Biological Terrorism: Are We Prepared?

Although a large-scale attack is unlikely, the consequences could be severe. There are steps physicians can take to improve their ability to cope with the crisis.

By Gregory J. Moran, MD

As terrible as biological terrorism is to contemplate, the current world situation dictates that we prepare for the possibility. If such an attack were to occur, many people could become ill in a very short time, putting an enormous, if not overwhelming, strain on local health care facilities.

Would you know what to do if, after a terrorist group released a biological agent in your community, scores of sick people suddenly appeared at your door seeking medical care? Would you be able to identify the causative agent? Would you know how to decontaminate the victims and otherwise prevent further spread of disease? Would you know what steps to take to protect yourself and your staff from illness? And finally, would you know how to treat the victims' illnesses, where to go for the necessary drugs and supplies, and whom to call for assistance? To have any chance of managing the catastrophe that would almost certainly result from a large-scale biological attack, you will need to know the answers to all those questions. This article will explain the nature of biological terrorism and some of the agents that are more likely to be used.

WHY BIOLOGICAL TERRORISM?

Why would someone intent on wreaking havoc resort to biological terrorism as opposed to other forms? One advantage of biological agents is that they can wreak devastation even when used in minuscule amounts. Odorless and easily concealed, they are difficult to detect. A terrorist could carry in his or her pocket enough botulinum toxin to kill–if it is properly dispersed–a large number of people. And because the toxin does not set off metal detectors, the terrorist would have no trouble boarding a commercial airplane and transporting the agent to any city in the world, where civilian populations are largely unprotected from this kind of attack.

Many biological agents are relatively easy to obtain, more so than materials such as plutonium, needed for other weapons of mass destruction. Up until a short time ago, one could simply order many of these agents from biological supply houses. Access to hazardous biological agents has been restricted recently, but they are still comparatively easy to get. And although manufacturing biological agents may be more difficult than making a pipe bomb, in many instances it can be done with only basic skills in microbiology. The agents are also difficult to trace. A terrorist could release a biological agent in a major metropolitan area and, because most people are not going to become sick for several days, be thousands of miles away by the time the authorities have any idea that an attack has occurred.

But perhaps the biggest advantage offered by biological agents is their capacity to produce terror, which is, after all, the terrorist's main objective. What could be more disruptive than convincing the citizens of a large city that they are all about to die from Ebola disease or the plague? One can imagine the panic that would ensue from such an attack, and not just among the ill. The uninfected, assuming that they have also been exposed to the biological agent, would also be terrified. Therefore, in addition to preparing for the medical emergency, we must prepare for the panic and chaos a biological attack would cause. It is possible that thousands of people, ill or healthy, could storm local hospitals and emergency departments convinced they are about to die.

LIKELY SCENARIOS AND PROBLEMS

The most likely method of a large-scale biological attack would be aerosolized dispersal of a biological agent, such as from an airplane flying over a populated area or from a small device planted in a ventilation system or crowded location. In all likelihood, the target would be in a major city. To maximize the publicity associated with such an attack, the terrorists might time the attack to coincide with a political or popular public event. Fortunately, very few biological agents remain infectious after prolonged exposure to air and sunlight, making a large-scale attack difficult.

Because most of the illnesses caused by biological agents involve incubation periods, several days are likely to elapse before people become sick. In addition, because the victims will probably seek medical care at different facilities, some time may pass before the medical community is even aware that anything unusual has occurred. The epidemiologic pattern will be an early sign that an attack has taken place, but with patients presenting at different locations, often with relatively nonspecific signs and symptoms, no one may suspect that an act of terrorism has occurred until the number of victims becomes significant.

In addition to the challenge of treating illnesses, clinicians will be faced with serious logistical problems if there are many victims. It is likely that personnel, medications, and other resources will be insufficient to deal with the sudden onslaught of so many patients. Prophylactic therapies are effective against some biological agents. Doxycycline or ciprofloxacin, for example, can help prevent illness in people exposed to anthrax, but even knowing which medications are needed will not help when the immediate demand for them puts them out of reach. The federal government has stockpiles of antibiotics in place, as do many large cities, but rapid distribution to large numbers of people will be difficult. Shortages of medicine could exacerbate the panic and chaos caused by the attack, not only among the victims streaming into clinics and hospitals but also among health care personnel.

