Anthrax is a zoonotic disease caused by Bacillus anthracis. There are three types of this disease: cutaneous anthrax, inhalation anthrax, and gastrointestinal anthrax. About 95% of the human anthrax cases in the United States have been in the former category. Cutaneous anthrax develops when a bacterial organism from infected animal tissues becomes deposited under the skin. When a patient contracts cutaneous anthrax, he develops a small elevated lesion on his skin which becomes a skin ulcer, frequently surrounded by swelling or edema. The lymph gland near the lesion may also swell from the infection. If the lesion occurs on the neck or on or about the eye, it may cause complications. The incubation period for cutaneous anthrax is from one to seven days. When a patient does not receive an effective antibiotic, the mortality rate for cutaneous anthrax is 10-20%. With treatment, the mortality rate falls to less than 1%.Inhalation anthrax develops when the bacterial organism is inhaled into the lungs. A progressive infection follows. Since inhalation anthrax is usually not diagnosed in time for treatment, the mortality rate in the United States is 90-100%. A biological attack with anthrax spores delivered by aerosol would cause inhalation anthrax, an extraordinarily rare form of the naturally occurring disease.A lethal dose of anthrax is considered to be 10,000 spores; 80 percent of a population that inhaled such a dose would die. Less than one millionth of a gram is invariably fatal within five days to a week after exposure. According to an estimate by the U.S. Congress’s Office of Technology Assessment, 100 kilograms of anthrax, released from a low-flying aircraft over a large city on a clear, calm night, could kill one to three million people.The disease begins after an incubation period varying from 1-6 days, presumably dependent upon the dose of inhaled organisms. Onset is gradual and nonspecific, with fever, malaise, and fatigue, sometimes in association with a nonproductive cough and mild chest discomfort. In some cases, there may be a short period of improvement. The initial symptoms are followed in 2-3 days by the abrupt development of severe respiratory distress with dyspnea, diaphoresis, strider, and cyanosis. Physical findings may include evidence of pleural effusions, edema of the chest wall, and meningitis. Chest x-ray reveals a dramatically widened mediastinum, often with pleural effusions, but typically without infiltrates. Shock and death usually follow within 24-36 hours of respiratory distress onset.An epidemic of inhalation anthrax in its early stage with nonspecific symptoms could be confused with a wide variety of viral, bacterial, and fungal infections. Progression over 2-3 days with the sudden development of severe respiratory distress followed by shock and death in 24-36 hours in essentially all untreated cases eliminates diagnoses other than inhalation anthrax. The presence of a widened mediastinum on chest x-ray, in particular, should alert one to the diagnosis. Other suggestive findings include chest-wall edema, hemorrhagic pleural effusions, and hemorrhagic meningitis. Other diagnoses to consider include aerosol exposure to SEB; but in this case onset would be more rapid after exposure (if known), and no prodrome would be evident prior to onset of severe respiratory symptoms. Mediastinal widening on chest x-ray will also be absent. Patients with plague or tularemia pneumonia will have pulmonary infiltrates and clinical signs of pneumonia (usually absent in anthrax).

Almost all cases of inhalation anthrax in which treatment was begun after patients were symptomatic have been fatal, regardless of treatment. Historically, penicillin has been regarded as the treatment of choice, with 2 million units given intravenously every 2 hours. Tetracycline and erythromycin have been recommended in penicillin-sensitive patients. The vast majority of anthrax strains are sensitive in vitro to penicillin. However, penicillin-resistant strains exist naturally, and one has been recovered from a fatal human case. Moreover, it is not difficult to induce resistance to penicillin, tetracycline, erythromycin, and many other antibiotics through laboratory manipulation of organisms. All naturally occurring strains tested to date have been sensitive to erythromycin, chloramphenicol, gentamicin, and ciprofloxacin.

Vaccines are available against some forms of anthrax, but their efficacy against abnormally high concentrations of the bacteria is uncertain. A licensed, alum-precipitated preparation of purified B.anthracis protective antigen (PA) has been shown to be effective in preventing or significantly reducing the incidence of inhalation anthrax. Limited human data suggest that after completion of the first three doses of the recommended six-dose primary series (0, 2, 4 weeks, then 6, 12, 18 months), protection against both cutaneous and inhalation anthrax is afforded. As with all vaccines, the degree of protection depends upon the magnitude of the challenge dose; vaccine-induced protection is undoubtedly overwhelmed by extremely high spore challenge.

