Transcript core functions of public health

BOTULISM
Los Angeles County
Department of Public Health
Acute Communicable Disease Control Program
David E. Dassey MD, MPH
and
Public Health Laboratory
Bioterrorism Response Unit
Patricia Bolivar MS, CLS, SM (ASCP)
Objectives
• Case report
• Botulinum toxins
• Clinical forms of botulism
• Clinical diagnosis & differential
• Laboratory confirmation
• Treatment
• Case report - conclusion
Case Report
• 34 y/o female nursing student
– Generalized weakness
– Bulbar palsies
• Admitting MD contacted Public Health
– Release of botulinum antitoxin for treatment
– Approval for botulism toxin testing by PH Lab
Serum & stool - direct toxin screen
Stool – culture for clostridia
Botulism
• Symmetrical cranial nerve palsies
• Descending, symmetric flaccid paralysis
•
of voluntary muscles
Progression to respiratory compromise
– Total paralysis
– Death
• German Botulismus: sausage poisoning,
from Latin botulus (sausage)
Botulism
• Neurotoxins produced by Clostridium
– C. botulinum: toxins A,B,E,F,G [human disease]
– C. botulinum: toxins C, D [non-human disease]
– C. butyricum: toxin E
– C. baratii: toxin F
• Obligate anaerobic, spore-former
• Toxin production in low-acid, pH>4.6
• All toxins are heat labile
Botulism Toxins
• Toxin Type A, B and E most common in
•
•
human cases
Toxin Type F occurs infrequently in human
cases
Toxin Types C and D are associated with
avian and animal botulism
– Toxin production is phage mediated
• Toxin Type G has been recovered from
humans, however role in disease is unclear.
– Toxin production is plasmid mediated
Botulism Toxins
• Dichain polypeptide
– zinc-containing metalloprotease
– 100-kd "heavy" chain
– joined by a single disulfide bond to a
– 50-kd "light" chain
• Distinguished by neutralization of
biological activity with type-specific
antisera (A – G)
– Mouse bioassay
Mode of Action
Normal neurotransmitter release
Arnon, SS et al. JAMA 2001;285:1059-1070.
Mode of Action
Exposure to botulinum toxin
Arnon, SS et al. JAMA 2001;285:1059-1070.
Toxin Lethal Dose
• Lethal human oral dose for BoNT type A
•
•
estimated to be between 100 – 1,000 ng
equivalent to 5,000 to 50,000 mouse
lethal injected dose (MLD).
Food implicated in cases of foodborne
botulism have contained toxin as high
as 10,000 MLD/gram
Some culture supernatants tested
contain over 1,000,000 MLD/ml
Growth and Toxin Production
• C. botulinum grows under anaerobic,
•
low salt, low acid, low water activity
Inhibited by
– temp <4°C or >121°C
– pH <4.5
• Spores inactivated
– 121°C under pressure of 15-20 lb/in²
• Toxin destroyed by
– Heating >85°C for 5 min
Naturally Occurring
Disease Forms
• Naturally occurring
– Food-borne
– Wound
– Infant
– Intestinal
– Other/Undetermined
Other Disease Forms
• Unintentional (iatrogenic)
– Following toxin injection for therapeutic or
cosmetic purposes
• Intentional act of terrorism
– Aerosolization, absorption through mucous
membranes or break in skin
– Distributed on food items
Botulism Cases, USA
2006-2010
18 0
Number of Cases
16 0
14 0
12 0
USA
10 0
80
60
40
20
0
2006
2007
2008
2009
2010
18 0
9
16 0
8
14 0
7
12 0
6
10 0
5
80
4
60
3
40
2
20
1
0
0
2006
2007
2008
2009
2010
USA
Deaths
Number of Cases
Botulism Cases, USA & CA
and Deaths, 2006-2010
CA
Deaths
Botulism Cases* by Toxin Type and Route
Los Angeles County, 2000-2012
9
Toxin Type
A B
U
8
7
A-food
A-other
Disease
F-food Route
U-wound
Wound
B-wound
Food
A-wound
6
5
4
3
2
Other
1
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
20
09
20
10
20
11
20
12
0
*Excludes infant botulism cases
16
Botulism, Foodborne – Case Definition
• Case Classification
– Probable: clinically compatible case with
epidemiologic link (eg, ingestion of home-canned
food within previous 48 hours)
– Confirmed: clinically compatible case that is
laboratory confirmed or that occurs among
persons who ate the same food as persons who
have laboratory-confirmed botulism
