Bubonic plague

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Overview

Yersinia pestis infection Microchapters
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Esther Lee, M.A.; João André Alves Silva, M.D. [2]; Serge Korjian, M.D.; Yazan Daaboul, M.D.; Rim Halaby, M.D. [3]

Overview

Yersinia pestis infection, an infectious disease of animals and humans, is caused by enterobacteriaYersinia pestis, a bacterium. Human yersinia pestis infection takes three main clinical forms: pneumonic, septicemic, and the bubonic plague. All three forms are widely believed to have been responsible for a number of high-mortality epidemics throughout human history, including the Plague of Justinian in 542 CE and the black death, accounted for the death of at least one-third of the European population between 1347 and 1353 CE. It is demonstrated conclusively that these plagues originated in rodent populations in China. Plague is a zoonotic, primarily carried by rodents (notably rats) and spread to humans via fleas. Plague is notorious throughout history, due to the unprecedented scale of death and devastation it wrought. Plague is still endemic in some parts of the world. Bubonic plague should be differentiated from other causes of lymphadenopathy, such as streptococcal or staphylococcal lymphadenitis, infectious mononucleosis, cat-scratch fever, and tularemia. Septicemic plague should be differentiated from non-specific sepsis syndrome and gram negative sepsis. Differential diagnosis for pneumonic plague includes infections that cause community-acquired pneumonia, such as pneumococcal or streptococcal pneumonia, viral pneumonia, hemophilus influenzae, and anthrax. Symptoms of plague may be differentiated by type: Bubonic, septicemic, and pneumonic. Although all 3 types share constitutional symptoms, key features differentiate them from one another. Not only do the 3 types differ in symptoms, but also in treatment and prognosis. Bubonic plague is characterized by the presence of painful and tender lymphadenopathy, called buboes. Less pathognomonic features are found in other types of plague, making their diagnosis more difficult. Septicemic plague follows the course, along with signs and symptoms, of a gram-negative bacilli and pneumonic plague presents with a virulent pneumonia. Antibiotic therapy is the mainstream of treatment. The drugs of choice are streptomycin or gentamicin, but tetracyclines, fluoroquinolones, and chloramphenicol are also effective.

Historical Perspective

It is suggested that Yersinia pestis infection was a contributing factor in some of (though possibly not all) the European plagues. The earliest account describing a possible plague epidemic is found in I Samuel 5:6 of the Hebrew Bible (Tanakh). In this account, the Philistines of Ashdod were stricken with a plague for the crime of stealing the Ark of the Covenant from the Children of Israel. These events have been dated to approximately the second half of the 11th century BC.

Classification

The classification of plague depends on the mode of infection and the clinical syndrome. Plague can be classified into bubonic plague, septicemic plague, or pneumonic plague.

Pathophysiology

Plague can be transmitted from flea bites or the inhalation of aerosol from an individual who has plague pneumonia. Pathogenesis due to the Yersinia pestis infection of mammalian hosts, results from several factors including the bacteria's avoidance of normal immune system responses, such as phagocytosis and antibody production.

Causes

Yersinia pestis (Y. pestis), a rod-shaped facultative anaerobe with bipolar staining (giving it a safety pin appearance) causes the infection in mammals and humans. The bacteria maintain their existence in a cycle involving rodents and their fleas. The genus Yersinia is gram-negative, bipolar staining coccobacilli, and, similarly to other Enterobacteriaceae, it has a fermentative metabolism. Y. pestis produces an antiphagocytic slime. The organism is motile when isolated, but becomes nonmotile in the mammalian host.

Differential Diagnosis

The differential diagnosis for yersina pestis infection is dependent on the clinical syndrome (bubonic plague, septicimic plague, pneumonic plague, or pharyngeal plague). Bubonic plague should be differentiated from other causes of lymphadenopathy, such as streptococcal or staphylococcal lymphadenitis, infectious mononucleosis, cat-scratch fever, and tularemia. Septicemic plague should be differentiated from non-specific sepsis syndrome and gram negative sepsis. The differential diagnosis for pneumonic plague includes infections that cause community-acquired pneumonia, such as pneumococcal or streptococcal pneumonia, viral pneumonia, hemophilus influenzae, and anthrax.

Epidemiology and Demographics

Given its ability to cause serious pandemics, plague is one of the three diseases subject to the International Health Regulations, the other two being yellow fever and cholera. From 1954 to 1997, plague affected 38 countries, with 80 613 cases and 6587 deaths. Between 2004 and 2009, the WHO reported that the number of cases of plague worldwide was 12,503, with 843 deaths, for a case-fatality rate of 6.7%.

Risk Factors

Risk factors for plague include living in rural areas, near animals such as rodents, or in houses where sanitation is poor. People who deal frequently with animals, such as veterinaries, are at higher risk for infection with Yersinia pestis.

Screening

Screening is not recommended for patients at risk of contracting plague. However, all suspected cases should be confirmed and reported to the World Health Organization upon discovery.

Natural History, Complications and Prognosis

The complications of Yersina pestis infection are dependent on the clinical syndrome (bubonic plague, septicimic plague, pneumonic plague, or pharyngeal plague). Bubonic plague can be complicated by septicemia, pneumonia, or meningitis. The complications of septicemic plague include gangrene of distal upper and lower extremities and tip of the nose due to small vessel thrombosis, disseminated intravascular coagulopathy (DIC), and adult respiratory distress syndrome (ARDS). The complications of pneumonic plague are septicemia, abscess formation, and cavitation. If plague patients are not administered specific antibiotic therapy, the disease can progress rapidly to death. Approximately 14% (1 in 7) of all plague cases in the United States are fatal.

Diagnosis

History and Symptoms

Symptoms of plague may be differentiated by type: Bubonic, septicemic, and pneumonic. Although all 3 types share constitutional symptoms, key features differentiate them from one another. Not only do the 3 types differ in symptoms, but also in treatment and prognosis. Bubonic plague is characterized by the presence of painful and tender lymphadenopathy, called buboes. Less pathognomonic features are found in other types of plague, making their diagnosis more difficult. Septicemic plague follows the course, along with signs and symptoms, of a gram-negative bacilli and pneumonic plague presents with a virulent pneumonia.

Physical Examination

Apart from the presence of buboes, which are tender lymph nodes in patients infected with bubonic plague, the physical examination findings are not specific to plague. Nonetheless, physical examination is crucial to evaluate for the presence of target organ damage or the progression and worsening of infection burden in these patients.

