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Bioterrorism The Basics for General Practitioners

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  1. Bioterrorism The Basics for General Practitioners

  2. Bioterrorism The use, or threatened use, of a micro-organism or the product of a micro-organism in order to generate fear, morbidity or mortality in a population.

  3. Bioterrorism Agents • Category A Diseases • Anthrax (Bacillus anthracis) • Smallpox (Variola virus) • Plague (Yersinia pestis) • Tularemia (Francisella tularensis) • Botulism (botulinum toxin) • Viral Hemorrhagic Fever

  4. Delivery Mechanisms • Aerosol route • Easiest to disperse • Highest number of people exposed • Most infectious • Undetectable to humans • Food / Waterborne less likely • Larger volumes required • More technically difficult

  5. Roles of Clinicians • General Concepts • High level of suspicion • Hoofbeats could be a zebra • Unusual epidemiologic trends • Case clustering • Severe, fulminant disease in otherwise healthy • Unusual for the region • Similar disease in animals

  6. Roles of Clinicians • For specific Bioterrorism (BT) diseases • Recognize typical BT disease syndromes • Perform appropriate diagnostic testing • Initiate appropriate treatment/prophylaxis • Report suspected cases to proper authorities 1) Local health department 2) Hospital epidemiologist 3) Infectious Disease consultants

  7. Anthrax Bacillus anthracis

  8. History • Sporadic disease in 20th century U.S. • Experience as biological weapon • U.S., 2001 • Most letter-associated • 22 cases (18 confirmed), 5 deaths • Sverdlovsk, Russia, 1979 • Accidental release from weapons facility • ≥77 cases, 66 deaths

  9. Epidemiology • Forms of disease • Inhalational (<5% cases; 45-89% mortality) • Cutaneous (95%; <1-20% mortality) • Gastrointestinal (<5%; >50% mortality) • Risk Factors • Exposure to infected animals • Exposure to aerosolized spores

  10. Microbiology • Bacillus anthracis • Aerobic, large Gram positive bacillus • Non-motile, non-hemolytic • Potential mislabeling as contaminant • Forms hardy spores • Triggered by harsh environment • Inert but infectious • 1m size

  11. Figure is not shown because the copyright permission granted to the Centers for the Study of Bioterrorism and Emerging Infections does not include usage on our website Jernigan, et al. EID. 2001;7:933-944.

  12. Figure is not shown because the copyright permission granted to the Centers for the Study of Bioterrorism and Emerging Infections does not include usage on our website Dixon, et al. NEJM. 1999;341:815-26.

  13. Figure is not shown because the copyright permission granted to the Centers for the Study of Bioterrorism and Emerging Infections does not include usage on our website Dixon, et al. NEJM. 1999;341:815-26.

  14. Clinical Features - Inhalational • Incubation • Range 2-43, median 4-7 days • Prodrome • “flu-like” - fever, malaise, dry cough • Nausea, vomiting, diarrhea • Lack of nasal symptoms • Fulminant • Respiratory failure, shock, toxemia

  15. Figure is not shown because the copyright permission granted to the Centers for the Study of Bioterrorism and Emerging Infections does not include usage on our website Inglesby, et al. JAMA. 1999;281:1735-45

  16. Differential Diagnosis Influenza, viral URI’s Pneumonia Community-acquired Atypical Pneumonic tularemia Pneumonic plague Mediastinitis Thoracic aortic aneurysm Bacterial meningitis Expect if anthrax Rapid diagnostics – Abnormal CXR No nasal symptoms Usually no sputum May be no infiltrate No prior surgery Fever Gram+ rods in CSF Clinical Features – Inhalational

  17. Clinical Features - Cutaneous • Most common areas of exposure • Hands/arms • Neck/head • Incubation period • 3-5 days (maximum 12 d.) • Mild constitutional symptoms • Systemic disease rare • Lymphangitis/lymphadenopathy • Sepsis, multiorgan failure, death

  18. Clinical Features - Cutaneous • Progression of painless lesions Papule/macule – pruritic Vesicle/bulla – clear or serosanguinous Ulcer – nonpitting, gelatinous edema Eschar – black, depressed, rarely scars 24-48 hrs days

  19. Figure is not shown because the copyright permission granted to the Centers for the Study of Bioterrorism and Emerging Infections does not include usage on our website Photo courtesy of the Tropical Medicine Institute, UPCH

  20. Clinical Features - GI • Oropharyngeal • Oral/esophageal ulcer, regional adenopathy • Edema/stridor, sore throat, fever, sepsis • Intestinal • Early - nausea, vomiting, malaise • Late - hematochezia, acute abdomen, ascites • Differential diagnosis • Gastroenteritis (early) • Any source of acute abdomen, peritonitis (late)

  21. Diagnosis • High index of suspicion necessary • Early diagnosis difficult • Gold Standard - culture blood, fluids • Prior to antibiotics • Confirmation by reference labs • PCR, special stains, serology, etc • Nasal swabs not a diagnostic tool

  22. Treatment • Hospitalization • IV antibiotics • Empiric until sensitivities known • Intensive supportive care • Electrolyte and acid-base imbalances • Mechanical ventilation • Hemodynamic support • Steroids • Consider for severe disease

  23. Treatment • Empiric therapy for inhalational (Adults) • Ciprofloxacin 400 mg IV q12° OR Doxycycline 100 mg IV q12° AND One or two other antibiotics - clindamycin - penicillin - vancomycin - chloramphenicol - rifampin - imipenem • Avoid macrolides, cephalosporins, sulfa