Because some of the diseases caused by biological agents can be spread from person to person, isolation of the victims may be necessary, which will be another formidable challenge, especially if there are thousands of victims. Many facilities do not have enough isolation beds even for their current needs, so it would probably be necessary to group victims in designated wards.

PROBABLE WEAPONS

Terrorists evaluate several characteristics of a biological agent when considering its suitability for an attack. The agent must make people sick, obviously, but it does not have to be lethal. Some biological agents such as anthrax, botulinum toxin, and the viruses that cause the hemorrhagic fevers can be fatal, but often terrorists can meet their goals just by making many people ill. Such diseases as brucellosis and tularemia are rarely lethal, but they can wreak havoc in a community if enough people are afflicted. Because the list of agents available to the terrorist is long (see table below), this discussion will be limited to those agents that are most likely to be used in an attack.

Fortunately, most biological agents would not be effectively dispersed via aerosol. Many of them are not stable enough to withstand temperature changes, exposure to sunlight, and drying. Anthrax is often cited as an agent likely to be used for biological terrorism because spores are stable for many years, even in extreme environments. The spores are also of an optimal size, 1 to 2 µm, that allows them to be inhaled into the lungs and deposited in the alveolar spaces. Most viral agents, such as those that cause hemorrhagic fevers and encephalitis, are unstable and would therefore be difficult to disperse through aerosolized large-scale attacks, but smallpox virus can remain viable after many years of storage. Bacterial agents vary in their stability during storage and dispersal. Although toxins such as botulinum toxin and staphylococcal enterotoxin B can remain stable for many years in storage, they can be difficult to disperse effectively to cause illness in a large population.

As part of their preparations for a possible biological terrorism event, the Centers for Disease Control and Prevention (CDC) have identified a number of organisms that are believed to have the greatest potential for use. Those that are given top priority for preparations because of their potential for weaponization and lethality are classified as category A agents (see table below). A number of other organisms (categories B and C) are given lower priority for specific preparations but are recognized as potential bioterrorism agents.

ANTHRAX

Cutaneous anthrax, the most common naturally occurring form, is usually spread through contact with infected animals, particularly cows, sheep, and horses, or their products (see photo below). Cutaneous anthrax typically produces large black eschars on the skin. Patients may also have such signs and symptoms as lymphadenopathy, fever, malaise, and nausea, but the infection is rarely fatal.

A far more potent threat is posed by the inhalational form of anthrax. This type of anthrax, also known as woolsorter's disease, is only rarely seen among wool or tannery workers, but it is the form of anthrax most likely to be spread by terrorist attack. Inhalational anthrax is almost uniformly and rapidly fatal once the symptoms have begun.

Victims of an anthrax attack will present with a fairly nonspecific prodrome resembling influenza, with malaise, dry cough, and mild fever. In most instances, this phase of the disease will be followed two days later by severe respiratory distress, with dyspnea, stridor, and cyanosis. Many patients will have hemorrhagic mediastinitis; roughly half will have meningitis. Septic shock and death usually occur 24 to 36 hours after the appearance of respiratory distress.

Generally speaking, the diagnosis must be made on clinical grounds alone for it to be of any use; by the time most laboratory tests yield positive results, most patients will be beyond help. Chest films may demonstrate a widened mediastinum and pleural effusions, but those findings are by no means universal, and they are usually seen only late in the disease. Gram's stains of the blood or blood cultures may reveal the causative organism, Bacillus anthracis, but that, too, usually becomes apparent only relatively late in the disease, well past the point where medical intervention has a chance of success. An enzyme-linked immunosorbent assay (ELISA) for the anthrax toxin exists, but most hospital laboratories do not have it readily available.

The mainstay of treatment is antibiotic therapy, but to be effective, the regimen usually must be started before significant symptoms develop (see table below). Once patients show signs of respiratory distress, they are almost certainly going to die in spite of treatment. A regimen of intravenous ciprofloxacin or another fluoroquinolone should be given as early as possible. Although naturally occurring B. anthracis is susceptible to penicillin and doxycycline, bioterrorists would most likely employ strains resistant to those antibiotics. Supportive therapy is also crucial to maintain the airway, replenish fluids, and alleviate shock. Standard universal precautions should be taken to prevent the spread of the disease, with all instruments used for invasive procedures carefully disinfected with sporicidal agents. Inhalational anthrax does not spread from person to person, however; therefore, the isolation of anthrax victims from one another will not be necessary.