If there is information indicating that a biological weapon attack is imminent, prophylaxis with ciprofloxacin (500 mg orally twice a day), or doxycycline (100 mg orally twice a day) is recommended. If unvaccinated, a single 0.5 mL dose of vaccine should also be given subcutaneously. Should the attack be confirmed as anthrax, antibiotics should be continued for at least 4 weeks in all exposed.

Botulism is caused by intoxication with any of the seven distinct neurotoxins produced by the bacillus, Clostridium botulinum. In humans, disease results from only four (A, B, E, and F) of those seven types of neurotoxins. The toxins are proteins with molecular weights of approximately 150,000, which bind to the presynaptic membrane of neurons at peripheral cholinergic synapses to prevent release of acetylcholine and block neurotransmission. The blockade is most evident clinically in the cholinergic autonomic nervous system and at the neuromuscular junction. A biological attack with botulinum toxin delivered by aerosol would be expected to cause symptoms similar in most respects to those observed with food-borne botulism.In pure form, the toxin is a white crystalline substance that is readily dissolvable in water, but decays rapidly in the open air. Symptoms of inhalation botulism may begin as early as 12-36 hours following exposure or as late as several days. Initial signs and symptoms include ptosis, generalized weakness, lassitude, and dizziness. Diminished salivation with extreme dryness of the mouth and throat may cause complaints of a sore throat. Urinary retention or ileus may also occur. Motor symptoms usually are present early in the disease; cranial nerves are affected first with blurred vision, diplopia, ptosis, and photophobia. Development of respiratory failure may be abrupt. Mucous membranes of the mouth may be dry and crusted. Neurological examination shows flaccid muscle weakness of the palate, tongue, larynx, respiratory muscles, and extremities. Deep tendon reflexes vary from intact to absent.The occurrence of an epidemic with large numbers of afebrile patients with progressive ocular, pharyngeal, respiratory, and muscular weakness and paralysis hints strongly at the diagnosis. Single cases may be confused with various neuromuscular disorders such as atypical Guillain-Barrè syndrome, myasthenia gravis, or tick paralysis. The edrophonium (tensilon) test may be transiently positive in botulism.Respiratory failure secondary to paralysis of respiratory muscles is the most serious complication and, generally, the cause of death. Reported cases of botulism prior to 1950 had a mortality of 60%. With tracheotomy and ventilator assistance, fatalities should be <5%. Intensive and prolonged nursing care may be required for recovery (which may take several weeks or even months).A pentavalent toxoid of Clostridium botulinum types A, B, C, D, and E is available under IND status. This product has been administered to several thousand volunteers and occupationally at-risk workers and induces serum antitoxin levels that correspond to protective levels in experimental animal systems. The currently recommended schedule (0, 2, and 12 weeks, then a 1 year booster) induces solidly protective antitoxin levels in greater than 90 percent of those vaccinated after 1 year.