  24. Treatment • Empiric therapy for inhalational (Children) Ciprofloxacin 10-15 mg/kg/d IV q12° (max 1 g/d) OR Doxycycline 2.2 mg/kg IV q12° (adult dose >8yo/45 kg) AND One or two antibiotics (same as adult) • Weigh risks (arthropathy, dental enamel)

  25. Treatment • Empiric therapy for cutaneous • Same as inhalational regimen if: • Systemic disease • Extensive edema • Head/neck lesions • Localized cutaneous • Ciprofloxacin 500mg po bid OR • Doxycycline 100mg po bid • Empiric therapy for GI • Same as inhalational

  26. Treatment • Antibiotic therapy – all forms • Adjust per sensitivities • Duration • 60 days - delayed spore germination • Follow closely after cessation • Switch to oral • Clinical improvement, able to tolerate po • 1 or 2 drugs including cipro or doxy initially • Children can complete course with amoxicillin • No role for vaccine in treatment

  27. Post-Exposure Prophylaxis • Indications • Exposure to anthrax spores • Not for contacts of cases • Oral antibiotics • Ciprofloxacin 500 mg po bid OR • Doxycycline 100 mg po bid • Duration 60-100 days • +/- Vaccination

  28. Vaccination • Inactivated, cell-free vaccine • Effective • >95% animals vs. inhalational • Protective for humans vs. cutaneous • Well-tolerated • Uncommon adverse effects • No reported deaths • Limited supply

  29. Infection Control • Person-to-person transmission • None for inhalational • Rarely reported for cutaneous • Patient handling • Standard precautions • Gloves for draining lesions • Laboratory safety • BSL-2 for clinical specimens • BSL-3 for environmental or large volume

  30. Smallpox Variola Virus

  31. History • Ancient scourge – many millions killed • Global eradication in 1977 • Bioweapon potential • Prior use in French-Indian War • Produced by USSR • Stocks still exist

  32. Epidemiology • No animal reservoir/vector • Mortality 25-30% • Transmission via droplets/aerosol • Person-to-person transmission • Secondary attack rate 25-40% • Up to 3-20 contacts infected • Hi risk of nosocomial spread

  33. Microbiology • Variola virus • Orthopoxviridae family • Variola strains • Variola major – high mortality • Variola minor – low mortality, 20th Century • Vaccinia • Current smallpox “vaccine” • Other pox viruses (cowpox, monkeypox)

  34. Pathogenesis Viruscontacts respiratory/oral mucosa Carried to nodes Viremia Organ seeding WBCs infected Dermal invasion Vesicle Sepsis

  35. Clinical Features • Stages of disease • Incubation • Asymptomatic • 12-14 days (range 7-17) • Prodromal • Nonspecific febrile prostrating flu-like illness • 3-5 days • Eruptive • Characteristic rash – location, grouping, depth • Marker of infectiousness

  36. Courtesy of National Archives

  37. Courtesy of National Archives

  38. Courtesy of World Health Organization

  39. Clinical Features • Differential Diagnosis • Chickenpox (varicella) • Vesicles • Shallow • Asynchronous development • Distribution of rash • Centripetal • Spares palms/soles

  40. Diagnosis • Clinical • Traditional confirmation • Electron microscopy • Culture • Newer rapid tests • Reference labs (e.g. CDC) • PCR, RFLP

  41. Treatment • No effective antivirals • Supportive care • Fluid balance • Electrolytes • Hemodynamic support • Antibiotics for secondary infections • Isolation

  42. Post-Exposure Prophylaxis • Vaccine • Reduces incidence 2-3 fold • Decreases mortality by ~50% • Vaccinia immune globulin(VIG) • 3 fold decrease in incidence and mortality • Passive immunity for 2 weeks • Cidofovir – antiviral agent • Effective vs other poxviruses in animals

  43. Vaccination • Vaccinia virus • Stock • ~15million doses • >20 years old, still viable • Efficacy • 10 fold reduction secondary attack rate • Substantial protection for 3-10 years • Multiple vaccinations boost duration

  44. Vaccination • Adverse Effects • 3/100,000 vaccinees • Death • 1/million vaccinees • Highest risk • Primary vaccinees • Infants

  45. Vaccination • Serious complications • Encephalitis • Vaccinia gangrenosum/necrosum • Eczema vaccinatum • Mild complications • Generalized vaccinia • Autoinoculation • VIG can treat/prevent

  46. Fenner F., D. A. Henderson, et al. Smallpox and its Eradication. Geneva: WHO; 1988. Original photo by C. H. Kempe.

  47. Infection Control • Isolation of Cases • Contact precautions • Gloves, gowns • Airborne precautions • Negative pressure HEPA filtered room, N95 masks • Home isolation an option • Avoids nosocomial spread • Assign immune persons for care

  48. Infection Control • Management of Case Contacts • Rash = Infectious, fever precedes rash • Contact identification • Exposure to case patient after fever onset • Contact with secretions or face-to-face <3 meters • All patients and staff in hospital with a case • Immediate vaccination • Observation (not isolation) • 17 day fever watch – isolate if >38°C • Quarantine may be necessary

  49. Plague Yersinia pestis

  50. History • 3 Pandemics • Justinian - 6th century Africa/Asia • Black Death – 14th century Europe • Worldwide – 19th/20th century • Potential for use as bioweapon • Unit 731 Manchuria • Former USSR production