Pediatric Annals

Bioterrorism

Theodore J Cieslak, MD, FAAP; Fred M Henretig, MD, FAAP

Abstract

1. American Academy of Pediatrics, Committee OD Environmental Health and Committee on Infectious Diseases. Chemical-biological terrorism and its impact on children: a subject review. Pediatrics. 2000;105:662-670.

2. OkumuraT. Takasu N, Ishimatsu S. et al. Repon on 640 victims of the Tokyo subway sarin attack. Ann EmergMed. 1996:28:129-135.

3. Torok TJ, Tauxe RV, Wise RP, et al. A large community outbreak of salmonellosis caused by intentional contamination of restaurant salad bars. JAMA, 1997:278:389-395.

4. Johnson KM, Martin DH. Venezuelan equine encephalitis. Adv Vet Sd Comp Med. 1974;18:79-116.

5. Centers for Disease Control and Prevention. Update: pulmonary hemorrhage/hemosiderosis among infants - Cleveland, Ohio, 19931996. MMWR Morb Mortal WkIy Rep. 1997;46:33-35.

6. Centers for Disease Control and Prevention. Update: pulmonary hemorrhage/hemosiderosis among infants - Cleveland, Ohio, 19931996. AfMWA Morb Mortal WkIy Rep. 2000;49:180-184.

7. Dance DB, Davis TM, Wattanagoon Y, et al. Acute suppurative parotitis caused by Pseitdomonas pseudomallei in children. J Infect Dis. 1 989; 1 59:654-660.

8. Inglesby TV, O'Toole T, Henderson DA, et al. Anthrax as a biological weapon, 2002: updated recommendations for management. JAMA. 2002:287:2236-2252.

9. Centers for Disease Control. Update: investigation of bioterrorism-reiated anthrax and interim guidelines for exposure management and antimicrobial therapy, October 2001. MMWR Morb Mortal WkIy Rep. 2001;50:909-919.

10. Inglesby TV, Dennis DT, Henderson DA, et al. Plague as a biological weapon: medical and public health management. JAMA. 2000;283:2281-2290.

11. Dennis DT, Inglesby TV, Henderson DA, et al. Tularemia as a biological weapon: medical and public health management. JAMA. 2002;285:2763-2773.

12. Centers for Disease Control and Prevention. Update: interim recommendations for antimicrobial prophylaxis for children and breastfeeding mothers and treatment of children with anthrax. MMWR Morb Mortal WkIy Rep. 2001;50:1014-1016.

13. Benavides S, Nahata MC. Anthrax: safe treatment for children. Ann Pharmacother. 2002:36:334-337.

14. Henretig FM, Mechem C, Jew R. Potential use of autoinjector-packaged antidotes for treatment of pediatrie nerve agent toxicity. Ann Emerg Med. 2002;40:405-408.

15. Centers for Disease Control and Prevention. Additional options for preventive treatment for persons exposed to inhalational anthrax. MMWR Morb Mortal WkIy Rep. 2001;50: 1142,1151.

16. Centers for Disease Control and Prevention. Prevention of plague: recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal WkIy Rep. 1996;45(RR-14):1-15.

17. Goldstein JA, Neff JM, Lane JM, Koplan JP. Smallpox vaccination reactions, prophylaxis, and therapy of complications. Pediatrics. 1975:55:342-347.

18. Hiss J, Arensburg B. Suffocation from misuse of gas masks during the Gulf war. BMJ. I992;304:92.

19. Amirav I, Epstein Y, Luder AS. Physiological and practical evaluation of a biological/chemical protective device for infants. Mil Med. 2000:165:663-666.

20. Epstein Y, Linder N, Lubìn D, Gale R, Gale J, Reichman B. The incubator as a chemical warfare protective device in neonatal intensive care units. The Israel Journal of Medical Science. 1991;27:648-651.

21. Havlak R, Gorman SE, Adams SA. Challenges associated with creating a pharmaceutical stockpile to respond to a terrorist event. Clinical Microbiology and Infection. 2002;8: 529-533.

22. Cieslak TJ, Eitzen EM. Bioterrorism: agents of concern. Journal of Public Health Management Practice. 2000;6: 19-29.

23. Centers for Disease Control and Prevention. Biological and chemical terrorism: strategic plan for preparedness and response. MMWR Morb Mon WkIy Rep. 2000;49(RR-4):1-14.

24. Khan AS, Morse S, Lillibridge S. Public health preparedness for biological terrorism in the USA. Lancet. 2000;356:1 179-1 182.

25. Meselson M, Guillemin J, Hugh-Jones M, et al. The Sverdlovsk anthrax outbreak of 1979. Science. 1994:266:1202-1208.

26. Abramova FA, Grinberg LM. Yampolskaya OV, Walker DH. Pathology of inhalational anthrax in 42 cases from the Sverdlovsk outbreak of 1979. Proc Nati Acad Sci USA. l993;90:2291-2294.

27. Earls JP, Cerva D, Berman E, et al. Inhalational anthrax after bioterrorism exposure: spectrum of imaging findings in…

Terrorism in general, and bioterrorism in particular, has risen to the forefront of national concern. Long a problem in some areas of the world, large-scale terrorism became a concern of Americans following the first attack on the World Trade Center in 1993. In April 1995, large-scale terrorism was brought to the heartland with the Oklahoma City bombings; this was significant because the perpetrators were Americans. Two months later, in June 1995, an attack on the Tokyo subway system by the Japanese doomsday cult, Aum Shirykyo, upped the ante further, demonstrating a willingness on the part of terrorists to use weapons of mass destruction, in this case the nerve agent sarin. In the face of these escalating developments, professionals in the medical, public health, policy, and law enforcement communities are devoting increasing attention and resources to the growing problem of terrorism.

WHY SHOULD CLINICIANS CONCERN THEMSELVES WITH BIOTERRORISM?

