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Anthrax
Anthrax: History
Caused by Bacillus anthracis
Human zoonotic disease
Spores found in soil worldwide
Primarily disease of herbivorous
animals
• Sheep, goats, cattle
• Many large documented epizootics
Occasional human disease
• Epidemics have occurred but uncommon
• Rare in developed world
Saint Louis Unversity School of
Public Health
Anthrax: Bioweapon Potential
Many countries have weaponized
anthrax
Former bioweapon programs
• U.S.S.R.,U.S.,U.K., and Japan
Recent bioweapon programs
• Iraq
Attempted uses as bioterrorism agent
• WW I: Germans inoculated Allied livestock
• WW II: Alleged Japanese use on prisoners
Saint Louis Unversity School of
Public Health
Anthrax: Bioweapon Potential
Features of anthrax suitable as BT
agent
Fairly easy to obtain, produce and store
Spores easily dispersed as aerosol
Moderately infectious
High mortality for inhalational (86-100%)
Saint Louis Unversity School of
Public Health
Anthrax: Bioweapon Potential
Aerosol method of delivery
Most likely method expected in BT attack
Would cause primarily inhalational disease
• Spores reside on particles of 1-5 μm size
• Optimal size for deposition into alveoli
• Form of disease with highest mortality
Would infect the largest number of people
Saint Louis Unversity School of
Public Health
Anthrax: Bioweapon Potential
Dispersed as powder
Frequent letter hoaxes since 1997
Recent letter deliveries
• Highest risk is for cutaneous
• Inhalational theoretically possible
– Particle size
– Likelihood of aerosolization
• GI theoretically possible
– Spores > hands > eating without handwashing
Saint Louis Unversity School of
Public Health
Anthrax: Bioweapon Potential
Sverdlovsk, Russia 1979
Accidental release from anthrax drying
plant
79 human cases
• All downwind of plant
• 68 deaths
• Some infected with multiples strains
Saint Louis Unversity School of
Public Health
Anthrax: Bioweapon Potential
Estimated effects of inhalational
anthrax
100 kg spores released over city size
of Washington DC
• 130,000 – 3 million deaths depending on
weather conditions
Economic impact
• $26.2 billion/100,000 exposed people
Saint Louis Unversity School of
Public Health
Anthrax: Epidemiology
Three forms of natural disease
Inhalational
• Rare (<5%)
• Most likely encountered in bioterrorism event
Cutaneous
• Most common (95%)
• Direct contact of spores on skin
Gastrointestinal
• Rare (<5%), never reported in U.S.
• Ingestion
Saint Louis Unversity School of
Public Health
Anthrax: Epidemiology
All ages and genders affected
Occurs worldwide
Endemic areas - Africa, Asia
True incidence not known
World 20,000-100,000 in 1958
U.S. 235 total reported cases 1955-1994
• 18 cases inhalational since 1900, last one 1976
• Until 2001, last previous case cutaneous 1992
Saint Louis Unversity School of
Public Health
Anthrax: Epidemiology
Mortality
Inhalational 86-100% (despite treatment)
• Era of crude intensive supportive care
Cutaneous <5% (treated) – 20%
(untreated)
GI approaches 100%
Saint Louis Unversity School of
Public Health
Anthrax: Epidemiology
Incubation Period
Time from exposure to symptoms
Very variable for inhalational
• 2-43 days reported
• Theoretically may be up to 100 days
• Delayed germination of spores
Saint Louis Unversity School of
Public Health
Anthrax: Epidemiology
Human cases – historical risk factors
Agricultural
• Exposure to livestock
Occupational
• Exposure to wool and hides
• Woolsorter’s disease = inhalational anthrax
• Rarely laboratory-acquired
Saint Louis Unversity School of
Public Health
Anthrax: Epidemiology
Transmission
No human-to-human
Naturally occurring cases
• Skin exposure
• Ingestion
• Airborne
Bioterrorism
• Aerosol (likely)
• Small volume powder (possible)
• Foodborne (unlikely)
Saint Louis Unversity School of
Public Health
Anthrax: Epidemiology
Transmission
Inhalational
• Handling hides/skins of infected animals
• Microbiology laboratory
• Intentional aerosol release
• Small volume powdered form
– In letters, packages, etc
– Questionable risk, probably small
Saint Louis Unversity School of
Public Health
Anthrax: Epidemiology
Transmission
Cutaneous
• Handling hides/skins of infected animals
• Bites from arthropods (very rare)
• Handling powdered form in letters, etc.