Laboratory Findings

Following a thorough history and physical exam, patients suspected to be infected by the plague, such as a patient presenting with fever living in an endemic region, require a confirmation of the initial diagnosis. Bubonic plague is diagnosed by gram stain and culture of aspirated material from suppurative lymph nodes. Collection of blood specimens, lymph node aspirates from buboes, sputum samples, and tracheal swabs are needed before the administration of antibiotics. Additionally, cerebrospinal fluid (CSF) collection is required in cases suspected to have meningeal complications of plague. In the United States, reporting of suspicious cases and sending collected material to specialized labs with expertise in Plague testing and to the State Health Department are mandatory procedures.

Chest X-Ray

A chest x-ray is required in patients suspected to have plague, especially those with pneumonic plague. Findings on chest x-ray may reveal the true burden of pulmonary disease when there are minimal findings on auscultation during physical examination.

Treatment

Medical Therapy

When a diagnosis of human plague is suspected upon clinical and epidemiological grounds, appropriate specimens for diagnosis should be obtained immediately and the patient should be started on specific antimicrobial therapy prior to a definitive answer from the laboratory. The drugs of choice are streptomycin or gentamicin, but tetracyclines, fluoroquinolones, and chloramphenicol are also effective. The regimens should be adjusted depending on the patient's age, medical history, underlying health conditions, and allergies. Upon evidence of pneumonia, suspect plague patients should be placed in isolation and managed under respiratory droplet precautions.

Primary Prevention

The plague may be prevented by the administration of prophylactic therapy and implementation of hospital and public risk reduction measures. Post-exposure prophylaxis is indicated in persons with known exposure to plague, such as close contact with a pneumonic plague patient or direct contact with infected body fluids or tissues. There is a vaccine available for professionals who work in laboratories with the bacteria, or who study infected rodents.

Cost-Effectiveness of Therapy

Without treatment, the plague can cause serious illness or death. With adequate antibiotic treatment the mortality rate is about 8-10%. Therefore the treatment of plague may be considered cost-effective.

Future or Investigational Therapies

Current research aims to develop new and less invasive vaccines that protect from airborne infection of Yersinia pestis.

References

Historical Perspective

Yersinia pestis infection Microchapters
Home
Patient Information
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Yersinia Pestis Infection from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms
Physical Examination
Laboratory Findings
Chest X Ray
Treatment
Medical Therapy
Primary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Bubonic plague On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Bubonic plague All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Bubonic plague
CDC on Bubonic plague
Bubonic plague in the news
Blogs on Bubonic plague
Directions to Hospitals Treating Yersinia pestis infection
Risk calculators and risk factors for Bubonic plague

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4]; Assistant Editors-In-Chief: Esther Lee, M.A.

Overview

It is suggested that Yersinia pestis infection was a contributing factor in some of (though possibly not all) the European plagues. The earliest account describing a possible plague epidemic is found in I Samuel 5:6 of the Hebrew Bible (Tanakh). In this account, the Philistines of Ashdod were stricken with a plague for the crime of stealing the Ark of the Covenant from the Children of Israel. These events have been dated to approximately the second half of the 11th century BC.

Historical Perspective

Plague has a remarkable place in history. For centuries, plague represented disaster for those living in Asia, Africa and Europe, where, it has been said, populations were so affected that sometimes there were not enough people left alive to bury the dead (Gross, 1995). Because the cause of plague was unknown, plague outbreaks contributed to massive panic in cities and countries where it appeared. The disease was believed to be delivered upon the people by the displeasure of the gods, by other supernatural powers or, by heavenly disturbance. Innocent groups of people were blamed for spreading plague and were persecuted by the panicked masses. Numerous references in art, literature and monuments attest to the horrors and devastation of past plague epidemics. So imprinted in the minds of people is the fear of plague that, even now, entering into the 21st century, a suspected plague outbreak can incite mass panic and bring much of the world's economy to a temporary standstill. The number of human plague infections is low when compared to diseases caused by other agents, yet plague invokes an intense, irrational fear, disproportionate to its transmission potential in the post-antibiotic/ vaccination era.

Antiquity

Nicolas Poussin (1594–1665), French. The Plague of Ashdod, 1630. Oil on canvas, 148 x 198 cm. Musée du Louvre, Paris, France, Giraudon/Bridgeman Art Library.

The earliest account describing a possible plague epidemic is found in I Samuel 5:6 of the Hebrew Bible (Tanakh). In this account, the Philistines of Ashdod were stricken with a plague for the crime of stealing the Ark of the Covenant from the Children of Israel. These events have been dated to approximately the second half of the 11th century BC. The word "tumors" is used in most English translations of the Bible to describe the sores that came upon the Philistines. The Hebrew language, however, can be interpreted as "swelling in the secret parts". The account indicates that the Philistine city and its political territory were stricken with a "ravaging of mice" and a plague, bringing death to a large segment of the population.

In the second year of the Peloponnesian War (430 BC), Thucydides described an epidemic disease which was said to have begun in Ethiopia, passed through Egypt and Libya, then come to the Greek world. In the Plague of Athens, the city lost possibly one third of its population, including Pericles. Modern historians disagree on whether the plague was a critical factor in the loss of the war. Although this epidemic has long been considered an outbreak of plague, many modern scholars believe that typhus, smallpox, or measles may better fit the surviving descriptions. A recent study of DNA found in the dental pulp of plague victims suggests that typhoid was actually responsible.

In the first century AD, Rufus of Ephesus, a Greek anatomist, refers to an outbreak of plague in Libya, Egypt, and Syria. He records that Alexandrian doctors named Dioscorides and Posidonius described symptoms including acute fever, pain, agitation, and delirium. Buboes—large, hard, and non-suppurating—developed behind the knees, around the elbows, and "in the usual places." The death toll of those infected was very high. Rufus also wrote that similar buboes were reported by a Dionysius Curtus, who may have practiced medicine in Alexandria in the third century BC. If this is correct, the eastern Mediterranean world may have been familiar with bubonic plague at that early date.

Historically each Yersinia pestis biovar is associated with one plague pandemic:

• Biovar Antiqua - First or Justinian plague
• Biovar Medievalis - Second or Black Death plague. Today is prevalent in the region of the Caspian Sea, being the cause of the modern plague.
• Biovar Orientalis - Currently circulating in the Western hemisphere and Asia

Medieval and Post-medieval Pandemics

Local outbreaks of the plague are grouped into three plague pandemics, whereby the respective start and end dates and the assignment of some outbreaks to either pandemic are still subject to discussion. According to Joseph P. Byrne from Belmont University, the pandemics were:

• The first plague pandemic from 541 to ~750, spreading from Egypt to the Mediterranean (starting with the Plague of Justinian) and northwestern Europe
• The second plague pandemic from ~1345 to ~1840, spreading from Central Asia to the Mediterranean and Europe (starting with the Black Death), and probably also to China
• The third plague pandemic from 1866 to the 1960s, spreading from China to various places around the world, notably the US-American west coast and India.

