and should only be done under BSL 3 containment. A fourfold increase in serum antibody is also diagnostic, but of retrospective importance.31,61

In a large series of inhalation-acquired tularemia 50% of the patients had chest x-ray abnormalities; 40% had infiltrates described as 2- to 8-cm oval-shaped lesions with indistinct borders, mostly in the juxtahilar position; 21% had unilateral hilar adenopathy always associated with other x-ray abnormalities; and 11% had pleural effusions.58 Pneumonia can occur in ulceroglandular disease, especially with the pharyngeal form. Interstitial patterns, cavitary lesions, bronchopleural fistulae, and frank ARDS have been reported on chest radiographs.59 Pleural fluid analysis shows a serosanguineous exudate with a lymphocytic predominance. Increased adenosine deaminase, lysozyme, and β2-microglobulin occur similarly to tuberculous effusions.53,55,60

Isolation of proven cases is not required since human-to-human transmission does not occur (see Table 61-4). Standard precautions should be applied to care of patients with draining lesions or pneumonia. Decontamination of soiled linen and equipment can be done with heat and standard disinfectants.

The Working Group on Civilian Biodefense's first-line therapy recommendations for treatment of adults in a contained casualty setting is streptomycin 1 g IM twice daily or gentamicin 5 mg/kg IM or IV once daily, for 10 days. Alternative therapies are doxycycline 100 mg IV twice daily for 14 to 21 days, chloramphenicol 15 mg/kg IV four times daily for 14 to 21 days, or ciprofloxacin 400 mg IV twice daily for 10 days. Of note, in the 1950s a fully virulent streptomycin-resistant strain was developed that could potentially be used in a bioterrorist attack. Fortunately the strain was sensitive to gentamicin. Since gentamicin has broader gram-negative coverage and is more readily available, it may be a more attractive first-line agent, especially if the diagnosis of tularemia is considered but in doubt.61

In a mass casualty setting where hospital resources are overwhelmed, adults can be treated with doxycycline 100 mg orally or ciprofloxacin 500 mg orally, twice daily for 14 days. Recovery from the illness is usually within 5 to 7 days. Currently vaccination is only recommended for microbiology laboratory workers handling cultures.53,57,61

Clostridium botulinum is a ubiquitous spore-forming anaerobic bacillus that produces a group of seven potent neurotoxins (types A through G). Botulism is the clinical syndrome produced by these toxins, and naturally occurs in three forms: food-borne, intestinal, and wound. Sporadic outbreaks of botulism occur throughout the U.S. due to contamination of food sources.62 No water-borne cases have ever been reported.63,64

All cases of botulism occur secondary to absorption of toxin from gut, lung, or wounds into the bloodstream. Toxin is not absorbed through intact skin. Once absorbed it is carried to the peripheral neuromuscular junctions, where it binds irreversibly. The toxin is made of two polypeptide subunits (light and heavy chains). Toxin is endocytosed into the nerve terminus by virtue of its heavy chain. Subsequently, the light chain cleaves various components of the synaptic fusion complex, preventing release of acetylcholine into the synaptic cleft. This causes presynaptic inhibition of neuromuscular transmission, affecting cholinergic, muscarinic, and nicotinic receptors. Recovery may take weeks or months and is dependent on regeneration of new motor axons to reinnervate muscle.65,66

Botulinum toxin is likely to be used as an aerosol agent in a bioterrorist attack. Aside from the general epidemiologic clues to a bioterrorist attack, identification of toxin types C, D, F, and G should arouse suspicion, since types A, B, and E are the most common forms found in the U.S.63 Botulinum toxin is the most potent toxic agent (per weight) known. Toxin A given in doses of 0.09 to 0.15 μg IV or IM, 0.7 to 0.9 μg inhaled, or 70 μg orally is enough to kill a 70-kg human. The toxin itself is colorless, odorless, and a relatively large protein (150,000-da). It quickly denatures under environmental conditions: 12 hours in air, 3 hours in sunlight, several minutes with heat >100° C, and 20 minutes at 0.4% mg/mL free available chlorine in water.67

