BIODEFENSE

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BIODEFENSE Epidemiology of Smallpox Shahid
Beheshti University of medical sciences,
2008 By Saghari H. MD. MPH Hatami H. MD. MPH
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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 IRAN case 1972 (1351) in Shiraz
• Last international case 1978
• Declared eradicated in 1979

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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
• Relatively high mortality
• Relatively 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 population 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
• Range 7-17 days
• Typical 10-14 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
• 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

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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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Modified Discrete Semi
Confluent Confluent Flat Hemorrhagic
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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 (and USA 2003)

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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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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 10-14 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
• 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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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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Clinical Features

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

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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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Confluent Type of Classical
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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

• 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
• Electron microscopy
• Culture on chick membrane
• Nucleic Acid Testing
• PCR
• Multiplex assays
• Real time PCR
• Histopathology and Immunohistochemistry

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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 eruption 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
• PCR, multiplex assays, real time PCR

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Diagnosis

• Histopathology and Immunohistochemistry
• Poxvirus inclusion bodies can be presumptively
  identified in hematoxylin and eosin (HE)-stained
  specimens using light microscopy
• B-type inclusion bodies are readily observed in
  HE
• Histopathologic staining of tissues for
  evaluating if orthopoxvirus

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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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Differential Diagnosis

• Chickenpox (varicella)
• Vesicles shallow, in crops, varied stages
• Centripetal, spares palms/soles
• Other orthopox viruses
• Monkeypox only in Africa, monkey contact, USA
  (2003)
• Vaccinia after exposure to vaccine
• Cowpox rare, only in UK

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Monkeypox

• Enzootic circulation in rainforestsof central
  and western Africa
• Arboreal squirrels and monkeys
• Transmissible to humans
• Direct contact with infected animals
• Airborne transmission possible
• Human-to-human transmission rarely can occur

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Monkeypox in Humans

• Smallpox-like syndrome
• Generalized rash that progresses to vesicles and
  pustules

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Monkeypox in Humans

• Direct contact with infected animals
• Airborne transmission possible
• Human-to-human transmission (Rarely) can occur
• Short duration

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Generalized Vaccinia
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Differential Diagnosis
Varicella (Chickenpox)
Chickenpox in an infant. Notice the rose-colored
macules, papules, vesicles, pustules, necrotic
pustules, and crusted lesions occurring
simultaneously.
Chickenpox on the hand. Notice the simultaneous
occurrence of lesions in different stages of
development.
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Differential Diagnosis
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Differential Diagnosis
Herpes Zoster (Shingles)
Varicella zoster on the face. Notice the
dermatomal distribution of the papules, vesicles,
and pustules.
Herpes (varicella) zoster on the arm. Notice the
characteristic grouping of vesicles
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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

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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

• 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

• 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
• 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

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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