Download Greg Gray`s final slides - 2

Agents of Bioterrorism We are
Most Likely to Encounter
Grand Rounds Series
February 21, 2002
Agents of Bioterrorism
We are Most Likely to
Encounter
Gregory C. Gray, MD, MPH
University of Iowa
College of Public Health
Department of Epidemiology
Photo from WWW.Washingtonpost.com
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“…Our Committee office was shut down yesterday
and again today because of its proximity to Sen.
Daschle’s office and our staff had to undergo
testing. Mr. Chairman, your own personal office
was shut down. Clearly we no longer have the
luxury of time to deal with the bioterrorism threat
and our government’s response. The challenge we
have before us now is to determine how we can, at
the federal level, best prepare our country for
chemical and biological attacks.”
Senator Fred Thompson October 17th, 2001
For less than $5 in mailing costs….
• Shut down our government
• Caused 11 cases of pulmonary anthrax with 5
deaths
• Caused 11 cases of cutaneous anthrax
• Caused thousands of persons to receive a
60-day antibiotic prophylactic regimen
• Caused billions of dollars in response cost
• Created fear and concern among the US
general population
http://abcnews.go.com/sections/us/terrorism_groups/
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NY Times 10/14/01
Many potential agents of bioterrorism are
endemic to areas where terrorists may dwell…
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Anthrax
Dengue
Q fever
Brucellosis
Cholera
West Nile virus
Rift Valley fever virus
Chikungunya virus
Yellow fever virus
Oldfield EC, Rodier GR, Gray GC. Endemic infectious diseases of Somalia. Clin
Infect Dis 1993;16(suppl 3):S132-157.
Ideal Biological Warfare Agents
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Inexpensive
Easy to produce
Aerosolized (1 to 10um diameter)
Survives sunlight, drying, and heat
Causes lethal or disabling disease
Results in person-to-person transmission
Has no effective therapy or prophylaxis.
Osterholm, MT. Bioterrorism: A real modern threat. In Emerging Infections 5. Scheld WM,
Craig, WA, and Hughes JM eds. ASM Press, Washington, DC. 2001. Pps 213-222
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Russian Bioweapons Program
• 25,000 and 32,000 people were employed in
a network of 20 to 30 military and civilian
laboratories and research institutions
• 40,000 metric tons of bioagents were
produced; much was weaponized
• The program was supposedly dismantled in
1992
Preston R. Annals of Warfare New Yorker 1998 March; Alibek K Biohazard Random House, NY, NY
2000; Emerg Infect Dis 1999;5:523-27.
Russian Bioweapons Program
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Smallpox
Anthrax
Plague
Equine encephalitis
viruses
• Tularemia
• Marburg virus
• Q fever
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Typhus
Melioidosis
Foot and mouth virus
African swine fever
virus
• Trichothecenes
mycotoxins
• Glanders
•Alibek K Biohazard Random House, NY, NY 2000
•Kortepeter MG, Parker GW. Potential Biological Weapon Threats Emerg Infect Dis 1999;5:523-27.
•Preston R. Annals of Warfare New Yorker 1998 March
Iraq’s Bioweapons Program
• Anthrax
• Congo-Crimean
hemorrhagic fever
virus
• Yellow fever virus
• Enterovirus 17
• Human rotavirus
• Trichothecenes
mycotoxins
• Botulism toxin
• Clostridium
perfringens
• Aflatoxin
• Ricin
• Camelpox
• Wheat cover smut
JAMA 1997;278:418-424
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Emerg Infect Dis 2002; 8:225-9
Public Health Assessment
• Many diseases caused by bioterrorism
actions will initially present with
nonspecific clinical symptoms
• Our responsibility is to be informed
regarding biowarfare threats and to
weigh this information along with clinical
and epidemiological data
Variola major
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History – first used as a biological warfare agent in the French
& Indian Wars (1754-1767) when British forces in North
American gave soiled blankets to the Indians
Endemic – Eradicated from US in 1949 and from the rest of the
world in 1977; held only in reference laboratories in United
States and Russia; thought that North Korea and Iraq may have
isolates for weapons program
Zoonotic reservoirs - none
Weaponized by Russia in a program that was supposedly
dismantled in the early 1990s
Transmission – aerosolized and contact with linens; human to
human transmission (close contact) after development of rash
Infective dose (aerosol) -10-100 organisms
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Variola major
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Incubation – 7-17 days
Attack rates – 30% of close contacts
Duration of illness – up to 4 weeks
Lethality – 30% mortality
Vaccines – Vaccinia (similar virus) used successfully for many
years; US has a supply of 15.4 million doses (78 million with
dilution) vaccines; should be given within 7 days of exposure;
new vaccines are under IND status.
