Anthrax is caused by Bacillus anthracis, a Gram-positive spore-forming bacillus found in soil worldwide (Figs. 133–1 and 133–2).B. anthracis causes disease primarily in herbivorous animals. Human anthrax cases generally occur in farmers, ranchers, and among workers handling contaminated animal carcasses, hides, wool, hair, and bones.32
A few clinically distinct forms of anthrax may occur, depending on the route of exposure. Cutaneous anthrax results from direct inoculation of spores into the skin via abrasions or other wounds and accounts for about 95% of endemic (naturally occurring) human cases. Patients develop a painless red macule that vesiculates, ulcerates, and forms a 1- to 5-cm brown-black eschar surrounded by edema.48 The eschar color gave rise to the name anthrax, from the Greek word anthrakos meaning “coal.” Most skin lesions heal spontaneously, although 10% to 20% of untreated patients progress to septicemia and death. When treated with antibiotics cutaneous anthrax rarely results in fatalities. Anthrax is not transmissible among humans.
Gastrointestinal (GI) anthrax results from ingesting insufficiently cooked meat from infected animals. Patients develop nausea, vomiting, fever, abdominal pain, and mucosal ulcers, which can cause GI hemorrhage, perforation, and sepsis. Mortality from GI anthrax is at least 50%, even with antibiotic treatment.32
Inhalational anthrax results from exposure to aerosolized B. anthracis spores. Although this form of anthrax is very rare, it is so closely associated with occupational exposures that it is called “wool-sorter’s disease.” Inhalational anthrax is also likely to be the form that occurs in a BW attack, because the anthrax spores would be most effectively disseminated by aerosol. After an incubation period of 1 to 6 days, the patient develops fever, malaise, fatigue, nonproductive cough, and mild chest discomfort, which may be easily mistaken for community acquired pneumonia.19 The initial symptoms may briefly improve for 2 to 3 days or the patient may abruptly progress to severe respiratory distress with dyspnea, diaphoresis, stridor, and cyanosis. Bacteremia, shock, metastatic infection such as meningitis, which occurs in about 50% of cases, and death may follow within 24 to 36 hours. Prior to the 2001 bioterrorist outbreak, mortality from inhalational anthrax was expected to be nearly 100%, even with antibiotics, once symptoms develop.30,32 With appropriate antibiotic therapy and supportive care, 5 of 11 patients with inhalational anthrax in 2001 died, and although this is still a high mortality rate, it is less than that previously predicted.40
Inhalational anthrax causes a mediastinitis. Diagnostic imaging typically shows mediastinal widening from enlarged hilar lymph nodes and pleural effusions, although pulmonary parenchymal infiltrates may also be seen.40 Inhaled spores are taken up into the lymphatic system where they germinate and the bacteria reproduce. B. anthracis produces three toxins: protective antigen, edema factor, and lethal factor. Protective antigen (PA) is so named because antibodies against it protect the individual from the effects of the other two toxins. PA forms a heptamer that inserts into plasma membranes, facilitating endocytosis of the other two toxins into target cells (Fig. 133–3). Edema factor is a calmodulin-dependent adenylate cyclase. Increased intracellular cyclic adenosine monophosphate (AMP) upsets water homeostasis, leading to massive edema and impaired neutrophil function. Lethal factor is a zinc metalloprotease that stimulates macrophages to release tumor necrosis factor α and interleukin-1β, contributing to death in systemic anthrax infections.25 The combination of PA plus edema factor is called edema toxin, while PA plus lethal factor is lethal toxin.34
Model of action of anthrax toxins. EF and LF are unable to enter cells until they complex with a PA heptamer, forming edema toxin and lethal toxin, respectively. Once intracellular, release from PA allows EF and LF to exert their intracellular effects. Antibodies against PA confer resistance to the toxic effects of anthrax. EF = edema factor; LF = lethal factor; PA = protective antigen; PK = protein kinase.