Bioterrorism differs from conventional, chemical, or nuclear terrorism because biological agents have inherent incubation periods. TTius, while conventional and chemical agent casualties are expected to present in close geographic and temporal proximity to the point of attack, biological agent casualties may not develop clinical illness for days or weeks following exposure. This permits their wide geographic dispersal and makes it likely that although policemen or paramedics likely would be the first responder to a conventional or chemical attack, primary care providers are likely to man the front lines of defense against biological terrorism.

Children almost certainly will be among the victims in future terrorist attacks. Timothy McVeigh's characterization of children as "collateral darnage" made this point quite clear, as does a recent attempt to release chlorine gas at Walt Disney World.1 In fact, the intentional release of sarin in the Tokyo subway affected 16 children and 5 pregnant women,2 and a 1984 attack in Oregon involved the deliberate contamination of restaurant salad bars with salmonellae.3 Of note, one of the restaurants attacked was a pizza parlor popular with high school students, many of whom became ill from eating at the restaurant after a football game. In all, 142 of the 751 victims of the Oregon attacks were younger than age 20.

ARE CERTAIN ASPECTS OF THE PROBLEM UNIQUE TO PEDIATRICS?

Children have many unique anatomical, physiological, immunological, and developmental considerations that potentially affect their vulnerability to biological agents (Table 1, page 156). The smaller blood volume of children renders vomiting and diarrhea caused by staphylococcal enterotoxins or pathogens such as Vibrio cholerae more problematic than in adults. Similarly, in children, the dermis is thinner and less keratinized; dermally active agents thus present special problems in children. Although few biological agents penetrate the intact dermis (certain fungal toxins are the exception), many chemical agents including vesicating agents (eg, mustard) and nerve agents are readily absorbed. The larger surface-area-tovolume ratio of children further hastens the absorption of such agents.

Additionally, children have higher minute ventilation rates compared to adults. Aerosolized biologica) (and chemical) agents would thus likely prove more problematic in children. Finally, since most biological aerosols are heavier than air, the fact that children live closer to the ground further complicates this problem. In addition to anatomic and physiologic differences, multiple other factors contribute to children's unique vulnerability to the effects of biological and chemical agents. These factors include the increased susceptibility of children to the effects of specific agents, unique manifestations of diseases in children, and the developmental level of children, as well as overcoming difficulties associated with drug dosing, pre-exposure immunoprophylaxis, post-exposure drug regimens, and protective and medical equipment use in children.

Increased Susceptibility

In certain cases, children have a unique susceptibility to the effects of specific agents. Venezuelan equine encephalitis, for example, can be a severe disease in young children, with a life-threatening encephalitis occurring in approximately 4% of cases.4 Many childhood survivors are left with devastating neurologic damage, despite the fact that Venezuelan equine encephalitis is usually a brief, self-limited illness in adults.

The same may be true with certain mycotoxins; a trichothecene-like toxin produced by Stachybotrys atra was implicated in the deaths of young infants naturally exposed in mold-infested older homes,5 although significant doubt has been cast on this theory recently.6 In any case, adults were not similarly affected.

Finally, in the case of smallpox, a lack of herd immunity would likely burden children disproportionately. Routine vaccination against smallpox ended in the United States in 1972. Although most experts believe that immunity wanes after several years, it is thought that adults immunized in the distant past, while not protected against infection, might be spared a fatal outcome.

Unique Disease Manifestations

With some diseases, children may experience unique disease manifestations. Melioidosis is caused by infection with Burkholderia pseudomallei, a potential threat studied by the Soviet Union during the Cold War. In Thailand, where melioidosis is endemic, suppurative parotitis is a characteristic presentation among children but not among adults.7

Developmental Considerations

Undoubtedly, development would impact a child's ability to survive a biological (or any) attack. Young children may be less likely able to flee a dangerous situation or to understand commands from public safety authorities. If parents or caregivers are affected, or if a child becomes separated from such adults, these difficulties would be magnified.

Table

TABLE 1Factors Enhancing Children's Vulnerability to Biological Agents or Complicating the Management of Children Exposed to Such Agents

TABLE 1

Factors Enhancing Children's Vulnerability to Biological Agents or Complicating the Management of Children Exposed to Such Agents

Although children and adults alike are vulnerable to the development of posttraumatic stress disorders, one might expect to see the symptoms of posttraumatic stress disorders magnified in children who have witnessed the death or injury of a parent. Additionally, young children are often unable to distinguish reality from fantasy and may be unable to differentiate between repeated media depictions of a single terroristic attack and new attacks. The perception that ongoing attacks were occurring would serve to increase the risk of posttraumatic stress disorder markedly. Similarly, in the event of a biological or chemical attack, responders dressed in protective suits could pose an especially frightening picture to the young child.

Drug Dosing

To the clinician faced with caring for children in the aftermath of a biological attack, an unavailability of (or unfamiliarity with) drugs, antidotes, and dosing regimens complicates these already daunting difficulties. For example, fluoroquinolones and tetracyclines are now widely regarded as drugs of choice for the therapy of, and prophylaxis against, anthrax,8,9 plague,10 and tularemia,11 as well as brucellosis, Q fever, and cholera. Although ciprofloxacin and doxycycline have been approved by the Food and Drug Administration for the treatment and post-exposure prophylaxis of anthrax in children12,13 (it is perhaps ironic to note that ciprofloxacin 's first licensed pediatrie indication was for the post-exposure prophylaxis of anthrax), many who care for children remain unfamiliar or uncomfortable with the use of these agents. Moreover, since the routine use of these medications in children is limited, few pharmacies and clinics stock significant amounts in liquid form.