Vaccine policy – last childhood vaccines given in 1972; last
military trainees received vaccines about 1989.
Immunoprophylaxis – None available save for vaccine;
vaccinia immune globulin (VIG) requires large dose (42ml / 70kg
man) is reserved for infections and vaccine reactions
Chemoprophylaxis – Animal studies indicate that cidofovir
might be useful (not FDA approved) as a postexposure
prophylaxis
Smallpox
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Clinical presentation
– After 12-14 days of incubation (range 7-17 days) patient develops
high fever, malaise, headache, backache and prostration. Patient
may also have severe abdominal pain and delirium. Soon there
after a maculopapular rash develops first on the oral mucosa, face,
forearms, trunk and legs.
– Within 1-2 days the rash becomes vesicular and later pustular.
Crusts begin to form about the 8th days of rash.
– Severe forms (hemorrhagic and malignant variola) have higher
mortality
Diagnosis
– Generally suspected clinically due to dense rash on the face and
extremities, palms and soles; skin lesions evolve at the same rate
(in contrast to varicella)
– Virus EM and PCR (dermatological lesions swab) – requires BSL4
lab
Management
– Supportive care with antibiotics if secondary bacterial infections
occur, isolation with precautions if hospitalized; in an epidemic
convalescence at home with vaccination of close contacts may be
required; bed linens can infect others.
3rd day of rash
5th day of rash
7th day of rash
From Medical Aspects of Chemical and Biological Warfare- Textbook of Military Medicine. Washington, DC: US
Department of the Army, Office of the Surgeon General, and Borden Institute; 1997: 666.) Reprinted with permission
from Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID. Smallpox and Its Eradication. Geneva, Switzerland: World
Health Organization; 1988: 10–14. Photographs by I. Arita.
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Smallpox vs. Chickenpox
Variola
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Incubation
Prodrome
Distribution
Progression
Scab formation
Scab separation
7-17 days
2- 4 days
centrifugal
synchronous
10-14 d p rash
14-28 d p rash
Varicella
14-21 days
minimal/none
centripetal
asynchronous
4-7 rash
<14 rash
Smallpox Case Studies
• 1947 New York – businessman traveling from
Mexico to New York City developed disease; NY
was near hysteria; 2 smallpox deaths; 6 vaccine
deaths; >6 million people vaccinated in less than
a month.
• 1970 Germany – electrician returned from
Pakistan developed disease and infected 19
other patients in the hospital some 2 floors
above his bed; 100,000 persons vaccinated
• 1972 Yugoslavia – man returned from a trip to
Saudi Arabia and caused 140 cases into 25
villages in Kosovo; 18 of the 20 million
population vaccinated
Baltimore Sun 10/27/01
Smallpox vaccination
with bifurcated needle
• Needle inserted in
vaccine ampoule
• 15 strokes of needle in
a 5mm diameter area
• Trace of blood should
appear in 15-30
seconds at the site
JAMA 1999;281:2134
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Smallpox Vaccination Morbidity
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Inadvertent inoculation
Progressive vaccinia – vaccinal lesion
spreads; often fatal; military trainee with
HIV successfully treated with VIG and
ribavirin
Generalized vaccinia - 2nd eruption 7-9
days post vaccination; bloodborne
Eczema vaccinatum – Eczematous
reaction; can be serious
Postvaccine encephalitis 1/300,000
Bacillus anthracis
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Endemic – Throughout the world but disease is uncommon in the
developed world. Primarily a disease of herbivores; an occupational
disease for wool sorters;
Natural Disease – Three forms: pulmonary; cutaneous,
gastrointestinal. Pulmonary 18 cases in the US 1900-78; cutaneous
224 cases reported in US 1944-94. Gastrointestinal exceedingly rare.
Pathogen – Bacillus anthracis, Gram-positive rod, easy to grow, forms
1-5 µm spores
Weaponized by the United States under a program that was
discontinued in 1969; weaponized by Russia and Iraq
Transmission – Aerosolized threat; No human to human transmission
Infective dose (aerosol) – ? (formerly thought to be 8-10K spores)
Strains – some strains more virulent than others; laboratory
experiments suggest that antibiotic resistant strains (tetracycline and
penicillin) are possible.