The incubation period for food-borne botulism can vary from hours to days, but typically is between 12 and 72 hours, similar to that of the inhalational form.59,63 The rapidity of the onset of symptoms varies with the dose of the toxin, but most often is acute. Patients present initially with cranial nerve palsies and prominent bulbar signs of blurred vision, mydriasis, ptosis, diplopia, dysphonia, dysarthria, and dysphagia. A progressive symmetric descending flaccid muscle paralysis follows, the rapidity of which is also variable. It is important to note that the patient remains conscious throughout this time and is not febrile. Patients may also manifest with anticholinergic signs and postural hypotension. Nausea and vomiting may occur as nonspecific sequelae of an ileus.62,65,68 The upper airway may collapse due to weakness of oropharyngeal musculature, and handling of secretions may be problematic if the gag reflex is absent. Later the diaphragm is involved and respiratory failure ensues. Progression to hypercapnic and secondary hypoxic respiratory failure has been noted to occur within 24 hours in severe food-borne botulism.63,65,68,69

The diagnosis of botulism in the scenario of a bioterrorist attack should be made on the basis of its clinical and epidemiologic features mentioned above. This is because the definitive diagnosis can be delayed for days. The differential diagnosis for isolated cases includes stroke syndromes, intoxication, Guillain-Barré (Miller-Fischer variant), myasthenia gravis, and tick paralysis. However, for multiple cases presenting within a short period of time, the differential would be organophosphate and nerve agent poisoning (Table 61-5).

Routine laboratory tests, CSF examination, and brain imaging are unremarkable. Electromyography (EMG) studies show normal nerve conduction velocity, normal sensory function, and decreased amplitude of action potentials in affected muscle groups. An incremental increase in amplitude after repetitive 30- to 50-Hz stimulation helps distinguish botulism from Guillain-Barré syndrome and myasthenia gravis, but not Eaton-Lambert syndrome. The edrophonium test can be transiently positive.70

Ventilatory failure should be watched for by following vital capacity and carbon dioxide tension on arterial blood gases. Patients without gag reflex are at high risk for aspiration and may need endotracheal intubation. In one large series of patients many had significant hypoxia without significant hypercapnia.69 The time to mechanical ventilation was up to 5 days after the onset of symptoms, and was required for an average of 97 days. Aspiration pneumonia was presumed to occur in 29% of patients, all of whom received mechanical ventilation. Patients generally regained respiratory muscle strength later than in other muscle groups. Death from sepsis and shock were related to aspiration or ventilator-associated pneumonia.69

Definitive diagnosis of botulism is by mouse neutralization (bioassay), where type-specific antitoxin is used to protect mice against toxin in a patient's serum. Serum should be obtained prior to administration of antitoxin, as it may interfere with the assay. Results may take up to 2 days. Gastric, stool, and vomitus samples can also be used.63 Samples should be handled under BLS 2 conditions at a level B lab.31

The mainstays of therapy are administration of antitoxin, ventilatory assistance, and supportive care. Patients presenting with food-borne botulism should be given activated charcoal and then antitoxin when available. Currently an equine botulinum antitoxin that provides passive immunity against types A, B, and E toxins is available from the CDC through state and local health departments. Prompt administration limits the severity of disease, but does not reverse existing paralysis. An investigational heptavalent antitoxin against types A through G is available in the U.S. Army for other toxin types. Unlike organophosphate poisoning, atropine is not indicated and would possibly exacerbate symptoms.67

Patients unable to handle oropharyngeal secretions should be placed in reverse Trendelenburg position with frequent pulmonary and oropharyngeal toilet to avoid aspiration. Patients with clinical signs of respiratory failure require mechanical ventilation. It is important to recognize that patients remain conscious throughout and may require sedation to relieve anxiety. Aminoglycosides, clindamycin, and steroids should be avoided, as they may worsen muscle atrophy and exacerbate neuromuscular blockade and myopathy.72,73

Postexposure prophylaxis with antitoxin is currently neither recommended nor practical. Exposed persons who are not symptomatic should be watched closely and given antitoxin if symptoms develop. Vaccination against botulinum toxin using a multivalent toxoid is advocated only for military personnel and laboratory workers who may be at great risk.74 Decontamination is not required, as the agent is not dermally active. However, the possible use of a nerve agent should be considered in a scenario with many patients presenting with muscular weakness, and dealt with appropriately with decontamination (see Table 61-5).

