Bioterrorism: What the Primary Care Physician Needs to Know
May 8, 2000
Bioterrorism: What the Primary Care Physician Needs to Know
Author: W. Paul McKinney, MD, Division of General Internal Medicine, University of Louisville, Louisville, KY.
Peer Reviewer: Frank J. Bia, MD, MPH, Professor of Medicine and Laboratory Medicine, Infectious Disease & Tropical Medicine, Yale University School of Medicine, New Haven, CT.
Editor’s Note—Few natural or intentional threats arouse the concern of emergency management planners in this country more acutely than the use of biological agents as an act of war or terrorism against citizens of the United States. While a vast array of first responders, including elements of the police, fire departments, emergency medicine services, and hazardous materials units have been preparing to respond to such emergencies, few physicians have been involved in comprehensive efforts to defend against possible acts of bioterrorism. Particularly in a covert attack, however, primary care physicians (PCPs) would nonetheless play a front-line role in the detection, evaluation, and response to this threat. Formal educational curricula to inform PCPs about the likely agents of bioterrorism are essential to ensure that cases are identified, reported, treated, and monitored as rapidly and efficiently as possible.
The Threat of Bioterrorism
Background
Evidence of attempts to induce fatal infectious illnesses among enemy combatants is hardly a recent concept and actually dates back in time to an era long before the acceptance of the germ theory of disease. The intentional use of biological agents as a weapon of warfare first occurred no later than the Middle Ages, when attacking 14th-century Tatar forces in what is now Ukraine catapulted the corpses of their troops who had died from plague into a besieged stronghold in an attempt to induce an outbreak of plague among their enemy.1 Other evidence of such intentional use of biological agents as a weapon can be found in North America during the mid-18th century, when British commander Sir Jeffrey Amherst ordered the transfer of blankets used by British smallpox victims to Native American tribal members, ostensibly as a gesture of goodwill, with the intention of inducing illness.1 Indeed, the United States had a program of developing biological agents for use in warfare well into the Vietnam War era until that strategy was abandoned and the offensive use of such weapons was forbidden by U.S. policy under executive orders of President Richard Nixon in 1969-1970.1
International Threats
Since the Persian Gulf conflict of the early 1990s, attention has focused on the arsenals of biological warfare agents amassed by Iraq and by the nations comprising the former Soviet Union. During the Cold War era, Soviet military experts oversaw the weaponization of a variety of bacteria and viruses; unfortunately, the whereabouts of much of this material is currently unknown.2 Also in the 1990s, Japan’s quasi-religious Aum Shinrykyo cult planned attacks using biological agents, specifically anthrax and botulinum toxin.3 While these biological attacks were unsuccessful, cult members later implemented the release of sarin nerve gas in the Tokyo subway system, killing 12 persons, affecting almost 1000 persons and inducing panic in the population.4
Incidents and Hoaxes in the United States
The United States has not escaped such assaults, as biological agent attacks against American citizens have already occurred, and plans for others were discovered before their successful implementation. In 1984, members of the Rajneesh cult contaminated salad bars in Oregon with salmonella, resulting in the infection of 751 persons.5 Moreover, a variety of feigned exposures to anthrax spores occurred in several U.S. cities in 1998, including Cincinnati, Louisville, and Indianapolis.6 In the latter city, a full-scale response by emergency services and public health personnel occurred before the episode was proven to be a hoax.
These exposures, both actual and potential, point out the need for a high level of preparedness in this country for bioterrorist activities. Currently, the network of local and state health departments throughout the nation, with the support of the national Centers for Disease Control and Prevention (CDC), forms the backbone of the surveillance and response system for such events. A variety of other federal entities, including the Department of Defense, the Office of Emergency Preparedness, the Federal Emergency Management Agency (FEMA), the Department of Veterans Affairs, the Central Intelligence Agency (CIA), and the Federal Bureau of Investigation (FBI), are also actively involved in integrated planning efforts on the national level. Additionally, the national surveillance arm is supplemented by arrangements with three elements of the medical care delivery system: emergency room physicians from hospitals serving selected large metropolitan areas, the network of infectious disease physicians throughout the nation, and selected international travel clinics.
| Table 1. Clinical Syndromes Suggestive of Bioterrorism-Associated Illness | |
| Agent | Clinical Presentation |
| Anthrax | Widened mediastinum, not associated with chest trauma |
| Smallpox | Characteristic vesiculopustular rash, with eruption of palms and soles, involving face sore than chest, and all lesions in same phase of development |
| Botulism | Prominent neurologic symptoms: descending paralysis beginning with cranial nerve palsies |
| Plague, Tularemia | Increased incidence of atypical pneumonia in population |
Why Should Primary Care Clinicians be Concerned about Bioterrorism?