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Anthrax
• Incubation – 1-6 days (range to 60 days)
• Duration of illness – Respiratory 3-5 days
• Lethality – Without treatment pulmonary
90%, cutaneous 20%
• Vaccines – cell-free filtrate of an attenuated
strain; 6 dose series, 1 manufacturer Bioport
Corp; not available to general public; local
reactions are common 30-60%; serious
adverse effects very rare 1:200,000
Anthrax
• Clinical presentation
– Pulmonary – brief flu-like illness prodrome (fever,
myalgias, malaise); hypoxia and dyspnea with
widening mediastinum on CXR
– Cutaneous – painless papular lesion > vesicular
state > black eschar. Fever, headache, myalgias,
malaise, and regional adenopathy
– Gastrointestinal – severe abdominal pain, fever,
bloody diarrhea, > septicemia
• Diagnosis
– rapid tests, blood culture; Gram-stain of vesicular
fluid
Infectious Diseases
Illustrated,
Lambert & Farrar
Saunders, NY 1992
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Infectious Diseases
Illustrated,
Lambert & Farrar
Saunders, NY 1992
Day 4
Day 7
Day5
Day 10
Photos by P. Brachman, M.D., Emory University, Rollins School of Public Health
Preventing Anthrax After Exposure: Options
• Antibiotic prophylaxis
– Doxycycline
– Ciprofloxacin
For the latest prophylaxis and treatment regimens consult:
http://www.cdc.gov/mmwr
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Preventing Anthrax After Exposure: Options
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Initial recommendation:
Antibiotics for 60 days
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New Option 1:
Antibiotics for 100 days
• New Option 2:
40 more days antibiotics plus vaccine (3
doses over 4 weeks)
Facts about Antibiotics
• To date, no cases of inhalation anthrax
have occurred among 10,000 persons
for whom antibiotic treatment was
recommended or made available
• Side effects are common, but not
usually serious
• Taking all 60 days of antibiotics is
difficult
Facts about Anthrax Vaccine
• What we know was learned from
vaccination of healthy military personnel
• Vaccine is effective, though not 100%
• Vaccine has short-term side effects
– Most are local and go away in days or
weeks
– Serious reactions have been rare
• Long-term vaccine evaluation is
incomplete
• May be associated with birth defects
among vaccinated pregnant women
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Vaccine Side Effects
Mild Problems
• Soreness, redness, or itching where the shot
was given (about 1 out of 10 men, about 1 out
of 6 women)
• A lump where the shot was given (about 1
person out of 2)
• Muscle aches or joint aches (about 1 person
out of 5)
• Headaches (about 1 person out of 5)
• Fatigue (about 1 out of 15 men, about 1 out of
6 women)
• Chills or fever (about 1 person out of 20)
• Nausea (about 1 person out of 20)
Vaccine Side Effects
Moderate Problems
• Large areas of redness where the shot
was given (up to l person out of 20)
Severe Problems
• Serious allergic reaction (very rare less than once in 100,000 doses)
Plague
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Pandemics –
– AD 541 an outbreak began in Egypt spread across Europe
with 40-50% population losses;
– AD 1346 (black death) killed 20-30 million in Europe (1/3
population) over 130 years;
– AD 1855 12 million people died in India and China along
During WWII, a secret group (Unit 731) of the Japanese army
dropped plague infected fleas over China causing human
epidemics.
Studied as a biological weapon by United States until 1969
and recently by the Soviet Union.
Infective dose (aerosol) - <100 organisms
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From http://www.cdc.gov/ncidod/dvbid/plague/world98.htm
Yersinia pestis
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Photo from CDC
Endemic – Vast areas of persistent rodent infections; human disease
often in developing countries
Pathogen – Yersinia pestis, Gram-negative bacillus or coccobacillus
Transmission – natural infection by flea bite (Xenopsylla cheopis)
Natural Disease
– Bubonic plague may lead to primary septicemic plague or rarely
secondary pneumonic plague (with human to human transmission
through aerosol – primary pneumonic plague)
– In the United States 84% of cases have been bubonic, 13%
septicemic, and 2% pneumonic in recent years
Zoonotic reservoirs – wild rodents (especially ground squirrels);
rabbits, hares, carnivores, and domestic cats may transmit disease to
man
Yersinia pestis
• Clinical presentation
– Bubonic – sudden onset of fever chills, weakness
acutely swollen tender lymph node (bubo)
– Septicemic – no buboes, disseminated
intravascular coagulation, necrosis of small
vesicles, and purpuric skin lesions with gangrene
of digits, nose (black death).