Smallpox vaccination ceased in 1980, after the disease was declared eradicated by the WHO.75 This has left a civilian population under the age of 30 totally susceptible. If the virus were ever intentionally released, its properties like high person-to-person transmission, viability outside its human host, and high fatality rate would cause colossal damage.76

Smallpox is caused by the variola virus of the orthopoxvirus family. Smallpox is highly infectious and person-to-person spread occurs by inhalation of expectorated respiratory droplet nuclei and by direct contact of the mucous membranes. Fomites such as contaminated linen of infected patients have also been responsible for spread. The incubation period is 12 to 14 days. Following deposition on the upper airway mucosa, the virus is transported to regional lymph nodes and then other lymphoid tissues. The virus then spreads systemically and localizes in small vessels of the dermis and oropharyngeal mucosa. This prodromal phase lasts for 3 days, and is marked by high fever, rigors, malaise, vomiting, headache, and backache.77

The clinical manifestations of smallpox are of five types. The classic or ordinary type accounted for 90% of cases with a fatality rate of 30%. Modified type occurred in 25% of unvaccinated and 2% of vaccinated cases with rare fatalities. Flat type occurred in 7% of cases and was characterized by slow evolution of flat, soft focal skin lesions and severe systemic toxicity. It had a fatality rate of 95% and 33% in the unvaccinated and vaccinated, respectively. Hemorrhagic type was almost uniformly fatal, occurring in 3%, and was characterized by diffuse hemorrhagic manifestations and rapid progression to death even before any skin lesions could be discerned. Variola sine eruptione was seen in vaccinated persons and was characterized by a 48-hour period of febrile illness. Unfortunately the various types cannot be distinguished until they start to manifest.77

The classical type of disease begins acutely with prodromal symptoms, followed by an enanthema of the tongue, mouth, and oropharynx. The next day a discrete centrifugal rash, characterized by 2- to 3-mm reddish macules begins on the face, hands, and forearms. These lesions progress to become papules and then vesicles of 3 to 5 mm in size, and spread centrally to cover the whole body by the fourth to seventh day. By the eighth day pustules of 4 to 6 mm are formed. Over the next 5 to 8 days, the pustules become larger and have a central depression (umbilicated). Later they become flattened and more confluent. During this phase of rash another fever spike occurs. By the thirteenth day the lesions start to crust and over the ensuing week start to scab and separate, leaving depressed depigmented lesions. The rash is typically more peripherally distributed and homogeneous in stage when compared to the rash of chickenpox.77,78 Secondary infections of the rashes were reportedly not common. Complications of the disease included panophthalmitis and secondary infection causing blindness in 1%, arthritis in 2% of children, and encephalitis in 1%. Bronchitis was occasionally reported; however, pneumonia was rare.76,77

Death from the classic type of disease was reported to be most common during the second week. The fatality rate in the classic type seems directly related to the degree of confluence among the lesions. This may have direct bearing on the degree of fluid sequestration and protein loss during the vesicular and pustular stage. Renal failure, electrolyte imbalance, protein loss, and metabolic derangements were reportedly similar to those of burn victims and likely accounted for the majority of the morbidity of shock, infection, and death.77,79

The two most dreaded forms of the disease are the hemorrhagic and flat types. Hemorrhagic type has a predilection for pregnant women. There was no difference in incidence between vaccinated and unvaccinated individuals. It was characterized by a shorter more severe prodromal phase and marked prostration. Diffuse hemorrhagic lesions (likely due to DIC) occurred in all mucous membranes and skin, leading to sloughing of these surfaces. Pulmonary edema and hemoptysis were common. Patients were reportedly conscious until the very end and death often occurred within a week.77 Flat type disease was rare in vaccinated individuals. The prodromal fever was present throughout the eruptive phase of the disease, and patients were extremely toxic in appearance. Mucous membrane sloughing was also characteristic.

