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5/9/01

Biological Terrorism Tularemia. 5/9/01. History. Disease of the 20 th century Only sporadic outbreaks, no epidemics First suspected case in humans in 1907 Isolated in ground squirrel in 1911 First documented human infection 1912 Edward Francis Isolated Bacterium tularense

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5/9/01

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  1. Biological Terrorism Tularemia 5/9/01

  2. History • Disease of the 20th century • Only sporadic outbreaks, no epidemics • First suspected case in humans in 1907 • Isolated in ground squirrel in 1911 • First documented human infection 1912 • Edward Francis • Isolated Bacterium tularense • postulated rabbit as reservoir

  3. Bioweapon Potential • One of top 6 agents listed by CDC • Weaponized in 1950s and 60s by U.S. • Former Soviet Union weaponizing in 1990s • Antibiotic and vaccine resistant strains developed • Used on prisoners 1932-45 by Japan

  4. Bioweapon Potential • Estimated Effect • 50kg F. tularensis over a city of 5 million • 250,000 incapacitated • 19,000 dead • Incapacitation occurring within 1 to 2 days • Incapacitation lasts for days –weeks • Untreated disease is persistent and relapsing

  5. Bioweapon Potential • Delivery Mechanism • Aerosol would be most likely mechanism • Could be weaponized wet or dry • Proven infectivity in humans via aerosol • Pneumonic form would be most likely

  6. Bioweapon Potential • Delivery particle size • Dictates severity and form of disease • Form determined by location of deposition along respiratory and GI tracts • Difference in severity due to tissue susceptibility

  7. Bioweapon Potential • Factors suggesting aerosol bioterrorism attack • Large number, previously healthy, with sudden constitutional symptoms (fever, myalgias, flu-like) • Many then develop cough and dyspnea • At first difficult to differentiate from community acquired pneumonia, influenza • Rapid worsening to critical illness in high percentage of patients

  8. Bioweapon Potential • Factors suggesting aerosol release • Point or line source outbreak pattern • Acute constitutional signs and symptoms • Pharyngitis • Bronchiolitis • Pleuropneumonitis • Hilar lymphadenitis

  9. Epidemiology • Epidemiology clues • Risk of disease & severity dependent on exposure instead of underlying illness, age • Epizootics, especially in nonendemic area • Unlikely oropharyngeal from water supply as chlorine adequate to kill organism • Urban epidemic suggests bioterrorism

  10. Epidemiology • Decline in U.S. • 2291 cases reported in 1939 • Less than 200/year in 1990s • 1409 cases (20 deaths) 1985-1992

  11. Epidemiology • Primarily rural • Endemic • Every continental U.S. state • Scandinavia, Russia, other parts of Europe • Epidemics • Vermont 1968 • Spain 1997 – 140 confirmed cases • Scandinavia less than 500 cases (waterborne) • Sweden 1996-97 (farm work creating aerosols) • Russia – 1000 cases

  12. Epidemiology • Untreated mortality • 5-15% Type A strains • 1-3% Type B strains • 5% Ulceroglandular (UG) form • 30-60% typhoidal/pneumonic • >70% fatal cases have pulmonary involvement

  13. Epidemiology • Summer peak related to ticks • 90% pediatric cases • Winter peak related to trapping and hunting of rabbits Photo courtesy of National Archives

  14. Epidemiology • Risk Factors • Handling infected animals • Hunting, trapping, farming, butchering • Ingestion of contaminated meat, water, soil • Bitten by arthropods in endemic areas • Microbiology laboratory workers

  15. Microbiology • Nomenclature • Initially named Bacterium tularensis • Later changed to Francisella tularensis • In honor of Edward Francis

  16. Microbiology • Taxonomy • Family - no human pathogens close relative • Jellison Type A (Biovar tularensis) • Predominant type in North America (90%) • No cases reported in Eurasia but isolated in animals • More severe disease • LD50 in mice and hares = 1-9 organisms

  17. Microbiology • Primary sources (Type A) • Lagamorphs • cottontail and wild hare, not domestic rabbit • Rodents • muskrat, vole, beaver, squirrel • Ticks feeding on above • Biochemical tests • Acidifies glycerol • +citrulline ureidase activity

  18. Microbiology • Jellison Type B (Biovar palaearctica) • Predominant type in Eurasia • Less severe disease, more often asymptomatic • Also common in U.S. • 108 bacteria intraperitonealy in hares not lethal

