BIOTERRORISM

Prepared by:
Bella Liza Bantug, BSN, RN, MN,
EMT-B

Definition

Bioterrorism is the use or threatened use of a

biological agent or the product of a biological
agent in order to generate fear, morbidity or
mortality in a population.

HISTORY
Microbial pathogens were used as potential
weapons of war or terrorism from ancient times:
- the poisoning of water supplies in the 6th
century B.C. with the fungus Calviceps
purpurea (rye ergot) by the Assyrians
- the hurling of the dead bodies of plague
victims over the walls of the city of Kaffa by
the Tartar army in 1346
- the spreading of smallpox via contaminated
blankets by the British to the native American
population loyal to the French in 1767.

Key Features of Biologic

Agents Used as
Bioweapons

O High morbidity and mortality

O Potential for person-to-person spread
O Low infective dose and highly infectious by aerosol
O Lack of rapid diagnostic capability
O Lack of universally available effective vaccine
O Potential to cause anxiety
O Availability of pathogen and feasibility of

production
O Environmental stability
O Database of prior research and development
O Potential to be weaponized

CLASSIFICATION

Category A agents are the highest-priority

pathogens:
o can be easily disseminated or transmitted
from person to person
o result in high mortality rates
o have the potential for major public health
impact
o might cause public panic and social
disruption
o require special action for public health
preparedness

Category B agents include those that are

Category C agents include emerging

pathogens
o the general population lacks immunity
o could be engineered for mass
dissemination in the future because of
availability, ease of production, ease of
dissemination
o The recent emergence of novel viruses
leading to outbreaks of severe acute
respiratory syndrome (SARS), Nipah,
hantavirus are examples

Category A agents

Anthrax (Bacillus anthracis)

Smallpox (Variola major)
Plague (Yersinia pestis)
Tularemia (Francisella tularensis)
Botulism (Clostridium botulinum toxin)
Viral hemorrhagic fevers:
Arenaviruses: Lassa, New World (Machupo, Junin,
Guanarito, and Sabia)
Bunyaviridae: Crimean Congo, Rift Valley
Filoviridae: Ebola, Marburg
Flaviviridae: Yellow fever; Omsk fever; Kyasanur
Forest

Category B agents

Brucellosis (Brucella spp.)

Epsilon toxin of Clostridium perfringens

Food safety threats: Salmonella sp., Escherichia coli
0157:H7, Shigella sp.
Water safety threats: Vibrio cholerae, Cryptosporidium
parvum
Glanders (Burkholderia mallei)
Melioidosis (B.pseudomallei)
Psittacosis (Chlamydia psittaci)
Q fever (Coxiella burnetii)
Ricin toxin from Ricinus communis (castor beans)
Staphylococcal enterotoxin B
Typhus fever (Rickettsia prowazekii)
Viral encephalitis

Delivery Mechanisms

Aerosol route
Easiest to disperse
Highest number of people exposed
Most infectious
Undetectable to humans
Food / Waterborne less likely
Larger volumes required
More technically difficult

Roles of Clinicians
General

Concepts
- High level of suspicion
Hoofbeats could be a zebra
- Unusual epidemiologic trends
Case clustering
Severe, fulminant disease in otherwise
healthy
Unusual for the region
Similar disease in animals

Roles of Clinicians
For

specific Bioterrorism (BT) diseases

- Recognize typical BT disease syndromes
- Perform appropriate diagnostic testing
- Initiate appropriate
treatment/prophylaxis
- Report suspected cases to proper
authorities
1) Local health department
2) Hospital epidemiologist
3) Infectious Disease consultants

Anthrax
BACILLUS ANTHRACIS

History

Sporadic disease in 20th century U.S.