It is likely that the vast majority of practicing clinicians would not be able to recognize smallpox in its early stages, by which time it would already be too late to prevent its spread. The differential diagnosis of the disease is quite vast, but the most common misdiagnosis would be that of chickenpox. Chickenpox has a less pronounced prodromal illness, a more centripetal rash, asynchronous evolution of the rash, quicker scab formation (1 week), and a fatality rate of <1%. Other illnesses that can be confused with smallpox are monkeypox, various cutaneous drug reactions, atypical measles, and molluscum contagiosum. Cases of hemorrhagic and flat type smallpox would be difficult to diagnose clinically, and would likely be misdiagnosed as severe meningococcemia, DIC from other diseases, Stevens-Johnson syndrome, or a filovirus hemorrhagic fever.80

Notification of local, state, and national public health authorities is of the utmost importance, as the diagnosis of smallpox is an international public health emergency. Specimens should be sent to state and national health authorities using the LRN, under BSL 4 precautions. Information regarding handling of specimens is detailed on the CDC website: http://www.bt.cdc.gov/agent/smallpox/response-plan/#guided.

Demonstration of the characteristic brick-shaped virus under electron microscopy is confirmatory for an orthopoxvirus, and aggregations of variola virus particles called Guarnieri bodies can be found under light microscopy. However, none of these tests are capable of discriminating variola from other orthopoxviruses. Definitive diagnosis is by isolation of the virus on chorioallantoic membrane culture and further testing with PCR.80,81

In a recent report, it was estimated that if as few as 10 persons were initially infected by a covert biological attack with smallpox, within 1 year as many as 224,000 persons would be infected if the disease went unchecked. Furthermore, a combination of quarantine (25% removal of cases from society daily) and a mass vaccination program (reducing the number of transmissions by 33%), would lead to halting of an epidemic within 1 year, and the cumulative number of cases would be 4200. In order for this scenario to be feasible it was estimated that over 9 million doses of vaccine would be necessary.82

Strict airborne and contact isolation in a negative pressure room is of primary importance in dealing with a case of smallpox. However, this is only feasible in a small, contained outbreak. In a massive outbreak separate hospitals would need to be designated for those with complications or more severe forms of the disease. More likely, people would have to be quarantined within their homes for routine supportive care. Patients requiring admission to the hospital in a scenario like this would likely be critically ill. Keeping pace with fluid losses, electrolyte imbalances, and nutritional needs would be a major goal of therapy in these patients. This is especially true for patients with more confluent rashes, as well as flat type and hemorrhagic type variants of the disease. Meticulous skin care should be performed. Early placement of central venous access and invasive hemodynamic monitoring catheters may be warranted in severe cases as progressive distortion of the superficial anatomy occurs.77,79 Patients with the flat and hemorrhagic types would be most likely to need some degree of mechanical ventilatory support, as the incidence of pulmonary edema is higher. In addition they would likely need transfusion therapy for complications related to DIC.

Currently there is no definitive treatment of the disease. Cidofovir (currently FDA approved for treatment of cytomegalovirus retinitis) is reportedly useful in preventing monkeypox and vaccinia in animals. It may have roles in postexposure prophylaxis and treatment of vaccinia vaccination complications. This drug would possibly be made available in a smallpox epidemic.81

Vaccination is done with reconstituted lyophilized vaccinia. It is applied with a bifurcated needle via 15 punctures at right angles into the skin overlying the deltoid without drawing blood. Successful vaccination is confirmed by the appearance of a characteristic Jennerian pustule after a week, and this provides immunity for up to 10 years, and 20 years with revaccination. The vaccinee must understand that there is viable vaccinia virus in the lesion from the moment the papule forms (2 to 5 days after vaccination) until the scab dislodges (on days 14 to 21). The lesions should be covered as there is a risk of transmission to an unvaccinated individual (“contact vaccinia”).101