The Threat of Announced and Covert Attacks
Thus, the threat of bioterrorist actions against citizens of the United States has generated extensive plans for detection and response involving several elements of our health care system. The rationale for such planning is singularly straightforward: failure to make the earliest possible diagnosis of cases in the first wave of illness following covert exposure risks substantially greater loss of human life. However, in an era of increased penetration of managed care and emphasis on the provision of care in rural areas, persons with acute infectious diseases are less likely to directly access either infectious disease specialists or emergency rooms. Instead, many are likely to be seen first by primary care providers. The process of referral of such individuals to infectious disease specialists would consume additional time, potentially resulting in many more cases or deaths before the source could be identified and contained. Moreover, in the event of a large-scale exposure, these clinicians would necessarily be called upon to support the civilian health sector response in the form of managing the determination of individual need for essential immunizations and chemoprophylaxis.
The Role Primary Care Clinicians Must Know About the Detection and Management of Bioterrorism-Associated Illness
Clearly, it is critical to involve the full spectrum of primary care clinicians in preparation for the possibility of bioterrorist events in the following ways:
• integrating them into this vital national surveillance network to enhance the capacity for early detection and large-scale response;
• educating them through enhanced curricula during medical school and residency training regarding syndromes or disease patterns suspicious for biological warfare agent exposures as well as preferred immunobiologic and pharmaceutical management strategies.
The remainder of the article will focus upon the six agents considered likely to be used in a bioterrorist event: smallpox, anthrax, botulism, tularemia, plague, and brucellosis. This is not an exhaustive list of possibilities.
Smallpox
Perhaps the worst-case scenario in bioterrorism in terms of both immediate consequences and the potential for secondary and further generations of infection is exposure to smallpox. Most physicians in practice have received lectures about the disease and many will remember being immunized; however, few have had significant experience in diagnosis, and even fewer have seen even one case of illness in the past 40 years. Therefore, the potential for the failure of physicians to recognize this disease in its first wave is great, allowing the propagation of further waves of infection.
Epidemiology and Clinical Features of Smallpox
Transmission of smallpox to humans may occur via fomites, but the risk of infection is greatest when aerosolized particles enter the respiratory tract. Following an incubation period of 12-14 days, symptoms begin with the abrupt onset of chills, fever, malaise, vomiting, headache, backache, and occasionally mental status changes or an erythematous macular rash. After 2-3 more days, an enanthem and discrete papular rash of the face, hands, and arms begin, later spreading to the legs and finally the trunk.7 The papules evolve into vesicles and finally pustules as fever and pain persist. Most lesions develop on the face and extremities and all are synchronous, that is, in the same phase of development at a given time. The pustules form scabs that are infectious until separation, and form deep, depigmented scars.7
Mortality from smallpox is 3% among vaccinated persons and 30% overall among those unvaccinated.8 Among those with a secondary bacterial pneumonia, mortality rises to 50%.9 Death usually occurs in the second week of illness, although 5-10% of cases with a more fulminant course progress to death within seven days.