However, the late medieval Black Death is sometimes seen not as the start of the second, but as the end of the first pandemic – in that case, the second pandemic's start would be 1361; also vary the end dates of the second pandemic given in literature, e.g. ~1890 instead of ~1840.

First Pandemic: Early Middle Ages (Plague of Justinian)

Main article: Plague of Justinian

The Plague of Justinian in AD 541–542 is the first known attack on record, and marks the first firmly recorded pattern of bubonic plague. This disease is thought to have originated in China. It then spread to Africa from where the huge city of Constantinople imported massive amounts of grain, mostly from Egypt, to feed its citizens. The grain ships were the source of contagion for the city, with massive public granaries nurturing the rat and flea population. At its peak the plague was killing 10,000 people in Constantinople every day and ultimately destroyed perhaps 40% of the city's inhabitants. It went on to destroy up to a quarter of the human population of the eastern Mediterranean.

In AD 588 a second major wave of plague spread through the Mediterranean into what is now France. It is estimated that the Plague of Justinian killed as many as 100 million people across the world. It caused Europe's population to drop by around 50% between 541 and 700. It also may have contributed to the success of the Arab conquests. An outbreak of it in the AD 560s was described in AD 790 as causing "swellings in the glands ... in the manner of a nut or date" in the groin "and in other rather delicate places followed by an unbearable fever". While the swellings in this description have been identified by some as buboes, there is some contention as to whether the pandemic should be attributed to the bubonic plague, Yersinia pestis, known in modern times.

Second Pandemic: from 14th century (Black Death) to 19th century

See also: Black Death

"Der Doktor Schnabel von Rom" ("Doctor Beak of Rome"). The beak is a primitive gas mask, stuffed with substances (such as spices and herbs) thought to ward off the plague.

Map showing the spread of the Black Death (bubonic plague) in Europe during the 1347–1351 pandemic which is believed to have started in China and spread west, reaching the Black Sea by 1347

From 1347 to 1351, the Black Death, a massive and deadly pandemic originating in China, spread along the Silk Road and swept through Asia, Europe and Africa. It may have reduced the world's population from 450 million to between 350 and 375 million. China lost around half of its population, from around 123 million to around 65 million; Europe around 1/3 of its population, from about 75 million to about 50 million; and Africa approximately 1/8 of its population, from around 80 million to 70 million (mortality rates tended to be correlated with population density so Africa, being less dense overall, had the lowest death rate). This makes the Black Death the largest death toll from any known non-viral epidemic. Although accurate statistical data does not exist, it is thought that 1.4 million died in England (1/3 of England's 4.2 million people), while an even higher percentage of Italy's population was likely wiped out. On the other hand, Northeastern Germany, Bohemia, Poland and Hungary are believed to have suffered less, and there are no estimates available for Russia or the Balkans. It is conceivable that Russia may not have been as affected due to its very cold climate and large size, hence often less close contact with the contagion.

The plague repeatedly returned to haunt Europe and the Mediterranean throughout the 14th to 17th centuries. According to Biraben, plague was present somewhere in Europe in every year between 1346 and 1671. The Second Pandemic was particularly widespread in the following years: 1360–1363; 1374; 1400; 1438–1439; 1456–1457; 1464–1466; 1481–1485; 1500–1503; 1518–1531; 1544–1548; 1563–1566; 1573–1588; 1596–1599; 1602–1611; 1623–1640; 1644–1654; and 1664–1667; subsequent outbreaks, though severe, marked the retreat from most of Europe (18th century) and northern Africa (19th century). According to Geoffrey Parker, "France alone lost almost a million people to plague in the epidemic of 1628–31."

In England, in the absence of census figures, historians propose a range of preincident population figures from as high as 7 million to as low as 4 million in 1300, and a postincident population figure as low as 2 million. By the end of 1350, the Black Death subsided, but it never really died out in England. Over the next few hundred years, further outbreaks occurred in 1361–62, 1369, 1379–83, 1389–93, and throughout the first half of the 15th century. An outbreak in 1471 took as much as 10–15% of the population, while the death rate of the plague of 1479–80 could have been as high as 20%. The most general outbreaks in Tudor and Stuart England seem to have begun in 1498, 1535, 1543, 1563, 1589, 1603, 1625, and 1636, and ended with the Great Plague of London in 1665.

In 1466, perhaps 40,000 people died of plague in Paris. During the 16th and 17th centuries, plague visited Paris for almost one year out of three. The Black Death ravaged Europe for three years before it continued on into Russia, where the disease hit somewhere once every five or six years from 1350 to 1490. Plague epidemics ravaged London in 1563, 1593, 1603, 1625, 1636, and 1665, reducing its population by 10 to 30% during those years. Over 10% of Amsterdam's population died in 1623–1625, and again in 1635–1636, 1655, and 1664. There were 22 outbreaks of plague in Venice between 1361 and 1528. The plague of 1576–1577 killed 50,000 in Venice, almost a third of the population. Late outbreaks in central Europe included the Italian Plague of 1629–1631, which is associated with troop movements during the Thirty Years' War, and the Great Plague of Vienna in 1679. Over 60% of Norway's population died from 1348 to 1350. The last plague outbreak ravaged Oslo in 1654.

In the first half of the 17th century, a plague claimed some 1.7 million victims in Italy, or about 14% of the population. In 1656, the plague killed about half of Naples' 300,000 inhabitants. More than 1.25 million deaths resulted from the extreme incidence of plague in 17th-century Spain. The Great plague of 1649 probably reduced the population of Seville by half. In 1709–1713, a The plague during the Great Northern War|plague epidemic that followed the Great Northern War (1700–1721, Sweden v. Russia and allies) killed about 100,000 in Sweden, and 300,000 in Prussia. The plague killed two-thirds of the inhabitants of Helsinki, and claimed a third of Stockholm's population. Western Europe's last major epidemic occurred in 1720 in Marseilles, in Central Europe the last major outbreaks happened during the plague during the Great Northern War, and in Eastern Europe during the Russian plague of 1770-1772

Worldwide distribution of plague-infected animals 1998

The Black Death ravaged much of the Islamic world. Plague was present in at least one location in the Islamic world virtually every year between 1500 and 1850. Plague repeatedly struck the cities of North Africa. Algiers lost 30,000–50,000 to it in 1620–21, and again in 1654–57, 1665, 1691, and 1740–42. Plague remained a major event in Ottoman society until the second quarter of the 19th century. Between 1701 and 1750, 37 larger and smaller epidemics were recorded in Constantinople, and 31 between 1751 and 1800. Baghdad has suffered severely from visitations of the plague, and sometimes two-thirds of its population has been wiped out.