A three phase smallpox vaccination program was recently put forth by the U.S. government, under which medical and health care personnel are offered smallpox vaccination on a voluntary basis. The plan also calls for the creation of smallpox vaccination teams comprised of health care workers and public health officials in each state. These teams will assist in epidemiologic investigation and vaccination efforts during the first 7 to 10 days of an outbreak. Vaccination within 4 days of exposure will provide some protection from getting disease and will decrease mortality.102 Vaccination of patients with suspected smallpox should also be considered for fear of misdiagnosis.81 Recently it has been established that an increase in the dilution of the vaccine from 1:5 to 1:10 establishes immunity, and this practice could substantially boost the availability of the vaccine to the public.83

Contraindications for vaccination include immunosuppression, human immunodeficiency virus (HIV) infection, history of exfoliative dermatologic conditions, and pregnancy. Complications of vaccination in order of frequency are infection, generalized vaccinia (usually self-limited), eczema vacciniatum, postvaccinial encephalitis (with 10% significant neurologic morbidity), and vaccinia gangrenosa (occurs in immunosuppressed individuals and has a high fatality rate). Vaccinia immune globulin (VIG) is indicated for eczema vacciniatum, and vaccinia gangrenosa.76,77,84

Viral hemorrhagic fever (VHF) is caused by a diverse group of RNA viruses that are transmitted to humans from their natural animal and arthropod reservoirs. They produce clinical syndromes characterized by fever, myalgias, prostration, increased vascular permeability, disturbances in regional circulation, and bleeding. Several of the hemorrhagic fevers (Marburg, Ebola, Lassa, Junin, and Machupo viruses) have been weaponized and experimented with for aerosol infectivity by the former Soviet Union, Russia, and the U.S. Experimental infection of animals via aerosol is highly effective. However, aerosol infection of humans has never been documented, except in the case of hantavirus. However, these agents are highly infective by direct contact with needles, fluids, and tissues of infected persons.85 Important human pathogens are:

• Arenaviruses: Lassa, Junin, and Machupo viruses that cause Lassa fever, Argentinean, and Bolivian hemorrhagic fevers, respectively.
• Bunyaviruses: Rift Valley fever (RVF) virus and Crimean-Congo hemorrhagic fever (CCHF) viruses cause RVF and CCHF. Hantaviruses cause hemorrhagic fever renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS).
• Filoviruses: Marburg and Ebola viruses.
• Flaviviruses: Dengue fever, Kyasanur forest disease, and Omsk hemorrhagic fever.

VHF viruses target vascular endothelium, causing microvascular damage and derangement in vascular permeability. Common presenting complaints are fever, myalgias, and prostration. On examination patients may have conjunctival injection, mild hypotension, flushing, and petechial hemorrhages. Bleeding is variable and generally not life threatening, but it is an index of severity. Progression to shock and generalized bleeding from the mucous membranes is often accompanied by neurological, hematopoietic, or pulmonary involvement. Hepatic involvement is common; however, jaundice and frank hepatic failure is seen in a small percentage patients with RVF, CCHF, Marburg, and Ebola hemorrhagic fevers, and yellow fever. Death is secondary to increased vascular permeability, intravascular volume loss, and multiorgan failure.86 The Working Group on Civilian Biodefense has concluded that CCHF and HFRS are unlikely to be employed as biowarfare agents, because they are technically difficult to produce in large quantities. Dengue is also an unlikely agent as it is not transmissible by aerosol, and only rarely causes VHF.

Each virus has unique features that set it apart clinically. Lassa fever is endemic in West Africa, and has a high mortality in children and pregnant women. Hemorrhagic and neurologic complications are not pronounced and occur only in the severely ill. Case-fatality rates in hospitalized patients average 15% to 25%.87 In survivors deafness is a frequent sequela. In contrast, the South American arenaviruses (Argentine and Bolivian hemorrhagic fevers) have prominent neurologic and hemorrhagic manifestations.

