Many countries, including the United States, have developed and amassed bacteria, viruses, and toxic products of these organisms for use against both military and civilian targets. After the Biological Weapons and Toxin Convention of 1972, 162 countries, including the U.S., pledged to halt the development, possession, or use of such agents. This has not completely eliminated the worldwide stockpiles, however, and several countries (notably Iraq and North Korea) have continued to develop biologic warfare programs. With the breakup of the Soviet Union and the decay of its armed forces and security, small nuclear and biological weapons are believed to have left that country.
Recognizing the signs and symptoms of diseases from biologic warfare agents and reporting suspicious cases are crucial to curtailing an outbreak. In Yugoslavia in 1972, it took four weeks to recognize a natural outbreak of smallpox that resulted in 175 cases and 35 deaths.1 One can hardly fathom the number of cases if this was an intentional exposure. This month, we focus on three of the most likely organisms that have been developed as weapons and suggest an approach to diagnosis and treatment of diseases related to biologic weapons.
Anthrax, the disease caused by Bacillus anthracis, is a prototypical biological agent. It is easily disseminated, very contagious, and has a high mortality rate. It also is relatively inexpensive, has an incubation period of only days, and is easily dispersed. The World Health Organization estimates that 50 kg of anthrax spores released from an aircraft over a city of 500,000 people would kill 95,000 and incapacitate another 125,000.2
Bacillus anthracis is a gram-positive spore-forming bacillus causing disease naturally in domesticated sheep, horses, cattle, goats, and cattle. Disease is caused by exposure via one of three routes: inhalational, cutaneous, or gastrointestinal. While inhalational anthrax is normally very rare (with only 18 cases in the United States in the past 100 years3) anthrax spores would cause an outbreak of the inhalational disease.
One to six days following dispersion of the spores by aircraft, a spray device or bomblets from a missile warhead, exposed individuals will present with nonspecific symptoms of malaise, myalgias, nonproductive cough, and fever. Two to three days later, these individuals may develop acute onset of chest pain, shortness of breath, diaphoresis, and hypoxia. A chest x-ray will show a wide mediastinum due to hemorrhagic mediastinitis, a syndrome pathognomonic of inhalational anthrax. At this point in the disease, most patients develop shock and die within 24 to 36 hours. Approximately half of inhalational anthrax cases develop hemorrhagic meningitis, another pathognomonic finding. Mortality, even with treatment, approaches 100 percent.4
Diagnosing anthrax is contingent upon recognition of the unique aspects of the disease, notably respiratory distress associated with a wide mediastinum and/or hemorrhagic meningitis. Blood cultures will not return in time to help with an ED diagnosis (although they will grow the organism) and because anthrax does not cause pneumonia, a sputum gram stain and culture will not be useful. The one opportunity an emergency physician has to make this diagnosis is detection of the organism in CSF Gram's stain of patients with meningitis.
While anthrax has historically been very sensitive to penicillin, military experts believe that weaponized anthrax will probably be penicillin-resistant. Therefore, ciprofloxacin (400 mg IV) or doxycycline (200 mg IV) are the drugs of choice for acute illness from weaponized anthrax; levofloxacin and ofloxacin are alternatives. The CDC recommends chemoprophylaxis and vaccination of potentially exposed individuals.5 The antibiotics of choice for prophylaxis are ciprofloxacin or doxycycline given for one month after exposure.
This recommendation also applies to at-risk children, although once antibiotic susceptibilities are obtained, children should be switched to penicillin or amoxicillin if appropriate. Anthrax Vaccine Adsorbed (AVA) is the only vaccine licensed in the U.S. for anthrax exposure. The vaccine, although never studied in humans, afforded immunity in nonhuman primates when used with antibiotics. The recommended schedule for vaccination is at weeks 0, 2, and 4. Antibiotics can be discontinued after the third vaccination. It should be noted that this protocol has never been studied in humans, but is expected to be highly effective in preventing disease in exposed individuals.5
Another infectious disease with potential as a modern biologic weapon is Yersinia pestis, the bacterium responsible for the “Black Death” of the Middle Ages. Y. pestis is a gram-negative bacterium that is transmitted through the bite of an infected flea. Squirrels are the most common disease reservoir in the U.S.8 In the United States there were nine cases reported in 1999, and in 1996 there was an outbreak of five cases, resulting in two deaths.9,10
Y. pestis can be weaponized by spraying droplets containing the organism or releasing infected fleas. Yersinia was first used as an intentional biological weapon in 1346 during a battle near Caffa, where infected corpses were catapulted at opposing sailors.6Y. pestis was used against Chinese civilians in World War II, where it was mixed in rice and wheat and dropped from the air.7
Manifestations of disease from weaponized plague would depend on the method of exposure: an aerosolized attack would result in the pneumonic form of disease while a flea-borne attack would result in a bubonic form. In the bubonic form, patients would present after a one- to eight-day incubation period with nonspecific complaints of fever, chills, malaise, and headache. During the first day of symptoms, buboes appear with marked swelling and tenderness of the lymph nodes that drain the bitten body part, and because fleas usually bite human's legs, the groin nodes are the most commonly affected.
