Bioterrorism

Most of the research on biological weapons deals with battlefield attacks, in which one army delivers the agent to another army through a bomb or missile. As we have already seen, a terrorist attack is likely to look entirely different. A terrorist group might disseminate an organism by introducing it into the ventilation system of a large building or by contaminating a sprinkler system. The means of a biological attack will be unpredictable. However, the organisms are known, since extensive research has shown that only a small number of agents are suitable for use as biological weapons.

Anthrax

Anthrax is caused by a bacterium known as Bacillus anthracis, which infects grazing herbivores, chiefly cattle, sheep, goats, and horses. When exposed to oxygen, the organism forms spores, which are resistant to heat, sunlight, and dessication and can survive for decades. Anthrax usually occurs in those handling infected animals or their products, including hides, hair, wool, or flesh. Spores are introduced through a break in the skin, leading to a small raised area on the skin which ulcerates and turns black. (The name anthrax is derived from the Greek word for coal.) When untreated, the illness may be complicated by high fevers, swelling of the area around the ulcer, enlargement of the lymph nodes, infection of the bloodstream, and death. However, the cure rate is high when appropriate antibiotics are given.

Rarely, inhalation of anthrax spores causes inhalational anthrax, known historically as Woolsorters' Disease, which progresses rapidly and is often fatal despite treatment. Inhalational anthrax begins with non-specific flu-like symptoms, including fever, malaise, fatigue, dry cough, and chest discomfort, followed by the abrupt onset of respiratory distress, cyanosis (purplish color), profuse sweating, confusion, and shock. The chief finding is hemorrhagic mediastinitis (bloody inflammation of the lymph nodes in the center of the chest). The chest film may show a widened mediastinum or effusions, but generally does not show infiltrates. Chest CT is often helpful in assessing the mediastinal lymph nodes, especially if plain chest films are non-diagnostic. The course is frequently complicated by hemorrhagic meningitis (blood in the spinal fluid).

The diagnosis of an anthrax skin infection is generally made by culturing the skin lesion, though cultures are usually negative after antibiotics have been given. Immunohistochemical staining of tissue specimens obtained from the edge of the skin lesion may be helpful. The diagnosis of inhalational anthrax is generally confirmed by positive blood cultures. The microbiology laboratory should be alerted that anthrax is to be ruled out, because most Bacillus species found in blood cultures are contaminants. If blood cultures are negative, serum and other body fluids may be sent for PCR. A nasal swab for culture or direct fluorescent antigen may be positive shortly after exposure to anthrax, but may be negative by the time of clinical illness.

Pending final culture results, initial therapy for inhalational anthrax should consist of cipro 400 mg every 12 hours or doxycycline 100 mg every 12 hours by vein, in combination with a second antibiotic. For children, the recommended dosages are cipro 5-7.5 mg/kg every 12 hours and doxycycline 2.5 mg/kg every 12 hours, up to the adult dosages. Data are limited, but other quinolones are likely to be equally effective. Options for the second antibiotic include rifampin, vancomycin, imipenem, chloramphenicol, penicillin and ampicillin, clindamycin, and clarithromycin (Biaxin), all of which have shown activity against the strains of anthrax recently isolated in the United States. After clinical improvement, treatment may be completed with either one or two drugs. Therapy should be continued for a total of 60-100 days. Penicillin should not be used alone for inhalational anthrax, even if the strain appears susceptible, because laboratory studies suggest the organism may become resistant during treatment. Steroids may be used as adjunct therapy in cases with extensive edema, respiratory compromise, or meningitis. Anthrax of the skin is usually treated with cipro or doxycycline alone. If the illness is complicated by extensive swelling or severe toxicity, a second antibiotic should be added, as for inhalational anthrax.

Because of potential adverse effects of prolonged use of cipro or doxycycline in children and pregnant women, penicillin or amoxicillin may be substituted for cipro or doxycycyline once the strain has been shown to be susceptible to penicillin and the patient is clinically improving. In pregnant women, cipro is thought to be preferable to doxycycline, because the latter drug may be associated with an increased risk of bone and dental abnormalities in the developing fetus.