– Secondary pneumonia (12% of cases) – severe
bronchopneumonia, chest pain, cough, and
hemoptysis; may be associated with nausea,
vomiting, abdominal pain and diarrhea, meningitis,
and pharyngitis.
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Yersinia pestis
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Incubation – 2-3 days primary pneumonic; 2-8 days bubonic
Duration of illness – pneumonic 1-6 days
Lethality – case fatality %: bubonic 14%, septicemic 22%, and
pneumonia 57% High unless treated within 12-24 hours
Vaccines – US licensed formalin-killed whole bacilli vaccine
was discontinued in 1999; new recombinant vaccine under
study
Immunoprophylaxis – none
Chemoprophylaxis – tetracycline and doxycycline (7 days) for
close contacts of pneumonic plague or exposed with fevers
A, Cervical bubo in patient with bubonic plague; B, petechial and ecchymotic bleeding
into the skin in patient with septicemic plague; and C, gangrene of the digits during the
recovery phase of illness of patient shown in B. CDC Photographs
Yersinia pestis
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Diagnosis
– Stains/culture of sputum,
bubo aspirate, or blood;
rapid antigen detection;
PCR
Management
– Supportive, antibiotics
(streptomycin,
gentamycin, doxycycline,
ciprofloxacin,
chloramphenical)
– JAMA 2000;283:22812290
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Toxins as Biowarfare Agents
• Botulinum toxin from Clostridium
botulism
• Staplococcal enterotoxin B
• Trichothecene mycotoxins
• Ricin
Comparative Lethality and Dose
for Toxins in Mouse Models
Agent
LD50 / Molecular wt
(ug/kg)/ (daltons)
Quantity of toxin
Open-air exposure to
100 km2
Botulinum
0.001 / 150,000
85kg
Ricin
3.0 / 64,000
400 metric tons
USAMRIID. Medical Management of Biological Casualties Handbook February
2001. http://usamriid.detrick.army.mil/
Botulinum toxins from
Clostridium botulinum
• Source – Several toxins (termed A-G) from Clostridium
bacteria; most potent neurotoxins known; 100,000
times more toxic than the nerve agent Sarin
• Iraq produced 19,000L of botulism toxin and
weaponized 10,000L
• Endemic – Worldwide distribution; 3 forms: foodborne,
intestinal, and wound botulism
• Transmission – aerosolized or food borne threat; no
human-to-human; inhalation syndrome is similar to food
borne disease
• Infective dose –0.001 ug/kg is LD50
• Method of Action – blocks neuromuscular
transmission
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Botulinum Toxin
• Detoxified – air (12 hours); sunlight (1-3 hours)
• Incubation – symptoms after inhalation can occur in
12 to 36 hours; low dose exposure delays sxs
• Duration of illness – death can occur in 24-72 hours
• Lethality – high without respirator support
• Vaccines – pentavalent toxoid vaccine is effective in
primates and is under IND status (3 dose series with
annual booster); available only for high risk groups
• Chemoprophylaxis – none
Francisella tularensis
Photo by William Beisel, MD
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Endemic – North American, former Soviet Union states, Europe,
China, Japan
Pathogen – Gram-negative coccobacillus, agent of tularemia
Transmission – natural infection by tick or mosquito bite; handling
carcasses of infected animals; inhalation of dust or drinking
contaminated water; a virulent laboratory hazard
Natural Disease - Often presents as a skin ulcer, ocular disease; if
inhaled symptoms include fever, fatigue, chills, headache, malaise,
pneumonia.
Zoonotic reservoirs – numerous wild animals especially rabbits,
hares, voles, muskrats, and beavers.
Germ warfare – Studied by Japanese during WW II; may have been
used by Russians against the Germans during WW II; studied by the
United States and Russia after WW II as a biological weapon
Infective dose (aerosol) –10-50 organisms
CDC/Emory U./Dr. Sellers
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Francisella tularensis
• Incubation – 1-21 days
• Duration of illness – > 2 weeks
• Lethality – mild disease 5-15% if untreated;
30-60% if untreated pneumonic or severe
systemic forms
• Vaccines – live attenuated vaccine with 80%
efficacy under IND
• Immunoprophylaxis – none
• Chemoprophylaxis – doxycycline or
ciprofloxacin
Francisella tularensis
• Clinical presentation - Depends upon site of infection
can begin as a pulmonary, ocular, ulceroglandular, or
oropharyngeal infection; initial presentation of
pulmonary disease would be flu-like; disease may lead
to sepsis and death
• Diagnosis - Gram-negative bacillus from blood, ulcers,
conjunctiva on special media; serologic testing; direct
antigen testing of sputum or skin ulcer.
