Frequently Asked Questions

GENERAL QUESTIONS SPECIFIC BIOTERROR AGENTS: ANTHRAX SPECIFIC BIOTERROR AGENTS: BOTULISM HEMORRHAGIC FEVER SMALLPOX SPECIAL POPULATIONS STRATEGIC NATIONAL STOCKPILE

How can pharmacists and nurses participate in emergency preparedness efforts?

Healthcare practitioners can participate in Disaster Medical Assistance Teams; specifically the National Pharmacist Response Team (NPRT) and the National Nurse Response Team (NNRT).  These response teams are part of the National Disaster Medical System under the Department of Homeland Security's Federal Emergency Management Agency.  The teams consist of a network of pharmacists and nurses who are charged with assisting other healthcare providers following a terrorist attack in the United States.  Members of the response teams are required to complete Web-based training, keep up with the field of disease caused by weapons of mass destruction, participate in training programs, and be available for deployment when necessary.

The responsibilities of the NPRT and NNRT include assisting in chemoprophylaxis and vaccination efforts by evaluating patients and dispensing /distributing or administering these agents.

Members of the team will be compensated for their services when activated and reimbursed for any travel expenses incurred.  Provisions have been made to accept any state registered pharmacist or pharmacy technician license as a temporary nationally recognized licensure, similar to how the Department of Veterans Administration recognizes such licensure.  Liability coverage is also provided.

A total of 10 Federal regions will exist corresponding to the following Public Health Service regions:

Practitioners interested in becoming part of the NPRT or NNRT may apply on-line through the National Disaster Medical System's internet site.  The application takes approximately 8 weeks to process and involves the participant being classified as a temporary federal employee.

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How does a healthcare provider recognize and/or differentiate between biological agents in a bioterrorist attack?

Biological agents can be classified into 3 different categories according to the Centers for Disease Control and Prevention (CDC), categories A, B, and C.  These categories are based on ease of dissemination or transmission, ability to result in high mortality, potential to cause panic or social disruption, and necessary requirements for public health preparedness.  Category A agents pose a major threat to national security due to their relative ease of production, high risk of mortality, and increased potential for a medical emergency associated with their use.  Subsequently these agents require diligent national security efforts and specific interventions to assure public health preparedness. According to the CDC , there are 6 main Category A agents that are most likely to be utilized in an attack: Bacillus anthracis (anthrax), Yersinia pestis (plague), variola major (smallpox), Clostridium botulinum toxin (botulism), Francisella tularensis (tularemia), and the viral agents of African hemorrhagic fevers (including Yellow fever, Lassa fever, Marburg virus disease, and Ebola virus).  Compared to Category A agents, those agents in Category B have a lower rate of mortality are not as easily disseminated among the public.  Category C agents are considered emerging agents that may pose a threat in the future.   

It is the responsibility of healthcare providers to recognize when an attack has occurred, to treat all victims as soon as possible, and to limit the spread of the biological agent via containment procedures and infection control measures.  For symptomatic patients, the most probable point of contact with a healthcare provider will be the emergency room.  Upon arrival, these patients should be evaluated based on clinical symptoms by trained emergency room personnel wearing appropriate protective gear.

It is at this point that the practitioner must recognize signs and symptoms of a bioterrorist attack and alert other staff that an outbreak may have occurred or be in progress. The immediate recognition of an attack is critical and the containment of infected individuals will be necessary; incorrect diagnosis after a biological weapon exposure could lead to widespread contamination and harm to other patients as well as medical staff.

Predominate clinical symptoms arise after a patient is exposed to one of these agents; key diagnostic factors (see Table 1) may help practitioners differentiate and identify the source of a potential biological weapon.  Significant factors for the prevention and medical management of bioterrorism include a rapid alert system, a high index of suspicion, and continued vigilance.

Table 1.  Category A bioterrorism agents: major bioterrorist modes of transmission and differential clinical symptoms. 


Biological agent

Major mode of transmission

Most common clinical symptoms*

Anthrax

Low potential for person to person transmission

Bacillus
 anthracis

Direct contact of organism onto arms, hands, or face

Inhalational

Cutaneous:
Small painless ulcer that develops a black area in the center; patient may also experience painful lymphadenopathy and lymphangitis.
Inhalation:
Phase 1 (prodrome) includes cold and flu-like symptoms including sore throat, mild fever, chest discomfort, fatigue, body aches, and mild gastrointestinal distress (stomach pain, nausea, loss of appetite).  Phase 2 (2-4 days later) includes high fever, severe chest pain, respiratory failure, and thoracic edema.

Plague

Low potential for person to person transmission

Yersini
 pestis

Inhalational

High fever, chills, headache, malaise, body aches, cough, blood-tinged sputum*, chest pain, diarrhea, vomiting, abdominal pain and lymphadenopathy.
[*Differentiate from anthrax]

Smallpox

High potential for person to person transmission

Variola major

Inhalational, direct or indirect contact (contaminated clothing or linens)

Initially a prodrome (2-4 days) of high fever, fatigue, headaches, backaches*, vomiting, and diffuse macropapular rash.  Subsequent appearance of vesicles over a 1-2 day period that evolve at the same rate; lesions appear mostly on face, arms and legs, deep in the dermis.
 
[Varicella (chickenpox) has no prodrome phase, lesions appear and persist in stages over more prolonged time, lesions primarily on truck as opposed to face and extremities (rarely on hands or feet).]

