Plague: Introduction, History, Microbiology, Epidemiology

Plague• Highly lethal infection

with the bacterium Yersinia pestis

• One of the most feared diseases in human history

• Three catastrophic pandemics

“The Plague” by Poussin

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Justinian Plague

• Named after Byzantine Emperor Justinian

• First epidemic (A.D. 541 to 544) began in Ethiopia

• First description of epidemic plague by Procopius

Justinian Plague• Second thru 11th epidemics (A.D.

558 to 654) in 8-12 year cycles• Constantinople experienced

eight epidemics with over 40% of the population lost

• Over 100 million deaths representing 50-60% population loss over the “known world”“Black Death” by Hutin

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The Black Death

• Imported into Europe from western movement on trans-Asian silk road – Siege of Caffa?

• First epidemic (1347 to 1351) killed 17-28 million in Europe, another 20 million by the end of the 14th century– Approximately 40% of the European population

• Cyclical epidemics lasting into the 17th century

The Black Death

Progression of the second pandemic

Modern Plague

• Began in 1855 in China, reaches Hong Kong by 1894

• Within 10 years (1894-1903) enters 77 ports on five continents– Arrives India 1898 and kills

over 13 million in 50 years

Modern Plague

• Epizootic foci now well-established worldwide except Australia– Three periods of increased activity• Mid- 1960’s• 1973 – 1978• Mid- 1980’s

1954 to 1997 plague affected 38 countries with 80,613 cases

• Maximum cases (6004) in 1967• Minimum cases (200) in 1981

58.4%

27.8%13.8%

WHO

1954 to 1997 plague deaths 6587 deaths (8% mortal i ty)

• Highest rate (23.8%) in 1961• Lowest rate (2.4%) in 1970

54.6%

34.4%11.0%

WHO

Modern Plague

• 1998-2006 cases have totaled 14,424 with 1,244 deaths (8.6% mortality)

• Africa represented over 90% of the world’s total cases

• Four areas have had recent human plague outbreaks– India – 1994, 2002– Indonesia – 1997– Algeria – 2003– Democratic Republic of Congo – 2005

BW Agent

• General Shiro Ishii (Dr.), leader of Japanese Unit 731, WW II– Infected POWs and performed vivisection (some while

living)

– Experimented weaponizing plague• Dropped infected fleas in at least three separate occasions on

Chinese cities with subsequent plague outbreaks

• Mission “Cherry Blossoms at Night” was a plan to repeat in California

• Plague researched or developed by former US and Soviet Union BW programs– US abandoned plague work

Microbiology - History• During the 1894 Hong

Kong epidemic, bacteria independently discovered by:– Alexandre J.E. Yersin– Shibasaburo Kitasato

• Yersin made connection between rat and plague

• Ogata and Simond, during 1897 epidemic, elucidated role of the flea

History

• W.M.W. Haffkine developed and implemented effective killed vaccine in Bombay, 1897

• Manchurian epidemic of 1910-11, Wu demonstrated aerosol spread of pneumonic form and implemented effective preventive measures

Microbiology• Family Enterobacteriaceae

– 11 species of Yersinia, 3 are human pathogens• Y.pestis• Y.pseudotuberculosis• Y.enterocolitica

• Gram-negative, non-motile, non-spore-forming– Bipolar (“safety pin”) staining

• Facultative intracellular (monocytes) pathogen

• Optimal growth at 30°C and pH 7.2-7.6

Microbiology

• Grows slowly on most standard laboratory media

• After 48-72 hours, grey-white to slightly yellow opaque raised, irregular (“fried egg”) morphology

• Alternatively colonies may have a “hammered copper” shiny surface

Plague Epidemiology Plague is a zoonotic diseasePlague is a zoonotic diseaseMany animal species are natural reservoirs for Many animal species are natural reservoirs for Y. pestisY. pestis

Resistant animals are enzootic reservoirsResistant animals are enzootic reservoirs Urban and domestic ratsUrban and domestic rats SquirrelsSquirrels MiceMice GerbilsGerbils

Susceptible animals are epizootic reservoirsSusceptible animals are epizootic reservoirs Domestic and feral catsDomestic and feral cats DogsDogs Rabbits and haresRabbits and hares CoyotesCoyotes

• Prairie dogsPrairie dogs• VolesVoles• ChipmunksChipmunks• MarmotsMarmots• Guinea pigsGuinea pigs

• CamelsCamels• GoatsGoats• DeerDeer• AntelopeAntelope

Epidemiology

Epidemiology

• More than 200 mammalian species in 73 genera are of epidemiological importance

• Humans are accidental hosts• Fleas transmit -- feed on bacteremic animals– Only 30 (of over 1500) flea species are proven

vectors of plague– Not transmitted transovarially

Yersinia pestis

Thirty flea species are vectors of Thirty flea species are vectors of Y. pestisY. pestisY. pestisY. pestis acquired the enzyme PLD, resistant to digestion acquired the enzyme PLD, resistant to digestion Y. pestisY. pestis creates a blood clot in the proventriculus of the flea creates a blood clot in the proventriculus of the fleaBlocks passage of the next blood meal, forces regurgitationBlocks passage of the next blood meal, forces regurgitation

Flea with blocked proventriculusFlea with blocked proventriculus

Epidemiology of Natural Transmission

Flea vector such asFlea vector such asXenopsylla cheopisXenopsylla cheopis

Enzootic and epizooticEnzootic and epizooticanimal reservoirsanimal reservoirs

Yersinia pestisYersinia pestis Primary Primary bubonic plaguebubonic plague

Primary Primary septicemic plaguesepticemic plague

Primary Primary pneumonic plaguepneumonic plague

AA

AA

SecondarySecondary plague plague

casescases

BB

BB

CCC,EC,E

D,ED,ED,ED,E

Routes of Plague TransmissionRoutes of Plague TransmissionA = Bite of FleaA = Bite of FleaB = Contact with animal or carcassB = Contact with animal or carcassC = Inhalation of respiratory dropletsC = Inhalation of respiratory dropletsD = Contact with sputum or fluidD = Contact with sputum or fluidE = Hematogenous spreadE = Hematogenous spread

Questions?