• Intentional aerosol release
– May see some cutaneous if large-scale
Saint Louis Unversity School of
Public Health
Anthrax: Epidemiology
Transmission
Gastrointestinal
• Ingestion of meat from infected animal
• Ingestion of intentionally contaminated food
– Not likely in large scale
– Spores not as viable in large volumes of water
• Ingestion from powder-contaminated hands
• Inhalational of spores on particles >5 m
– Land in oropharynx
Saint Louis Unversity School of
Public Health
Anthrax: Microbiology
Bacillus anthracis
Aerobic, Gram positive rod
Long (1-10μm), thin (0.5-2.5μm)
Forms inert spores when exposed to O2
• Infectious form, hardy
• Approx 1μm in size
Vegetative bacillus state in vivo
• Result of spore germination
• Non-infectious, fragile
Saint Louis Unversity School of
Public Health
Anthrax: Microbiology
Colony characteristics
Large (4-5mm)
Non-hemolytic
Opaque white, gray
Retain shape when manipulated (“egg
white”)
Forms capsule at 37º C, 5-20% CO2
Saint Louis Unversity School of
Public Health
Anthrax: Microbiology
Classification
Same family: B. cereus, B. thuringiensis
Differentiation from other Bacillus species
• Non-motile
• Non β-hemolytic on blood agar
• Does not ferment salicin
Note: Gram positive rods are usually
labeled as “contaminants” by micro labs
Saint Louis Unversity School of
Public Health
Anthrax: Microbiology
Environmental Survival
Spores are hardy
• Resistant to drying, boiling <10 minutes
• Survive for years in soil
• Still viable for decades in perma-frost
Favorable soil factors for spore viability
•
•
•
•
High moisture
Organic content
Alkaline pH
High calcium concentration
Saint Louis Unversity School of
Public Health
Microbiology
Virulence Factors
All necessary for full virulence
Two plasmids
• Capsule (plasmid pXO2)
– Antiphagocytic
• 3 Exotoxin components (plasmid pXO1)
– Protective Antigen
– Edema Factor
– Lethal Factor
Saint Louis Unversity School of
Public Health
Anthrax: Microbiology
Protective Antigen
Binds Edema Factor to form Edema Toxin
Facilitates entry of Edema Toxin into cells
Edema Factor
Massive edema by increasing intracellular cAMP
Also inhibits neutrophil function
Lethal Factor
Stimulates macrophage release of TNF-α, IL-1β
Initiates cascade of events leading to sepsis
Saint Louis Unversity School of
Public Health
Anthrax: Pathogenesis
Disease requires entry of spores into body
Exposure does not always cause disease
Inoculation dose
Route of entry
Host immune status
May depend on pathogen strain characteristics
Saint Louis Unversity School of
Public Health
Anthrax: Pathogenesis
Forms of natural disease
Inhalational
Cutaneous
Gastrointestinal
Determined by route of entry
Disease occurs wherever spores germinate
Saint Louis Unversity School of
Public Health
Anthrax: Pathogenesis
Inhalational
Spores on particles 1-5 m
Inhaled and deposited into alveoli
Estimated LD50 = 2500 – 55,000
spores
• Dose required for lethal infection in 50%
exposed
• Contained in imperceptibly small volume
Saint Louis Unversity School of
Public Health
Anthrax: Pathogenesis
Inhalational
Phagocytosed by alveolar macrophages
Migration to mediastinal/hilar lymph nodes
Germination into vegetative bacilli
• Triggered by nutrient-rich environment
• May be delayed up to 60 days
– Factors not completely understood
– Dose, host factors likely play a role
– Antibiotic exposure may contribute
– Delayed germination after antibiotic
suppression
Saint Louis Unversity School of
Public Health
Anthrax: Pathogenesis
Inhalational
Vegetative bacillus is the virulent phase
• Active toxin production
• Hemorrhagic necrotizing mediastinitis
– Hallmark of inhalational anthrax
– Manifests as widened mediastinum on CXR
• Does NOT cause pneumonia
• Followed by high-grade bacteremia
– Seeding of multiple organs, including meninges
Saint Louis Unversity School of
Public Health
Anthrax: Pathogenesis
Inhalational
Toxin production
• Has usually begun by time of early symptoms
• Stimulates cascade of inflammatory mediators
– Sepsis
– Multiorgan failure
– DIC
• Eventual cause of death
– Symptoms mark critical mass of bacterial burden
– Usually irreversible by this time
– Clearance of bacteria unhelpful as toxin-mediated
– Early research on antitoxin promising
Saint Louis Unversity School of
Public Health
Anthrax: Pathogenesis
Cutaneous
Spores in contact with skin
• Entry through visible cuts or micro-trauma
Germination in skin
Disease begins following germination
• Toxin production
– Local edema, erythema, necrosis, lymphocytic infiltrate
– No abscess or suppurative lesions
• Eventual eschar formation
Saint Louis Unversity School of
Public Health
Anthrax: Pathogenesis
Cutaneous
Systemic disease
• Can occur, especially if untreated
• Spores/bacteria carried to regional lymph
nodes
– Lymphangitis/lymphadenitis
– Same syndrome as inhalational
– Sepsis, multi-organ failure
Saint Louis Unversity School of
Public Health
Anthrax: Pathogenesis
Gastrointestinal
Spores contact mucosa
• Oropharynx
– Ingestion
– Aerosolized particles >5 m
• Intestinal mucosa – terminal ileum, cecum
– Ingestion
Larger number of spores required for disease
Incubation period 2-5 days
Saint Louis Unversity School of
Public Health
Anthrax: Pathogenesis