In patients known to have been exposed to anthrax but who are not yet sick, illness and death can be prevented by administering anthrax vaccine in addition to antibiotics. The anthrax vaccine probably will not be available in adequate amounts in the event of a large biological attack. The vaccine is given repeatedly in a series of six subcutaneous injections over 18 months. If administered with vaccine, antibiotic therapy should be continued for at least four weeks after exposure; if given without vaccine, therapy should last eight weeks.

A series of anthrax hoaxes have been perpetrated in several cities in the U.S. Public health officials, working with law enforcement and first-response personnel, should determine the necessity for decontamination and prophylactic therapy after alleged exposures. Any persons coming into direct contact with a substance alleged to be anthrax spores should simply bathe with soap and water and store contaminated clothing in a plastic bag, but decontamination procedures for other persons in the area should not be necessary. Until the identity of the substance can be determined, chemoprophylaxis may be a reasonable precaution if the threat is credible.

PLAGUE

Few illnesses carry as many terrifying connotations as the plague. Bubonic plague is the form that most commonly comes to mind; it is usually spread from rodent to man through the bites of infected fleas and is characterized by adenopathy and fever. But plague, like anthrax, also has a pneumonic form, which can be transmitted through the inhalation of droplets spread by the cough of patients who have bubonic plague or, in the event of a terrorist attack, through the inhalation of an aerosol containing the causative, gram-negative bacillus Yersinia pestis. As with anthrax, the pneumonic form of the disease is by far the more dangerous. Left untreated, pneumonic plague is nearly always fatal within two days of the onset of symptoms.

After an incubation period of two to three days, patients with pneumonic plague typically suffer fulminant pneumonia, with malaise, high fever, cough, hemoptysis, and ecchymoses. Findings on chest films are generally typical of patients with pneumonia. The disease progresses rapidly, leading to dyspnea, stridor, cyanosis, and septic shock. Death is normally the result of respiratory failure and circulatory collapse.

A presumptive diagnosis can often be made by identifying Y. pestis in Gram's stains of blood, sputum, or lymph node aspirate samples. Immunofluorescent stains can also be very useful. A definitive diagnosis is generally made with culture studies. An ELISA test for plague exists, but it is not widely available.

Unlike pulmonary anthrax, pneumonic plague is very contagious; therefore, strict respiratory isolation is necessary until infected patients have undergone treatment for at least three days. Unfortunately, since the initial presentation resembles that of severe pneumonia, the actual diagnosis will not be known for some time. Therefore, patients who present with fulminant pneumonia after a suspected biological attack should be held in respiratory isolation until the cause of the pneumonia has been determined.

Early treatment with antibiotics, within 24 hours of the appearance of symptoms, is crucial to the survival of patients with pneumonic plague. Streptomycin is the traditional agent of choice, but doxycycline and chloramphenicol are also effective. Quinolones have proved effective in animal studies but as yet have not been evaluated in humans.

VIRAL HEMORRHAGIC FEVERS

Like plague, the viral hemorrhagic fevers, which include Ebola and Marburg disease, Lassa fever, and Bolivian hemorrhagic fever, tend to strike fear into people's hearts-and for good reason. Many of these viruses cause rapidly progressive illnesses that carry extremely high mortality rates. Normally, viral hemorrhagic fevers are spread in a variety of ways; Lassa fever, for instance, is usually spread through the ingestion of food contaminated with rodent urine, although person-to-person transmission, via contact with urine, feces, or saliva, can also occur. Many hemorrhagic fevers, however, could also be spread by terrorist attack, through the dispersal of an aerosol containing their causative agents.

The incubation periods of the hemorrhagic fevers range from 4 to 21 days; generally speaking, the more severe fevers, such as Ebola, have the shorter incubation periods. Patients typically present with a nonspecific prodrome that includes fever, myalgia, and prostration. On physical exam, the only findings may be conjunctival injection, mild hypotension, flushing, and scattered petechiae. Laboratory testing may reveal thrombocytopenia or other signs of disseminated intravascular coagulation or elevated levels of liver enzymes or creatinine. During a period of hours or days after the initial presentation, patients will suffer a quick deterioration of their status, followed by mucous membrane hemorrhage and shock, often with signs of neurologic, pulmonary, and hepatic involvement.

