The History, Agents, and Potential
Impact of Bioterrorism
David Lakey, M. D.
Associate Professor of Medicine
Chief, Division of Infectious Disease
Medical Director, CPIDC
The University of Texas Health Center at Tyler
The World Has Changed
•
•
•
•
World Trade Center
Anthrax
We are at war
Modern Molecular Biology
Biological warfare vs.
Bioterrorism
• Biological warfare
– Goal:
– History:
Kill a large number of soldiers
Dates to the 6th Century BC
• Bioterrorism
– Goals
• 1) kill a small number of people
• 2) cause panic in the civilian population
• 3) disrupt essential government agencies
– History: the last 20 years
Advantages of Biologics as
Weapons
•
•
•
•
•
Infectious via aerosol
Organisms fairly stable in environment
Susceptible civilian populations
High morbidity and mortality
Person-to-person transmission (smallpox,
plague, viral hemorrhagic fever)
• Difficult to diagnose and/or treat
• Previous development for BW
Advantages of Biologics as Weapons
• Easy to obtain
• Inexpensive to produce
• Potential for dissemination
over large geographic area
• Creates panic
• Can overwhelm medical
services
• Perpetrators escape easily
Vector, Russia
– A large and sophisticated former bioweapons facility
– In the early 1990s
• 4,000-person
• 30-building facility with ample biosafety level 4 laboratory
facilities
• Surrounded by electric fences
• Protected by an elite guard
• Housed the smallpox virus, Ebola, Marburg, and the
hemorrhagic fever viruses
– Autumn of 1997
• A half-empty facility
• Protected by a handful of guards who had not been paid for
months (P. Jahrling, pers. comm., 1998).
• No one can say where the scientists have gone
Henderson DA. Bioterrorism as a public health threat. Emerg Infect Dis 1998;4(3):488-92
Tokyo
March 20 , 1995
• Two small bombs released the nerve gas
Sarin in the subway during the morning
rush hour
• Tokyo fire department responded to a
“bomb”. Many firemen were themselves
harmed.
• 5,510 people harmed, 12 die
• Trial run by Aum Shinrikyo
Aum Shinrikyo
• Mission: End the world as we know it and place
themselves in control
• 40,000 devotees
• Global (Japan, Russia, Europe and the United
States)
• Stockpile of Sarin enough kill 4.2 million people
• Previous attacks included at least 2 prior gassings,
several botulism toxin assaults, and attempts to
kill Japan’s leader with anthrax
• Attempted to acquire and develop Q fever and
Ebola
Salmonellosis Caused by Intentional
Contamination

The Dalles, Oregon in Fall of 1984
 751
cases of Salmonella
 Eating
at salad bars in 10 restaurants
 Criminal
investigation identified perpetrators
as followers of Bhagwan Shree Rajneesh
SOURCE: Torok et al. JAMA 1997;278:389
Shigellosis Caused by Intentional
Contamination
 Dallas,
Texas in Fall of 1996
 12 (27%) of 45 laboratory workers in a large medical
center had severe diarrheal illness
 8 (67%) had positive stool cultures for S. dysenteriae
type 2
 Risk Factor: Eating muffins or donuts in staff break
room implicated
 DNA patterns indistinguishable for stool, muffin, and
laboratory stock isolates
SOURCE: Kolavic et al. JAMA 1997;278:396
Chemical & Biological
Terrorism
1984:
1991:
1994:
1995:
1995:
1997:
1998:
1998:
The Dalles, Oregon, Salmonella (salad bar)
Minnesota, ricin toxin (hoax)
Tokyo, Sarin and biological attacks
Arkansas, ricin toxin (hoax)
Ohio, Yersinia pestis (sent in mail)
Washington DC, “Anthrax” (hoax)
Nevada , non-lethal strain of B. anthracis
Multiple “Anthrax” hoaxes
2001: Anthrax via mail
CDC’s Category A Agents
•
•
•
•
•
•
•
High priority agents
Pose a risk to national security
Can be easily disseminated or transmitted
Cause high mortality
Major public health impact
Public panic and social disruption
Require special public health preparedness
Category A Agents
•
•
•
•
•
•
Anthrax
Plague
Smallpox
Tularemia
Botulinum toxin
Viral Hemorrhagic Fevers
Anthrax
• Bacillus anthracis
– A spore forming bacteria
– Infects sheep, goats, and
cattle
– “woolsorter’s disease”
• Three forms of
Clinical Disease
– Inhalational
– Cutaneous
– Gastrointestinal
The Sverdlovsk Incident
• 1979, Sverdlovsk, Soviet Union
– City of 1 million people
– Accidental aerosolization of anthrax spores from a
microbiology facility
– 79 cases of anthrax, 68 deaths