Ebola hemorrhagic fever is one of the most virulent viral diseases known to humankind, causing death in 50-90% of all clinically-ill cases. Consequently, it has figured prominently in popular discussions of biological weapons, although its practical applications as a biological threat agent remain speculative. The disease has its origins in the jungles of Africa and Asia and several different forms of Ebola virus have been identified and may be associated with other clinical expressions, on which further research is required.The Ebola virus is transmitted by direct contact with the blood, secretions, organs or semen of infected persons. Transmission through semen may occur up to 7 weeks after clinical recovery, as with Marburg hemorrhagic fever. Health care workers have frequently been infected while attending patients. In the 1976 epidemic in Zaire, every Ebola case caused by contaminated syringes and needles died.After an incubation period of 2 to 21 days, Ebola is often characterized by the sudden onset of fever, weakness, muscle pain, headache and sore throat. This is followed by vomiting, diarrhea, rash, limited kidney and liver functions, and both internal and external bleeding. Specialized laboratory tests on blood specimens (which are not commercially available) detect specific antigens or antibodies and/or isolate the virus. These tests present an extreme biohazard and are only conducted under maximum containment conditions.No specific treatment or vaccine exists for Ebola hemorrhagic fever. Severe cases require intensive supportive care, as patients are frequently dehydrated and in need of intravenous fluids. Experimental studies involving the use of hyperimmune sera on animals demonstrated no long-term protection against the disease after interruption of therapy.Suspected cases should be isolated from other patients and strict barrier nursing techniques practiced. All hospital personnel should be briefed on the nature of the disease and its routes of transmission. Particular emphasis should be placed on ensuring that high-risk procedures such as the placing of intravenous lines and the handling of blood, secretions, catheters, and suction devices are done under barrier nursing conditions. Hospital staff should have individual gowns, gloves, and masks. Gloves and masks must not be reused unless disinfected. Patients who die from the disease should be promptly buried or cremated.As the primary mode of person-to-person transmission is contact with contaminated blood, secretion, or body fluids, any person who has had close physical contact with patients should be kept under strict surveillance, i.e. body temperature checks twice a day, with immediate hospitalization and strict isolation recommended in case of temperatures above 38.3° C (101° F). Casual contacts should be placed on alert and asked to report any fever. Surveillance of suspected cases should continue for three weeks after the date of their last contact. Hospital personnel who come into close contact with patients or contaminated materials without barrier nursing attire must be considered exposed and put under close supervised surveillance.The Ebola virus was first identified in a western equatorial province of Sudan and in a nearby region of Zaire in 1976 after significant epidemics in Yamkubu, northern Zaire, and Nzara, southern Sudan. Between June and November 1976 the Ebola virus infected 284 people in Sudan, with 117 deaths. In Zaire there were 318 cases and 280 deaths in September and October. An isolated case occurred in Zaire in 1977 and a second outbreak in Sudan in 1979. In 1989 and 1990, a filovirus, named Ebola-Reston, was isolated in monkeys being held in quarantine in laboratories in Reston, VA, Alice, TX, and Pennsylvania. In the Philippines, Ebola-Reston infections occurred in a quarantine area near Manila for monkeys intended for exportation. A large epidemic occurred in Kikwit, Zaire in 1995 with 315 cases, 244 with fatal outcomes. One human case of Ebola hemorrhagic fever and several cases in chimpanzees were confirmed in Côte d’Ivoire in 1994-95. In Gabon, Ebola hemorrhagic fever was first documented in 1994 and recent outbreaks occurred in February 1996 and July 1996. In all, nearly 1,100 cases with 793 deaths have been documented since the virus was discovered. The natural reservoir of the Ebola virus seems to reside in the rain forests of Africa and Asia but has not yet been identified.

Different hypotheses have been developed to try to uncover the cycle of Ebola. Initially, rodents were suspected, as is the case with Lassa Fever whose reservoir is a wild rodent (Mastomys). Another hypothesis is that a plant virus may have caused the infection of vertebrates. Laboratory observation has shown that bats experimentally infected with Ebola do not die and this has raised speculation that these mammals may play a role in maintaining the virus in the tropical forest.

• In bubonic plague, the incubation period ranges from 2 to 10 days. The onset is acute and often fulminant with malaise, high fever, and one or more tender lymph nodes. Inguinal lymphadenitis (bubo) predominates, but cervical and axillary lymph nodes can also be involved. The involved nodes are tender, fluctuant, and necrotic. Bubonic plague may progress spontaneously to the septicemia form with organisms spread to the central nervous system, lungs (producing pneumonic disease), and elsewhere. The mortality is 50 percent in untreated patients with the terminal event being circulatory collapse, hemorrhage, and peripheral thrombosis.
• In primary pneumonic plague, the incubation period is 2 to 3 days. The onset is acute and fulminant with malaise, high fever, chills, headache, myalgia, cough with production of a bloody sputum, and toxemia. The pneumonia progresses rapidly, resulting in dyspnea, strider, and cyanosis. In untreated patients, the mortality is 100 percent with the terminal event being respiratory failure, circulatory collapse, and a bleeding diathesis.

In cases where bubonic type is suspected, tularemia adenitis, staphylococcal or streptococcal adenitis, meningococcemia, enteric gram negative sepsis, and rickettsiosis need to be ruled out. In pneumonic plague, tularemia, anthrax, and staphylococcal enterotoxin B (SEB) agents need to be considered. Continued deterioration without stabilization effectively rules out SEB.

Plague may be spread from person to person by droplets. Strict isolation procedures for all cases are indicated. Streptomycin, tetracycline, and chloramphenicol are highly effective if begun early. Significant reduction in morbidity and mortality is possible if antibiotics are given within the first 24 hours after symptoms of pneumonic plague develop.

