Plague Review: Info & Updates

Bubonic plague, Pneumonic plague, Septicemic plague, Factfile, FAQ, Q&A, Info, outbreak in China, Images, Global Map Outbreaks, WHO, CDC



The recent outbreak of plague in China resulting in deaths of 3 persons led to the complete sealoff or quarantine of a town of 10000 persons. This episode brings back the spotlight on Plague. A multimedia rich article is provided. The impact of plague from the Black Death of the middle ages in Europe, its coverage in our mainstream literature classics and the fear it still provokes in humans is discussed. Plague if left untreated kills 60% of its victims. The disease if detected early can be treated with antibiotics, vaccine use is limited to healthcare persons dealing with the patients and infected animals. Plague was never wiped out from the globe and outbreaks occur fairly regularly in communities in close contacts/interactions with animals mainly in the developing countries. The last outbreak of Plague in India in 1996 resulted in loss of $3 billion due to ban of imports and travel advisory by rich countries. Financial impact of the disease is huge in poor economies. The first pandemic to strike the humanity mentioned in the Exodus.
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Overview [1][2][3]

Importance of plague

The recent outbreak of plague in China and complete quarantine of a town of 10,000 persons once again brought Plague along with animal-human interactions and microbial threats to human health. Chinese authorities had informed WHO in December 2008 about the suspected plague outbreak. This was to show that authorities were open to share information unlike the cover up of the recent SARS outbreak. WHO estimates that 1000-3000 persons each year have plague contacted in remote rural areas in countries with poor sanitation and in remote communities living in close contact with wild and domestic animals. The mortality rate is estimated to be in the range of 14% for all reported cases of plague.

Plague has accompanied mankind since prehistoric times and is mentioned in ancient scriptures. It has killed over 200 million patients during our history. During the rapid urbanization of Europe and poor hygienic and sanitary conditions during the 14th century, outbreaks of plague (Black death) were frequent and the disease wiped out almost 50% of European population. Plague outbreaks continued till the 19th century and disease was contained gradually by improved sanitation and hugiene. The discovery of antibiotics and their use after World war II finally defeated the bacteria which had struck terror, fear and anguish in humans. Plague has been described as a human scourge since antiquity.

Microbial agent


Plague is caused by a bacterium, the bacillus Yersinia pestis which parasitizes fleas and vertebrates. It is highly virulent to fleas, many rodents and humans. The bacillus can easily overcome the hosts’ defenses by resisting phagocytosis and even multiplying in the phagocytes. Using genomic and current biotechnology tools the culprit agent of 1347 European Black Death was identified as Y. pestis. Two additional plague pandemics of 1590 and 1722 in France were attributed to the bacterium Y. pestis.

Images from CDC  PHIL

Under Creative Commons Attribution 3.0 License

CDC PHIL 6721    Image of Y pestis with a fluorescent antibody

PHIL Image 6721


Yersinia pestis bacteria Imaged with a Fluorescent Antibody


Stained bloodsmear showing red and white blood cells, and Yersinia pestis bacteria

Hosts of the infection

Hosts of the bacterium are many (more than 200) species of rodents including rats (Rattus rattus and R. norvegicus), lagomorphs (rabbits and hares), but also humans. Even birds have been found to be infected, and they may spread the bacterium over long distances. Some rodents are highly resistant to the disease, i.e., show no or few symptoms although harbouring the bacterium. Such species are important because they act as reservoirs that contribute to the maintenance of so-called “natural foci” (i.e., areas in which the bacterium is naturally maintained, containing communities of bacteria, vectors, reservoir and other hosts).

Fleas of many (more than 120) species are capable of transmitting the infection (including the common flea of humans Pulex irritans), but the most important vector is the cosmopolitan oriental rat flea Xenopsylla cheopis, with several other species of Xenopsylla as well as Nosopsyllus fasciatus of secondary importance. Pulex irritans is less important as a vector because it is rarely in contact with rats and other rodents. Nevertheless, it has contributed to smaller outbreaks of the disease.