It is absolutely critical to distinguish smallpox from primary varicella, or chickenpox. As opposed to smallpox, the lesions of chickenpox are more superficial and appear in crops or waves and thus are asynchronous in development, with groups of vesicles, pustules, and scabs appearing adjacent to one another. The lesions of chickenpox are clustered much more densely over the trunk and do not appear on palms or soles.7 Also to be distinguished are monkeypox, which typically causes cervical and inguinal adenopathy, and skin eruptions from exposures to certain drugs or skin contact agents, such as erythema multiforme and allergic dermatitis.9
| Table 2. Agents with Risk for Secondary Transmission of Illness | |
| Agent | Secondary Transmission Risk |
| Smallpox | Yes |
| Anthrax | No |
| Botulism | No |
| Tularemia | No |
| Plague | Yes |
| Brucellosis | No |
Postexposure Management
Any person exposed to smallpox should be immunized immediately with either the calf-lymph-derived or cell culture vaccine developed by the Department of Defense.9 Vaccination against smallpox is effective in preventing death if given up to five days after exposure and in preventing illness if given within 72 hours. Quarantine of those exposed should continue for 17 days, as they may transmit infection asymptomatically through oral and pharyngeal secretions.9
Treatment of Clinical Cases
There are currently no agents with proven efficacy against active smallpox infection in humans. Treatment of active smallpox might be attempted with cidofovir, an agent with activity against many pox viruses; three other agents, adefovir dipivoxide, cyclic cidofovir, and ribavirin, may also be candidates for use in this setting.9
Anthrax
Anthrax exposure has received perhaps the greatest notoriety of all the potential agents of bioterrorism. It is unique among the six agents discussed in this article in that an exposure of a population to weaponized organisms was recognized in the Soviet city of Sverdlovsk. This outbreak occurred in 1979 in proximity to a biological weapons development facility following the unintentional release of aerosolized anthrax spores, resulting in 66 deaths.1 Additionally, anthrax appears to be the favored purported agent used in the exposure hoaxes reported in cities across the nation. While the exposure of a population to anthrax spores would wreak heavy casualties, there is no potential for a second generation of illness since anthrax cannot be transmitted from person to person. However, there could be delayed exposures if decontamination of spores does not occur promptly.
| Table 3. Availability of Licensed, Pre-exposure Vaccines for Prevention of Bioterrorism-Associated Disease | |
| Agent | Vaccine |
| Smallpox | Yes—currently approved on as-needed basis for lab workers |
| Anthrax | Yes—vaccine for civilian use must be approved by Dept of Defense |
| Botulism | No |
| Tularemia | No |
| Plague | Yes—but not proven effective against pneumonic plague |
| Brucellosis | No |
Epidemiology and Clinical Features of Infection
Infection of humans with anthrax can occur via three routes:
1) Cutaneous, by the inoculation of skin lesions with spores carried by infected animals, chiefly cattle, sheep, or goats. This form is rarely fatal and has not been reported in the United States since 1992.10
2) Gastrointestinal, by eating meat from infected animals. This exposure route is only rarely encountered.
3) Inhalation, by the deposition of spores in the respiratory tract. Naturally occurring inhalational infection, associated with exposure to hides, wool, or other animal products during processing, is known as woolsorter’s disease and has been essentially eliminated among workers in the developed world by use of the anthrax vaccine. After inhalational exposure, the spores enter pulmonary macrophages and the mediastinal lymph nodes. After germination, the vegetative phase begins with necrosis of the nodes, followed by bacterial entry into the general circulation and ensuing fatal sepsis with generalized hemorrhage and necrosis. It is anticipated that a bioterrorist attack would attempt human infection by this route, given that the cutaneous and gastrointestinal routes of exposure are less reliable and do not lend themselves as readily to mass exposure.
