From the Naval Medical Center San Diego, San Diego, California.

Presented on December 5, 2000, at Baylor University Medical Center internal medicine grand rounds.

Corresponding author: John D. Malone, MD, Naval Medical Center San Diego, 34800 Bob Wilson Drive, San Diego, California 92134-5000 (e-mail: JDMalone@NMCSD.MED.NAVY.MIL).

The views, opinions, assertions, and findings contained herein are those of the author and should not be construed as official positions, policies, or decisions of the US Department of Defense or US Navy.

An appropriate planned response to a bioterrorist attack will minimize morbidity and mortality. The response centers on a public health approach, as in any other infectious disease outbreak. The basic steps remain the same: identify the organism, form a case definition, identify cases, plot cases daily on a curve, and develop effective prevention strategies, including vaccinations, antimicrobial medications, and case cohorting and isolation. Each year, the same techniques are used to respond to the influenza epidemic that infects millions, with an annual mortality that exceeds 20,000 people.

The risk of bioterrorism comes from several countries, as well as from misguided Americans. According to a 1993 report (Office of Technology Assessment, US Congress), Iran, Iraq, Israel, North Korea, China, Libya, Syria, and Taiwan all have access to biological agents. Fortunately, efforts at developing these agents into large-scale weapons are complicated by the need for an effective delivery system. A simple delivery method is use of a commercial agricultural sprayer in a small airplane or vehicle to create a line source aerosol dispersion upwind from a large population center. Dissemination of agents from a point source explosion such as bombs or missiles is not as effective in infecting a large number of people. For example, an aircraft carrying an advertising banner could follow the parade route of the Cotton Bowl and disperse 100 kg of anthrax spores. On a clear, sunny day, such a release may cause over 100,000 casualties; on an overcast day or calm night, up to 1 million casualties. Anthrax is the most lethal of all potential biological weapons (Table 1). In contrast, aerial release of 1000 kg of sarin gas would cause several hundred casualties.

The focus of this article is on treatment and prophylaxis of 4 agents that are of particular concern: anthrax, botulinum toxin, plague, and smallpox. Some specific guidelines for institutional preparedness and prevention of psychological sequelae are also addressed.

ANTHRAX

Bacillus anthracis forms spores. The spores exist in a viable state almost indefinitely, since they require neither a stable temperature nor growth medium. Being 3 to 5 microns in size, the spores can lodge in the terminal alveoli. Larger particles tend to get trapped in the upper airways, and smaller particles move in and out of the airways without being deposited. When the spores germinate, they produce viable bacilli, and the bacilli produce toxins such as edema factor and lethal factor. The lethal dose for 50% of individuals is estimated at 4000 spores, an amount inhaled in one breath. These characteristics make anthrax an effective agent for bioterrorism.

Spores deposited in the alveoli are transported to the mediastinum by macrophages. Upon germination, the toxins produce edema, hemorrhagic necrosis, and mediastinitis. Inhalational anthrax can be recognized radiographically by a wide mediastinum and clear lung fields. Small pleural effusions may be present. Meningitis through bloodstream transmission is also possible.

Anthrax may first be suspected in the laboratory by a positive blood culture with anaerobic gram-positive rods. The organism should not be dismissed as diphtheroids and skin contaminants, since this is a key identifier of initial patients. When anthrax was accidentally released from a bioweapons production facility in Sverdlovsk, Russia, deaths occurred primarily in older men, many of whom were smokers and welders. This may be a clue about those who are most at risk.

In keeping with the Greek name anthracis, meaning black, cutaneous anthrax manifests with a black eschar and a surrounding area of edema from toxin production. This localized cutaneous infection is not life threatening.

Anthrax spores wash off with soap and water. Anthrax pulmonary infection and cutaneous lesions are not contagious to health care workers; however, pathologists conducting an autopsy require protective respiratory equipment to prevent spore exposure when opening the chest. Any health care worker who receives a needle stick from a potentially bacteremic anthrax-infected patient should receive prophylactic antibiotics.