RVF is endemic in sub-Saharan Africa. Frank hemorrhagic disease is seen in a minority of patients. Retro-orbital pain and blindness from retinitis occurs in 10%. In 1% of patients, fulminant disease with hemorrhage, jaundice, and hepatitis develops, with a 50% fatality rate. Fatal encephalitis occurs in <1%.88 Marburg and Ebola viruses produce prominent maculopapular rashes and DIC is a major component in their pathogenesis. Both are characterized by pronounced bleeding. Forty-one percent of patients manifest bleeding from puncture sites and mucous membranes; however, this form of bleeding does not distinguish nonsurvivors from survivors. Pulmonary involvement is uncommon and death usually results from multiorgan system failure and cardiovascular collapse.89,90 Fatality rates for Ebola and Marburg hemorrhagic fevers are 80% and 25%, respectively.86

Routine laboratory tests in patients with VHFs are nonspecific, but the presence of early thrombocytopenia and coagulation abnormalities should arouse suspicion. Definitive diagnosis of VHF is done by isolation in cell culture or immunohistochemical staining of formalin-fixed tissues. These techniques should only be attempted under BSL 4 conditions at the CDC or USAMRIID. In the field, viral identification can safely be done following chemical inactivation with ELISA to detect viral antigen as well as IgM and IgG antibodies. Reverse transcriptase PCR has also been successfully applied to field diagnosis.86

Medical management for VHF is largely supportive. Patients should be handled as gently as possible as they are especially prone to bleeding. Aspirin and other antiplatelet drugs should be avoided. Immunosuppression with steroids or other agents is contraindicated. Uncontrolled clinical observations support the transfusion of red cells for severe hemorrhage and platelet and clotting factors for DIC. Hemodialysis is of particular help in treatment of HFRS. Mechanical ventilation may be necessary. Treatment of hypotension and shock is often difficult and the use of invasive hemodynamic monitoring techniques may help to guide therapy. Limited experience has shown that rapid infusion of fluids may quickly worsen pulmonary edema because of increased vascular permeability. Fluids are best administered carefully using crystalloids first, and later with the addition of colloids.86,91 In cases of HPS the use of inotropes may be warranted.92

The only specific antiviral therapy available for VHF is ribavirin, a nonimmunosuppressive nucleoside analogue with broad antiviral properties. It has been shown to reduce mortality in Lassa fever and shows promise with the treatment of other arena- and bunyaviruses. Passive immunotherapy has been used successfully in Argentine hemorrhagic fever and shows promise in Bolivian hemorrhagic fever. However, passive immunization is contraindicated in HFRS since an active immune response is already evolving in most patients who are diagnosed. Currently the only licensed vaccine is for yellow fever and is mandatory for all travelers to endemic areas.86

Isolation of suspected VHF cases is essential as secondary infections of close contacts and medical personnel are well documented. Until the definitive diagnosis has been made, patients with suspected VHF should be isolated in a single room with an adjoining anteroom serving as an entrance. Negative pressure rooms and strict respiratory precautions may be more appropriate in confirmed severe end-stage disease where the viral load is maximal (see Table 61-4). These precautions may not be possible in the case of large outbreaks. However, it is essential to enforce stringent barrier nursing, with the use of mask, glove, gown, and needle precautions, along with hazard labeling of all laboratory specimens. Patient access should be restricted and the incineration or autoclaving of all contaminated materials including linens is mandatory. Decontamination of areas can likely be carried out by detergents, bleach, and hypochlorite solutions, as these viruses have lipid envelopes making them susceptible.85

Discussion of all the possible biological weapons is beyond the scope of this chapter. However, Coxiella burnetii (Q fever), staphylococcal enterotoxin B (SEB toxin), viral equine encephalitides, and ricin toxin deserve attention, as they have been weaponized. Furthermore they can all present as an upper respiratory viral illness, making differentiation of biological attack from a natural viral epidemic difficult (see Table 61-3).