The primary antibiotics recommended to treat anthrax are ciprofloxacin and doxycycline. Although other fluoroquinolones would be expected to have similar activity against anthrax, only the manufacturer of ciprofloxacin applied for and received a US Food and Drug Administration (FDA)-approved indication for use in this infection. In a mass-casualty setting or for postexposure prophylaxis, adults should be treated with ciprofloxacin 500 mg orally (PO) every 12 hours. Alternate therapies are doxycycline 100 mg PO every 12 hours, or amoxicillin 500 mg PO every 8 hours, if the anthrax strain is proven susceptible.40 The recommended duration of therapy is 60 days, stemming from case experience in Sverdlovsk where some patients developed disease several weeks (6–7 weeks) after the spore release.51 Children can also be treated with ciprofloxacin (15 mg/kg; maximum 500 mg/dose) or amoxicillin (80 mg/kg/d divided every 8 hours; maximum 500 mg/dose). The relative pediatric contraindication to fluoroquinolones is outweighed by the risk of potentially fatal disease. Cutaneous anthrax is treated with the same drugs and doses as for postexposure prophylaxis.
Inhalational anthrax should be treated initially with intravenous antibiotics. Adults should receive ciprofloxacin 400 mg intravenously (IV) or doxycycline 100 mg IV every 12 hours, along with one or two additional antibiotics with in vitro activity against anthrax (eg, rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, clindamycin, clarithromycin). Children should be given ciprofloxacin 10 mg/kg IV (maximum 400 mg/dose), or doxycycline 2.2 mg/kg IV (maximum 100 mg/dose), and additional antibiotics, as indicated above.40 However, in a true mass-casualty event, when resources are strained and inpatient care is not available for every victim, oral therapy, as described above, may be instituted. When clinically appropriate, PO antibiotic therapy can be substituted for IV forms, with total treatment duration of 60 days. Some patients in the 2001 outbreak were specifically treated with additional antibiotics that inhibit protein synthesis in attempts to reduce bacterial production of toxins.
An effective vaccine against anthrax is available.33,50,72 In the United States, the Bioport Corporation (formerly Michigan Biologic Products Institute) is licensed by the FDA to produce anthrax vaccine adsorbed (AVA). The vaccine consists of a membrane-sterilized culture filtrate of B. anthracis V770-NP1-R, an avirulent, nonencapsulated strain that produces protective antigen, adsorbed to aluminum hydroxide, formulated with benzethonium chloride (preservative) and formaldehyde (stabilizer).72 In human and animal experiments, the vaccine is highly effective in preventing all forms of anthrax, and the vaccine is recommended for workers in high-risk occupations. As with any vaccine, local reactions to AVA occur in some recipients (up to 20% with mild, local reactions), and self-limited systemic reactions occur more rarely (< 1.5%). Women have more frequent injection-site reactions and other adverse events, although this sex difference is also noted with other common vaccines.34 Serious adverse events are very rare, with only 22 potentially related cases of serious adverse events from over 1 million doses administered to US armed forces.33 The dosage schedule for AVA is 0.5 mL subcutaneously at 0, 2, and 4 weeks and 6, 12, and 18 months, followed by yearly boosters. Preclinical studies have also been conducted on a human monoclonal antibody against protective antigen, which has been developed as an antitoxin for use in the treatment of inhalational anthrax.
2001 bioterrorist anthrax outbreak.
Starting on September 27, 2001, a 63 year-old Florida man developed malaise, fatigue, fever, chills, anorexia, and diaphoresis. He was admitted to a local hospital on October 2, after presenting with additional complaints of nausea, vomiting, and confusion. Chest radiography showed cardiomegaly, a left perihilar infiltrate, small left pleural effusion, and a prominent superior mediastinum. Lumbar puncture revealed hemorrhagic meningitis with many Gram-positive bacilli. Bacillus anthracis was isolated from the cerebrospinal fluid after only a 7-hour incubation and from blood cultures within 24 hours. The patient had progressive clinical deterioration and died on hospital day four.10,42
On October 4, the US Centers for Disease Control and Prevention (CDC) released a public health message regarding this case, which initially appeared to be an isolated, perhaps naturally occurring sporadic event.15 Nevertheless, the rarity of inhalational anthrax especially outside of a high-risk occupation, combined with increased suspicion in the wake of the September 11, 2001, attacks led to intense investigation of a potential bioterrorist event. Within days, epidemiologic investigation suggested workplace exposure to anthrax spores, and personnel working in the same building were started on prophylactic ciprofloxacin.16 On October 12, a case of cutaneous anthrax was reported in New York associated with a suspicious letter opened on September 25.17 Anthrax cases and environmental contamination were also soon detected in Washington, DC, and in a New Jersey postal facility. The public response to the reports of these serious and fatal cases included misuse and hoarding of antibiotics, purchasing gas masks (often with inappropriate filtering mechanisms for BW), reporting numerous miscellaneous powdery substances, and perpetrating or reporting copycat hoaxes.