For the past few years, many local jurisdictions have significantly bolstered their ability to respond to an attack with biological or chemical weapons. Often, such increased emphasis on preparedness has led to the stockpiling of prepackaged drugs and antidote kits. Unfortunately, these kits are often inappropriate for use in children. For example, the military provides nerve agent antidote kits containing autoinjectors of atropine and pralidoxime to soldiers on the battlefield. Civilian emergency departments and rescue squads often stock such kits. The doses of drugs administered by the autoinjectors are far in excess of those recommended for infants and young children, although methods of adapting such injectors for use in children are being developed.14

Pre-exposure Immunoprophylaxis and Post-exposure Drug Regimens

With the possible exception of smallpox, pre-exposure immunoprophylaxis likely will not play a major role in the defense against bioterrorism for some time. However, the difficulties posed by any such pre-exposure strategy would be compounded in children. At present, for example, an effective anthrax vaccine (Anthrax Vaccine Adsorbed, Bioport Corp., Lansing, MI) is licensed by the Food and Drug Administration. Used by the military in a pre-exposure strategy, Anthrax Vaccine Absorbed has been offered as an adjunct to antibiotics in the post-exposure prophylaxis of anthrax.15 Anthrax Vaccine Absorbed is approved, however, only for use in adults (18-65 years).

Similarly, although plague vaccine is now out of production, it was licensed for use in those aged 18 through 61. 16 In the case of smallpox, the previously licensed vaccinia-based vaccine, Dryvax, had been approved for use in even the youngest infants. Pediatrie recipients, however, were over-represented among those experiencing severe complications. Post-vaccinial encephalitis, for example, affected primarily those younger than age 1 17 and was often fatal, as is a similar encphalitis that occasionally occurs in young infants given yellow fever vaccine. Moreover, lethal fetal vaccinia can result when pregnant women are vaccinated.

Protective and Medical Equipment Use

External protection, in the form of protective clothing and gas masks, is unlikely to play a significant role in the defense against a bioterrorist attack. Such ensembles, even if offered to civilians, likely would be unavailable at the precise moment of release of an agent. In an unannounced attack, there wouldn't be an to don such gear, even if it were available. Importantly for children, the misuse of protective equipment in the past has led to fatalities from suffocation.18 Nonetheless, some advocate the distribution of gas masks to civilians principally for defense against more readily detectable chemical agents. In Israel, extensive consideration has been given to innovative physical protective gear for children and infants.19,20 At present, little such gear is available in the United States.

Similar problems exist with conventional medical equipment. Ambulances, clinics, and emergency departments typically carry only limited quantities of pediatrie resuscitative equipment, and personnel often have limited training in the treatment of children. Likewise, current disaster response plans do not always address the specific needs of children. In the event of a large-scale terrorist attack, as with any large disaster, hospital bed surge capacity might be provided at military, civilian, and Veterans Affairs hospitals under the auspices of the National Disaster Medical System. The National Disaster Medical System makes no provision for specific pediatrie beds, which of course are lacking within the Veterans Affairs' system.

Fortunately, public health and policy planners are beginning to address the gaps in readiness as they apply to children. The Centers for Disease Control and Prevention's (CDC) national pharmaceutical stockpile, for example, includes push-packages pre-positioned at various sites around the country. These packages are designed to be available at a disaster site within hours, and each contains enough medications and supplies to treat 6,000 (and provide prophylaxis for 357,000) victims of a biological or chemical attack. Included in the packages are significant quantities of oral ciprofloxacin and doxycycline in pediatrie suspensions.21

WHICH AGENTS SHOULD PEDIATRICIANS FOCUSTHEIR EFFORTS ON?

Although virtually any biological agent might be spread intentionally for sinister purposes, certain agents possess characteristics that contribute to their attractiveness as terrorist weapons.22 Included among these characteristics are infectivity via the aerosol route, high disease-to-infection ratio, ability to survive ex vivo, and brand-name recognition. Nonetheless, in the past terrorists and other disgruntled individuals have used weapons of opportunity, ie, any agent that a member of the group might be able to procure. Additionally, because the motivations of terrorists are often unclear, deriving a list of potential agents is difficult. The CDC, given the task of preparedness planning, elected to focus not on those agents most likely to be used but rather on those agents that, if used, might pose the greatest threats to public health and safety.23-24 They divided potential agents of bioterrorism into three categories (A, B, C). Category A agents pose the greatest potential threat and for which a significant gap in public health preparedness was felt to exist. Table 2 (page 158) lists agents in categories A, B, and C.

WHAT SHOULD THE PEDIATRICIAN KNOW ABOUT CATEGORY A AGENTS?

Anthrax

Anthrax is caused by infection with Bacillus anthracis, a Gram-positive rod whose spore form is able to survive long periods without nutrients or moisture. Anthrax spores lend themselves well to aerosolization, behave like a gas when aerosolized in small particles (drifting readily with air currents), and resist environmental degradation. When aerosolized in 2- to 6-µm particles, anthrax spores impinge on the lower respiratory mucosa, optimizing the chance for infection.

Table

TABLE 2Critical Agents for Health Preparedness

TABLE 2

Critical Agents for Health Preparedness

Most endemic anthrax cases occur in Africa and Asia, and they consist of cutaneous disease, acquired by close contact with the hides, wool, bone, and other by-products of infected cattle, sheep, and goats. Cutaneous anthrax is rare in the United States, with no cases being reported between 1992 and the 2001 outbreak associated with contaminated mail. Of note, one of the 1 1 victims to contract cutaneous anthrax in that 2001 outbreak was an 8-month-old infant. Cutaneous anthrax causes black, painless ulcers and is quite amenable to therapy with many different antibiotics and is thus rarely fatal. In fact, 80% of cutaneous anthrax victims spontaneously recover without any therapy. Cutaneous anthrax in the setting of a terrorist attack presents a special consideration, however. In such cases, it is prudent to assume that victims may have also encountered an infectious inoculum via the inhalational route. Therapy in such cases should mirror the therapy of inhalational anthrax as outlined below and in Table 2.

Gastrointestinal anthrax occurs following the consumption of contaminated meat and has never been reported in the United States. Inhalational anthrax, or woolsorter's disease in the past was an occupational hazard of abattoir and textile workers; improvements in occupational safety and animal husbandry practices, as well as immunization, has all but eliminated this hazard in western nations. It is the inhalational form of the disease, however, that poses the most significant threat from a bioterrorism perspective.