  19. Microbiology • Primary sources (Jellison Type B) • Aquatic rodents • voles, muskrats, lemmings • Contaminated water/soil from rodents • Hares • Mosquito bites • Biochemical tests • Does not acidify glycerol • No citrulline ureidase activity

  20. Microbiology • No differences in in vitro susceptibility testing between Types A and B • Type C (Biovar novicida) • Other nonpathogenic types • Biovar palaearactica mediasiatica in C. Asia • Biovar palaearcticia japonica in Japan

  21. Microbiology • Staining • Gram negative pleomorphic coccobacillus • Faint staining • Motility • Non-motile • Spore formation • Non-sporulating

  22. Microbiology • Size • Small, 0.2 m x 0.2-0.7 m • Cell wall • LPS • Metabolism • Aerobic • Facultative intracellular (macrophages)

  23. Microbiology • Metabolism – Colony growth • Slow • May start to appear 24-48 hours under optimal conditions • Usually slower • Should hold cultures 10 days before calling negative • Requires cysteine-enriched medium • Grows very slowly if at all on standard media • Cysteine heart blood agar • Buffered charcoal-yeast agar • Chocolate agar

  24. Microbiology • Colony morphology • Small 3-5 mm on cysteine-enriched agar by 96 hours • Opalescent, opague

  25. Pathogenesis • Environmental Survival • Hardy (weeks to 3-4 months) in cold (even frozen) and moist conditions, weeks in water, carcasses/hides, soil, hay, frozen rabbit meat • Killed by heat (55 C x 10 min) • In aerosol, likely short lifespan (sun, drying, oxidation, open exposure to environment)

  26. Pathogenesis • Natural Life Cycles • Tick-rabbit • Ticks maintain infection in reservoirs of rabbits, voles • Animal-animal • Aquatic rodents infect each other and through environment (e.g. contaminated water) • Humans • Infected when they get in the way of natural cycles

  27. Pathogenesis • Forms of Disease • Depends on route of infection, dose, strain, virulence • Ulceroglandular (UG) • 45-85% of all cases • Glandular • 5-25% of all cases • Typhoidal • 5-15% of all cases • Usually but not always from inhalation • Most common form for lab-related disease

  28. Pathogenesis • Forms of disease • Oculoglandular • 1-5% • Oropharyngeal • 1-7% of cases • Pneumonic • Most cases develop some pulmonary symptoms • Need CXR findings (pleural or parenchymal) to diagnosis • Some discrepancies because many studies do not consider this to be separate entity

  29. Pathogenesis • Pneumonic • Primary • Inhalational exposure • Secondary • Hematogenous spread generally coincident with UG • 30% UG cases develop pneumonia • 80% typhoidal cases develop pneumonia • Unable to differentiate by pathologic findings

  30. Pathogenesis • Pneumonic • Complications • ARDS • Respiratory failure • Rhabdomyolysis • Sepsis • Death

  31. Pathogenesis • Routes of infection • Infectious dose • 10-50 organisms by inhalation/intradermal • 108 organisms orally • Skin inoculation • Susceptible animals are hosts but not reservoirs as they die or recover without carrier state • Handling diseased animal carcasses • Mostly wild mammals, also birds, fish, amphibian, reptiles • Occasionally domestic cats and dogs that have preyed on infected animals

  32. Pathogenesis • Routes of Infection • Arthropod vector bites • May be true reservoirs as well as vectors • Causes 1/3 to ½ tularemia cases now • Dog tick, wood tick • Deer fly, horse fly • Mosquito

  33. Pathogenesis • Routes of infection • Inhalation of aerosols/dusts • Most humans exposed to aerosol become infected, only 25-50% of those will get radiographic evidence of pulmonary involvement • Handling contaminated hay • Contaminated water sprays • Dust from contaminated soil • Handling or in vicinity of dead rabbits • Route of most lab-associated infections

  34. Pathogenesis • Routes of infection • Ingestion • Inadequately cooked meat from infected animal • Contaminated water and soil • Inoculation into eye • Usually contaminated fluids or hand

  35. Pathogenesis • Transmission • No person to person documented cases • Virulence factors • Poorly understood • LPS envelope

  36. Pathogenesis • Sequence of events • Growth at inoculation site • Lymphatic spread to regional nodes • May disseminate hematogenously, especially untreated • Reticuloendothelial organs (liver, spleen, nodes), lungs, kidneys, skin, meninges • Bacteremia common early in course but not usually detected • Intense violent tissue inflammatory reaction at sites of infection give way to typical suppurative necrosis