By November 7, 2001, a total of 22 cases of anthrax were reported: 10 inhalational and 12 cutaneous.18 One additional death from inhalational anthrax occurred on November 21, 2001,4 and a case of cutaneous anthrax also occurred in a laboratory worker analyzing samples obtained during the investigation.20 In two of the fatal cases, no contact with contaminated letters could be established.4,53 One infant hospitalized in New York with cutaneous anthrax was initially misdiagnosed as suffering from a brown recluse spider envenomation.31 The total number of medical victims of anthrax by Spring 2002 was 23:11 cases of inhalational anthrax (with five fatalities), and 12 cases of cutaneous anthrax (eight confirmed and four suspected).20
Although the overall number of individuals infected by this bioterrorist event was relatively low, the psychosocial-economic impact was exceptionally high. Several hundred postal and other facilities were tested for B. anthracis spore contamination, and public health authorities recommended antibiotic prophylaxis be initiated for approximately 32,000 persons.18 Additional indirect costs and effects are more difficult to quantify, including the number of persons self-initiating antibiotic treatment without an evident indication, lost production and wages, environmental and biological sample testing, decontamination efforts, and an international sense of unease.
Published estimates of tens of thousands of deaths from a military-style anthrax attack43 depend on efficient BW dispersion. The technically easier anthrax letter has clearly proven itself to be a “weapon of mass disruption.” As predicted, the psychological impact far exceeded the actual medical emergency, and events with a modest number of medical patients are probably more likely than true mass-casualty BW incidents. On the other hand, prior assumptions regarding the clinical aspects of anthrax were not as reliable. The mortality rate among the 11 cases of inhalational anthrax was 45%, considerably lower than expected and probably because of earlier diagnosis, improved supportive care measures, and a wider choice of antibiotics, compared to historic controls. Presentation with fulminant illness, such as sepsis, still appears to be predictive of a fatal outcome, yet the initial phase of illness does not necessarily lead to death, if treated with appropriate antibiotics.6,42,46 Pleural effusions were the most common radiographic abnormality, rather than a widened mediastinum, and pulmonary parenchymal infiltrates were seen in seven patients, whereas earlier teaching had been that pneumonia does not commonly occur with inhalation anthrax.32,42
Yersinia pestis is a Gram-negative bacillus (Fig. 133–4) responsible for more than 200 million human deaths and three major pandemics in recorded history.48,49 Naturally occurring plague is transmitted by flea vectors from rodent hosts, or by respiratory droplets from infected animals or humans. Bubonic plague could result from an intentional release of plague-infested fleas. Plague is a particularly frightening BW because it can be released as an aerosol to cause a fulminant communicable form of the disease for which no effective vaccine exists. Antibiotics must be initiated early after exposure because once symptoms develop, mortality is reportedly extremely high.
