Bioterrorism The New Threat

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Bioterrorism The New Threat

• Robert A. Wilson, MD
• LTC, CFS, NCANG, MC

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Definition

• Intentional release of a virus, bacteria, or
  toxin upon a population with the purpose of
  causing wide scale illness or death and resulting
  in a state of panic.

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History of Bioterrorism
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History Remote

• 600 BC - Assyrians contaminated enemy wells with
  Rye ergot.
• 1346 - Tartar army catapult bodies of plague
  victims over city walls of Kaffa, Italy.
• French and Indian War - British gave American
  Indians blankets infected with smallpox.

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History Recent

• 1969 - President Nixon halts all U.S. Biological
  Weapons Research.
• 1975 - Convention on the Prohibition of the
  Development, Production, and Stockpiling of
  Bacteriological and Toxin Weapons and on their
  Destruction went into effect.

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History Recent

• 1979 - Sverdlovsk, former USSR - 68 deaths from
  79 cases of inhalational anthrax follows
  accidental release of aerosolized anthrax spores.
• 1984 - The Dallas, Oregon - 751 cases of
  Salmonellosis, 44 hospitalized after
  Rajneeshpuram cult contaminated 2 local salad
  bars with Salmonella Entiritidis.

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History Recent

• 1995 - Tokyo, Japan - Aum Shinrikyo cult released
  Sarin in subway station. Previous attacks with
  Anthrax and Botulism were unsuccessful.
• 1999 - West Nile Virus outbreak in New York, New
  York. (Possibly due to terrorism)
• 2001 - 12 Cases of Inhalational Anthrax , 5
  deaths following mail-based anthrax attack.

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Impact of an Attack

• 1970 - WHO (World Health Organization) estimates
  250,000 deaths following aerosolized attack with
  50 kg of Anthrax spores over city of 5 million.
• 1993 - U.S. Congressional Office of Technology
  Assessment estimates 1,300,000 to 3 million
  deaths after aerosolized attack of 100 kg of
  Anthrax on Washington D.C..
• Match or exceed Hydrogen Bomb of 1.0 Megaton over
  same area

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Impact of an Attack

• Dark Winter - Biological war game played in
  early part of 2001
• ? Variola Major (smallpox) virus released in
• 3 states.
• ? No disease was detected for 9 days
• ? After 13 days, thousands were infected in
• 25 states and 15 countries.

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Impact of an Attack

• Senator Sam Nunn
• - Senate Defense Expert Observer -
• ?  Raised doubts about U.S. ability to respond
  and contain such an epidemic.
• ?  U.S. hospitals lacked isolation rooms,
  infection control equipment.
• ?  Poor communication between local, state, and
  national officials.
• ? 15 million vaccine doses were inadequate.

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Impact of an Attack

• May 2000 - Exercise in which terrorist sprayed
  concert with plague in Denver, CO.
• 1000 people died but participants were able to
  contain epidemic.
• Wetter et al - Invoke theoretical attack with
  anthrax causes 32,000 deaths.
• Survey of hospital Emergency Departments in 4
  states demonstrate a lack of preparedness for
  effective treatment.

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The Threat

• ? Category A - Agents most likely to cause mass
  casualties if deliberately disseminated
  generally as aerosol.
• ?    Category B - Agents moderately easy to
  disseminate with moderate morbidity and low
  mortality could be used to contaminate
  food/water.
• ?    Category C - Emerging agents that could be
  engineered for mass dissemination.

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The Threat Critical Biological Agents

• CATEGORY A
• Variola major (smallpox)
• Bacillus enthracis (anthrax)
• Yersinia pestia (plague)
• Clostridium botulinum toxin (botulism)
• Francisella tularensis (tularemia)
• Areneviruses
• Lassa (lassa fever)
• Junin (Argentine hemorrhagic fever)
• Filoviruses
• Ebola (ebola hemorrhagic fever)
• Marburg (marburg hemorrhagic fever)

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The Threat Critical Biological Agents

• CATEGORY B
• Coxiella burnetti (Q-fever)
• Brucella spp (burcellosis)
• Burkolderia mattei (glanders)
• Alphaviruses
• Ricin toxin from Ricinus communis (castor beans)
• Epsiton toxin of Clostridium perfingens
• Staphlococcus enterotoxin B
• A subset of Category-B agents includes pathogens
  that are spread by food and water. These
  pathogens include but are not limited to
• Selmonella spp
• Shigella dysenteriae
• Escherichia coli 0157H7
• Vibrio cholerae
• Cryptosporidium parium

