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Plague & Tularemia

Plague & Tularemia. WKY University ACVPM Exam Review Marc E. Mattix, DVM, MSS Diplomate, ACVP Colonel, VC, USAR Asst. Chief, US Army Veterinary Corps (MRA). Strategic Context. Post-Cold War Era End of Bipolar Geopolitics Diffusion of State power Failed Nation-States

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Plague & Tularemia

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  1. Plague & Tularemia WKY University ACVPM Exam Review Marc E. Mattix, DVM, MSS Diplomate, ACVP Colonel, VC, USAR Asst. Chief, US Army Veterinary Corps (MRA)

  2. Strategic Context • Post-Cold War Era • End of Bipolar Geopolitics • Diffusion of State power • Failed Nation-States • Regional instability • CBRNE threats • Era of Globalization • Technology-Informatics-Transportation • “Superempowered” Individuals • Explosion in EIDs

  3. Reduced PH influence Depleted infrastructure Rampant urbanization Ecological manipulation Global transportation CNN effect Public reaction Expansion of human, reservoir and vector populations Changing human susceptibility Microbial adaptation Terrorism Factors

  4. The Physical Protection of Critical Infrastructures & Key Assets • Agriculture & Food • Water • Public Health • Emergency Services • Defense Industrial Base • Telecommunications • Energy • Transportation • Banking & Finance • Chemicals & HAZMAT • Postal & Shipping (Feb 2003)

  5. RESERVOIR ENVIRONMENT VECTOR AGENT Predictive Epidemiology

  6. Transportation • #1 Global growth industry • Year 2000 • 700 million international tourists in to the US • 1.3 million tourists/day in to the US • 38,000 imported animals/day in to the US • 4000# smuggled meat confiscated from Haiti per month www.world-tourism.org

  7. Speed of Global Travel in Relation to World Population Growth 1.3 million international tourists enter the US each day

  8. Plague

  9. The Great Pestilence (1346-1352)

  10. 3rd Pandemic: 1860 (China) • Etiology: 1894 (Yersin & Kitasato) • Transmission: 1898 (Simond) • Introduced to US: 1900

  11. Current pandemics • Tanzania • 1983-1995 • Madagascar • 1989 – present • India • 1994 - present

  12. Plague as an EID • Expansion of human cases • Four endemic states up to 1983 • 13 endemic western states 1983-1998 • Increased incidence • Multidrug resistance

  13. Yersinia pestis • Family Enterobacteriaceae • Gram-negative coccobacillus • Bipolar staining 1-2 x 0.5 µm • Nonspore-forming & nonmotile • Slow-growing on standard media • CAT A Critical Biological Agent (CDC) • Plague is a reportable disease • CDC & WHO

  14. Yersinia pestis • 3 Biovars • Ability to ferment Glycerol & reduce Nitrate • Orientalis • Medievalis • Antigua • Clone of Y. pseudotuberculosis • Emerged between 1,500-20,000 years ago • Y. pseudotuberculosis • Asymptomatic in rats • Confers protective immunity to Y. pestis

  15. Virulence factors • Multiple virulence determinants encoded on 3 plasmids (9.5, 70 & 110 kb) and chromosome • One or more genes on the 110 kb plasmid are required for vector transmission • Fraction 1 (F1) • Capsular protein • Protective immunogen • Basis of vaccines and diagnostic assays • NOT an essential virulence factor • F1 - negative strains isolated from fatal cases

  16. Virulence factors • Current research is directed at defining essential virulence factors as immunogens • V protein • Essential virulence factor and protective immunogen • Encoded by the 70-kb low-calcium response plasmid • Inhibits PMN chemotaxis invitro and in vivo • Linear peptides prepared from B-cell epitopes in the V protein are immunogenic but not protective • The protective B-lymphocyte epitope(s) in the V protein is likely to be conformational

  17. Epidemiology Infectious disease of rodents transmitted by the bites of fleas • Maintenance (Enzootic) • Peromyscus (mice) • Microtus (voles) • Kangaroo rats • Amplification (Epizootic)SUPERFAMILY Sciuromorpha • Ground squirrels • Rock squirrels • Fox squirrels • Prairie dogs • Rats

  18. Transmission • Vector-borne: Infected fleas • Oriental rat flea (Xenopsylla cheopis) • Western US: Oropsylla montana • Direct contact via breaks in skin • Bite from infected animal • Aerosolization • Carnivore to human • Human to human • Environmental • Human cases follow rodent epizootics

  19. Environmental persistence • Rodent-flea cycle • Flea data • >31 species are competent vectors • No transovarial transmission • Organisms multiply and block gut • Maintain viable organisms for up to 2 years • Nonculturable form in soil & water • Survival within plants

  20. Clinical Signs • Infectious dose: <500 orgs • Incubation: 2-3 days • Symptoms • High fever, chills, headache • Malaise, cough • Tender lymph nodes (buboes) • Pneumonia, sepsis • Cyanosis, respiratory failure • Disease syndrome related to route of transmission • Fatality rate: 60%

  21. Pneumonic Plague Inhalation Fever, chills, cough, respiratory distress Exposure to infected domestic cats Pharyngeal Plague Inhalation, ingestion Septicemic Plague Bacteremia Fever, chills, shock, DIC Bubonic Plague (90%) Flea or cat bite Enlarged lymph nodes Fever, chills, prostration Plague syndromes

  22. Non-rodent hosts • >200 species of susceptible mammals • Felids • Highly susceptible, with marked bacteremia • Fever, lethargy & anorexia • >50% Bubonic with cervical lymphadenopathy • 40% fever without lymphadenopathy or pneumonia • Outcome • Untreated: 30% mortality • Treated: 90% survival

