Transcript No Slide Title

‫بسم هللا الرحمن الرحيم‬
BIODEFENSE
Epidemiology of
Smallpox
Shahid Beheshti University of
medical sciences, 2008
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By: Saghari H. MD. MPH & Hatami H. MD. MPH
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
– <20% 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 7
Epidemiology
• All ages and genders affected
• Incubation period
1) Range 7-17 days
2) 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
• <10 virions sufficient to cause infection
• Aerosol exposure <15 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
(>40%)
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
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Hemorrhagic
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
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monkeys in Africa (and USA 2003)
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 (>24hr) 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
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• Mucosal lesions onset of infectiousness
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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‫روز هفتم‬
‫‪24‬‬
‫روز پنجم‬
‫روز سوم‬
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
• >90% all cases
• Subdivided based on confluence
of lesions:
– Discrete (<10% 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
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• Mortality 100%
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
1) Clinical diagnosis
2) Electron microscopy
3) Culture on chick membrane
4) Nucleic Acid Testing
1)
2)
3)
PCR
Multiplex assays
Real time PCR
5) Histopathology and
Immunohistochemistry
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Diagnosis
• Clinical diagnosis
– Sufficient in outbreak setting
– >90% 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 33
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 (H&E)-stained
specimens using light microscopy
 B-type inclusion bodies are readily
observed in H&E
 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 rainforests
of 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 on the hand.
Notice the simultaneous
occurrence of lesions in
different stages of
development.
Chickenpox in an infant. Notice
the rose-colored macules,
papules, vesicles, pustules,
necrotic pustules, and crusted
lesions occurring simultaneously.
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Differential Diagnosis
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Differential Diagnosis
Herpes Zoster (Shingles)
Herpes (varicella) zoster
on the arm. Notice the
characteristic grouping of
vesicles
Varicella zoster on the face.
Notice the dermatomal
distribution of the papules,
vesicles, and pustules.
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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 49
1721
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
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• Immunity not lifelong
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
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– Newer more attenuated Japanese strain
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 >20 years
• Lower morbidity & mortality (3 fold)
– Revaccination leads to >30 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 <1 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 <2yo
• 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
–Doesn’t 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 <1 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
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fever onset
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 > 38.0º C
70
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
– <6 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
73
Decontamination
• If known recent release
– HEPA filtration
– Sterilization of surfaces
• Standard disinfectants such as
bleach
74
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
75
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
76
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
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>38.0
Smallpox Essential Pearls
• Report any suspected smallpox cases
to your State and Local Health
Departments
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