The bioterrorism agents of greatest concern are classified by the US Centers for Disease Control and Prevention as Category A agents, so designated because they are easily disseminated or transmitted from person to person and have high mortality rates. These include B. anthracis (anthrax), Clostridium botulinum (botulism), F. tularensis (tularemia), Y. pestis (plague), smallpox, and viral hemorrhagic fevers.
Anthrax is a zoonotic infection of large herbivores, maintained in nature by spores that are viable in the environment for many decades. B. anthracis infections have a high morbidity and mortality due mainly to their production of two toxins, edema factor and lethal factor, which lead to tissue necrosis and hypotension. Cultures of B. anthracis may be weaponized by drying, milling into fine particles, and adding an agent to counter electrostatic clumping and allow greater airborne dispersal. Anthrax is a proven bioweapon. Accidental release of spores from a bioweapons facility in Sverdlosk (now Yekaterinburg), Russia in 1979 caused at least 66 deaths. The 2001 US outbreak from contaminated mail led to 22 cases, including five deaths.
Inhalational anthrax is the form most likely to result from a bioterror attack. The incubation period is usually from 1 to 7 days, but may be longer; the exact incubation period in any given case may be difficult to ascertain, as spores may settle on surfaces and become airborne again when the environment is disturbed. After initial flu-like symptoms, patients develop high fever, respiratory distress, and shock within 1 to 5 days. Chest radiography may reveal pulmonary infiltrates and pleural effusions. Widening of the mediastinum from hemorrhagic mediastinitis is a frequent and characteristic finding. The death rate of inhalation anthrax in the 2001 US attack was 45%, lower than the historical mortality of 85%.
Cutaneous anthrax is the most common form of naturally-acquired anthrax, and comprised about half of cases in the 2001 attack. It begins as a pruritic papule, and evolves into a hemorrhagic vesicle. Tissue necrosis results in the formation of a black eschar within 7 to 10 days (Figure e5-2). The eschar is usually painless, and is surrounded by impressive nonpitting edema. Without antibiotics, 20% will die of systemic infection. In the rest, the eschar eventually sloughs off, with symptom resolution in 2 to 6 weeks.
Cutaneous anthrax, with central black eschar and surrounding brawny edema. (Public Health Image Library, Centers for Disease Control and Prevention.)
Two other forms of anthrax are less likely to be seen in the context of a bioterrorism event. Gastrointestinal anthrax presents with nausea, anorexia, vomiting, and fever, with progression to severe abdominal pain, hematemesis, and bloody diarrhea. An acute abdomen with rebound tenderness may develop. Mesenteric adenopathy is usually found on abdominal CT. Within 2 to 5 days of symptom onset, ascites, shock, and death may ensue. The purposeful inoculation of food with B. anthracis is one scenario whereby this could occur. Oropharyngeal anthrax presents with fever, severe throat pain, and dysphagia. On examination, patients have marked unilateral or bilateral cervical lymphadenopathy. There may be ulcers on the tonsils, posterior pharynx, or hard palate. Tissue necrosis and edema may lead to airway compromise.
Inhalational anthrax, oropharyngeal anthrax, and gastrointestinal anthrax in adults are treated with intravenous ciprofloxacin 400 mg every 12 hours, or intravenous doxycycline 100 mg every 12 hours. Many authorities recommend the addition of one or two additional antibiotics, such as penicillin or ampicillin, clindamycin, or rifampin. Cutaneous anthrax with systemic symptoms is treated similarly to inhalational anthrax. Otherwise, a prolonged course (60 days) of oral ciprofloxacin 500 mg twice daily or oral doxycycline 100 mg twice daily is recommended.
Infection control and prevention
Inhalational, oropharyngeal, and gastrointestinal anthrax are not spread from person to person, and standard precautions may be employed. Cutaneous anthrax may rarely be transmitted from contact with the wound or its drainage; contact precautions, including gloves and gowns, should be used, and dressings should be autoclaved or incinerated. Long courses of postexposure prophylaxis are given, because of the extended survival of B. anthracis spores. Exposed persons should receive 60 days of either oral ciprofloxacin 500 mg twice daily or oral doxycycline 100 mg twice daily. Oral amoxicillin is an alternative in pregnant or nursing women.