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The Threat Critical Biological Agents

• CATEGORY C
• Nipah virus
• Hantaviruses
• Tick-borne hemorrhagic fever viruses
• Tick-borne encephalitis viruses.
• Yellow fever
• Multidrug-resistant tuberculosis
• Preparedness for Category-C agents requires
  research to improve disease detection, diagnosis,
  treatment, and prevention

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Detection

• ED physicians, physicians offices, and clinics
  will be the first responders.
• Epidemiological Warning networks such as
  hospitals, local, state, and national public
  health agencies will collect, analyze, and
  disseminate information.
• EMERGency ID NET and The Food borne disease
  Active Surveillance Network could act as
  framework for syndrome surveillance
• Key to recognition is a high index of suspicion.

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Detection Features Indicative of Bioterrorism

• Multiple simultaneous patients with similar
  clincal syndromes
• Severe illness, especially among the young and
  otherwise healthy individuals
• Predominantly respiratory symptoms (if that was
  the route of attack)
• Unusual (nonendemic) organism(s)
• Unusual antibiotic resistance patterns
• Atypical clinical presentation of disease
• Unusual patterns of disease such geographic
  co-location of victims
• Intelligence information tips from law
  enforcement, discovery of delivery devices, etc.
• Reports of sick or dead animals or plants

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Detection

• Rapid Laboratory Confirmation
• Tier based Laboratory Network
• ? Level A labs refer suspicious isolates and
  samples to higher level county or state
  laboratories.
• ? CDC provides a rapid response and advanced
  technology laboratory.
• - Process samples from suspect cases
• - Provide round the clock diagnostic support to
  bioterrorism response teams.
• - Help maintain chain of custody
• - Assess new rapid diagnostic assays before
  dissemination to laboratory network.

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Detection
Specimen testing and referral
Level D Diagnosis Rare Agents
Training and Consultation
Highest level of Containment and Expertise
Level C Rapid Identification
Level B Agent Isolation
Level A Early Detection
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Epidemiology

• ?  Analyze incoming data from the field perhaps
  through a single nationwide toll free number,
  24-hour hot line.
• ?   Contact appropriate authorities to initiate a
  response to include the FBI, FEMA, OEP, and
  Metropolitan Medical Response System for
  individual cities.
• ?   Rapid dissemination of public health
  information through media
• - Disease prevention information
• - Avoid possible public panic

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Epidemiology

• Roles of National Organizations
• ?  FBI (Federal Bureau of Investigation)
• - Collect evidence for possible arrests and
  prevention of future attacks.
• ?   FEMA (Federal Emergency Management Agency)
• - Coordinates disaster consequence management.
• ?  OEP (Office of Emergency Preparedness)
• - Coordinates all direct medical assistance.
• ?   Metropolitan Medical Response System
• - Teams of local personnel from 120 major
  cities.
• - First responders to a local disaster with
  help of state military units.
• ?    CDC (Center of Disease Control)
• - Provides advice and support to all agencies
  involved.

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Health Care Defense

• ?  Decontamination
• - Not effective or necessary for aerosol
  exposures.
• - Patients may shower at home.
• - Skin contamination - wash patient with soap
  and water, surfaces may
• be washed with dilute bleach (0.5
  hypochlorite)
• ?  Isolation
• - Any patient with respiratory or skin rashes
  should have respiratory
• and contact precautions.
• - Smallpox requires HEPA mask (High Efficiency
  Particulate Air).
• - Pneumonic Plague requires droplet
  precautions.
• - Viral hemorrhagic fevers requires strict
  barrier precautions.

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Treatment of Patients

• Hospitals must have access to pharmaceuticals and
  supplies in large quantities.
• CDC will coordinate regional antibiotic and
  vaccine stockpiles under National Pharmaceutical
  Stockpile Program.
• Push Packs will be delivered by regional
  airlift on 24-hour call.
• Incorporate all public and willing private
  institutions including the VA system.

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Psychiatric Impact

• Survivors of any disaster may require prolonged
  care.
• 1/3 of all hospitalized patients following Tokyo
  Sarin attack suffered psychiatric problems.
• 26 of local population following Three Mile
  Island meltdown suffered from psychiatric
  disorder 18 months later
• Following tragedy, 75 are temporarily
  bewildered, 25 become hysterical or paralyzed by
  fear.