Following an incubation period of 1-6 days11 after respiratory exposure, a nonspecific prodrome of fever, malaise, myalgia, fatigue, cough, and chest pain develops. An interval of improvement often occurs over the next 2-3 days before the final phase is introduced by high fever, dyspnea, and cyanosis, followed by septic shock, hematogenous dissemination of infection, and death within 36 hours.12,13 Hemorrhagic meningitis may occur as a manifestation of metastatic infection in up to half of the cases.14
The physical findings in human anthrax are rather nonspecific. Radiographically, anthrax does not usually present as a pneumonia. Rather, the chest x-ray classically will show mediastinal widening with pleural effusions—manifestations of a necrotizing hemorrhagic mediastinitis.12-15 There are generally no pulmonary infiltrates. Clinical conditions that produce similar radiographic findings, such as blunt chest trauma or deceleration injury, especially following motor vehicle accidents, and the post-thoracic surgery state should be readily distinguishable.16
| Table 4. Potential Treatment Regimens for Agents of Bioterrorism9 | |
| Variola | Treatment of active smallpox can be attempted with cidofovir, an agent with activity against many pox viruses; three other agents—adefovir dipivoxide, cyclic cidofovir, and ribavirin—may also be candidates for use in this setting. |
| Anthrax | IV administration of ciprofloxacin 400 mg every 8-12 hours. |
| Botulism | Trivalent equine antitoxin if the disease is in a phase of progression. Contact the CDC for release of antitoxin. Skin testing should be done first to avoid the occurrence of anaphylaxis or serum sickness. |
| Tularemia | Streptomycin given 30 mg/kg/day IM in two divided doses for 10-14 days. |
| Plague | Streptomycin 30 mg/kg IM per day in two divided doses. (Gentamicin is considered a substitute agent.) IV chloramphenicol may be given for plague meningitis or in sepsis syndrome. IV doxycycline (100 mg every 12 hours for 10-14 days, after an initial loading dose of 200 mg) is also effective |
| Brucellosis | Preferred for severe brucellosis (bone, joint, heart, CNS infection) is a combination of doxycycline (100 mg BID) plus rifampin 600-900 mg/day orally for six weeks. |
Postexposure Prophylaxis
If individuals can be reached soon after exposure, the use of ciprofloxacin 500 mg orally b.i.d. or doxycycline 100 mg b.i.d. orally should be given17 together with initiation of anthrax immunization if available. Currently, control and distribution of the anthrax vaccine is under the direction of the Department of Defense and cannot readily be obtained by practitioners without special authorization. Antibiotic prophylaxis should continue for at least four weeks and until three doses of vaccine have been given.9
Treatment of Cases
Without treatment, death is certain to occur, and only 5% of those infected by the respiratory route will survive if therapy is not instituted within 48 hours after symptoms appear.16 Historically, IV treatment with 2 million units of penicillin every two hours (24 million U/d) has been the standard of care. Nonetheless, IV administration of ciprofloxacin 400 mg every 8-12 hours is now the treatment of choice; nevertheless, since anthrax has not shown significant resistance to erythromycin, chloramphenicol, or gentamicin,9 these drugs could be considered as alternative agents.
Botulism
On a per gram basis, botulinum toxin is one of the most toxic substances known. Practitioners are perhaps most familiar with botulism as a food-borne illness from instruction in microbiology and the immediate attention the illness receives following consumption of prepared food or restaurant exposure. However, natural clinical illness may also follow exposure from wounds or ingestion of certain uncooked food products by infants.
Epidemiology and Clinical Features of Infection
Botulinum toxin causes illness in humans by binding to presynaptic nerve endings and blocking acetylcholine release, thus interrupting neurotransmission and causing weakness of muscles supplied by the affected nerves.18 While natural intoxication most often follows ingestion, the inhalation route is expected to be the target of bioterrorists.9 Symptoms will begin within 24-36 hours to several days of respiratory exposure, depending on the magnitude of the dose,19,20 starting with abnormalities of cranial nerve function. These manifest by ocular symptoms, with blurred and double vision as well as light-induced pain; disordered speech, as evidenced by articulation problems, hoarseness, and trouble swallowing; and a descending, symmetrical, skeletal muscle paralysis.9
The clinical examination of persons with botulism reveals them to be alert, awake, and oriented, with no fever or sensory findings. Involvement of the autonomic nervous system may be evidenced by orthostatic hypotension. Eyes may show disconjugate gaze, pupillary dilatation, and eyelid drooping. The gag reflex is absent. Constipation and urinary retention are common.21 Cyanosis with advancing respiratory compromise signals severe impairment of phrenic nerve function and the need for immediate ventilatory support. Fortunately, less than 5% of cases are fatal if adequate treatment of respiratory failure is instituted promptly.9
A variety of clinical conditions may be confused with botulism. Guillain-Barré syndrome typically causes an ascending paralysis with notable sensory findings and elevated protein in the cerebrospinal fluid. Myasthenia gravis is usually, but not always, distinguished by a positive edrophonium (Tensilon) test, has a typical electromyographic profile, and induces antibodies to acetylcholine receptors. Additionally, the Eaton-Lambert syndrome, acute poliomyelitis, tick paralysis, diphtheria, hypermagnesemia, and mushroom or chemical intoxications all may induce similar neurologic manifestations and may be confused with botulism.21
Prophylactic Management
The horse-serum-derived antitoxin against botulism is most effective if given immediately postexposure, before the appearance of clinical symptoms,19 though in clinical practice such opportunities rarely arise. A trivalent antitoxin is available from the CDC and a heptavalent product developed by the U.S. Army of as-yet-undetermined efficacy in humans19 is available as an investigational new drug.
