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Bioterrorism Agents: Smallpox,
Botulism, and Tularemia
Jeff Kuper, Pharm.D., BCPS
Clinical Associate Professor
Ernest Mario School of Pharmacy
Rutgers, The State University of New
Jersey
Outline
Topics
Diseases
Smallpox
Botulism
Tularemia
History
Epidemiology
Manifestations
Diagnosis
Prevention and
treatment
Smallpox
Variola Virus
Smallpox
History
1754-67: British distribute blankets used by
smallpox patients to Native Americans during the
French and Indian Wars
1796: Edward Jenner demonstrates that deliberate
infection with cowpox protects people from
smallpox, introducing the practice of “vaccination”
1967-77: WHO campaign to eradicate smallpox
1980: WHO recommends transfer of all remaining
variola virus to two reference labs
Smallpox
Epidemiology
Person-to-person transmission
– Aerosol droplets
– Direct contact with lesions or contaminated
clothing, bedding, etc.
Transmission usually slower than chickenpox
– Not contagious until rash appears
Incubation period is typically 12-14 days
Smallpox
Variola Major
Initial presentation: high fever, prostration,
headache, backache, ± abdominal pain
Maculopapular rash begins on the face and
arms, spreading to the trunk and legs
– vesicles pustules scabs over 7-10 days
Lesions in one area appear at same stage
May leave residual scarring
Complications: toxemia, encephalitis
Mortality rate > 30% in the unvaccinated
Henderson DA. JAMA 1999; 281:2127
Smallpox
Other Clinical Manifestations
Hemorrhagic smallpox
Malignant smallpox
Variola minor
In partially immune patients, the rash may
be milder and more atypical and evolve
more quickly
Smallpox
Diagnosis
Clinical diagnosis in the setting of a known
outbreak
Lab diagnosis requires biolevel 4 facility
– Sample vesicular fluid or scab
– Characteristic appearance under an electron
microscope
– Culture and/or PCR for confirmation
Smallpox
Chickenpox vs. Smallpox
Chickenpox
Smallpox
Prodrome
none or mild
pronounced
Lesion types
superficial, different
stages
deep-seated, same
stage
Lesion
distribution
mostly on trunk, face;
palms/soles
uncommon
mostly on face,
extremities;
palms/soles common
Lesion evolution
rapid
slow
Systemic
symptoms
minimal
toxic, moribund
From http://www.bt.cdc.gov/agent/smallpox/diagnosis
Smallpox
Management
Post-exposure vaccination: ring vaccination
– For all contacts and emergency/essential
workers
– Vaccination within 4 days of exposure may
prevent or reduce the severity of illness
Isolation of persons with fever
? Cidofovir
Smallpox
Vaccine
Consists of live vaccinia virus (cowpox)
Dryvax® is the only FDA-licensed vaccine
– Other vaccines held in reserve by CDC
Smallpox
Vaccination Method
Multiple-puncture technique using bifurcated
needle
– Needle prongs are calibrated to hold the correct
dose when dipped into vaccine vial
Hold needle perpendicular to skin and make
rapid, vigorous punctures
– Should see trace blood
– 2-3 punctures for primary vaccination
Smallpox
Vaccine “Take”
From http://www.bt.cdc.gov/agent/smallpox/
Smallpox
Vaccine “Take”
Take
Non-Take
From http://www.bt.cdc.gov/agent/smallpox/
Smallpox
Vaccine Site Care
Cover with gauze and semipermeable dressing to
decrease risk of transmission of vaccinia virus
– Vaccinia is shed from time lesion appears until scab falls
off
Rate of transmission during the ’60s was 2-6 cases per
100,000 first-time vaccinees
No evidence of respiratory transmission
– Routine infection control procedures
– Avoid direct contact with the vaccination site
Healthcare workers do NOT need to be furloughed
from work
Smallpox
Relative Vaccine Contraindications
Atopic dermatitis or eczema (active or
history)*
Other active exfoliative skin conditions*
Immunosuppressive conditions*
– Steroid doses ≥ 2 mg/kg or 20 mg/day of
prednisone for > 2 weeks within past week
– Other immunosuppressive meds within past 3
weeks
* Also contraindicated for household contacts
Smallpox
Relative Vaccine Contraindications
Pregnancy*
Breastfeeding
Infants < 1 year old
Allergy to vaccine component
– Including neomycin, tetracycline, polymyxin B,
streptomycin, glycerin, and phenol
?? Cardiac disease
* Also contraindicated for household contacts
Smallpox
Expected Vaccine Reactions
Regional LAD
Vacc. Site Pain
Fever
Chills
Nausea
Myalgias
Headache
Fatigue
0
20
40
60
80
% Incidence
SE Frey et al. NEJM 2002; 346:1265-74
Smallpox
Vaccine Complications
Satellite lesions
Nonspecific rashes
Smallpox
Vaccine Complications
Cases per million vaccinees
Non-life threatening
Inadvertent inoculation
25-529
Generalized vaccinia
23-242
Erythema multiforme
165
Life-threatening
Encephalitis
3-12
Progressive vaccinia
1-2
Eczema vaccinatum
10-39
Death
1-2
MMWR 2003; 52(RR-4):9
Smallpox
Erythema Multiforme
Smallpox
Inadvertent Inoculation
Smallpox
Generalized Vaccinia
Smallpox
Eczema Vaccinatum
Smallpox
Progressive Vaccinia
Smallpox
Encephalitis/Encephalomyelitis
Diagnosis of exclusion
Encephalitis in infants < 2yo
– Onset 6-10 days post-vaccination