Botulism

No potential for person to person transmission

Clostridium botulinum

Inhalational

Symetric cranial neuropathies (double vision, blurred vision, drooping eyelids, fatigue, dizziness,  slurred speech, difficulty swallowing, dry mouth, extreme muscle weakness, difficulty with vision, swallowing, and talking, respiratory paralysis.
 
[Patients are afebrile* unless secondary infection is present; the onset and severity of paralysis depend on dose absorbed.]

Tularemia

No potential for person to person transmission

Francisella tularensis

Inhalational

Clinical presentation similar to atypical pneumonia; must be differentiated from inhalational anthrax (both present with mediastinal widening and pleural effusions) and Legionnaires disease.  Abrupt onset of acute flu-like symptoms; fever, chest pain, headache, cough, body aches, low back pain, and sore throat.  Nausea, vomiting, and diarrhea sometimes occur. Sweats, fever and chills, progressive weakness, malaise, anorexia, and weight loss characterize the continuing illness.  Aerosol exposures can incapacitate some persons in the first 1 or 2 days of illness, and significant impairment in performing tasks can continue for days after antibiotic treatment is begun.
                           
[Pulse-temperature dissociation* in the presence of acute respiratory symptoms in otherwise healthy individuals will differentiate this from other agents.]

Hemorrhagic fever

High potential for person to person transmission

Ebola or Marburg viruses, Yellow fever, Lassa fever, Rift Valley fever

Direct contact (secretion contact or inhalational)

Abrupt onset of acute illness, including fever, fatigue, dizziness, nausea, vomiting, abdominal pain, body aches, diarrhea, chest pain, extreme physical exhaustion, and a maculopapular rash mostly on the trunk.  Also leukopenia, lymphopenia, and thrombocytopenia.  [Bleeding* (petechia, ecchymoses, hemorrhages) occurs as the disease progresses*.]

*Differential diagnostic symptoms

References
Cunha BA. Anthrax, tularemia, plague, ebola, or smallpox as agents of bioterrorism:  recognition in the emergency room.  Clin Microbiol Infect 2002;8:489-503.
Recognition of illness associated with intentional release of a biological agent.  Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5041a2.htm.  Accessed September 2005.

Inglesby TV, Henderson DA, Bartlett JC, et al.  Smallpox as a biological weapon: medical and public health management.  JAMA 1999;281:2127-37.

Dennis DT, Ingelsby TV, Henderson DA, et al.  Tularemia as a biological weapon.  JAMA 2001;285:2763-73.

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What are the abilities of physicians to diagnose and manage illness due to bioterrorism?


With the growing concern of bioterrorism in the United States, the government has focused on increasing the country's preparedness in the event of a bioterror attack.  Physicians will, undoubtedly, be amongst the first responders to such an attack.  Therefore, accurate and early diagnosis and management of patients infected by an agent of bioterror is of crucial importance.  One study, conducted prior to the anthrax attacks in 2001, reported that more than 70% of physicians rated their knowledge on diagnosis and management of bioterrorism-induced illness as less than adequate or very poor.   Another study published in 2004 reported 68% of emergency room physicians rated their knowledge of bioterrorism as limited.  These results indicate the need for incorporating bioterrorism into physician education.

A recent article in the Archives of Internal Medicine by Cosgrove and colleagues evaluated baseline and post-education bioterrorism knowledge of resident and attending physicians in 16 different states and Washington, DC.  The educational intervention consisted of an online tutorial focusing on the diagnosis and management of four diseases (smallpox, anthrax, botulism, and plague) caused by Category A bioterrorism agents along with other common illnesses (not caused by bioterrorism) that have overlapping clinical presentations.

A total of 631 physicians completed a pretest before using the online tutorial.  Upon completion of the tutorial, a posttest was given to assess efficacy of the educational intervention.  At baseline, 70.5% of the participants were able to recognize anthrax, whereas only 16.3% correctly diagnosed plague. The average pretest score for diagnosis of all 4 agents was 46.8% compared with 79% for the average posttest score (an increase of 32.2%, P<0.001).  At baseline, 60.2% treated botulism correctly but only 14.6%, 17% and 9.7% were able to correctly manage smallpox, anthrax and plague, respectively.  For disease management, the average pretest score was 25.4% which increased to 79.1% on the posttest (an increase of 53.7%, P<0.001).  The scores did not differ based on year of residency training or by geographic location. However, attending physicians did have statistically significantly higher average scores compared to residents.

The study results indicate room for improvement in the knowledge of physicians in diagnosing and treating smallpox, anthrax, botulism and plague.  The use of an online didactic module can significantly improve these deficiencies.  However, the authors do recognize that this study did not assess long term knowledge retention.  The use of an online curriculum could still be beneficial as it can be re-introduced on a regular basis.

References
Pesik N, Keim M, Sampson TR. Do US emergency medicine residency programs provide adequate training for bioterrorism? Ann Emerg Med 1999;34:173-6.

Chung S, Mandl KD, Shannon M, Fleisher GR. Efficacy of an educational Web site for educating physicians about bioterrorism. Acad Emerg Med 2004;11:143-8.

Cosgrove SE, Perl TM, Song X, Sisson SD. Ability of physicians to diagnose and manage illness due to category A bioterrorism agents. Arch Intern Med 2005;165:2002-6.

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What should be done with drug products exposed to suboptimal storage temperatures?

