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A tabloid worker dies in Florida. Two postal workers die in Washington, D.C. A homebound retiree dies in Connecticut. An envelope packed with a white substance raises alarm when it is opened for routine screening at a US correctional facility. The common link? Spores from Bacillus anthracis. Fortunately, the white powder at the correctional facility did not contain anthrax spores, and moreover, correctional officials recognized the potential anthrax threat, deposited the envelope in a secure receptacle, quarantined the area and alerted the authorities. Proper training and access to appropriate protocols for handling suspect substances (Table 1) allowed the correctional officers to maintain calm while experts were consulted.
Bioterrorism is an offshoot of biological warfare. Biological warfare is the use of bacterial or viral agents as weapons. Waging biological warfare is a violation of the Geneva Convention of 1925, which was reaffirmed by the UN General Assembly in 1966. Despite these affirmations, bioterrorism has recently occurred.
Medical events related to exposure to anthrax have been reviewed in detail in several publications.1,2 Lane, La Montagne and Fauci, and others have reviewed the etiologic agents of biological terrorism.3,4 A wealth of bioterrorism resources are also now available in medical journals5,6,7,8 and on the web (see Resources). Because knowledge is the best defense against terror, this article will review some biological agents of terror, appropriate medical responses, and available means of treatment or prevention.
The seven characteristics of a bioterrorism agent are listed in Table 2. Of the seven, four (virulence, infectivity, stability and transmissibility) can be affected by modifying the genetic sequence of the bioterrorism pathogen. Research on these four characteristics is the primary thrust of most modern biological warfare research laboratories, and antibiotic resistance will be a significant concern during future bioterrorist events. On the other hand, mutations introduced in the anthrax used in the most recent outbreak may eventually yield up its identity.6 Lethal agents are also very effective bioterrorism tools because of the “panic effect” on susceptible populations (recent events certainly confirm this observation).7 Potentially lethal agents that have been placed in category A (high threat) include smallpox (Variola), bubonic plague (Yersinia pestis), tularemia (Francisella tularensis) and anthrax (Bacillus anthracis). (Table 3) These will be reviewed here.
Pathogen and Immunopathogenesis
Bacillus anthracis is a gram-positive spore-forming bacteria. The bacterium only sporulates under adverse conditions (lower oxygen availability or declining pH); thus production of anthrax spores requires familiarity with these conditions. Anthrax disease is initiated by introduction of endospores by inhalation or via cutaneous contact (usually with skin that is otherwise compromised). At the site of entry, macrophages endocytose the anthrax spores and transport them to regional (in cutaneous anthrax) and thoracic (in inhalation anthrax) lymph nodes. Within the first few hours of infection, anthrax bacilli escape from the phagocytic vesicles of macrophages and replicate within the cytoplasm of these cells. The next phase of infection
involves release of the mature bacilli from infected macrophages, four to six hours after the initial phagocytosis.11 Proteins secreted by the mature bacilli combine to form the two anthrax toxins: lethal toxin (LT) and edema toxin (ET).12 These toxins attack and destroy macrophages, causing them to spill their contents and damage surrounding tissues.
Anthrax: Clinical course
Of 10 recent cases described in JAMA, all but one was known to have handled mail contaminated with spores; the time of exposure to onset of symptoms (when known) was four to six days.2 Symptoms at presentation included fatigue or malaise, fever or chills with sweats, dyspnea, minimal or nonproductive cough, and nausea or vomiting. The white blood count was elevated but not markedly so, at 9.8 X 103/mm3 (range 7.5 to 13.3). Increased neutrophils and band forms were present. Six of the 10 patients were hypoxic, and all 10 chest X-rays were abnormal. On the X-rays, pulmonary infiltrates, pleural effusions, or mediastinal widening were noted, and involvement of the mediastinal nodes was confirmed
with chest CTs. It is notable that inhalation of anthrax spores was previously believed to be lethal even at low doses. In the most recent reports, there was a 60% survival rate after exposure, which improved with prompt treatment, and chemoprophylaxis may have decreased the number of individuals who became overtly ill. Given a high enough index of suspicion and early aggressive treatment with effective antibiotics, recovery has now been shown to be possible. Thus, the threat of anthrax is much diminished in a vigilant clinical environment.