Gastrointestinal
Spores migrate to lymphatics
• Submucosal, mucosal lymphatic tissue
• Mesenteric nodes
Germination to vegetative bacilli
Toxin production
• Massive mucosal edema
• Mucosal ulcers, necrosis
Death from perforation or systemic disease
Saint Louis Unversity School of
Public Health
Anthrax: Clinical Features
Symptoms depend on form of disease
Inhalational
Cutaneous
Gastrointestinal
Saint Louis Unversity School of
Public Health
Anthrax: Clinical Features
Inhalational
Asymptomatic incubation period
• Duration 2-43 days, ~10 days in Sverdlovsk
Prodromal phase
• Correlates with germination, toxin production
• Nonspecific flu-like symptoms
– Fever, malaise, myalgias
– Dyspnea, nonproductive cough, mild chest
discomfort
• Duration several hours to ~3 days
• Can have transient resolution before next
phase
Saint Louis Unversity School of
Public Health
Anthrax: Clinical Features
Inhalational
Fulminant Phase
• Correlates with high-grade bacteremia/toxemia
• Critically Ill
– Fever, diaphoresis
– Respiratory distress/failure, cyanosis
– Septic shock, multi-organ failure, DIC
• 50% develop hemorrhagic meningitis
– Headache, meningismus, delirium, coma
– May be most prominent finding
• Usually progresses to death in <36 hrs
– Mean time from symptom onset to death ~3 days
Saint Louis Unversity School of
Public Health
Anthrax: Clinical Features
Laboratory Findings
Gram positive bacilli in direct blood smear
Electrolyte imbalances common
Radiographic Findings
Widened mediastinum
• Minimal or no infiltrates
Can appear during prodrome phase
Saint Louis Unversity School of
Public Health
Anthrax: Clinical Features
Cutaneous
Most common areas of exposure
• Hands/arms
• Neck/head
Incubation period
• 3-5 days typical
• 12 days maximum
Saint Louis Unversity School of
Public Health
Anthrax: Clinical Features
Cutaneous – progression of painless lesions
Papule – pruritic
24-36 hrs
Vesicle/bulla
Ulcer – contains organisms, sig. edema
days
Eschar – black, rarely scars
Saint Louis Unversity School of
Public Health
Anthrax: Clinical Features
Cutaneous
Systemic disease may develop
• Lymphangitis and lymphadenopathy
• If untreated, can progress to sepsis, death
Saint Louis Unversity School of
Public Health
Anthrax: Clinical Features
Gastrointestinal
Oropharyngeal
• Oral or esophageal ulcer
– Regional lymphadenopathy
– Edema, ascites
– Sepsis
Abdominal
• Early symptoms - nausea, vomiting, malaise
• Late - hematochezia, acute abdomen, ascites
Saint Louis Unversity School of
Public Health
Anthrax: Diagnosis
Early diagnosis is difficult
Non specific symptoms
Initially mild
No readily available rapid specific tests
Saint Louis Unversity School of
Public Health
Anthrax: Diagnosis
Presumptive diagnosis
History of possible exposure
Typical signs & symptoms
Rapidly progressing nonspecific illness
Widened mediastinum on CXR
Large Gram+ bacilli from specimens
• Can be seen on Gram stain if hi-grade bacteremia
Appropriate colonial morphology
Necrotizing mediastinitis, meningitis at autopsy
Saint Louis Unversity School of
Public Health
Anthrax: Diagnosis
Definitive diagnosis
Direct culture on standard blood agar
• Gold standard, widely available
• Alert lab to work up Gram + bacilli if found
• 6-24 hours to grow
• Sensitivity depends on severity, prior antibiotic
– Blood, fluid from skin lesions, pleural fluid, CSF, ascites
– Sputum unlikely to be helpful (not a pneumonia)
• Very high specificity if non-motile, non-hemolytic
• Requires biochemical tests for >99% confirmation
– Available at Reference laboratories
Saint Louis Unversity School of
Public Health
Anthrax: Diagnosis
Definitive diagnosis
Rapid confirmatory tests
• Role is to confirm if cultures are negative
• Currently available only at CDC
– Polymerase Chain Reaction (PCR)
– Hi sensitivity and specificity
– Detects DNA
– Viable bacteria/spores not required
– Immunohistochemical stains
– Most clinical specimens can be used
Saint Louis Unversity School of
Public Health
Anthrax: Diagnosis
Other diagnostic tests
Anthraxin skin test
• Chemical extract of nonpathogenic B. anthracis
• Subdermal injection
• 82% sensitivity for cases within 3 days
symptoms
• 99% sensitivity 4 weeks after symptom onset
• Not much experience with use in U.S. – not used
Saint Louis Unversity School of
Public Health
Anthrax: Diagnosis
Testing for exposure
Nasal swabs
• Can detect spores prior to illness
• Currently used only as epidemiologic tool
– Decision for PEP based on exposure risk
– May be useful for antibiotic sensitivity in exposed
• Culture on standard media
• Swabs of nares and facial skin
Serologies
• May be useful from epidemiologic standpoint
• Investigational – only available at CDC
Saint Louis Unversity School of
Public Health
Anthrax: Diagnosis
Environmental samples
Suspicious powders
• Must be sent to reference laboratories as part
of epidemiologic/criminal investigation
• Assessed using cultures, stains, PCR
Air sampling
First responders
• Handheld immunoassays
– Not validated
– Useful for detecting massive contamination
Saint Louis Unversity School of
Public Health
Anthrax: Diagnosis
Test
Availability Time
Culture
Most labs
1-3 days Mod
High
Biochemical
Large labs
Hours
High
Skin test
None
1-2 days High
?