Those exposed to anthrax spores should be promptly started on cipro 500 mg twice daily or doxycycline 100 mg twice daily by mouth, to be continued for 60-100 days. If the strain is found to be susceptible to penicillin, high-dose penicillin or amoxicillin may be given.

Anthrax is not transmissible from person-to-person. In the hospital, standard barrier precautions should be adequate (i.e. masks are not necessary once the diagnosis is confirmed). Anthrax vaccine may be effective, but supplies are limited and have been reserved for military personnel and laboratory workers. A total of six doses over 18 months is recommended. Because of manufacturing problems, anthrax vaccine has not been produced since 1998.

The recent reports of envelopes containing anthrax spores have generated much concern. However, outside of mail handling facilities, the number of serious infections remains small. Pending further investigation, it would be prudent not to open any letter or parcel which looks suspicious or which doesn't have a recognizable return address. If you open a letter or parcel and find a powdery or granular substance, you should close it, cover it, go to a different room, wash your hands and face with soap and water, and call the local police or health department. If the substance is identified as anthrax, a 60-100 day course of antibiotics should be prescribed. Nasal swabs are useful chiefly as a means of tracking the spread of the disease when anthrax has been identified in the environment. The test is not useful in determining whether or not any given individual needs antibiotics, because a negative nasal swab does not exclude the possibility of exposure. No one should take antibiotics for anthrax unless instructed to do so by his or her physician or by public health officials because of a documented anthrax exposure.

Plague

The plague is caused by a bacterium known as Yersinia pestis, which primarily infects rodents and their fleas. The disease is usually transmitted to humans by flea bites. Historically, outbreaks occur when rodents die off and large numbers of fleas seek alternative hosts. The disease may also be transmitted by inhalation of infected droplets, which may be coughed into the air by a person with plague pneumonia or aerosolized as the result of a biological attack, or by direct exposure to infected blood or tissues.

The plague occurs in several forms. A bite by an infected flea usually results in bubonic plague, characterized by an acutely swollen, exquisitely painful lymph node, known as a bubo, near the site of the flea bite, in association with fever, chills, muscle aches, and malaise. By contrast, a biological attack with aerosolized plague bacteria would lead to plague pneumonia, characterized by rapid onset of fever, chills, headache, body aches, weakness, dizziness, and chest discomfort, followed by cough, increasing chest pain, and difficulty breathing. The sputum is often bloody. Severe cases are complicated by respiratory failure, circulatory collapse, and death.

Bubonic plague is diagnosed by gram stain and culture of an aspirate from the bubo. Plague pneumonia is diagnosed by sputum and blood cultures. Rapid diagnostic tests, including direct fluorescent antibody staining of sputum, PCR, and IgM immunoassay, may be helpful when available.

The drug of choice for plague is streptomycin one gram twice daily by intramuscular injection or gentamicin 5 mg/kg daily by vein. For those who cannot take streptomycin or gentamicin, doxycycline 100 mg twice daily or cipro 400 mg twice daily by vein are the recommended alternatives. If none of the above can be given, chloramphenicol 25 mg/kg four times daily by vein is advised. For those who have been exposed to a case of plague pneumonia or a biological attack with plague organisms, a seven-day course of doxycycline 100 mg twice daily or cipro 500 mg twice daily by mouth is recommended. Although cipro and doxycycline are not approved for use in children and pregnant women, as above, they may be used for the prophylaxis or treatment of plague in children and pregnant women in view of the lack of proven alternatives. In children, the recommended dosages for prophylaxis are cipro 20 mg/kg (maximum 500 mg) every 12 hours and doxycycline 2.2 mg/kg (maximum 100 mg) every 12 hours by mouth.

Strict isolation , including the use of masks, gowns, gloves, and eye protection, are essential for any suspected case of plague pneumonia. Precautions should be continued until the patient has received at least 48 hours of an appropriate antibiotic and is clinically improving. The laboratory should be alerted when Yersinia pestis is suspected, since laboratory transmission has been reported.

The manufacture of plague vaccine, which was effective against bubonic but not pneumonic plague, was discontinued in 1999.