Nature of the Black Death

Main articles: Black Death, Theories of the Black Death, and Bubonic plague

A hand showing acral gangrene of the digits due to plague, the black appearance of the necrotized tissue which occurs in gangrene, one of the symptoms of plague

In the early 20th century, following the identification by Yersin and Kitasato of the plague bacterium that caused the late 19th and early 20th century Asian bubonic plague (the Third Pandemic), most scientists and historians came to believe that the Black Death was an incidence of this plague, with a strong presence of the more contagious pneumonic and septicemic varieties increasing the pace of infection, spreading the disease deep into inland areas of the continents. It was claimed that the disease was spread mainly by black rats in Asia and that therefore there must have been black rats in north-west Europe at the time of the Black Death to spread it, although black rats are currently rare except near the Mediterranean. This led to the development of a theory that brown rats had invaded Europe, largely wiping out black rats, bringing the plagues to an end, although there is no evidence for the theory in historical records. Some historians suggest that marmots, rather than rats, were the primary carriers of the disease.

The view that the Black Death was caused by Yersinia pestis has been incorporated into medical textbooks throughout the 20th century and has become part of popular culture, as illustrated by recent books, such as John Kelly's The Great Mortality. Many modern researchers have argued that the disease was more likely to have been viral (that is, not bubonic plague), pointing to the absence of rats from some parts of Europe that were badly affected and to the conviction of people at the time that the disease was spread by direct human contact. According to the accounts of the time the Black Death was extremely virulent, unlike the 19th and early 20th century bubonic plague. Samuel K. Cohn has made a comprehensive attempt to rebut the bubonic plague theory. In the Encyclopedia of Population, he points to five major weaknesses in this theory:

• Very different transmission speeds — the Black Death was reported to have spread 385 km in 91 days (4.23 km/day) in 664, compared to 12–15 km a year for the modern bubonic plague, with the assistance of trains and cars
• Difficulties with the attempt to explain the rapid spread of the Black Death by arguing that it was spread by the rare pneumonic form of the disease — in fact this form killed less than 0.3% of the infected population in its worst outbreak (Manchuria in 1911)
• Different seasonality — the modern plague can only be sustained at temperatures between 10 and 26°C and requires high humidity, while the Black Death occurred even in Norway in the middle of the winter and in the Mediterranean in the middle of hot dry summers
• Very different death rates — in several places (including Florence in 1348) over 75% of the population appears to have died; in contrast the highest mortality for the modern bubonic plague was 3% in Bombay in 1903
• The cycles and trends of infection were very different between the diseases — humans did not develop resistance to the modern disease, but resistance to the Black Death rose sharply, so that eventually it became mainly a childhood disease

Cohn also points out that while the identification of the disease as having buboes relies on accounts of Boccaccio and others, they described buboes, abscesses, rashes and carbuncles occurring all over the body, the neck or behind the ears. In contrast, the modern disease rarely has more than one bubo, most commonly in the groin, and is not characterised by abscesses, rashes and carbuncles.

Researchers have offered a mathematical model based on the changing demography of Europe from 1000 to 1800 AD demonstrating how plague epidemics, 1347 to 1670, could have provided the selection pressure that raised the frequency of a mutation to the level seen today that prevent HIV from entering macrophages and CD4+ T cells that carry the mutation (the average frequency of this allele is 10% in European populations). It is suggested that the original single mutation appeared over 2,500 years ago and that persistent epidemics of a haemorrhagic fever struck at the early classical civilizations.

However recent research published in the open-access scientific journal PloS Pathogens in October 2010 presented conclusive evidence that two previously unknown clades (variant strains) of Y. pestis were responsible for the Black Death. A multinational team conducted new surveys that used both ancient DNA analyses and protein-specific detection to find DNA and protein signatures specific for Y. pestis in human skeletons from widely distributed mass graves in northern, central and southern Europe that were associated archaeologically with the Black Death and subsequent resurgences. The authors concluded that this research, together with prior analyses from the south of France and Germany,

"... ends the debate about the etiology of the Black Death, and unambiguously demonstrates that Y. pestis was the causative agent of the epidemic plague that devastated Europe during the Middle Ages."

The study also identified two previously unknown but related strains of Y. pestis that were associated with distinct medieval mass graves. These were found to be ancestral to modern isolates of the present-day Y. pestis strains 'Orientalis' and 'Medievalis', suggesting that these variant strains (which are now presumed to be extinct) may have entered Europe in two waves. Surveys of plague pit remains in France and England indicate that the first variant entered Europe through the port of Marseille around November 1347 and spread through France over the next two years, eventually reaching England in the spring of 1349, where it spread through the country in three successive epidemics.

However, surveys of plague pit remains from the Netherlands town of Bergen op Zoom showed evidence of a second Y. pestis genotype which differed from that found in Britain and France and this second strain is now thought to have been responsible for the pandemic that spread through the Low Countries from 1350. This discovery implies that Bergen op Zoom (and possibly other parts of the southern Netherlands) was not directly infected from England or France c. AD 1349, and the researchers have suggested that a second wave of plague infection, distinct from that which occurred in Britain and France, may have been carried to the Low Countries from Norway, the Hanseatic cities, or another site.

Third Pandemic: 19th and 20th centuries

The Third Pandemic began in China's Yunnan province in 1855, spreading plague to all inhabited continents and ultimately killing more than 12 million people in India and China alone. Casualty patterns indicate that waves of this pandemic may have come from two different sources. The first was primarily bubonic and was carried around the world through ocean-going trade, transporting infected persons, rats, and cargoes harboring fleas. The second, more virulent strain was primarily pneumonic in character, with a strong person-to-person contagion. This strain was largely confined to Manchuria and Mongolia Researchers during the "Third Pandemic" identified plague vectors and the plague bacterium (see above), leading in time to modern treatment methods.

Plague occurred in Russia\ in 1877–1889 in rural areas near the Ural Mountains and the Caspian Sea. Efforts in hygiene and patient isolation reduced the spread of the disease, with approximately 420 deaths in the region. Significantly, the region of Vetlianka in this area is near a population of the bobak marmot, a small rodent considered a very dangerous plague reservoir. The last significant Russian outbreak of Plague was in Siberia in 1910 after sudden demand for Marmot skins (a substitute for Sable) increased the price by 400 percent. The traditional hunters would not hunt a sick Marmot and it was taboo to eat the fat from under the arm (the axillary lymphatic gland that often harboured the plague) so outbreaks tended to be confined to single individuals. The price increase, however, attracted thousands of Chinese hunters from Manchuria who not only caught the sick animals but also ate the fat, which was considered a delicacy. The plague spread from the hunting grounds to the terminus of theChinese Eastern Railway and then followed the track for 2,700 km. The plague lasted 7 months and killed 60,000 people.