• Laboratory Criteria for Diagnosis
– Detection of botulinum toxin in serum, stool, or
patient's food, or isolation of C. botulinum from
stool
Foodborne Botulism
• Incubation dependent on quantity and
rate of absorption of toxin
– as early as 2 – 8 hours after meal
consumption
– typical incubation is 12-72 hours after
consumption
– GI symptoms may occur
• Mild cases may not be detected
– Botulism from Chopped Garlic: Delayed
Recognition of a Major Outbreak. Ann Intern
Med. 1 March 1988
Foodborne Botulism Cases, USA
2006-2010
Number of Cases
30
25
20
USA
15
10
5
0
2006
2007
2008
2009
2010
Foodborne Botulism Cases, USA & CA
2006-2010
Number of Cases
30
25
20
USA
CA
15
10
5
0
2006
2007
2008
2009
2010
Foodborne Botulism Cases, USA & CA
and Type A Cases, 2006-2010
30
10 0 %
25
80%
70 %
20
60%
15
50 %
40%
10
30%
20%
5
10 %
0
0%
2006
2007
2008
2009
2010
Per Cent Type A
Number of Cases
90%
USA
CA
Type A, %
Foodborne and Unknown Botulism
Cases by Toxin Type
Los Angeles County, 2000-2012
4
Toxin Type
A
3
A-other
Disease
Route
F-food
Food
A-food
Unk
2
1
0
00 001 002 003 004 005 006 007 008 009 010 011 012
0
2
2
2
2
2
2
2
2
2
2
2
2
2
22
Foodborne Botulism Vehicles
•
•
Home-canned or
home processed
foods
Low-acid (pH >4.6)
–
–
–
–
–
–
–
Vegetables
Relish, salsa
Peppers
Meats
Fish
Fermented, salted fish
Whale, seal
•
•
•
•
•
•
•
Baked potatoes in foil
Garlic in oil
Sautéed onions in
butter sauce
Cheese sauce
Pot pie
Canned chili
“Pruno”
Botulism, Wound – Case Definition
•
•
Case Classification
– Confirmed: clinically compatible case that is laboratory
confirmed in a patient who has no suspected exposure to
contaminated food and who has a history of a fresh,
contaminated wound during the 2 weeks before onset of
symptoms, or a history of injection drug use within the 2
weeks before onset of symptoms
– Probable: a clinically compatible case in a patient who has
no suspected exposure to contaminated food and who has
either a history of a fresh, contaminated wound during the 2
weeks before onset of symptoms, or a history of injection
drug use within the 2 weeks before onset of symptoms
Laboratory Criteria for Diagnosis
– Detection of botulinum toxin in serum, or isolation of C.
botulinum from wound
Wound Botulism
•
•
Growth of C. botulinum in wounds
with toxin production in vivo
Neurological presentation is
indistinguishable from other forms
of botulism, tho more insidious
Majority of current cases associated
with injection drug use – skin
popping
No gastrointestinal involvement
•
Type A – 80%
•
•
Type B – 20%
Wound Botulism in California, 1951–1998:
Recent Epidemic in Heroin Injectors
S. B. Werner, D. Passaro, J. McGee, R. Schechter, and D. Vugia
Clinical Infectious Diseases 2000;31:1018–24
Wound Botulism in California, 1951–1998:
Recent Epidemic in Heroin Injectors
S. B. Werner, D. Passaro, J. McGee, R. Schechter, and D. Vugia
Clinical Infectious Diseases 2000;31:1018–24
Wound Botulism Cases, USA
2006-2010
Number of Cases
50
40
30
USA
20
10
0
2006
2007
2008
2009
2010
Wound Botulism Cases, USA & CA
2006-2010
Number of Cases
50
40
30
USA
CA
20
10
0
2006
2007
2008
2009
2010
Wound Botulism Cases, USA & CA
and %Type A Cases, 2006-2010
50
10 0 %
40
80%
70 %
30
60%
50 %
20
40%
30%
10
20%
10 %
0
0%
2006
2007
2008
2009
2010
Per Cent Type A
Number of Cases
90%
USA
CA
Type A, %
Wound Botulism Cases by Toxin Type
Los Angeles County, 2000-2012
7
6
5
4
3
Toxin Type
A BU
U-wound
Disease
Route
B-wound
Wound
A-wound
2
1
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
20
09
20
10
20
11
20
12
0
31
Infant (Intestinal) Botulism
• Most common form of botulism reported
– 50% type A, 50% type B
– Intestinal tract becomes colonized with
spores of C. botulinum with subsequent
production of toxin
– Lethargy, poor feeding, floppy head with
progression to more severe disease if not
treated
• Adult intestinal botulism
– GI anatomical defect, rare