PCR
Reference
Hours
High
High
ELISA
Reference
Hours
Mod
High
Saint Louis Unversity School of
Public Health
Sens
N/A
Spec
Anthrax: Differential Diagnosis
Inhalational
Expect if anthrax
Influenza
Flu rapid diagnostic –
More severe in young pts
No infiltrate
Pneumonia
•
•
•
•
Community-acquired
Atypical
Pneumonic tularemia
Pneumonic plague
Mediastinitis
Bacterial meningitis
Thoracic aortic aneurysm
No prior surgery
Bloody CSF with GPBs
Fever
Saint Louis Unversity School of
Public Health
Anthrax: Differential Diagnosis
Cutaneous
Spider bite
Ecthyma
gangrenosum
Pyoderma
gangrenosum
Ulceroglandular
tularemia
Mycobacterial ulcer
Cellulitis
Expect if
anthrax
fever
no response to 3º
cephalosporins
painless, black
eschar
+/lymphadenopathy
usually sig. local
edema
Saint Louis Unversity School of
Public Health
Anthrax: Differential Diagnosis
Gastrointestinal
Gastroenteritis
Typhoid
Peritonitis
Perforated ulcer
Bowel obstruction
Expect if anthrax
Critically ill
Acute abdomen
Bloody diarrhea
Fever
Saint Louis Unversity School of
Public Health
Anthrax: Differential Diagnosis
Impact of suspected BT during flu season
Early disease mimics influenza
Affects same population
Increased role for rapid flu tests
• Possible development of ER protocols
– In settings of high suspicion for BT release
– Observation until flu test results obtained
• Caveats
– Possible addition of influenza to aerosol release
– False positives/negatives
– Must still use clinical judgement
Saint Louis Unversity School of
Public Health
Anthrax: Treatment
Immediately treat presumptive cases
Prior to confirmation
Rapid antibiotics may improve survival
Differentiate between cases and exposed
Cases
• Potentially exposed with any signs/symptoms
Exposed
• Potentially exposed but asymptomatic
• Provide Post-Exposure Prophylaxis
Saint Louis Unversity School of
Public Health
Anthrax: Treatment
Hospitalization
IV antibiotics
Empiric until sensitivities are known
Intensive supportive care
Electrolyte and acid-base imbalances
Mechanical ventilation
Hemodynamic support
Saint Louis Unversity School of
Public Health
Anthrax: Treatment
Antibiotic selection
Naturally occurring strains
• Rare penicillin resistance, but inducible β-lactamase
• Penicillins, aminoglycosides, tetracyclines, erythromycin,
chloramphenicol have been effective
• Ciprofloxacin very effective in vitro, animal studies
• Other fluoroquinolones probably effective
Engineered strains
• Known penicillin, tetracycline resistance
• Highly resistant strains = mortality of untreated
Saint Louis Unversity School of
Public Health
Anthrax: Treatment
Empiric Therapy
Until susceptibility patterns known
Adults
• Ciprofloxacin 400 mg IV q12°
OR
Doxycycline 100mg IV q12°
AND (for inhalational)
One or two other antibiotics
Saint Louis Unversity School of
Public Health
Anthrax: Treatment
Other antibiotic considerations
Other fluoroquinolones possibly equivalent
High dose penicillin for 2nd empiric agent
• 50% present with meningitis
Clindamycin for severe disease
• May reduce toxin production
Chloramphenicol for known meningitis
• Penetrates blood brain barrier
Saint Louis Unversity School of
Public Health
Anthrax: Treatment
Empiric Therapy
Children
• Ciprofloxacin 10-15 mg/kg/d IV q12°, max 1
g/d
OR
Doxycycline 2.2 mg/kg IV q12°
(adult dosage if >8 years and >45 kg)
• Add one or two antibiotics for inhalational
• Weigh risks (arthropathy, dental enamel)
Saint Louis Unversity School of
Public Health
Anthrax: Treatment
Empiric therapy
Pregnant women
• Same as other adults
• Weigh small risks (fetal arthropathy) vs benefit
Immunosuppressed
• Same as other adults
Saint Louis Unversity School of
Public Health
Anthrax: Treatment
Alternative antibiotics
If susceptible, or cipro/doxy not possible
• Penicillin, amoxicillin
• Gentamicin, streptomycin
• Erythromycin, chloramphenicol
Ineffective antibiotics
Trimethoprim/Sulfamethoxazole
Third generation cephalosporins
Saint Louis Unversity School of
Public Health
Anthrax: Treatment
Susceptibility testing should be done
Narrow antibiotic if possible
Must be cautious
• Multiple strains with engineered resistance to
different antibiotics may be co-infecting
• Watch for clinical response after switching
antibiotic
Saint Louis Unversity School of
Public Health
Anthrax: Treatment
Antibiotic therapy
Duration
• 60 days
– Risk of delayed spore germination
– Vaccine availability
– Could reduce to 30-45 days therapy
– Stop antibiotics after 3rd vaccine dose
Switch to oral
– Clinical improvement
– Patient able to tolerate oral medications
Saint Louis Unversity School of
Public Health
Anthrax: Treatment
Other therapies
Passive immunization
• Anthrax immunoglobulin from horse serum
• Risk of serum sickness
Antitoxin
• Mutated Protective Antigen
– Blocks cell entry of toxin
– Still immunogenic, could be an alternative vaccine
– Animal models promising
Saint Louis Unversity School of
Public Health
Anthrax: Postexposure Prophylaxis
Who should receive PEP?