The bubonic plague continued to circulate through different ports globally for the next fifty years; however, it was primarily found in Southeast Asia. An epidemic in Hong Kong in 1894 had particularly high death rates, 90%. As late as 1897, medical authorities in the European powers organized a conference in Venice, seeking ways to keep the plague out of Europe. Mumbai plague epidemic struck the city of Bombay (Mumbai) in 1896. The disease reached the Territory of Hawaii in December 1899, and the Board of Health's decision to initiate controlled burns of select buildings in Honolulu's Chinatown turned into an uncontrolled fire which led to the inadvertent burning of most of Chinatown on January 20, 1900. Shortly thereafter, plague reached the continental US, initiating the San Francisco plague of 1900–1904. Plague persisted in Hawaii on the outer islands of Maui and Hawaii (The Big Island) until it was finally eradicated in 1959.

Although the outbreak that began in China in 1855 is conventionally known as the Third Pandemic, (see above), it is unclear whether there have been fewer, or more, than three major outbreaks of bubonic plague. Most modern outbreaks of bubonic plague amongst humans have been preceded by a striking, high mortality amongst rats, yet this phenomenon is absent from descriptions of some earlier plagues, especially the Black Death. The buboes, or swellings in the groin, that are especially characteristic of bubonic plague, are a feature of other diseases as well.

Research done by a team of biologists from the Institute of Pasteur in Paris and Johannes Gutenberg University Mainz in Germany by analyzing the DNA and proteins from plague pits was published in Oct., 2010, reported beyond doubt that all 'the three major plagues' were due to at least two previously unknown strains of Yersinia pestis and originated from China. A team of medical geneticists led by Mark Achtman of University College Cork in Ireland reconstructed a family tree of the bacterium and concluded in an online issue of Nature Genetics published on 31 Oct., 2010 that all three of the great waves of plague originated from China. Europe’s Plagues Came From China, Study Finds.

Fundamental Works

The fundamental but separate works by Yersin and Kitasato in 1894 on the discovery of the etiologic agent of plague in Hong Kong opened the way for investigating the disease and how it is spread. Kitasato and Yersin described, within days of each other’s findings, the presence of bipolar staining organisms in the swollen lymph node (bubo), blood, lungs, liver and spleen of deadpatients (Bibel et al., 1976). Cultures isolated from patient specimens were inoculated into a variety of laboratory animals, including mice. These animals died within days after injection, and the same bacilli as those found in patient specimens were present in the animal organs. Though both investigators reported their findings, there were a series of confusing and contradictory statements by Kitasato that eventually led to the acceptance of Yersin as the primary discoverer of the organism now named after him, Yersinia pestis (Bibel et al., 1976). Yersin had recorded that rats were affected by plague not only during plague epidemics but also often preceding such epidemics in humans. In fact, plague was designated, in local languages, as a disease of the rats: villagers in China, India and Formosa (Taiwan) described that when hundreds and thousands of rats lie dead in and out of houses, plague outbreaks in people soon followed (Gross, 1995). The transmission of plague was described by Simond in 1898. He noted that persons who became ill did not have to be in close contact with each other to acquire the disease. In Yunnan, China, inhabitants would run away from their homes as soon as they saw dead rats. On the island of Formosa, residents considered handling dead rats a risk for developing plague. These observations led Simond to suspect that the flea might be an intermediary factor in the transmission of plague since people acquired plague only if they were in contact with recently dead rats and were not affected if they touched rats that were dead for more than 24 hours. Simond demonstrated that the rat flea (Xenopsylla cheopis) transmitted the disease in a now classic experiment in which a healthy rat, separated from direct contact with a recently plague-killed rat, died of plague after the infected fleas jumped from the first rat to the second.

Plague as a biological weapon

Plague has a long history as a biological weapon. Historical accounts from ancient China and medieval Europe detail the use of infected animal carcasses, such as cows or horses, and human carcasses, by the Xiongnu/Huns, Mongols, Turks, and other groups, to contaminate enemy water supplies. Han Dynasty General Huo Qubing is recorded to have died of such a contamination while engaging in warfare against the Xiongnu. Plague victims were also reported to have been tossed by catapult into cities under siege.

During World War II, the Japanese Army developed weaponised plague, based on the breeding and release of large numbers of fleas. During the Japanese occupation of Manchuria, Unit 731 deliberately infected Chinese, Korean, and Manchurian civilians and prisoners of war with the plague bacterium. These subjects, termed "maruta", or "logs", were then studied by dissection, others by vivisection while still conscious. Members of the unit such as Shiro Ishii were exonerated from the Tokyo tribunal by Douglas MacArthur but twelve of them were prosecuted in the Khabarovsk War Crime Trials in 1949 during which where some admitted having spread Bubonic plague within a 36-km radius around the city of Changde.

After World War II, both the United States and the Soviet Union developed means of weaponising pneumonic plague. Experiments included various delivery methods, vacuum drying, sizing the bacterium, developing strains resistant to antibiotics, combining the bacterium with other diseases (such as diphtheria), and genetic engineering. Scientists who worked in USSR bio-weapons programs have stated that the Soviet effort was formidable and that large stocks of weaponised plague bacteria were produced. Information on many of the Soviet projects is largely unavailable. Aerosolized pneumonic plague remains the most significant threat. The plague can be easily treated with antibiotics, thus a widespread epidemic is highly unlikely in developed countries.

Worldwide distribution of plague infected animals 1998

1994 Epidemic in Surat, India

In 1994, there was a pneumonic plague epidemic in Surat, India that resulted in 52 deaths and in a large internal migration of about 300,000 residents, who fled fearing quarantine .

A combination of heavy monsoon rain and clogged sewers led to massive flooding which resulted in unhygienic conditions and a number of uncleared animal carcasses. It is believed that this situation precipitated the epidemic.. There was widespread fear that the flood of refugees might spread the epidemic to other parts of India and the world, but that scenario was averted, probably as a result of effective public health response mounted by the Indian health authorities .

Much like the Black Death that spread through medieval Europe, some questions still remain unanswered about the 1994 epidemic in Surat.

Initial questions about whether it was an epidemic of plague arose because the Indian health authorities were unable to culture Yersinia pestis, but this could have been due to poor laboratory procedures. Yet, there are several lines of evidence strongly suggesting that it was a plague epidemic: blood tests for Yersinia were positive, a number of individuals showed antibodies against Yersinia and the clinical symptoms displayed by the affected were all consistent with the disease being plague .

Other Contemporary cases

Two non-plague Yersinia - Yersinia pseudotuberculosis and Yersinia enterocolitica - still exist in fruit and vegetables from the Caucasus Mountains east across southern Russia and Siberia, to Kazakhstan, Mongolia, and parts of China; in Southwest and Southeast Asia, Southern and East Africa (including the island of Madagascar); in North America, from the Pacific Coast eastward to the western Great Plains, and from British Columbia south to Mexico; and in South America in two areas: the Andes mountains and Brazil. There is no plague-infected animal population in Europe or Australia.

