Transcript Inhalational Expect if 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
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
 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
 Mortality
 Inhalational 86-100% (despite treatment)
 Era of crude intensive supportive care
 Cutaneous <5% (treated) – 20% (untreated)
 GI approaches 100%
 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
 Human cases – historical risk factors
 Agricultural
 Exposure to livestock
 Occupational
 Exposure to wool and hides
 Woolsorter’s disease = inhalational anthrax
 Rarely laboratory-acquired
 Transmission
 No human-to-human
 Naturally occurring cases
 Skin exposure
 Ingestion
 Airborne
 Bioterrorism
 Aerosol (likely)
 Small volume powder (possible)
 Foodborne (unlikely)
 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
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
 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
 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
 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
 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
 Virulence Factors
 All necessary for full virulence
 Two plasmids
 Capsule (plasmid pXO2)
 Antiphagocytic
 3 Exotoxin components (plasmid pXO1)
 Protective Antigen
 Edema Factor
 Lethal Factor
 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
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
 Forms of natural disease
 Inhalational
 Cutaneous
 Gastrointestinal
 Determined by route of entry
 Disease occurs wherever spores germinate
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
 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
 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
 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
Pathogenesis of cutaneous
form.
 Cutaneous
 Spores in contact with skin
 Entry through visible cuts or microtrauma
 Germination in skin
 Disease begins following germination
 Toxin production
 Local edema, erythema, necrosis, lymphocytic
infiltrate
 No abscess or suppurative lesions
 Eventual eschar formation
 . In cutaneous anthrax, a malignant pustule
develops at the infection site. This pustule is a
central area of coagulation necrosis (ulcer)
surrounded by a rim of vesicles filled with
bloody or clear fluid. A black eschar forms at
the ulcer site. Extensive edema surrounds the
lesion.
 The organisms multiply locally and may
spread to the bloodstream or other organs
(eg, spleen) via the efferent lymphatics. B
anthracis remains in the capillaries of invaded
organs, and the local and fatal effects of the
infection are due, in large part, to the toxins
elaborated by B anthracis.
 Dissemination from the liver, spleen, and
kidneys back into the bloodstream may result
in bacteremia. Secondary hemorrhagic
intestinal foci of anthrax result from B
anthracis bacteremia.
 Cutaneous
 Systemic disease
 Can occur, especially if untreated
 Spores/bacteria carried to regional lymph nodes
 Lymphangitis/lymphadenitis
 Same syndrome as inhalational
 Sepsis, multiorgan failure
Pathogenisis GI form
 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
 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
Oropharyngeal anthrax
 Oropharyngeal anthrax is a variant of
intestinal anthrax and occurs in the
oropharynx after ingestion of meat products
contaminated by anthrax. Oropharyngeal
anthrax is characterized by throat pain and
difficulty in swallowing. The lesion at the site
of entry into the oropharynx resembles the
cutaneous ulcer.
Clinical Features
 Symptoms depend on form of disease
 Inhalational
 Cutaneous
 Gastrointestinal
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
 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 <36 hrs
 Mean time from symptom onset to death ~3
days
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
Cutaneous
 Most common areas of exposure
 Hands/arms
 Neck/head
 Incubation period
 3-5 days typical
 12 days maximum
 Cutaneous – progression of painless lesions
Papule – pruritic
Vesicle/bulla
Ulcer – contains organisms, sig. edema
Eschar – black, rarely scars
 Systemic disease may develop
 Lymphangitis and
lymphadenopathy
 If untreated, can progress to
sepsis, death
Gastrointestinal
 Oropharyngeal
 Oral or esophageal ulcer
 Regional lymphadenopathy
 Edema, ascites
 Sepsis
 Abdominal
 Early symptoms - nausea, vomiting,
malaise
 Late - hematochezia, acute abdomen,
ascites
Diagnosis.
 Early diagnosis is difficult
 Non specific symptoms
 Initially mild
 No readily available rapid specific
tests
 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
 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
 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
 Testing for exposure
 Nasal swabs
 Can detect spores prior to illness
 Currently used only as epidemiologic tool
 Decision 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
Differential diagnostics
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 with GPBs
Fever
 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
 Gastrointestinal
 Gastroenteritis
 Typhoid
 Peritonitis
 Perforated ulcer
 Bowel obstruction
Expect if anthrax
Critically ill
Acute abdomen
Bloody diarrhea
Fever
Treatment.
 Hospitalization
 IV antibiotics
 Empiric until sensitivities are known
 Intensive supportive care
 Electrolyte and acid-base imbalances
 Mechanical ventilation
 Hemodynamic support
 Antibiotic selection
 Naturally occurring strains
 Rare penicillin resistance, but inducible βlactamase
 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
 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
 Pregnant women
 Same as other adults
 Weigh small risks (fetal arthropathy) vs
benefit
 Immunosuppressed
 same as other adults
 Susceptibility testing should be done
 Narrow antibiotic if possible
 Must be cautious
 Multiple strains with engineered
resistance to different antibiotics may
be coinfecting
 Watch for clinical response after
switching antibiotic
 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
 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
Postexposure Prophylaxis
 Who should receive PEP?
 Anyone exposed to anthrax
 Not for contacts of cases, unless also exposed
 Empiric antibiotic therapy
 Vaccination
 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
Post exposure prophylaxis.
 Antibiotic therapy
 Treat ASAP
 Prompt therapy can improve survival
 Continue for 60 days
 30-45 days if vaccine administered
 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
Prevention.
 Vaccine
 Anthrax Vaccine Adsorpbed (AVA)
 Supply
 Limited, controlled by CDC
 Production problems
 Single producer – Bioport, Michigan
 Failed FDA standards
 None produced since 1998
 Vaccine
 Inactivated, cell-free filtrate
 Adsorbed onto Al(OH)3
 Protective Antigen
 Immunogenic component
 Necessary but not sufficient
 Vaccine
 Administration
 Dose schedule
 0, 2 & 4 wks; 6, 12 & 18 months initial
series
 Annual booster
 0.5 ml SQ
 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
Infection control.
 No person to person transmission
 Standard Precautions
 Laboratory safety
 Biosafety Level (BSL) 2 Precautions
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)