A formalin-killed Y. pestis vaccine that was produced in the United States and extensively used is no longer manufactured. Efficacy against flea-borne plague was inferred from population studies, but the utility of this vaccine against aerosol challenge was unknown. Immunity was maintained through boosters every 1-2 years. Live-attenuated vaccines are available elsewhere but are highly reactogenic and without proven efficacy against aerosol challenge.

Ricin is a glycoprotein toxin (66,000 daltons) from the seed of the castor plant. It blocks protein synthesis by altering the rRNA, thus killing the cell. Ricin’s significance as a potential biological threat agent relates to its availability worldwide, ease of production, and extreme pulmonary toxicity when inhaled.Overall, the clinical picture seen depends on the route of exposure. All reported serious or fatal cases of castor bean ingestion have taken approximately the same course: rapid onset of nausea, vomiting, abdominal cramps, and severe diarrhea with vascular collapse; death has occurred on the third day or later. Following inhalation, one might expect nonspecific symptoms of weakness, fever, cough, nausea, and hypothermia followed by hypotension and cardiovascular collapse. High doses by inhalation appear to produce severe enough pulmonary damage to cause death.In oral intoxication, fever, gastrointestinal involvement, and vascular collapse are prominent, the latter differentiating it from infection with enteric pathogens. With regard to inhalation exposure, nonspecific findings of weakness, fever, vomiting, cough, hypothermia, and hypotension in large numbers of patients might suggest several respiratory pathogens.Therapy is supportive and should include maintenance of intravascular volume. Standard management for poison ingestion should be employed if intoxication is by the oral route. There is presently no antitoxin available for treatment.There is currently no prophylaxis approved for human use. Active immunization and passive antibody prophylaxis are under study, as both are effective in protecting animals from death following exposure by intravenous or respiratory routes.

Smallpox virus, an orthopoxvirus with a narrow host range confined to humans, was an important cause of morbidity and mortality in the developing world until recent times. Although the World Health Organization declared the virus eradicated in 1980, eradication of the natural disease was completed in 1977 and the last human cases, associated with laboratory infections, occurred in 1978. The virus exists today in only 2 laboratory repositories, one in the U.S. and the other in Russia. Appearance of human cases outside the laboratory would signal use of the virus as a biological weapon. Under natural conditions, the virus is transmitted by direct (face-to face) contact with an infected case, by fomites, and occasionally by aerosols. Smallpox virus is highly stable and retains infectivity for long periods outside of the host. A related virus, monkeypox, clinically resembles smallpox and causes sporadic human disease in West and Central Africa.The incubation period is typically 12 days (range, 10-17 days). The illness begins with a prodrome lasting 2-3 days, with generalized malaise, fever, rigors, headache, and backache. This is followed by defervescence and the appearance of a typical skin eruption characterized by progression over 7-10 days of lesions through successive stages, from macules to papules to vesicles to pustules. The latter finally form crusts and, upon healing, leave depressed depigmented scars. The case fatality rate is approximately 30% in unvaccinated individuals. Permanent joint deformities and blindness may follow recovery. Vaccine immunity may prevent or modify illness.The eruption of chickenpox (varicella) is typically centripetal in distribution (worse on trunk than face and extremities) and characterized by crops of lesions in different stages on development. Chickenpox papules are soft and superticial, compared to the firm, shotty, and deep papules of smallpox. Chickenpox crusts fall off rapidly and usually leave no scar. Monkeypox cannot be easily distinguished from smallpox clinically. Monkeypox occurs only in forested areas of West and Central Africa as a sporadic, zoonotic infection transmitted to humans from wild squirrels. Person-to-person spread is rare and ceases after 1-2 generations. Mortality is 15%. Other diseases that are sometimes confused with smallpox include typhus, secondary syphilis, and malignant measles. Skin samples (scrapings from papules, vesicular fluid, pus, or scabs) may provide a rapid identification of smallpox by direct electron microscopy, agar gel immunoprecipitation, or immunofluorescence.There is no specific treatment available although some evidence suggests that vaccinia-immune globulin is of some value in treatment if given early in the course of the illness.Vaccinia virus is a live poxvirus vaccine that induces strong crossprotection against smallpox for at least 5 years and partial protection for 10 years or more. The vaccine is administered by dermal scarification or intradermal jet injection; appearance of a vesicle or pustule within several days is indication of a “take.” Vaccinia-immune human globulin at a dose of 0.3 mg/kg body weight provides >70% protection against naturally occurring smallpox if given during the early incubation period. Administration immediately after or within the first 24 hours of exposure would provide the highest level of protection, especially in unvaccinated persons. The antiviral drug, n-methylisatin ß-thiosemicarbazone (Marboran^®) afforded protection in some early trials, but not others, possibly because of noncompliance due to unpleasant gastrointestinal side effects.Patients with smallpox should be treated by vaccinated personnel using universal precautions. Objects in contact with the patient, including bed linens, clothing, ambulance, etc.; require disinfection by fire, steam, or sodium hypochlorite solution.

