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BIODEFENCE

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??? ???? ?????? ??????. BIODEFENSE ... Source of toxin - Clostridium botulinum ... 12-18 hours in primate studies. 72 hours in 3 known inhalational cases ... – PowerPoint PPT presentation

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Title: BIODEFENCE


1
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BIODEFENSE Epidemiology of Botulism Shahid
Beheshti University of medical sciences, April
2005 By Vahdani P. MD. MPH, Hatami H. MD. MPH
2
Definition
  • Disease botulism
  • Agent botulinum toxin
  • Source of toxin - Clostridium botulinum

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(Botulinum) ????? ??? ?????? ???? ??????
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3
History
  • Therapeutic use of botulinum toxin
  • FDA approved for neuromuscular disorders
  • Blepharospasm
  • Strabismus
  • Torticollis
  • Many other unapproved uses
  • Packaged in dilute preparations
  • Not feasible to use licensed toxin for weapon

4
Therapeutic Uses of Botulism Toxin
  • Focal dystonias - involuntary, sustained, or
    spasmodic patterned muscle activity
  • Spasticity - velocity-dependent increase in
    muscle tone
  • Nondystonic disorders of involuntary muscle
    activity
  • Strabismus (disorder of conjugate eye movement)
    and nystagmus
  • Disorders of localized muscle spasms and pain
  • Smooth muscle hyperactive disorders
  • Cosmetic use
  • Sweating disorders

5
Bioweapon Potential
  • Known unsuccessful uses as weapon
  • 1990 -1995 aerosol releases by Aum Shinrikyo
  • Downtown Tokyo, Japan
  • 3 times at US Military bases in Japan
  • Weapons Programs
  • 1930s Japanese fed C. botulinum to prisoners
  • U.S. produced botulinum toxin during WWII
  • Soviet Union spliced genome into other bacteria
  • 1991 Iraq weaponized 19,000L during Persian Gulf
    War

6
Bioweapon Potential
  • Botulinum toxin a major threat because
  • Extreme potency and lethality
  • Ease of production
  • Ease of transport
  • Need for prolonged intensive care
  • Top 6 potential biological warfare agents
  • Listed as Category A agent High priority

7
Critical Biological Agents Category A
  • Variola major
  • Bacillus anthracis
  • Yersinia pestis
  • Clostridium botulinum
  • Francisella tularensis
  • Ebola hemorrhagic fever
  • Marburg hemorrhagic fever
  • Lassa Junin

8
Bioweapon Potential
  • Factors suggesting intentional release
  • Large cases
  • Acute flaccid paralysis with bulbar palsies
  • Unusual botulinum toxin type
  • Type C, D, F, or G
  • Type E not acquired from aquatic food
  • Common geographic factor among cases
  • No common dietary exposure - Suggests aerosol
  • Multiple simultaneous outbreaks without common
    source

9
Bioweapon Potential
  • Estimated Effect
  • Most toxic substance known
  • 1 gram crystalline toxin can kill gt 1 million
    people if dispersed and inhaled evenly
  • Point source aerosol release
  • Incapacitate/kill 10 of people downwind within
    500 meters

10
Bioweapon Potential
  • Naturally occurring botulism
  • Foodborne (preserved or non-preserved)
  • Wound
  • Intestinal
  • Bioterrorism routes of intoxication
  • Aerosol (inhaled into lungs)
  • Foodborne
  • Waterborne ???

11
Bioweapon Potential
  • Inhalational exposure
  • One documented accidental outbreak
  • Germany 1962
  • 3 laboratory workers
  • Exposed to re-aerosolized toxin type A
  • Confirms that aerosol route is effective means of
    intoxication

12
Bioweapon Potential
  • Food-borne botulism
  • Foods that are higher pH
  • corn, pepper, carrots, beans,
  • Contaminated condiments
  • Commercial foods
  • Difficult to distinguish intentional

13
Bioweapon Potential
  • Water-borne botulism
  • No instances of water-borne botulism have ever
    been reported
  • Contamination of water supply is possible
  • Toxin would be rapidly inactivated by the
    chlorine used to purify drinking water
  • Harrison 2005 pp. 1286

14
Bioweapon Potential
  • Municipal water plants unlikely source
  • Botulinum toxin inactivated by standard potable
    water treatments (chlorination, aeration)
  • Slow turnover time of large-capacity reservoirs
  • However, in untreated water or beverages the
    toxin may be stable for several days

15
Epidemiology
  • U.S. incidence
  • lt 200 annual cases of all forms
  • Approx 9 annual outbreaks of food-borne
  • median of 24 cases
  • Recent trend toward restaurant rather than
    home-preserved foods
  • All ages and genders equally susceptible
  • Mortality
  • 25 prior to 1960
  • 6 during 1990s