Anyone exposed to anthrax
Not for contacts of cases, unless also
exposed
Empiric antibiotic therapy
Vaccination
Saint Louis Unversity School of
Public Health
Anthrax: Postexposure Prophylaxis
Avoid unnecessary antibiotic usage
Potential shortages of those who need them
Potential adverse effects
•
•
•
•
Hypersensitivity
Neurological side effects, especially elderly
Bone/cartilage disease in children
Oral contraceptive failure
Future antibiotic resistance
• Individual’s own flora
• Community resistance patterns
Saint Louis Unversity School of
Public Health
Anthrax: Postexposure Prophylaxis
Antibiotic therapy
Treat ASAP
Prompt therapy can improve survival
Continue for 60 days
• 30-45 days if vaccine administered
Saint Louis Unversity School of
Public Health
Anthrax: Postexposure Prophylaxis
Antibiotic agents
Same regimen as active treatment
• Substituting oral equivalent for IV
• Ciprofloxacin 500 mg po bid empirically
• Alternatives
– Doxycycline 100 mg po bid
– Amoxicillin 500 mg po tid
Saint Louis Unversity School of
Public Health
Anthrax: Postexposure Prophylaxis
Antibiotic agents
Children
• Same dose adjustments as treatment
• Weigh benefits vs. risks
• Recommended switch if PCN-susceptible
– Amoxicillin 80 mg/kg/day, max 500 mg tid
Saint Louis Unversity School of
Public Health
Anthrax: Prevention
Vaccine
Anthrax Vaccine Absorbed (AVA)
Supply
• Limited, controlled by CDC
• Production problems
– Single producer – Bioport, Michigan
– Failed FDA standards
– None produced since 1998
Saint Louis Unversity School of
Public Health
Anthrax: Prevention
Vaccine
Inactivated, cell-free filtrate
Purified with Al(OH)3
Protective Antigen
• Immunogenic component
• Necessary but not sufficient
Saint Louis Unversity School of
Public Health
Anthrax: Prevention
Vaccine
Administration
• Dose schedule
– 0, 2 & 4 wks; 6, 12 & 18 months initial series
– Annual booster
• 0.5 ml SQ
Saint Louis Unversity School of
Public Health
Anthrax: Prevention
Vaccine – Effective and Safe
Efficacy
• >95% protection vs. aerosol in animal models
• >90% vs. cutaneous in humans
– Older vaccine that was less immunogenic
– Protection vs inhalational but too few cases to
confirm
Saint Louis Unversity School of
Public Health
Anthrax: Prevention
Vaccine
Adverse Effects
• >1.6 million doses given to military by 4/2000
• No deaths
• <10% moderate/severe local reactions
– Erythema, edema
• <1% systemic reactions
– Fever, malaise
Saint Louis Unversity School of
Public Health
Anthrax: Infection Control
No person to person transmission
Standard Precautions
Laboratory safety
Biosafety Level (BSL) 2 Precautions
Saint Louis Unversity School of
Public Health
Anthrax: Decontamination
Highest risk of infection at initial release
Duration of aerosol viability
• Several hours to one day under optimal conditions
• Covert aerosol long dispersed by recognition 1st
case
Risk of secondary aerosolization is low
• Heavily contaminated small areas
– May benefit from decontamination
• Decontamination may not be feasible for large
areas
Saint Louis Unversity School of
Public Health
Anthrax: Decontamination
Skin, clothing
Thorough washing with soap and water
Avoid bleach on skin
Instruments for invasive procedures
Utilize sporicidal agent
Sporicidal agents
Sodium or calcium hypochlorite (bleach)
Saint Louis Unversity School of
Public Health
Anthrax: Decontamination
Suspicious letters/packages
Do not open or shake
Place in plastic bag or leak-proof container
If visibly contaminated or container unavailable
• Gently cover – paper, clothing, box, trash can
Leave room/area, isolate room from others
Thoroughly wash hands with soap and water
Report to local security / law enforcement
List all persons in vicinity
Saint Louis Unversity School of