Prophylaxis for aerosol exposure consists of antibiotic medication for 30 days and anthrax toxoid vaccination immediately and 2 and 4 weeks afterwards. If the toxoid vaccination is not available, the exposed person requires antibiotic prophylaxis for 8 weeks. This recommendation comes from the results of a study in rhesus monkeys. After inhalational exposure to 11 times the lethal dose of anthrax spores, the mortality rate was significantly lower (1/9) in monkeys that received ciprofloxacin as postexposure prophylaxis within 24 hours than in monkeys that received placebo. The one ciprofloxacin-treated monkey that died of anthrax expired after 30 days of antibiotic administration. The toxin, especially the component labeled decades ago as “protective antigen,” is responsible for developing immunity. The antibiotics may not be bactericidal to the intracellular encapsulated spores; they only prevent the spores from becoming viable bacilli and producing toxin with protective immunity. The anthrax toxoid vaccination initiates the immune response.

The suggested antibiotics for prophylaxis are listed in Table 2.

Treatment consists of the same antibiotics (Table 3).

If the strain of anthrax is susceptible, penicillin is the most effective drug, with a reported minimum inhibitory concentration (MIC) of <0.03. Ciprofloxacin and ofloxacin have also shown good activity in vitro, with MICs of 0.03-0.06. All fluoroquinolones, including levofloxacin and the more recent arrivals such as gatifloxacin and moxifloxacin, will probably be effective. The only fluoroquinolone for which animal efficacy data are available is ciprofloxacin. Ciprofloxacin was recently approved by the Food and Drug Administration (FDA) for anthrax postexposure prophylaxis and treatment. Ciprofloxacin is not FDA approved for children but may be used for postexposure inhalational anthrax in time of crisis until penicillin sensitivity can be confirmed. Over 120 articles have documented ciprofloxacin safety in children with minimal effects on cartilage. Third-generation cephalosporins perform poorly in vitro against anthrax.

Pets can develop anthrax as well; they usually develop the cutaneous form rather than the inhalational form. For most pet exposures, a bath with soap and water is sufficient to remove the spores. In cases of heavy contamination, the owners may wish to bathe animals in a 0.5% hypochlorite solution (household bleach diluted 1 to 10) or Exspor solution (Alcide Corp, Conn). Veterinarians are an important resource in a bioterrorism incident, since a majority of the possible bioterrorism agents originated in early domesticated livestock and then spread to the human population.

BOTULINUM TOXIN

The 7 botulinum toxins produced by Clostridium botulinum are neurotoxins that act presynaptically to prevent the release of acetylcholine. People exposed to this toxin would present with a variety of signs and symptoms, such as dilated pupils, ptosis, diplopia due to extraocular palsies, dysphonia, dysarthria, hypotension, respiratory failure, and paralysis. They would be afebrile. Those who receive a sublethal dose may have delayed symptoms. Mental status changes, such as cognition problems or depression weeks to months later, have been reported. Toxin release should be considered a chemical exposure, since no viable organisms are involved. Antibiotics are not indicated for bioterrorism botulism; ventilatory support may be required. There is no nosocomial transmission, and routine standard precautions for infection control apply.

A vaccine is available for prophylaxis and treatment. An effective pentavalent toxoid vaccine for prophylaxis was developed by the US Army and used under an investigational new drug status. This formalin-fixed culture supernatant, administered subcutaneously immediately, 2 and 12 weeks afterwards, and then yearly, develops antibody titers at 14 weeks with an 80% effectiveness rate. Passive protection can be afforded with a heptavalent antibotulinum toxin immunoglobulin for the 7 serotypes (A through G). Since this immunoglobulin was developed from horse serum, 20% of recipients have a serum sickness reaction, and a skin test for hypersensitivity is recommended. This vaccine is held at the US Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Maryland. In addition, the Centers for Disease Control and Prevention (CDC) has a trivalent equine antitoxin for serotypes A, B, and E, which has been approved by the FDA.

PLAGUE

In a bioterrorism incident, viable Yersinia pestis bacilli would be transmitted through aerosolization, resulting in pneumonic plague, an overwhelming, rapidly advancing, severe gram-negative coccobacillary pneumonia, which may be confused with Haemophilus influenzae on Gram stain. This pneumonic process differs from bubonic plague, which is characterized by regional adenopathy (buboes) draining the site of initial infection after inoculation from an infected flea that obtained a blood meal from a bacteremic animal (i.e., rat, vole, prairie dog). Occasional cases of bubonic plague are reported from the southwestern USA in summer months.

