The History, Agents, and Potential Impact of Bioterrorism

1
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

2
The World Has Changed

• World Trade Center
• Anthrax
• We are at war
• Modern Molecular Biology

3
Biological warfare vs. Bioterrorism

• Biological warfare
• Goal Kill a large number of
  soldiers
• History 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

4
(No Transcript)
5
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

6
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

7
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 19984(3)488-92
8
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

9
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 Japans leader with anthrax
• Attempted to acquire and develop Q fever and Ebola

10
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 1997278389
11
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 1997278396
12
Chemical Biological Terrorism

• 1984 The Dalles, Oregon, Salmonella (salad
  bar)
• 1991 Minnesota, ricin toxin (hoax)
• 1994 Tokyo, Sarin and biological attacks
• 1995 Arkansas, ricin toxin (hoax)
• 1995 Ohio, Yersinia pestis (sent in mail)
• 1997 Washington DC, Anthrax (hoax)
• 1998 Nevada , non-lethal strain of B. anthracis
• 1998 Multiple Anthrax hoaxes
• 2001 Anthrax via mail

13
CDCs 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

14
Category A Agents

• Anthrax
• Plague
• Smallpox
• Tularemia
• Botulinum toxin
• Viral Hemorrhagic Fevers

15
Anthrax

• Bacillus anthracis
• A spore forming bacteria
• Infects sheep, goats, and cattle
• woolsorters disease
• Three forms of Clinical Disease
• Inhalational
• Cutaneous
• Gastrointestinal

16
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

17
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

18
Inhalation Anthrax

• Initially non-specific flu-like 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

19
Gastrointestinal Anthrax

• Upper GI disease
• Oral or esophageal ulcer
• Regional enlargement of lymphnodes
• Edema
• Sepsis
• Lower GI Disease
• Nausea, vomiting, bloody diarrhea, acute abdomen

20
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

21
Plague
22
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

23
Smallpox
24
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
25
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

26
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

27
Smallpox as a Biological Weapon

• Smallpox was used as a biological weapon in 1763
  during the Pontiacs Rebellion in the
  French-Indian 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

28
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

29
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

30
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

31
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 2002346(17)1265-74

32
(No Transcript)
33
What is the Risk Benefit Ratio?Smallpox
Vaccinia
34
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

35
Laboratory Capacity for Botulinum Toxin Testing
36
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

37
Reported Cases of Tularemia - 1990-1998
38
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

39
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

40
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 199710.1-10.26).
41
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

42
(No Transcript)
43
(No Transcript)
44
(No Transcript)
45
(No Transcript)
46
(No Transcript)
47
(No Transcript)
48
(No Transcript)
49
(No Transcript)
50
(No Transcript)
51
(No Transcript)
52
(No Transcript)
53
(No Transcript)
54
(No Transcript)
55
(No Transcript)
56
Cumulative Number of Reported Probable Cases of
Severe Acute Respiratory Syndrome (SARS)
Cases Deaths

• China 5327 348
• Hong Kong 1755 298
• China, Tiawan 671 84
• Singapore 206 32
• Canada 250 38
• United States 75 0
• Vietnam 63 5
• Phillipines 14 2
• Total 8437 813

From 1 Nov 20021 To 11 July 2003, 1700 GMT2
57
Economic Consequences of SARS

• Medical Costs
• Affected tourism, entertainment, restaurant, and
  travel industries
• Decreased exports
• Hong Kongs growth rate decreased from 7 to 6
• Hong Kongs financial relief package totals 11.8
  billion
• Foreign spending in Canada for Jan-March 2003 is
  down 5.3

58
The Potential Impact of Bioterrorism

• Martin Meltzers, 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 5000 lives
• Medical care costs 128 million
• Cost including lost productivity 3.6 billion
• If prophylaxis begins on day 6
• Human cots 35,000 lives
• Medical care costs 26.2 billion

59
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.

60
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

61
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
• He who does not learn from history is doomed to
  repeat it.
• - The public health infrastructure is essential

62
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

63
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)

64
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

65
Lessons Learned from Previous Epidemics(Daves
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.

66
Lessons Learned from Previous Epidemics(Daves
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.

67
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.

68
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.go
  v
• Public Health Education in Emerging Infectious
  Disease/ UTHCT
• http//192.88.11.22182/Links.htm
• Betrayal of Trust The Collapse of Global Public
  Health by Laurie Garrett

Thank you
69
Normal Reactions to Vaccinia Immunization

• Soreness at vaccination site
• Mild 46
• Moderate 27
• Severe 3
• Lymphadenopathy 25.0 -
  50.0
• Myalgia, headache, chills, 0.3 - 37.0
• nausea, fatigue
• Fever gt 37.7 C 2.0 - 16.0

70
(No Transcript)
71
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

72
Autoinoculation

• Rates (per million Vaccinations)
• 529.2 for primary vaccinees
• 42.1 for revaccinees

73
Autoinoculation
74
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.

75
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 5.6-14.3 percent of
  adult vaccinees develop rashes at sites other
  than the vaccination.

76
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

77
Eczema vaccinatum in contact to recently
vaccinated child
78
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

79
Progressive vaccinia (vaccinia necrosum), which
was fatal, in a child withan immunodeficiency.
80
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.

81

• Frey SE, Couch RB, Tacket CO, et al. Clinical
  responses to undiluted and diluted smallpox
  vaccine. N Engl J Med 2002346(17)1265-74

82
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

83
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