Public Health
Anthrax: Decontamination
Opened envelope with suspicious substance
Gently cover, avoid all contact
Leave room and isolate from others
Thoroughly wash hands with soap and water
Notify local security / law enforcement
Carefully remove outer clothing, put in plastic
Shower with soap and water
List all persons in area
Saint Louis Unversity School of
Public Health
Anthrax: Outbreak Investigations 2001
Case definitions
Confirmed case
• Clinically compatible syndrome
• +culture or 2 +non-culture diagnostics
Presumptive case
• Clinically compatible syndrome
• 1 +non-culture diagnostic or confirmed exposure
Exposures
• Confirmed exposure
– May be aided by nasal swab cultures, serology
• Asymptomatic
Saint Louis Unversity School of
Public Health
Anthrax: Outbreak Investigations 2001
Florida (Palm Beach)
1st U.S. case since 1976 reported 10/4/01
1st ever cases of intentional infection
Inhalational Index Case
• 63yo man presented with fever and altered MS
• Preceding flu-like symptoms
• Reported by astute clinician
– Noticed GPB’s in CSF on 10/2
– Lab confirmation by State and CDC on 10/4
• Rapid deterioration, died on 10/5
Saint Louis Unversity School of
Public Health
Anthrax: Outbreak Investigations 2001
Florida Case #2
73yo man
Admitted 10/1 for pneumonia
Nasal swab culture + on 10/5
PCR+ on pleural fluid, serology +
Responding to antibiotics, still in hospital
Saint Louis Unversity School of
Public Health
Anthrax: Outbreak Investigations 2001
Florida
Exposed
• Anyone at worksite for >1 hour since 8/1
• 1/1075 nasal swabs +, all given PEP
Confirmed powder exposure from mail
Saint Louis Unversity School of
Public Health
Anthrax: Outbreak Investigations 2001
New York City - cutaneous cases
Case #1 – 38 yo woman, NBC employee
• Handled suspicious letter with powder marked
9/18
• 9/25 developed raised skin lesion on chest
– Progressive erythema, edema over 3 days
• 9/29 malaise and HA, lesion painless
• 10/1 5cm oval, raised border, satellite vesicles
– Left cervical lymphadenopathy
– Black eschar over next few days
Saint Louis Unversity School of
Public Health
Outbreak Investigations 2001
New York City – cutaneous cases
Case#1
• Vesicle fluid –cx and Gram stain
• Eschar biopsy +immuno-histochemical stain
• Powder in letter confirmed anthrax spores
• Improving on oral ciprofloxacin
Saint Louis Unversity School of
Public Health
Anthrax: Outbreak Investigations 2001
New York City – cutaneous cases
Case #2 – 7 month old son of ABC worker
• Visited worksite on 9/28
• 9/29 large weeping skin lesion left arm
–
–
–
–
Nontender, massive edema
Progressed to ulcerative with black eschar
Initial Dx- spider bite
Complicated by hemolytic anemia, thrombocytopenia
• 10/12 anthrax considered
– 10/2 blood PCR+, 10/13 skin bx IHC stain+
• No source identified, improving with ciprofloxacin
Saint Louis Unversity School of
Public Health
Anthrax: Outbreak Investigations 2001
New York City
Exposures by nasal/facial swab cx’s
• Police officer transporting the NBC sample
• 2 lab techs processing NBC sample
Saint Louis Unversity School of
Public Health
Anthrax: Outbreak Investigations 2001
Washington, D.C.
Letter sent to Senator Daschle
• Originated from Trenton, NJ
• 28 Senate staff confirmed exposure
• Evacuation of Senate then House
Saint Louis Unversity School of
Public Health
Anthrax: Outbreak Investigations 2001
Trenton, New Jersey
2 confirmed inhalational cases
• Postal workers in distribution center
• Others with symptoms, results pending
2 suspicious deaths
• Probable inhalational anthrax
Saint Louis Unversity School of
Public Health
Anthrax: Outbreak Investigations 2001
As of 10/22/01
FL
NY
NJ
DC
Inhalational
2
0
4
0
Cutaneous
0
4
0
1
Total Cases
2
4
4
1
Exposure
6
3
?
