Biological Terrorism

1

Biological Terrorism Smallpox
5/9/01
2
History

• Caused by variola virus
• Most deaths of any infectious disease
• 500 million deaths in 20th Century
• 2 million deaths in 1967
• Known in ancient times
• Described by Ramses
• Natural disease eradicated
• Last U.S. case 1949 (imported)
• Last international case 1978
• Declared eradicated in 1979

Photo National Archives
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Bioweapon Potential

• Features making smallpox a likely agent
• Can be produced in large quantities
• Stable for storage and transportation
• Known to produce stable aerosol
• High mortality
• Highly infectious
• Person-to-person spread
• Most of the world has little or no immunity

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Bioweapon Potential

• Prior attempted use as bioweapon
• French and Indian Wars (1754-1767)
• British gave Native Americans infected blankets
• Outbreaks ensued, some tribes lost 50
• Allegations of use in U.S. Civil War
• Alleged use by Japanese in China in WWII

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Bioweapon Potential

• Current concerns
• Former Soviet Union scientists have confirmed
  that smallpox was successfully weaponized for use
  in bombs and missiles
• Active research was undertaken to engineer more
  virulent strains
• Possibility of former Soviet Union virus stock in
  unauthorized hands

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Bioweapon Potential

• Nonimmune population
• lt20 of U.S. with substantial immunity
• Availability of virus
• Officially only 2 stocks (CDC and Russia)
• Potential for more potent attack
• Combined with other agent (e.g. VHF)
• Engineered resistance to vaccine

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Bioweapon Potential

• Delivery mechanisms
• Aerosol
• Easiest to disperse
• Highest number of people exposed
• Most contagious route of infection
• Most likely to be used in bioterrorist attack
• Fomites
• Theoretically possible but inefficient

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Epidemiology

• All ages and genders affected
• Incubation period
• From infection to onset of prodrome
• Range 7-17 days
• Typical 12-14 days

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Epidemiology

• Transmission
• Airborne route known effective mode
• Initially via aerosol in BT attack
• Then person-to-person
• Hospital outbreaks from coughing patients
• Highly infectious
• lt10 virions sufficient to cause infection
• Aerosol exposure lt15 minutes sufficient

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Epidemiology

• Person-to-person transmission
• Secondary Attack Rate (SAR)
• 25-40 in unvaccinated contacts
• Relatively slow spread in populations (compared
  to measles, etc.)
• Higher during cool, dry conditions
• Historically 3-4 contacts infected
• May be 10-20 in unvaccinated population
• Very high potential for nosocomial spread
• Usually requires face-to-face contact

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Epidemiology

• Transmission via fomites
• Contaminated hospital linens/laundry
• May have been successfully used as weapon in
  French-Indian War

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Epidemiology

• Infectiousness Rash is marker
• Onset approx one day before rash
• Peaks during first week of rash
• ? Carrier state possible
• Some data show virus detectable in saliva of
  contacts who never become infected
• Unclear if they can transmit infection, but
  theoretically possible

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Epidemiology

• Infectious Materials
• Saliva
• Vesicular fluid
• Scabs
• Urine
• Conjunctival fluid
• Possibly blood

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Epidemiology

• Role of index case severity
• Does not predict transmissibility
• Does not predict severity of 2 cases
• Role of prior vaccination
• Immunity wanes with time
• Maintain partial immunity for many years
• Partial immunity reduces disease severity
• Reduces transmissibility (less virus shed)

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Epidemiology

• Mortality
• 25-30 overall in unvaccinated population
• Infants, elderly greatest risk (gt40)
• Higher in immunocompromised
• May be dependent on ICU facilities
• Dependent on virus strain
• Dependent on disease variant

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Epidemiology

• Factors that allowed smallpox eradication
• Slow spread
• Effective, relatively safe vaccine
• No animal/insect vectors
• No sig. carrier state (infected die or recover)
• Infectious only with symptoms
• Prior infection gives lifelong immunity
• International cooperation