Q fever is a zoonotic disease of herded animals. Humans acquire it via inhalation. It is extremely infectious, requiring as few as 10 organisms to produce disease. The incubation time is 2 to 14 days. Patients present with signs and symptoms of a seasonal viral syndrome that can be prolonged in two thirds for up to 2 weeks. The most frequent physical finding is rales on chest exam. Chest x-rays are abnormal in 50% to 60% of cases, most often showing consolidation, but effusions also occur. Routine blood tests commonly show elevations of liver transaminases and alkaline phosphatase up to three times normal. Fatalities are extremely rare; however, the disease is incapacitating. Treatment and prophylaxis is with doxycycline or tetracycline.93

SEB is a heat-stable pyrogenic toxin produced by Staphylococcus aureus. This toxin can be mass produced and is stable as an aerosol. When inhaled it binds to the MHC class II molecules that stimulate T cells with a massive release of cytokines including interferon-γ, interleukin-6, and tumor necrosis factor (TNF)-α. Within 3 to 12 hours of exposure high fever (up to 106°F), myalgias, nonproductive cough, chest tightness, dyspnea, headache, and vomiting develop. Conjunctival signs are notably absent. On chest examination, rales are the prominent finding. Chest x-ray typically is normal, but can show interstitial pulmonary edema. Postural hypotension as well as profound vasodilatory shock can occur. Patients usually progress rapidly to a relatively stable level of disease, but can be incapacitated for weeks. Lethality is low. Diagnosis is clinical, but serum detection of the toxin is possible with ELISA. Therapy is currently limited to supportive care.24,94

The viral equine encephalitides include Venezuelan, eastern, and western viruses (VEE, EEE, and WEE) of the alphavirus family. Humans are accidental hosts, acquiring the virus via a mosquito vector. However, they are highly infectious by aerosol and readily grow in cell cultures. All three of the viruses are capable of killing with varying degrees of neurologic involvement. EEE is most virulent with 50% to 70% mortality, WEE follows with <10% mortality, and VEE has <1% mortality. A febrile prodrome of 1 to 5 days marks replication in bone marrow and lymphoid tissue resulting in lymphopenia. Subsequently high viremia seeds the brain and spinal cord. Central nervous system symptoms and signs include menigismus, hyper- or hypoactive reflexes, and spastic paralysis that can progress to death. Loss of airway protection and status epilepticus may require mechanical ventilation and ICU management. CSF shows elevated protein and 50 to 2000 WBCs/mL with lymphocyte predominance. Definitive diagnosis relies on viral culture of serum or CSF, or antibody detection from serum by ELISA. Therapy is limited to supportive treatment. A live-attenuated vaccine for VEE is available, along with inactivated vaccines for VEE, WEE, and EEE. These vaccines are available under investigational new drug (IND) release status from the US government but are only 50–85% effective for <1 year.95

Ricin toxin is an extract of castor beans. It is highly lethal via ingestion, injection, and inhalation. At the cellular level it kills through the inhibition of protein synthesis. Its clinical features are route-specific. Studies in primates show that within several hours of inhalation a severe diffuse acute tracheobronchitis manifests, followed by fibrin purulent pneumonia with diffuse severe alveolar flooding, peribronchovascular edema, and mediastinal lymphadenitis. Respiratory failure and ARDS are likely to occur within 30 hours. Distinguishing an attack with ricin from either anthrax or pneumonic plague would be extremely difficult. Diagnosis would be largely clinical, but antigen ELISA of nasal swabs should be done within 24 hours. Treatment would be largely supportive, though vaccination with a toxoid in animals is very effective and in development by the U.S. Army.96

The scenario of a biological weapons attack poses several unique challenges for the intensivist. Although most external disasters will occur with some degree of warning, biological agent exposure is an exception. Here the diagnosis is more likely to be made within a hospital, perhaps a few days after the environmental release.97 Patients are more likely to seek medical care at the most convenient medical facility instead of responders going to the patients.98,99 Unlike natural disasters or conventional wars, victims in a biological attack are likely be a more homogenous population. Potentially enormous numbers of ill and exposed patients presenting with the same level of severity will rapidly overwhelm the health care system, its infrastructure, and supplies. Issues of supplies and distribution of medical resources would be a major problem, as already predicted in the TOPOFF exercise.4 Applying conventional mass disaster triaging schemes may therefore not be possible to a such homogeneously affected population. It is thus important to consider these unique features related to biological agent attacks in both preparation and acute disaster management.

