BIODEFENSE

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BIODEFENSE Epidemiology of Anthrax Shahid
Beheshti University of medical sciences,
2007 By Hatami H. MD. MPH
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• Human zoonotic disease
• Primarily disease of herbivorous animals
• Sheep, goats, cattle
• Many large documented epizootics
• Occasional human disease
• Epidemics have occurred but uncommon
• Rare in developed world

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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 Japanese use on prisoners

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Bioweapon Potential

• Features of anthrax suitable as BT agent
• Spores easily dispersed as aerosol
• Moderately infectious
• High mortality for inhalational (86-100)
• Fairly easy to obtain, produce and store

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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

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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

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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

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1 ???? ?????? (Incubation period) 2 ???
?????(Natural course) 3 ??????
?????????(Geographical distribution) 4 ????
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?????(Predisposing factors) 7 ?????? ?
??????(Susceptibility Resistance) 8 ?????
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?????? ? ???? ?????? ????? (Mode of transmission
period of communicability)
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• Incubation Period
• Time from exposure to symptoms
• Cutaneous, 3-10 days
• Very variable for inhalational
• 2-43 days reported
• Theoretically may be up to 100 days
• Delayed germination of spores

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• Caused by Bacillus anthracis
• Spores found in soil worldwide

• 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

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• Environmental Survival
• Spores are hardy
• Resistant to drying, boiling lt10 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

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• 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-a, IL-1ß
• Initiates cascade of events leading to sepsis

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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

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2 ? ??? ?????

• Three forms of natural disease
• Inhalational
• Rare (lt5)
• Most likely encountered in bioterrorism event
• Cutaneous
• Most common (95)
• Direct contact of spores on skin
• Gastrointestinal
• Rare (lt5),
• Ingestion
• Mortality
• Inhalational 86-100 (despite treatment)
• Era of crude intensive supportive care
• Cutaneous lt5 (treated) 20 (untreated)
• GI approaches 100

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??????? 85-1333
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Anthrax Disease Complex Summary
Inhalational
Tracheobronchial Lymphadenitis
Cutaneous
Mediastinitis, cyanosis, stridor, pulmonary edema
Hemorrhagic Meningitis
Papule vesicle, edema eschar
50
24 - 36 hours
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Resolve
Toxic shock and Death
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Bioweapon Potential

• 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
• Fulminant Phase

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Clinical Features

• Inhalational
• Fulminant Phase
• Correlates with high-grade bacteremia/toxemia
• Critically Ill
• Fever, diaphoresis
• Respiratory distress/failure, cyanosis
• Septic shock, multiorgan failure, DIC
• 50 develop hemorrhagic meningitis
• Headache, meningismus, delirium, coma
• May be most prominent finding
• Usually progresses to death in lt36 hrs
• Mean time from symptom onset to death 3 days

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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

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Clinical Features

• Cutaneous
• Most common areas of exposure
• Hands/arms
• Neck/head
• Incubation period
• 3-5 days typical
• 12 days maximum

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Clinical Features

• Cutaneous progression of painless lesions
• Papule pruritic
• Vesicle/bulla
• Ulcer contains organisms, sig. edema
• Eschar black, rarely scars

24-36 hrs
days
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Clinical Features

• Cutaneous
• Systemic disease may develop
• Lymphangitis and lymphadenopathy
• If untreated, can progress to sepsis, death

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Clinical Features

• Gastrointestinal
• Oropharyngeal
• Oral or esophageal ulcer
• Regional lymphadenopathy
• Edema, ascites
• Sepsis
• Abdominal
• Early symptoms - nausea, vomiting, malaise
• Late - hematochezia, acute abdomen, ascites

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• Occurs worldwide
• Endemic areas - Africa, Asia
• True incidence not known

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• All ages and genders affected
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Transmission

• Human cases historical risk factors
• Agricultural
• Exposure to livestock
• Occupational
• Exposure to wool and hides
• Woolsorters disease inhalational anthrax
• Rarely laboratory-acquired

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Transmission
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Transmission

• No human-to-human
• Naturally occurring cases
• Skin exposure
• Ingestion
• Airborne
• Bioterrorism
• Aerosol (likely)
• Small volume powder (possible)
• Foodborne (unlikely)

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• Primordial Prevention minimize hazards to
  health
• Primary Prevention
• Prevention of disease in well individuals
• Secondary Prevention
• Identification and intervention in early stages
  of disease
• Tertiary Prevention
• Prevention of further deterioration, reduction in
  complications