Plague occurs in three clinical forms: bubonic, septicemic, and pneumonic. Bubonic plague has an incubation period of 2 to 10 days followed by fever, malaise, and painful, enlarged regional lymph nodes called buboes. The inguinal nodes are most commonly affected, presumably because the legs are more prone to flea bites, although cervical or axillary buboes are more common in children.58 In the United States, 85% to 90% of human plague patients have the bubonic form, 10% to 15% have a primary septicemic form without lymphadenopathy, and about 1% present with pneumonic plague. Secondary septicemia occurs in 23% of patients presenting with bubonic plague.49 Various skin lesions at the site of inoculation (pustules, vesicles, eschars, or papules) occur in some patients, although the petechiae and ecchymoses that occur in advanced cases may resemble meningococcemia.48 Distal gangrene may occur from small artery thrombosis, explaining why plague pandemics are sometimes called the Black Death. If left untreated, bubonic plague carries a 60% mortality rate.48
Pneumonic plague is an infection of the lungs with Y. pestis. Between 5% and 15% of bubonic plague patients develop secondary pneumonic plague through septicemic spread of the organism.49 Primary pneumonic plague occurs from inhalation of infected respiratory droplets or an intentionally disseminated BW aerosol. The incubation period of pneumonic plague is 2 to 3 days after inhalation. The onset of disease is acute and often fulminant. Patients develop fever, malaise, and cough productive of bloody sputum, rapidly progressing to dyspnea, stridor, cyanosis, and cardiorespiratory collapse. Plague pneumonia is almost always fatal unless treatment is begun with 24 hours of symptom onset.30
Plague can be diagnosed by various staining techniques, immunologic studies, or by culturing the organism from blood, sputum, or lymph node aspirates. When gram stained, Y. pestis appears as a Gram-positive safety pinshaped bipolar coccobacillus.30,58 Chest radiographs in patients with pneumonic plague reveal patchy or consolidated bronchopneumonia. Leukocytosis with a left shift is common, as are markers of low-grade disseminated intravascular coagulation (DIC) and elevations of unconjugated bilirubin and hepatic aminotransferases.30
Antibiotic treatment options are similar to those for anthrax. In a mass-casualty setting or for postexposure prophylaxis, adults are treated with doxycycline 100 mg PO twice daily or ciprofloxacin 500 mg orally twice daily. Children receive doxycycline 2.2 mg/kg or ciprofloxacin 20 mg/kg, up to a maximum of the adult doses. Chloramphenicol 25 mg/kg orally four times daily is an alternative. The duration of treatment is 7 days for postexposure prophylaxis and 10 days for mass-casualty incidents.39 Patients with pneumonic plague need to be isolated to prevent secondary cases. Respiratory droplet precautions are necessary in pneumonic plague until the patient has received antibiotics for 3 days.30 In a contained-casualty setting, pneumonic plague is treated with parenteral streptomycin or gentamicin; alternative antibiotics include doxycycline, ciprofloxacin, and chloramphenicol.39 A killed whole-cell vaccine effective against bubonic plague is available, but does not reliably protect against pneumonic plague in animal studies.48,50
Francisella tularensis is a small, aerobic, Gram-negative coccobacillus (Fig. 133–5) weaponized by the United States and probably other countries as well. Tularemia occurs naturally as a zoonotic disease spread by blood-sucking arthropods or by direct contact with infected animal material. Tularemia in humans may occur in ulceroglandular or typhoidal forms, depending on the route of exposure. Ulceroglandular tularemia is more common, occurring after skin or mucous membrane exposure to infected animal blood or tissues. Patients develop a local ulcer with associated lymphadenopathy, fever, chills, headache, and malaise. Typhoidal tularemia presents with fever, prostration, and weight loss without adenopathy. Exposure to aerosolized bacteria, as employed in BW, will most likely result in typhoidal tularemia with prominent respiratory symptoms such as a nonproductive cough and substernal chest discomfort. Diagnosing tularemia is often difficult, as the organism is hard to isolate by culture and the symptoms are nonspecific. Chest radiography may demonstrate infiltrates, mediastinal lymphadenopathy, or pleural effusions.24,28,30,50
Antibiotic treatment options are similar to those for anthrax and plague. In mass-casualty settings, or for postexposure prophylaxis, adults are treated with doxycycline 100 mg twice daily or ciprofloxacin 500 mg PO twice daily for 14 days. Pediatric dosing for doxycycline is 2.2 mg/kg or ciprofloxacin 15 mg/kg (maximum = adult dose) twice daily. When dealing with a limited number of casualties, the preferred antibiotics are streptomycin 1 g intramuscularly (IM) twice daily, or gentamicin 5 mg/kg IM/IV once daily. Alternatives include parenteral doxycycline, chloramphenicol, and ciprofloxacin.24
Brucellosis could potentially be used as an incapacitating BW, because it causes disease with low mortality but significant morbidity. Brucellae (Brucella melitensis, abortus, suis, and canis) are small, aerobic, Gram-negative coccobacilli (Fig. 133–6) that generally cause disease in ruminant livestock. Humans develop brucellosis by ingesting contaminated meat and dairy products or by aerosol transmission from infected animals. The United States weaponized B. suis and other countries are also believed to have developed Brucella bioweapons. Brucellosis commonly presents with nonspecific symptoms such as fever, chills, and malaise, with either an acute or insidious onset. Because brucellae are facultative intracellular organisms that localize in the lung, spleen, liver, central nervous system (CNS), bone marrow, and synovium, organ-specific signs and symptoms may occur. Diagnosis is made by serologic methods or culture. Because single-drug treatment often results in relapse, combined therapy is indicated. Treatments of choice (adult doses) are doxycycline 200 mg/day PO, plus rifampin 600 to 900 mg/day PO for 6 weeks, or doxycycline 200 mg/day PO for 6 weeks, with either streptomycin 15 mg/kg twice daily IM or gentamicin 1.5 mg/kg IM q8h for the first 10 days.30,38,50