Treatment of Cases
Treatment of active botulism involves the use of the equine antitoxin if the disease is in a phase of progression. For treatment of one or a small number of cases, direct contact of the CDC for release of antitoxin is most efficient. If large quantities are required, local, regional, or national stockpiles will need to be tapped. All antitoxin products are of equine origin, so skin testing should be done first to avoid the occurrence of anaphylaxis or serum sickness.
Tularemia
Named for the first recognition of clinical cases from Tulare County, California, tularemia is an organism understandably feared by microbiologists for its potential to cause infection of laboratory workers via aerosolization. An endemic infectious disease primarily of the western United States, tularemia is a well-known risk for hunters and persons venturing into wilderness areas. Its ability to cause severe disease following respiratory exposure has made it a target for biological weapons developers.
Epidemiology and Clinical Features of Infection
The forms of Francisella tularensis infection recognized in humans include glandular/ulceroglandular/oculoglandular, pulmonary, gastrointestinal, and typhoidal. These result from direct penetration of the skin or exposure of mucous membranes with blood or tissue of infected animals or indirectly from bites of deerflies, ticks, or mosquitoes; inhalation; or ingestion of contaminated food or water. The typhoidal and pulmonary forms result primarily from aerosol exposures.22
After an incubation period of 2-10 days, patients present with fever, headache, myalgias, weight loss, fatigue, but no lymphadenopathy.23-25 Chest pain, nonproductive cough, and pneumonia with pleural effusions may occur. Radiographically, such infection may result in patchy, lobar, or cavitary infiltrates; mortality in such cases that go untreated is about 35%.23,26 Despite evident pulmonary involvement, secondary human-human transmission is unusual. High fever, meningitis, hepatitis, endocarditis, osteomyelitis, and septic shock may occur in the final stages of typhoidal tularemia.
The differential diagnosis of pulmonary tularemia should include all the atypical pneumonias, including psittacosis, Legionellosis, Q fever, mycoplasma, and C. pneumoniae infections.22
Treatment of Clinical Cases
Beta lactam antibiotics are notoriously ineffective in tularemia. The drug of choice for severe infections is streptomycin given 30 mg/kg/d IM in two divided doses for 10-14 days.27 Gentamicin may also be used.25,28
| Table 5. Postexposure Prophylaxis Against Agents of Bioterrorism9 | |
| Variola virus | Smallpox vaccine is effective in preventing death if given up to five days after exposure and in preventing illness if given within 72 hours. |
| Anthrax | Ciprofloxacin 500 mg orally b.i.d. or doxycycline 100 mg b.i.d. orally. Also initiate anthrax immunization, if available. Antibiotic prophylaxis should continue for at least four weeks and until three doses of vaccine have been given. |
| Botulism | Trivalent equine antitoxin, available from CDC |
| Tularemia | Doxycycline 100 mg orally b.i.d. for 14 days |
| Plague | Doxycycline 100 mg orally b.i.d. for seven days |
| Brucellosis | Doxycycline 100 mg b.i.d. plus rifampin 600-900 mg/d for three weeks |
Postexposure Prophylaxis
Prophylaxis immediately after recognized exposure may be given with doxycycline 100 mg b.i.d. for 14 days.9 For long-term advanced prophylaxis, a live attenuated vaccine is available in the United States under an investigational new drug protocol.29
Plague
A well-recognized risk for residents of the four corners region of the Southwest and contiguous areas, Yersinia pestis is thought of in this country primarily as a flea-borne illness and is perhaps easiest to recognize in its bubonic form. Sometimes a complication of other routes of exposure, the pneumonic form is transmissible from person to person and could result in secondary infection following a bioterrorist event.