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Psychiatric Impact

• ? Therapists should provide crisis intervention
  to include
• - Psychologic debriefing within hours or days
• - Encourage survivors to verbalize their
  experiences and concerns
• - Spend time with injured and frightened
• - Help reunite children with parents
• - Refer psychiatric disorders for
  hospitalization

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Preparedness Planning and Readiness Assessment

• Current Level of Preparedness not acceptable
• ? Recent study by Wetter et al evaluated US
  hospitals level
• of preparedness for Biological Attack.
• - Only 12 met the studys minimal requirements
  for preparedness.
• - 1/2 of hospitals did not have a
  decontamination unit (Portable or ED).
• - 62 did not have pralidoxime for possible
  sarin attack.
• - Only 1/2 hospitals had enough Cipro or
  Doxycycline for 2-day supply for 50
  patients.
• - Fewer than 20 had plans for
  Biological/Chemical attacks.

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Preparedness Planning and Readiness Assessment

• Necessary steps to enhance Preparedness
• ?  All hospitals require either portable or
  isolated ED decontamination unit.
• ?  Access to large quantities of medication
  locally.
• ?  Respiratory Protection and Chemical protection
  garments.
• ?  Chemical/Biological attack plan with defined
  performance standards.
• ?  Regular training to meet standards.
• PDLS (Physician Disaster Life Support).

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Preparedness Planning and Readiness Assessment

• PDLS
• ?  Types of disaster and Initial Triage
• ?      Prehospital Management
• ?      Hospital Disaster Management
• ?      Terrorism - NBC and conventional.
• ?      Personal/Family Preparedness
•  

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Types of Bioterrorism
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Anthrax
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Anthrax

• Disease produced by Bacillus anthracis.
• High Mortality.
• Relatively easy to manufacture.
• Long term storage in spore form.
• Easy to weaponize and disseminate

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Anthrax

• 3 types of Anthrax
• Cutaneous most common (2000 cases annually)
• GI follows ingestion of insufficiently cooked,
  infected meat
• Inhalational very rare but high mortality
• Commonly occurs in herbivores.
• Wool and goat skin workers traditionally at high
  risk.

Inglesby TV, et al. for the Working Group on
Civilian Biodefense JAMA. 19992811735-1745
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Anthrax Microbiology

• Aerobic, gram positive, spore-forming, nonmotile
  bacillus
• Bamboo rod appearance
• Spores form in nutrient poor environment

Inglesby TV, et al. for the Working Group on
Civilian Biodefense JAMA. 19992811735-1745
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Anthrax Inhalational

• Caused by inhalation of spores
• Pathogenesis
• Deposition of spores in alveolar spaces.
• Macrophages ingest spores.
• Transported via lymphatics to mediastinal lymph
  nodes.
• Leads to release of toxins.
• Causes hemorrhagic mediastinal lymphadenitis
• May cause concurrent hemorrhagic meningitis
• Overwhelming sepsis and shock

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Anthrax Inhalational

• Clinical presentation 2 Stages
• Stage 1
• Mediastinal Widening
• Spectrum of nonspecific symptoms
• Fever, dyspnea, cough, abdominal and chest pain,
  weakness, and vomiting
• Stage 2
• Rapidly fulminant stage
• Fever, dyspnea, cyanosis, meningimus, delerium
• Rapid progression of shock to death
• Mortality rate of 89 in US

Inglesby TV, et al. for the Working Group on
Civilian Biodefense. JAMA. 19992811735-1745
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Anthrax Inhalational

• Physiological Sequella of Severe Infection
• Hypoglycemia/Hypokalemia
• Depression of Respiratory Center
• Anoxia/ Respiratory Alkalosis
• Hypotension/Terminal Acidosis

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Anthrax Cutaneous

• Infection follows deposition into previous wounds
• Pruritic macule progresses to vesicle and then to
  round ulcer (Day 2)
• Forms painless, black escar heals in 1-2 weeks
• Without antibiotics, 20 will develop systemic
  anthrax and die

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Anthrax

• Results from ingestion of insufficiently cooked,
  infected meat
• Oral Pharyngeal or esophageal ulcers
• Can lead to regional adenopathy, sepsis, and
  death.
• Terminal ileum or ceceum
• Causes nausea, vomiting, and diarrhea
• Progresses to bloody, diarrhea, massive ascites,
  acute abdomen and death.