Following inhalation of an infectious inoculum, spores are taken up by pulmonary macrophages. These macrophages transport the spores to regional lymph nodes in the mediastinum, where they vegetate and begin to produce two protein toxins, edema toxin and lethal toxin. These toxins lead to necrosis of the lymph node, releasing organisms, which then gain access to the circulation. An overwhelming fatal septicemia rapidly follows. At autopsy, widespread hemorrhage and necrosis involving multiple organs is observed.

Anthrax acquired via the inhalational route typically occurs following an incubation period of 1 to 6 days, although incubation periods as long as several weeks have been reported.25 Following this, a flu-like illness ensues, characterized by fever, myalgia, headache, and cough. A brief intervening period of improvement may follow, but rapid deterioration then ensues, manifested by high fever, dyspnea, cyanosis, and shock. Hemorrhagic meningitis occurs in 50% of cases.26 Chest radiographs obtained late in the course of illness may reveal a widened mediastinum; computed tomography of the chest is potentially useful in revealing mediastinal involvement earlier in the course of illness.27 Gram stain of peripheral blood smears may demonstrate the organism in the later stages of illness.

Prompt treatment is imperative; historically, death occurred in as many as 95% of inhalational anthrax cases when treatment was initiated more than 48 hours after the onset of symptoms. Following the 2001 attacks, 6 of 1 1 patients with symptomatic inhalational disease survived following aggressive therapy with multiple antibiotics.

A diagnosis of anthrax should be suspected on finding large boxcar-shaped gram-positive bacilli in skin biopsy material (in the case of cutaneous disease), in cerebrospinal fluid, or in blood smears. Chest radiographs demonstrating a widened mediastinum in the context of fever and constitutional signs, without any other obvious explanation (such as blunt trauma or post-surgical infection) also should lead one to consider anthrax. Confirmation is obtained by blood culture. B. anthracis grows readily on standard media including sheep's blood agar.

Most endemic strains of B. anthracis remain sensitive to penicillin G, but because penicillin-resistant strains of B. anthracis can be isolated readily in laboratories, many experts consider ciprofloxacin (10-15 mg/kg administered intravenously every 12 hours) the drug of choice for treating victims of intentional anthrax exposure. Doxycycline (2.2 mg/kg administered intravenously every 12 hours) is an acceptable alternative, although rare doxycycline-resistant strains of B. anthracis have been reported.

Recently, awareness of the toxinmediated pathogenesis of anthrax led some experts to recommend the therapy of inhalational anthrax initially consist of multiple antibiotics,8·28 including agents that inhibit bacterial protein synthesis as well as those with good central nervous system penetration. Clindamycin, rifampin, and clarithromycin are logical choices as protein synthesis inhibitors, while penicillin, ampicillin, imipenem, meropenem, and chloramphenicol provide good central nervous system penetration. Most strains of B. anthracis are sensitive to these agents in vitro. Many experts currently recommend that such therapy be continued for at least 60 days after exposure.

Assuming adequate available resources, antibiotics initially should be administered parenterally. Patients who are stable clinically can probably be switched to a single oral agent after 14 days. Amoxicillin is a reasonable choice following such a switch in children, assuming the organism proved to be sensitive. Our recommendations for therapy of anthrax and other potential diseases of bioterrorism are summarized in Table 3 (page 160).

Post-exposure prophylaxis against anthrax is accomplished with oral ciprofloxacin (10-15 mg/kg every 12 hours) or oral doxycycline (2.2 mg/kg every 12 hours). Potentially exposed individuals should receive antibiotics as soon as possible; such chemoprophylaxis should be continued for 60 days. The anthrax vaccine, licensed for use in those aged 1 8 to 65 years, may play a role in post-exposure prophylaxis and may permit shortening the course of post-exposure chemoprophylaxis if given concurrently (three doses, at time zero and at 2 and 4 weeks). Recently, some authorities called for trials of such a regimen and, specifically, recommended that such trials include pediatrie patients.29

Anthrax has little or no potential for person-to-person transmission; standard precautions are adequate for health care workers caring for anthrax victims. Because of the 1 to 6 day incubation period, decontamination of victims presenting days after exposure would only rarely be necessary.

Smallpox

Smallpox is caused by infection with variola, an orthopoxvirus that no longer survives in the wild. The world's last case of smallpox occurred in 1978. In 1980, the disease was declared eradicated by the World Health Organization; the re-appearance of smallpox anywhere on earth would almost certainly represent intentional release. Multiple factors might make smallpox an attractive weapon to potential terrorists: immunization of civilians was discontinued in the United States in 1972; coupled with the fact that immunity following vaccination may last only 3 to 5 years, this renders susceptibility to smallpox universal. There is no effective therapy for smallpox, and modern health care providers are unfamiliar with the disease. Finally, the potential for rapid spread potentially permits a terrorist to cause widespread disease and panic with a minimum of infectious material.

Table

TABLE 3Recommended Therapy for Children With Select Diseases Associated With Bioterrorism

TABLE 3

Recommended Therapy for Children With Select Diseases Associated With Bioterrorism

The incubation period of smallpox is 7 to 17 days, which would permit wide dispersal of exposed individuals before signs and symptoms appear. During the incubation period, the virus replicates in the upper respiratory tract, ultimately giving rise to a primary viremia. The liver and spleen are seeded, and a second viremic phase then develops. The skin is seeded during the secondary viremia, and clinical illness begins abruptly at this time. Symptoms include fever, rigors, vomiting, headache, backache, and extreme malaise. The classical exanthem by which smallpox is usually identified begins 2 to 4 days later. Macules are initially seen on the face and extremities. These macules progress in synchronous fashion to papules, then to pustules, and finally to scabs. As the scabs separate, survivors can be left with disfiguring, de-pigmented scars.

The synchronous nature of the rash and its centrifugal distribution (heaviest on the face and extremities) distinguish smallpox from chickenpox (heaviest on the trunk), which has a centripetal distribution. In the past, death occurred in approximately 30% of classical variola major patients. Eye involvement can lead to blindness in a small number of victims. In addition to classical variola major, uncommon variants with lower (variola minor) or higher (hemorrhagic, flat-type smallpox) mortality were described during the smallpox era. No antivirals are currently approved for the treatment of smallpox although cidofovir, licensed for cytomegaloviral retinitis, appears to show promise in animal models.30

A single case of smallpox occurring anywhere in the world today would represent the gravest of public health emergencies, and any suspicion of a case should prompt immediate consultation with health authorities. Strict quarantine (airborne and contact precautions) should be instituted immediately for victims (until all scabs separate) as well as for their contacts (for 17 days from last exposure). Multiple victims ideally would be managed as a cohort at dedicated sites removed from conventional hospital facilities.