Botulinum toxin, an odorless, tasteless compound, is acquired from food contaminated with preformed toxin (such as home-preserved goods), ingestion of C. botulinum in food or environmental dust, with toxin production in the gut (most commonly seen in infants), or by wound colonization with C. botulinum, with local toxin production. Aerosolization is a likely method of dispersal of botulinum toxin in a bioterrorism event. Botulinum toxin could be added to water supplies, but would be degraded by the chlorine disinfectant used by most water utilities. The toxin could also be added to food, though it is inactivated by cooking. Botulinum toxins are the most potent known. As little as 30 ng may cause a case of human botulism.
The toxin irreversibly blocks the neuromuscular junction by inhibiting presynaptic acetylcholine release. Neurologic symptoms usually begin 12 to 36 hours after exposure. There is progressive symmetric involvement of cranial nerves, with blurred vision, diplopia, ptosis, dysphagia, and dysarthria. Descending flaccid paralysis follows. This may involve the respiratory musculature, and require intubation and mechanical ventilation. Sensation is preserved, and mental status is clear. Recovery from severe cases requires sprouting of new presynaptic nerve terminals, which takes up to 6 months.
Therapy is equine-derived heptavalent (A-G) botulism antitoxin and supportive care. Experience with the heptavalent antitoxin in children is limited, and a tetravalent antitoxin may be provided for the treatment of children. Except for wound botulism, antibiotics have no role in treatment.
Infection control and prevention
Botulism is not transmitted from person to person. Isolation is not required for affected patients. No postexposure prophylaxis is currently available. Due to limited quantities, antitoxin is reserved for symptomatic individuals.
F. tularensis, the agent of tularemia, is a small Gram-negative coccobacillus. It may be naturally acquired from tick, deerfly, or mosquito bites, contact with infected mammals or their meat and hides, ingestion of contaminated food or water, or inhalation, as from mowing a contaminated lawn. Tularemia is endemic in parts of North America, Europe, and Asia. The inoculum for pneumonia may be as low as 10 inhaled organisms, making it an attractive candidate for aerosol dispersal for bioterrorism.
After a typical incubation period of 3 to 5 days, fever, chills, and malaise develop, with local signs at the exposure site. In ulceroglandular tularemia, an ulcer forms at the site of inoculation with enlarged regional lymph nodes. Regional adenopathy may also occur without an ulcer at the inoculation site (glandular tularemia). In oculoglandular tularemia, there is involvement of the inoculated conjunctiva and the draining lymph node(s). If the organism is swallowed, patients may develop pharyngeal tularemia, with exudative pharyngitis or tonsillitis, sometimes ulcerative, and regional adenopathy.
Pneumonic tularemia is often lethal, even with appropriate therapy. It is most commonly due to inhalation, but it can also occur due to seeding of the lung from another infected site. Typhoidal tularemia is not associated with adenopathy or an obvious portal of entry. In addition to fever, chills, and malaise, severe disease can result in multiple end organ dysfunction, including pneumonia. Mortality is high.
The mainstay of treatment is streptomycin. Gentamicin can be used if streptomycin is unavailable, but it is associated with higher rates of failure and relapse than streptomycin. Intravenous doxycycline and chloramphenicol are also used, but are associated with higher relapse rates than either streptomycin or gentamicin. Chloramphenicol is useful in tularemic meningitis. The clinical experience with ciprofloxacin is limited and somewhat ambiguous.
Infection control and prevention
Tularemia is not transmitted from person to person, and infected patients may be placed on standard precautions. A 14-day course of either oral doxycycline or oral ciprofloxacin may be used as postexposure prophylaxis in those exposed to aerosols of F. tularensis. Tularemia is a major laboratory hazard, as very few organisms are required for infection. If tularemia is suspected, the microbiology laboratory should be warned immediately. Serologic testing does not carry the risks of culture, but it may be unrevealing early in the course of illness.