• Lessons
–
–
–
–
No deaths in patients with cutaneous anthrax
Cases occurred 2 to 43 days after exposure
No decontamination performed
No further cases
Cutaneous Anthrax
• Deposition of spores on skin
with previous cuts or abrasion
• Initially local edema/swelling
of infected area
• Then an itchy bump,
progressing to a blister
• Finally a painless, depressed
scab (eschar)
• Untreated, mortality is 20%
• Treated, mortality is about 0%
Inhalation Anthrax
• Initially non-specific “flulike” symptoms
– Fever, fatigue, chest pain,
muscle aches
• Abrupt onset respiratory
failure staring 2 to 4 days
after presentation
• Chest radiograph findings
• Blood cultures are positive
• Treatable in early stage
Gastrointestinal Anthrax
• Upper GI disease
–
–
–
–
Oral or esophageal ulcer
Regional enlargement of lymphnodes
Edema
Sepsis
• Lower GI Disease
– Nausea, vomiting, bloody diarrhea, acute
abdomen
Plague
• Caused by the bacteria
Yersinia pestis
• About 10 cases of
naturally occurring plague
in US per year
• Incubation period 2-3 days
• Carried by fleas
• Usually lymphnode or
blood infection
• Pneumonic plague if used
by bioterrorist
Plague
Pneumonic Plague
• Signs and symptoms
– High fevers, chills,
headache, coughing up
blood, shortness of breath,
toxic appearing
• Diagnosis
– Staining of sputum (safety
pin Gram negative rod)
• Isolation: Respiratory
• Treatment: antibiotics
(gentamicin, doxycyline, cipro)
• Post exposure
prophylaxis: antibiotics
for 7 days
Smallpox
The History of Smallpox
• Probably originated in agricultural
settlements in NE Africa, China, or the
Indus River Valley as early as 10,000
BC
• Term “smallpox” was coined to
differentiate the disease from the “Great
Pox,” syphilis
• Introduced in the New World by
Spanish conquistadors, it decimated the
local population, was instrumental in
the fall of the Aztec and Inca empires
• Boston (1901-03) epidemic, 1,596 cases
and 270 deaths were reported
 Mummy of Pharaoh
Ramesses V (d. 1157 BC)
showing eruptions
suggestive of smallpox
The Global Eradication of Smallpox
• Ali Maow Maalin, Somalia,
1977
• The world was declared free of
smallpox in December 1979
• One of the greatest triumphs of
public health
• Routine vaccination stopped in
the United States in 1972
Smallpox
• Incubation period of 7 to
17 days
• Clinical Presentation
– Fatigue, headache, vomiting
– Rash
• Diagnosis: clinical
• Isolation: Droplet and
Airborne for 17 days
• Treatment: ?cidofovir
• Prognosis: 30 % mortality
• Prophylaxis:
– Vaccination within 7 days
(live virus)
– Vaccinia immune globulin
Smallpox as a Biological Weapon
• Smallpox was used as a biological
weapon in 1763 during the
Pontiac’s Rebellion in the FrenchIndian War
• “You will do well to try to
inoculate the Indians by means of
[smallpox-infected] blankets, as
well as to try every other method
that can serve to extirpate this
execrable race.” General Jeffrey
Amherst in a letter to Colonel
Henry Bouquet, July 1763
Smallpox as a Biological Weapon
• Infectious, stable via aerosol
• Small infectious dose, severe morbidity
• Discontinuation of routine vaccination and
large-scale vaccine production
• Immunologically naïve population
• Person-to-person transmission
• Relatively simple production techniques
• Recombinant technology: enhanced
virulence
Smallpox as a Biological Weapon
 1972 Biological Weapons Convention
Treaty: response to indiscriminate and
unpredictable biological weapon research
 A signatory to the treaty, the Soviet Union
conducted clandestine research for the next 20
years
 Kanatjan Alibekov, a Soviet biological
weapons expert and defector, claimed that the
Soviets manufactured 20 tons of smallpox
Edward Jenner (1749-1823)
• Jenner inoculated a boy with
fluid taken from cowpox
pustules and exposed him to
smallpox several weeks later
• “Vaccination,” the word
Jenner coined (from the Latin
vacca, for cow), was adopted
by Pasteur for immunization
against any disease
Smallpox Vaccine Supply
• 15.4 million doses of licensed vaccine
• 85 million doses of frozen, not licensed
• Total stockpile = 400 million doses
•
Frey SE, Couch RB, Tacket CO, et al. Clinical responses to undiluted and diluted
smallpox vaccine. N Engl J Med 2002;346(17):1265-74
What is the Risk Benefit Ratio?