Based on past experience, vaccination of smallpox-exposed individuals within the first 4 days after exposure would likely prevent disease. Vaccinia is an orthopoxvirus related to variola and useful in inducing immunity to other orthopox viruses. Vaccinia-based vaccine production ceased in the United States in 1972, but 15.4 million doses (Dryvax) remain in stockpiles. These doses remain potent and have been re-licensed by the Food and Drug Administration. Moreover, recent studies have shown them to be immunogenic at a 1:5 dilution,31 thereby increasing the supply of readilyavailable vaccine five fold. Finally, discovery of other vaccine stockpiles, as well as the anticipated delivery of a new vaccine, ensures that adequate vaccine supplies will likely be available for most of the US population. Nonetheless, vaccinia administration is fraught with potential complications, many of which would likely be more common or more problematic in children.

In order to induce adequate immunity, a pock containing live vaccinia virus is raised by inoculating the arm with 15 stabs of a bifurcated needle dipped in vaccine. Scratching the resultant purulent lesion risks autoinoculation of distant skin sites or of the eye (potentially producing a vision-threatening keratitis). Clearly, young children are at increased risk for such manipulation. In order to manage complications, vaccinia immune globulin (VIG) must be stockpiled and available when undertaking a vaccination campaign. Vaccinia immune globulin (0.6 mL/kg administered intramuscularly) may be given to vaccine recipients who experience severe complications or to other individuals (pregnant women, the immunocompromised, those with significant dermatoses such as eczema) exposed to smallpox in whom vaccination would be problematic. Additional guidelines for the medical and public health management of an intentional smallpox release have been published recently.32

Plague

Plague is caused by infection with the bipolar-staining, gram-negative bacillus, Yersinia pestis. In nature, the infection typically is acquired via the bite of certain fleas. As a facultative intracellular organism, Y. pestis is able to survive within the macrophage, and this ability aids its dissemination to distant sites following inoculation (or inhalation). Following the flea bite, the organism typically reaches a regional lymph node, which becomes markedly swollen and exquisitely tender, leading to the characteristic "bubo" of bubonic plague.

Fever and malaise typically are present among patients with bubonic plague; septicemia often develops as bacteria gain access to the circulation. Eighty percent of bubonic plague victims have positive blood cultures. Petechiae, purpura, and an overwhelming picture of disseminated intravascular coagulation commonly occur. Testimony to the extreme infectivity and lethality of plague can be obtained by considering that the "black death" eliminated one third of the population of Europe during the Middle Ages.

Intentional aerosol dissemination of Y. pestis likely would result in a preponderance of pneumonic plague cases. Pneumonic plague also may occur secondarily after seeding of the lungs of septicémie patients. Pneumonic plague (along with smallpox) is one of the few bioterrorist threats readily transmissible from person to person; coughing patients are often highly contagious. Symptoms of pneumonic plague include fever, chills, malaise, headache, and cough. Chest radiographs may reveal patchy consolidation, and a classic clinical finding is blood-streaked sputum. Disseminated intravascular coagulation and overwhelming sepsis typically develop as the disease progresses, while meningitis occurs in 6% of cases. Untreated pneumonic plague has a fatality rate approaching 100%.

Plague can be suspected by the finding of bipolar "safety-pin"-staining bacilli in Gram or Wayson stains of sputum or aspirated lymph node material; confirmation is obtained by culturing Y. pestis from blood, sputum, or lymph-node aspirate. The organism grows on standard blood or MacConkey agars but is often misidentified by automated systems.

Gentamicin (2.5 mg/kg administered intravenously every 8 hours) is the preferred therapy for plague. Doxycycline (2.2 mg/kg administered intravenously every 12 hours) and ciprofloxacin (15 mg/kg administered intravenously every 12 hours) are acceptable alternatives. Chloramphenicol (25 mg/kg intravenously, every 6 hours) should be used in cases of plague meningitis. In order to be effective, therapy for pneumonic plague must be initiated within 24 hours of the onset of symptoms.

Post-exposure prophylaxis should be provided to asymptomatic victims of a bioterrorist attack, as well as to close contacts (including medical personnel) of pneumonic plague patients. Such prophylaxis may be oral ciprofloxacin (20 mg/kg every 1 2 hours) or oral doxycycline (2.2 mg/kg every 12 hours). Those in contact with suspected pneumonic plague patients should employ droplet precautions. Such precautions should be continued among patients with confirmed disease until sputum cultures are negative. Standard precautions are appropriate for managing bubonic plague victims.

Tularemia

Tularemia is a highly infectious plague-like illness caused by infection with Francisella tularensis a gram-negative coccobacillus. The low inoculum required for infection (estimated to be 10 or fewer organisms), contributes significantly to its inclusion on the CDC's list of Category A agents. Several clinical forms of endemic tularemia are known, but inhalational exposure in a terrorist attack would likely lead to pneumonia or to the typhoidal form of the disease, manifest as a variety of nonspecific symptoms including fever, malaise, and abdominal pain. Gentamicin, in doses similar to those recommended for plague, is recommended as therapy. Post-exposure prophylaxis consists of doxycycline or ciprofloxacin administered for 2 weeks.

Botulism

Botulism is caused by exposure to one of seven related botulinum neurotoxins (A-G) produced by certain strains of Clostridium botulinum, an anaerobic spore- forming, gram-positive bacillus that is ubiquitous in soil. Botulinum toxins are the most toxic substances known; as little as 0.001 µg/kg represents a lethal dose. These toxins act at presynaptic nerve terminals where they block the release of acetylcholine. The result is a generalized flaccid paralysis and autonomie dysfunction. While in theory any of the seven toxin types might cause human disease, only types A, B, and E toxin appear to do so naturally. For this reason, a licensed antitoxin against only these three serotypes is produced.

