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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 - PowerPoint PPT Presentation
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Differential DiagnosisDifferential Diagnosis
■ Inhalation anthrax
■ Tularemia
■ Viral Pneumonia Influenza, Hantavirus, RSV, CMV
■ Other Bacterial Pneumonia
■ Q Fever
■ Meningococcemia
■ Septicemia caused by other Gram-Negative Bacteria
Pneumonic Plague Septicemic Plague
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)
DiagnosisDiagnosisSuspected Plague Both of the following conditions are met:
DiagnosisDiagnosis
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.*
DiagnosisDiagnosis
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.
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)
TreatmentTreatment
Adult Child Pregnant ♀
Streptomycin * 1g IM or IV x1/day
*15mg/kg IMx2/day
---------------------------
Gentamicin *5mg/kg IM or IV x1/day
*2.5mg/kg IM or IV x3/day
*5mg/kg IM or IVx1/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 < 2 years of age)
---------------------------
*Preferred Treatment (others are alternatives)
Antibiotic Therapy
Antibiotics – Mechanism of Action
PrognosisPrognosis
Fatality Bubonic 1 or 2 Septicemic
1 or 2 Pneumonic
Untreated50%-90% 50%-100%
100%most within 48 hrs of onset
Treated5%-20% 30%-50%
?treatment must begin w/i 18hrs of onset
1 Pneumonic Plague progresses the most rapidly
PreventionPrevention■ Education on modes of transmission
■ Control Rat & Flea Populations ( traps, insecticides)
■ Integrated Vector Management (surveillance of animal reservoirs)
San Jose, CA; 1991
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
PreventionPrevention
PreventionPrevention
Vaccine Strategy Status Remarks
EV76 Live AttenuatedMutant Strain
Introduced in 1908
Limited availability in former Soviet Union
- Not avirulent- Questionable Safety- No protection Pnemonic form
USP
Formalin-Inactivated Whole Cell
Manufactured1940-1999
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!
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/VCombo(separateproteins)
Recombinant Subunit
Phase 1 clinical trialscompleted (phase 2trials 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
PreventionPreventionImproved Vaccines – In Development
PreventionPreventionProphylactic 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 < 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)
Y. Y. PestisPestis StrainStrain
IsolatedIsolated DrugDrug
ResistanceResistance
HowHow New New GenesGenes
16/9516/95 Madagascar,Madagascar,
19951995
StreptomycinStreptomycin streptomycin streptomycin phosphotransferasephosphotransferase
Genes in Genes in the acquired the acquired self-self-transferable transferable plasmid plasmid pIP1203pIP1203
17/9517/95 Madagascar,Madagascar,
19971997
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 Genes in thethe
acquiredacquired
conjugative conjugative
plasmid plasmid
pIP1202pIP1202
Caution: Drug Resistant Strains in PatientsCaution: Drug Resistant Strains in Patients
Weaponization of the PlagueWeaponization of the Plague
History of WeaponizationHistory of Weaponization
Mongols throw plague infected bodies over the walls of Mongols throw plague infected bodies over the walls of the besieged city of Kaffa in 1346the besieged city of Kaffa in 1346
In WWII, Japanese army dropped Plague-infected fleas In WWII, Japanese army dropped Plague-infected fleas packed into bombs over Manchuria and infected their packed into bombs over Manchuria and infected their water supply resulting in an outbreak.water supply resulting in an outbreak.
During The Cold War, the U.S. and Soviet Union During The Cold War, the U.S. and Soviet Union developed methods of aerosolizing Plague-thereby developed methods of aerosolizing Plague-thereby eliminating the flea vector.eliminating the flea vector.
CDC Classification of PlagueCDC Classification of Plague Plague is in Category A, it is a high-Plague is in Category A, it is a high-
priority organismpriority organism
High-priority agents include High-priority agents include organisms that pose a risk to organisms that pose a risk to national security because:national security because:
can be easily disseminated or can be easily disseminated or transmitted from person to persontransmitted from person to person
result in high mortality rates and have result in high mortality rates and have the potential for major public health the potential for major public health impactimpact
might cause public panic and social might cause public panic and social disruptiondisruption
require special action for public health require special action for public health preparednesspreparedness
Plague is a Suitable Pathogen Plague is a Suitable Pathogen For Use As a Weapon Because…For Use As a Weapon Because…
It is accessible, simple to It is accessible, simple to reproduce, economical and reproduce, economical and efficient.efficient.
It can be delivered in It can be delivered in aerosol formaerosol form
Pneumonic plague causes Pneumonic plague causes serious illness with a high serious illness with a high case fatality ratecase fatality rate
Pneumonic plague is Pneumonic plague is communicablecommunicable
100-500 bacteria are 100-500 bacteria are enough to cause pneumonic enough to cause pneumonic plague, whereas it takes plague, whereas it takes between 1,000-10,000 between 1,000-10,000 spores to cause pulmonary spores to cause pulmonary anthraxanthrax
Are We Prepared?Are We Prepared? A 1970 WHO report estimated that an aerosol release of 50kg of A 1970 WHO report estimated that an aerosol release of 50kg of
Y.PestisY.Pestis over a city of 5 million people would produce 150,000 over a city of 5 million people would produce 150,000 illnesses and up to 36,000 deaths. (This report didn’t take into illnesses and up to 36,000 deaths. (This report didn’t take into account the secondary cases that would occur through person-to-account the secondary cases that would occur through person-to-person contact.person contact.
A simulated bioterror attack (TOPOFF) involving aerosolization of A simulated bioterror attack (TOPOFF) involving aerosolization of the plague was carried out in May 2001, in Colorado. By the end 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 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 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 third day the number stood at 3,060. At the end of the exercise 950 people had “died” of pneumonic plague.people had “died” of pneumonic plague.
In The Event of An Attack…In The Event of An Attack…
Early treatment with antibiotics (gentamicin, Early treatment with antibiotics (gentamicin, streptomycin, tetracycline, fluoroquinoline)streptomycin, tetracycline, fluoroquinoline)
Use of surgical masks to prevent further Use of surgical masks to prevent further transmission.transmission.
The Bad News…The Bad News…ResistanceResistance
Sequence of Sequence of Y.pestisY.pestis could have could have boomerang effect, enabling boomerang effect, enabling terrorists to create antibiotic terrorists to create antibiotic resistant strands.resistant strands.
According to Alastair Hay, the According to Alastair Hay, the Soviet Union has already Soviet Union has already developed a form of developed a form of Yersinia Yersinia pestispestis that was resistant to 16 that was resistant to 16 different antibiotics.different antibiotics.
Right: Picture of Right: Picture of Staphylococcus Staphylococcus AureusAureus next to next to Y. PestisY. Pestis. A . A transfer of antibiotic resistant transfer of antibiotic resistant genes from Staph to genes from Staph to Y. PestisY. Pestis could result in a uncontrollably could result in a uncontrollably lethal bacterium.lethal bacterium.
The Good News…The Good News…
Requires a high level of knowledge to distinguish Requires a high level of knowledge to distinguish between virulent and non-virulent strain, between virulent and non-virulent strain, efficiently produce the virulent strains, and efficiently produce the virulent strains, and aerosolize it.aerosolize it.
Plague bacteria is a fragile organism because it Plague bacteria is a fragile organism because it is non-spore forming, so it can only remain is non-spore forming, so it can only remain viable for only about 1hr after aerosolization.viable for only about 1hr after aerosolization.