16
Epidemiology
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17
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18
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19
Epidemiology
  • Incubation period
  • Depends on inoculated dose
  • Inhalational
  • 12-18 hours in primate studies
  • 72 hours in 3 known inhalational cases
  • True incubation period is unknown
  • Foodborne
  • 6 hours to 8 days
  • Wound
  • 7.5 days (range 4-18 days) after injury

20
Microbiology
  • C. Botulinum
  • Gram-positive obligate anaerobic bacillus
  • Spore-forming
  • Produces botulinum toxin
  • Heat sensitive as bacillus
  • Prefers low acid environment

21
Microbiology
  • C. Botulinum spores
  • Ubiquitous
  • Soil
  • Airborne dust
  • Surfaces of raw fruits and vegetables
  • Seafood
  • Heat resistant, hardy

22
Microbiology
  • Botulinum toxins
  • Consist of light and heavy chains
  • Light chain zinc endopeptidase
  • The bioactive component
  • Colorless, odorless
  • Environmental survival
  • Inactivated by heat gt85ºC for 5 min
  • pH lt4.5

23
Microbiology
  • Toxin Classification
  • All have same clinical effect
  • Types A-G, antigenically distinct
  • Type A- 54, Type B- 15, Type E- 27
  • Type A- Western U.S., Type B- Eastern
  • Types C, D reported in animals only
  • Type G in soil samples only
  • Humans likely susceptible to all types

24
Pathogenesis
  • Possible routes of exposure
  • Inhalation of toxin (in a biological attack)
  • Food or water toxin contamination
  • Wound infected with C. Botulinum
  • Ingestion of C. botulinum

25
Botulism Toxin Mechanism
26
Pathogenesis
  • Estimated lethal human dose
  • Crystalline type A toxin
  • 0.09-0.15 ?g given iv or im
  • 0.70-0.90 ?g inhalationally
  • 70 ?g given po

27
Pathogenesis
  • Toxin must enter body
  • Direct toxin absorption from mucosal surface
  • Gut foodborne
  • Lungs inhalational
  • Via toxin produced by infection with C.botulinum
  • Skin breaks wound botulism after trauma, IV
    drugs
  • Gut intestinal botulism
  • Would not be seen in BT event, as toxin would be
    used
  • Does not penetrate intact skin

28
Pathogenesis
  • All forms of disease lead to same process
  • Toxin absorbed into bloodstream
  • Irreversibly binds peripheral cholinergic
    synapses
  • Cleaves fusion proteins used by neuronal vesicles
    to release acetylcholine into neuromuscular
    junction
  • Blocks Acetylcholine release permanently
  • Results in paralysis of that muscle
  • Reinnervation via regeneration of axon twigs
  • Takes weeks to months

29
Clinical Features
  • Symptoms
  • All forms same neuro symptoms
  • Diplopia / blurred vision
  • Ptosis
  • Slurred speech
  • Dysphagia / dry mouth
  • Muscle weakness

30
Infant Botulism
  • Most common form in U.S.
  • Spore ingestion
  • Germinate then toxin released and colonize large
    intestine
  • Infants lt 1 year old
  • 94 lt 6 months old
  • Spores from varied sources
  • Honey, food, dust, corn syrup

31
Infant Clinical Signs
  • Constipation
  • Lethargy
  • Poor feeding
  • Weak cry
  • Bulbar palsies
  • Failure to thrive

32
Clinical Features
  • Classic Triad
  • Symmetric, descending flaccid paralysis with
    prominent bulbar palsies
  • Afebrile
  • Clear sensorium
  • Bulbar palsies summarized as "4 Ds"
  • Diplopia, dysarthria, dysphonia, dysphagia

33
Clinical Features
Requested to perform max. smile. Ptosis,
disconjugate gaze, mild asymmetric smile.
Patient at rest, bilateral mild ptosis,
disconjugate gaze, symmetric facial muscles.
34
Clinical Features
  • Symptom progression
  • Descending paralysis
  • Lose head control
  • Lose gag require intubation
  • Lose diaphragm mechanical ventilation
  • Loss of deep tendon reflexes

35
Clinical Features
36
Clinical Features
  • 4 clinical forms of botulism
  • Food-borne (first described in 1897)
  • Wound (1943)
  • Infant (1976)
  • Indeterminate (1977)

37
Clinical Features
  • Infant
  • Occurs in children lt one year old
  • Ingests spores, grows in bowel release toxin
  • Intestinal colonization of organisms
  • Normal intestinal flora not developed

38
Clinical Features
  • Indeterminate
  • No specific food or wound source identified
  • Similar to infant but occurs only in adults
  • Risk factor surgical alterations of the GI tract
    and/or antibiotic therapy
  • Leads to colonization

39
Diagnosis
  • Clinical diagnosis
  • Diagnostic tests help confirm
  • Toxin neutralization mouse bioassay
  • Serum, stool, or suspect foods
  • Infant botulism
  • C botulinum organism or toxin in feces