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Anthrax Diagnosis

• Sudden appearance of large number of patients
  with flu-like symptoms and high mortality rate.
• Rapid diagnostic test (Mayo Clinic recently
  developed 5 minute Antigen Assay).
• Recognition of widened mediastrium with
  associated overwhelming flu.
• Sputum or blood analysis gram-positive bacillus
• Post mortem evidence of thoracic hemorrhagic
  necrotizing lymphadenitis or hemorrhagic
  meningitis

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Anthrax Transmission

• Inhalation of spores
• Direct contact
• Ingestion of infected meat
• No person to person transmission

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Anthrax Treatment

• Treat all suspected cases initially with
  Ciprofloxin, Doxycycline,
• or PCN G.
• Delay of antibiotic even for a few hours may
  decrease chance for survival.
• Initial studies on monkeys done with Ciprofloxin
  and Doxycycline.
• Treatment for 60 days Inhibit secondary or
  tertiary infections.

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Anthrax Vaccine

• US Anthrax Inactivated Cell-Free filtrate
  produced by Bioport Corp.
• Principal antigen is the protective antigen.
• A human live attenuated vaccine is produced and
  used in countries of former Soviet Union
• Study of experimental monkeys demonstrated high
  rate of protection.
• 590,000 doses have been given to US Armed Forces
  with minimal side effects and no serious causal
  effects.
• Post exposure vaccination is recommended if
  available after known attack

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Anthrax Treatment of Special Groups

• Children less that 6 years old
• Ciprofloxin initially then change to PCN after
  susceptibility testing.
• Doxycycline should be used initially if
  Ciprofloxin not available.
• Pregnant Women/ Immunocompromised same as
  children

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Anthrax Treatment

• Recent Study by Shin et al, in Cell Biology and
  Toxicology
• Treatment with DHEA (dihydroepiandosterone) and
  melatonin decreased release of TNF (tumor
  necrosis factor).
• TNF is responsible for necrotic lymphadenitis.
• May have a therapeutic role in late infection.

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Smallpox
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Smallpox

• Caused by Variola Major or Minor, large DNA virus
• Routine vaccinations stopped in the United States
  in 1972.
• Declared eradicated in 1980
• Protective Factor vaccine estimated to be
  approximately 10 years
• 15 million doses in United States, 20 million
  stored at WHO

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Smallpox

• Incubation- Usually 12-14 days, Range 7-17 days
• Symptoms
• High fever, myalgias, malaise, vomiting, and
  headache.
• Abdominal pain
• Followed by synchronous rash which progresses
  from

Macules
Papules
Pustular lesions
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Smallpox

• Signs
• Synchronous rash, progresses from extremities and
  face to trunk
• Pocks seen on palms and soles
• Involves mucous membranes
• Transmission
• Person to person, airborne, or direct contact
• Highly transmissible after patient becomes
  febrile or until all lesions resolved

Henderson DA, et al. for the Working Group on
Civilian Biodefense JAMA. 19992812127-2137
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Smallpox Comparsion

• Smallpox
• Palms and soles
• Begins on face/ext
• Synchronous evolution
• Fever and malaise 2-4 days prior to rash

• Chickenpox
• Seldom on palms or soles
• Begins on trunk
• Asynchronous evolution
• No fever prior to rash

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Smallpox Treatment

• Index case and all contacts should be quarantined
  for 17 days or until resolution
• Vaccination recommended within 4 days of exposure
• Vaccine and Vaccina Immune Globulin (VIG)
  recommended if more than 1 week elapsed
• All immunocompromised or exfoliative skin
  disorders should be given VIG
• Cidofir has shown significant in vitro and in
  vivo activity in animals

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Plague
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Plague

• Infectious disease carried by fleas
• Two forms
• Pneumonic
• Bubonic

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Plague Pneumonic

• Spread by droplet through respiratory exposure
• Incubation time 2-3 days
• Symptoms Sudden onset of fever, chills,
  headache, vomiting, diarrhea, purpura, cough with
  hemoptysis
• Signs Bronchopneumonia with patchy or
  consolidated infiltrates
• Progression to sepsis, dyspnea, respiratory and
  circulatory failure
• Death 12-24 hours if not treated

Inglesby TV, et al. for the Working Group on
Civilian Biodefense. JAMA. 20002832281-2290
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Plague Bubonic