Infant Botulism Cases
USA & CA, 2006-2010
Number of Cases
120
100
CA
USA
80
60
40
20
0
2006
2007
2008
2009
2010
Botulism, Other – Case Definition
• Case Classification
– Confirmed: a clinically compatible case that
is laboratory-confirmed in a patient aged
greater than or equal to 1 year who has no
history of ingestion of suspect food and
has no wounds
• Laboratory Criteria for Diagnosis
– Detection of botulinum toxin in clinical
specimen, or isolation of C. botulinum from
clinical specimen
Iatrogenic Botulism
• Therapeutic use of botulinum toxins
–
–
–
–
Strabismus
Cervical dystonia
Blepharospasm
Spasticity (not FDA approved)
• Cosmetic uses
– Botulism Disaster Uncovers Fake Botox Market
2004 South Florida outbreak
Botulinum Toxin
As Possible Bioweapon
• Inhalational botulism
– Japanese biological warfare group
Unit 731, 1930s
– Germany, WW-II
– Cold War
Soviet Union, Aralsk-7
USA - ended in 1970
– Aum Shinrikyō cult
Attempted on at least 3 occasions 1990-1995
– Iran, Iraq, North Korea, Syria
Features That Suggest Deliberate
Release of Botulinum Toxin
• Outbreak of a large number of cases of acute
•
•
•
flaccid paralysis with prominent bulbar palsies
Outbreak with an unusual botulinum toxin
type (ie, type C, D, F, or G, or type E toxin not
acquired from an aquatic food)
Outbreak among cases with a common
geographic factor (eg, airport, work location)
but without a common dietary exposure
Multiple simultaneous outbreaks with no
common source
Clinical Presentation
• Bilateral descending flaccid paralysis
beginning with cranial nerves
–
–
–
–
–
Diplopia
Difficulty in swallowing, dysarthria
Vertigo, dizziness, unsteadiness
Neck and extremity muscle weakness
Chest, diaphragm involvement lead to
respiratory paralysis
Fatal if supportive therapy not provided
• Alert, normal vital signs, afebrile
• Normal sensory exam
Clinical Diagnosis
• Autonomic findings
– Dry mouth, sore throat, anhydrosis
– Constipation
• GI (foodborne only)
– Nausea, vomiting may precede neuro signs
• Absence of cranial nerve palsies nearly
always rules out botulism
• History of
– Home-canned or spoiled food
– Similar illness in persons sharing food
– Injection or wound ĉ/ŝ visible abscess
Incubation Period
• Dependent on rate and amount of toxin
•
•
absorbed
More rapid in foodborne botulism
Wound botulism is generally very
insidious
– Days to weeks of very minor symptoms
Workup
• Detailed history
• Complete physical exam, particularly
•
looking for minor wounds
Thorough neurological exam
– Normal sensory
• Head – MRI, CT
• Lumbar puncture for CSF
Workup
• Edrophonium (Tensilon) challenge test
– Falsely positive in 25%
• EMG
– Decreased action potentials in affected muscles
– Repetitive stimulation @ high frequency (20-50 Hz)
yields increased amplitude (facilitation)
• Appropriate toxicological studies
Differential Diagnosis
major conditions
• Guillain-Barré & Miller-Fisher Syndromes
– Ascending / Descending paralysis
MFS: ophthalmoplegia, ataxia, areflexia
– Pain, parasthesias
– Elevated CSF protein (delayed)
– Electromyography
Marked slowing of NCV
No MAP augmentation (facilitation) at hi
frequency 20-50 Hz
– Anti-ganglioside antibodies
Clinical Infectious Diseases 2000;31:1018–24
Differential Diagnosis
major conditions
• Myasthenia gravis
– Muscle fatigability, resolves with
edrophonium test
~25% mild botulism cases also respond
– EMG - decrement in MAP with rapid
stimulation at 3 Hz
• Cerebrovascular accident of midbrain
– May not be visualized early
Clinical Infectious Diseases 2000;31:1018–24
Differential Diagnosis
minor conditions
•
•
•
•
•
Polio, other
•
encephalitides
•
Tick paralysis
•
Wernicke
•
encephalopathy
Eaton Lambert
myasthenic syndrome •
Electrolyte abnormalities
Clinical Infectious Diseases 2000;31:1018–24
Paralytic shellfish poisoning
Carbon monoxide poisoning
Organophosphate poisoning
Aminoglycoside paralysis
– gentamicin, tobramycin,
streptomycin, etc.