Features of rickettsiae favoring their use as BW include environmental stability, aerosol transmission, persistence in infected hosts, low infectious dose, and high associated morbidity and mortality. Rickettsiae that have been weaponized include Coxiella burnetti, the causative organism of Q fever, and Rickettsia prowazekii, the causative organism of louseborne typhus. Release of R. prowazekii into a crowded louse-infested population might induce a typhus outbreak with rapid transmission and high mortality.3
Q fever was first described in 1937, and was given its name—Q for “query”—because the causative organism was not then known. Q fever occurs naturally as a self-limited febrile, zoonotic disease contracted from domestic livestock. Q fever is now known to be caused by Coxiella burnetti, a unique rickettsialike organism that can persist on inanimate objects for weeks to months and can cause clinical disease with the inhalation of only a single organism. These features are of obvious benefit for use as a potential BW. After a 10- to 40-day incubation period, Q fever manifests as an undifferentiated febrile illness, with headache, fatigue, and myalgias. Patchy pulmonary infiltrates on chest radiography that resemble viral or atypical bacterial pneumonia occur in 50% of cases, although only half of patients have cough and even fewer have pleuritic chest pain. Uncommon complications include hepatitis, endocarditis, meningitis, encephalitis, and osteomyelitis. Patients are generally not critically ill, and the disease can last as long as 2 weeks. Treatment with antibiotics will shorten the course of acute Q fever and can prevent clinically evident disease when given during the incubation period. Tetracyclines are the mainstay of therapy, and either tetracycline 500 mg PO q6h or doxycycline 100 mg PO q12h should be given for 5 to 7 days.11,30
Smallpox is caused by the variola virus, a large DNA orthopoxvirus (Fig. 133–7) with a host range limited to humans. Prior to global World Health Organization (WHO) efforts to eradicate naturally occurring smallpox by immunization, recurrent epidemics were common and the disease carried roughly a 30% fatality rate in unvaccinated populations.37,47 Smallpox is highly contagious (Fig. 133–8). Outbreaks during the 1960s and 1970s in Europe often resulted in 10 to 20 secondary cases per index case. One German smallpox patient with a cough, isolated in a single room, infected persons on three floors of a hospital.37 However, the overwhelming majority of secondary infections occur among close family contacts, especially those sleeping in the same room or even in the same bed.26
In 1980, the United Nations’ WHO certified that smallpox had been eradicated from the world, and recommended ceasing vaccinations and either destroying or transferring remaining stocks of variola virus to one of two designated biosafety level 4 facilities: the CDC in Atlanta or the Russian State Research Center of Virology and Biotechnology.9 All remaining known variola stocks were scheduled for destruction in 1999; however, before this was done, a WHO resolution called for a delay based on an Institute of Medicine report concluding that live virus should be retained to develop new antivirals or vaccines to protect against any potential future release of smallpox.62 The Soviet Union is known to have weaponized smallpox, and other countries are believed to maintain stocks of variola virus. In addition to the known stockpiles of smallpox vaccine, several types of new vaccines are being produced.56,70 Smallpox vaccination for military personnel was reinstated in 2002 and was made available for some civilians in 2003.21,22
Transmission of smallpox typically occurs through inhalation of droplets or aerosols, but may also occur through contaminated fomites. The infectious dose is not known, but is probably only a few virions. After a 12- to 14-day incubation period, the patient develops fever, malaise, and prostration with headache and backache. Oropharyngeal lesions appear, shedding virus into the saliva. Two to three days after the onset of fever, a papular rash develops on the face and spreads to the extremities. The fever continues while the rash becomes vesicular and then pustular. Scabs form from the pustules and eventually separate, leaving pitted and hypopigmented scars. Deaths usually occur during the second week of the illness. Vaccination before exposure, or within 2 to 3 days after exposure, provides almost complete protection against smallpox. The disease most likely to be confused with smallpox is chickenpox (varicella). Although the individual lesions of smallpox and varicella are physically indistinguishable, the person infected with smallpox may still be differentiated clinically. The lesions of smallpox should all appear at the same stage of development (synchronous), whereas chickenpox lesions occur at varying stages (asynchronous). Smallpox lesions tend to be found in a centrifugal distribution (face and distal extremities), whereas chickenpox lesions are more centripetal and tend to appear first on the trunk.