File:Xenopsylla cheopis flea PHIL 2069

Xenopsylla cheopis, the oriental rat flea and most important vector of plague

Scanning Electron Micrograph of a flea CDC PHIL 11436

Mode of infection

Fleas transmit the infection to vertebrates by injecting bacteria when biting them, although – more rarely – infection can also occur by rubbing fleas’ faeces or bodies into wounds, or by ingesting fleas. An important factor in the effectiveness of a flea species as a vector is the degree to which its proventriculus (part of the foregut) can be blocked by the bacteria: enzymes produced by the fleas and the bacteria cause coagulation of the ingested blood and thus blockage; consequently fleas begin to starve and become dehydrated, leading to repeated attempts to suck blood and an increase in the likelihood of infecting hosts. In Xenopsylla cheopis, blockages occur rapidly and frequently, which partly explains its importance as a vector of human plague. Other reasons include its world-wide distribution, and association with domestic rats and humans (on which it readily feeds). – The role of temperature is important. The blockages of the fleas’ proventriculus are dissolved at temperatures above 27.5o C, as a result the bacteria are eliminated from the gut. On the other hand, Xenopsylla cheopis thrives best at temperatures of about 23.5oC. Therefore the worst plague epidemics can be expected  at 20-25oC, which corresponds to summer/autumn in temperate and to the cooler months in tropical countries.

Epizootics (among animals) and epidemics (among humans)

Plague epidemics among humans appear to commonly follow epizootics among rats: large numbers of rats are killed by the disease and fleas now jump to humans as alternative hosts, thus spreading the disease to them. But there also is a sylvatic and campestral cycle involving humans: during epizootics among wild rodents (in wooded = sylvatic habitats, or in open = campestral habitats) humans in contact with them may become infected.




A rapid test using a monoclonal antibody to F1 antigen of Yersinia pestis has been developed. The test has 100% sensitivity and specificity and has a 89% correlation with laboratory confirmatory test for identification of Y. pestis.

The incubation period may last from 2-6 days after first infection. when untreated, bacteria spread from the bubo to invade the blood stream leading to the severe and often fatal form Septicemic plague. infections of the lungs by Y. pestis leads to Pneumonic plague.

Bubonic Plague is indicated by swollen lymph glands (Bubo) and pain. The highly contagious Pneumonic plague is due to infections of the lungs by Yersinia pestis and is characterized by Flu like symptoms. The patient may have high fever, cough, bloody sputum and breathing difficulty.

CDC PHIL 4140 Plague infection acquired through abrasions in the upper right leg in a patient
PHIL Image 4140

Types of plague symptoms

Three main types of human plague can be distinguished, i.e. bubonic plague, primary septicemic plague and primary pneumonic plague. The first is characterized by “buboes”, swollen lymph nodes in the groins, arm pits or neck as large as a chicken egg, which contain bacteria and may rupture. The second is a general infection of the blood with no or little evidence of a prior swelling of the lymph nodes. In the third, the lungs are heavily involved and the pneumonia-like symptoms (coughing or sneezing) lead to direct (i.e. without involvement of fleas) spreading between humans. – Secondary septicemic plague occurs usually in pneumonic and occasionally in bubonic plague. It is a generalized blood infection following symptoms of bubonic or pneumonic plague. – The incubation period in humans (the symptomless period after an infected flea has bitten) is normally 2 – 4 days. First symptoms include chill and high fever, and a swelling of the lymph nodes. If a patient survives (as the great Roman emperor Justinian did in the  5th  century AD), the fever goes down after 2-5 days. Death may occur within 5 days, preceded by mental dullness, delirium, lethargy and coma.