• On 31 August, 1984, the Centers for Disease Control and Prevention reported a case of pneumonic plague in Claremont, California. The CDC believes that the patient, a veterinarian, contracted plague from a stray cat. This could not be confirmed since the cat was destroyed prior to the onset of symptoms.
• From 1995 to 1998, annual outbreaks of plague were witnessed in Mahajanga, Madagascar as per a study done by Pascal Boisier and other scientists and publish in Emerging Infectious Diseases journal in March 2002.

• In the U.S., about half of all food cases of plague since 1970 have occurred in New Mexico. There were 2 plague deaths in the state in 2006, the first fatalities in 12 years.

• In Fall of 2002, a New Mexico couple contracted the disease, just prior to a visit to New York City. They both were treated by antibiotics, but the male required amputation of both feet to fully recover, due to the lack of blood flow to his feet, cut off by the bacteria.

• On 19 April 2006, CNN News and others reported a case of plague in Los Angeles, California, lab technician Nirvana Kowlessar, the first reported case in that city since 1984.

• In May 2006, KSL Newsradio reported a case of plague found in dead field mice and chipmunks at Natural Bridges about 40 miles (64 km) west of Blanding in San Juan County, Utah.

• In May 2006, AZ Central reported a case of plague found in a cat.

• One hundred deaths resulting from pneumonic plague were reported in Ituri district of the eastern Democratic Republic of the Congo in June 2006. Control of the plague was proving difficult due to the ongoing conflict.

• It was reported in September 2006 that three mice infected with Yersinia pestis apparently disappeared from a laboratory belonging to the Public Health Research Institute, located on the campus of the University of Medicine and Dentistry of New Jersey, which conducts anti-bioterrorism research for the United States government.

• On 16 May 2007, an 8-year-old hooded capuchin monkey in the Denver Zoo died of the bubonic plague. Five squirrels and a rabbit were also found dead on zoo grounds and tested positive for the disease.

• On 5 June 2007 in Scotland, UK a 68 year old woman developed bubonic plague, which progressed to pneumonic plague.

• On 2 November 2007, Eric York, a 37 year old wildlife biologist for the National Park Service's Template:PDFlink and The Felidae Conservation Fund, was found dead in his home at Grand Canyon National Park. On 27 October, York performed a necropsy on a mountain lion that had likely perished from the disease and three days afterward York complained of flu-like symptoms and called in sick from work. He was treated at a local clinic but was not diagnosed with any serious ailment. The discovery of his death sparked a minor health scare, with officials stating he likely died of either plague or hantavirus, and 49 people who had come in to contact with York were given aggressive antibiotic treatments. None of them fell ill. Autopsy results released on November 9th, confirmed the presence of Y. pestis in his body, confirming plague as a likely cause of death.

Literary and popular culture references

• The Decameron by Giovanni Boccaccio (1350). Takes place in Florence in 1348, during the outbreak of the Black Death.
• Romeo and Juliet (1597) Friar John was unable to go to Mantua and deliver a letter to Romeo because of Bubonic Plague quarantine.
• A Journal of the Plague Year by Daniel Defoe (1722). A fictional first hand account of the London outbreak of 1665. Probably based on the experiences of Defoe's uncle.
• "The Masque of the Red Death" (1842) by Edgar Allan Poe includes a vivid description of pestilence that some scholars have interpreted to be septicemic plague.
• I Promessi Sposi (The Betrothed) (1842) by Alessandro Manzoni set in early 17th century in Northern Italy, is one of the most read and better known classical novels in Italian literature. Contains a detailed and vivid account of society during the plague outbreak in its time.
• Narcissus and Goldmund by Hermann Hesse (1930). A fictional account in which the main character ends up witnessing the effects of the plague first-hand.
• The Plague by Albert Camus (1947) depicts an outbreak of plague at the Algerian city of Oran. The disease, often interpreted as a metaphor for the German occupation of France in World War II, serves as a means for the author to examine his characters' responses to hardship, suffering and death.
• Panic in the Streets (1950) by Elia Kazan. A murder victim is found to be infected with pneumonic plague. To prevent a catastrophic epidemic, the police must find and inoculate the killers and their associates.
• (Don't Fear) The Reaper (1976) by Blue Öyster Cult. The line "40,000 men and women everyday... Like Romeo and Juliet - 40,000 men and women everyday... Redefine happiness - Another 40,000 coming everyday... We can be like they are" is a reference to the number of people dying daily during The Black Plague"
• The Plague Dogs (1977), by Richard Adams. A fictional story in which two dogs, Rowf and Snitter, escape from a British government research laboratory and are hunted down by the government as potential carriers of the plague.
• Doomsday Book by Connie Willis (1992). A Hugo award and Nebula award-winning historical science fiction novel, in which a time-traveler inadvertently ends up in the plague-ridden England of 1348.
• King of Shadows (1999), by Susan Cooper. Nathan Field, an actor, is infected with the bubonic plague while staying in London, which sends him back in time to the Elizabethan ages.
• Confessions of an Ugly Stepsister (1999), a novel by Gregory Maguire, takes place in 17th Century Haarlem, Netherlands, where a resurgence of the plague occurred.
• Year of Wonders by Geraldine Brooks (2001), a fictional story of an historical event in which the small Derbyshire village of Eyam quarantines themselves once infected with the plague.
• The Years of Rice and Salt by Kim Stanley Robinson (2002). Presents an alternate history of the world where the population of Europe is obliterated by the Black Death setting the stage for a world without Europeans and Christianity.
• In Dies the Fire by S. M. Stirling in (2004), an epidemic of the Black Death is described around the city of Portland, Oregon.
• Episode 18 of the second season of American television show House features the bubonic plague.
• In the season one episode of Torchwood, "End of Days", a woman from the 14th century infected by the plague falls through the rift into Cardiff, causing an infection of dozens of people in a local hospital.
• Third Watch In the third episode of the fifth season, a number of illegal immigrants are discovered in the back of a truck and brought to hospital where they are diagnosed with the plague. The situation is complicated by the fact one of the immigrants managed to flee.
• In The Keys to the Kingdom by Garth Nix, Suzy Turquoise Blue, one of the Piper's children, was led to the House by the Piper from London during the Great Plague of London.
• Grey's Anatomy In the first episode of the third season, a couple comes into the hospital because of flu symptoms, but get in a car crash along the way because the woman passed out while driving. Different rooms in the hospital are quarantined, and the woman in the crash dies after surgery, due to complications from the plague.
• In Grand Theft Auto Advance, Liberty City is said to be affected by Bubonic plague.
• The band Modest Mouse references "the rats and the fleas" that caused the disease to spread to humans in their song March into the Sea.
• An episode of the TV show Wire in the Blood features a strain of bubonic plague as a biological weapon.
• In Spooks Series 6 (episodes one and two) a fictional virus that causes symptoms mimicking pneumonic plague is accidentally released in London.
• Lux perpetua (2006) by Andrzej Sapkowski. One of the main characters is murdered by magically induced septicemic plague.
• World Without End (2007) by Ken Follett. The plague's spread throughout Europe in the 14th century is an integral part of the book's storyline.
• The Shifting Tide (2004) by Anne Perry. The plague enters England via a ship transporting ivory.
• In an episode of the TV show NCIS, SWAK, a team member gets infected with an engineered variant of pneumonic plague after opening a contaminated envelope.