Two antivirals commercially available in the United States, cidofovir and ribavirin, are effective in vitro against variola.50 However, current evidence suggests that although cidofovir may prevent smallpox when given within 1 or 2 days of exposure, it is unlikely to be effective once symptoms develop.37 Even a single case of smallpox should be considered a potential international health emergency and immediately reported to the appropriate public health authorities.
Rapid postexposure vaccination confers excellent protection against smallpox. The smallpox vaccine employs a live vaccinia virus (derived from cowpox vaccine) rather than the actual variola virus that causes smallpox. Although contracting smallpox from the vaccine is impossible, other adverse reactions may occur. The two most serious reactions are postvaccinal encephalitis and progressive vaccinia. Postvaccinal encephalitis occurs in about three cases per million primary vaccinees. Forty percent of cases are fatal, and some survivors are left with permanent neurologic sequelae. Progressive vaccinia can occur in immunosuppressed individuals and is treated with vaccinia immune globulin (VIG;Fig. 133–9).70 Another historically common complication of smallpox vaccination was ocular vaccinia, which typically occurred among health care personnel administering vaccine when it was inadvertently placed in the eye. Ocular vaccinia is also treated with VIG. Because smallpox was eradicated before the emergence of HIV, there is limited clinical experience with smallpox vaccination in patients with AIDS who theoretically are at increased risk of progressive vaccinia.37,47 However, among 10 individuals with undiagnosed HIV at the time of recent smallpox vaccination, none developed complications.65 Routine vaccination is contraindicated in the immunosuppressed, persons with a history or evidence of eczema and other chronic dermatitis, close household or sexual contacts of patients with these contraindications, and during pregnancy. Because the vaccine is a live virus, it can be transmitted from the vaccinee to close contacts. Thirty secondary and tertiary cases of vaccinia were reported resulting from recent US military vaccinations.21 The number of serious adverse events from modern smallpox vaccination is very low22; however, rare cardiac complications not reported in previous decades were noted with the recent reinstitution of smallpox vaccination in the early 2000s. More than 1 million military vaccinations given by 2006 resulted in 120 cases of myopericarditis, while 21 cases of myopericarditis occurred among nearly 40,000 civilian vaccine recipients between 2002 and 2003.56 The number of cardiac ischemic events among vaccinees was not significantly higher than age-matched controls. After a true exposure to variola, most authorities would agree that the only absolute contraindication to smallpox vaccination is significant impairment of systemic immunity. Concomitant administration of vaccinia immune globulin would be recommended for pregnant women and persons with eczema.47
Viral Hemorrhagic Fevers.