Disasters such as the 2003 Northeast Power Outage and Hurricane Katrina have created power outages lasting several days.  Manufacturers of medications, vaccines, and biological products are required to provide information on the stability of their products when they are stored at optimal temperatures.  However, certain circumstances, including power outages, may necessitate storage in suboptimal conditions.  Patient safety may be compromised by administering drug products exposed to extreme temperatures, but unnecessary disposal may result in drug shortages.  Therefore, the Centers for Disease Control (CDC) and the Food and Drug Administration (FDA) have provided some general guidelines.

To obtain the phone number of a manufacturer Drug Facts and Comparisons, Physicians' Desk Reference, or the Red Book may be consulted.  As an additional reference, the Food and Drug Administration may be contacted at 888-463-6332 for specific product information or for information regarding biological products at 800-835-4709 (301-443-1240 after business hours).

References
United States Food and Drug Administration.  Impact of Severe Weather Conditions on Biological Products.  Available at: http://www.fda.gov/cber/weatherimpact.htm. Accessed October 1, 2005.

United States Food and Drug Administration.  Safe Drug Use after a Natural Disaster.  Available at: http://www.fda.gov/cder/emergency/water-refrig.htm. Accessed October 1, 2005.

Centers for Disease Control.  Impact of Power Outage on Vaccine Storage.  Available at http://www.cdc.gov/nip/new/poweroutage_orig.htm. Accessed October 1, 2005.

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What is an easy-to-access and thorough on-line resource for the management of bioterrorism-related infections?

Although many on-line resources exist that discuss bioterrorism, the most thorough source for treatment guidelines, infection control considerations, laboratory testing, and patient education regarding this issue remains the Centers for Disease Control and Prevention – Emergency Preparedness and Response site.  This resource is available at:  http://www.bt.cdc.gov/.  Other bioterrorism resources on the internet include the American Academy of Pediatrics), American Society of Health-System Pharmacists, and the Infectious Disease Society of America.

References:
Terriff CM, Schwartz MD, Lomaestro BM.  Bioterrorism: pivotal clinical issues.  Consensus review of the society of infectious diseases pharmacists.  Pharmacotherapy 2003;23:274-90.

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Can the anthrax vaccine be administered in both pre- and postexposure settings?

The anthrax vaccine (BioThrax®) may be administered in both pre- and postexposure settings; however, dosage regimens vary.  In the preexposure setting, the current dosing recommendation for the anthrax vaccine includes a total of 6 doses over an 18-month period.  The initial 3 doses (0.5 mL/dose) are injected at 2-week intervals, with an additional 3 doses given  6, 12, and 18 months after the first dose.  The anthrax vaccine is not licensed for postexposure prophylaxis of anthrax; however, 3 doses of vaccine may be administered in conjunction with appropriate antibiotic therapy.  The initial dose should be given as soon as possible with the second and third doses administered at 2 and 4 weeks after the first dose, respectively.

References:
Grabenstein JD.  Immunofacts: vaccines and immunologic drugs.  St. Louis, MO: Wolters Kluwer Health, Inc., 2004.

Centers for Disease Control and Prevention.  Use of anthrax vaccine in response to terrorism: supplemental recommendations of the advisory committee on immunization practices.  MMWR 2002;51:1024-6.

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Can other fluoroquinolones be used to treat infections due to Bacillus anthracis besides ciprofloxacin?

Treatment and postexposure prophylaxis recommendations for inhalational and cutaneous anthrax have been developed by the Working Group on Civilian Biodefense.  Ciprofloxacin and doxycycline are preferred agents, and oral ciprofloxacin is first-line therapy for treating inhalational anthrax in mass casualty settings and for postexposure prophylaxis.

Ciprofloxacin received FDA-approval for management of postexposure to inhalational anthrax in August 2000 based on experimental data.  The Working Group's recommendation and approval of ciprofloxacin have led practitioners to question whether or not other fluoroquinolone antibiotics would be effective against B. anthracis.  This information could be important if ciprofloxacin was not immediately available at an institution (such as not on formulary or routinely stocked) or if the drug was on national shortage.

A search of the medical literature identified 2 in vitro studies that have evaluated the activity of fluoroquinolones against B. anthracis.  Results of these studies reveal that ofloxacin, moxifloxacin, and levofloxacin have sufficient activity and are potential options for clinical use in patients with anthrax.    

References:
Inglesby TV, O'Toole T, Henderson DA, Bartlett JG, Ascher MS, Eitzen E, et al.  Anthrax as a biological weapon, 2002.  JAMA 2002;287:2236-52.

Meyerhoff A, Albrecht R, Meyer JM, Dionne P, Higgins K, Murphy D.  US Food and Drug Administration approval of ciprofloxacin hydrochloride for management of postexposure inhalational anthrax.  Clin Infect Dis 2004;39:303-8.

Athamna A, Massalha M, Athamna M, Nura A, Medlej B, Ofek I, et al.  In vitro susceptibility of Bacillus anthracis to various antibacterial agents and their time-kill activity.  J Antimicrob Chemother 2004;53:247-51.

Kihira T, Sato J, Shibata T.  Pharmacokinetic-pharmacodynamic analysis of fluoroquinolones against Bacillus anthracis.  J Infect Chemother 2004;10:97-100.

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How is botulinum antitoxin obtained and administered?

Prompt administration of botulinum antitoxin (passive immunity) is crucial to prevent the progression of botulism; however, pharmacies do not routinely stock this antidote.  Botulinum antitoxin is available through the Centers for Disease Control and Prevention (CDC) through a coordinated effort with state and local health departments.  In addition, the antitoxin is stored at large airport quarantine sites.