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• Vaccine
• Inactivated, cell-free filtrate
• Adsorbed onto Al(OH)3
• Protective Antigen
• Administration
• Dose schedule
• 0, 2 4 wks 6, 12 18 months initial series
• Annual booster
• 0.5 ml SQ

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• Vaccine
• Efficacy
• gt95 protection vs. aerosol in animal models
• gt90 vs. cutaneous in humans

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• Adverse Effects
• gt1.6 million doses given to military by 4/2000
• No deaths
• lt10 moderate/severe local reactions
• Erythema, edema
• lt1 systemic reactions
• Fever, malaise

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Postexposure Prophylaxis

• Who should receive PEP?
• Anyone exposed to anthrax
• Empiric antibiotic therapy
• Vaccination
• Not for contacts of cases, unless also exposed

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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
• Individuals own flora
• Community resistance patterns

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Postexposure Prophylaxis

• Antibiotic therapy
• Prompt therapy can improve survival
• Continue for 60 days
• 30-45 days if vaccine administered

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Postexposure Prophylaxis

• Antibiotic therapy
• 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

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Postexposure Prophylaxis

• Antibiotic therapy
• Children
• Same dose adjustments as treatment
• Weigh benefits vs. risks
• Recommended switch if PCN-susceptible
• Amoxicillin 80 mg/kg/day, max 500 mg tid

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• 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

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• 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 gt99 confirmation
• Available at Reference laboratories

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• 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

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Diagnosis
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Differential Diagnosis

• Inhalational
• Influenza
• Pneumonia
• Community-acquired
• Atypical
• Pneumonic tularemia
• Pneumonic plague
• Mediastinitis
• Bacterial meningitis
• Thoracic aortic aneurysm

• Expect if anthrax
• Flu rapid diagnostic
• More severe in young pts
• No infiltrate
• No prior surgery
• Bloody CSF
• Fever

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Differential Diagnosis

• Cutaneous
• Spider bite
• Ecthyma gangrenosum
• Pyoderma gangrenosum
• Ulceroglandular tularemia
• Mycobacterial ulcer
• Cellulitis

• Expect if anthrax
• fever
• no response to 3º cephs
• painless, black eschar
• /- lymphadenopathy
• usually sig. local edema

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Differential Diagnosis

• Gastrointestinal
• Gastroenteritis
• Typhoid
• Peritonitis
• Perforated ulcer
• Bowel obstruction

• Expect if anthrax
• Critically ill
• Acute abdomen
• Bloody diarrhea
• Fever

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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

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Treatment

• Hospitalization
• IV antibiotics
• Empiric until sensitivities are known
• Intensive supportive care
• Electrolyte and acid-base imbalances
• Mechanical ventilation
• Hemodynamic support

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Treatment

• Antibiotic selection
• Naturally occurring strains
• Rare penicillin resistance, but inducible
  ß-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

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Treatment

• Empiric Therapy
• Adults
• Ciprofloxacin 400 mg IV q12
• OR
• Doxycycline 100mg IV q12
• AND (for inhalational)
• One or two other antibiotics

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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

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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 gt8 yo and gt45 kg)
• Add one or two antibiotics for inhalational
• Weigh risks (arthropathy, dental enamel)

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Treatment

• Empiric therapy
• Pregnant women
• Same as other adults
• Weigh small risks (fetal arthropathy) vs benefit
• Immunosuppressed
• same as other adults

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Treatment

• Alternative antibiotics
• If susceptible, or cipro/doxy not possible
• Penicillin, amoxicillin
• Gentamicin, streptomycin
• Erythromycin, chloramphenicol

• Ineffective antibiotics
• Trimethoprim/Sulfamethoxazole
• Third generation cephalosporins

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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

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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

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Infection Control

• No person to person transmission
• Standard Precautions
• Laboratory safety
• Biosafety Level (BSL) 2 Precautions

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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

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Decontamination

• Skin, clothing
• Thorough washing with soap and water
• Avoid bleach on skin
• Instruments for invasive procedures
• Sterilize, e.g. 5 hypochlorite solution
• Sporicidal agents
• Sodium or calcium hypochlorite (bleach)

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Decontamination

• Suspicious letters/packages
• Do not open or shake
• Place in plastic bag or leakproof 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

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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

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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

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Anthrax Essential Notes

• 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
• Single inhalational case is an emergency
• Contact Local Health Departments

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Characteristics of inhalational anthrax cases
among employees of the Washington, D.C.,
Processing and Distribution Center
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