Differential Diagnosis

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Differential Diagnosis
Pneumonic Plague
Septicemic Plague
Inhalation anthrax Tularemia Viral
Pneumonia Influenza, Hantavirus,
RSV, CMV Other Bacterial Pneumonia Q
Fever
Meningococcemia Septicemia caused by
other Gram-Negative Bacteria
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Diagnosis
Suspected Plague Both of the following
conditions are met
1. Clinical symptoms of Plague in person who
resides in or has recently traveled to a
plague-endemic region 2. Smear taken from
affected tissues shows small gram-negative
and/or bipolar-staining coccobacilli
(Polychromic stains Wright, Giemsa, or
Wayson stain ) Sample taken from Bubo
(bubonic plague), Blood (septicemic plague),
or Tracheal/lung aspirate (pneumonic
plague)
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Diagnosis
Presumptive Plague
One or both of the following conditions are met
1. Immunofluorescence stain of smear ve for
the presence of Yersinia pestis F1 antigen.
2. Only a single serum specimen is tested
the anti-F1 antigen titer by agglutination is
gt110.
Agglutination testing must be shown to be
specific to Y. pestis F1 antigen by
hemagglutination inhibition.
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Diagnosis
Confirmed Plague
One of the following conditions is met
1. Isolated culture lysed by specific
bacteriophage. 2. 2 serum specimens demonstrate
a 4 fold anti-F1 antigen titer difference by
agglutination testing. 3. Single serum
specimen tested by agglutination has a titer of
gt1128 and the patient has no known previous
plague exposure or vaccination history.
Agglutination testing must be shown to be
specific to Y. pestis F1 antigen by
hemagglutination inhibition.
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Treatment
Isolation For the first 48 hours following
treatment, in case pneumonia develops By
law, patients with pneumonic plague must be
isolated If patients have no pneumonia or
draining lesions at 48 hours, they may be
taken out of strict isolation. Antibiotics
For a minimum of 10 days (or 3-4 days after
clinical recovery)
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Antibiotic Therapy
Adult Child Pregnant ?
Streptomycin 1g IM or IV x1/day 15mg/kg IM x2/day ---------------------------
Gentamicin 5mg/kg IM or IV x1/day 2.5mg/kg IM or IV x3/day 5mg/kg IM or IV x1/day
Doxycycline 100 mg IM x2/day or 200mg IV x1/day 2.2mg/kg IV x2/day 100mg IV x2/day or 200mg IV x1/day
Ciprofloxacin 400 mg IV x2/day 15mg/kg IV x2/day 400mg IV x2/day
Chloramphenicol 25mg/kg IV x4/day 25mg/kg IV x4/day (but not if lt 2 years of age) ---------------------------
Preferred Treatment (others are alternatives)
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Antibiotics Mechanism of Action
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Prognosis
Fatality Bubonic 1? or 2? Septicemic 1? or 2? Pneumonic
Untreated 50-90 50-100 100 most within 48 hrs of onset
Treated 5-20 30-50 ? treatment must begin w/i 18hrs of onset
?
1? Pneumonic Plague progresses the most rapidly
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Prevention
Integrated Vector Management (surveillance
of animal reservoirs)
Education on modes of transmission
Control Rat Flea Populations ( traps,
insecticides)
San Jose, CA 1991
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Prevention
Personal Sanitation Measures Veterinary
workers in endemic areas gloves, eye
protection, surgical masks when treating
suspect cats Hunters and Outdoorsmen
avoid rodent nests, use insect repellents/insectic
ides, wear gloves when handling potentially
infected animals In the Lab - Standard
Control when handling Y. Pestis organisms -
Biosafety Level 2 when processing clinical
specimens cultures - Biosafety Level 3 with
large amounts of bacteria or with potential for
aerosolization
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Prevention
Existing Vaccines None Available for Use!
Vaccine Strategy Status Remarks
EV76 Live Attenuated Mutant Strain Introduced in 1908 Limited availability in former Soviet Union - Not avirulent - Questionable Safety - No protection Pnemonic form
USP Formalin-Inactivated Whole Cell Manufactured 1940-1999 No Longer Available - Induces F1 antigen response - Not tested in controlled studies - Severe inflammatory reactions - Multiple Booster Shots - No protection Pneumonic form
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Prevention
Improved Vaccines In Development
Vaccine Strategy Status Remarks
F1/V Fusion Protein Recombinant Subunit Preclinical testing in mice and nonhuman primates Effective in aerosol challenge in mice monkeys
F1/V Combo (separate proteins) Recombinant Subunit Phase 1 clinical trials completed (phase 2 trials due to begin in late 2002/early 2003) - 21 F1/V ratio - Protection via IgG - Also F1V-specific IgA response - Adjuvanted with alhydrogel Protection Bubonic Pneumonic
V antigen in Plasmid DNA construct DNA Preclinical testing in mice mice immunization plus booster shot with recombinant antigens developed protective immunity against lethal dose
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Prevention
Prophylactic Antibiotics
only following high-risk exposure to pneumonic
plague
Adult Child Pregnant ?
Doxycycline 100 mg PO x2/day 2.2mg/kg POx2/day 100 mg PO x2/day
Ciprofloxacin 500 mg PO x2/day 20mg/kg PO x2/day 500 mg PO x2/day
Chloramphenicol 25mg/kg PO x4/day 25mg/kg PO x4/day (not lt 2 yrs of age) 25mg/kg PO x4/day
Preferred Treatment (others are alternatives)
treat for 10 days (if fever/cough develops
during prophylactic treatment, then follow
standard therapy for Y. Pestis)
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Caution Drug Resistant Strains in Patients
Y. Pestis Strain Isolated Drug Resistance How New Genes
16/95 Madagascar, 1995 Streptomycin streptomycin phosphotransferase Genes in the acquired self-transferable plasmid pIP1203
17/95 Madagascar, 1997 1. Ampicillin 2. Chloramphenicol 3. Kanamycin 4. Minocycline 5. Streptomycin 6. Spectinomycin 7. Sulfonamides 8. Tetracycline 1. production ? Lactamase 2. Production chloramphenicol acetyltransferase 3. synthesis of a type I 3'-aminoglycoside phosphotransferase 5. 6. 3''-9 Aminoglycoside adenylyltransferase Genes in the acquired conjugative plasmid pIP1202
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Weaponization of the Plague
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History of Weaponization