Epidemiology and Clinical Features of Infection
Three forms of plague infection are recognized in the human host:
1) Bubonic, transmitted by the bite of infected fleas, leading to regional lymph node infection with pain, tenderness, swelling, and, rarely, to meningitis.
2) Septicemia, beginning commonly with gastrointestinal symptoms, then proceeding to systemic symptoms with disseminated intravascular coagulation (DIC), adult respiratory distress syndrome (ARDS), and circulatory collapse.
3) Pneumonic, the form following respiratory exposure and that most likely to be targeted by a bioterrorist attack.30,31
Following an incubation period of 2-3 days, primary respiratory infection with plague bacilli causes the rapid onset of fever, chills, malaise, myalgia, and headache and an acute pneumonia syndrome, accompanied by chest pain, dyspnea, and cough.9 Sputum production is usually watery and blood-tinged, but may be frankly bloody.32 There follows a rapid progression to respiratory failure and shock.
The chest x-ray of pneumonic plague victims shows patchy or consolidated airspace disease with involvement of a single lobe or multiple lobes on both sides of the chest; cavitation of the pneumonia may be evident early on in the course of disease.32
Treatment of Clinical Cases
Pneumonic plague is fatal if not treated in the first 24 hours. Appropriate antibiotic therapy includes streptomycin 30 mg/kg IM per day in two divided doses or gentamicin IV for 10 days. IV chloramphenicol may be given for plague meningitis or in sepsis syndrome. IV doxycycline (100 mg every 12 hours for 10-14 days, after an initial loading dose of 200 mg) is also effective.9
Postexposure Prophylaxis
Unfortunately, there is no proven benefit of the plague vaccine against pneumonic infection.33 Exposed individuals should be treated prophylactically with 100 mg of doxycyline orally every 12 hours for seven days.9
Brucellosis
Epidemiology and Clinical Presentation of Illness
Human brucellosis may occur following enteric, percutaneous, or respiratory exposure, and subsequent patterns of illness are similar in all forms of infection. This fact reflects the distribution of these intracellular organisms to macrophages in bone, joints, brain, liver, spleen, and lung, and accounts for the wide range of involved systems and the protean manifestations of illness. After an incubation period ranging from 5-60 days, fever, chills, diaphoresis, headache, myalgia, fatigue, anorexia, joint and low back pain, weight loss, constipation, sore throat, or dry cough are common.34 Although respiratory symptoms of cough and pleuritic chest pain occur in 20% of patients, overt pneumonia is uncommon.9 Skeletal involvement is evidenced by osteomyelitis of the vertebrae as well as by major joint infections including the knees, hips, shoulders, and sacroiliac joints.35-37 While bone marrow involvement with declines in all hematopoietic cell lines, hepatitis, and genitourinary tract infections may also occur, most fatalities result from CNS infection and endocarditis, which occur in only 5% of untreated patients.38 Symptoms may persist for weeks to months, but most patients will eventually recover within a year, regardless of treatment39; however, subsequent relapses are frequent.
Treatment of Clinical Cases
The treatment of choice for severe brucellosis (bone, joint, heart, CNS infection) is a combination of doxycycline (100 mg b.i.d.) plus an aminoglycoside for four weeks, followed by the same dose of doxycycline plus rifampin 600-900 mg/d for six weeks.40,41
Postexposure Prophylaxis
The latter regimen may be used as prophylaxis for three weeks following recognized exposure. At present, no vaccine is licensed in the United States for prevention of brucellosis among high-risk individuals.9
Conclusion
A bioterrorist attack against Americans could result in morbidity and mortality on a scale unknown to this nation since the influenza pandemic of 1918-1919. The inclusion of primary care clinicians as first responders in strategic planning for the defense against bioterrorism could be among the most cost-effective interventions available in health care in the event of such a biological agent attack. It is imperative that the nation’s professional organizations, academic health centers, and governmental agencies work together to ensure the appropriate education of primary care clinicians at all levels of training to reduce the likelihood of catastrophic consequences of such an event.
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