  23. Non-rodent hosts • Antelope • Uncommon, associated with a 1987 MT mortality • Deer • Necrotizing lymphadenitis & pneumonia • Canids • Seroconvert, clinical cases uncommon • Fever, anorexia, lethargy, stomatitis & salivation • Cervical lymphadenopathy • Cutaneous draining lesions in cervical region • YNP adult coyotes: 86% seropositivity

  24. Cervical lymphadenopathy

  25. Plague Diagnosis • History/Epidemiology • Symptoms • Serology (anti-F1 antibody) • Culture • Gross lesions • Histopathology • Mouse inoculation • Fluorescent antibody • PCR

  26. Culture • Biologic safety level II practices • General nutrient agar- sheep blood agar • 28° in a CO2-enriched environment • Slow-growing • 48+ hours • Maintain out to 5 days

  27. Plague Diagnosis • Speciation • API 20E system • Small human-oriented database • BBL Crystal Enteric/Nonfermenter ID • 30 well system of carbohydrate substrates • Traditionally preferred ID system • Small human-oriented database • Biolog (Hayward, CA) • 96 wells of carbon substrates • Large comparative database

  28. Packing and Shipping • Blot dry • Absorbent material • Double wrap • Ship with cold packs • NO WET ICE • Prevent bioterrorism!

  29. Plague: New and interesting • Diagnostics • DNA microarray • Multiple locus variable-number of tandem repeat markers • F1 - Negative Strains • Capsular protein • Protective immunogen • Basis of currentvaccines and diagnostic assays • Multidrug resistant isolates • Emerged in Madagascar in 1995 • Plasmid pIP1202 • Origin: Enterobacteriaceae family • Highly transferable via conjugation

  30. Plague: New and interesting • Antibiotic therapy • Traditionally very effective if administered early in course of disease • Aminoglycosides • CHPC • Tetracyclines • Sulfonamides • Cephalosporins • Penicillins

  31. Multidrug resistant Yersina pestis • Penicillin resistance • Beta-lactamase and TEM-1 penicillinase • Chloramphenicol resistance • Chloramphenicol acetyltransferase • Kanamycin resistance • I 3’ - aminoglycoside phosphotransferase • Streptomycin-Spectinomycin resistance • 3” -9 - aminoglycoside adenyltransferase • Sulfonamide resistance • Hydropteroate synthase

  32. New and interesting • Conformational change • ß-lactam antibiotic-induced filamentous change • Potential for misdiagnosis on culture • Persistence in the environment • PCR positive / culture negative soil samples • Experimental loss of culturable forms in <7 days in soil or distilled water • Complete reversion of nonculturable forms with addition of fetal serum • Pathogen survival within plants

  33. Control and prevention • Education • Reservoir control • Vector control • Dusting burrows with permethrin • Urban habitat and food control • Minimize rodent-human contact • Prompt diagnosis and treatment • Surveillance & reporting • Emergency management of endemic foci

  34. Plague: Risk Behaviors • Urbanization • 23 cat-associated human cases in the US, 1977-1998 • Cat exposure most likely during a rodent epizootic • Transportation

  35. Texas, May 1998 500 animals died prior to shipment Texas, June-August 2002 250/3600 died after shipments Texas, 2002 3600 infected PDs shipped to 10 states & 7 countries Human Tularemia Facility animal handler 3-yr-old child in Spain Captive Prairie Dog Outbreaks

  36. Tularemia • Francisella tularensis • 4 subsp. (F.t. subsp tularensis & holarctica) • Aerobic gram-negative coccobacilli • Category A Critical Biological Agent (CDC) • Features • Large number of transmission routes • Tremendous species susceptibility • >100 invertebrates, >150 vertebrate spp. • Wide array of clinical syndromes • Environmental Persistence • Soil, water, amoeba, invertebrates, rodents

  37. Vectors HARD TICKS Transstadial/transovarian Human transmission MT: Dermacenter variabilis BITING FLIES Chrysops Tabanus Mechanical transmission Infective for 14 days Direct contact Skinning infected animals Ingestion Infected tissues Water (esp. Microtus spp) Inhalation Tularemia Transmission

  38. Tularemia Clinical Presentations • Ulceroglandular (75-85%) • Ulcer and regional lymphadenopathy • Glandular (5-10%) • Oculoglandular • Conjunctivitis, cervical lymphadenopathy • Typhoidal (5-15%) • Oropharyngeal (1-2%) • Intestinal • Pulmonary

  39. Tularemia Diagnosis • History of exposure • Culture • Paired serology • ELISA, tube agglutination, microagglutination for IgM • Histopathology • Immunohistochemistry • FA • PCR

  40. Courtesy of LTC K Steele USAMRIID

  41. Plague: Risk Behaviors • “Public Backlash” • Anti-pesticide use • Anti-reservoir control • Increased wildlife exposure • Epizootic reservoir recovery • Prairie dog outbreaks, MT • N. Central Montana (2001-5) • Prairie Dog Reintroduction site

  42. Public Backlash • Prior to 1992, >1,000,000 acres of prairie dog habitat were poisoned • “… due to the alarming disintegration of Prairie Dog ecosystem, we recommend that ADC operations concerning Prairie Dogs be terminated on the basis that they are at cross purposes with federal wildlife management programs that seek to perpetuate and recover wildlife species that depend on the Prairie Dog ecosystem.” DEPT OF ENVIRONMENTAL STUDIES, U of Montana

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