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Microbiology

• Variola virus the agent of smallpox
• Orthopoxviridae family
• 2 strains of variola
• Variola major
• Variola minor
• Vaccinia
• Used for current vaccine
• Namesake of vaccine
• Cowpox used by Jenner in first vaccine
• Monkeypox rare but serious disease from monkeys
  in Africa

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Microbiology

• Variola major
• Classic smallpox
• Predominant form in Asian epidemics
• Highest mortality (30)

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Microbiology

• Variola minor
• Same incubation period, mode of transmission,
  clinical presentation
• Causes milder disease
• Less severe prodrome and rash
• Mortality 1
• Discovered in 20th century
• Started in S. Africa
• Was most predominant form in N. America

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Microbiology

• Environmental survival
• Longest (gt24hr) in low temp/low humidity
• Inactive within few hours in hi temp/humidity
• Dispersed aerosol
• completely inactivated within 2 days of release

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Pathogenesis

• Virus lands on respiratory/oral mucosa
• Macrophages carry to regional nodes
• Primary viremia on Day 3
• Invades reticuloendothelial organs
• Secondary viremia on Day 8

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Pathogenesis

• White Blood Cells infected
• WBCs migrate capillaries, invade dermis
• Infects dermal cells
• Influx of WBCs, mediators cause vesicle
• Systemic inflammatory response
• Triggered by viremia
• Sepsis, multiorgan failure, often DIC

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Pathogenesis

• Severity of disease
• Not influenced by severity of source case
• Probably related to degree of viremia
• Inoculation dose
• Longer exposure, higher concentration at release
• Virulence of variola
• strain, engineered resistance
• Host immune status
• Type of rash predictive of outcome
• More severe rashes poorer outcomes

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Clinical Features

• Three stages of disease
• Incubation
• Asymptomatic
• Prodromal
• Nonspecific febrile illness, flu-like
• Eruptive
• Characteristic rash

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Clinical Features

• Incubation Stage
• From time of infection to onset of symptoms
• Average 12-14 days (range 7-17)
• Important for epidemiologic investigation
• Considered non-infectious during this stage
• Virus sometimes culturable

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Clinical Features

• Prodromal Stage
• Common symptoms
• High fever, prostration, low back myalgias, HA
• Occasional symptoms
• Vomiting, abdominal pain, delirium
• Duration typically 3-5 days
• End of stage heralded by mucosal lesions
• Mucosal lesions onset of infectiousness

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Clinical Features

• Eruptive Stage (Rash)
• May start with transient defervescence
• Characteristic rash
• Centrifugal (in order of appearance severity)
• Initially oral mucosa borders pre-eruptive stage
• Head, face
• Forearms, hands, palms
• Legs, soles, /- trunk

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Classic Centrifugal Rash of Smallpox Involving
Face and Extremities, Including the Soles.
Photo National Archives
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Classic Centrifugal Rash of Smallpox Involving
Face and Extremities.
Photo National Archives
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Clinical Features

• Rash stages of development
• All lesions in one region at same stage
• Starts macular, then papular
• Deep, tense vesicles by Day 2 of rash
• Turns to round, tense, deep pustules
• Pustules dry to scabs by Day 9
• Scabs separate

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Classic Smallpox Rash, Demonstrating Same
Development Stage (Pustular) of All Lesions in a
Region
Photo National Archives
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Clinical Features

• Scarring
• From separated scabs
• Fibrosis, granulation in sebaceous glands
• Pink, depressed pock marks
• Prominent on face, usually gt5 lesions
• Permanent

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Clinical Features

• Rash variations
• Sine eruptione variant
• Prodrome without rash
• Clinically less severe

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Clinical Features

• Modified variant
• Previously vaccinated with partial immunity
• Milder rash, better outcome, faster resolution

Photo National Archives
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Clinical Features

• Rash variations
• Ordinary (Classic presentation) variant
• gt90 all cases
• Subdivided based on confluence of lesions
• Discrete (lt10 mortality)
• Semiconfluent (25-50 mortality), most common
• Confluent (50-75 mortality)