Poisoning with belladonalike alkaloids
Laboratory Diagnosis
• Toxin detection in clinical samples
– Serum, stool, vomitus, wound tissue or exudates
– Collect specimens from patients prior to
administering anti-toxin
• Food – detection of toxin or a toxigenic
organism in implicated food item
• Culture and isolation of toxigenic organism
from wound, feces, gastric contents
Laboratory Diagnosis
• Mouse toxicity and neutralization
bioassay for toxin
• Diffusion-in-gel ELISA – ABEF proteins
• Real time PCR for botulinum toxin gene
• Mass spectrometry – toxins AB
Mouse Bioassay
• Confirmatory test
• Detects functionally active toxin
• Sensitivity: 10 – 30 pg
• Requires extensive animal use
• Results obtained within 1- 4 days
Toxin Neutralization Bioassay
Untreated
serum
Serum with
Antitoxin A
Serum with
Antitoxin B
Serum with
Antitoxin E
Toxin Neutralization Bioassay
Untreated
serum
Serum with
Antitoxin A
Serum with
Antitoxin B
Serum with
Antitoxin E
Toxin Neutralization Bioassay
Serum with
Antitoxin B
Serum with
Antitoxin E
1 B
2E
Serum with
Antitoxin A
1E
Untreated
serum
1U
1A
2U
2A
Interpretation: botulinum toxin type B is present
Botulinum Toxin DIG-ELISA
• Presumptive test for toxins ABEF
• Detects toxin protein structural elements
• Sensitivity <10 pg
• Animals are not required
• Results obtained within 4.5 h
Real-time PCR for Detection of
Neurotoxin Genes (types A-G)
• Presumptive identification and
differentiation of BoNT
– A, B, C, D, E, F, or G
• Clostridia in enrichment broths from
– Foods
– Environmental samples
Evolving Diagnostics
• Matrix-assisted laser desorption/
ionization - time of flight (MALDI-TOF)
mass spectrometry
– capable of detecting and differentiating
botulinum toxins, A, B, E and F
– Concentrations starting from 5 pg/mL
– Clinical, food and environmental samples
LA County 2000-2007
• 54 reports of suspected botulism cases
– 18 confirmed botulism cases
– 17 unconfirmed cases of clinical botulism
– 19 patients with other/unk diagnoses
• 32 (62%) reports were in IDU
– 14 confirmed botulism cases
– 14 unconfirmed cases of clinical botulism
– 4 patients with other/unk diagnoses
55
LA County 2000-2007
• 54 reports of suspected botulism cases
– 18 confirmed botulism cases
– 17 unconfirmed cases of clinical botulism
– 19 patients with other/unk diagnoses
• 32 (62%) reports were in IDU
– 14 confirmed botulism cases
– 14 unconfirmed cases of clinical botulism
– 4 patients with other/unk diagnoses
56
LA County 2000-2007
• 54 reports of suspected botulism cases
– 18 confirmed botulism cases
– 17 unconfirmed cases of clinical botulism
– 19 patients with other/unk diagnoses
• 32 (62%) reports were in IDU
– 14 confirmed botulism cases
– 14 unconfirmed cases of clinical botulism
– 4 patients with other/unk diagnoses
57
LA County 2000-2007
• 54 reports of suspected botulism cases
– 18 confirmed botulism cases
– 17 unconfirmed cases of clinical botulism
– 19 patients with other/unk diagnoses
• 32 (62%) reports were in IDU
– 14 confirmed botulism cases
– 14 unconfirmed cases of clinical botulism
– 4 patients with other/unk diagnoses
58
LA County 2000-2007
• 54 reports of suspected botulism cases
– 18 confirmed botulism cases
– 17 unconfirmed cases of clinical botulism
– 19 patients with other/unk diagnoses
• 32 (62%) reports were in IDU
– 14 confirmed botulism cases
– 14 unconfirmed cases of clinical botulism
– 4 patients with other/unk diagnoses
59
Alternative Diagnoses for
19 Botulism Suspects, 2000-2007
• Reported botulism suspects that did not
confirm
– 9 Guillain-Barré / MF syndrome
2 with campylobacteriosis
1 with unspecified diarrheal illness
– 2 circulatory: brain stem; multi-infarcts
– 2 neoplasia: brain stem, cervical chord
– 4 inflammatory: vasculitis, paraneoplastic
syndrome, encephalitis, polyneuropathy
– 2 no other diagnosis or unknown
60
Report to Public Health
Immediately
• Authorization for specific confirmatory
•
•
testing in Public Health Lab
Release of antitoxin for treatment
Rule out possible foodborne outbreak or
intentional release of toxin
• REPORT to Public Health AS SOON
AS BOTULISM IS CONSIDERED
Treatment
• Antitoxin released upon consultation
with PH physician
– stored by CDC at LAX Airport
– ABCDEFG heptavalent antitoxin
• Treatment is NEVER dependent on
results of specific botulism toxin tests.