29
Deaths
1
0
2
0
(all inhalational)
Saint Louis Unversity School of
Public Health
Anthrax Essential Pearls
Rapidly fatal flu-like illness in previous healthy
Widened mediastinum on Chest X-ray
Painless black skin ulcer
Non-motile gram positive bacilli in specimens
Diagnosis primarily by routine culture
No person-to-person transmission
Rx prior to prodrome essential for survival
Empiric therapy - ciprofloxacin
Saint Louis Unversity School of
Public Health
Anthrax Essential Pearls
Single inhalational case is an
emergency
Contact Local Health Departments ASAP
Saint Louis Unversity School of
Public Health
Viral Hemorrhagic Fever
Hemorrhagic Fever Viruses
Families Responsible for VHF:
Arenaviridae
Bunyaviridae
Filoviridae
Flaviviridae
Centers for Disease Control and
Prevention
Hemorrhagic Fever Viruses
Arenaviruses
Argentine Hemorrhagic Fever
Bolivian Hemorrhagic Fever
Sabia Associated Hemorrhagic Fever
Lassa Fever
Centers for Disease Control and
Prevention
Hemorrhagic Fever Viruses
Bunyaviruses
Crimean-Congo Hemorrhagic Fever
Rift Valley Fever
Hantavirus Pulmonary Syndrome Hemorrhagic
Fever
Centers for Disease Control and
Prevention
Hemorrhagic Fever Viruses
Filoviruses
Ebola Hemorrhagic Fever
Marburg Hemorrhagic Fever
Centers for Disease Control and
Prevention
Hemorrhagic Fever Viruses
Flaviviruses
Tick-borne Encephalitis
Kyasanur Forest Disease
Omsk Hemorrhagic Fever
Centers for Disease Control and
Prevention
Viral Hemorrhagic Fevers
Contagious --- Moderate
Infective dose --- 1-10 particles
Incubation period --- 4-21 days
Duration of illness --- 7-16 days
Mortality ---variable
Persistence of organism --- unstable
Non-endemic in U.S.
No vaccine
Centers for Disease Control and
Prevention
VHF Specimens
Diagnosis is clinical, not laboratory
No specimen accepted without prior
consultation
Centers for Disease Control and
Prevention
Handling VHF Specimens
Sample for serology - 10-12 ml
ship on dry ice
Tissue for immunohistochemistry
formalin-fixed or paraffin block
ship at room temperature
Tissue for PCR/virus isolation
ante-mortem, post-mortem; ship on dry ice
Ship serum cold or on dry ice in a plastic
tube
Centers for Disease Control and
Prevention
Pneumonic Plague
Pneumonic Plague
Yersinia pestis
Gram-negative coccobacillus
Flea bite in natural conditions
Easily transmitted direct contact personperson
High mortality
Pneumonic form most deadly
Plague Epidemiology
U.S. averages 13 cases/yr (10 in 1998)
30% of cases are in Native Americans in
the Southwest. 15% case fatality rate
Most cases occur in summer
Centers for Disease Control and
Prevention
Plague Epidemiology
U.S. averages 13 cases/yr (10 in 1998)
30% of cases are in Native Americans in
the Southwest. 15% case fatality rate
Most cases occur in summer
Centers for Disease Control and
Prevention
Plague Epidemiology
Bubonic
Painful adenopathy (bubo) groin or axillae
Septicemic
Septicemia w/o adenopathy
Pneumonic
Severe Respiratory Symptoms (Yersinia
aerosol transmission-bioterroism threat)
Plague Epidemiology
Pneumonic Plague
CAP-like Respiratory symptoms
Sudden Onset
Severe headache
Abdominal pain
Adenopathy
Plague Differential Diagnosis
Pneumonic Plague
Cavitation
Multilobar consolidation
Highly variable CXR
May have alveolar infiltrates
May have massive consolidation
(Yersinia) Schoenlein-Henoch
Disease-bacterial vasculitis
Safety pin Appearance Y. pestis
Yersinia pestis
Technical Hints
Small gram-negative, poorly staining rods
from blood, lymph node aspirate, or
respiratory specimens
Safety pin appearance in Gram, Wright,
Giemsa, or Wayson stain
Centers for Disease Control and
Prevention
Plague Treatment
Streptomycin, Gentamycin
Effectiveness
Time of initiation
Access to advanced supportive care
Dose of inhaled bacilli
Centers for Disease Control and
Prevention
Plague Alternative Treatments-&
Prophylaxis of Close Contacts
Adults, Children, Pregnant Women
Doxycycline, Ciprofloxacin
Mass Casualty Setting
Alternative
Above or Tetracycline
Plague Infection Control
Facemasks for close patient contact
Avoid unnecessary close contact until
on antibiotics 48 hours
Biosafety level-2 labs for simple cultures
No need for environmental
decontamination of areas exposed to
plague aerosol.
