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BOTULISM

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

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BOTULISM

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  1. 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)

  2. Objectives • Case report • Botulinum toxins • Clinical forms of botulism • Clinical diagnosis & differential • Laboratory confirmation • Treatment • Case report - conclusion

  3. 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

  4. Botulism • Symmetrical cranial nerve palsies • Descending, symmetric flaccid paralysis of voluntary muscles • Progression to respiratory compromise • Total paralysis • Death • GermanBotulismus: sausage poisoning, from Latin botulus (sausage)

  5. 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

  6. 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

  7. 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

  8. Mode of Action Normal neurotransmitter release Arnon, SS et al. JAMA 2001;285:1059-1070.

  9. Mode of Action Exposure to botulinum toxin Arnon, SS et al. JAMA 2001;285:1059-1070.

  10. 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

  11. 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

  12. Naturally OccurringDisease Forms • Naturally occurring • Food-borne • Wound • Infant • Intestinal • Other/Undetermined

  13. 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

  14. Botulism Cases, USA2006-2010

  15. Botulism Cases, USA & CAand Deaths, 2006-2010 Deaths

  16. Botulism Cases* by Toxin Type and RouteLos Angeles County, 2000-2012 Toxin Type ABFU Disease Route Wound Food Other *Excludes infant botulism cases

  17. 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. botulinumfrom stool

  18. 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

  19. Foodborne Botulism Cases, USA2006-2010

  20. Foodborne Botulism Cases, USA & CA2006-2010

  21. Foodborne Botulism Cases, USA & CAand Type A Cases, 2006-2010 Per Cent Type A

  22. Foodborne and Unknown Botulism Cases by Toxin Type Los Angeles County, 2000-2012 Toxin Type AF Disease Route Food Unk

  23. 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” Foodborne Botulism Vehicles

  24. 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. botulinumfrom wound

  25. 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%

  26. Wound Botulism in California, 1951–1998: Recent Epidemic in Heroin InjectorsS. B. Werner, D. Passaro, J. McGee, R. Schechter, and D. Vugia Clinical Infectious Diseases 2000;31:1018–24

  27. Wound Botulism in California, 1951–1998: Recent Epidemic in Heroin InjectorsS. B. Werner, D. Passaro, J. McGee, R. Schechter, and D. Vugia Clinical Infectious Diseases 2000;31:1018–24

  28. Wound Botulism Cases, USA2006-2010

  29. Wound Botulism Cases, USA & CA2006-2010

  30. Wound Botulism Cases, USA & CAand %Type A Cases, 2006-2010 Per Cent Type A

  31. Wound Botulism Cases by Toxin TypeLos Angeles County, 2000-2012 Toxin Type ABU Disease Route Wound

  32. 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

  33. Infant Botulism Cases USA & CA, 2006-2010

  34. 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

  35. 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

  36. 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

  37. 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

  38. 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

  39. Clinical Diagnosis • Autonomic findings • Dry mouth, sore throat, anhydrosis • Constipation • GI (foodborne only) • Nausea, vomitingmay 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

  40. 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

  41. Workup • Detailed history • Completephysical exam, particularly looking for minor wounds • Thorough neurological exam • Normal sensory • Head – MRI, CT • Lumbar puncture for CSF

  42. 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

  43. Differential Diagnosismajor 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

  44. Differential Diagnosismajor 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

  45. Differential Diagnosis minor conditions • Polio, other encephalitides • Tick paralysis • Wernicke encephalopathy • Eaton Lambert myasthenic syndrome • Electrolyte abnormalities • Paralytic shellfish poisoning • Carbon monoxide poisoning • Organophosphate poisoning • Aminoglycoside paralysis • gentamicin, tobramycin, streptomycin, etc. • Poisoning with belladona-like alkaloids Clinical Infectious Diseases 2000;31:1018–24

  46. 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

  47. 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

  48. Mouse Bioassay • Confirmatory test • Detects functionally active toxin • Sensitivity: 10 – 30 pg • Requires extensive animal use • Results obtained within 1- 4 days

  49. Untreated serum Serum with Antitoxin E Serum with Antitoxin A Serum with Antitoxin B Toxin Neutralization Bioassay

  50. Untreated serum Serum with Antitoxin E Serum with Antitoxin A Serum with Antitoxin B Toxin Neutralization Bioassay

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