The need for the critical care personnel to be involved in the planning process cannot be overstated. The intensivist will become a key figure in governing the flow of patient traffic, making triage decisions, and allocating ICU resources for patients in the ER, OR, recovery room, and the rest of the hospital. Intensivists should understand capabilities, resources, and limitations of various governmental and nongovernmental disaster-related agencies, as well as consider their hospital's location and community resources in anticipating a likely disaster scenario.97

Although the full details of a hospital's preparedness plan are beyond the scope of this chapter, certain key issues deserve attention in coping with such a disaster. Readers are referred to the CDC web site for preparation and planning for a bioterrorist attack at http://www.bt.cdc.gov/planning/index.asp, as well as individual state health department guidelines for preparedness, and their own hospital's disaster management plans.

1. Define the area to be covered during a disaster scenario. Intensivists should familiarize themselves with their hospital disaster plan, and know their responsibilities relative to other departments in the plan.

2. Identification and assignment of key personnel in the hospital, emergency response personnel, state and local authorities, and key members of the community.

3. Assessment of hospital infrastructure, supplies at hand, and manpower for a given situation. This would also include knowing the vendor lists to meet sudden demand for supplies and knowledge of the absolute limits of the hospital resources (inventory of ventilators, oxygen tanks, intravenous catheters, isolation capabilities of the hospital, etc).

4. Establishing secure lines of communication internally via a central command post or incident center, as well as externally with the LRN, National Pharmaceutical Stockpile (NPS), and local, state, and federal authorities. Successful interaction with these agencies will likely define the successful management of a disaster response (Table 61-6).

5. Defining portals of entry to the hospital and creating safe arrival and triage areas, in addition to decontamination areas.

6. Establishing algorithms for triage from the ED and clinics, as well as criteria for ICU admission. As surge capacity nears, the risks and benefits of treating existing patients in the hospital and carrying out elective surgeries needs to be weighed. Knowledge of alternative beds and transfer agreements with nearby ICUs would be crucial in this regard.

7. Early efforts must be made to contain the agent. This can be achieved by education of staff and public, early efforts to identify the agent through the LRN, reporting of the agent to the local, state, and federal health authorities, early intervention and treatment of the disease, and early implementation of appropriate infection control measures (Tables 61-6 and 61-7).

8. Ensuring the safety of workers. This includes issues of isolation precautions, evaluation of the potential for spread among other patients and staff once the agent has been confirmed, postexposure prophylaxis, and vaccination. Staff exhaustion and posttraumatic stress disorder should be anticipated, and dealt with by scheduling adequate rest periods, appropriate use of volunteer staff, and a program of critical incident stress management.

9. Carrying out drills and mock events for continual assessment of flaws in organization and execution of the plan.

A bioterrorist attack of any kind has the potential to overwhelm a community and indeed an entire nation. A high degree of suspicion and prompt recognition of an event will be required in order to contain it. The likelihood of exposed patients to require hospitalization and specifically critical care is high, and specific knowledge of the possible agents and estimating the needs of a health care facility and community will be the cornerstones in disaster preparedness for a biological attack. Aside from the delivery of critical care to the patient in the ICU, the intensivist will be involved in making triage decisions (which automatically dictates how other non-ICU beds are used and managed), managing resources related to the ICU, and coordinating a multidisciplinary effort in caring for the exposed.

This chapter is adapted from a previous publication: Karwa M, Bronzert P, Kvetan V: Bioterrorism and critical care. Crit Care Clin 19:279, 2003. Reproduced with permission from Elsevier.