Treatment
• Investigational Heptavalent Botulinum
Antitoxin (HBAT) to Replace Licensed
Botulinum Antitoxin AB and
Investigational Botulinum Antitoxin E
MMWR, March 19, 2010 / 59(10);299
IND and post-treatment data required
Treatment
• Botulinum antitoxin
– Most effective given early in course of illness
– Neutralizes only circulating toxin
– Does not reverse neurological symptoms
Motor recovery with regrowth of nerve endings
– Circulating half life of antitoxin is 5 – 8 days
Rarely is second dose needed
– Determine if patient is hypersensitive to
equine derived products with skin prick test
Treatment
• Foodborne botulism
– Cathartic to empty GI tract
• Wound botulism
– Debridement only after antitoxin
administration
– Antibiotic coverage
• Respiratory and supportive therapy
– Patient is alert, not comatose !
Treatment of Infant Cases
• BabyBIG®
– Botulism Immune Globulin Intravenous (Human)
(BIG-IV) (Baby-BIG)
– human-derived anti-botulism toxin antibodies
manufactured by California DPH
– approved by US FDA for treatment of infant
botulism types A and B
– Released by State on consultation
– 510-231-7600 [24-hour hotline]
Case Follow-Up - 1
• Suspected case lived with married couple
– Recent immigrants from Middle East
– Denied current symptoms, denied home
canned food
• Environmental Spec. and PHN found
– 30 gallons (5 opened) of home-pickled
eggplant, onions, garlic
– All were embargoed for possible toxin tests.
Case Follow-Up - 2
• Husband admitted to different hospital
12 hours later with dysphonia, dysphagia
– Additional jar of eggplant at bedside
• Wife had been admitted 6 weeks earlier
for 3 weeks with neck weakness
– 8 months pregnant
– Diagnosed with myasthenia gravis, r/o
botulism
Not reported by attending MD or hospital lab
– Normal infant delivered 2 weeks later
Case Follow-Up - 3
• Eggplant + for botulinum toxin type A
– All jars were destroyed
• Index case +toxin A in serum and stool
– Prolonged hospitalization, complications and
rehabilitation
• Husband hospitalized ~ 5 days
• Both were preventable if original suspect
case had been reported.
How to Report ?
For emergent communicable disease
reports, outbreaks, or unusual disease
occurrences (possible zebras):
Acute Communicable Disease Control
(213) 240-7941
References
•
•
•
•
•
Botulism in the United States: a clinical and epidemiological
review. Shapiro RL, Hathaway C, Swerdlow DL. Ann Intern
Med 1998;129(3):221-8.
Wound botulism in California, 1951-1998: recent epidemic in
heroin injectors. Werner SB, Passaro D, McGee J, Schechter
R, Vugia DJ. Clin Infect Dis. 2000 Oct;31(4):1018-24.
Botulinum toxin as a biological weapon - medical and public
health management. Arnon SS, et al. for the Working Group
on Civilian Biodefense. JAMA. 2001;285:1059-1070.
Botulism. Sobel J. Clin Infect Dis. 2005 Oct 15;41(8):1167-73.
CDC: Botulism in the United States, 1899-1996. Handbook for
epidemiologists, clinicians, and laboratory workers. Atlanta,
GA. Centers for Disease Control and Prevention, 1998.
Confirmed Botulism Cases
Los Angeles County, 2000-2012
Year
Foodborne
Wound
2000
-
-
2001
2 AF
-
2002
-
2 AA
2003
-
-
2004
-
3 AA U
2005
2 AA
6 AAAA B U
2006
-
2 AA
2007
-
1 A
2008
-
5 AAAAA
-
2009
1 A
-
-
2010
-
1 A
-
2011
-
1 A
1 AA
2012
2 AA
Total
7
1 A
22
Other
1 A
3
73