Specific tests for some of the hemorrhagic fevers exist, but because they are not available at most laboratories, only your clinical suspicion will enable you to make the initial diagnosis. Contact precautions are necessary for all health care personnel who manage persons who have hemorrhagic fever. In several outbreaks in Africa, hospital personnel were able to halt transmission of hemorrhagic fever to themselves and other patients simply by wearing gowns, gloves, and masks. Respiratory isolation, however, may be necessary for patients who have massive hemorrhage into the lungs. Aerosol transmission of hemorrhagic fever has been demonstrated in animal studies but does not appear to be a significant mode among humans.

Good supportive care is the mainstay of therapy for patients who have any of the viral hemorrhagic fevers. Special care must be taken during fluid resuscitation, because fluid transudation into the lungs will occur in some patients. In addition, because the risk of hemorrhage is high among these patients, caution is also necessary when placing intravenous and other lines. For patients with Lassa fever, Bolivian hemorrhagic fever, Congo-Crimean hemorrhagic fever, or Rift Valley fever, the antiviral agent ribavirin may offer some benefit.

SMALLPOX

Because of its propensity for secondary human-to-human transmission, variola virus, the cause of smallpox, may be one of the most feared agents that could be unleashed in a biological attack. Although naturally occurring variola virus was once a common cause of serious illness, the agent was eradicated through an aggressive program of worldwide vaccination; the last natural case occurred in Africa in 1977. Because the disease has been eradicated, vaccination is no longer given, leaving most persons today susceptible to infection. Even those persons who were vaccinated as children are likely to be susceptible, because immunity wanes over time.

Stocks of variola virus are supposedly stored at only two WHO-approved storage facilities: the CDC in Atlanta and the NPO (Scientific and Production Association) in the Novosibirsk region of Russia. Many experts believe that some virus samples may be in the hands of potential terrorists. Because the virus is difficult to obtain, an intentional smallpox exposure would require extensive resources that might be out of reach for small groups.

The incubation period associated with smallpox is approximately 12 days. Early symptoms are nonspecific, with fever, malaise, and aches lasting for two to four days. The characteristic rash develops on the extremities and spreads centrally, starting as papules that progress to vesicles and then to pustules that scab over in approximately one to two weeks. Mortality is approximately 30% overall among unvaccinated persons. Mortality is higher among infants and the elderly, and would likely be much less among healthy adults and older children. Although the appearance of the lesions and the pattern of progression are distinct from those of varicella, early cases of the disease would most likely be mistaken initially for chicken pox. The diagnosis of smallpox can be confirmed by electron microscopy or gel diffusion on vesicular scrapings, but this is not available in most hospital laboratories. Because testing for varicella virus is usually available, a vesicular eruption in which varicella cannot be identified should alert clinicians to possible smallpox.

The most important issue concerning smallpox exposure is the containment of any subsequent outbreak. Because delays in the initial diagnosis are likely, some secondary exposures will already have occurred by the time smallpox virus is identified as the cause of illness. Aggressive quarantine measures will be necessary to prevent further spread. Anyone who has had direct contact with an infected person should undergo strict quarantine with respiratory isolation for 17 days. If an initial outbreak cannot be contained within a single community, it is possible that a long eradication effort would have to be begun anew.

There is no known effective treatment against smallpox. The drug cidofovir, used to treat cytomegalovirus infections, may be active against variola virus, but no data currently demonstrate the drug's efficacy in humans. A vaccine based on the vaccinia virus is effective for immunization against smallpox, but only a relatively small stockpile of about 7 million doses remains. No facilities currently produce the vaccine, and the current stockpile would be depleted quickly if a large-scale exposure occurred. Modern methods are now being developed to manufacture new vaccine, but new supplies are probably still at least a couple of years away.

BOTULISM

Botulism is a syndrome caused by exposure to one or more of the seven neurotoxins produced by the bacillus Clostridium botulinum. The botulinum toxins are among the most potent toxins in existence. They are 100,000 times more toxic per microgram than the nerve agent sarin, which is what the cult Aum Shinri Kyo used in their terrorist attack in the Tokyo subway system in 1995.