• Management
– Supportive, streptomycin, gentamycin, ciprofloxacin
– See JAMA 2001; 285:2763-2773
Hemorrhagic Fevers and Viral Families
Filoviruses
Arenaviruses
Bunyaviruses
Flaviviruses
Ebola Hemorrhagic
Fever
Argentine Hemorrhagic
Fever
Crimean-Congo
Hemorrhagic Fever
Tick-borne
Encephalitis
Marburg
Hemorrhagic Fever
Bolivian Hemorrhagic
Fever
Rift Valley Fever
Kyasanur Forest
Disease
Sabia-associated
Hemorrhagic Fever
Hantavirus Pulmonary
Syndrome
Omsk
Hemorrhagic
Fever
Lassa Fever
Hemorrhagic Fever with
Renal Syndrome
Lymphocytic
Choriomeningitis
Venezuelan
Hemorrhagic Fever
From http://www.cdc.gov/ncidod/dvrd/spb/mnpages/factmenu.htm
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Ebola: Background and Epidemiology
Ebola hemorrhagic fever (Ebola HF) is a severe, often-fatal
disease in humans and nonhuman primates (monkeys and
chimpanzees) that has appeared sporadically since its initial
recognition in 1976.
Three of the four species of Ebola virus identified so far have
caused disease in humans: Ebola-Zaire,
Ebola-Zaire, Ebola-Sudan,
Ebola-Sudan, and
Ebola-Ivory Coast.
Coast. The fourth, Ebola-Reston,
Ebola-Reston, has caused disease
in nonhuman primates, but not in humans.
The exact origin, locations, and natural reservoir of Ebola virus
remain unknown.
Likely endemic in Democratic Republic of the Congo, Gabon,
Sudan, the Ivory Coast, and Uganda
From www.cdc.gov
Ebola Outbreaks
From http://www.mindspring.com/~cinque/ebola.html
Ebola: Background and Epidemiology
Primary human infection likely due to animal contact
Secondary infections have been associated with direct contact
with the blood and/or secretions of an infected person.
person.
Nosocomial infection has been common.
Initial symptoms include: high fever, headache, muscle aches,
stomach pain, fatigue, diarrhea sore throat, hiccups, rash, red
and itchy eyes, vomiting blood, bloody diarrhea. Within days:
chest pain, shock, blindness, bleeding, and death.
Incubation period: 2-21 days
No effective treatment is known. Mortality is 50-90%. A vaccine
is under development.
development.
From www.cdc.gov
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Epidemiologic Clues of a Biowarfare Attack
• Large epidemic with similar disease in a discrete
population
• Many cases of unexplained disease
• More severe disease than expected
• Disease unusual for the population
• Disease normally transmitted by a vector uncommon
in your area
• Uncommon disease
• Unusual strains of pathogens
From USAMRIID’s Medical Management of Biological Casualties
Handbook, 2001
Published Wednesday, October 10, 2001
Dade overwhelmed with `powder' calls
Most prove to be hoaxes
Published Wednesday, October 10, 2001
Anthrax fear close to epidemic level
Published Wednesday, October 10, 2001
A RASH OF FALSE ALARMS
Calls put strain on county teams
``From where the disease is at this point,
probably the panic is more dangerous than the
actual disease,'' said David Roach, administrator
of the Broward County Health Department.
October 10, 2001 Miami Herald
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In 1918 influenza pandemic Camp Funston, Kansas
References
Univ of Iowa COPH - http://www.public-health.uiowa.edu/icphp/index.html
Iowa DPH - http://www.idph.state.ia.us/Terrorism/default.htm
Alibek K, Haldelman S. Biohazard : The Chilling True Story of the Largest
Covert Biological Weapons Program in the World-Told from Inside by the
Man Who Ran It. Random House, Inc. New York, NY 1999.
USAMRIID. Medical Management of Biological Casualties Handbook February
2001. http://usamriid.detrick.army.mil/
CDC - http://www.bt.cdc.gov/
American Society Microbiology - http://www.asmusa.org/pcsrc/bioprep.htm
JHU - http://www.hopkins-biodefense.org/
California DHS - http://www.dhs.ca.gov/ps/dcdc/bt/index.htm
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