Anthrax: Treatment and Vaccine
Since anthrax is only contagious by spores, isolation and quarantine of infected individuals is not thought to be necessary. Prompt antibiotic treatment with potent anti-gram positive agents such as ciprofloxacin, clindamycin, amoxacillin, clarithomycin, imipenem, vancomycin, rifampin, or even choramphenicol is recommended (see Table 4). All of these agents have been shown to be active in vitro against the Ames strain of anthrax associated with recent exposures. Penicillin (in combination with another agent), choramphenicol, vancomycin or rifampin should be considered when CNS involvement is suspected. Because of concern about possible antibiotic resistance of B. anthracis used in a bioterrorist attack, doxycycline or ciprofloxacin was
chosen initially for antibiotic chemoprophylaxis until the susceptibilities were known. Recommendations switched to penicillin VK or amoxicillin once antibiotic susceptibilities were known. The required duration of prophylaxis is unknown, but is believed to be at least 90 days post exposure, based on available information on the persistence of vegetative spores.13
The BioPort Company makes the existing anthrax vaccine from a cell-free filtrate of B. anthracis cultures. The strain used to prepare the vaccine is V770-NP1-R, a toxigenic, nonencapsulated strain.14 Vaccination using the inactivated cell-free filtrate vaccine requires six injections. As many as 30% of recipients experience local reactions, and life-threatening anaphylaxis has been associated with the existing vaccine.15,16,17 Currently, the vaccine is neither recommended nor required, except for military personnel. Vaccine may be available to individuals who wish to be immunized, but not to children and pregnant women. Development of a new anthrax immunization strategy has become a national priority.
Plague: Pathogen
The very threat of exposure to Yersinia pestis, the causative agent of plague, strikes fear in the heart of any individual who is familiar with world history: Between one third to one-half the population (approximately 50 million people) died from Y. pestis during the years of Black Death in Europe. During the epidemic of plague in London during the late 1600’s, physicians abandoned the hospitals to the care of orderlies and fled, aware that exposure to diseased individuals could lead to transmission of the disease and death.18 While antibiotics such as tetracycline and streptomycin can now prevent plague after exposure and treat all forms of the disease, Black Death remains a
bioterrorist threat19 that is compounded by the existence of antibiotic resistant strains20 and widespread availability of the pathogen due to recurrent epidemics.21 Airborne dissemination of drug-resistant plague by terrorists would have a devastating impact on civilians, hospital staff, and military personnel. Yersinia pestis, the etiologic agent of plague, is a gram-negative obligate aerobe belonging to Enterobacteriacieae. The bacterium has several chromosomal and plasmid-associated factors that are linked with virulence and survival in mammalian hosts (such as rats) as well as the flea
vector. Plague is endemic in certain areas of the world, causing epidemics when local conditions contribute to rodent infestation of human living quarters. More than 18,000 cases of plague were reported to WHO between 1980 and 1994.22 One recent outbreak (Madagascar, 1996) was also marked by the discovery of two strains of multi-drug resistant Y. pestis, raising concern about the efficacy of antibiotics against plague in the future.21
Plague: Clinical course
Infection follows transmission by flea bite, by direct contact with infectious body fluids or by inhalation of airborne aerosolized bacteria. Infection causes an illness that is characterized by severe fever, myalgia, malaise, shaking chills, prostration, and gastrointestinal symptoms. The three forms of plague are bubonic, pneumonic, and septicemic.
Bubonic plague is the most common form of the disease, or 80 to 90% of the cases reported to the CDC in the United States. The incubation period of bubonic plague is two to six days. The most striking physical manifestations of bubonic plague are enlarged, necrotic lymph nodes (buboes) of the groin or armpit closest to the site of infection. Buboes are caused by Y. pestis infected macrophages migrating to the local lymph nodes. Septicemic plague occurs when Y. pestis invades and multiplies in the blood stream. The case-fatality rate of septicemic plague is 50% (most of these cases received treatment). Pneumonic plague is the most dangerous and fatal form of the disease, and the form most likely to occur when used as a terrorist weapon. The incubation period is one to three days, and patients who do not receive adequate treatment within 18 hours after the onset of respiratory symptoms are unlikely to survive.