Plague is caused by the Gram-negative rod Y. pestis. Humans acquire plague from flea bites, handling sick or dead mammals, especially cats and rodents, or inhalation of respiratory secretions from patients with pneumonic plague. Plague is endemic in the United States west of the Mississippi River, and in parts of South America, Africa, and Asia. Plague is potentially an excellent agent of bioterrorism, given its high mortality and person-to-person transmission.
Bubonic plague, the most common naturally occurring type, results from infected flea bites. An eschar may form at the bite site. After 2 to 6 days, there is rapid and painful swelling of regional lymph nodes (buboes), with fever, chills, headache, and malaise. Bacteremia is common. In primary septicemic plague, patients have massive bacteremia, with multisystem organ failure and septic shock, but without buboes. Gangrene of the extremities may occur (the probable origin of the term “the Black Death”). Pneumonic plague is acquired from bacteremic seeding of the lungs in bubonic plague, or from inhalation of infectious aerosols from patients with plague pneumonia. This would likely be the most common presentation after a bioterrorist attack involving dispersal of aerosols of Y. pestis. It is difficult to distinguish from other causes of bacterial pneumonia, aside from its high propensity to progress to septic shock.
Streptomycin is the antibiotic of choice for plague. Gentamicin may be used when streptomycin is not available. Tetracyclines and chloramphenicol are also effective. Close contacts of a plague patient, particularly patients with plague pneumonia, should be identified and evaluated. In a bioterrorist event, clinicians should be alert to the possibility of antibiotic resistance, either due to the use of a naturally occurring resistant strain or an engineered strain. Cultures of blood, aspirates of buboes, and cultures of other affected areas (including cerebrospinal fluid in cases of meningitis) should be obtained prior to the initiation of antibiotic therapy.
Infection control and prevention
Respiratory droplet precautions (gloves, masks, gowns, and protective eyewear) are required for at least 48 hours after antibiotics are initiated or sputum cultures are negative. All clinical specimens should be placed in doubly sealed containers. Prophylactic antibiotic therapy with 7 days of oral doxycycline or oral ciprofloxacin should be considered for persons exposed to aerosols of Y. pestis or patients with plague pneumonia.
The World Health Organization declared smallpox eradicated in 1980. However, the Soviet Union manufactured weaponized smallpox during the Cold War, and some of this material may have been smuggled out of the country after the fall of the Communist regime. In addition, as the DNA sequence of a number of variola virus strains are in the public domain, there is the possibility of its de novo synthesis. Routine immunization with vaccinia virus ended in 1972 in the United States and at similar times in other nations, leaving most of the world’s current population susceptible to smallpox. Smallpox is highly contagious and frequently lethal. Variola major, the most common and virulent strain of smallpox, has an overall mortality of 25%.
Prodromal symptoms begin after an incubation period of 7 to 17 days. After 2 to 4 days of headache, malaise, fever, and body aches, a macular rash appears, usually starting in the mouth. The rash spreads to the face, moves rapidly to the arms and legs, and then the hands and feet. The entire body is usually involved within 24 hours (Figure e5-3). The fever may remit, and the patient feels somewhat better. The rash becomes papular by the third day. The papules then fill with a thick, opaque fluid, becoming round, firm, raised pustules with a central depression. The fever may worsen. The pustules gradually crust over. By the end of the second week of the rash, most of the sores have scabbed over, and the fever has subsided. The scabs begin to fall off, and heal to leave pitted scars. Most scabs will have fallen off 3 weeks after the rash appears.
Smallpox patient with pustular rash. Lesions are more dense on the face and extremities than the trunk, and all are in similar stages of development. (Public Health Image Library, Centers for Disease Control and Prevention.)