Most cases of naturally occurring botulism result from the ingestion of improperly prepared or canned foods; the disease is also associated, although rarely, with infected wounds or abscesses related to intravenous drug use. Although terrorists could conceivably contaminate food supplies with the botulinum toxins, a large-scale attack could result from dispersing the toxins via aerosol over a vast area.

Unlike the other illnesses discussed so far, botulism has a fairly characteristic presentation and can therefore usually be diagnosed from the clinical signs and symptoms alone. The syndrome is more or less the same regardless of whether the botulinum toxins are ingested or inhaled; once absorbed, the toxins block the cholinergic synapses and thereby interfere with neurotransmission. After an incubation period of one to five days, patients generally present with neurologic manifestations. Bulbar palsies are extremely common, with such ocular signs as diplopia and mydriasis. Other bulbar effects may include dysarthria and dysphagia. Eventually, patients will suffer progressive weakness, followed by skeletal muscle paralysis. The cause of death is usually respiratory failure.

On physical examination, infected patients are generally afebrile, alert, and oriented. They may have postural hypotension; some complain of dry mouth.

Laboratory testing is generally not helpful; therefore, the diagnosis usually must be made on clinical and epidemiologic grounds. Botulinum toxins are generally difficult to detect, and most patients do not have antibody responses, because the amount of toxin required to produce clinical symptoms is so small.

Standard universal procedures should be taken whenever a patient presents with botulism. Patients who may have the toxin on their skin as a result of aerosol exposure should bathe thoroughly with soap and water and discard their clothes.

The mainstay of treatment is ventilatory support. Most patients who have botulism will survive if they are given proper ventilatory assistance. Full recovery, however, generally takes several weeks or months-a long time to be on a ventilator-because new synapses must grow to replace the ones damaged by the botulinum toxin. Unfortunately, such a strategy would present insurmountable logistical problems in the event of a terrorist attack in which hundreds or thousands of people may be afflicted with respiratory failure. Obviously, mechanical ventilators will be in short supply, and bag ventilation would be impractical during the months needed for the victims' synapses to regenerate. Ultimately, the sudden demand for limited resources could make proper care for the many victims nearly impossible.

A botulinum antitoxin is available from the Centers for Disease Control and Prevention and from some state health departments. Unfortunately, it is effective only in preventing further deterioration; it will not reverse muscle weakness that has already developed. Because the antitoxin is a horse serum product, skin testing for horse serum sensitivity is necessary before the drug can be administered.

TULAREMIA

Otherwise known as rabbit or deer fly fever, tularemia is usually contracted after contact with infected animals or from the bites of infected deerflies, mosquitoes, or ticks. It can also be caused by the ingestion of contaminated food and water and by the inhalation of contaminated air. The causative organism, Francisella tularensis, is a small, intracellular gram-negative coccobacillus.

Tularemia can manifest in several ways, depending on the route of infection. Ulceroglandular tularemia resulting from contact with infected animals is the most common form, accounting for up to 85% of cases, but typhoidal tularemia, which is caused by infectious aerosols, is the form most likely to appear after a terrorist attack. After an incubation period of 2 to 10 days, most victims present with fever, headache, chills, myalgia, nausea, vomiting, and diarrhea. They may also have cough and other respiratory symptoms. A sizable percentage of patients will have pneumonia.

Such nonspecific signs and symptoms makes the diagnosis difficult. In addition, the organism in most instances cannot be identified in sputum stains, and culturing can be difficult as well. The diagnosis can be confirmed with serologic tests, but only after the patient has been ill for at least a week. The traditional treatment for patients with tularemia is a 10- to 14-day course of streptomycin. Other agents that have proved effective against the disease include gentamicin, tetracycline, and chloramphenicol. Although person-to-person transmission of tularemia is rare, health care personnel should follow standard universal precautions whenever managing patients with the disease.

Q FEVER

Not all potential agents of biological terrorism cause fulminant, life-threatening illnesses; some produce milder, longer-lasting illnesses. Q fever is a good example of the latter. The disease has a relatively long incubation period, after which it tends to produce nonspecific, fairly mild symptoms. Only very rarely is it fatal; however, a terrorist group does not need to kill people to disrupt and terrify a community.