Treatment of plague




The dawn of antibiotic era after World war II rolled back the progress of plague. The discovery and development streptomycin proved to be the first effective treatment of plague causing bacteria Y. pestis. Streptomycin use, production and availability has declined over the years due to widespread development of resistance in bacterial infections although it still remains an effective treatment for plague. Plague is curable if treated early during the onset of the disease. Plague can now easily be treated with a number of very effective antibiotics including tetracycline and streptomycin, among others.
The current aminoglycoside used as first line treatment of choice for plague is Gentamicin. Gentamicin intereferes with protein synthesis and is bactericidal for Y. pestis. The dose is 3-6 mg/kg/day intramuscular for 7 to 10 days of treatment. The higher dose > 3 mg/kg/day or intravenours route is recommended for life threatning or complicated infections. The dose can be divided into BID or TID doses to reduce side effects and improve tolerance. In case of no response or slow response, a tetracycline antibiotic (doxocycline) or fluoroquinolone antibiotic (ciprofloxacin) can be added to speed up recovery. The doxocycline recommended dosage is 100-200 mg per day for 7-14 days. The dose can be divided into smaller fractions. Ciprofloxacin  (tablets 250 mg, 500 mg, 750 mg, oral solution 5% suspension or iv 200-400 mg ) for 7-14 days can be used. Low cost generic alternatives are available for all the drugs mentioned.
19 Years of Power and Confidence






Plague vaccines have been used since the 19th century but their safety and efficacy has never been measured in double blind clinical trials. The current plague vaccine approved by the FDA is extracted from Yersinia pestis grown in culture media (agar, peptone, beef extract, soy and casein), is extracted with formaldehyde and preserved in 0.5% phenol.
Three doses of intramuscular doses are recommended, the first of 1 ml im, the second after 4 weeks at 0.2 ml im and the third after 6 months as 0.2 ml. Booster doses are required after every 6 months and later every year. The vaccine is recommended for all healthcare and field workers coming in contact with wild animals and working with Yersinia pestis in the laboratory or hospital. The vaccine is not recommended for populations living in plague endemic areas. Irrespective of vaccination, antibiotic treatment is recommended for healthcare providers and laboratory workers coming in contact or dealing with plague. The efficacy of the vaccine and its protection period  is not known, hence reliance on the antibiotic therapy.
CDC PHIL 4133   Histopathologic changes in splenic tissue in a case of fatal human plague
PHIL Image 4133

Field Investigations

Mass and sudden deaths of rodents (rat falls) have remained the first indication of likely plague outbreaks since human history. Field investigation of small wild animals is conducted to determine the extent of Y. pestis contamination and its danger to humans.





Quarantine and Containment

The concept of Quarantine dates back to 1377 when the rulers of Venice imposed a 30-40 days isolation period for the port of Regusa for ships, crew and all travellers to the the port city. Similar laws and bans were imposed by the Italian and French ports to contain the spread of plague.


Global Map of Recent plague Outbreaks  CDC/WHO

Plague in China at YouTube





Thanks are due to Mr. Jean-Antoine de Mandato (PDP, Geneva) for providing office facilities and administrative support.
About authors and list of knols

Krishan Maggon                                              

Krishan Maggon Knols

Klaus Rohde

Klaus Rohde knols English



Books and Monographs                                                                                                                

Plague Literature

Albert Camus: La Peste
by Albert Camus

Journal of the Plague Year
by Daniel Defoe

The Decameron
by Giovanni Boccaccio

The Scarlet Plague
by Jack London

Justinian’s Flea. Plague, Empire and the Birth of Europe. Jonathan Cape, London.
by William Rosen (2007). 