An aerosolized plague weapon could cause fever, cough, chest pain, and hemoptysis with signs consistent with severe pneumonia one to six hours after exposure. Rapid evolution of disease would occur in the two to four days after symptom onset and would lead to septic shock with high mortality without early treatment. If 50 kg of Y. pestis were released as an aerosol over a city of five million, pneumonic plague would occur in as many as 150,000 persons, and 36,000 could die.2323
Plague: Treatment and Vaccine
Early treatment and prophylaxis with tetracycline (doxycycline) or fluoroquinolones (Ciprofloxacin, ofloxacin) is effective. Streptomycin or gentamicin is also effective.19 Killed bacteria have been used in plague vaccine since 1896. The only whole cell (killed) vaccine produced in the U. S. was discontinued by its manufacturers in 1999. Plans for future production or licensing are unclear. The vaccine was prepared from formalin-inactivated Y. pestis organisms. Reactions to the vaccine were reported, tended to increase in number and severity as the number of doses increased, and, on occasion, were fatal.24 However, the vaccine appears to be effective. Only eight cases of plague were
diagnosed among U.S. personnel in Vietnam who received plague vaccine (one case per 106 person years of exposure). In contrast, there were thousands of cases of plague among citizens in Vietnam during the same period (333 cases per 106 person years of exposure, 1961-1971). It is not clear whether the vaccine protects against pneumonic plague, as there were at least two reported cases of pneumonic plague in successfully vaccinated military personnel.25
Tularemia: Pathogen
Tularemia is a disease caused by the facultative intracellular bacterium, Francisella tularensis. Infection is usually associated with exposure to rabbits, and tick bites appear to be the main means of transmission to humans. The peak incidence was in 1939, when about 2,300 cases were reported. An outbreak of tularemia recently occurred on Martha’s Vineyard.26.
Tularemia: Clinical Course
After cutaneous exposure, Tularemia can presents as slow to heal ulcer at the site of contact, along with swelling of the regional lymph nodes. Oral ingestion can cause pharyngitis, abdominal pain, diarrhea and vomiting. Inhalation of infectious material may be followed by pneumonic involvement or a primary septicemic syndrome. The pneumonic/septicemic syndrome is associated with a 30%-60% case-fatality rate if untreated, and it is very similar to the presentation of anthrax.
Tularemia: Treatment and Vaccine
Prompt treatment with streptomycin, gentamicin, doxycycline, or ciprofloxacin is recommended. Prophylactic use of doxycycline or ciprofloxacin may be useful in the early postexposure period.27 Immediately after a bioterrorist event, 14 days of oral doxycycline or ciprofloxacin should be administered to exposed persons, as only 10 organisms are required to produce disease. If the attack is only recognized after several persons have become ill, persons who may have been exposed should not take prophylaxis, instead, they should be instructed to begin a “fever watch” (notifying their physician if a fever develops and seeking prompt treatment). Any unexplained fever or flu-like
illness that occurs within 14 days of exposure would indicate that treatment should begin.
The existing Tularemia vaccine is a live organism derived by attenuation (LVS). The molecular basis of attenuation of the LVS strain and the degree of attenuation is unclear. Protective immunity is incomplete.28 Furthermore, quality control type problems with “scale up” of the existing vaccine may impede the use of the LVS as a preventive vaccine in the context of large-scale vaccination campaigns.
Smallpox: Pathogen
Smallpox is the most feared and potentially devastating of all commonly discussed bioterrorism agents because of the potential for dissemination from person to person after a terrorist event, and the lack of antiviral agents for treatment. Smallpox spreads from person to person via respiratory secretions, direct contact with lesions, and by contaminated clothing and linens (infected blankets were once used by British troops to disseminate smallpox among American Indians). Smallpox is fatal in approximately a third of previously unvaccinated persons. Smallpox can be manufactured in large quantities, can be stored for long periods of time, and is infectious as when distributed as an aerosol. Furthermore, because the WHO campaign in the
1970’s eradicated circulating virus, vaccination was discontinued and therefore, a large percentage of the current population has no immunity to the virus. The stockpile of smallpox vaccine currently available is controlled by the CDC and is decades old. It is thought not to be nearly enough to contain a US outbreak.29
The incubation period for smallpox (variola) has been estimated to be from nine to 13 days. Onset is marked by the occurrence of the first lesions - as these are usually flattened, brown, macules and not vesicles, so the prodromal stage may be missed by inexperienced medical personnel. The infected individual is contagious once these macules have occurred. Fever develops late in the prodrome (2nd or 3rd days). The overtly symptomatic stage, which coincides with the onset of a vesicular rash predominantly on the extremities and face and less prominent on the trunk (that progresses, over weeks, to eschars), typically occurs 48 to 72 hours after the onset of fever, and lasts up to 21 days. The infected individual is contagious during the entire symptomatic period, however, the prodromal phase (when the patient is not yet confined to bed by severe illness) is the period when dissemination is expected to occur. Quarantine is an extremely effective measure.