Experience as biological weapon
- U.S., 2001
Most letter-associated
22 cases (18 confirmed), 5 deaths
- Sverdlovsk, Russia, 1979
Accidental release from weapons facility
77 cases, 66 deaths

EPIDEMIOLOGY

Forms of disease
- Inhalational (<5% cases; 45-89% mortality)
- Cutaneous (95%; <1-20% mortality)
- Gastrointestinal (<5%; >50% mortality)

Risk Factors
- Exposure to infected animals
- Exposure to aerosolized spores

MICROBIOLOGY

Bacillus anthracis
Aerobic, large Gram positive bacillus
Non-motile, non-hemolytic
Potential mislabeling as contaminant
Forms hardy spores
Triggered by harsh environment
Inert but infectious
1m size

B.ANTHRACIS, FORMING SPORES

Typical, wavy chains of bacilli, appearance like

railway trucks

B. ANTHRACIS TOXINS

Lethal toxin (LeTx): intracellular endopeptidase,

probably directly damages endothelial cells; also
immunosuppressive.

Oedema toxin (ETx): potent adenyl cyclase;

contributes to shock and potentiates LeTx.

Protective antigen: the portion of the binary LeTx

and ETx complexes which mediates attachment
to target cells

Clinical Features - Inhalational

Incubation

- Range 2-43, median 4-7 days

Prodrome
- flu-like - fever, malaise, dry cough
- Nausea, vomiting, diarrhea
- Lack of nasal symptoms
Fulminant
- Respiratory failure, shock, toxemia

Clinical Features - Cutaneous

Most common areas of exposure
Hands/arms
Neck/head
Incubation period
3-5 days (maximum 12 d.)
Mild constitutional symptoms
Systemic disease rare
Lymphangitis/lymphadenopathy
Sepsis, multiorgan failure, death

CLINICAL FEATURES - GI

Oropharyngeal
Oral/esophageal ulcer, regional adenopathy
Edema/stridor, sore throat, fever, sepsis
Intestinal
Early - nausea, vomiting, malaise
Late - hematochezia, acute abdomen, ascites
Differential diagnosis
Gastroenteritis (early)
Any source of acute abdomen, peritonitis (late)

DIAGNOSIS

High index of suspicion necessary

Early diagnosis difficult
Gold Standard - culture blood, fluids
- Prior to antibiotics
Confirmation by reference labs
- PCR, special stains, serology, etc
Nasal swabs not a diagnostic tool

TREATMENT

Hospitalization
IV antibiotics
Empiric until sensitivities known
Intensive supportive care
Electrolyte and acid-base imbalances
Mechanical ventilation
Hemodynamic support
Steroids
Consider for severe disease

TREATMENT
Empiric therapy for inhalational (Adults)
Ciprofloxacin 400 mg IV q12 OR
Doxycycline 100 mg IV q12 AND
One or two other antibiotics
- clindamycin
- penicillin
- vancomycin
- chloramphenicol
- rifampin
- imipenem
- Avoid macrolides, cephalosporins, sulfa

TREATMENT
Empiric therapy for inhalational (Children)
Ciprofloxacin 10-15 mg/kg/d IV q12 (max 1
g/d)
OR
Doxycycline 2.2 mg/kg IV q12 (adult dose
>8yo/45 kg)
AND
One or two antibiotics (same as adult)
- Weigh risks (arthropathy, dental enamel)

TREATMENT
Empiric therapy for cutaneous
Same as inhalational regimen if:
Systemic disease
Extensive edema
Head/neck lesions
Localized cutaneous
Ciprofloxacin 500mg po bid
OR
Doxycycline 100mg po bid
Empiric therapy for GI
Same as inhalational

TREATMENT
Antibiotic therapy all forms
Adjust per sensitivities
Duration
60 days - delayed spore germination
Follow closely after cessation
Switch to oral
Clinical improvement, able to tolerate po
1 or 2 drugs including cipro or doxy initially
Children can complete course with
amoxicillin
No role for vaccine in treatment

Vaccination
o Inactivated, cell-free vaccine
o Effective
- >95% animals vs. inhalational
- Protective for humans vs. cutaneous
o Well-tolerated
- Uncommon adverse effects
- No reported deaths
o Limited supply

INFECTION CONTROL
Person-to-person

transmission
None for inhalational
Rarely reported for cutaneous
Patient handling
Standard precautions
Gloves for draining lesions
Laboratory safety
BSL-2 for clinical specimens
BSL-3 for environmental or large volume

SMALLPO
X
Variola Virus

History

o Ancient scourge many millions killed

o Global eradication in 1977
o Bioweapon potential
Prior use in French-Indian War
Produced by USSR
o Stocks still exist