Clinically, it is important to be able to differentiate smallpox from the rash of chicken pox, caused by varicella-zoster virus (Table e5-1). A large outbreak of monkeypox, which is related to smallpox, occurred in the United States in 2003 following the importation of infected animals. Clinically, monkeypox is very similar to smallpox, except that marked lymphadenopathy is more common in monkeypox.
TABLE e5-1Differences Between Rashes of Smallpox and Chicken Pox (Varicella)* |Favorite Table|Download (.pdf) TABLE e5-1 Differences Between Rashes of Smallpox and Chicken Pox (Varicella)*
|Smallpox (Variola) ||Chicken Pox (Varicella) |
|Pox lesions are all in the same stage ||Pox lesions are in several different stages |
|Slow development ||Rapid development |
|More pox on arms and legs ||More pox on trunk |
|Pox are often present on palms and soles ||Pox are usually absent from palms and soles |
Variola major has a hemorrhagic variant with a mortality rate of 90%. It evolves rapidly, with an average time from prodromal symptoms to death being 6 days. As a result, the first patients presenting after a bioterrorist attack may have hemorrhagic smallpox, which may easily be misdiagnosed as meningococcemia or other illnesses. Hemorrhagic smallpox is more common in pregnant women than in other patients.
There is currently no antiviral agent approved for the management of smallpox. Cidofovir, which is licensed for the treatment of cytomegalovirus retinitis, may be used off-label or under an investigational new drug protocol for the management of smallpox. Otherwise, treatment is supportive.
Infection control and prevention
Smallpox is spread by large respiratory droplets and less efficiently by contact with sloughed skin matter. While smallpox is contagious during the prodrome, it is most infectious immediately after the rash develops. Patients are contagious until all of the scabs are gone. Hospitalized patients should be cared for in negative pressure rooms by vaccinated providers wearing gowns, gloves, and N95 respirators. In a large outbreak, home care and quarantine should be strongly considered for less ill patients, as the supply of negative pressure rooms is likely to be inadequate.
Vaccination with vaccinia virus within 96 hours of exposure to the index case, or to the point of aerosol attack, is part of a concerted public health response to a smallpox outbreak. Vaccinia is a live virus, with occasional major side effects, including myopericarditis, eczema vaccinatum, and disseminated infection. However, for those exposed to smallpox, there are no absolute contraindications to vaccination. Complications of vaccination can often be managed with vaccinia immune globulin.
Hemorrhagic fever in humans may be caused by filoviruses (Ebola virus and Marburg virus), arenaviruses (Lassa virus, Junin virus, and Machupo virus), bunyaviruses (Crimean-Congo hemorrhagic fever, Rift Valley fever virus, Hantaan virus, Seoul virus), and others. Some have exceptionally high mortality rates and are efficiently transmitted from person to person, especially Ebola, Marburg, and Crimean-Congo hemorrhagic fever virus.
These RNA viruses, while biologically diverse and having different animal or arthropod reservoirs, share important clinical manifestations. These include nonspecific signs and symptoms such as fever, malaise, muscle aches, pharyngitis, and rash, as well as increased vascular permeability, disseminated intravascular coagulation, and shock.
Patients who have returned from endemic areas with an illness compatible with viral hemorrhagic fever (VHF) should be assessed for other illnesses that may have overlapping symptoms, such as malaria, meningococcemia, and rickettsial disease.
Specific therapy with ribavirin is available for the arenaviruses. Convalescent serum may also be efficacious for arenavirus infection. For the other VHF agents, therapy is supportive.
Infection control and prevention
Isolation precautions for suspected VHF include barrier precautions and isolation in negative pressure rooms. High-efficiency particulate air (HEPA) filter masks should be used in patients with respiratory or gastrointestinal symptoms. Blood draws should be minimized when VHF is highly suspected, and all specimens should be double bagged. Patients with suspected VHF should not be transferred from one hospital to another. Autopsies should only be performed with maximal protection, and prompt cremation of cadavers is recommended.