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