Epidemiology

No animal reservoir/vector
Mortality 25-30%
Transmission via droplets/aerosol
Person-to-person transmission
Secondary attack rate 25-40%
Up to 3-20 contacts infected
Hi risk of nosocomial spread

Microbiology

Variola virus
- Orthopoxviridae family
Variola strains
Variola major high mortality
Variola minor low mortality, 20th
Century
Vaccinia
Current smallpox vaccine
Other pox viruses (cowpox, monkeypox)

Pathogenesis

Virus contacts respiratory/oral mucosa

Carried to nodes
Viremia
Organ seeding
WBCs infected
Dermal invasion
Vesicle
Sepsis

Clinical Features

Stages of disease
Incubation
o Asymptomatic
o 12-14 days (range 7-17)
Prodromal
o Nonspecific febrile prostrating flu-like
illness
o 3-5 days
Eruptive
o Characteristic rash location, grouping,
depth

Courtesy of National Archives

Courtesy of World Health

Clinical Features

Differential Diagnosis
Chickenpox (varicella)
- Vesicles
Shallow
Asynchronous development
- Distribution of rash
Centripetal
Spares palms/soles

Diagnosis

Clinical
Traditional confirmation
Electron microscopy
Culture
Newer rapid tests
Reference labs (e.g. CDC)
PCR, RFLP

Treatment

No effective antivirals

Supportive care
Fluid balance
Electrolytes
Hemodynamic support
Antibiotics for secondary infections
Isolation

Post-Exposure
Prophylaxis
Vaccine

Reduces incidence 2-3 fold

Decreases mortality by ~50%

Vaccinia immune globulin (VIG)

3 fold decrease in incidence and mortality
Passive immunity for 2 weeks

Cidofovir antiviral agent

Effective vs other poxviruses in animals

Vaccination

Vaccinia virus

Stock
~15million doses
>20 years old, still viable
Efficacy
10 fold reduction secondary attack rate
Substantial protection for 3-10 years
Multiple vaccinations boost duration

Vaccination

Adverse Effects
3/100,000 vaccinees
Death
1/million vaccinees
Highest risk
Primary vaccinees
Infants

Vaccination

Serious complications

Encephalitis
Vaccinia gangrenosum/necrosum
Eczema vaccinatum
Mild complications
Generalized vaccinia
Autoinoculation
VIG can treat/prevent

Fenner F., D. A. Henderson, et al. Smallpox and its

Eradication. Geneva: WHO; 1988. Original photo by C. H.
Kempe.

Infection Control

Isolation of Cases
Contact precautions
- Gloves, gowns
Airborne precautions
- Negative pressure HEPA filtered room,
N95 masks
Home isolation an option
- Avoids nosocomial spread
Assign immune persons for care

Infection Control

Management of Case Contacts

Rash = Infectious, fever precedes rash
Contact identification
Exposure to case patient after fever onset
- Contact with secretions or face-to-face <3
meters
All patients and staff in hospital with a case
Immediate vaccination
Observation (not isolation)
17 day fever watch isolate if >38C
Quarantine may be necessary

Smallpox vs.
Chickenpox
Chicken pox
Smallpox

Incubation 14-21 d

Incubation 7-17d
Severe illness
Prodrome
Headache and back
pain
Centrifugal
Synchronous
Rash not initially itchy
Lesions round
Scabs form 10-14d
Scabs separate 14-28d

Usually mild
Prodrome
Mild malaise
Centripetal
Asynchronous
Rash initially itchy
Lesions oval
Scabs form 4-7d
Scabs separate
<14d

Plague
Yersinia pestis

History
3

Pandemics
Justinian - 6th century Africa/Asia
Black Death 14th century Europe
Worldwide 19th/20th century
Potential for use as bioweapon
Unit 731 Manchuria
Former USSR production

Epidemiology
Distribution

Global ~1700 cases/yr

Southwestern U.S. 5-10 cases/yr

Epidemiology
Forms of Disease
Pneumonic (2-12% of cases)
Inhalation (1) or hematogenous (2)
Mortality 57% (>90% if treatment delayed)
Most likely route for bioterrorism
Bubonic (84%)
Flea bite or animal handling
Mortality <5% (40-60% untreated)
Septicemic (13%)
Mortality 30-50% (>90% untreated)