Centers for Disease Control and
Prevention
Tularemia
Tularemia
Francisella tularensis
Flu-Like Illnesses, atypical pneumonias
Inhalation route
10-50 microbes -> Infection & Disease
No Human-to-Human transmission
Isolation not necessary
Tularemia
Plague-like disease in rodents (California)
Deer-fly fever (Utah)
Glandular tick fever (Idaho and Montana)
Market men’s disease (Washington, DC)
Rabbit fever (Central States)
O’Hara’s disease (Japan)
Centers for Disease Control and
Prevention
Tularemia
Contagious --- no
Infective dose --- 10-50 organisms
Incubation period --- 1-21 days (average=3-5
days)
Duration of illness --- ~2 weeks
Mortality --- treated
: low
untreated: moderate
Persistence of organism ---months in moist soil
Vaccine efficacy --- good, ~80%
Centers for Disease Control and
Prevention
Tularemia Clinical Features
Targets kidney, liver, lungs,lymph,
spleen
Spread bloodstream/lymph
Organs-PMNs and focal suppurative
necrosis
Alternate Sites-Tularemia
Aerosol bioterrorism attack: lower
respiratory infection, eyes, pharynx,
skin
Broken skin-->ulcerative form
GI involvement if ingested
Tularemia
Chills, coryza,
cough, fever,
headache, malaise,
myalgia, sore throat
Relative bradycardia
ie, pulsetemperature
dissociation
Variable severity
Influenza
Same
No dissociation
Most symptoms
similar
Lab Tularemia
WBC normal or high
UA= sterile pyuria
5-15% have
elevated LFTs
Culture pharynx,
sputum or gastric
aspirates high yield
for Francisella
tularensis
Influenza
WBC may be
normal,
No pyuria
No LFT elevation
CXR Tularemia
25-50% abnormal CXR inhalation
tularemia
Peri-vascular infiltrates early
May resemble symptoms and CXR of
Anthrax, plague or Q-fever
Tularemia Differs from Similar
Bio Weapons
Plague
Anthrax
Q Fever
Rapid
progression
Symmetrical
mediastinal
widening
Absence of
bronchopneumonia
Clinically same
as tularemia
Copious
sputum
Hemoptysis
Lab testing
differentiates
Tularemia: Gram Negative Coccobacilli
Most likely
Acinetobacter
Actinobacillus
H. aphrophilus
Bordetella
spp.
Pasturella spp.
Least likely
DF-3
Brucella spp.
Francisella
spp.
Francisella tularensis
Technical Hints
If you see:
Tiny, gram-negative coccobacilli from blood,
lymph node aspirate, or respiratory specimens
Blood isolates that grow slowly on chocolate
agar but poorly on blood agar
Robust growth in BCYE; requires cysteine
Centers for Disease Control and
Prevention
Tularemia Treatment
Streptomycin & Gentamycin
Alternatives:
Doxycycline, Ciprofloxacin
Tularemia: Mass Casualty RX
Exposed Persons Only
Their contacts not at high risk
Streptomycin or Gentamycin, or
Ciprofloxacin, Doxycycline
CDC has stockpiles, ventilators and
emergency equipment
Botulism
Botulism
Clostridium botulinum
Most Potent Neurotoxin
169 USA cases in 2001
Foodborne or in wounds, usually IVDU
FOODBORNE BOTULISM
Infective dose: 0.001 g/kg
Incubation period: 18 - 36 hours
Dry mouth, double vision, droopy eyelids,
dilated pupils
Progressive descending bilateral muscle
weakness & paralysis
Respiratory failure and death
Mortality 5-10%, up to 25%
Centers for Disease Control and
Prevention
FOODBORNE BOTULISM
Among 309 persons with clinically
diagnosed botulism reported to CDC
from 1975 to 1988:
Stool cultures for C. botulinum: 51% +
Serum botulinum toxin testing: 37% +
Stool botulinum toxin testing: 23% +
Overall, at least one of the above tests
was positive for 65% of all patients
Centers for Disease Control and
Prevention
Botulism Transmission
Home Canned foods, baked potatoes in
aluminum foil, cheese, fish
Wound botulism-spores germinate in
open wounds
Botulism Features
Symmetric descending paralysis
Motor and autonomic nerves
Cranial nerves first affected
Death rate 5%, respiratory failure
Recovery takes months
Botulism Incubation
2 hours to 8 days (dose related)
Heat inactivates (>85°C for 5 minutes)
Lab testing –Call Public Health Lab
Should be suspected if multiple persons
simultaneously present with similar
symptoms – need to get good history of
each persons’ past activities
Botulism Symptoms
Alert mental status
Fatigue, dizziness, dysarthria, facial palsy
Vision blurred, double, ptosis
Dysphagia, dry mouth
Dyspnea
Constipation
Weakness, progressive
Botulism Differential Diagnosis
Notable symmetrical weakness
Absence of sensory nerve damage
Descending flaccid paralysis
Prominent cranial nerve palsies
Botulism Confused with:
Myasthenia Gravis
Tick Paralysis
Organophosphate intoxication
CNS infections
More likely than, but confused with
polyradiculoneuropathy:
Guillain-Barre´ or Miller-Fisher syndrome
BOTULISM
Diagnosis of botulism is made clinically
Health care providers suspecting botulism
should contact their State Health
Department
Centers for Disease Control and
Prevention
Botulism Treatment
Antibiotics not useful
Equine Antitoxin risky
Neurologic support
No neuromuscular blockade drugs
Ventilatory support
Botulism Biosafety Alert
Botulism toxins are extremely poisonous
Minute quantities acquired by ingestion,
inhalation, or by absorption can cause death
All materials suspected of containing toxin must
be handled with CAUTION!
Centers for Disease Control and
Prevention
Questions?