Smallpox

The last case of smallpox in the United States occurred in 1949. In 1972, routine immunization with smallpox vaccine was discontinued in the United States. In 1978, the last case in the world occurred in Somalia. Two years later, the World Health Organization declared that smallpox had been eradicated. Only two laboratories, one in the United States and one in Russia, still have stocks of smallpox virus, which have been maintained for research purposes. There have been reports that the Russians manufactured large quantities of virus for possible wartime use. The question is whether or not some of the Russian supplies might have fallen into other hands, though there is no evidence at present that this happened.

The incubation period for smallpox ranges from 7-to-17 days (usually 12-to-14 days), which is relatively long for a viral illness. Initial symptoms consist of high fevers, malaise, headache, and backache, followed by the appearance of small raised red spots (maculopapular rash) that begin inside the mouth and on the face and forearms, then spread sequentially to the legs and trunk. The skin lesions evolve into small blisters, then pustules. Scabs develop, which eventually separate, leaving pitted scars. In its early stages, the rash may resemble that of chickenpox, with two key differences. (1) In smallpox, the lesions are densest on the face and outermost extremities, whereas in varicella, the greatest number of lesions are on the trunk. (2) In smallpox, all lesions are at the same stage of development, whereas in varicella, the lesions are at different stages of evolution, i.e. some may be blisters while others are scabbing.

A small percentage of patients develop flat-type smallpox, characterized by large, flat lesions with a soft, velvety texture, or hemorrhagic smallpox, characterized by severe toxicity, diffuse ecchymoses (bleeding into the skin), and high mortality. Partially immune individuals (including those who were vaccinated many years ago) may develop a milder illness with an abbreviated course.

Complications include arthritis, osteomyelitis, keratitis, encephalitis, and pulmonary edema.

Skin lesions should be cultured to confirm the diagnosis. Specimens must be referred to a specialized high-containment laboratory. Once the presence of smallpox is established, additional cases do not require laboratory confirmation.

Smallpox patients must be confined to negative pressure isolation rooms. Visitors and staff must wear gowns, gloves, and masks at all times. In a large outbreak, patients who are less ill should be cared for at home. Patients do not become infectious until the rash appears and remain infectious until all scabs separate. Those who have been exposed to smallpox but are asymptomatic do not need to be quarantined, but must be closely observed for 17 days after their last exposure to the disease. If they become febrile during this time, they must be immediately quarantined, preferably at home, until the fever has resolved and it is certain that they do not have smallpox. The ability to identify and quarantine potential smallpox cases before they become infectious is of great assistance in controlling an outbreak.

There is no known treatment for smallpox. Historically, overall mortality was 30% in unvaccinated patients. However, there has never been a smallpox outbreak in a country with modern hospital and ICU facilities. Given the substantial advances in supportive care, outcomes would probably be considerably better if an outbreak were to occur today in an industrialized country. However, mortality would be high in a developing nation.

Smallpox vaccine consists of live vaccinia virus, an organism that is closely related to the virus which causes smallpox, but which typically causes only a mild, localized skin infection when injected into humans. Rare complications of smallpox vaccine include progressive or generalized vaccinia infection, postvaccinial encephalitis, and eczema vaccinatum, characterized by vaccinial infection of current or previous eczematous skin lesions. The duration of protection from smallpox vaccine is thought to be about ten years, so it is presumed that those who were vaccinated before the 1970's are no longer immune. The Centers for Disease Control has stockpiled approximately 12-15 million doses of smallpox vaccine, which were produced in the 1970's and may have lost their potency. Current supplies are being reserved for use in a possible outbreak situation. Current supplies are being reserved for use in a possible outbreak situation. Studies are in progress to determine if the vaccine will retain its effectiveness when diluted, to produce more doses if needed. New vaccines are under development, but will not be available for the foreseeable future.

Botulism

Botulinum toxin, which is produced by a bacterium known as Clostridium botulinum, is the most poisonous substance known to man. In animals, only 0.001 microgram per kilogram of body weight results in a fatality rate of 50%. Recent concern has focused on the possible use of botulinum toxin as a biological weapon, either by contamination of water supplies or aerosol dissemination. However, botulinum toxin is readily inactivated by sunlight, heat, and chlorine, which would limit though not eliminate its potential as a biological weapon.