40
Diagnosis
  • What to do at first suspicion of a case
  • Immediately notify public health dept
  • Acquire therapeutic antitoxin
  • Send samples for diagnostic testing
  • Serum, vomit, gastric aspirate, suspect food,
    stool
  • Collect serum before antitoxin given
  • If enema required, use sterile water
  • Refrigerate samples and suspect foods
  • Get medication list to rule out
    anticholinesterases

41
Diagnosis
  • Confirmation
  • Takes 1-4 days
  • Available only at CDC and state public health
    labs
  • Mouse Bioassay
  • Type-specific antitoxin protects vs. toxin in
    sample
  • The assay can detect at minimal 0.03ng of toxin.
  • Culture
  • Fecal and gastric specimens cultured
    anaerobically
  • Results in 7 to 10 days

42
Diagnosis
  • Differential diagnosis
  • Guillain-Barre, myasthenia gravis
  • Unique features to help in diagnosis
  • Disproportionate cranial nerve palsies
  • More hypoxia in facial muscles than below neck
  • Lack of sensory changes
  • The diagnosis is suspected on clinical grounds
    and confirmed by a mouse bioassay or toxin
    immunoassay. HA 2005

43
Botulism Differential Diagnoses
  • Guillain-Barré syndrome
  • Myasthenia gravis
  • Stroke
  • Tick paralysis
  • Lambert-Eaton syndrome
  • Psychiatric illness
  • Poliomyelitis
  • Diabetic Complications
  • Drug intoxication
  • CNS infection
  • Overexertion

44
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45
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46
Treatment
  • Supportive care
  • Enteral tube feeding or parenteral nutrition
  • Mechanical ventilation
  • Treatment of secondary infections
  • Avoid aminoglycosides and clindamycin
  • Worsens neuromuscular blockade

47
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Do not give aminoglycosides and clindamycin
48
Treatment
  • Passive immunization - equine antitoxin
    (5000-9000 IU)
  • Antibodies to Types A, B and E toxins
  • Binds and inactivates circulating toxin
  • Stops further damage but doesnt reverse
  • Administer ASAP for best outcome
  • Dose per package insert
  • Heptavalent antitoxin
  • Investigational
  • Effective against all toxins

49
Treatment
  • Antitoxin action
  • Food-borne botulism
  • Neutralizing antibody levels exceed toxin levels
  • Single dose adequate
  • Large exposure (e.g. biological weapon)
  • can confirm adequacy of neutralization
  • recheck toxin levels after treatment
  • Antitoxin adverse effects
  • Serum sickness (2-9), anaphylaxis (2)

50
Treatment
  • Recovery takes weeks
  • Until motor axon twigs regenerate
  • Special groups - same treatment strategy
  • Children
  • Pregnant women
  • Immunocompromised

51
Levels of Prevention
  • 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

52
Post Exposure Prophylaxis
  • 2 possibilities
  • Antitoxin
  • Prevents disease if start prior to symptom onset
  • Specific human hyperimmune globulin

53
Post Exposure Prophylaxis
  • Antitoxin not recommended for PEP
  • Limited supply
  • Substantial adverse effects
  • Exposures have variable clinical effects
  • Recommendation
  • Closely monitor known/suspected exposed
  • treat with antitoxin at first sign of disease

54
Prevention
  • Natural disease
  • Boil home-canned foods 10 minutes
  • Follow USDA instructions on home-canning
  • Restrict honey from lt 1 year old
  • Seek medical care for wounds
  • Avoid injectable street drugs

55
Prevention
  • Vaccine
  • Botulinum pentavalent toxoid
  • Not available to general public
  • Limited supply provided by CDC
  • In use for laboratory workers, military
  • Protects vs. types A-E
  • Long-lasting immunity
  • Prohibits future therapeutic use of toxin
  • Onset too slow to be effective PEP

56
Infection Control
  • Standard precautions only
  • No person-to-person transmission

57
Decontamination
  • Heat all food 85ºC x 5 min
  • Aerosolized toxin viability
  • Inactivate by 2 days in optimal conditions
  • Re-aerosolization a theoretical concern
  • Mask over the face may be protective
  • Exposed clothing and surfaces
  • Wash with 110 hypochlorite solution

58
  • References
  • Botulism, bioterrorism Center for the study of
    bioterrorism and emerging infections, Saint Louis
    University School of Public Health.
  • Hatami H. Clinical Epidemiology and Control of
    Infectious Diseases related to Bioterrorism,
    Second edition.(http//www.elib.hbi.ir/persian/lib
    rary.htm)
  • Glenda Dvorak,Botulism, the center for food
    security public health, Iowa state university.
  • Vahdani P. Botulism food borne disease, Shahid
    Beheshti University of Medical Sciences,
  • Mandell 2000
  • Harrison 2005
  • CDC Internet site
  • WHO Internet site
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