When botulism is diagnosed, the physician should contact the hospital infection control practitioner and the local or state health department to report the case/outbreak and obtain antitoxin.  Treatment should not be withheld pending laboratory results; clinical diagnosis is sufficient.  Links and contact information for these health departments are available from the CDC website http://www.cdc.gov/doc.do/id/0900f3ec80226c7a/.  If the local or state health department cannot be reached, the CDC should be contacted directly (404) 639-2206; (404) 639-2888 (after hours, weekends, holidays); or CDC assistance (770) 488-7100.  

The currently available antitoxin is a trivalent preparation that contains antibodies to botulinum toxin types A, B, and E.  The dosage is 1 vial diluted 1:10 with normal saline.  Botulinum antitoxin should be administered by slow intravenous infusion (over 30 to 60 minutes).  One vial is generally sufficient because the amount of each antitoxin present greatly exceeds the amount of botulinum toxin present in the serum following exposure via foodborne illness.  For patients who have had a large exposure, serum toxin levels may be checked after treatment to determine if further antitoxin is required.

Botulinum antitoxin is derived from horse immunoglobulin and has been noted to precipitate allergic reactions.  Patients receiving antitoxin should be monitored for signs and symptoms of anaphylaxis.  A skin test is recommended in the prescribing information; however, the practicality of performing one has been challenged since timing of administration is crucial.  The literature also describes that patients who have tested positive on the skin test have safely received the antitoxin, and patients with a negative skin test have reacted to the full dose.  Diphenhydramine, epinephrine, and emergency care should be readily available at the bedside while antitoxin is administered.  Premedication with corticosteroids and diphenhydramine should be considered for patients who have a positive skin test as desensitization protocols may take 3 to 4 hours to complete.    

References:
Horowitz BZ.  Botulinum toxin.  Crit Care Clin 2005;21:825-39.

Arnon SS, Schechter R, Inglesby TV, et al.  Botulinum toxin as a biological weapon:  medical and public health management.  JAMA 2001;285:1059-70.

Centers for Disease Control and Prevention.  Information networks and other information sources.  Available at:  http://www.cdc.gov/doc.do/id/0900f3ec80226c7a/.  Accessed January 2, 2006.

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Do the household contacts of patients exposed to botulism, who themselves were not directly exposed to the toxin, need to be administered therapy?

No.  Person-to-person transmission of botulinum toxin does not occur; therefore, household contacts of individuals exposed to the toxin would not be administered therapy.  The only documented modes of transmission of botulinum toxin are absorption via the gastrointestinal tract or open wounds or through inhalation.

References:
Arnon SS, Schechter R, Inglesby TV, et al.  Botulinu m toxin as a biological weapon.  Medical and public health management.  JAMA 2001;285:1059-70.

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Should individuals who have been exposed to hemorrhagic fever viruses receive postexposure prophylaxis?

Currently, there is no recommended postexposure prophylactic therapy for individuals exposed to hemorrhagic fever viruses.  High-risk and close contacts of patients with viral hemorrhagic fever and individuals with a direct exposure to hemorrhagic fever viruses should be placed on fever watch for 21 days after exposure.  If fever (≥ 101º F) develops, ribavirin should be initiated as soon as possible if the pathogen is susceptible to therapy.
 
References:
Borio L, Inglesby T, Peters CJ, et al.  Hemorrhagic fever viruses as biological weapons.  Medical and public health management.  JAMA 2002;287:2391-405.

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How does a clinician differentiate between smallpox and chickenpox?

Several diseases and drug reactions can result in the occurrence of rash, fever, and malaise; therefore, a diagnosis of smallpox based solely on clinical manifestations may be difficult.  In particular, a differentiation between the signs and symptoms of smallpox and chickenpox may be complicated for many clinicians, especially in adults presenting with an extensive rash.  The table below summarizes the major differences between the 2 disease states.  As noted in the table, the main clinical differences between smallpox and chickenpox involve the features of the skin lesions and related complications.  Smallpox lesions are concentrated more on the face and extremities, have a round shape, and protrude somewhat deep into the skin.  In contrast, chickenpox lesions are concentrated on the torso, have an oval shape, and are fairly superficial.  Facial scarring is a common occurrence with smallpox infection, in contrast, scarring occurs infrequently with chickenpox.  In addition, smallpox has been associated with the development of pneumonia, blindness, and encephalitis.  These complications occur rarely to never in patients experiencing chickenpox.

Table.  Differentiation between smallpox and chickenpox based on clinical signs and symptoms.*


Criteria

Smallpox

Chickenpox

Length of incubation period (days)

7 – 17

14 - 16

Prodromal phase

     Duration (days)

2 – 4

0 - 2

     Headache, backache

Yes

Possible

     Muscle pain, malaise

Yes

Possible

     Fever

Yes

Possible

     Pallor, transient rash

Possible

No

Skin lesions

     Distribution

Concentration of lesions on face and extremities

Concentration of lesions on torso

     Evolution of lesions

Same stage

Different stages

     Shape

Round

Oval

     Depth

Deep

Superficial

     Lesions on palms and soles

Common

Uncommon

     Diameter (mm)

4 to 6

2 to 4

     Peak of rash (days)

7 to 10

3 to 5

Complications

     Skin infection

Occurs sometimes

Occurs sometimes

     Facial scarring

Common

Occurs sometimes

     Pneumonia

Occurs sometimes

Rare

     Blindness

Occurs sometimes

Never

     Encephalitis

Occurs sometimes

Rare

*Source:  N Engl J Med 2002;346:1300-6.

Reference:
Breman JG, Henderson DA.  Diagnosis and management of smallpox.  N Engl J Med 2002;346:1300-6.

