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Differential Diagnosis ■ Inhalation anthrax ■ Tularemia ■ Viral Pneumonia Influenza, Hantavirus, RSV, CMV ■ Other Bacterial Pneumonia ■ Q Fever ■ Meningococcemia.

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Presentation on theme: "Differential Diagnosis ■ Inhalation anthrax ■ Tularemia ■ Viral Pneumonia Influenza, Hantavirus, RSV, CMV ■ Other Bacterial Pneumonia ■ Q Fever ■ Meningococcemia."— Presentation transcript:

1 Differential Diagnosis ■ Inhalation anthrax ■ Tularemia ■ Viral Pneumonia Influenza, Hantavirus, RSV, CMV ■ Other Bacterial Pneumonia ■ Q Fever ■ Meningococcemia ■ Septicemia caused by other Gram-Negative Bacteria Pneumonic PlagueSepticemic Plague

2 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) Diagnosis Suspected Plague Both of the following conditions are met:

3 Diagnosis Presumptive Plague *Agglutination testing must be shown to be specific to Y. pestis F1 antigen by hemagglutination inhibition. 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 >1:10.*

4 Diagnosis Confirmed Plague 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 >1:128 and the patient has no known previous plague exposure or vaccination history.* One of the following conditions is met: *Agglutination testing must be shown to be specific to Y. pestis F1 antigen by hemagglutination inhibition.

5 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) Treatment

6 AdultChildPregnant ♀ 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/day100mg IV x2/day or 200mg IV x1/day Ciprofloxacin 400 mg IV x2/day15mg/kg IV x2/day400mg IV x2/day Chloramphenicol 25mg/kg IV x4/day25mg/kg IV x4/day (but not if < 2 years of age) --------------------------- *Preferred Treatment (others are alternatives) Antibiotic Therapy

7 Antibiotics – Mechanism of Action

8 Prognosis FatalityBubonic 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 

9 Prevention ■ Education on modes of transmission ■ Control Rat & Flea Populations ( traps, insecticides) ■ Integrated Vector Management (surveillance of animal reservoirs) San Jose, CA; 1991

10 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/insecticides, 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 Prevention

11 Prevention VaccineStrategyStatusRemarks EV76Live 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 Existing Vaccines – None Available for Use!

12 VaccineStrategyStatusRemarks 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) - 2:1 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 Prevention Improved Vaccines – In Development

13 Prevention Prophylactic Antibiotics ■ only following high-risk exposure to pneumonic plague AdultChildPregnant ♀ 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/day25mg/kg PO x4/day (not < 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)

14 Y. Pestis Strain IsolatedDrugResistanceHow New Genes 16/95Madagascar,1995Streptomycin streptomycin phosphotransferase Genes in the acquired self- transferable plasmid pIP1203 17/95Madagascar,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 acquiredconjugativeplasmidpIP1202 Caution: Drug Resistant Strains in Patients

15 Weaponization of the Plague

16 History of Weaponization Mongols throw plague infected bodies over the walls of the besieged city of Kaffa in 1346 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. 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. During The Cold War, the U.S. and Soviet Union developed methods of aerosolizing Plague-thereby eliminating the flea vector.

17 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

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

19 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 didn’t take into account the secondary cases that would occur through person-to- person contact. 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 didn’t 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. 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.

20 In The Event of An Attack… Early treatment with antibiotics (gentamicin, streptomycin, tetracycline, fluoroquinoline) Early treatment with antibiotics (gentamicin, streptomycin, tetracycline, fluoroquinoline) Use of surgical masks to prevent further transmission. Use of surgical masks to prevent further transmission.

21 The Bad News… Resistance Sequence of Y.pestis could have boomerang effect, enabling terrorists to create antibiotic resistant strands. 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. 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. 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.

22 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. 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. Plague bacteria is a fragile organism because it is non-spore forming, so it can only remain viable for only about 1hr after aerosolization.


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