• Spread by vector or hemotogenous spread
• Incubation 2-3 days
• Symptoms
• High fever, severe headache, nausea/vomiting and
  rigors
• Altered mentation, abdominal pain, and chest pain
• Signs
• Bubo formation in 6-8 hours especially in groin,
  axilla or cervical areas
• Tachycardia, hypotension, and leukocytosis

Inglesby TV, et al. for the Working Group on
Civilian Biodefense. JAMA. 20002832281-2290
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Plague

• Diagnosis
• Culture of sputum, bubo aspirate, blood, or CSF
• Serum Immunoassays
• Suspect if large numbers of fulminant gram
  negative pneumonia
• Mortality 50

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Plague Treatment

• Streptomycin in 30 mg/kg/day IM daily in 2
  divided doses
• Doxycycline 100 mg po every 12 hours
• Gentamycin 5 mg/kg IV/IM daily
• Chloramphenicol 15 mg/kg IV 4 times per day for
  meningitis
• Prophylactic Doxycycline for known exposure

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Botulism
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Botulism

• Toxin produced by Clostridium Botulinum
• Neurotoxin which blocks release of acetylcholine
• 15,000 times more potent than Sarin gas
• Symptoms
• Cranial nerve palsies such difficulty speaking or
  swallowing
• Descending paralysis, generalized weakness,
  progresses to respiratory failure

Arnon SS, et al. for the Working Group on
Civilian Biodefense JAMA. 20012851059-1070
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Botulism

• Signs
• Dilated or unreactive pupils
• Drooping eyelids
• Diploplia
• Slurred speech
• Descending paralysis with intact mental status
• Transmission
• Aerosol inhalation
• Food ingestion
• No person to person spread

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Botulism Treatment

• Botulinum Equine Antitoxin A, B, C, D, or E.
• Supportive therapy Mechanical ventilation
  Experimental vaccine has been used in high-risk
  lab workers and military
• Vaccine is NOT effective post-exposure
• Decontaminate individuals with soap and water
• Surface decontamination with heat or a chlorox
  solution (bleach)

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Tularemia
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Tularemia

• Aerosolized Francisella Tularenis can cause
  systemic illness and pneumonia
• Incubation 3-10 days
• Symptoms
• Flu-like illness
• Cough with associated pleuritic pain
• Rare hemoptysis

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Tularemia

• Signs
• Bilateral patchy infiltrates with associated
  hilar adenopathy and pleural effusions
• Diffuse, varied rash
• Mortality 35 without treatment
• Transmissions
• Inhalational
• No person to person

Dennis DT, et al. for the Working Group on
Civilian Biodefense JAMA. 20012852763-2773
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Tularemia Treatment

• Live attenuated vaccine available but NOT
  recommended post-exposure
• Gentamycin, Streptomycin, or IV Ciprofloxin once
  symptomatic
• Prophylaxis with Ciprofloxin, Doxycycline, or
  Tetracycline during incubation for possible
  exposure

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Viral Hemorrahagic Fever
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Viral Hemorrhagic Fevers

• Include Ebola, Marburg, Lassa, and Congo Crimean
• Incubation periods vary
• Transmission
• Contact with infected blood or secretions

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Viral Hemorrhagic Fevers

• Symptoms
• Fever/chills, flushing, myalgias, dizziness, and
  headaches
• Nausea, vomiting, and diarrhea
• Petechia, bleeding, and edema
• Signs
• Disseminated Intravascular Coagulopathy (DIC)
• Hypotension and shock
• Mortality 50-80

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Viral Hemorrhagic Fevers

• Intensive supportive care with hemodynamic
  resuscitation.
• Ribarvirin IV Lassa fever
• Investigational vaccine is available.
• Isolation most require anteroom and contact
  precautions.
• Ebola, Marburg, Lassa, and Congo Crimean require
  negative air pressure room, respiratory isolation
  with a HEPA mask, and contact precautions.
• Surfaces should be cleaned with a chlorine
  solution
• Lab specimens double bagged and exterior cleaned.
• Extreme caution with all sharps.

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Role of the Primary Care Physician

• Have a high level of suspicion
• Keep bioterrorism agents in differential
  diagnosis
• Recognize typical bioterrorism syndromes
• Be aware of unusual epidemiologic trends
• Know treatment/prophylaxis of bioterrorism agents
• Know how to report suspected bioterrorism cases

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Questions