  37. Pathogenesis • Pathology • Focal areas of necrosis, initially PMNs / macros then caseating granulomata like TB • May be surrounded by fibroblasts • Small firm reddish lesions look like miliary TB, especially in lung

  38. Pathogenesis • Pneumonic cases pathology • Hemorrhagic airway inflammation early • Early purulent bronchiolitis, atelectasis • Pleuritis with adhesions, effusion common • Hilar LAD common • 50% have subcentimeter subpleural yellow nodules • 30% bronchopneumonia • 15% necrotizing lobar pneumonia with consolidation • Late complication fibrosis • Exudative glomerulitis also common

  39. Pathogenesis • Immunity • Antibody appearance • Begin to appear in approximately 1 week • Usually not to diagnostic levels until 2 weeks • Peak in 3-4 weeks • Remains at high levels for 6 months • Levels do not correspond with form or severity of disease

  40. Pathogenesis • Immunity • Antibody disappearance • Persisted 11 years at titre  80 in 6/6 subjects • Agglutinin titres dropped from  160 to  40 in 51/53 cases infected 25 years previously • Negative serology does not rule out past infection or lack of cell mediated immunity

  41. Pathogenesis • Immunity • Cell mediated immunity most important • Probably 2/2 intracellular infection • 44/52 cases who had tularemia 25 years prior showed substantial in vitro proliferation in response to challenge to F. tularensis membrane proteins • Many of these also responded with IFN-gamma production • DTH skin testing positive 40 years after infection • Reinfection unlikely but possible, > 12 reported

  42. Clinical Features • Epidemiological features • Animal (rabbit) tick exposure • Hi-risk occupation or outdoor activity • Symptoms • Nonspecific • Acute onset flu-like • Low-back myalgias

  43. Clinical Features • Signs • Skin ulcer • Regional LAD • Pulse/temperature dissociation • Unresponsive to antibiotic therapy • Test findings • Slow growing small gram negative coccobacilli • Pneumonia with pleural involvement & hilar LAD

  44. Clinical Features • For all 6 forms • Very variable – asymptomatic to fulminant • Incubation • < 24 hours experimentally aerosol infected monkeys • Typically 2-5 days • Range 1-21 days, practical range 1-14 days, > 30 days in 2% in Japan • Dependent on inoculation dose, type/virulence

  45. Clinical Features • For all 6 forms • Usually sudden onset nonspecific constitutional, flu-like symptoms • Fever – most common feature (74-91%), chills, profuse sweats • May briefly subside without treatment transiently on 3-4th day • Temperature may reach 104 F • Lasts 2-3 weeks without antibiotics • Malaise, fatigue • Myalgias, especially low back • Headache, sometimes severe

  46. Clinical Features • For all 6 forms • If more chronic, untreated • F/C, sweats, anorexia • Weight loss if > 2-3 weeks before diagnosis • Lymphadenopathy (except in typhoidal) • Most common exam finding • Up to 50% suppurate • Sometimes hepatomegaly

  47. Clinical Features • For all 6 forms • Pulmonary • Cough 23-40%, usually non- or slightly productive • Effusion 21-31% • Chest pain • Pharyngitis 15-40%, sore throat (resembles Strep, EBV) • Temperature/pulse dissociation – up to 42% • Can be asymptomatic, 20%, more likely with B type • Symptoms usually progress if untreated

  48. Clinical Features • Ulceroglandular • Most common form in U.S. • Papule at inoculation site few days after onset • Maculopapular, painful, inflamed • Turns pustular, necrotic core, painful ulcer over a few days • 0.5 cm diameter • Punched out with raised edges • Ulcer may have eschar (thing anthrax) • Can persist months

  49. Clinical Features • Ulceroglandular • Regional lymphadenopathy – proximal to inoculation • Usually present but not necessary for diagnosis if ulcer present • Appears about same time as lesion ulcerates • May be single or multiple nodes • May have overlying erythema • Painful, swollen, may suppurate – even with antibiotics

  50. Clinical Features • Ulceroglandular • Regional lymphadenopathy – proximal to inoculation • Locations • Hand lesions – axillary (65%) > epitrochlear (8%), most common or animal exposures • Thumb – can go to supra/infraclavicular • Leg lesions – femoral/inguinal nodes, most common for arthropod bites • Slow resolution • Even with treatment • 2-3 months tenderness without treatment

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