Smallpox: Treatment and Vaccine
One antiviral agent, Cidofovir, has recently proven useful in the treatment of cowpox infections in mice. Whether or not it can be used to treat smallpox in a bioterrorist event is not clear (and is not approved.)30
Smallpox (variola) immunity is achieved by vaccination with a live, related virus (vaccinia, or cowpox), using methods first described by Jenner in the late 1700’s. If mass vaccination were necessary now, it would be difficult to screen out individuals at risk for adverse vaccination effects. Severe, occasionally fatal, cases of cowpox have occurred in eczematous and immunosuppressed individuals, although cowpox has not yet been reported in anyone infected with the human immunodeficiency virus.31 Furthermore, because the smallpox vaccine is live, the infection can be passed from person to person. Although this is not a complication for healthy people, it has the potential to cause problems for immunocompromised (i.e. HIV-positive) people, if they were to come into contact with vaccinated individuals. The impact of vaccination of large populations, especially in cities where HIV infection is common, is difficult to assess.
Another problem with the smallpox vaccine is the medium used to propagate the virus. Smallpox vaccine was made by Wyeth Laboratories from a strain originally isolated by the New York City Board of Health. Live vaccine strain vaccinia (cowpox) was originally harvested from the lesions on vaccinia-infected cows. Wyeth discontinued making the vaccine available for public use in 1983, however, they recently received several billion dollars from the department of defense to re-develop the facilities, infrastructure, and expertise to produce the smallpox vaccine, using cell culture techniques. Continued use of cows or other live animals for vaccine production may pose many complications including contamination with bacteria, viruses, or prions, and animal proteins causing adverse reactions in humans. Regardless of the type of vaccine that is made, in the U.S. alone at least 40 million doses of small pox vaccine are needed in order to stop an outbreak following a bioterrorist event.29
The four most important lessons learned in the context of recent bioterrorist events are that: 1) Delay in intervention can be costly, leading to an increase in the number of cases that occur and mortality associated with those cases; 2) Post-attack intervention should combine rapid treatment of individuals who have the disease, quarantine (if smallpox), antibiotic prophylaxis (if indicated) and vaccination (if available); 3) Proper planning includes training of medical, public health and public safety personnel to recognize the infectious agent or event and respond appropriately; and 4) Stockpiles of vaccines and antibiotics should be developed by the authorities. Public health authorities and policymakers need to make detailed response plans available (on the web and in other public locations). And, as we learned from our own experience in corrections, a large part of the preparation for bioterrorist events involves educating medical personnel and staff so that they are familiar with bioterrorism agents and aware of the appropriate procedures and protocols to follow.
* Consultant & Speaker’s Bureau: Abbott, Agouron Pharmaceuticals, Merck, Roche, Boehringer-Ingelheim/Roxane Laboratories.
** Nothing to disclose
1. Borio L, Frank D, et al., "Death due to bioterrorism-related inhalational anthrax: report of 2 patients", JAMA 2001 Nov 28;286(20):2554-9.
2. Jernigan JA, Stephens DS, et al. "Bioterrorism-related inhalational anthrax: the first 10 cases reported in the United States", Emerg Infect Dis 2001 Nov-Dec;7(6):933-44.
3. Lane HC, La Montagne JR, Fauci AS. "Bioterrorism: a clear and present danger", Nat Med 2001 Dec;7(12):1271-3.
4. Kortepeter, MF, Parker, GW. "Potential biological weapons threats", Emerg Infect Dis 1999 Jul-Aug;5(4):523-7.
5. Inglesby TV, Henderson DA, Bartlett JG, et al. "Anthrax as a biological weapon: medical and public health management. Working Group on Civilian Biodefense", JAMA 1999 May 12;281(18):1735-45.
6. Henderson DA, Inglesby TV, Bartlett JG, et al. "Smallpox as a biological weapon: medical and public health management. Working Group on Civilian Biodefense", JAMA 1999 Jun 9;281(22):2127-37.