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How is the smallpox vaccine administered?

To administer the smallpox vaccine, the World Health Organization recommends use of a bifurcated needle.  Typically, the vaccine is given in the deltoid area of the nondominant arm in order to avoid limitation of use should a reaction to the vaccine occur.  Unless the injection site is grossly contaminated, cleansing of the area is generally not required.  If cleansing of the injection site is needed, use of soap and water is preferred.  Cleansing with acetone or alcohol should be avoided as these substances can inactivate the vaccine.  Once the site is prepared (if necessary), the bifurcated needle is dipped into a multi-dose vaccine vial; a droplet of vaccine should be observed in the needle once removed from the vial.  The vaccinator should then make 3 (for primary vaccination) to 15 (for revaccination) perpendicular insertions into the injection site in rapid succession.  The insertions should be confined to an area approximately 5 mm in diameter.  The injection procedure should be performed vigorously, resulting in a trace of blood within 15 to 30 seconds post vaccination.  After completion of the vaccination, any excess vaccine should be absorbed from the skin with sterile gauze.  The gauze should then be discarded in a biohazard waste receptacle.  Normally, the injection site should be covered with only a single, loosely applied gauze pad.  However, if the patient receiving the vaccine is a healthcare worker, a doubled-over sterile gauze pad with a semipermeable membranous covering should be applied to the site.  This latter approach aids in preventing the spread of infection in high-risk areas such as hospitals.

Reference:
Fulginiti VA, Papier A, Lane JM, Neff JM, Henderson DA.  Smallpox vaccination: a review, part I.  Background, vaccination technique, normal vaccination and revaccination, and expected normal reactions.  Clin Infect Dis 2003;37:241-50.

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What are the most common adverse effects associated with smallpox vaccination?

Because routine vaccination against smallpox was discontinued in 1971 for civilians and in 1990 for military personnel, most young adults and children have not been exposed to the smallpox vaccine.  Subsequently, healthcare providers have limited experience administering the smallpox vaccine and monitoring for potential adverse reactions, particularly in the adult population.  Now that smallpox (variola major) has been recognized by the Centers for Disease Control and Prevention (CDC) as a potential bioweapon, designated individuals (such as military and public health personnel) who may be first responders to a smallpox bioterrorism event need to receive an initial vaccination or be re-vaccinated.  In response to this need, the US Department of Health and Human Services (DHHS) implemented a vaccination program in January 2003 for eligible volunteers (primarily health care workers), and the safety outcomes spanning the first 9 months of the smallpox vaccination program have recently been published.  The smallpox vaccine administered in this program was the calf-lymph derived New York City Board of Health (NYCBOH) vaccinia strain (Dryvax®, Wyeth), which was produced before 1982.
           
In this report, 37,901 adult volunteers received 38,885 smallpox vaccinations and 92% achieved smallpox immunity; most of these individuals had been previously vaccinated (76%), were women (64%), and aged 40-64 years (78%). Adverse reactions were reported at an overall rate of 217 per 100,000 vaccinees (based on a total of 822 reports).  Fever (18.9%), rash (18.4%), pain (16%), headache (15.2%), fatigue (13.5%), and pruritus (13.4%) were most commonly reported in the volunteers.  Most of these non-serious events (72%) occurred within 14 days of vaccination.  The most common non-serious adverse reactions in patients less than 40 years (assumed to be previously unvaccinated), were fever, rash, pain, pruritus, and headache; patients 40 years and older experienced chest pain, fever, pain, headache, and fatigue most frequently.
           
Serious adverse reactions were reported by 12% of the volunteers (100 adverse reaction reports), yielding a rate of 26.4 per 100,000 vaccinees.  Of these 100 patient reports, many patients required hospitalization (n=85); other findings included life-threatening illness (n=10), death to due myocardial infarction (n=3), and permanent disability (n=2).  Additional serious adverse events included inadvertent inoculation (n=10), generalized vaccinia (n=2), superinfection at the injection site (n=2), and atypical postvaccinial encephalitis (n=1).  Most major neurologic events were mild and consisted of headache, no major dermatologic events were reported, and no vaccinia immune globulin was administered to any personal involved in this study.    

Of the total 822 adverse events, 203 reports of cardiac events were received and most were categorized as non-serious (n=170) and characterized by symptoms including chest pain (n=107), arrhythmias (n=6), palpitations (n=47), dyspnea (n=16) and hypertensive episodes (n=27, of which 18 cases were new onset hypertension).  Serious cardiac events included myocarditis/pericarditis (n=21), myocardial infarction (n=6), angina (n=4), and dilated cardiomyopathy (n=2).  In this vaccination series, cardiac adverse events occurred at a median onset of 8 days (range 0-42 days) after vaccination. However, it is important to note that most (78%) of these cardiac events had occurred before the implementation of specific cardiac screening (deferral) criteria for the DHHS vaccination program.  These criteria preclude smallpox vaccine administration to individuals with a history of cardiac disease or several risk factors (including dyslipidemia, hypertension, diabetes mellitus, etc) for atherosclerotic heart disease.

This interesting cohort study describes a smallpox vaccine administration program designed by the US government to provide safe and effective protection from the threat of bioterrorism with the smallpox virus. 

References:
Casey CG, Iskander JK, Roper MH, et al.  Adverse events associated with smallpox vaccination in the United States, January-October 2003.  JAMA 2005;294:2734-43.

Grabenstein JD, Winkenwerder W.  US military smallpox vaccination program experience.  JAMA 2003;289:3278-82.