Several taxonomically diverse RNA viruses produce acute febrile illnesses characterized by malaise, prostration, and increased vascular permeability that can result in bleeding manifestations in the more severely affected patients. Viral hemorrhagic fevers (VHFs) are all highly infectious by the aerosol route, making them candidates for use as BW. These include the viruses causing Lassa fever, dengue, yellow fever, Crimean-Congo hemorrhagic fever, and the Marburg, Ebola virus, and Hanta viruses. Hanta virus is endemic to North America; occasional natural epidemics of human infection occur, which may initially be difficult to differentiate from a BW release. Clinical features, such as the extent of renal, hepatic, and hematologic involvement, vary according to the specific virus, but they all carry the risk of secondary infection through droplet aerosols. Ribavirin is used for some VHFs, but supportive care is the mainstay of therapy.7,30,41
Three antigenically related α viruses of the Togaviridae family pose risks as BWs: western equine encephalitis (WEE), eastern equine encephalitis (EEE), and Venezuelan equine encephalitis (VEE). Birds are the natural reservoir of these viruses, and natural outbreaks occur among equines and humans by mosquito transmission. Eastern equine encephalitis infections are the most severe in humans, with a 50% to 70% fatality rate and high incidence of neurologic sequelae among survivors. WEE is less neurologically invasive, and severe encephalitis from VEE is rare, except in children. Adults infected with VEE usually develop an acute, febrile, incapacitating disease with prolonged recovery. The equine encephalitides have many properties helpful for weaponization, in that they can be produced in large quantities, they are relatively stable and highly infectious to humans as aerosols, and a choice is available between lethal or incapacitating infections.63
Venezuelan equine encephalitis is considered the most likely BW threat among the viral encephalitides. After a 1- to 5-day incubation period, victims experience the sudden onset of malaise, myalgias, prostration, spiking fevers, rigors, severe headache, and photophobia. Nausea, vomiting, cough, sore throat, and diarrhea may follow. This acute phase lasts 24 to 72 hours. Between 0.5% and 4% of cases develop encephalitis, with meningismus, seizures, coma, and paralysis, which carries up to a 20% fatality rate. The diagnosis is usually established clinically, although the virus can sometimes be isolated from serum or from throat swabs, and serologic tests are available. The white blood cell count often shows a striking leukopenia and lymphopenia. Treatment is supportive. Person-to-person transmission can theoretically occur from droplet nuclei. Recovery takes 1 to 2 weeks.30,63
Several toxins derived from bacteria, plants, fungi, and algae could theoretically be used as BW, if produced in sufficient quantities. Because of their high potency, only small amounts would be needed to kill or incapacitate exposed victims. Fortunately, obstacles in manufacturing weaponizable amounts limit the number of toxins that are practical for use as biological weapons. Discussion here is limited to those toxins known or highly suspected to have been weaponized. Toxins themselves are not living organisms and therefore cannot reproduce; for this reason, they are arguably equivalent to chemical weapons. But because toxin weapons are derived from living organisms, they are categorized here as biological weapons.
Botulinum toxin has been developed as a biological weapon in the United States and other countries.1,55,61,71 The two most likely means of employing botulism are by food contamination or by aerosol. Either method would result in the clinical syndrome of botulism (Chap. 41), characterized by multiple bulbar nerve palsies and a symmetric descending paralysis, ending in death from respiratory failure. Inhalational botulism from laboratory incidents has occurred rarely in humans and has also been investigated in animal experiments.52
Ricin is derived from the castor bean plant (Ricinus communis) and is the only biological toxin to exist naturally in more than microscopic quantities, comprising 1% to 5% of the beans by weight.8 Its easy accessability, relative ease of preparation, and low cost may make ricin an attractive BW for terrorists or poor countries. Although ricin has never been used in battle, it has attracted the attention of domestic extremists and terrorists and has been used in politically motivated assassinations.2,23,29 Ricin is a glycoprotein lectin (or toxalbumin) composed of two protein chains linked by a disulfide bond. The B chain facilitates cell binding and entry of the A chain into cells. The A chain inhibits protein synthesis, inactivating eukaryotic ribosomes by removing an adenine residue from ribosomal RNA.2
Clinical toxicity from ricin will vary depending on the dose and route of exposure. Inhalation of aerosolized ricin results in increased alveolar-capillary permeability and airway necrosis following a latent phase of 4 to 8 hours. Ingestion causes gastrointestinal hemorrhage with necrosis of the liver, spleen, and kidney. Intramuscular administration produces severe local necrosis with extension into the lymphatics. In the absence of specific immunologic testing, differentiating ricin poisoning from sepsis may be difficult, because of the presence of leukocytosis and fever. Vaccination of laboratory animals with an investigational toxoid (a modified toxin that does not cause disease, but still induces an antibody response) is protective.29
Staphylococcal Enterotoxin B.