Books and Monographs                                                                                                                


Plague Historical

Science Direct Search  5 August 2009

Plague and theatre in ancient Athens
The Lancet, Volume 373, Issue 9661, 31 January 2009-6 February 2009, Pages 374-375
Robin Mitchell-Boyask

The history of the plague and the research on the causative agent Yersinia pestis
International Journal of Hygiene and Environmental Health, Volume 207, Issue 2, 2004, Pages 165-178
Björn P. Zietz, Hartmut Dunkelberg

Plague: the dreadful visitation occupying the human mind for centuries
Transactions of the Royal Society of Tropical Medicine and Hygiene, Volume 98, Issue 5, May 2004, Pages 270-277
Iqbal Akhtar Khan

Modelling the black death. A historical case study and implications for the epidemiology of bubonic plague
International Journal of Medical Microbiology, In Press, Corrected Proof, Available online 27 June 2009
Stefan Monecke, Hannelore Monecke, Jochen Monecke

The concept of quarantine in history: from plague to SARS
Journal of Infection, Volume 49, Issue 4, November 2004, Pages 257-261
Gian Franco Gensini, Magdi H. Yacoub, Andrea A. Conti


 CDC List

1. Dennis, DT, Gage KL, Gratz N, Poland JD, and Tikhomirov E. (Principal authors). Plague  Manual. World Health Organization.  Geneva, Switzerland.  172 pp., 1999.

2. Parmenter RR, Yadav EP, Parmenter CA, Ettestad P, and Gage KL. Incidence of plague associated with increased winter-spring precipitation in New Mexico, USA. Am. J. Trop. Med. Hyg.  61:814-821.  1999.

3. Gage KL, Dennis DT, Orloski KA, Ettestad P, Brown TL, Reynolds PJ, Pape WJ, Fritz CL, Carter LG., and Stein JD.  Cases of human plague associated with exposure to infected domestic cats. Clin. Infect. Dis. 30:893-900. 2000.

4. Enscore, RE, Biggerstaff BJ, Brown TL, Fulgham RF, Reynolds PJ, Engelthaler DM, Levy CE, Parmenter RR, Montenieri JA, Cheek JE, Grinnell RK, Ettestad PJ, and Gage KL. Modeling relationships between climate and the frequency of human plague cases in the southwestern United States, 1960-1997.  Am. J. Trop. Med. Hyg.  66:186-196, 2002.

5. CDC. Imported Plague —New York City, 2002. Reported by Perlman DC, Primas R, Raucher B, Lis R, Weinberg B, Davilman A, Yampierre C, Protic J, Weiss D, Ackelsberg J, Lee L, Layton M, Beatrice ST, Smith PF, Ettestad PJ, Reynolds PJ, Sewell CM, Enscore RE, Kosoy MY, Kubota K, Lowell JL, Chu M, Kool J, Gage KL. Morbidity and Mortality Weekly Report. 52(31):725-728, 2003.

6. Dennis DT and Gage KL. Plague.  In: Infectious Diseases, 2nd ed.  Armstrong, D. and Cohen, J. Mosby, Ltd. London. Vol. 2, Section 6:1641-1648, 2003.

7. Seery DB, Biggins DE, Montenieri JA, Enscore RE, Tanda DT, and Gage KL.  Treatment of black-tailed prairie dog burrows with deltamethrin to control fleas (Insecta:Siphonaptera) and plague. J. Med Entomol.  40:718-722, 2003.

8. Lowell JL,  Wagner DM, Atshabar B, Antolin M, Vogler AJ, Keim P, Chu MC, and Gage KL. Identifying sources of human plague exposure.  J Clin Microbiol.  43:650-656, 2005.

9. Gage KL and Kosoy MY. The natural history of Plague: Perspectives from more than a century of research.  Ann Rev Entomology.  50:505-528, 2005.

10. Collinge SK, Johnson WC, Ray C, Matchett R, Grentsen J, Cully JF, Jr., Gage KL, Kosoy MY, Loye JE and Martin AP. Testing the generality of a trophic-cascade model for plague. Ecohealth 2:1-11, 2005.

11. Guarner J, Shieh W-J, Chu M, Perlman DC, Kool J, Gage KL, Ettestad P, Zaki SR. 2005.  Persistent Yersinia pestis antigens in ischemic tissues of a patient with septicemic plague. Human Pathology. 36:850-853, 2005.

