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5/9/01

Biological Terrorism Plague. 5/9/01. History. Importance One of three WHO quarantinable diseases Estimated 200 million deaths recorded Three prior pandemics Justinian 541 AD Black Death 1346 China 1855. Plague Doctor wearing protective clothing Image: National Library of Medicine.

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5/9/01

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  1. Biological Terrorism Plague 5/9/01

  2. History • Importance • One of three WHO quarantinable diseases • Estimated 200 million deaths recorded • Three prior pandemics • Justinian 541 AD • Black Death 1346 • China 1855 Plague Doctor wearing protective clothing Image: National Library of Medicine

  3. Bioweapon Potential • One of top 6 agents identified by CDC • Known attempted uses • Japanese (Unit 731) WWII infected fleas released over China • Larry Wayne Harris, microbiologist, with suspect motives obtained sample thru mail • Weapons programs • U.S. terminated 1970 • Russia – prior program’s status unknown

  4. Bioweapon Potential • Estimated Effect • WHO worst-case scenario • Aerosol release 50kg Y.pestis over city of 5 million people • 150,000 infected • 36,000 die Photo courtesy of the National Archives

  5. Bioweapon Potential • Delivery Mechanism • Aerosol • Bioweapons programs developed techniques to aerosolize plague directly • Pneumonic form would be expected • Proven infectivity of primates

  6. Epidemiology • Three forms of plague • Bubonic • Septicemic • Pneumonic • Human plague most commonly occurs when plague-infected fleas bite humans • Any suspected case in non-endemic areas without risk factors – report immediately

  7. Epidemiology • Naturally occurring human outbreaks parallel and follow epizootics • BT event may also spawn sylvatic plague • Following disasters • Disruption of rat habitats • Transport of disease through rat relocation Photo courtesy of the National Archives

  8. Epidemiology • Incidence naturally occurring plague • Globally • Approximately 1500 cases/year since 1965 • 25 countries reported cases • > 50% Eastern, S. Africa, esp. Madagascar • U.S. • 390 cases/year reported 1947-96 • Southwest region of U.S. endemic

  9. Epidemiology • Transmission • Historically, rat-borne urban epidemics • Now mostly endemic sylvatic plague with sporadic outbreaks • Pneumonic is only form capable of person to person spread • Higher risk in overcrowding, indoor contacts, cold/wet weather

  10. Epidemiology • Risk Factors • Close contact with case • Contact with infected animal • Living or recent travel in endemic area • Peridomestic animals running loose • Residing in crowded conditions • Cool, wet weather • Exposure to a known intentional release

  11. Epidemiology • Factors suggesting BT aerosol • Several cases of primary pneumonic (no or few bubonic) • Peak in number of previously healthy persons with cough, fever, SOB, death • Many with GI symptoms • Occurs in non-endemic area

  12. Epidemiology • Factors suggesting BT aerosol • Epidemic of severe/fatal pneumonia (hemoptysis) • Symptoms 1-6 days after exposure • Occurs in persons without risk factors • No preceding rat-falls

  13. Epidemiology • Surveillance • Any clinical or laboratory suspicion of plague cases should be immediately reported to the local health department and laboratory and if applicable the hospital epidemiologist or infection control practitioner

  14. Microbiology • Nomenclature progression • Bacillus pestis • Pastuerella pestis • Yersinia pestis

  15. Microbiology • Taxonomy • Family Enterobacteriaceae • 11 Yersinia species – 3 human pathogens • Y. pestis • Y. pseudotuberculosis • Y. enterocolitica

  16. Microbiology • Staining • Gram negative coccobacillus • Giemsa, Wright, Wayson stains – bipolar “safety pin” staining Image courtesy of CDC

  17. Pathogenesis • Environmental Survival • Requires host • Does not survive in environment well • Can live weeks in water, grains, moist soil • Lives months/years at just above freezing temperature • Lives only 15 minutes in 55 C • Lives in dry sputum, corpses, flea feces • Inactivated by sunlight in a few hours

  18. Pathogenesis • Highly virulent and invasive • Four routes human disease • Flea-bite (most common) • Handling infected animals- skin contact, scratch, bite • Inhalation – from humans or animals • Ingesting infected meat

  19. Pathogenesis • Intracellular organism • Survives in monocytes/macrophages • Inhalation (pneumonic form) • Deposition into alveoli • Classic lobular pneumonia • Resulting manifestation • liquefaction necrosis, residual scarring