Q fever is a zoonotic disease that is most commonly spread through the inhalation of air contaminated with the rickettsial organism Coxiella burnetii. The organism's natural reservoirs are domesticated animals, especially sheep, cattle, and goats. One would expect the Q fever caused by a terrorist attack to be very much like the Q fever occasionally seen in people who work with livestock. Patients typically present with fever, headache, myalgia, and malaise. For approximately 50% of patients with the disease, chest films will be abnormal with indications suggestive of pneumonia with patchy infiltrates, and some patients with abnormal films also have cough or rales. On routine laboratory testing, the white blood cell count is usually normal, although many patients have elevated liver function levels. The prognosis for most patients is good, but the malaise can last for months. Complications such as endocarditis or hepatitis may develop. Because C. burnetii is difficult to culture, the diagnosis is usually based on clinical suspicion and evidence of antibodies in the patient's serum after indirect fluorescent antibody (IFA), ELISA, or complement fixation testing. Because an antibody response may take weeks to develop, acute and convalescent sera may be required for diagnosis.

Although Q fever most often resolves on its own without treatment, antibiotics are usually recommended to shorten the course of the disease. Tetracycline is generally the preferred agent for adults, whereas chloramphenicol is the traditional agent for children. Other antibacterial agents that have proved effective against C. burnetii include erythromycin, azithromycin, the quinolones, and trimethoprim-sulfamethoxazole. Treatment for uncomplicated infections or prophylaxis is generally given for five to seven days, but prolonged combination treatment may be needed for chronic infections such as endocarditis.

BRUCELLOSIS

Brucellosis is caused by four species of Brucella, which are slow-growing, zoonotic gram-negative, rod-shaped bacteria. The disease, which can affect the lungs, spleen, liver, bone marrow, and central nervous system, is most commonly caused by direct contact with infected livestock; it can also occur after the ingestion of milk and other products from infected animals. Brucella organisms are highly infectious when aerosolized; consequently, inhalation will most likely be the route of infection during a terrorist attack.

Like Q fever, brucellosis can begin insidiously, with an influenza-like illness. After an incubation period of 5 to 60 days, or even longer, most patients present with intermittent fever, headache, chills, sweats, malaise, and myalgia; cough and pleuritic chest pain may also be present. Gastrointestinal symptoms, such as anorexia, nausea, vomiting, diarrhea, and constipation, are also common.

In most instances, the intermittent fever phase lasts for several weeks, followed by a period of remission, during which symptoms may wane or disappear altogether. The fever and other symptoms then recur. This pattern of periodic febrile waves and remission can last for months or even years.

Other frequently seen features of the disease include joint pain, hepatomegaly, and splenomegaly. Serious complications from the disease are relatively rare but include endocarditis, meningitis, and encephalitis. Although chronic cases of brucellosis can be very debilitating, the disease is rarely fatal.

Routine laboratory testing may demonstrate leukopenia, anemia, or thrombocytopenia. The serum agglutination test, which generally documents both IgM and IgG antibodies, can be very helpful in making the diagnosis; titers of 1:160 or greater are signs of active disease. The organism can sometimes be identified in blood or bone marrow cultures. Because the organism is slow-growing, the laboratory should be notified to hold cultures for at least 4 weeks.

Standard universal practices should be followed for most cases of brucellosis; contact isolation is necessary when patients have open lesions. The preferred treatment is a combination of antibiotics, usually doxycycline and rifampin or doxycycline and trimethoprim-sulfamethoxazole. Quinolones are also active. In especially severe cases, such as endocarditis or CNS infection, gentamicin or streptomycin should be added to those regimens. Most patients will recover even without antibacterial therapy.

ELEMENTS OF PREPAREDNESS

Although many of the potential problems associated with a biological terrorism attack seem intimidating, there are preparations that could improve our ability to deal with such an event. Physicians should be familiar with their contacts in the local public health department so that any suspicious illness can be reported promptly. Specific plans for biological terrorism should be incorporated in disaster planning. Important topics would include infection control measures, communications with key agencies such as public health and law enforcement, mobilizing resources in the laboratory and pharmacy, plans for processing large numbers of patients, and increased security. A little preparation could go a long way in mitigating the effects of a biological attack.

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