Biological weapons have been used since antiquity, with documented cases dating back to the 6th century BC, when the Assyrians poisoned wells with ergots. In the late 1930s and early 1940s, the Japanese Army (Unit 731) experimented on prisoners of war in Manchuria with biological agents that are thought to have resulted in at least 10,000 deaths. Although in 1972 over 100 nations signed the Biological Weapons Convention, both the former Soviet Union and Iraq have admitted to the production of biological weapons, and many other countries are suspected of continuing their programs. Today, bioweapons are considered the cheapest and easiest weapons of mass destruction to produce.

The US government groups bioterrorism agents into three categories: A, B, and C. Category A includes organisms or toxins that pose the highest risk to the public and national security because they can be easily spread or transmitted from person to person; result in high death rates and have the potential for major public health impact; might cause public panic and social disruption; and require special action for public health preparedness. Category B agents are the second highest priority: they are moderately easy to spread; result in moderate illness rates and low death rates; and require specific enhancements of CDC's laboratory capacity and enhanced disease monitoring. Category C agents are the third highest priority and include emerging pathogens that could be engineered for mass spread in the future because they are easily available; easily produced and spread; and have potential for high morbidity and mortality rates and major health impact. See http://emergency.cdc.gov/bioterrorism/overview.asp.

Category A agents (see the following text and Table II-60) include Bacillus anthracis (anthrax), Yersinia pestis (plague), Clostridium botulinum toxin (botulism), Variola major (smallpox), and Francisella tularensis (tularemia), and viral hemorrhagic fevers. All these agents can be weaponized easily for aerial dispersion.

The effect of a biological weapon on a population was demonstrated in an attack on the east coast of the United States in September 2001. Anthrax spores were delivered through the mail and resulted in 11 cases of inhalational anthrax and 12 cases of the cutaneous form of the disease. Even on that small scale, the effect on the public health system was enormous, and an estimated 32,000 people received prophylactic antibiotic therapy.

Are variable but generally extremely small. As few as 10-50 F. tularensis organisms may cause tularemia, and less than 100 mcg of botulinum toxin can result in botulism.

1. Anthrax spores penetrate the body's defenses by inhalation into terminal alveoli or by penetration of exposed skin or the GI mucosa. They are then ingested by macrophages and transported to lymph nodes, where germination occurs (this may take up to 60 days). The bacteria multiply and produce two toxins: “lethal factor” and “edema factor.” Lethal factor produces local necrosis and toxemia by stimulating the release of tumor necrosis factor and interleukin 1-beta from macrophages.
2. Plague bacteria (Y. pestis) penetrate the body's defenses either by inhalation into terminal alveoli or by the bite of an infected flea. Dissemination occurs through lymphatics, where the bacteria multiply, leading to lymph node necrosis. Bacteremia, septicemia, and endotoxemia result in shock, coagulopathy, and coma. Historically, plague is famous as the “Black Death” of the 14th and 15th centuries, which killed 20-30 million people in Europe.
3. Botulinum toxins are one of the most potent toxins known, with microgram quantities potentially lethal to an adult. Botulinum toxin cannot penetrate intact skin but can be absorbed through wounds or across mucosal surfaces. Once absorbed, the toxins are carried to presynaptic nerve endings at neuromuscular junctions and cholinergic synapses, where they bind irreversibly, impairing the release of acetylcholine.
4. Smallpox virus particles reach the lower respiratory tract, cross the mucosa, and travel to lymph nodes, where they replicate and cause a viremia that leads to further spread and multiplication in the spleen, bone marrow, and lymph nodes. A secondary viremia occurs, and the virus spreads to the dermis and oral mucosa. Death results from the toxemia associated with circulating immune complexes and soluble variola antigens.
5. Tularemia.F. tularensis bacteria usually cause infection by exposure to bodily fluids of infected animals or through the bites of ticks or mosquitoes. Aerosolized bacteria can also be inhaled. An initial focal, suppurative necrosis is followed by bacterial multiplication within macrophages and dissemination to lymph nodes, lungs, spleen, liver, and kidneys. In the lungs, the lesions progress to pneumonic consolidation and granuloma formation and can result in chronic interstitial fibrosis.

(See Table II-60 and the Centers for Disease Control and Prevention website on biological and chemical terrorism at http://emergency.cdc.gov/bioterrorism)

1. Anthrax may present in three different forms: inhalational, cutaneous, and GI. Inhalational anthrax is extremely rare, and any case should raise the suspicion of a biological attack. Cutaneous anthrax typically follows exposure to infected animals and is the most common form, with over 2,000 cases reported annually. GI anthrax is rare and follows the ingestion of contaminated meat.
2. Plague. Although plague traditionally is spread through infected fleas, biological weapons programs have attempted to increase its potential by developing techniques to aerosolize it. Depending on the mode of transmission, there are two forms of plague: bubonic and pneumonic. The bubonic form would be seen after dissemination of the bacteria through infected fleas into a population (this was investigated by the Japanese in the 1930s in Manchuria). After an aerosolized release, the predominant form would be pneumonic.
3. Botulism poisoning is described in more detail on botulism. Patients may present with blurred vision, ptosis, difficulty swallowing or speaking, and dry mouth, with progressive muscle weakness leading to flaccid paralysis and respiratory arrest within 24 hours. Because the toxins act irreversibly, recovery may take months.
4. Smallpox infection causes generalized malaise and fever due to viremia, followed by a characteristic diffuse pustular rash in which most of the lesions are in the same stage of development.
5. Tularemia. After inhalation, victims may develop nonspecific symptoms resembling those of any respiratory illness, including fever, nonproductive cough, headache, myalgias, sore throat, fatigue, and weight loss. Skin inoculation causes an ulcer, painful regional lymphadenopathy, fever, chills, headache, and malaise.