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Describe possible adverse neurologic effects associated with the smallpox vaccine.

A recent publication in the Journal of the American Medical Association presents a major cohort report of the neurologic adverse effects associated with the administration of the smallpox vaccine.  This assessment summarizes the experience of both the US Department of Defense and the Department of Health and Human Services (DHHS) in efforts to immunize and effectively prevent serious adverse effects from the smallpox vaccine.  Based upon published reports dating back to the 1950's, several neurologic complications have been associated with the administration of smallpox vaccine, including postvaccinial encephalomyelitis (PVE), Guillain-Barre syndrome, acute cranial neuropathies, poliomyelitis-like syndrome, Bell palsy, and transverse myelitis.

From December 2002 to March 2004, nearly 665,000 civilian and military personnel received the smallpox vaccine, which was the calf-lymph derived New York City Board of Health (NYCBOH) vaccinia strain (Dryvax®, Wyeth).  In this report, the majority of vaccinees (66%) were receiving the smallpox vaccine for the first time, and a total of 214 adverse events were investigated as having a neurologic etiology.  Most adverse neurologic events occurred in vaccinees aged 18-29 years and were reported within 30 days of vaccination.  Headache (sometimes requiring hospitalization) was the most common adverse effect (44%); the observed rate of headache was 14.3 per 100,000 vaccinees.  Other reported neurologic adverse events included limb paresthesias (8%), dizziness (6%), and limb pain (6%).

Of the 214 cases of neurologic events, 39 (18.2%) of these were classified as serious neurologic adverse events.  These included aseptic meningitis (n=13), Bell palsy (n=11), seizures (n=8), Guillain-Barre syndrome (n=3), and encephalitis/myelitis (n=3).  All of these serious events were reported within 14 days of immunization with the smallpox vaccine.  From these data, the authors concluded that the rates of serious neurologic adverse effects closely resemble expected and previously published rates. Table 1 summarizes the incidence of 3 serious neurologic adverse effects reported in this cohort assessment.

Table 1. Serious neurologic adverse effects and overall incidence

Syndrome                                                               Incidence

Bell palsy                                                                 1.7 per 100,00 vaccinees

Guillain-Barre                                                          0.5 per 100,000 vaccinees

Encephalitis/myelitis                                               3 per 5,000,000 vaccinees

 
Reference:
Sejvar JJ, Labutta RJ, Chapman LE,  et al.  Neurologic adverse events associated with smallpox vaccination in the United States, 2002-2004.  JAMA 2005;294:2744-50.

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Should a patient with a heart condition be administered the smallpox vaccine?


After the initiation of a smallpox vaccination campaign among selected healthcare workers and military personnel, cases of cardiac effects post-vaccination were reported.  Specifically, patients receiving the vaccine experienced myocarditis, pericarditis, myopericarditis, angina, myocardial infarction, and heart failure.  These cases could not be specifically linked to the smallpox vaccine and most were of mild to moderate severity.  However, due to these effects, patients with a known heart condition should not receive the smallpox vaccine in a pre-outbreak setting.  The Centers for Disease Control and Prevention (CDC) list the following as conditions where the smallpox vaccine should be avoided:

In addition, the CDC recommends that any patient with 3 or more of the following cardiovascular disease risk factors should not receive the vaccine:  hypertension, hyperlipidemia, diabetes, current smoker, or having a first degree relative with a heart condition before 50 years of age.  In the setting of an actual smallpox outbreak, clinicians may weigh the benefit of vaccine protection against the potential cardiovascular risks associated with vaccine administration and choose to administer vaccine to this patient population.

References:
Centers for Disease Control and Prevention.  Smallpox vaccine and heart problems.  Available at:  http://www.bt.cdc.gov/agent/smallpox/vaccination/pdf/heartproblems.pdf.  Accessed:  10 November, 2004.

Halsell JS, Riddle JR, Atwood JE, et al.  Myopericarditis following smallpox vaccination among vaccinia-naïve US military personnel.  JAMA 2003;289:3283-9.

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Can vaccinia immune globulin (VIG) be used to treat smallpox infection?

Vaccinia immune globulin (VIG) provides transient passive immunity and has been used with success in patients with vaccine-associated adverse reactions such as eczema vaccinatum, severe generalized vaccinia, milder forms of progressive vaccinia, and in patients who have experienced severe reactions after inadvertent implantation of the vaccinia virus.  VIG is not effective for treating an active smallpox infection and should not be administered in such a setting.

References: 
Fulginiti VA, Papier A, Lane JM, Neff JM, Henderson DA.  Smallpox vaccination: a review, part II.  Adverse events.  Clin Infect Dis 2003;37:251-71.

Grabenstein JD.  Immunofacts: vaccines and immunologic drugs.  St. Louis, MO: Wolters Kluwer Health, Inc., 2004.

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Are there any special concerns regarding antibiotic therapy in pregnant women with regard to bioterrorism?

Pregnant women are considered a "vulnerable" population in the setting of a bioterror attack.  Not only are clinicians concerned about providing appropriate therapy to the woman, but they also must consider any effects that therapy may have on the fetus.  In the bioterrorism setting, ciprofloxacin and doxycycline are recommended antibiotic treatments for anthrax, plague, and tularemia.  Generally, ciprofloxacin is not recommended for use in pregnant women due to the potential for fetal arthropathy; however, no studies have been performed confirming the occurrence of this adverse event in this patient population.  In addition, doxycycline is a pregnancy category D medication; pregnant women receiving this medication have reported hepatotoxicity and retarded skeletal growth has been observed in the fetus.  Pregnant women receiving doxycycline should have periodic liver function monitoring.