Signs and symptoms of botulism develop following a latent period that ranges from several hours to several days and initially include cranial nerve dysfunction with bulbar palsies, ptosis, photophobia, and blurred vision (due to difficulty in accommodation). Symptoms progress to include dysphonia and dysphagia, as well as a descending symmetric paralysis. In fatal cases, death typically results from respiratory muscle failure.

Botulism may mimic other neurological disorders such as myasthenia gravis and Guillan-Barre syndrome, but the occurrence of multiple cases of descending, symmetric, flaccid paralysis clustered in time and space should make diagnosis of a botulism outbreak relatively easy. Supportive care measures, including meticulous attention to ventilatory support, are the mainstay of botulism management. Patients may require such support for several months, making the management of a large-scale botulism outbreak especially problematic in terms of medical resources.

The licensed trivalent (types A, B, E) botulinum antitoxin is available through the CDC. Although administration of antitoxin is unlikely to reverse disease, it may prevent progression when administered to exposed individuals. Botulinum antitoxin is prepared from horse serum; a test dose should thus be administered before therapy. Patients reacting to a test dose require horse serum desensitization prior to treatment. An investigational heptavalent de-speciated (Fab2) antitoxin, also produced in horses, is available through the US Army Medical Research Institute of Infectious Diseases on a compassionate use protocol.33 Administration of a test dose is required with this product. Of interest to pediatricians, an investigational pentavalent (toxin types A-E) human-derived product (Botulism Immune Globulin Intravenous) has been developed by the California Department of Health Services specifically for the treatment of infant botulism.34

Viral Hemorrhagic Fevers

Viral hemorrhagic fevers are a heterogeneous group of diseases caused by infection with lipid-enveloped RNA viruses belonging to one of four taxonomic families: the Arenaviridae, Filoviridae, Flaviviridae, and Bunyaviridae. Although the diseases produced by these agents differ in their clinical manifestations, severity, and modes of transmission, collectively they should be suspected by the clinician faced with a patient who presents with fever and hemorrhage. The severity of hemorrhagic manifestations also varies considerably among the various viruses, but all are potentially infectious by the aerosol route and most are stable as respirable aerosols. These factors make them agents of concern from a terrorism perspective. The potential for human-to-human transmission makes the filoviruses (such as Ebola and Marburg viruses) and arenaviruses (such as Lassa Fever Virus) particularly concerning.

Therapy of the various viral hemorrhagic fevers is principally supportive in nature, although intravenous ribavirin appears somewhat efficacious in treating arenaviral disease. A licensed vaccine is available only for yellow fever virus.

HOW CAN THE CLINICIAN RESPOND WHEN THE IDENTITY OF THE AGENT IS UNKNOWN?

A working familiarity with the diagnosis and management of patients infected with individual Category A agents unfortunately has become a mandatory component of modern medical practice. Nonetheless, the management of an individual patient with a known disorder is relatively straightforward. Many resources now exist to guide the clinician in such management. A larger problem concerns the mass casualty situation in which the identity of the agent may be unknown. In fact, outbreaks may occur wherein the offending agent might be biological, chemical, both, or neither. Moreover, natural infectious disease outbreaks may mimic bioterrorist attacks. The 1999 West Nile virus outbreak in New York initially raised suspicions of a terrorist attack. In such cases, busy clinicians should use an algorithmic approach, akin to the Advanced Trauma Life Support approach to trauma management.

We propose a ten-step approach we call the 'Ten Commandments" (sidebar, page 1 59) to guide clinicians in managing an attack with an unknown biological agent.35 Moreover, we believe that such an approach is also applicable to chemical casualties and to outbreaks of naturally occurring infectious diseases and unintentional toxic exposures.

I. Thou shall maintain a healthy index of suspicion. Some diseases caused by agents of bioterrorism may present with characteristic clinical findings, each of which has a very limited differential diagnosis. The classic finding in inhalational anthrax is a widened mediastinum; in botulism, it is a descending, symmetric, flaccid paralysis. Plague victims often develop hemoptysis in the later stages of illness, otherwise uncommon among previously healthy children. Smallpox presents with a unique exanthem. Yet, by the time each of these classic findings develops, treatment is likely to be ineffective. Therefore, therapy is best instituted during the incubation or prodromal phases of these diseases to be of benefit. Because of this, and because many potential BW diseases, such as tularemia, brucellosis, Q fever, and Venezuelan equine encephalitis, are likely to present simply as undifferentiated febrile illnesses, prompt diagnosis is a possibility only with the maintenance of a high index of suspicion.

II. Thou shall protect thyself. The clinician is of little use if he or she becomes a casualty. Before managing victims of a potential terrorist attack, clinicians should be familiar with basic steps to protect themselves. Public health authorities have developed a plan to offer smallpox vaccination to selected health care providers and to the military. Similarly, anthrax immunization, now used in the military, may likewise be considered for use by civilians in the future. It should be noted, however, that a simple surgical mask protects against inhalation of infectious aerosols of virtually any of the biological agents in CDC categories A, B, or C. The lone exception is smallpox, for which a high efficiency paniculate air filter mask would be ideal. With the exception of smallpox, pneumonic plague, and, to a lesser degree, certain viral hemorrhagic fevers, the agents in categories A and B are not contagious via the respiratory route. Respiratory protection is thus necessary when operating in an area of release but not required in many patient care settings.

III.Thou shall first save the patient's life. The clinician is now ready to assess patients. (This is known as the primary survey, in keeping with Advance Trauma Life Support guidelines.36) This initial assessment must be brief and limited to discovering and treating those conditions that present an immediate threat to life or limb. Victims of biological (or chemicaJ) terrorism also may have conventional injuries; attention should thus be focused at this point on maintaining a patent airway and providing for adequate breathing and circulation. The need for decontamination and for the administration of antidotes for rapidacting chemical agents (nerve agents and cyanide) should be determined at this time.