  20. Clinical Features • Three types of Disease • Bubonic • Septicemic • Pneumonic

  21. Clinical Features • Bubonic • Classic • Predominates - 84% all U.S. cases • From contact with infectious material • Usually from bite of infectious flea • Contact with or ingestion of infected animals

  22. Clinical Features • Bubonic • Buboes • Enlarged tender lymph nodes • Usually unilateral • Usually inguinal/femoral in adults • Cervical/submaxillary more common in age < 10 Image: Armstrong & Cohen

  23. Clinical Features • Bubonic • Mortality • 40-60% untreated, <5% treated • Overall case fatality 14% in U.S. • Usually from delayed Dx and Rx • Complications • Often develop bacteremia • Some develop: • Septicemia (secondary septicemic plague) • Pneumonic (secondary pneumonic plague) • meningitis

  24. Clinical Features • Septicemic • Historically 12.6% U.S. cases are 1º septicemic • Secondary if complication of bubonic • If clinical sepsis develops • Primary if no buboes detected • More difficult to diagnose • May gain access through breaks in skin • May be flea-bite without bubo detectable

  25. Clinical Features • Septicemic • Similar to other gram-negative sepsis • Mortality • Overall 30-50% • Overall case fatality 22% in U.S. for primary • > 90% untreated • Still very high with treatment • Usually from late diagnosis and Rx • Empiric antibiotics for sepsis ineffective • 3rd generation cephalosporins

  26. Clinical Features • Pnuemonic • Numbers • Approx. 2% all plague in U.S. are 1º pneumonic • 12% are secondary pneumonic • Usually small % of cases in endemic areas • Secondary if preceding bubonic (most cases) or septicemic • Spread hematogenously to lungs • Interstitial pattern initially

  27. Clinical Features • Pneumonic • Primary if result of droplet inhalation • From other pneumonic plague patients or infected animals • Form expected if aerosolized as a bioweapon • Extremely infectious via droplets and purulent sputum

  28. Clinical Features • Pneumonic • Mortality • Nearly 100% untreated or if delayed > 18-24 hrs after symptom onset • High despite treatment • Overall case fatality 57% in U.S.

  29. Clinical Features • Other complications • Meningitis • Cutaneous disease • Pharyngeal disease • Enteric disease • Sustained occult fever from abscessed intraabdominal buboes

  30. Clinical Features • In BT event pneumonic form most likely • Pneumonic • incubation 1-6 (6 max, 2-4 typical) days for primary • Probably dose dependent • Initial–acute flu-like–F/C, myalgia, malaise, HA • Often prominent GI sx’s – N/V/D, abd pain • Severe pneumonia • Within 24hr of sx onset • Cough, hemoptysis, CP, SOB • Progresses to cyanosis, stridor, severe SOB

  31. Clinical Features • Radiography – usually patchy bilateral infiltrates, consolidation • Death • Usually occurs 2-4 (max 6) days after exposure if untreated • Cause – sepsis, overwhelming pneumonia with respiratory failure Image: Armstrong & Cohen

  32. Clinical Features • Immunity • Several days after infection before detectable antibodies develop • Earliest 5 days • Typical 1-2 weeks (3 weeks max) • Delayed by early successful antibiotics • <5% never • Transient, not life-long immunity after surviving • Antibody levels normalize in months-years

  33. Diagnosis • No rapid tests available – treat first • Report suspected cases to local health dept if no risk factor for naturally occurring disease • Send out samples if not done in hospital • Obtain specimens as indicated: • Blood – attempt 4 samples q30 min • Bubo aspirate (inject 1-2cc saline and aspirate with 20 Ga needle) • Sputum • CSF

  34. Diagnosis • CXR • Inoculate on/in infusion broth, blood agar, McConkey agar • Biochemical profiles if automated system has capacity to detect • Stains – Gram and Wayson’s or Giemsa • DFA testing • Acute serum for F1 antibody • CDC sample for bacteriophage lysis

  35. Treatment • Start immediately upon suspicion of diagnosis delay >1day after symptoms usually fatal

  36. Treatment • Antibiotics • General • Contained casualties – IV • Mass casualties – po equivalent, same as post-exposure prophylaxis • Also need intensive supportive care • Ventilation • Pressors usually not needed • Who to treat • Suspected cases • Index • If suspected release – anyone with fever, cough

  37. Treatment • Special populations • Children • Same as adults but try avoid TCN if <8yo • No chloramphenicol for <2 yo (grey baby syndrome) • Pregnant women • Try to avoid streptomycin • 1st choice gentamicin, same adult dose • 2nd choice doxy, same adult dose • 3rd choice cipro, same adult dose • Breastfeeding women • Same recommendations as pregnant • Immunosuppressed – no different than competent