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Discrete Type of Classical Smallpox Rash
Photo National Archives
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Confluent Type of Classical Smallpox Rash
Photo National Archives
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Clinical Features

• Rash variations
• Flat (Malignant) variant
• Uncommon
• Prodrome more sudden, severe
• More likely severe abdominal pain
• Rash never forms pustules/scabs
• Leathery in appearance
• Sometimes hemorrhagic or exfoliating
• DDX acute abdomen, hemorrhagic varicella
• gt90 mortality

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Clinical Features

• Rash variations
• Hemorrhagic
• Rare
• Prodrome more acute and severe
• Bleeding diathesis before onset of rash
• Rash is also hemorrhagic
• Pregnant women at highest risk (?immune state)
• Higher risk of transmission (more fluid shedding)
• DDX meningococcemia, DIC
• Mortality 100

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Clinical Features

• In an outbreak setting atypical or variant rashes
  must be considered smallpox until proven otherwise

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Clinical Features

• Complications
• Sepsis/toxemia
• Usual cause of death
• Associated with multiorgan failure
• Usually occurs during 2nd week of illness
• Encephalitis
• Occasional
• Similar to demylination of measles, varicella

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Clinical Features

• Complications
• Secondary bacterial infections uncommon
• Staphylococcus aureus cellulitis
• Responds to appropriate antibiotics
• Corneal ulcers
• A leading cause of blindness before 20th Century
• Conjunctivitis rare
• During 1st week of illness

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Diagnosis

• Clinical diagnosis
• Sufficient in outbreak setting
• gt90 have classical syndrome
• Prodrome followed by rash
• Rarely, variants can be difficult to recognize
• Hemorrhagic mimics meningococcemia
• Malignant more rapidly fatal
• Sine eruptione prodrome without rash
• Partially immune milder, often atypical

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Diagnosis

• Traditional confirmatory methods
• Electron microscopy of vesicle fluid
• Rapidly confirms if orthopoxvirus
• Culture on chick membrane or cell culture
• Slow, specific for variola
• Newer rapid tests
• Available only at reference labs (e.g. CDC)
• PCR, RFLP

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Diagnosis

• Specimen procurement/handling
• By recently successfully immunized person
• Open vesicle with blunt end of blade
• Collect with cotton swab
• Place swab into sealed vacuum blood tube
• Place tube in larger jar, tape lid

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Diagnosis

• Differential Diagnosis
• Chickenpox (varicella)
• Vesicles shallow, in crops, varied stages
• Centripetal, spares palms/soles
• Other orthopox viruses
• Monkeypox only in Africa, monkey contact
• Vaccinia after exposure to vaccine
• Cowpox rare, only in UK

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Treatment

• Management of cases
• Supportive
• Post-exposure prophylaxis
• Vaccine
• Vaccinia immunoglobulin
• Primary prophylaxis
• Vaccine

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Treatment

• Managing confirmed or suspected cases
• No specific effective antiviral treatment
• Supportive care is critical
• Electrolytes / Volume / Ventilation / Pressors
• Antibiotics only for secondary infections
• e.g. S. aureus cellulitis
• Isolation
• Vaccinate (in case diagnosis is wrong)

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Post-Exposure Prophylaxis

• Vaccine
• Protective if given within 3-4 days exposure
• 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
• Very limited supply (at CDC)

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Post-Exposure Prophylaxis

• Antivirals
• Cidofovir
• Limited experimental data
• May be beneficial in first 2 days post-exposure
• Available IV only
• Significant renal toxicity

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Prevention

• Vaccination History
• Variolation
• Inoculation with infectious smallpox
• Scabs or pustular material
• 1 mortality
• Immunized were infectious - outbreaks
• Provided full immunity
• Originated in Eastern countries in ancient times
• Started in U.S. by Rev. Cotton Mather 1721

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Prevention

• Vaccination - History
• Introduced by Jenner
• Inoculated boy with pustular fluid from cowpox
• 1st immunization using virus of similar disease
• Initially passed arm-to-arm
• Also passed syphilis, hepatitis
• Eventually passed calf-to-calf on scarified leg
• Immunity not lifelong

