Bioterrorism: Potential Microbiological Agents

By Maged Botros, MD

Special
Feature

The use of biological warfare is not a new concept to Americans. Our very existence stems from a covert operation by early settlers to sell smallpox-laden blankets to Native American Indians. It is ironic that this same weapon now has many fearing their own mortality in this land. As recently as during the first and second World Wars, America and other countries operated secret development programs for offensive biowarfare. However, in 1969 the United States terminated its offensive biological weapons program for microorganisms and has concentrated its efforts on defensive measures only.1 In 1975, the Convention on the Prohibition of the Development, Production, and Stockpiling of Bacteriologic and Toxin Weapons and on their Destruction went into effect.1 Despite this treaty, bioterrorism is still a real threat to humanity. To date, the former Soviet Union, Iraq, North Korea, Syria, and South Africa are signatories who are believed to have violated the treaty.1 This article will concentrate on three potential organisms that may be encountered during an act of bioterrorism: Variola major (smallpox), Yersinia pestis (pneumonic plague), and Bacillus anthracis (inhalation anthrax).

Smallpox

Although smallpox was discounted in the past as a "rational" weapon because its spread might be uncontrollable, recent events have challenged this traditional belief. Some terrorists may be undeterred by the havoc that would result from the reintroduction of smallpox into society, the younger half of which is unvaccinated and the remainder probably not having retained immunity. Because a large proportion of the world’s population is not immune to smallpox, no effective treatment exists, and the case fatality rate is between 20% and 50%, the smallpox virus is a potentially dangerous agent of biologic terrorism.2

Smallpox is caused by the variola virus, which is an orthopoxvirus that infects only humans. Smallpox has an incubation period of 12-13 days that is followed by the abrupt onset of fever, malaise, headache, and backache.4 The exanthem appears within 2-4 days and evolves from macules to papules to vesicles to pustules, and finally, crusts form. All the lesions are in a similar stage at any one time. The initial lesions occur on the palms and soles and feel firm (like BB pellets) when palpated.3 The rash is highly characteristic, with profuse involvement of the face, forearms, and lower legs, and relative sparing of the trunk and abdomen. After 8-9 days, the pustules become umbilicated and form crusts. Although this rash may be mistaken for chickenpox (varicella), its distribution and evolution (all the lesions being in the same stage) are unique.4

If the diagnosis of smallpox is considered, the patient should be placed immediately in respiratory isolation, patient contacts should be identified, and the Centers for Disease Control and Prevention (CDC) should be contacted. Spread of smallpox generally occurs through intimate contact, with entry through the respiratory tract, so population density as well as immunity affects the extent of spread. Infected people are contagious from the onset of illness until the last crusts are gone. In the United States, routine vaccination continued until 1971; the vaccine was given sporadically after this until 1983, when vaccine producers were urged to reserve the vaccine for military personnel only.4 Given recent concerns about bioterrorism, there is a push in Congress to reinstate the smallpox vaccination program.

Although no proven treatment for smallpox exists, recent in vitro data and studies in animals suggest that intravenous cidofovir may shorten the course of disease in infected individuals. Clinical trials to evaluate intravenous cidofovir therapy are being planned, but until then only isolation, supportive care, and treatment of complicating bacterial infections are indicated.2

Plague

Since 1977 there have been 18 documented cases of Yersinia pestis, the etiologic agent for plague, in the United States. Y. pestis has three separate clinical presentations: bubonic plague (acute regional lymphadenitis), septicemic plague (blood-borne), and pneumonic plague (pulmonary). The most common clinical form is bubonic plague, which historically was contracted from rodents or cats infested with fleas carrying the microorganism. Although this would be an effective medium for bioterrorists to utilize, the pneumonic form of the plague seems to be a more likely choice given that direct, person-to-person transmission occurs only in the setting of pneumonic plague.5

Bubonic plague generally occurs after an incubation period of 2-6 days and results in the sudden onset of fever, chills, weakness, and headache. Shortly thereafter, patients note an intensely painful swelling in one region of lymph nodes, usually the groin, axilla, or neck. This swelling, or bubo, is typically oval, varying from 1 to 10 cm in length; the overlying skin is elevated and warm and may appear stretched or erythematous. The bubo itself is firm, extremely tender to palpation, and non-fluctuant. In the absence of therapy, the disease progresses rapidly to a septicemic phase, with marked toxicity, prostration, and shock.