Recognition of a bioweapon attack most likely will be made retrospectively, based on epidemiologic investigations. Specific indicators might include patients presenting with exotic or nonendemic infections, clusters of a particular disease, and infected animals in the region where an outbreak is occurring. A historical example is the downwind pattern of disease and proximity of animal deaths that helped prove that the anthrax outbreak in Sverdlovsk (in the former Soviet Union) in 1979 was caused by the release of anthrax spores from a biological weapons plant.

1. Anthrax
   1. Obtain a Gram stain and culture of vesicle fluid and blood. Rapid diagnostic tests (enzyme-linked immunosorbent assay [ELISA], polymerase chain reaction [PCR]) are available at national reference laboratories.
   2. Chest radiograph may reveal widened mediastinum and pleural effusions. Chest CT may reveal mediastinal lymphadenopathy.
2. Plague
   1. Obtain a Gram stain of blood, cerebrospinal fluid, lymph node aspirate, or sputum. Other diagnostic tests include direct fluorescent antibody testing and PCR for antigen detection.
   2. Chest radiograph may reveal patchy or consolidated bilateral opacities.
3. Botulism (see also botulism)
   1. The toxin may be present on nasal mucous membranes and be detected by ELISA for 24 hours after inhalation. Refrigerated samples of serum, stool, or gastric aspirate can be sent to the CDC or specialized public health laboratories that can run a mouse bioassay.
   2. Electromyography (EMG) may reveal normal nerve conduction velocity; normal sensory nerve function; a pattern of brief, small-amplitude motor potentials; and, most distinctively, an incremental response to repetitive stimulation, often seen only at 50 Hz.
4. Smallpox virus can be isolated from the blood and scabs and can be seen under light microscopy as Guarnieri bodies or by electron microscopy. Cell culture and PCR may also be employed.
5. Tularemia
   1. Obtain blood and sputum cultures. F. tularensis may be identified by direct examination of secretions, exudates, or biopsy specimens with the use of direct fluorescent antibody or immunohistochemical stains. Serology may confirm the diagnosis retrospectively.
   2. Chest radiograph may reveal evidence of opacities with pleural effusions that are consistent with pneumonia.

Contact the Centers for Disease Control and Prevention (CDC) 24-hour emergency operations center at 1-770-488-7100 for assistance with diagnosis and management.

1. Emergency and supportive measures.
   1. Provide supportive care. Treat hypotension with IV fluids and vasopressors and respiratory failure with assisted ventilation.
   2. Isolate patients with suspected plague, smallpox, or viral hemorrhagic fevers, who may be highly contagious. Patient isolation is not needed for suspected anthrax, botulism, or tularemia because person-to-person transmission is not likely. However, health care workers should always use universal precautions.
2. Specific drugs and antidotes
   1. Antibiotics are indicated for suspected anthrax, plague, or tularemia. All three bacteria are generally susceptible to fluoroquinolones, tetracyclines, and aminoglycosides. The following drugs and doses often are recommended as initial empiric treatment, pending results of culture and sensitivity testing (see also MMWR. 2001;50(42):909-919, which is available on the Internet at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5042a1.htm).
      1. Ciprofloxacin, 400 mg IV every 12 hours (children: 20-30 mg/kg/d up to 1 g/d).
      2. Doxycycline, 100 mg orally or IV every 12 hours (children 45 kg: 2.2 mg/kg). Note: Doxycycline may discolor teeth in children younger than 8 years of age.
      3. Gentamicin, 5 mg/kg IM or IV once daily, or streptomycin.
      4. Antibiotics should be continued for 60 days in patients with anthrax infection. Postexposure antibiotic prophylaxis is recommended after exposure to anthrax, plague, and tularemia.
      5. Antibiotics are not indicated for ingested or inhaled botulism; aminoglycosides can make muscle weakness worse.
   2. Vaccines. Anthrax, smallpox, and ebola vaccines can be used before exposure and also for postexposure prophylaxis. Vaccines are not currently available for plague or tularemia.
   3. Antitoxins
      1. Botulism. A heptavalent antitoxin (H-BAT; see botulism antitoxin) for botulism is an equine-derived antibody that covers toxin types A, B, C, D, E, F, and G. It is accessible only through the CDC.
      2. Anthrax Immune Globulin is purified human immune globulin G (IgG) containing polyclonal antibodies that bind the protective antigen component of Bacillus anthracis lethal and edema toxins. Raxibacumab is a human IgG₁ gamma monoclonal antibody directed at the protective antigen of B. anthracis. Obiltoxaximab is a chimeric IgG₁ kappa monoclonal antibody directed at the protective antigen of B. anthracis.
      3. Vaccinia Immune Globulin (VIG-IV) is a purified human immunoglobulin G (IgG) with trace amounts of IgA and IgM. It is derived from adult human plasma collected from donors who received booster immunizations with the smallpox vaccine. VIG-IV contains high titers of antivaccinia antibodies. It is accessible only through the CDC.
3. Decontamination. Note: The clothing and skin of exposed individuals may be contaminated with spores, toxin, or bacteria. Rescuers and health care providers should take precautions to avoid secondary contamination.
   1. Remove all potentially contaminated clothing and wash the patient thoroughly with soap and water.
   2. Dilute bleach (0.5%) and ammonia are effective for cleaning surfaces possibly contaminated with viruses and bacteria.
   3. All clothing should be cleaned with hot water and bleach.
4. Enhanced elimination. These procedures are not relevant.