U.S. National Library of Medicine Archives

Plague: Diagnosis and Treatment

Course Number

TRNHUM-00343

Rev.00

Document prepared by: USAMRIID/J. Lawler

Info Works # 24914-101-G8L-GEG-00343

Activated June 2006

Differential Diagnosis for Septicemic Plague

• Meningococcemia• Gram-negative sepsis• Rickettsiosis

• For Pneumonic plague: Gram negative bacteria recovered from sputum, fulminate pneumonia and bloody sputum in a healthy, non-immunocompromised patient

Diagnosis• Diagnostic specimens for smear and culture include:

– Whole blood, bubo aspirates, sputum, CSF, tracheal washes – Two-fold greater chance of isolating bacteria from bubo than blood

• 1 cc saline repeatedly injected and withdrawn until blood tinged, air dry and stain (Gram’s, Wayson’s, Wright-Giemsa)

– DFA also available and more specific than staining

Diagnosis

• Rapid diagnostic testing– Murine monoclonal antibody against F1 bound to

nitro cellulose strips– 10-15 minute result– Field tested with good results

Lancet 361: 18 Jan 2003

Management Standard precautions PLUS: Suspect pneumonic plague:

Droplet precautions Until 48-72 hrs of appropriate antibiotics therapy

Confirmed pneumonic plague: Droplet precautions Until sputum cultures negative

Aspirate bubo, do not I&DMMWR 1996;45:RR-14

Management Laboratory Precautions

Microbiology laboratory personnel must be alerted when Y. pestis is suspected, as four laboratory-acquired cases of plague have been reported in the United States

Burmeister et.al. Ann. Intern. Med. 56:789-800.1962

Treatment

• Since 1948, streptomycin has remained the drug of choice for bubonic, septicemic and pneumonic plague and is FDA approved

• Streptomycin is rarely used in U.S. due to limited supply

• Gentamicin is used instead• No controlled comparative trials for plague therapy,

but a recent review of 75 cases in New Mexico, demonstrated that gentamicin alone or in combination with doxycycline was as efficacious as streptomycin for treating humans with plague

Boulangerf et. Al. Clin. Infect. Dis 38:663-669.2004

Treatment

• Parenteral antibiotics recommended initially– Streptomycin 1gm IM bid; or*– Gentamicin 5 mg/kg IV daily or 2mg/kg loading dose then

1.7 mg/kg IV q8h; or*– Doxycycline 200 mg load followed by 100mg q12h; or*– Ciprofloxacin 400 mg IV or 500mg PO q12h*

Add Chloramphenicol 25 mg/kg IV loading dose then 15 mg/kg IV q6h for plague meningitis

• Switch to oral antibiotics after clinical improvement• Duration of 10-14 days

Treatment – Pediatrics

• Parenteral antibiotics recommended initially– Streptomycin 15 mg/kg IM bid (up to 2g/day), or*– Gentamicin 2.5 mg/kg IV q8h, or*

– Doxycycline 2.2 mg/kg IV q12h for children < 45kg, or*– Ciprofloxacin 15mg/kg IV q12h (up to 1g/day)*

Add Chloramphenicol 25 mg/kg IV loading dose then 15 mg/kg IV q6h for plague meningitis except <2yo (avoid)

• Risk benefit with tetracyclines and quinolones• Switch to oral antibiotics after appropriate clinical

improvement• Duration of 10-14 days

Treatment – Pregnancy

• Risk-benefit to fetus– Streptomycin may be ototoxic and nephrotoxic– Tetracycline adverse effect on teeth and bones– Chloramphenicol low-risk of bone-marrow

suppression– Quinolones risk on developing bone and cartilage• Gentamicin would appear to be the safest• Dose 3mg/kg/day q8 hours

Treatment

• Sulfonamides– Used extensively but some studies have shown

higher mortality, increased complications, and longer fever

• Tetracyclines– Bacteriostatic with higher rate of failure– There are naturally occurring strains of resistant

bacteria

Prophylaxis

MMWR 45:RR-14; 13 Dec 1996

Prophylaxis

• Asymptomatic individuals such as family members health care providers or other close contacts with persons with untreated pneumonic plague should receive antibiotic prophylaxis for 7 days

• Close contact is contact with a patient at < 2 meters

• Laboratory workers exposed to an accident which may have generated an infectious aerosol need prophylaxis

Prophylaxis

• Hospital personnel who are observing recommended isolation procedures do not require prophylactic therapy, nor do contacts of patients with bubonic plague

• However, people who were in the same environment and who were potentially exposed to the same source of infection as the contact cases should be given prophylactic antibiotics