  38. Treatment • Antibiotics for contained casualties • (For mass casualties, same as PEP) • 1st choices • Streptomycin - FDA-approved • 30 mg/kg IM divided q8-12 kids (max 2g/day) • 1g IM bid adult • bacteriocidal • gentamicin –as effective, more avail, qd dosing • 5mg/kg iv qd, w/levels or load 2mg/kg then 1.7mg/kg q8 • 2.5mg/kg im/iv q8h kids (q12hr for <1wk or premature)

  39. Treatment • 2nd choices • tetracyclines - as good in vitro, good human data • doxycycline • single 200mg iv loading dose (some sources) • 100mg iv bid or 200 mg iv qd adults& kids >45kg • 2.2mg/kg iv q12hr (max 200mg) kids <45kg • Better absorption, distribution, half-life than TCN • 1st choice po therapy for mass casualties • tetracycline • 500 mg po qid adults • 6.25-12.5 mg/kg po qid kids >9yo

  40. Treatment • 2nd choices • Fluoroquinolones–better in vitro, no human data • ciprofloxacin • 400 mg iv q12hr adults • 15 mg/kg iv q12hr kids (max 1g/day) • Levofloxacin • Ofloxacin • Chloramphenicol • 1st choice for meningitis +/- aminoglycoside • Crosses blood-brain barrier • 25mg/kg iv q6hr adults & kids, keep level 5-20 μg/ml • Avoid in kids <2 yo (grey baby syndrome)

  41. Treatment • 2nd choices • Alternatives – sulfonamides • If other antibiotics not available • Ineffective for pneumonic • TMP-SMX • Generally ineffective • Β-lactams, rifampin, aztreonam, macrolides

  42. Treatment • Antibiotic resistance rare • May be expected in BT scenario (engineered agents)

  43. Treatment • Switch to po when improved, tolerates • Usual response • Bubonic – improved in 2-3d, afebrile 2-5d • Duration – 10-14 days or 3+ days after afebrile, improving • Supportive care • Volume status maintenance • Hemodynamic monitoring • pressors not usually needed • Support of multiorgan failure

  44. Treatment • Bubo care • Usually recedes with antibiotics • Rarely become fluctuant/abscessed • Unnecessary I & D increases contact’s risks

  45. Post-exposure Prophylaxis • Also for mass causalities • For all asymptomatic contacts of suspected untreated pneumonic cases • Contact within last 6 days • Untreated pneumonic = <48hr approp treatment • Those within 2 meters of case • Household, hospital contacts • Those who might have been exposed to initial aerosol • Seek out homeless, mental handicaps, homebound

  46. Post-exposure Prophylaxis • Antibiotics • 1st choices • Tetracyclines • Doxycycline • 100 po bid adults and kids >45 kg • 2.2 mg/kg po bid for kids <45 kg • Tetracycline – equivalent dosages • Fluoroquinolones • Ciprofloxacin • 500 mg po bid for adults • 20 mg/kg po bid (max 1g/day) for kids • Others at equivalent dosages

  47. Post-exposure Prophylaxis • Alternatives • Chloramphenical 25 mg/kg po qid • Not in kids <2yo • For pregnant & breastfeeding women • Same as adults above but no tetracycline • Doxycycline may be used • Duration • 7 days since last exposure PEP • 10 days for mass casualties

  48. Prevention • Vaccination - Bubonic only • Killed virulent strain – used in U.S. • Formalin-fixed, no longer commercially available • Future production and licensure unknown • Series • 3 primary (1.0cc, 0.2 cc at 1-3 mo and 5-6 mo later) • 2 boosters 0.2cc at 6 mo intervals then q1-2yrs

  49. Prevention • Vaccination • Indications • Lab workers with fully virulent strains • Military personnel stationed in endemic areas • Efficacy • Based on WWII (0 cases) and Vietnam (3 cases) troops • Protects vs. bubonic only, not pneumonic • Adverse effects • Significant number have mild reactions • May be severe

  50. Infection Control • Mechanism for person-person spread • Not completely understood • Respiratory droplets most likely, not droplet nuclei • Historically prevented by masks • Respiratory Droplet Precautions • Wear mask, gown, gloves, eye protection • Suspected cases - isolate • Immediately respiratory (even for bubonic) • Avoid unnecessary close contact 1st 48 hrs of abx • Duration • 2 days after initiating antibiotics and clinically improved • After sputum cultures negative

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