These nodes can be aspirated and the aspirate sent for Gram's stain which is diagnostic. If untreated, bubonic disease leads to septicemic plague after two to six days.11 This variant presents with signs of sepsis, including nausea, vomiting, diarrhea, fevers, and chills. Unlike other sepsis syndromes, Y. pestis sepsis is associated with acral cyanosis and necrosis of the extremities. Septicemic plague is rarer than bubonic, but carries a higher mortality (33% vs. 11.5%).12 Pneumonic plague, the form acquired from inhalation, presents like a typical pneumonia, usually producing bilateral alveolar infiltrates. The drug of choice is streptomycin (15 mg/kg BID), but gentamicin or doxycycline can be used. If meningitis is present, chloramphenicol is the drug of choice.13
Variola is the organism responsible for smallpox. Although the last naturally acquired case was in 1977 and the last laboratory-acquired case in 1978, there are still laboratory stores of the virus in the U.S. and Russia. Smallpox has a long history of use as a biological weapon with reports of its use against Native Americans14 in the 18th Century and during World War II.7 The virus is very stable outside of the host and spreads by aerosol.
After inhalation and a 12-day incubation period, infected individuals develop malaise, fever, rigors, vomiting, headache, and backache. Two to three days later, a characteristic rash begins on the face, hands, and forearms. The rash then spreads to the trunk (in contrast to varicella, which spreads centrifugally). Variola lesions begin as macules then develop into papules then pustules, which scab over and fall off, leaving a scar. Unlike varicella, the lesions are at approximately the same stage on each body part. Furthermore, the lesions are deeply embedded in the dermis, giving the feel of subcutaneous nodules. Of note, the scabs themselves carry the virus and are considered infectious. Oropharyngeal secretions also are highly infective.
Treatment for either exposure to smallpox or acute disease is first achieved by vaccination with a live vaccine. While the CDC currently has 12 million doses in storage, there are concerns that many batches have lost potency. For those of us old enough to have the scar of smallpox vaccination (routine vaccinations ended in 1971), there is little comfort in knowing that maximum immunity only lasts for approximately three years after vaccination. Individuals who were immunized as children may retain some degree of immunity as long as approximately 10 years after immunization. Vaccination within three days of exposure to smallpox affords immunity equal to primary vaccination. The vaccine itself has dangers, and should not be used in patients with HIV, dermatitis, or who are pregnant.
In a biological attack, however, these become relative contraindications, and all who are symptomatic, potentially exposed, or in close contact with exposed individuals should be immunized.15 There is a vaccinia immune globulin (VIG) indicated for treatment of vaccine-related complications but not for post-exposure prophylaxis. Two antivirals, ribavirin, and cidofivir, are considered the drugs of choice for treatment of variola.13
Anyone suspected of having smallpox should be placed in contact and respiratory isolation, and state health officials must be contacted immediately. Mortality from naturally occurring variola is approximately 30 percent, but a more rare and more deadly variant has a 90 percent mortality.15
The pathogens discussed in this article are considered three of the most likely organisms to be weaponized. The frightening reality is that there are many other naturally occurring bacteria, viruses, and even byproducts of these organisms that have been weaponized and may be used in an attack.
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. Aurora, Colo. September 1995.
9. Summary of Notifiable Diseases, United States, 1999. MMWR
10. Fatal Human Plague-Arizona and Colorado,1996. MMWR
11. Conrad FG, Le Cocq FR, et al. A recent epidemic of plague in Vietnam. Arch Int Med
12. Hull HF, Montes JM, et al. Septicemic plague in New Mexico. J Infect Dis
13. Drugs and Vaccines against Biological Weapons. The Medical Letter on Drugs and Therapeutics
14. Stearn EW, Stearn AE. The Effects of Smallpox on the Destiny of Amerindians
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New Authors for ID Rounds
EMN is proud to announce the addition of two new physicians to our already distinguished complement of authors for ID Rounds. Joining Katherine Heilpern, MD, and David J. Karras, MD, are Lawrence Isaacs, MD, and Stephen J. Playe, MD. Dr. Isaacs' first and timely column on bioterrorism appears in this issue. Dr. Playe's first ID Rounds will appear in December.
Dr. Isaacs is an assistant professor of medicine at Temple University School of Medicine. Dr. Playe is an assistant professor of emergency medicine at Tufts University School of Medicine in Medford, MA, and the emergency medicine residency program director at Baystate Medical Center in Springfield, MA.
15. Vaccinia Vaccine Recommendations of the Advisory Committee on Immunization Practices, 2001. 2001;50(RR-10);1.