IV. Thou shall decontaminate when appropriate. After patients have been stabilized, decontamination can be accomplished when appropriate. It should be pointed out, however, that decontamination is rarely necessary after a biological attack (the same cannot always be said following a chemical attack). This is because of the inherent incubation periods of biological agents. Because most victims do not become symptomatic until several days after exposure, they will likely have bathed and changed clothing (often several times) before presenting for medical care, thus effectively accomplishing self-decontamination. Exceptions might include personnel near ground zero in an observed attack or individuals encountering a substance in a threatening letter, where common sense might dictate topical disinfection. Even in these situations, bathing with soap and water and conventional laundry measures would likely be adequate.

V. Thou shalt make a diagnosis. After decontamination has been considered, the clinician may perform a more thorough assessment aimed at establishing a diagnosis. (This is known as the secondary survey.) An AMPLE (A = allergies, arthropod exposures; M = medications; P = past illnesses & immunizations; L = last meal; E = environment) history may aid in establishing this diagnosis. If resources and access to subspecialty consultants are limited, emphasis should be placed on syndromic diagnosis, since most victims of a biological or chemical attack will likely present with a predominance of respiratory, neuromuscular, or dermatologie findings. Victims of bioterrorism also might present with little more than an undifferentiated febrile illness. By categorizing victims in this manner, logical empiric therapy decisions can be facilitated.37'39

VL Thou shalt render prompt therapy. The clinician must provide prompt therapy. In most mass casualty emergency settings, this involves empiric therapy administered before a definitive diagnosis is established. For example, we advocate that doxycycline or ciprofloxacin be administered empirically to patients with significant pulmonary symptoms when exposure to a bioterrorist attack is considered a strong possibility.

VII. Thou shalt practice good infection control. The clinician must practice proper infection control procedures in order to ensure that contagious diseases are not propagated among patients. Current guidelines40 advocate the use of standard precautions in all patient care encounters. More stringent transmission-based precautions are applied to patients with certain infectious diseases. Three subcategories of transmissionbased precautions exist: (1) droplet precautions (ie, ordinary surgical masks are adequate protection against plague) should be used in managing the pneumonic plague victim; (2) contact precautions should be used in managing certain viral hemorrhagic fever patients; and (3) airborne precautions, ideally including a high efficiency air particlefilter mask, should be used when managing smallpox victims. Anthrax, tularemia, brucellosis, Q fever, the toxin-mediated diseases, the equine encephalitides, and other diseases in CDC categories A and B may be managed safely using standard precautions.

VIII. The proper authorities must be alerted so that the appropriate warnings may be issued and outbreak control measures implemented. Typically, such notification would be made through local and state health department channels. Each practitioner should have a point of contact with such agencies and should be familiar with mechanisms for contacting them before a crisis arises.

IX. Thou shalt assist in an epidemiologie investigation. The clinician must be prepared to assist in an epidemiological investigation, which is necessary in the case of a suspected terrorist attack. Although health department personnel are invaluable in conducting such an investigation, the clinician should, nonetheless, have a working knowledge of basic epidemiology and of the steps necessary to conduct an epidemiological investigation. These steps, the so-called "epidemiological sequence," are published elsewhere.41

X. Thou shalt retain and spread the gospel. The clinician must maintain a certain level of proficiency in the management of terrorism victims. Many resources are now available to assist the pediatrician in this regard. Moreover, electronic resources of a similar nature have been developed42,43 and multiple Web sites provide a wealth of training materials and information online (sidebar, page 157). Finally, numerous governmental and civilian organizations are now ready to provide assistance and consultation to clinicians faced with managing the victims of a potential terrorist attack. It is assistance that most of us hopefully will never require.

REFERENCES

1. American Academy of Pediatrics, Committee OD Environmental Health and Committee on Infectious Diseases. Chemical-biological terrorism and its impact on children: a subject review. Pediatrics. 2000;105:662-670.

2. OkumuraT. Takasu N, Ishimatsu S. et al. Repon on 640 victims of the Tokyo subway sarin attack. Ann EmergMed. 1996:28:129-135.

3. Torok TJ, Tauxe RV, Wise RP, et al. A large community outbreak of salmonellosis caused by intentional contamination of restaurant salad bars. JAMA, 1997:278:389-395.

4. Johnson KM, Martin DH. Venezuelan equine encephalitis. Adv Vet Sd Comp Med. 1974;18:79-116.

5. Centers for Disease Control and Prevention. Update: pulmonary hemorrhage/hemosiderosis among infants - Cleveland, Ohio, 19931996. MMWR Morb Mortal WkIy Rep. 1997;46:33-35.

6. Centers for Disease Control and Prevention. Update: pulmonary hemorrhage/hemosiderosis among infants - Cleveland, Ohio, 19931996. AfMWA Morb Mortal WkIy Rep. 2000;49:180-184.

7. Dance DB, Davis TM, Wattanagoon Y, et al. Acute suppurative parotitis caused by Pseitdomonas pseudomallei in children. J Infect Dis. 1 989; 1 59:654-660.

8. Inglesby TV, O'Toole T, Henderson DA, et al. Anthrax as a biological weapon, 2002: updated recommendations for management. JAMA. 2002:287:2236-2252.

9. Centers for Disease Control. Update: investigation of bioterrorism-reiated anthrax and interim guidelines for exposure management and antimicrobial therapy, October 2001. MMWR Morb Mortal WkIy Rep. 2001;50:909-919.

10. Inglesby TV, Dennis DT, Henderson DA, et al. Plague as a biological weapon: medical and public health management. JAMA. 2000;283:2281-2290.

11. Dennis DT, Inglesby TV, Henderson DA, et al. Tularemia as a biological weapon: medical and public health management. JAMA. 2002;285:2763-2773.

12. Centers for Disease Control and Prevention. Update: interim recommendations for antimicrobial prophylaxis for children and breastfeeding mothers and treatment of children with anthrax. MMWR Morb Mortal WkIy Rep. 2001;50:1014-1016.