Pneumonic plague may result from primary person-to-person transmission or from hematogenous spread of Y. pestis to the lung in patients with bubos.5 Patients develop cough and chest pain and may have hemoptysis. Radiographically, there is patchy bronchopneumonia or confluent consolidation. Sputum is purulent and contains Y. pestis. Pneumonic plague is highly contagious by airborne transmission; persons inhaling the organism, from either an infected person or an animal, are susceptible to infection. The diagnosis is confirmed by using Gram’s stain or fluorescent antibodies to isolate Y. pestis from blood, a bubo aspirate, or from sputum. The Gram’s stain will reveal leukocytes and gram-negative coccobacilli.

Untreated bubonic plague has an estimated mortality rate of more than 50% and can evolve into a fulminant illness complicated by septic shock.5 Pneumonic plague is invariably fatal when antibiotic therapy is delayed more than one day after the onset of illness; therefore, the early institution of effective antibiotic therapy is mandatory after appropriate cultures. Streptomycin should be administered intramuscularly in two divided doses daily, totaling 30 mg/kg of body weight per day for 10 days. Doxycycline 200 mg IV once, followed by 100 mg orally twice a day, is a satisfactory alternative.6 Given the risk of person-to-person transmission, all patients with suspected pneumonic plague should be placed on strict standard and airborne precautions. Close contacts of suspected or confirmed pneumonic plague cases should be provided with chemoprophylaxis with doxycycline.5 A formalin-killed vaccine is commercially available but does not protect against the pneumonic form of the disease. New, subunit vaccines for plague are currently under development.5

Anthrax

B. anthracis, the etiologic agent responsible for anthrax, is a large, aerobic, gram-positive rod with a centrally located spore. There are three predominant clinical forms of anthrax which are determined by the route of entry. Cutaneous anthrax constitutes more than 95% of reported cases and results from entry of spores through skin abrasions. The remaining 5% of cases are due to gastrointestinal (never reported in the United States) or inhalation anthrax.7

Cutaneous anthrax becomes apparent within five days of exposure, beginning as small, painless, often pruritic papules that enlarge and become vesicular within 1-2 days. Fever, malaise, and regional adenopathy often are associated features. The lesion ulcerates near the end of the first week and progresses to the black eschar responsible for the name of this disease (from the Greek word for coal, describing the characteristic color and appearance of the eschar).7 If it is recognized and treated promptly, the disease is rarely fatal. The case-fatality rate of cutaneous anthrax is 20% without antibiotic treatment and less than 1% with antibiotic treatment.8

Inhalation anthrax results from the inhalation of a large sum of aerosolized spores. The estimated infectious dose that is required to cause inhalation anthrax in humans has been estimated to be roughly 8,000-50,000 spores.8 The large load that is required is believed to be why person-to-person transmission of inhalation anthrax has never been documented.

Aerosolized anthrax spores greater than 5 micrometers in size are deposited in the upper airways (pharynx, larynx, and trachea) and effectively trapped or cleared by the mucociliary system. Spores between 2 micrometers and 5 micrometers in size are able to reach the alveolar ducts and alveoli. These spores are engulfed by pulmonary macrophages and transported to mediastinal and hilar lymph nodes.7 Following a period of germination, a large amount of anthrax toxin is produced. Regional lymph nodes are quickly overwhelmed and the toxin finds its way into the systemic circulation, resulting in edema, hemorrhage, necrosis, and septic shock; death soon follows. Since the organisms are initially transported to mediastinal lymph nodes, a major site of involvement is the mediastinum. Edema and lethal toxin cause the massive hemorrhagic mediastinitis that is typical of inhalation anthrax.7

Inhalation anthrax has an incubation period of about six days. This is followed by an initial stage that results in four days of myalgia, malaise, fatigue, nonproductive cough, sensation of retrosternal pressure, and fever. The second stage, which usually lasts 1-2 days, develops suddenly with the onset of acute respiratory distress, hypoxemia, and cyanosis, and usually culminates in death.7 A chest radiograph typically shows normal lung parenchyma with a widening of the mediastinum and pleural effusions.

