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Richard Chae, Steven Leong, Anton Matveev, Akshar Yagnik, Anuj Goyal

Group 6

IntroductionHistory EpidemiologyMechanism of Disease Signs, Symptoms, and Disease ProgressionDiagnosis/Treatment/Vaccination Bioterrorism Potential

Outline

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Plague is a severe and potentially deadly infection

caused by the bacteria, Yersinia pestis. It is named after the French-Swiss bacteriologist,

Alexandre Yersin.Until June 2007, it was one of three epidemic diseases

specifically reportable to WHO. It is rare in the United States, but can still be found in

Africa, Asia, and South America. The most common route of infection is through flea

bites.

Introduction

3 common forms of plague:

(1) Bubonic Plague – Infection of lymph nodes(2) Pneumonic Plague – Infection of the lungs(3) Septicemic Plague – Infection of the blood

Other forms include: Pharyngeal Plague – Uncommon, Resembles tonsilitis Meningeal Plague – Cross BBB, causing infectious

meningitis

Introduction

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3 Major Plague Pandemics:(1) The Justinian Plague

• Began in 541AD until its last occurrence in 750AD• Accepted cause is Bubonic Plague

(2) Black Death / Great Plague• Occurred from 1347-1351• Largest death toll from any known non-viral epidemic• Mortality: 300 million deaths

(3) Modern Plague• Originated in China in 1855• Two suspected sources:

Bubonic – Spread through ocean trade via infected individuals, rats, and fleasPneumonic – More virulent, Person-to-person

History

Richard Chae

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Plague is a Re-emerging Infectious Disease

Worldwide - Approximately 2,000 to 3,000 reported cases each year (WHO)

10% mortality rate

Most human cases since the 1990s have occurred in Africa

Most cases occur in rural areas, equator – ideal climate for rodents

First instance of plague on continental U.S.Rat–infested steamshipsGovernor denied existence for first two years 113 deaths/121 casesCampaign launched to eradicate as many rats as

possible - $2 million +

San Francisco plague, 1900 – 1907

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1 - Northern New Mexico, northern Arizona, and

southern Colorado 2 - California, Southern Oregon, and far Western

NevadaNM – 64/134 cases Each dot = 1 case

Plague Concentrated in Two U.S. Regions, 1970-2010

Number of plague cases in the U.S. from 1900–2010

1907 – San Francisco earthquake, displaced rodents and people alike, refugee camps

Current – ~5-10 cases annually

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Associate Professor of Molecular Genetics and Cell

Biology and of Microbiology at the University of Chicago

Weakened/Attenuated – Fe deficient strainUndiagnosed hereditary hemochromatosis – Fe

overload

Dr. Malcom Casadaban, 1949 - 2009

September 6, 2012 Camping in southwestern Colorado Dead squirrel Fleas on sweater Vomiting, seizures, high fever Blood test showed she had coagulopathy – blood wasn’t clotting Luckily the pediatrician cross-referenced her symptoms to a

previous plague case

Girl Saved by Quick-Thinking Doctor

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Anton Matveev

Transmission Pathways

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Multiplication Proventriculus occlusionCoagulase expression PLD/ Ymt expression StarvationRepeated attempts to feedRegurgitation of blood Infected human

Life within a Flea

Subcutaneous/ intradermal inoculation (1-10 organisms) Spread to local LN via subcutaneous lymphatics Phagocytosis at the LN

PMNs and mononuclear macrophages allow intracellular proliferation and cell lysis

Hemorrhagic necrosis at LN Destruction of the LN architecture

Inflammation triggered buboes Bloodstream entrance (septicemic plague) and spread to

other LN Hemorrhagic lesions in LN and organs such as liver and spleen Replication in spleen macrophages in the later stages of infection

DIC and shock Death

Spread within a Human

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LCR plasmid activated by low calcium conditions includes the V antigen and YOPs proteins (Yersinia outer-surface

proteins) Phagocytosis resistance, survival within macrophages, downregulation of