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Prevention

• Vaccine modern times
• Vaccinia virus
• Related to cowpox and variola
• Source calf lymph
• Now cell culture methods available
• Strains
• Lister used by WHO for eradication campaign
• New York Board of Health only U.S. strain
• Newer more attenuated Japanese strain

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Prevention

• Vaccine administration
• Jet gun
• Rapid
• High maintenance
• Bifurcated needle
• High efficacy, sterilizable, simple, rapid
  (1500/day)
• Uses less vaccine
• Mainstay for the WHO eradication campaign

Photo National Archives
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Prevention

• Vaccination policies
• Last mandated in U.S. in 1972
• World travelers until 1979
• Laboratory workers
• Stability
• Freeze-dried lasts decades
• Current stock probably still potent

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Prevention

• Supply
• 7-15 million doses in U.S. as of 1999
• gt20 years old
• Stock controlled by CDC
• Production
• No current active production
• New vaccine production scheduled for 2004

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Prevention

• Vaccine efficacy
• Nearly complete protection for responders
• Effective for all ages except neonates
• Reduces secondary attack rate 10 fold
• Highest efficacy
• Those who are vaccinated 3-4 times
• Successful vaccination in previous 3 years
• Also protects from monkeypox

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Prevention

• Duration of efficacy single dose
• Probably 5-10 years
• Some immunity gt20 years
• Lower morbidity mortality (3 fold)
• Revaccination leads to gt30 years protection
• Neutralizing antibody used as marker

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Prevention

• Successful vaccination reaction (take)
• Pruritic hyperemic papule Day 3-4
• Jennerian vesicle by Day 7-9
• Dries by Day 14
• Marks immunity
• If no vesicle, revaccinate from different lot

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Prevention

• Vaccine adverse effects
• Pregnancy
• Rare fetal vaccinia
• No known malformations
• Mild symptoms nearly universal
• 1º take reaction in all successful vaccinations
• Mild tender axillary lymphadenopathy common
• 70 infants have prolonged fever

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Prevention

• Serious complications
• Occur in 74-250 per million (1/10,000)
• 3-4 fold higher risk in infants lt1 y.o.
• Highest risk in primary vaccinees

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Prevention

• Types of reactions
• Severe cutaneous
• Most common
• Associated with vaccinia viremia
• Encephalitis
• 1 in 300,000
• 25 mortality, survivors usually neuro sequelae
• Similar to measles, varicella
• Fever, headache, lethargy, paralysis, meningitis,
  coma
• No effective treatment

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Prevention

• Types of reactions
• Vaccinia gangrenosum/necrosum
• Original lesion spreads and does not heal
• Mortality 100 in untreated, 20-36 treated
• Highest risk in immunocompromised
• Treatment
• Vaccinia immunoglobulin (VIG)
• Thiosemicarbazone

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Prevention

• Types of reactions
• Eczema vaccinatum
• Vaccinees or their contacts with h/o eczema
• Vaccinial lesions away from inoculation site
• Mortality 30-40 in children lt2yo
• Treatment - VIG reduces mortality 5-fold

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Prevention

• Types of reactions
• Generalized vaccinia
• Distant vaccinial lesions
• 6-9 days after vaccine
• Usually mild, self-limited
• Autoinoculation
• Touching vesicle then others or self (eyes)

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Prevention

• Vaccinia immunoglobulin
• Limited stock available via CDC
• Uses
• Post-exposure prophylaxis
• Vaccine adverse effects very effective
• Pre-vaccine prophylaxis
• Very effective for hi-risk vaccinees
• For all severe adverse effects except
  encephalitis
• Doesnt alter vaccine efficacy

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Prevention

• No absolute contraindications to vaccinate
• Relative contraindications (Hi Risk Groups)
• History of eczema or chronic skin disorder
• Age lt1 y.o.
• Pregnant
• Immunosuppressed (HIV, malignancy)
• Use VIG if hi-risk must be vaccinated