References

Notes

Bibliography

• Weatherford 2004: 242-250
• Benedictow, Ole J. The Black Death 1346-1353: The Complete History. DS Brewer, 2006. ISBN 978-1843832140.
• Biraben, Jean-Noel. Les Hommes et la Peste The Hague 1975.
• Buckler, John and Bennet D. Hill and John P. McKay. "A History of Western Society, 5th Edition." New York: Houghton Mifflin Co., 1995.
• Cantor, Norman F., In the Wake of the Plague: the Black Death and the World It Made New York: Harper Perennial, 2002. ISBN 978-0060014346.
• de Carvalho, Raimundo Wilson; Serra-Freire, Nicolau Maués; Linardi, Pedro Marcos; de Almeida, Adilson Benedito; and da Costa, Jeronimo Nunes (2001). Small Rodents Fleas from the Bubonic Plague Focus Located in the Serra dos Órgãos Mountain Range, State of Rio de Janeiro, Brazil. Memórias do Instituto Oswaldo Cruz 96(5), 603–609. PMID 11500756. this manuscript reports a census of potential plague vectors (rodents and fleas) in a Brazilian focus region (i.e. region associated with cases of disease); free PDF download Retrieved 2005-03-02
• Chase, Marilyn. The Barbary Plague: The Black Death in Victorian San Francisco. New York: Random House Trade Paperbacks, 2004. ISBN 978-0375757082.
• Cohn, Samuel K. (2003). The Black Death Transformed: Disease and Culture in Early Renaissance Europe. A Hodder Arnold. p. 336. ISBN 0-340-70646-5.
• Gregg, Charles T. Plague!: The shocking story of a dread disease in America today. New York, NY: Scribner, 1978, ISBN 0-684-15372-6.
• Ernest Jawetz, et al. Medical Microbiology. 18th ed. United States: Prentice-Hall International Inc., 1989. ISBN 0-8385-6238-8
• Kelly, John. The Great Mortality: An Intimate History of the Black Death, the Most Devastating Plague of All Time. New York: HarperCollins Publishers Inc., 2005. ISBN 0-06-000692-7.
• McNeill, William H. Plagues and People. New York: Anchor Books, 1976. ISBN 0-385-12122-9. Reprinted with new preface 1998.
• Mohr, James C. Plague and Fire: Battling Black Death and the 1900 Burning of Honolulu's Chinatown. New York, NY: Oxford University Press, 2005, ISBN 0-19-516231-5.
• Moote, A. Lloyd, and Dorothy C. Moote. The Great Plague: The Story of London's Most Deadly Year. Baltimore, MD: Johns Hopkins University Press, 2004. ISBN 978-0801877834.
• Orent, Wendy. Plague: The Mysterious Past and Terrifying Future of the World's Most Dangerous Disease. New York: Free Press, 2004. ISBN 0-7432-3685-8.
• Papagrigorakis, Manolis J., Christos Yapijakis, Philippos N. Synodinos, and Effie Baziotopoulou-Valavani. "DNA examination of ancient dental pulp incriminates typhoid fever as a probable cause of the Plague of Athens," International Journal of Infectious Diseases 10 (2006): 206-214. ISSN 1201-9712.
• Patrick, Adam. "Disease in Antiquity: Ancient Greece and Rome," in Diseases in Antiquity, editors: Don Brothwell and A. T. Sandison. Springfield, Illinois; Charles C. Thomas, 1967.
• Platt, Colin. King Death: The Black Death and its Aftermath in Late-Medieval England Toronto University Press, 1997.
• Rosen, William (2007). Justinian's Flea: Plague, Empire, and the Birth of Europe. Viking Penguin. p. 367. ISBN 978-0-670-03855-8.
• Simpson, W. J. A Treatise on Plague. Cambridge, England: Cambridge University Press, 1905.
• Spielvogel, Jackson J. Western Civilization: A Brief History Vol. 1: to 1715. Belmont, Calif.: West/Wadsworth, 1999, Ch. 3, p. 56, paragraph 2. ISBN 0-534-56062-8.

External links

• World Health Organization
  • Health topic
  • Communicable Disease Surveillance & Response - Impact of plague & Information resources
• Centers for Disease Control and Prevention
  • CDC Plague map world distribution, publications, information on bioterrorism preparedness and response regarding plague
  • Infectious Disease Information more links including travelers' health
• Symptoms, causes, pictures of bubonic plague
• Secrets of the Dead . Mystery of the Black Death PBS
• Template:PDFlink
• Researchers sound the alarm: the multidrug resistance of the plague bacillus could spread
• Plague - LoveToKnow 1911
• Genome information is available from the NIAID Enteropathogen Resource Integration Center (ERIC)

References

Pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [5]

Overview

Yersinia pestis is the bacteria that causes the bubonic plague, or black death. Typically during the incubation period of the disease, buboes form under the armpits and in the groin area. These buboes are located where the lymph nodes are because that is the location that the bacteria congregates during infection. If untreated, the plague will spread rapidly and cause infection of many other organs.

Pathophysiology

Yersinia was formerly classified in the family Pasteurellaceae, but based on DNA- DNA hybridization similarities to Escherichia coli, the Yersinia group has been reclassified as members of the Enterobacteriaceae family by Farmer in 1995. Differentiation of the Enterobacteriaceae family members is based on biochemical and antigenic profiles. More recently, nucleic acid techniques have been applied to assist the definition of genera and species within this family; hence, as more techniques are applied, newly defined genetic relationships sometimes lead to changes in classification. Though there are 11 named species in the genus Yersinia, only 3 are considered important human pathogens: Y. pestis, the etiologic agent of plague, and the enteropathogenic strains, Y. pseudotuberculosis and Y. enterocolitica. Y. pseudotuberculosis is the closest genetic relative to Y. pestis but can be distinguished from the plague bacteria by its clinical manifestations and by laboratory test results. Both Y. pestis and Y. pseudotuberculosis do not frequently infect humans in contrast to Y. enterocolitica, which may be more commonly found in clinical specimens.