IFN- γ and TNF- α production

Pesticin plasmid codes for PLA Pla degrades fibrin and other extracellular proteins and facilitates system

spread from the inoculation site (Pneumonic plague) codes for pesticin a bacteriocin important for iron uptake by Y. pestis

pMT1 (also called pFra) = Tox plasmid codes for F1 glycoprotein envelope antigen – a capsular protein

important in evading phagocytosis codes for a phospholipase D

Virulence Factors

Type III Secretion System

http://upload.wikimedia.org/wikipedia/commons/c/c5/T3SS_needle_complex.svg

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Macrophage Function

YOPs and Phagocytic Resistance

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Akshar Yagnik

3 types of plague Bubonic, Septicemic, Pneumonic

Different incubation timesLots of differential diagnoses > 25

Variable fatality rate – depends on type

Overview

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Infectious dose: 1-10 organisms Incubation period of 1-7 days Sudden onset of fever, chills, malaiseDay 1 – Painful swollen lymph nodes or clusters

of nodes (bubo); groin, axilla, cervical regions Bubo’s present with 1-10 cm smooth egg-shelled

uniform masses; seldom bursting

Bubonic Plague

Bubonic Plague

http://www.rightdiagnosis.com/phil/html/plague/2044.html

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Symptoms Fever (103°F) Chills Bubo (groin, axillary, cervical) Altered mental status (confusion, delirium, seizures) Vomiting Cough Rash (petechiae, papular lesions)

Bubonic Plague

Complications Secondary septicemia Disseminated Intravascular Coagulation (DIC) Lack of blood coagulation

Meningitis (inadequately treated individuals) Buboes susceptible for secondary infection Gangrene and acral necrosis

Fatality rate is 50% in untreated individuals but <5% in individuals undergoing antibiotic therapy.

Bubonic Plague

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Gangrene

http://www.diabetesandrelatedhealthissues.com/gangrene.html

Septicemia Bacteria in the blood that causes severe infection

Incubation period of 1-4 days 10% to 25% of cases Yersinia pestis manifests with

Primary Septicemic plague Fatality rate 30% to 50%; increases in delay of

prophylactic treatment, approaches 100% with lack of treatment

Septicemic Plague

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Symptoms Fevers Chills Malaise Nausea Headache Vomiting Diarrhea Abdominal Pain

Septicemic Plague

Complications Rapid progression to sepsis syndrome Sepsis Syndrome

Hyperthermia >101°F Tachycardia >90 bpm Tachypnea >20 bpm Hypoxemia PaO2 of < 75 torr Oliguria < 30ml urine output Elevated plasma lactate (acid imbalance) At least one organ with severe dysfunction

Secondary pneumonic plague Meningitis

Septicemic Plague

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Infectious dose: 100-500 organisms Incubation period of 1-4 days Fatality rate close to 100% without antibiotic

treatment Rates increase with delayed treatment specifically in

the first 24 hours; however patients can survive with long term antibiotic treatment after 24th hour of exposure.

Pneumonic Plague

Symptoms Fever Chest pain Dyspnea Productive cough (expectoration of watery sputum) Hemoptysis Expectoration of blood

Tachypnea Complications Sepsis Syndrome Meningitis

Pneumonic Plague

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Tuleremia Cat-scratch disease Mycobacterial infection Lymphogranuloma venereum Chancroid Genital herpes Meningococcemia Inhalation anthrax Psittacosis Influenza Hantavirus CMV RSV

Differential Diagnosis

Anuj Goyal

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Lymph nodes (buboes) Bubonic plague Culture of aspirate

Blood Septicemic plague Blood culture

Lungs Pneumonic plague Fluid extracted from lungs

Diagnosis

After specimens for diagnosis taken, start

antimicrobial therapyDon’t wait for lab results Patients with evidence of pneumonia should be

placed in isolation Bubonic plague untreated: 50% mortality rate Pneumonic plague untreated: almost all Pneumonic plague treated: reduced to 50%

Treatment

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Aminoglycosides: streptomycin and gentamicin Streptomycin Most effective against Y. pestis Drug of choice for treatment, particularly pneumonic 2 g/day for 10 days or until 3 days after temp normal

Gentamicin Effective in animal studies Successfully treated human plague Can be dosed once daily