Despite these concerns, the Working Group on Civilian Biodefense states that the benefits of these therapies significantly outweigh the risks associated with bioterror infections and both medications remain appropriate therapeutic options during pregnancy.  The recommended prophylaxis and treatment antibiotic regimens for pregnant women exposed to a bioterror organism are summarized in the table below.

Table.  Recommended prophylaxis and treatment regimens.

Contained casualty setting

Bioterror agent

Preferred treatment

Alternative treatment

Anthraxa (inhalational)

Ciprofloxacin 400 mg IV every 12 hrs  OR
Doxycycline 100 mg IV every 12 hrs  PLUS
1 or 2 additional antibiotics

None

Anthrax (cutaneous)

Ciprofloxacin 500 mg PO every 12 hrs OR  
Doxycycline 100 mg PO every 12 hrs

Amoxicillin 500 mg PO three times daily (if a quinolone or doxycycline is not tolerated)

Plague

Gentamicin 5 mg/kg IM/IV every 24 hrs or 2 mg/kg IV loading dose then 1.7 mg/kg IM/IV every 8 hrs

Doxycycline 100 mg IV every 12 hrs or 200 mg IV every 24 hrs  OR
Ciprofloxacin 400 mg IV every 12 hrs

Tularemia

Gentamicin 5 mg/kg IM/IV every 24 hrs OR
Streptomycin 1 gm IM every 12 hrs

Doxycycline 100 mg IV every 12 hrs  OR

Ciprofloxacin 400 mg IV every 12 hrs

Mass casualty setting (postexposure prophylaxis)

Anthrax

Ciprofloxacin 500 mg PO every 12 hrs

Amoxicillin 500 mg PO every 8 hrs (if strain is susceptible; appropriate only after 10 to 14 days of quinolone or doxycycline therapy and then only if contraindications to these treatments exist)

Plague

Doxycycline 100 mg PO every 12 hrs OR
Ciprofloxacin 500 mg PO every 12 hrs

Chloramphenicol 25 mg/kg orally four times daily (the oral formulation of chloramphenicol is not available within the United States)

Tularemia

Ciprofloxacin 500 mg PO every 12 hrs OR
Doxycycline 100 mg PO every 12 hrs

None

aIntravenous therapy should be continued until the condition of the patient improves significantly.  Total therapy for anthrax should be continued for a total duration of 60 days.

References:
Inglesby TV, O'Toole T, Henderson DA, Bartlett JG, Ascher MS, Eitzen E, et al.  Anthrax as a biological weapon, 2002.  Updated recommendations for management.  JAMA 2002;287:2236-52.

White SR, Henretig FM, Dukes RG.  Medical management of vulnerable populations and co-morbid conditions of victims of bioterrorism.  Emerg Med Clin N Am 2002;20:365-92.

Adkins-Bley K, Greenhill LM.  Bioterrorism and pregnant women.  AWHONN Lifelines 2002;6:209-11.

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Are there any special concerns with regard to prophylaxis and treatment of bioterror-related infections in elderly patients?

Consensus statements for the management of bioterror-related illnesses contain specific recommendations for treatment in adults, children, pregnant women, and immunocompromised persons (certain infections only).  The statements are silent on the management of elderly patients so it is assumed that they would be treated the same as adults.  Astute clinicians should be aware that elderly patients are likely to have decreased renal function, co-morbid conditions, and to be taking multiple medications.  Therefore, it will be important to recognize the potential for drug-drug interactions and to carefully monitor elderly patients for adverse drug reactions.

Reference:
White SR, Henretig FM, Dukes RG.  Medical management of vulnerable populations and co-morbid conditions of victims of bioterrorism.  Emerg Med Clin N Am 2002;20:365-92.

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Are there any specific medication safety concerns with regard to prophylaxis and treatment of bioterror-associated infections in children?

For some bioterror-related infections including anthrax, plague, and tularemia, ciprofloxacin and doxycycline are preferred or alternative treatments for children; however, specific safety concerns exist with regard to the use of these medications in this patient population.  Tetracycline use in children less than 8 years of age has been associated with a negative impact on tooth development.  Doxycycline carries the same warnings as tetracycline; however, it is potentially a safer alternative.  Doxycycline is not thought to bind to calcium to the same degree that tetracycline does; therefore, it may cause less staining of the teeth.  The administration of fluoroquinolones to children is generally not recommended due to concerns regarding potential cartilage damage and arthropathy.  Clinicians caring for children in bioterror settings need to assess the risks and benefits of therapy with these medications on an individual basis; however, the significant benefits of therapy on morbidity and mortality may greatly outweigh the risks of exposure to these medications when a bioterror infection is suspected or proven.

References:
Benavidas S, Nahata MC.  Anthrax: safe treatment for children.  Ann Pharmacother 2002;36:334-7.

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What is the Strategic National Stockpile, and how is it deployed?

The Strategic National Stockpile (SNS), is a collection of life-saving pharmaceuticals and medical supplies that was created as a resource to re-supply communities during an emergency such as an act of terrorism or a natural disaster.  The Departments of Health and Human Services and Homeland Security oversee the SNS.  One key component of the SNS is the 12-hour Push Packages, designed to arrive within 12 hours of deployment.  The SNS is not to be depended upon for first response efforts due to the potential lag-time of 12 hours.