Most cases of botulism are caused by ingestion of pre-formed toxin in contaminated foods. In newborns, botulism may develop from multiplication of Clostridium botulinum organisms in the immature gut. Rarely, botulinum toxin enters the body through an open wound. Though this does not happen in nature, the toxin can be aerosolized and absorbed from the respiratory tract. Regardless of how the toxin enters the body, the resulting clinical syndrome is essentially the same.

Botulinum toxin acts by blocking acetylcholine release at peripheral cholinergic synapses, chiefly at the neuromuscular junction. Clinically, botulism presents as a symmetric, descending flaccid paralysis that begins in the head and face and spreads downward. Initial findings may include drooping eyelids, blurred vision, double vision, dry mouth, slurred speech and difficulty swallowing, followed by loss of muscle tone, generalized weakness, and loss of the gag reflex, which may require intubation to protect the airway. Patients may appear lethargic, but mentation is otherwise normal. Sensory abnormalities do not occur. There is no fever. The cerebrospinal fluid is normal. Electromyography may be helpful in distinguishing botulism from other flaccid paralyses,

Diagnosis is usually made on the basis of symptoms and physical examination. The diagnosis should be confirmed by assaying blood, stool, gastric aspirate, and possibly other body fluids for botulinum toxin, which is performed at a small number of reference laboratories. Samples must be obtained before the patient has received antitoxin.

The treatment of botulism is to give antitoxin, which is available from the health department, and to support aggressively, preferably in an ICU. The licensed antitoxin contains antibodies against three of the seven types of botulinum toxin (A, B, and E), which cause most cases of human disease. An investigational antitoxin which is active against all seven types is held by the US Army. Because botulinum antitoxin is derived from horses, hypersensitivity reactions, including hives, serum sickness, and anaphylaxis, occur in a significant minority of patients.

Those who have been exposed to botulinum toxin but remain asymptomatic are generally observed closely and not given antitoxin, due to short supplies of antitoxin and the frequency of hypersensitivity reactions. An investigational vaccine containing botulinum toxoid (analogous to tetanus toxoid) has been used for more than thirty years to immunize laboratory workers, but is not routinely given to the general population due to the rarity of botulism and the scarcity of the vaccine. The vaccine is not effective when given after exposure.

How to protect yourself

If you develop a flu-like illness (high fevers, headache, body aches), it may be prudent to consult your physician instead of assuming the illness is benign, since many of the infections caused by biological weapons begin with flu-like symptoms. If you develop a rash, cough, chest tightness, or difficulty breathing in conjunction with a fever, you should promptly seek medical advice.

Make sure you're up-to-date on all vaccinations, including influenza and chickenpox. Influenza vaccine is recommended for those with chronic illnesses, such as diabetes and lung disease, and for those over age 50. Chickenpox vaccine is recommended for those who never had chickenpox if they might be in contact with young children. There is no need to stock up on antibiotics, since supplies will be adequate. A gas mask is useless unless you intend to carry it around with you for the indefinite future.

As above, don't open or shake any letters or parcels unless you recognize the return address.

Most importantly, there is no cause for undue anxiety. The efforts so far to spread anthrax have simply proven how difficult it is to do so. Before releasing sarin nerve gas in a Tokyo subway station in 1995, killing 12 people, the Japanese cult Aum Shinrikyo made a number of attempts to disseminate anthrax and botulinum toxin, all of which failed. A successful biological attack will require considerable technical sophistication as well as much ingenuity. It is essential to be prepared for a biological attack, because terrorists may develop this capability in the future, but it appears at present that they still have significant obstacles to overcome.

Useful links

The recent JAMA consensus statements on anthrax, plague, smallpox, botulinum toxin, and tularemia are an excellent place to start if you want to learn more. Full-text versions are available on both the CDC and the Johns Hopkins sites.

CDC Bioterrorism Preparedness and Response
http://www.bt.cdc.gov/