Diagnosis of inhalation anthrax during the first stage is difficult. The symptoms and signs of disease are similar to the common cold or a viral infection and often are mistaken for the latter diagnoses. Advanced disease may be recognizable by virtue of the shock-like symptoms and characteristic chest radiograph abnormality, but by then the disease progression is rapid and treatment is less likely to be effective.

Although a vaccine exists for human use, it currently is recommended only for military use and for patients with documented exposure. Primary vaccination consists of three subcutaneous injections at 0, two, and four weeks, and three booster vaccinations at six, 12, and 18 months. To maintain immunity, the manufacturer recommends an annual booster injection.1

Postexposure prophylaxis for exposure to B. anthracis consists of chemoprophylaxis and vaccination. Oral fluoroquinolones (e.g., ciprofloxacin 500 mg twice daily) are the drugs of choice for adults, including pregnant women. If fluoroquinolones are not available or are contraindicated, doxycycline (100 mg twice daily) is acceptable. Children should receive prophylaxis with oral ciprofloxacin or oral doxycycline. Since tetracyclines and fluoroquinolones have well known side effects, children should receive oral amoxicillin as soon as penicillin susceptibility of the organism has been confirmed. If exposure is confirmed, prophylaxis should continue for four weeks if three doses of vaccine have been administered, or for eight weeks if vaccine is not available.1,9

Conclusion

A biologic attack on a major city can approximate the devastation of a nuclear weapon. The Office of Technology Assessment estimated that 100 kg of anthrax spread over Washington, DC, could kill between 1 million and 3 million people. When comparing this to nuclear warfare, a 1-megaton nuclear warhead detonating over Washington would result in only 759,000 to 1.9 million deaths.1 Biologic weaponry also has the added advantage of easier acquisition, storage, and transport. It is for these reasons that the fear of bioterrorism has surfaced as a major concern for the American public as well as health care workers. For health care workers to fight bioterrorism, we need to become familiar with the possible agents that may be used and become comfortable with aiding in the early recognition, reporting, and treating of these diseases.

References

1. Moran GJ. Update on emerging infections from the Centers for Disease Control and Prevention. Bioterrorism alleging use of anthrax and interim guidelines for management—United States, 1998. Ann Emerg Med 1999;34: 229-232.

2. Neff JM. Vaccinia virus (cowpox). In: Mandell Gl, et al, eds. Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill Livingstone; 2000: 1552-1555.

3. Diven DG. An overview of poxviruses. J Am Acad Dermatol 2001;44:1-16.

4. Mayers DL. Advances in military dermatology: Exotic virus infections of military significance. Hemorrhagic fever viruses and poxvirus infections. Dermatol Clin 1999;17:29-40.

5. Morris GJ Jr. Yersinia infections. In: Goldman L, et al, eds. Cecil Textbook of Medicine. 21st ed. Philadelphia: W.B. Saunders Company; 2000:1700-1716.

6. Anonymous. Drugs and vaccines for biological weapons. Med Lett Drugs Ther 2001;1115:87-89.

7. Shafazand S. Inhalational anthrax: Epidemiology, diagnosis, and management. Chest 1999;116:1369-1376.

8. Centers for Disease Control and Prevention. Use of anthrax vaccine in the United States: Recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep 2000;49(RR-15):1.

9. Centers for Disease Control and Prevention. Update: Investigation of bioterrorism-related anthrax and interim guidelines for exposure management and anitmicrobial therapy. MMWR Morb Mortal Wkly Rep 2001;50:909-919.

(Dr. Botros is an Assistant Professor of Emergency Medicine at Temple University School of Medicine, and serves as the Assistant Research Director for Sponsored Projects within the Department of Emergency Medicine at Temple University Hospital, Philadelphia, PA.)