– Encephalomyelitis in older persons
Onset 11-15 days post-vaccination
Mortality 25%, neurological sequelae 25%
Management: supportive, symptomatic
Smallpox
Fetal Vaccinia
Smallpox
Vaccinia Management
Vaccinia immune globulin (VIG)
– Indications
Eczema vaccinatum
Progressive vaccinia
Generalized vaccinia (severe or
immunocompromised)
Inadvertent inoculation (severe or ocular
other than keratitis)
– Dose: 100-500 mg/kg x 1
Smallpox
Vaccinia Management
Topical trifluridine for ocular infection
Cidofovir (Vistide®)
– In vitro activity against orthopoxviruses
– Nephrotoxic—administer with probenecid
and hydration
– Will be released by CDC as IND if:
Patient fails VIG treatment OR
Patient is near death OR
VIG supplies have been exhausted
Botulism
Clostridium botulinum toxin
From “Todar’s Online Textbook of Bacteriology”
Botulism
History
1812: link recognized between sausage (botulus in
Latin) and paralytic illness in Germany
1897: C. botulinum and associated toxin first
identified
1930s: Japanese army feeds botulinum toxin to
Chinese POWs
1990-95: Aum Shinrikyo cult disperses aerosolized
botulinum toxin at multiple sites in Japan, but no
illnesses result
1990s: Iraq produces 19,000 L of toxin, half of
which is loaded into weapons
Botulism
Epidemiology
Transmission from exposure of mucous
membranes to spores or toxin
Outbreaks most often associated with
home-canned vegetables, fruits, and fish
12-72 hr. incubation period
Clues to intentional release
– Large number of cases
– Unusual toxin type
– Simultaneous outbreaks with no common source
Botulism
Clinical Manifestations
Most poisonous substance known
Toxin blocks acetylcholine release,
resulting in flaccid muscle paralysis
Disease forms
– Wound botulism
natural
– Infant botulism
– Foodborne botulism
man-made
– Inhalational botulism
Botulism
Clinical Manifestations
Symmetric, descending muscle weakness
with prominent cranial nerve palsies
– Acute onset
– 4 D’s: diplopia, dysarthria, dysphonia, dysphagia
– May later involve autonomic system (e.g.,
bradycardia, hypotension, hypothermia, urinary
retention)
Afebrile
No cognitive or sensory defects (other than
blurred vision)
Botulism
Diagnosis
Testing only available in specialty labs
– Mouse bioassay of blood, stool, vomit,
food for toxin (results in 1-2 days)
– Culture of stool (results in 7-10 days)
Electromyogram
Common misdiagnoses: Guillain-Barré
syndrome, myasthenia gravis, stroke,
intoxication, tick paralysis
Botulism
Equine Antitoxin Treatment
Give as soon as diagnosis made to decrease
severity and further damage
– Does NOT reverse existing paralysis
Available from CDC via state health depts.
Antibodies against toxins A, B, and E
Dose: 1 10-mL vial given by IV infusion +
2nd vial given IM
– First skin test and desensitize if necessary
Botulism
Supportive Treatment
Fluid and nutrition support
Mechanical ventilation
Antibiotics for secondary infections
– Avoid aminoglycosides, tetracyclines, and
clindamycin
? Role for activated charcoal
? Botulism immune globulin (BIG)
Tularemia
Francisella tularensis
From http://www.denniskunkel.com/
Tularemia
Epidemiology
MMWR 2002; 51:183
Tularemia
Epidemiology
Routes of human transmission
–
–
–
–
–
Bites by infected insects
Handling infectious animals
Contact with infected food, water, soil
Aerosol inhalation
NOT contagious from person to person
Clues to intentional release
– Abrupt onset of large numbers of people with febrile, mild
respiratory illness, many of whom progress to lifethreatening pneumonitis ± sepsis
– Young, healthy people affected
– Multiple cases in urban setting
Tularemia
Clinical Manifestations
Ulceroglandular, glandular, oculoglandular disease
Oropharyngeal tularemia
Pneumonic tularemia
Typhoidal tularemia
Septic tularemia
Tularemia
Diagnosis
Routine Gram staining and culturing
will miss tularemia
Direct microscopic examination of
infected fluids or tissues
Confirmed by special culture media
– Results may take 10 days
– Special safety precautions necessary
Other tests available at reference labs
Tularemia
Treatment
Preferred: streptomycin 1 Gm IM q12h
OR gentamicin 5 mg/kg IV/IM q24h
Alternatives:
– Doxycycline 100 mg IV/PO q12h
– Ciprofloxacin 400 mg IV q12h OR
500 mg PO q12h
– Chloramphenicol 15 mg/kg IV q6h
Tularemia
Treatment
Duration of therapy:
– Aminoglycoside or quinolone: 10 days
– Doxycycline or chloramphenicol: 14-21 days
– Mass casualty setting (Rx entirely PO): 14 days
Pediatrics:
– Same agents as for adults
– Strepto., gent., doxy., cipro. dosing as for plague
– Chloramphenicol 15 mg/kg q6h
Tularemia
Prophylaxis
Live, attenuated vaccine is not currently available
– Previously available to lab workers, others at high risk
– Would NOT be useful as post-exposure prophylaxis
Post-exposure antibiotics
– Recommended for persons known to have had high-risk
exposures and who are identified during incubation period
Oral doxycycline or ciprofloxacin x 14 days
– If exposure is unclear, start treatment for persons who
develop fever or flu-like illness within 14 days