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Prevention

• Summary of vaccine strategy in outbreak (unless
  vaccinated in last 3-5 years)
• All confirmed or suspected cases
• All contacts of confirmed/suspected cases
• All hospital personnel of hospitalized cases
• All other patients in hospital with cases
• Home care-givers
• Mortuary workers handling deceased cases
• Prophylactic VIG for hi-risk groups

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Infection Control

• Vital component of outbreak management
• Transmission is key
• No animal/arthropod vectors
• No known asymptomatic reservoirs
• carrier state hypothetical but not confirmed
• Higher rate in cool, dry conditions

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Infection Control

• Transmission
• Overall secondary attack rate 25-40
• Historically 3-4 cases per index patient
• Outbreak in mostly nonimmune population
• Anticipate 10-20 cases per contact
• All body fluids infectious
• Respiratory secretions main culprit
• Cough dramatically increases transmission

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Infection Control

• Period of infectiousness
• Onset usually 1 day before rash
• associated with mucosal lesions
• sometimes transient defervescense at end of
  prodromal stage
• Lasts until all lesions scabbed over
• Longer duration with more severe cases

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Infection Control

• Isolation of Cases
• Home isolation is preferable
• Avoids nosocomial spread
• Droplet and inoculation protection
• Contact precautions glove, gown, face shield
• Aerosol protection
• Negative pressure room, HEPA filter
• Assign immune persons for care

73
Infection Control

• Management of Case Contacts
• Carefully identify true contacts
• Exposure to a case patient after fever onset
• Contact with secretions OR
• Face-to-face contact OR
• In nosocomial setting with a case
• Includes ALL hospital patients and staff
• Except for nosocomial, large group exposure
  unlikely usually bedridden by fever onset

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Infection Control

• Management of Case Contacts
• Vaccination
• Proven benefit given within 3-4 days of exposure
• Observation for 17 days
• Twice daily temperature check
• Isolation if fever gt 38.0º C

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Infection Control

• Handling of specimens
• BSL4 laboratory containment only
• Disposal of linens/laundry
• Dispose in biohazard containers
• Autoclave before laundering
• Launder in hot water bleach
• Cremation recommended for corpses

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Infection Control

• Surveillance and containment critical
• Correct identification of those at risk
• Conservation of vaccine
• Target only those with true risk
• Limited national supply
• Components
• Aggressive case-seeking
• Aggressive contact-seeking observation

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Decontamination

• Original aerosol release setting
• Likely no decontamination applicable
• Rapid dispersion of virus
• lt6 hours in higher heat, humidity
• Most gone by 24 hours even under ideal conditions
• Completely dissipated by 2 days
• Delayed onset of symptoms (at least 1 week)
• Virus long gone by time of index case recognition
  in covert release

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Decontamination

• If known recent release
• HEPA filtration
• Sterilization of surfaces
• Standard disinfectants such as bleach

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Smallpox Essential Pearls

• Smallpox has been weaponized
• Case fatality will likely approach 30
• Clinical diagnosis
• Asymptomatic incubation period 7-17 days
• Prodrome with high fever 3-5 days
• Eruptive phase with typical rash
• Centrifugal (head, face, hands/palms, feet/soles)
• Vesicles all same stage of development

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Smallpox Essential Pearls

• Highly infectious
• Not infectious prior to fever onset
• Infectiousness starts one day before rash
• Lasts until all lesions scabbed over
• Secondary attack rate 25-40
• Expect 10-20 2º cases per index case
• No specific treatment, only supportive

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Smallpox Essential Pearls

• Case identification isolation essential
• Droplets / secretions (contact isolation)
• Aerosols (negative pressure isolation)
• Isolate at home if possible (quarantine)
• Post-exposure prophylaxis for contacts
• Vaccine (with VIG for hi-risk groups)
• Fever observation x 17days, isolate if gt38.0

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Smallpox Essential Pearls

• Report any suspected smallpox cases to your State
  and Local Health Departments