• Mongols throw plague infected bodies over the
  walls of the besieged city of Kaffa in 1346
• In WWII, Japanese army dropped Plague-infected
  fleas packed into bombs over Manchuria and
  infected their water supply resulting in an
  outbreak.
• During The Cold War, the U.S. and Soviet Union
  developed methods of aerosolizing Plague-thereby
  eliminating the flea vector.

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CDC Classification of Plague

• Plague is in Category A, it is a high-priority
  organism
• High-priority agents include organisms that pose
  a risk to national security because
• can be easily disseminated or transmitted from
  person to person
• result in high mortality rates and have the
  potential for major public health impact
• might cause public panic and social disruption
• require special action for public health
  preparedness

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Plague is a Suitable Pathogen For Use As a Weapon
Because

• It is accessible, simple to reproduce, economical
  and efficient.
• It can be delivered in aerosol form
• Pneumonic plague causes serious illness with a
  high case fatality rate
• Pneumonic plague is communicable
• 100-500 bacteria are enough to cause pneumonic
  plague, whereas it takes between 1,000-10,000
  spores to cause pulmonary anthrax

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Are We Prepared?

• A 1970 WHO report estimated that an aerosol
  release of 50kg of Y.Pestis over a city of 5
  million people would produce 150,000 illnesses
  and up to 36,000 deaths. (This report didnt
  take into account the secondary cases that would
  occur through person-to-person contact.
• A simulated bioterror attack (TOPOFF) involving
  aerosolization of the plague was carried out in
  May 2001, in Colorado. By the end of the third
  day, 783 people had contracted pneumonic plague,
  by the next day the number of plague cases had
  risen to 1,871 and by the third day the number
  stood at 3,060. At the end of the exercise 950
  people had died of pneumonic plague.

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In The Event of An Attack

• Early treatment with antibiotics (gentamicin,
  streptomycin, tetracycline, fluoroquinoline)
• Use of surgical masks to prevent further
  transmission.

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The Bad NewsResistance

• Sequence of Y.pestis could have boomerang effect,
  enabling terrorists to create antibiotic
  resistant strands.
• According to Alastair Hay, the Soviet Union has
  already developed a form of Yersinia pestis that
  was resistant to 16 different antibiotics.
• Right Picture of Staphylococcus Aureus next to
  Y. Pestis. A transfer of antibiotic resistant
  genes from Staph to Y. Pestis could result in a
  uncontrollably lethal bacterium.

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The Good News

• Requires a high level of knowledge to distinguish
  between virulent and non-virulent strain,
  efficiently produce the virulent strains, and
  aerosolize it.
• Plague bacteria is a fragile organism because it
  is non-spore forming, so it can only remain
  viable for only about 1hr after aerosolization.