Smallpox
Vaccinia
Botulinum Toxin
• A protein produced by the bacteria
Clostridium botulinum
• Paralysis of facial muscles, and then
respiratory muscles
• Treatment
– supportive care
– antitoxin
• No special isolation
Laboratory Capacity for
Botulinum Toxin Testing
1
1
1
1
2
2
1
1
1
11
1 1
1
1
1
1
Tularemia
•
•
•
•
•
•
•
Francisella tularensis
Incubation period: 1 to 21 days
Clinical: Skin, lymphnode or lung infections
Diagnosis: blood tests (serology)
Treatment (Gentamicin, Streptomycin)
Standard isolation measures
Mortality --- treated : low
untreated: moderate
• Persistence of organism ---months in moist soil
Reported Cases of Tularemia - 1990-1998
Hemorrhagic Fever Viruses
• Arenaviruses
–
–
–
–
Argentine Hemorrhagic Fever
Bolivian Hemorrhagic Fever
Sabia Associated Hemorrhagic Fever
Lassa Fever
• Bunyaviruses
– Crimean-Congo Hemorrhagic Fever
– Rift Valley Fever
– Hantavirus Pulmonary Syndrome Hemorrhagic Fever
• Filoviruses
– Ebola Hemorrhagic Fever
– Marburg Hemorrhagic Fever
• Flaviviruses
– Tick-borne Encephalitis
– Kyasanur Forest Disease
– Omsk Hemorrhagic Fever
Hemorrhagic Fever Viruses
• Ebola, Marburg, Lassa
fever, Dengue fever,etc
• Produces microvascular
damage
• Fever, myalgia,
hemorrhaging, shock
• Mortality rate between 5
to 90%, depending on the
virus
• The antiviral medicine
Ribavirin may be effective
• No vaccine
Ocular manifestations associated with hemorrhagic fever viruses range
from conjunctival injection to subconjunctival hemorrhage, as seen in
this patient.
Reprinted with permission from Current Science/Current Medicine (Peters CJ, Zaki SR, Rollin
PE. Viral hemorrhagic fevers. In: Fekety R, vol ed. Atlas of Infectious Diseases, Volume VIII.
Philadelphia, Pa: Churchill, Livingstone; 1997:10.1-10.26).