12. Webb CT, Brooks CP, Gage KL, Antolin MF. Classic fleaborne transmission does not drive plague epizootics in prairie dogs. Proc Natl Acad Sci USA 103(16):6236-41, 2006

13. Eisen RJ, Bearden SW, Wilder AP, Montenieri JA, Antolin MF, Gage KL.  Early-phase transmission of Yersinia pestis by unblocked fleas as a mechanism explaining rapidly spreading plague epizootics.  Proc Natl Acad Sci.USA 103:42:15380-15385, 2006.

14. Human Plague – Four States, 2006. Reported by Bertram-Sosa L, Jaso C, Valadez  A, Nix B, Jones R, Sidwa T, Walker J, Anglim A, Reporter R, Mascola L, Van Gordon G, Ramirez J, Fritz C, Davis R, Ross J, Chongsiriwatana K, DiMenna M, Sheyka J, Ettestad P, Smelser C, Powers N, Reynolds P, Fowler J, Pape J, Tanda D, Mead P, Griffith K, Gage KL, Montenieri J, Dietrich G, Kubota K, Young J, Gould LH. Morbidity Mortality Weekly Report. 55:34:940- 943, 2006.

15. Lowell JL, Zhansarina A, Yockey B, Meka-Mechenko T, Stybayeva GS, Atshabar B, Nekrassova L. Tashmetov R, Kenghebaeva K, Chu MC, Kosoy M, Antolin MF, Gage KL. Phenotypic and molecular characterizations of Yersinia pestis isolates from Kazakhstan and adjacent regions. Microbiology. 153(Pt.1):169-177, 2007

16. Adjemian JC, Foley P, Gage KL, Foley JE. Initiation and spread of traveling waves of plague,Yersinia pestis, in the western United States. Am J Trop Med Hyg. 76:365-375, 2007.

17. Eisen RJ, Lowell JL, Montenieri JA, Bearden SW, Gage KL.  2007.  Temporal dynamics of   early-phase transmission of Yersinia pestis by unblocked fleas: secondary infectious feeds prolong efficient transmission by Oropsylla montana (Siphonaptera: Ceratophyllidae).  J Med Entomol, 44:672-677, 2007.

18. Eisen, RJ, Wilder AP, Bearden SW, Montenieri JA, Gage KL.  2007.  Early-phase transmission of Yersinia pestis by unblocked Xenopsylla cheopis (Siphonaptera:Pulicidae) is as efficient as transmission by blocked fleas.  J Med Entomol,  44:678-682, 2007. 19. Eisen RJ, Enscore RE, Biggerstaff BJ, Reynolds PJ, Ettestad P, Brown T, Pape J, Tanda D, Levy CE, Engelthaler DM, Cheek J, Bueno Jr. R, Targhetta, Montenieri JA, Gage KL. Human plague in the southwestern United States, 1957-2004: Spatial models of elevated risk of human exposure to Yersinia pestis. J Med Entomol, 44:530-537, 2007.

20. Eisen RJ, Reynolds PJ, Ettestad P, Brown T, Enscore RE, Biggerstaff BJ, Cheek J, Bueno R, Targhetta J, Montenieri JA, Gage KL. Residence-linked human plague in New Mexico: A habitat suitability model. Am J Trop Med Hyg, 77:121-125, 2007.

21. Gage KL.  Yersinia. In: Cecil’s Textbook of Medicine, 23rd Edition. Ed. Goldman L, Ausiello D. Suanders Elsevier, Philadelphia, pp. 2253-2259, 2007.