7. Inglesby TV, Dennis DT, Henderson DA, et al. "Plague as a biological weapon: medical and public health management. Working Group on Civilian Biodefense", JAMA 2000 May 3;283(17):2281-90.
8. Arnon SA, Schecter R, Inglesby TV, et al. "Botulinum toxin as a biological weapon: medical and public health management", JAMA 2001 Feb 28;285(8):1059-70.
9. Parker L, Johnson K, Sternberg S. USA Today. Nov. 11 2001.
10. Stern J. "The prospect of domestic bioterrorism", Emerg Infect Dis 1999 Jul-Aug;5(4):517-22.
11. Dixon TC, Fadl AA, Koehler TM, Swanson JA, Hanna PC. "Early Bacillus anthracis-macrophage interactions: intracellular survival survival and escape", Cell Microbiol 2000 Dec;2(6):453-63.
12. Bhatnagar R, Batra S. "Anthrax toxin", Crit Rev Microbiol 2001;27(3):167-200.
13. Dixon TC, et al. "Anthrax", N Engl J Med 1999 Sep 9;341(11):815-26.
14. "Use of Anthrax Vaccine in the United States", MMWR, December 15, 2000 / 49(RR15);1-20.
15. Hayes SC, World MJ. "Adverse reactions to anthrax immunisation in a military field hospital", J R Army Med Corps 2000 Oct;146(3):191-5.
16. Charatan F. "Fears over anthrax vaccination driving away US reservists", BMJ 2000 Oct 21;321(7267):980.
17. Swanson-Biearman B, Krenzelok EP. "Delayed life-threatening reaction to anthrax vaccine", J Toxicol Clin Toxicol 2001;39(1):81-4.
18. Sally Thompson, St Bartholomew’s Hospital Website on the Plague, http://www.medmicro.mds.qmw.ac.uk/yersinia/Plague_history.html, accessed Jan 2001.
19. Inglesby TV, Dennis DT, et al., "Plague as a biological weapon: medical and public health management. Working Group on Civilian Biodefense", JAMA 2000 May 3;283(17):2281-90.
20. Galimand M, Guiyoule A, Gerbaud G, Rasoamanana B, Chanteau S, Carniel E, Courvalin P. "Multidrug resistance in Yersinia pestis mediated by a transferable plasmid", N Engl J Med 1997 Sep 4;337(10):677-80.
21. Chanteau S, Ratsitorahina M, Rahalison L, Rasoamanana B, Chan F, Boisier P, Rabeson D, Roux "Current epidemiology of human plague in Madagascar", Microbes Infect 2000 Jan;2(1):25-31.
22. Fritz, CL, Dennis, DT, Tipple, MA, Campbell, GL, McCance, CR, Gubler, D. "Surveillance for pneumonic plague in the United States during an international emergency: a model for control of imported emerging diseases", Emerg Infect Dis 1996 Jan-Mar;2(1):30-6.
23.Health Aspects of Chemical and Biological weapons, Geneva Switzerland: World Health Oraganization 1970: 98-109.
24. CDC. Prevention of Plague: recommendations of the advisory committee on immunization practices ACIP, MMWR December 13, 1996 / 45(RR-14);1-15.
25. Cohen, RJ, Stockard, JL. "Pneumonic plague in an untreated plague-vaccinated individual.", JAMA 1967 Oct 23;202(4):365-6.
26. Seldman KA, Enscore RE, et al. "An outbreak of primary pneumonic tularemia on Martha's Vineyard", N Engl J Med 2001 Nov 29;345(22):1601-6.
27. Dennis DT, et al. "Tularemia as a biological weapon: medical and public health management", JAMA 2001 Jun 6;285(21):2763-73.
28. Tarnvik A. "Nature of protective immunity to Francisella tularensis", Rev Infect Dis 1989 May-Jun;11(3):440-51.
29. Meltzer MI, Damon I, et al., "Modeling potential responses to smallpox as a bioterrorist weapon", Emerg Infect Dis 2001 Nov-Dec;7(6):959-69.
30. Bray M, Martinez M, et al., "Cidofovir protects mice against lethal aerosol or intranasal cowpox virus challenge", J Infect Dis 2000 Jan;181(1):10-9.
31. Baxby D, Bennett M, Getty B. "Human cowpox 1969-93: a review based on 54 cases.", Br J Dermatol 1994 Nov;131(5):598-607.
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