Tularemia is a zoonotic disease caused by Francisella tularensis, a gram-negative bacillus. Humans acquire the disease under natural conditions through inoculation of skin or mucous membranes with blood or tissue fluids of infected animals, or bites of infected deerflies, mosquitoes, or ticks. A BW attack with F. tularensis delivered by aerosol would primarily cause typhoidal tularemia, a syndrome expected to have a case fatality rate which may be higher than the 5-10% seen when disease is acquired naturally.A variety of clinical forms of tularemia are seen, depending upon the route of inoculation and virulence of the strain. In humans, as few as 10-50 organisms will cause disease if inhaled or injected intradermally, whereas 10⁸ organisms are required with oral challenge. Under natural conditions, ulceroglandular tularemia generally occurs about 3 days after intradermal inoculation (range 2-10 days), and manifests as regional lymphadenopathy, fever, chills, headache, and malaise, with or without a cutaneous ulcer. Gastrointestinal tularemia occurs after drinking contaminated ground water, and is characterized by abdominal pain, nausea, vomiting, and diarrhea. Bacteremia may be common after primary intradermal, respiratory, or gastrointestinal infection with F. tularensis and could result in septicemia or “typhoidal” tularemia. The typhoidal form also may occur as a primary condition in 5-15% of naturally-occurring cases; clinical features include fever, prostration, and weight loss, but without adenopathy. Diagnosis of primary typhoidal tularemia is difficult, as signs and symptoms are nonspecific and there frequently is no suggestive exposure history. Pneumonic tularemia is a severe atypical pneumonia that may be fulminant, and can be primary or secondary. Primary pneumonia may follow direct inhalation of infectious aerosols, or may result from aspiration of organisms in cases of pharyngeal tularemia. Pneumonic tularemia causes fever, headache, malaise, substernal discomfort, and a non-productive cough; radiologic evidence of pneumonia or mediastinal lymphadenopathy may or may not be present. A biological warfare attack with F. tularensis would most likely be delivered by aerosol, causing primarily typhoidal tularemia. Many exposed individuals would develop pneumonic tularemia (primary or secondary), but clinical pneumonia may be absent or non-evident. Case fatality rates may be higher than the 5-10% seen when the disease is acquired naturally.The clinical presentation of tularemia may be severe, yet nonspecific. Differential diagnoses include typhoidal syndromes (e.g., salmonella, rickettsia, malaria) or pneumonic processes (e.g., plague, mycoplasma, SEB). A clue to the diagnosis of tularemia delivered as a BW agent might be a large number of temporally clustered patients presenting with similar systemic illnesses, a proportion of whom will have a nonproductive pneumonia. Identification of organisms by staining ulcer fluids or sputum is generally not helpful. Routine culture is difficult, due to unusual growth requirements and/or overgrowth of commensal bacteria.Streptomycin (1 gm every 12 hours intramuscularly (IM) for 10-14 days) is the treatment of choice. Gentamicin also is effective (3-5 mg/kg/day parenterally for 10-14 days). Tetracycline and chloramphenicol treatment are effective as well, but are associated with a significant relapse rate. Although laboratory-related infections with this organism are very common, human-to-human spread is unusual and isolation is not required.A live, attenuated tularemia vaccine is available as an investigational new drug (IND). This vaccine has been administered to more than 5,000 persons without significant adverse reactions and is of proven effectiveness in preventing laboratory-acquired typhoidal tularemia. Its effectiveness against the concentrated bacterial challenge expected in a BW attack is unproven. The use of antibiotics for prophylaxis against tularemia is controversial.