Specific Therapy

Chloramphenicol Alternative to aminoglycosides in treatment of bubonic or

septicemic plague Drug of choice for Y. pestis invasion of tissue spaces when other

drugs pass poorly or not at all 50 mg/day for 10 days

Specific Therapy

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Tetracyclines Effective in uncomplicated plague Can be used with other antibiotics

Sulfonamides Used extensively in treatment Some studies have shown higher mortality, increased

complications, longer duration of fever

Specific Therapy

Fluoroquinolones Ex: ciprofloxacin Effective against Y. pestis both in vitro and animal studies no studies published on treating human plague

Levofloxacin Approved 4/27/12 by FDA Reduces risk of getting plague after exposure to Y. pestis

Specific Therapy

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Available for human useDo not protect against pneumonic plagueVaccinating communities not feasible Little use during outbreaks – a month or more

required to develop immune response Beneficial for those who work in close contact with

Y. pestis

Vaccination

Steven Leong

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Experience with plague as a biological weapon is limited: Middle Ages – Armies catapulted dead plague victims. World War II Japan dropped plague-infected fleas over populated areas in China. Following WWII, the United States and Soviet Union developed

methods of aerosolizing pneumonic plague.

Aerosolized pneumonic plague remains the most significant threat. Antibiotic treatment can prevent widespread epidemic in

developed countries.

Bioterrorism Potential

Plague can be used as biological weapons: Y. pestis is readily available and can be produced in large

quantities. Y. pestis can be delivered in an aerosol form. Pneumonic plague can cause fatal illness and is communicable,

thus resulting in large outbreaks. Due to its communicable nature, bioterrorist attack can cause

widespread fear and panic.

Genetic Mutation: Enhance virulence Antibiotic resistance

Bioterrorism Potential

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In 1970, WHO estimated that aerosol release of 50kg

dried powder containing 6x1015 spores over a city of 5 million can produce 150,000 incapacitating illnesses and 36,000 deaths. Estimates are conservative. Did not take into account secondary cases via person-

to-person contact.

Bioterrorism Potential

"ADAM Medical Encylcopedia." ADAM Medical Encylcopedia. n. page. Web. 12 Nov. 2012 Bone, RC, CJ Fishcer, TP Clemmer, and GJ Slotman. "Critical Care Medicine." Critical Care Medicine. 17.5 (1989):

389-393. Web. 12 Nov. 2012 Centers for Disease Control and Prevention. 2012. Plague. http://www.cdc.gov/plague/maps/index.html Cornelis, GR. 2001. “Molecular and cell biology aspects of plague”. PNAS. 97: 8783

http://www.pnas.org/content/97/16/8778.full.pdf Dolak , Kevin. ”Girl With Bubonic Plague Saved by Quick-Thinking Doctor.” . ABC News. September 6th, 2012.

http://abcnews.go.com/Health/girl-bubonic-plague-saved-quick-thinking-doctor/story?id=17170384 Infectious Diseases Society of America. 2011.

http://biodefense.idsociety.org/idsa/bt/plague/biofacts/plague_agent.html Kellogg, WH. "Present Status of Plague, with Historical Review". American Journal of Public Health. November

1920. http://books.google.com/books?id=sFg7AAAAIAAJ&pg=PA835#v=onepage&q&f=false Miller, MJR, RD Dawson, and H Schwantje. University of Northern British Columbia. 2003.

http://www.unbc.ca/nlui/wildlife_diseases_bc/plague.htm O'Loughlin JL, JL Spinner, SAMinnich, and SD Kobayashi. 2010. “Yersinia pestis Two-Component Gene

Regulatory Systems Promote Survival in Human Neutrophils.” Infection and Immunity. 78(2): 773–782. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812203/

Sarah E. Rollins, Sean M. Rollins,and Edward T. Ryan. American Journal of Clinical Pathology 2003;119:S78-S85 http://ajcp.ascpjournals.org/content/supplements/119/Suppl_1/S78.full.pdf

UChicago News. “Malcolm Casadaban, molecular genetics specialist, 1949-2009.” September 25, 2009.http://news.uchicago.edu/article/2009/09/24/malcolm-casadaban-molecular-genetics-specialist-1949-2009

World Health Organisation. 2010. Evidence-Based Public Health Initiatives. http://www.who.int/topics/plague/en

References

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Any Questions?