Nosocomial transmission of pneumonic plague is possible until the patient has completed 72 hours of antimicrobial therapy. Until the patient has received effective therapy for at least that period, health care personnel should use droplet precautions, wearing a surgical-type mask when they are within 3 feet of the patient or upon entering the patient's room.

Prophylactic therapy for pneumonic plague exposure involves 7 days of therapy with doxycycline (100 mg twice a day), tetracycline (500 mg 4 times a day), a quinolone, or a combination of trimethoprim and sulfamethoxazole. Historically, therapy for those with active disease has consisted of one of the following: streptomycin (30 mg/kg/day divided into 2 doses intramuscularly for 10 days), gentamicin (3 mg/kg/day), doxycycline (200 mg initially, then 100 mg daily for 10 to 14 days), or chloramphenicol (1 g every 6 hours for 10 to 14 days). The plague vaccine does not protect against aerosolized transmission in animal studies.

SMALLPOX

Smallpox (variola virus) presents as vesicles starting peripherally on the extremities (palms and soles) and face and spreading centrally to the trunk. The lesions are in the same stage at the same time (synchronous). In contrast, varicella (chickenpox) vesicles begin centrally on the trunk and appear in multiple stages. The severity of smallpox varies from patient to patient: some are mildly affected while others have a very serious case. The death rate from smallpox is 30%.

A smallpox patient is infectious from the onset of rash until the scabs separate, a period of about 3 weeks. Airborne precautions (respirators) and contact precautions (gowns, gloves, and antimicrobial handwash) are necessary to minimize transmission.

The only effective prophylaxis available is the vaccinia vaccine, licensed in the USA under the trade name Dryvax (manufactured by Wyeth, Philadelphia, Pa). Vaccination within 3 days of exposure will prevent the disease, and vaccination within 5 days is life saving. Currently, the CDC has 12 to 14 million doses of smallpox vaccine, and the World Health Organization has about 20 million doses. The US government recently set aside $28 million to develop an oral form of smallpox vaccine by the year 2004.

The vaccinia virus in Dryvax has an obscure origin; it is based primarily upon the cowpox virus and may represent a reassortment of smallpox and cowpox viruses. Antigenically similar to smallpox, this reconstituted live infectious virus delivered intradermally through multiple skin passages with a bifurcated needle (scarification process) results in a localized vesicular skin eruption and production of T cells and B-cell antibodies. The current vaccine was created in a unique process. The shaved skin of a calf was scraped and inoculated with vaccinia virus. The external lymphatic drainage from the cutaneous infection was collected, purified, and lyophilized. Because it is a live virus vaccination, complications can occur with dissemination in immunocompromised persons or those with severe eczema (eczema vaccinatum). Ocular autoinoculation is also a risk.

Treatment options for confirmed cases of smallpox are limited. Cidofovir has shown some effectiveness in vitro. The recommended dosage is 5 mg/kg intravenously per week for 2 weeks and then every other week. Prehydration is required. Adefovir dipivoxil is probably not effective, although theoretically it can inhibit replication of variola virus DNA. Vaccinia immune globulin (VIG) (0.6 mL/kg intramuscularly within 3 days of exposure) is another possibility for treatment and may also be useful for complications of smallpox infection. Unfortunately, a majority of the available VIG is in very poor condition.

RESPONSE TO A BIOTERRORISM INCIDENT

Treatment of bioterrorism exposure is multifactorial, multidisciplinary, and longitudinal--similar to the response for multiple trauma victims. Psychological aspects must be addressed.

Overall, the Federal Bureau of Investigation (FBI) is in charge of the domestic terrorism response at the crime scene and has access to many other governmental resources (Figure). Throughout the complex “task force” response effort, the FBI will depend upon the local public health department and local health care personnel. A military-style command, control, communications, and intelligence model has limitations in this situation. Intense cooperation, communication, and trust between differing levels of civilian and military authorities are necessary to maximize an effective and timely response. For example, the governor has control of the National Guard and the state health department; the mayor has control of the local police department, fire department, and public health department; and the hospitals and local physicians oversee their patients and personnel. Quarantine authority resides with the local public health officer.