Microbiology
Enterobacteriaceae

family, Yersinia genus

Y.pestis,Y.enterocolitica,Y.pseudotuberculosi
s
Aerobic Gram negative (cocco)bacillus
Intracellular
Bipolar staining (special stains)
Highly virulent
F1 antiphagocytic capsule
LPS endotoxin

CDC. Available at
http://www.ohd.hr.state.or.us/phl/bt/plague/levelaproced
ures.pdf. Accessed June 21, 2002.

Pathogenesis

Primary pneumonic plague

Organisms inhaled
Lobular
Lobar pneumonia
Pulmonary necrosis
Bacteremia
Multiorgan seeding, failure
Sepsis

Clinical Features
Primary

pneumonic plague
Incubation 1-4 days (range 1-6)
Initial symptoms
Influenza-like syndrome (F/C/HA/myalgias)
N/V/D, abdominal pain common
2nd day
Severe pneumonia cough, hemoptysis, SOB
Multi-organ disease, sepsis
Skin manifestations purpura, acral gangrene
Differential Diagnosis any severe pneumonia

Clinical Features
Bubonic

Plague
Constitutional symptoms
Lymphadenopathy
bubo
May drain
Septicemic Plague
Same flu-like illness progressing to sepsis
No discernible adenopathy

Diagnosis
High

index of suspicion necessary

- No readily available rapid tests
Samples - blood, sputum, CSF, bubo fluid
Preliminary bipolar staining bacilli
Confirmation
Culture requires special biochemicals
Serology retrospective
Rapid tests (PCR, DFA, etc) at reference
labs

Post-Exposure Prophylaxis
Oral

Antibiotics
Doxycycline 100 mg po bid
Ciprofloxacin 500 mg po bid
Duration 7 days
Who should receive PEP?
Exposed to initial aerosol release
Asymptomatic contact of pneumonic
case
Household, Hospital
Within two meters

Vaccination
No

available vaccine in U.S. since 1999

Previous vaccine
Killed virulent strain
Effective versus bubonic only
Minor adverse effects

Infection Control
Pneumonic

Plague
- Respiratory (droplet) isolation
Surgical mask when within 3 feet
- Isolate until treated 48 hours
Must have clinical improvement
Bubonic Plague
- Contact isolation if draining buboes
Specimens BSL-2 (BSL-3 for hi-risk)

Tularemia
Francisella tularensis

HISTORY
Discovered early 20th century
- Tulare county, California
- deerfly fever
Bioweapon potential
- Incapacitating
- Former US and USSR production
- Prior use
Unit 731, Manchuria

EPIDEMIOLOGY
Distribution
- Moderate climates U.S., Europe, Russia, Japan
- 125 annual U.S. cases mostly Midwest
Zoonosis
- Small mammals (rabbits)
Transmission
- Skin contact - e.g. infected animal
- Arthropod bite ticks
- Aerosolization - BT attack; lawn mowers
Mortality
- <2% overall, 30-60% untreated pneumonic

EPIDEMIOLOGY
Forms of disease
- Pneumonic (<5% of cases)
Expected in aerosol release
- Ulceroglandular (45-85%)
- Glandular (5-25%)
- Oculoglandular (<5%)
- Oropharyngeal (<5%)
- Typhoidal (<5-15%)

MICROBIOLOGY
Pleomorphic Gram negative coccobacillus
- Usually not visible in clinical specimens
- Small (0.2 m), aerobic
- Non-motile, non-sporulating
Fastidious
- Slow growth (2-3+ days)
- Requires cysteine-enriched media
2 major strains (A and B)
- A predominates in U.S., higher mortality

PATHOGENESIS
Inoculation virulent organisms
Local infection at site
- Lung bronchiolitis, pneumonitis,
pleuritis
Migrate to regional lymph nodes
Hematogenously seed multiple organs
Suppurative immune response