Modern Molecular Biology and
Bioterrorism
• Dual use technology
– Aerosol technology that allows large insulin molecules
to avoid the respiratory defense and be inhaled deep
into lungs
– Antibiotic resistance
• Novel Pathogens
• Synthetic viruses
• Results are openly published with sufficient
technical detail to allow duplication
Cumulative Number of Reported
Probable Cases of Severe Acute
Respiratory Syndrome (SARS)
Cases
Deaths
•
•
•
•
•
•
•
•
•
China
Hong Kong
China, Tiawan
Singapore
Canada
United States
Vietnam
Phillipines
Total
5327
1755
671
206
250
75
63
14
8437
From: 1 Nov 20021 To: 11 July 2003, 17:00 GMT+2
348
298
84
32
38
0
5
2
813
Economic Consequences of
SARS
• Medical Costs
• Affected tourism, entertainment, restaurant, and
travel industries
• Decreased exports
• Hong Kong’s growth rate decreased from 7% to
6%
• Hong Kong’s financial relief package totals $11.8
billion
• Foreign spending in Canada for Jan-March 2003
is down 5.3%
The Potential Impact of
Bioterrorism
• Martin Meltzer’s, CDC economists, model
• Crop duster spreads anthrax over a city of 100,000
• If prophylaxis begins immediately: (Assumptions:
physicians immediately recognized the problem
and ideal treatments were administered)
• Human cost
• Medical care costs:
• Cost including lost productivity:
5000 lives
$128 million
$3.6 billion
• If prophylaxis begins on day 6:
• Human cots
• Medical care costs
35,000 lives
$26.2 billion
Factors not included in model
• Drug resistant bacteria
• Viruses
– Most not treatable
– They would spread, causing a man made
epidemic
– Note: Smallpox killed 500 million people
during the last century. All the wars combined
killed 320 million.
Other Potential Cost of a
Bioterrorism Attack
• All out panic leading to collapse of the stock
market
• Example
– Surat India, 1994
– Natural occurring plague epidemic following an
earthquake
– 56 deaths an approximately 6,500 cases
– Mass fleeing by physicians and citizens, tourist
cancelled trips, importers banned all flights/goods/ and
citizens from India, and the Bombay Stock Market
crashed
– Cost $2 Billion
Perspective
1) History repeats itself
–
–
This is not the first new infectious disease to
suddenly emerge
This will not be the last new infectious
disease to suddenly emerge
2) “He who does not learn from history is
doomed to repeat it.”
- The public health infrastructure is essential
Infectious Diseases Identified last in 30 years
(partial list)
•
•
•
•
•
•
•
•
•
•
•
Rotovirus
Parvovirus B19
Cryptosporidium
Ebola
Legionella
Hantaan virus
Campylobacter
HTLV I and II
Staphylococcus toxin
E. coli 0157 H7
Lyme
•
•
•
•
•
•
•
•
•
•
•
HIV
H. pylori
HHV-6 (roseola), HHV-7,
HHV-8
Ehrlichia
Hepatitis C
Guanarito
Bartonella
Hantavirus
Sabia virus
BSE
Metapneumovirus
SARS
Other Emerging/ Re-emerging
Infectious Disease
• West nile
• Pertussis
• Tuberculosis
– Multidrug resistant tuberculosis
• Drug resistant bacteria
–
–
–
–
Pneumococcus
Methicillin Resistant Staphylococcus aureus
Gram negative bacteria (ESBLs)
Vancomycin resistant Enterococcus
• Malaria (Drug Resistant Strains)
By Improving the Public Health
Infrastructure You:
• Prepare for man made bioterrorism
– Smallpox
– Plague
– Anthrax
• Prepare for nature made bioterrorism / epidemics
– SARS
– New influenza strains
• Prepare for common infectious diseases
– Tuberculosis
– Meningococcus
– AIDS
• Improve the health of everyone
Lessons Learned from Previous Epidemics
(Dave’s top 10 list)
10)Microbes do not need passports to travel , and do
not respect borders.
– An infectious disease in any part of the world is of
concern to the whole world.
9) Epidemics, and rumors of epidemics, have serious
economic consequences
– Decreased tourism
– Animals may need to be sacrificed
– This leads to decreased reporting.
Lessons Learned from Previous Epidemics
(Dave’s top 10 list)
8) People like to place blame for an epidemic
– Political consequences
7) Epidemics frequently lead to discrimination
against those in whom the disease began.
6) Many people will want to “Do something”, even if
that “something” is unproven, and potentially
dangerous.
5) Health care workers are at the frontlines of
epidemics, and frequently have the highest
casualties.
Lessons Learned from Previous Epidemics
(3)
4) Epidemics frequently start in a remote setting,
spread to a large urban area, and then disseminate
back to the rural areas as people travel.
3) Infection Control is essential
2)Public Health infrastructure is essential to
diagnose and control infectious diseases/
epidemics, but is frequently under funded.
1)Predict the unpredictable.