In a bioterrorism incident, health care institutions would be expected to secure and control all access and egress by locking doors and posting guards. Tunnels, walkways, and roof access require special attention. The goal of such security is to prevent hospital contamination and protect the health of medical personnel so that they may continue to provide service. By preventing exit in the setting of communicable diseases such as smallpox or plague (pending vaccinations or antibiotic prophylaxis), transmission of disease from potentially contagious health care workers to their families and the community is minimized.

Institutions should also maintain order with the media. Communication with the public is critical; “not what you say but how you say it” is important. Institutional leaders should consider risk communication training and ensure strong working relationships between the chief executive officer, public affairs spokesperson, legal counsel, and clinical care directors. Risk communication is best done as a dialogue and is more effective when trusted community leaders are involved. Leaders may also want to make use of the Internet to share key messages.

Emergency department personnel are the first line of defense for hospitals in the response to bioterrorism. During influenza outbreaks, they treat hundreds of patients, recording basic demographic data, diagnosing pneumonia, delivering antibiotics, and minimizing morbidity and mortality.

Institutions should ensure that their emergency personnel are prepared for decontamination and triage. Regarding decontamination, the clothing of those who have been exposed should be removed and placed in a plastic bag. Generally, a shower (with warm water to prevent hypothermia and minimize additional distress) with soap is all that is required; bleach is needed only for chemical decontamination.

Somatization disorders following an attack can quickly overwhelm an emergency department. For example, in the 1995 Tokyo sarin attack, 5000 people sought medical treatment: 12 died, 17 were critically injured, and 1300 were affected mildly or moderately. The vast majority of patients had no injuries yet quickly and severely congested the health care delivery system. In such settings, rapid and accurate triage to provide effective treatment, offer a supportive environment, and convey a return to normal activities is most important. Sensitive risk communication will support the efforts. Health care providers need to be protected from extreme stress by work/rest cycles and debriefing.

An uninhabitable condition of the emergency department due to secondary aerosols from a bacterial-contaminated patient is unlikely. For example, an Aberdeen Proving Ground study during the Persian Gulf War estimated that only 120 spores remained on an average-sized adult after heavy exposure to a large anthrax cloud. Spores reside primarily in hair, including men's beards.

If the specific agent released during a bioterrorist attack--and its antibiotic sensitivity--have not been identified, public health departments and health care workers can administer fluoroquinolone antibiotic prophylaxis. Fluoroquinolones are active against anthrax, plague, cholera, tularemia, brucellosis, Q fever, and community-acquired pneumonia. Engineering resistance to quinolones is difficult since they act as DNA gyrase inhibitors. Fluoroquinolones with once-daily dosing would allow daily observed therapy and permit a large number of people to be initially treated with limited regional supplies. The CDC recently spent $52 million stockpiling pharmaceuticals and equipment in 12 different US locations to increase immediate access.

PSYCHOLOGICAL ASPECTS

Mental health resources--social workers, psychologists, psychiatrists, and clergy--will be essential during a bioterrorism incident. Clergy members are especially important because they enjoy a very high level of trust in the community.

The invisible agents of bioterrorism are very frightening to people, and some may have strong responses. Administering antibiotics and immunizations for prophylaxis is also stressful. Some people can demonstrate acute autonomic arousal: muscle tension, tachycardia, hyperventilation, sweating, tremor, and a sense of foreboding. They may attribute these symptoms to infection and be concerned or upset if a health care worker dismisses their complaints. Again, accurate triage is important. Fever is a definitive sign.

Those with somatic symptoms need further care as well. Posttraumatic stress disorder is a possibility, as are depression, panic attack, alcohol/drug abuse, or antisocial behavior. Patients who have had major depression in the past are at risk for a relapse. The criteria for posttraumatic stress disorder include the following: a traumatic stressor exposure, intrusive reexperience (memories, nightmares, reminders), avoidance and numbing (interest loss, detachment, affect blunting), and hyperarousal (insomnia, anger, difficulty concentrating). Sertraline and fluoxetine are effective adjuncts.

CONCLUSION

The major enemies during a bioterrorism incident are fear, panic, stress, and misinformation. Four agents of particular concern are anthrax, botulinum toxin, plague, and smallpox. Institutions require security and decontamination plans. The major defense is the trust developed among colleagues, employees, supervisors, and institutional authorities. We can handle a bioterrorism incident. The better prepared we are, the less likely the event will occur.

For further reading

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Emergency response

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