Staphylococcal enterotoxin B (SEB) is one of seven enterotoxins produced by Staphylococcus aureus. SEB is recognized as a “superantigen,” because of its profound activation of the immune system on exposure to even minute quantities. As a BW, SEB could be ingested through contaminated food or water, resulting in acute gastroenteritis identical to classic staphylococcal food poisoning. If inhaled as an aerosol, SEB produces fever, myalgias, and a pneumonitis after a 3- to 12-hour latent period. SEB inhalation can be fatal, but more often would simply be incapacitating for several days to weeks. Treatment is supportive.67
Fungi and Other Fungal Toxins
Fungi may at first appear to be ideal BW, given their relative ease of handling, dissemination, and resistance of spores to physical stressors.12 The only fungi to be included on lists of microbes with potential use as biological weapons are Coccidioides species, probably based on the high incidence of symptomatic infection in endemic areas. Nevertheless, the risk of serious disease is low, limiting the utility of Coccidioides as an effective weapon.12,57
Fungal toxins considered to have potential use as BWs include trichothecene mycotoxins, aflatoxins, and amanita toxins. Although α-amanitin is extremely potent, water soluble, and heat stabile, its use as a weapon would be limited by difficulties in mass production.57 Aflatoxin would be ineffective on the battlefield, since its acute toxicity is uncertain and the carcinogenetic potential is a delayed phenomenon.5 However, both of these toxins may still be effective as terror agents.
The trichothecene mycotoxins are low-molecular-weight (250–500 Da), nonvolatile compounds produced by filamentous fungi (molds) of various genera, including Fusarium, Myrothecium, Phomopsis, Trichoderma, Tricothecium, and Stachybotrys.5,68 Tricothecene mycotoxins are unusual among potential BW in that toxicity can occur with exposure to intact skin. Naturally occurring trichothecene toxicity results from ingesting contaminated grains or by inhaling toxin aerosolized from contaminated hay or cotton. Outbreaks of ingested trichothecene toxins result in a clinical syndrome called alimentary toxic aleukia, characterized by gastroenteritis, fevers, chills, bone marrow suppression with granulocytopenia, and secondary sepsis—a syndrome clinically similar to acute radiation poisoning. Survival beyond this stage is characterized by the development of GI and upper airway ulceration, and intradermal and mucosal hemorrhage. Trichothecene toxins are potent inhibitors of protein synthesis in eukaryotic cells, producing widespread cytotoxicity, particularly in rapidly proliferating tissues; different tricothecene toxins interfere with initiation, elongation, and termination stages of protein synthesis.5 Exposure to any mucosal surface results in severe irritation. Dermal exposure can produce inflammatory lesions lasting for 1 to 2 weeks, vesiculation, and, in higher doses, death.68
Several reports from the 1970s and 1980s suggested that Soviet-supported forces were using trichothecene mycotoxins, particularly the toxin T-2 (Fig. 133–10), as BW. Aerosol and droplet clouds called Yellow Rain were associated with mass casualty incidents in Southeast Asia.68 Such incidents would involve multiple routes of exposure, with skin deposition likely being the major site. Early symptoms included nausea, vomiting, weakness, dizziness, and ataxia. Diarrhea would then ensue, at first watery and then becoming bloody. Within 3 to 12 hours victims would develop dyspnea, cough, chest pain, sore mouths, bleeding gums, epistaxis, and hematemesis. Exposed skin areas would become intensely inflamed, with the appearance of vesicles, bullae, petechiae, ecchymoses, and frank necrosis.68
T-2, a trichothecene mycotoxin.
Nonetheless, evidence that trichothecene mycotoxins were used as BWs was mostly circumstantial. Although T-2 toxin was found in victims’ blood and urine, it was also found in samples from unexposed individuals, probably from baseline ingestion of contaminated foods. Environmental samples containing Yellow Rain droplets were inconsistently found to contain mycotoxins. Eyewitness accounts of Yellow Rain attacks varied widely (including various descriptions of the alleged agent’s color), and, despite the large number of such attacks, no contaminated ordinance or dispersal device was ever recovered.60 It was also discovered that Yellow Rain droplets were composed mostly of pollen grains. Supporters of the Yellow Rain as BW theory retorted that pollen grains would be an ideal carrier for biotoxins, given that their size is ideal for aerosolization. However, the pollen in Yellow Rain samples did not contain protein, similar to pollen that has been digested by bees. Further, the distribution of pollen species found in Yellow Rain was indistinguishable from the contents of feces of the Asian honeybee, and mass bee defecation resulting in showers of yellow droplets has been observed.60 The Yellow Rain “bee feces theory” assumes that any mass-casualty incidents were from endemic disease outbreaks, other chemical or biological agents not yet identified, or a combination of both.