CLINICAL FEATURES
All forms of disease
Incubation 2-5 days (range 1-21)
Acute onset
Initial flu-like illness
- Fevers, chills, sweats, headache
Lower back myalgias
Pulmonary symptoms
- Cough, dyspnea, chest pain (40%)
Pulse/temperature dissociation (40%)

CLINICAL FEATURES
Pneumonic form
Symptoms
Nonproductive cough, +/- hemoptysis
Dyspnea, pleuritic pain
Chest radiograph
Infiltrates patchy, bilateral
Effusions common
Ulceroglandular form
Ulcer painful maculopapule, pustule, ulcer

CDC/Emory University/Dr. Sellers. PHIL1344

DIAGNOSIS
High index of suspicion
No readily available rapid tests
- Gram stain unhelpful
Gold Standards
- Serology (retrospective)
- Culture (insensitive, hazardous, slow)
Rapid presumptive tests
- DFA, IFA, PCR, IHC at reference labs

TREATMENT
Supportive care
Parenteral antibiotics ASAP
Aminoglycosides
Streptomycin 1 g IM q12
Gentamicin
- Once-daily or traditional dosing
Tetracyclines higher relapse rate
Doxycycline 100 mg IV q12
Tetracycline - oral

TREATMENT
Parenteral antibiotics
Others
Chloramphenicol for meningitis
Ciprofloxacin
Duration of therapy
10 (aminoglycosides) 21 (tetracyclines) days
Switch to oral therapy when clinically improved

POST-EXPOSURE PROPHYLAXIS
Who should receive PEP?
Suspected very recent exposure (<3
days)
Not contacts of cases
Antibiotics
Oral doxycycline or ciprofloxacin
Duration - 14 days
Fever watch without antibiotics
Suspected exposure in last 3-14 days

VACCINATION
Live, attenuated vaccine
Commercially available
- For researchers
No proven efficacy versus pneumonic
Minimal adverse effects

INFECTION CONTROL
No documented person-person spread
- Standard precautions
Laboratory specimens
- Routine handling for clinical specimens
- Alert microbiology lab if tularemia
suspected
Pure culture hazardous to lab personnel
Requires BSL-2 handling with safety
cabinet

Botulism
Botulinim toxin

History
Neurologic disease from botulinum toxin
- Most lethal substance known
History as bioweapon
- Japanese in WWII (Unit 731)
- Former US and USSR programs
- Iraqi deployed weapons
- Japanese cult in early 1990s

Epidemiology
Found worldwide
U.S. incidence
- ~100 cases annually (1/4 foodborne)
Mechanisms of intoxication
- No person-to-person transmission
- Toxin ingestion (foodborne)
- Toxin generated from wound infection
(wound)
- Toxin from intestinal colonization (infant,
intestinal)
- Toxin inhalation (aerosol release)

Microbiology
Clostridium botulinum
Large, anaerobic Gram positive bacillus
Spore-forming
Rarely infects humans
Produces potent neurotoxin
- 7 types (A-G)
- Types A,E,B most common in U.S.
- Same general mechanism

Clinical Features
Incubation 12-72 hours
- Probably faster if inhalational exposure
Classic syndrome
- Acute symmetric cranial nerve palsies
Blurry vision, ptosis, dysphasia
- Descending flaccid paralysis
Complete skeletal muscle paralysis
Respiratory (ventilatory) failure
- Autonomic urinary retention, orthostasis
- Afebrile, normal mentation

Clinical Features
Differential Diagnosis
Myasthenia Gravis anticholinesterase
response
Guillaine-Barre Syndrome - ascending
Stroke asymmetric, abnormal brain imaging
Tick paralysis ascending, presence of tick
Poliomyelitis asymmetric, preceding viral
illness
Other features
Foodborne nausea, diarrhea, dry mouth
Infant - constipation

Diagnosis
High index of suspicion necessary
- No readily available rapid confirmatory
tests
Clinical diagnosis
Laboratory confirmation
- Specimens blood, stool
- At reference labs
- Mouse bioassay
- ELISA

Treatment
Supportive care
Mechanical ventilation, nutritional support
Prevention of secondary infections
Avoid aminoglycosides, clindamycin
Passive immunization (antitoxin)
Halts paralysis, doesnt reverse
Must be given ASAP
Equine antitoxin (Types A, B and E toxins)
- Serum sickness (9%), anaphylaxis (2%)
Heptavalent antitoxin (Types A-G)
- Investigational, less hypersensitivity