For More Information
• World Health Organization
http://www.who.int/en/
• Center for Disease Control http://www.cdc.gov
• Texas Department of Health http://www.tdh.texas.gov
• Public Health Education in Emerging Infectious
Disease/ UTHCT
– http://192.88.11.221:82/Links.htm
• Betrayal of Trust: The Collapse of Global Public
Health by Laurie Garrett
Thank you
Normal Reactions to Vaccinia
Immunization
• Soreness at vaccination site
– Mild
– Moderate
– Severe
46%
27%
3%
• Lymphadenopathy
25.0 - 50.0 %
• Myalgia, headache, chills,
nausea, fatigue
• Fever > 37.7° C
0.3 - 37.0 %
2.0 - 16.0 %
Generalized Vaccinia
• Occurs 6 to 9 days
after vaccination
• Usually self limiting
• Rates (per million
vaccinations)
– 241.5 for Primary
Vaccinees
– 9.0 for revaccinees
Autoinoculation
• Rates (per million
Vaccinations)
– 529.2 for primary
vaccinees
– 42.1 for revaccinees
Autoinoculation
Vaccinia keratitis
• Implantation of virus into
diseased or injured conjunctiva
and cornea
• Initially virus replicates causing
ulceration
• An antigen-antibody interaction
follows leading to corneal
cloudiness.
• Results in scarring as the lesion
heals with significant
impairment of vision.
• VIG is contraindicated
• Topical antiviral agents are the
treatment of choice.
Erythema multiforme
• Many vaccinees develop skin
rashes after vaccination, almost
all of which are benign.
• Either toxic or allergic and
require only symptomatic
therapy.
• Stevens Johnson Syndrome
may rarely occur, requiring
more aggressive steroid therapy.
• Recent studies indicate that 5.614.3 percent of adult vaccinees
develop rashes at sites other
than the vaccination.
Eczema vaccinatum
• Dissemination of vaccinia in persons
with preexisting eczema or other
chronic or exfoliating skin
conditions
• Lesions cover all or most of the area
once or currently afflicted by
eczema
• Usually mild or self limited, but
occasionally severe or fatal
• Rates (per million Vaccinations)
– 38.5 for primary vaccinees
– 3.0 for revaccinees
Eczema vaccinatum in contact to
recently vaccinated child
Progressive vaccinia (vaccinia necrosum)
(Patient with chronic granulocytic leukemia)
• Vaccinia lesions fail to
heal and progresses with
associated tissue necrosis
• Necrosis can spread to to
bones and viscera
• Frequently fatal in
immunodeficient
individuals
• Rates (per million
Vaccinations)
– 1.5 for primary vaccinees
– 3.0 for revaccinees
Progressive vaccinia (vaccinia necrosum), which was fatal, in
a child with
an immunodeficiency.
Congenital Vaccinia
• Infection of the fetus in the last
trimester with evidence of
disease in the newborn infant.
• No proven instance of
congenital abnormalities has
been attributed to vaccination
during any stage of pregnancy.
• Some have postulated that
vaccination in the first trimester
results in some fetal loss but
this has not been substantiated.
•Frey SE, Couch RB, Tacket CO, et al. Clinical responses to undiluted and diluted smallpox vaccine.
N Engl J Med 2002;346(17):1265-74
Postexposure Prophylaxis with
Vaccinia (Theoretical)
• Immunity to smallpox develops 8 to 11 days after
immunization with vaccinia
• Incubation period of smallpox is 12 days for
naturally occurring disease
• Therefore vaccination within 4 days of exposure
should confer some immunity and decrease
likelihood of death
• Most beneficial in those immunized sometime in
past
Postexposure Prophylaxis with
Vaccinia (Clinical Experience)
• Italy, 1946
– 21 contacts immunized within 5 days post exposure in
whom smallpox developed all had mild disease
– 31 contacts who were vaccinated 6 to 10 days after
exposure had a case-fatality rate of 19%
• India, 1973
– 34 patients vaccinated during the incubation period
– 4 of 9 (44%) of those immunized 8 days or more
before illness onset died
– 10 of 25 (40%) vaccinated 7 or fewer days before
illness onset died