Bubonic plague – Wikipedia, the free encyclopedia
Plague – Wikipedia, the free encyclopedia

Scholar Search 3 August 2009

Gentamicin and tetracyclines for the treatment of human plague: review of 75 cases in New …

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– ► [PDF]
RD Perry, JD Fetherston – Clinical Microbiology Reviews, 1997 – Am Soc Microbiol
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The impact of infectious diseases on wild animal populations: a review

FMD Gulland – Ecology of infectious diseases in natural populations, 1995 –
… ‘* Pasteurella multocida Hawaiian land birds Wide range of vertebrates Reviews:
Red grouse (Lagvpus lagopus) South American primates Wide range of avian …
Cited by 85Related articlesAll 2 versions
NATURAL HISTORY OF PLAGUE: Perspectives from More than a Century of Research*

KL Gage, MY Kosoy – 2004 – Annual Reviews
… This article provides a selective review of research on plague and its natural history
since Yersin’s initial discovery of the plague bacillus in 1894. …
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Pathogenesis and sepsis caused by organisms potentially utilized as biologic weapons: …

MJ Hepburn, BK Purcell, J Paragas – Current Drug Targets, 2007 –
… Anthrax; Drug development; Exploration; Hemorrhagic fever; Infection; Microorganisms;
Plague; Reviews; Sepsis; Septic shock; Smallpox; Tularemia; J 02490 …
Cited by 5Related articlesBL DirectAll 3 versions
Structure and biology of house mouse populations that plague irregularly: an evolutionary …

GR SINGLETON, TD REDHEAD – Biological Journal of the Linnean Society, 1990 –
… litter size appears to be density dependent (see Pelikan, 198 1 for review). … during
the spring/summer breeding season immediately after the plague trigger(s …
Cited by 43Related articlesAll 3 versions
A review of plague and its relevance to prairie dog populations and the black-footed ferret

AM Barnes – Biological report. US Fish and Wildlife Service. …, 1993 –
A review of plague and its relevance to prairie dog populations and the black-footed
ferret. AM Barnes Biological report. US Fish and Wildlife Service. …
Cited by 57Related articles
Plague in India: a new warning from an old nemesis

GL Campbell, JM Hughes – Annals of internal medicine, 1995 – Am Coll Physicians
Yersiniosis I: microbiological and clinicoepidemiological aspects of plague and non-plague …

RA Smego, J Frean, HJ Koornhof – European Journal of Clinical Microbiology & Infectious …, 1999 – Springer
Vaccination antipesteuse: le passé et les perspectives d’avenir.

M Merlin – Bulletin de la Société de pathologie exotique, 1999 –

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Science Direct Search  5 August 2009
Epidemiological features of pneumonic plague outbreak in Himachal Pradesh, India
Transactions of the Royal Society of Tropical Medicine and Hygiene, Volume 103, Issue 5, May 2009, Pages 455-460
Kamlesh Joshi, J.S. Thakur, Rajesh Kumar, A.J. Singh, Pallab Ray, Sanjay Jain, S. Varma

Plague in the United States: the “Black Death” is still alive
Annals of Emergency Medicine, Volume 9, Issue 6, June 1980, Pages 319-322
Stephen L. Hoffman

Current epidemiology of human plague in Madagascar
Microbes and Infection, Volume 2, Issue 1, January 2000, Pages 25-31
Suzanne Chanteau, Mahery Ratsitorahina, Lila Rahalison, Bruno Rasoamanana, Fabien Chan, Pascal Boisier, Dieudoné Rabeson, Jean Roux

Molecular and physiological insights into plague transmission, virulence and etiology
Microbes and Infection, Volume 8, Issue 1, January 2006, Pages 273-284
Dongsheng Zhou, Yanping Han, Ruifu Yang

Vaccination against bubonic and pneumonic plague
Vaccine, Volume 19, Issue 30, 20 July 2001, Pages 4175-4184
Richard W. Titball, E. Diane Williamson

Molecular insights into the history of plague
Microbes and Infection, Volume 4, Issue 1, January 2002, Pages 105-109
Michel Drancourt, Didier Raoult

Medicine, Volume 33, Issue 7, 1 July 2005, Pages 30-31
Jehangir S Sorabjee

Plague: Past and future implications for India
Public Health, Volume 109, Issue 1, January 1995, Pages 7-11
G.C. Cook

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