Post-Exposure Prophylaxis
Antitoxin not recommended
- High incidence hypersensitivity
- Limited supplies
Clinical monitoring
- Extreme vigilance for symptoms
- At least 72 hours
- Antitoxin immediately for any
symptoms

Vaccination
Botulinum toxoid
No role for post-exposure
prophylaxis
- Immunity develops over months
Excellent efficacy
- Not tested versus aerosol
exposure
Few adverse effects

Infection Control
No person-to-person transmission
Patient handling
- Standard precautions
Clinical specimens
- Standard precautions

C
I
G
A
H
L
R
A
R
R O S
I
V EM R
E
H V
E
F

HISTORY
Variety of viral illnesses
- Similar syndrome with fevers and
bleeding
No known use as bioweapon
Great potential for fear
- High mortality/morbidity
- Attention in media, entertainment

EPIDEMIOLOGY

Multiple RNA viruses, similar syndrome

Filoviruses
- Ebola, Marburg
Arenaviruses
- Junin [Argentinian HF], Machupo [Bolivian HF],
Guanarito [Venezuelan HF], Lassa
Flaviviruses
- Dengue [Dengue HF], Yellow Fever
Bunyaviruses
Hantaviruses [HF with Renal Syndrome], CongoCrimean HF, Rift Valley Fever

EPIDEMIOLOGY

Transmission variable
Endemic (sporadic or epidemic)
Arthropod bites
Contact with infected animals
Person-to-person
Blood, body fluids
- Filoviruses, CCHF, probably arenaviruses

Respiratory route
- Uncommon
- All but dengue infectious as aerosol
Mortality up to 90%

Atlanta, Georgia: Electron Micrograph: Ebola virus causing African

Hemorrhagic Fever. (Courtesy of the National Archives, 82-424)

PATHOGENESIS
Entry
- Mucous membrane, needlestick
Inhaled
Viremia and spread to liver, spleen, lungs
Mucosal shedding preceded by fever
Incubation period 2 days-3 weeks
Vascular endothelium disruption
- Loss of integrity of vascular endothelium
- Edema
Coagualation system defects
- Hemorrhage, fibrin deposition

CLINICAL FEATURES

Early symptoms - Fever, myalgias, malaise

Severity - mild to fulminant
Hallmarks
Disrupted vascular permeability
- Edema, shock in severe cases
Bleeding diathesis
- Mucous membrane hemorrhage, petechiae
Thrombocytopenia, leukopenia, hepatitis
DDX malaria, typhoid, rickettsia, DIC

DIAGNOSIS

High index of suspicion

No readily available rapid specific test
Presumptive
Clinical diagnosis in outbreak setting
Confirmation only at reference labs
Serology
- Retrospective
Culture from blood
- Requires BSL-4 lab
PCR, etc

TREATMENT

Supportive therapy
Volume, electrolyte, hemodynamic
support
Treatment of hemorrhage
Minimize sedation
Ribavirin
Useful for some (CCHF, Lassa)
No useful for others (filo-,flavivirus HFs)

POST-EXPOSURE PROPHYLAXIS

Close monitoring for all

Oral ribavirin
Investigational
CCHF
Lassa fever
No role for vaccination
Immunity takes too long to develop

VACCINATION
Vaccines available
Yellow Fever
Effective for travelers to endemic areas
Safe

Rare adverse effects

Others

in various stages of development

INFECTION CONTROL
All

patients strict isolation

Respiratory droplet precautions
- Surgical mask
Contact (barrier) precautions
- Including face shield or goggles
Those with the highest potential of spread
(severe cough, hemorrhage, diarrhea)
Airborne precautions
- Negative pressure room
- HEPA filtered respirator

REFERENCES
O Web sites
O www.bioterrorism.slu.edu (SLU-CSBEI)
O www.bt.cdc.gov (CDC)
O www.hopkins-biodefense.org/ (JH-CCB)
O www.apic.org (APIC)
O www.usamriid.army.mil (USAMRIID)