13. Benavides S, Nahata MC. Anthrax: safe treatment for children. Ann Pharmacother. 2002:36:334-337.

14. Henretig FM, Mechem C, Jew R. Potential use of autoinjector-packaged antidotes for treatment of pediatrie nerve agent toxicity. Ann Emerg Med. 2002;40:405-408.

15. Centers for Disease Control and Prevention. Additional options for preventive treatment for persons exposed to inhalational anthrax. MMWR Morb Mortal WkIy Rep. 2001;50: 1142,1151.

16. Centers for Disease Control and Prevention. Prevention of plague: recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal WkIy Rep. 1996;45(RR-14):1-15.

17. Goldstein JA, Neff JM, Lane JM, Koplan JP. Smallpox vaccination reactions, prophylaxis, and therapy of complications. Pediatrics. 1975:55:342-347.

18. Hiss J, Arensburg B. Suffocation from misuse of gas masks during the Gulf war. BMJ. I992;304:92.

19. Amirav I, Epstein Y, Luder AS. Physiological and practical evaluation of a biological/chemical protective device for infants. Mil Med. 2000:165:663-666.

20. Epstein Y, Linder N, Lubìn D, Gale R, Gale J, Reichman B. The incubator as a chemical warfare protective device in neonatal intensive care units. The Israel Journal of Medical Science. 1991;27:648-651.

21. Havlak R, Gorman SE, Adams SA. Challenges associated with creating a pharmaceutical stockpile to respond to a terrorist event. Clinical Microbiology and Infection. 2002;8: 529-533.

22. Cieslak TJ, Eitzen EM. Bioterrorism: agents of concern. Journal of Public Health Management Practice. 2000;6: 19-29.

23. Centers for Disease Control and Prevention. Biological and chemical terrorism: strategic plan for preparedness and response. MMWR Morb Mon WkIy Rep. 2000;49(RR-4):1-14.

24. Khan AS, Morse S, Lillibridge S. Public health preparedness for biological terrorism in the USA. Lancet. 2000;356:1 179-1 182.

25. Meselson M, Guillemin J, Hugh-Jones M, et al. The Sverdlovsk anthrax outbreak of 1979. Science. 1994:266:1202-1208.

26. Abramova FA, Grinberg LM. Yampolskaya OV, Walker DH. Pathology of inhalational anthrax in 42 cases from the Sverdlovsk outbreak of 1979. Proc Nati Acad Sci USA. l993;90:2291-2294.

27. Earls JP, Cerva D, Berman E, et al. Inhalational anthrax after bioterrorism exposure: spectrum of imaging findings in two surviving patients. Radiology. 2001:222:305-312.

28. Jeraigan JA, Stephens DS, Ashford DA, et al. Bioterrorism-reiated inhalational anthrax: the first 10 cases reported in the United States. Emerg Infect Dis. 2001 ;7:933-944.

29. Centers for Disease Control and Prevention. Notice to readers: use of anthrax vaccine in response to terrorism: supplemental recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2002:51:1024-1026.

30. Bray M, Martínez M, Smee DF, Kefauver D, Thompson E, Huggins JW. Cidofovir protects mice against lethal aerosol or intranasal cowpox virus challenge. J Infect Dis. 2000:181:10-19.

31. Frey SE, Couch RB, Tacket CO. et al. Clinical responses to undiluted and diluted smallpox vaccine. N EngU Med. 2002;346:1265-1274.

32. Henderson DA, Inglesby TV, Bartlett JG. et al. Smallpox as a biological weapon. JAMA. 1999:281:2127-2137.

33. Hibbs RG, Weber JT, Corwin A, et al. Experience with the use of an investigational F(ab') 2heptavalent botulism immune globulin of equine origin during an outbreak of type E botulism in Egypt. Clin Infect Dis. 1996:23:337-340.

34. Amon SS. Clinical trial of human botulism immune globulin. In: DasGupta BR, ed. Botulinum and Tetanus Neurotoxins: Neurotransmission and Biomédical Aspects. New York, NY: Plenum; 1993:477-482.

35. Cieslak TJ, Henretig FM. Medical consequences of biological warfare: the ten commandments of management. Mil Med. 2001;166(suppl2):ll-12.

36. Committee on Trauma, American College of Surgeons. Initial assessment and management. In: Advanced Trauma Life Support Student Manual. Chicago, 111: American College of Surgeons; 1989:9-30.

37. Cieslak TJ. Rowe JR, Kortepeter MG, et al. A field-expethent algorithmic approach to the clinical management of chemical and biological casualties. Mil Med. 2000;165:659-662.

38. Henretig FM, Cieslak TJ, Kortepeter MG, Fleisher GR. Medical management of the suspected victim of bioterrorism: an algorithmic approach to the undifferentiated patient. Emerg Med Clin North Am. 2002;20:351-364.

39. Cieslak TJ, Henretig FM. Biological and chemical terrorism. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. 17th ed. Philadelphia Pa: WB Saunders; 2003.

40. Gamer JS. Guideline for isolation precautions in hospitals. The Hospital Infection Control Practices Advisory Committee. Infect Control Hosp Epidemial. 1996:17:53-80.

41. Centers for Disease Control and Prevention. Investigating an outbreak. In: Principles of Epidemiology: Self Study Course SS3030. 2nd ed. Atlanta, Ga: Centers for Disease Control and Prevention; 1998:347-424.

42. Medical Management of Biological Warfare Casualties [handbook on CD-ROM]. Fort DeIrick, Frederick, Md: US Army Medical Research Institute of Infectious Diseases; 2000.

43. US Army Medical Research Institute of Infectious Diseases, US Food and Drug Administration. Biological warfare and terrorism: medical issues and response [satellite television broadcast]. 2000.

TABLE 1

Factors Enhancing Children's Vulnerability to Biological Agents or Complicating the Management of Children Exposed to Such Agents

TABLE 2

Critical Agents for Health Preparedness

TABLE 3

Recommended Therapy for Children With Select Diseases Associated With Bioterrorism

10.3928/0090-4481-20030301-06

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