A pitfall of the SNS is that the precise contents are not public knowledge due to security concerns.  This has created confusion in preparedness efforts; however, practitioners can rest assured that inventory is sufficient.  According to the CDC, content is driven by likelihood of a specific agent being used for terrorism and the susceptibility of the population.  According to the CDC Web site, contents include antibiotics, antidotes for chemical agents, antitoxins, life-support drugs, blast, trauma, and burn care supplies, and medical supplies used to gain intravenous access and maintain an airway.      

A request for the SNS must come from the affected state's governor's office.  Requests will be evaluated by the CDC, the Department of Homeland Security, and the Department of Health and Human Services.  Transportation of the SNS employs trucks and cargo aircraft.  Members of the Technical Advisory Response Unit (TARU) will be deployed with the SNS to coordinate with local officials to receive and distribute the contents.  The TARU's function is largely advisory in nature since the authority for the SNS is transferred from federal agencies to the local authorities.

Notably, healthcare facilities are not the preferred destinations for arrival of the SNS.  In an emergency situation healthcare facilities will be focused on providing direct patient care and cannot take on additional responsibility of dispensing prophylactic medications and administering vaccinations.  Larger venues such as gymnasiums and convention centers are better suited for distribution sites and can accommodate larger numbers of people.      

References:
Centers for Disease Control and Prevention.  Emergency preparedness & response:  Strategic National Stockpile.  Available at:  http://www.bt.cdc.gov/stockpile/.  Accessed April 1, 2005.

Krenzelok EP.  Biological and chemical terrorism:  a pharmacy preparedness guide.  Bethesda:  American Society of Health-System Pharmacists; 2003.

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Given that the current US strategic national stockpile of smallpox vaccine was produced in the 1950s to the 1980s before standardized sterility testing, should we now consider testing these vaccines for the presence of adventitious agents (mycoplasma, viruses, etc)?

Although naturally occurring smallpox (Variola major) was eradicated in the 1970s, this virus has recently been recognized as a potential bioterrorist weapon against U.S. domestic and military populations. At this time, the U.S. strategic national stockpile of smallpox vaccine consists of old lots of two types of smallpox vaccine.  The largest part of the U.S. strategic national stockpile consists of Dryvax®, a lyophilized powder produced by Wyeth from 1980 to 1982, and a frozen preparation of Aventis Pasteur smallpox vaccine (APSV) which was produced in the mid-1950s.

Compared to modern day vaccine manufacturing and quality assurance methods, the smallpox vaccine that comprises our national stockpile (Dryvax® and APSV) was produced via an uncontrolled and non-standardized system.  These "first generation" smallpox vaccines were grown in the skin of calves or sheep, and seed virus was passaged in tissues of calves, sheep and rabbits in this production process.  The animals were infected by scarification, and the skin containing viral lesions was physically removed by scraping.  As a result, human contamination of the vaccine material is possible as a result of the crude manufacturing techniques utilized during that time.

While these vaccines were tested and lots rejected based upon the presence of specific microbial species, low concentrations of nonpathogenic bacteria and fungi were allowed in the final vaccine product. In addition, smallpox vaccine was never tested for the presence of mycoplasma, or for contamination with human, bovine, ovine, or rabbit viruses; regulations that required specific testing for adventitious infectious agents came into effect years after smallpox vaccine had been manufactured.

Current recommendations and federal guidelines require testing for adventitious infectious agents during vaccine production; meanwhile, an investigational, cell culture-based smallpox vaccine intended for the strategic national stockpile has been subject to this testing.  While many pragmatic obstacles exist, it has been suggested that this available technology should be utilized to test the older lots of smallpox vaccine in our strategic national stockpile for the presence of adventitious agents.  While no specific problems related to smallpox vaccine contamination have been suspected based on historic or recent vaccination programs, concern may be warranted given that smallpox vaccine was produced in animal skin.  Testing for adventitious agents may also increase our understanding of the potential risks and adverse effects of smallpox vaccine in the adult population, as well as provide information to delineate the risk of myopericarditis, which has been associated with smallpox vaccination.   

References

Murphy FA, Osburn BI. Adventitious agents and smallpox vaccine in strategic national stockpile. Emerg Infect Dis [serial on the Internet]. 2005 Jul [date cited]. Available from http://www.cdc.gov/ncidod/EID/vol11no07/05-0277.htm

Rosenthal SR.  Merchlinsky M, Kleppinger C, Goldenthal KL.  Developing new smallpox vaccines.  Emerg Infect Dis 2001;2001;7(6):920-6.

Grabenstein JD, Winkenwerder W.  US military smallpox vaccination program experience.  JAMA 2003;289(24):3278-82.

Talbot TR, Stapleton JT, Brady RC et al.  Vaccination success rate and reaction profile with diluted and undiluted smallpox vaccine.  JAMA 2004;292:1205-12.

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Is stockpiling medications an appropriate strategy when preparing for a potential bioterror attack?

In preparation for a potential bioterror attack, stockpiling of medications used for the prevention and treatment of associated bioterror illnesses is not an appropriate strategy.  Stockpiling not only depletes the existing supplies of necessary drugs, but also significantly increases inventory cost and reduces access to drugs for patients who actually need them.  A better approach is for clinicians to work together with local institutions to coordinate sufficient amounts of needed medications.  In addition, institutions should survey drug wholesalers to determine inventory levels in order to delineate a clearer picture of medication availability.

References:
Krenzelok EP, editor.  Biological and chemical terrorism: a pharmacy preparedness guide.  Bethesda, MD: American Society of Health-System Pharmacists, Inc., 2003.

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