A very small number of the Yersinia Pestis organisms are needed to infect a mammal. As little as 1 to 10 organisms would be enough to infect a small mammal, such as a rodent or primate, with the plague via subcutaneous, oral, intravenous, and intradermal routes. On the other hand, the respiratory route will take approximately 100 to 200,000 organisms for nonhuman primates. When the bacteria enters the host, there are a multitude of environmental signals that are believed to induce the synthesis and many other factors the contribute to the virulence of the bacteria. These environmental signals include things such as:

• Elevated temperature
• Location within cells at low pH
• Contact with eukaryotic cells

During the incubation phase, the common symptom of bubonic plague, the bubo, is because the bacilli most commonly spreads to regional lymph nodes. The infection will rapidly progress if it is left untreated and then septicemia will develop and the infection will spread to other organs. Cyanosis and necrosis are commonly seen in septicemic plague, which may be caused by coagulase activity of the plasminogen activator. There are a few tissues that are most commonly infected. They include:

• Liver
• Lungs
• Skin
• Mucous membranes
• Spleen
• Also, late infection of meninges possible

Yersinia pestis is a Gram-negative facultative anaerobic bipolar-staining (giving it a safety pin appearance) bacillus bacterium belonging to the family Enterobacteriaceae. The infectious agent of bubonic plague, Y. pestis infection can also cause pneumonic and septicemic plague. All three forms have been responsible for high mortality rates in epidemics throughout human history, including the Black Death that accounted for the death of approximately one-third of the European population in 1347 to 1353.

The genus Yersinia is Gram-negative, bipolar staining coccobacilli, and, similarly to other Enterobacteriaceae, it has a fermentative metabolism. Y. pestis produces an antiphagocytic slime. The organism is motile when isolated, but becomes nonmotile in the mammalian host.

Pathophysiology

A scanning electron micrograph depicting a mass of Yersinia pestis bacteria

• Pathogenicity of Y. pestis is in part due to two anti-phagocytic antigens, named F1 (Fraction 1) and V, both important for virulence. These antigens are produced by the bacterium at 37°C.
• Furthermore, Y. pestis survives and produces F1 and V antigens within blood cells such as monocytes, but not in polymorphonuclear neutrophils. * Natural or induced immunity is achieved by the production of specific opsonic antibodies against F1 and V antigens; antibodies against F1 and V induce phagocytosis by neutrophils.
• A formalin-inactivated vaccine once was available for adults at high risk of contracting the plague until removal from the market by the FDA. It was of limited effectiveness and may cause severe inflammation.
• Experiments with genetic engineering of a vaccine based on F1 and V antigens are underway and show promise; however, bacteria lacking antigen F1 are still virulent, and the V antigens are sufficiently variable, that vaccines composed of these antigens may not be fully protective.

Genetics

• The complete genomic sequence is available for two of the three sub-species of Y. pestis: strain KIM (of biovar Medievalis), and strain CO92 (of biovar Orientalis, obtained from a clinical isolate in the United States); as of 2006, the genomic sequence of a strain of biovar Antiqua has not yet been completed.
• The chromosome of strain KIM is 4,600,755 base pairs long; the chromosome of strain CO92 is 4,653,728 base pairs long. Like its cousins Y. pseudotuberculosis and Y. enterocolitica, Y. pestis is host to the plasmid pCD1.
• In addition, it also hosts two other plasmids, pPCP1 and pMT1 which are not carried by the other Yersinia species. Together, these plasmids, and a pathogenicity island called HPI, encode several proteins which cause the pathogenicity for which Y. pestis is famous.
• Among other things, these virulence factors are required for bacterial adhesion and injection of proteins into the host cell, invasion of bacteria into the host cell, and acquisition and binding of iron harvested from red blood cells.
• Y. pestis is thought to be descendant from Y. pseudotuberculosis, differing only in the presence of specific virulence plasmids.
• A recent comprehensive and comparative proteomics analysis of Y. pestis: strain KIM was recently performed , this analysis focused on the transition to a growth condition mimicking growth in host cells.

Susceptibility

• The traditional first line treatment for Y. pestis has been streptomycin, chloramphenicol, tetracycline, and fluoroquinolones.
• There is also good evidence to support the use of doxycycline or gentamicin.
• It should be noted that strains resistant to one or two agents specified above have been isolated: treatment should be guided by antibiotic sensitivities where available.

References

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Epidemiology and Demographics

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [6]; Associate Editor(s)-in-Chief: Serge Korjian, Yazan Daaboul, Aravind Reddy Kothagadi M.B.B.S[7]

Overview

Given its ability to cause serious pandemics, plague is one of the three diseases subject to the International Health Regulations, the other two being yellow fever and cholera. From 1954 to 1997, plague affected 38 countries, with 80 613 cases and 6587 deaths. Between 2004 and 2009, the WHO reported that the number of cases of plague worldwide was 12,503, with 843 deaths, for a case-fatality rate of 6.7%.

Epidemiology and Demographics

Incidence

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

• Between 2004 and 2009, the WHO reported that the number of cases of plague worldwide was 12,503.

Age

• Patients of all ages are susceptible to disease; however, cases in the last few decades have been more common in children.

Gender

• Patients of both sexes are susceptible to disease.

Mortality

• Known as the black death, plague pandemics have caused significant casualties in the last 2 millennia. The first certain pandemic recorded in the sixth century AD spread across Asia, Africa and Europe claiming approximately 100,000,000 lives. The fourteenth century witnessed the second pandemic, with no less than 50,000,000 casualties. The third pandemic came in the late nineteenth century mostly affecting India with 13,000,000 recorded deaths.

• From 1954 to 1997, plague affected 38 countries, with 6587 deaths.

• Between 2004 and 2009, the WHO reported 843 deaths from plague and a case-fatality rate of 6.7%.

Geographic Distribution

• Yersinia pestis in found in animal reservoirs, especially in rodents which are often responsible for the rapid spread of the disease. Natural foci of plague are found all over the world, particularly in tropical and sub-tropical latitudes and in warm regions of the temperate latitudes.
• All continents are known to harbor natural plague foci except Australia.
• It is important to note that natural foci of plague shift in response to changes in climate, landscape, and rodent population migration.

Chronology of Yersinia pestis infection Outbreaks("WHO | Plague".)
Date	Region Affected	Suspected, Probable & Confirmed Cases	Deaths	Details
15 October 2017	Seychelles - Suspected Plague (Ex- Madagascar)	1	0	On 10 October 2017, the Seychellois Ministry of Health notified WHO of a probable case of pneumonic plague The probable case is a 34-year-old man who had visited Madagascar and returned to Seychelles on 6 October 2017. He developed symptoms on 9 October 2017 and presented to a local health centre(pneumonic plague infection suspected, isolated and treated) 11 October, rapid diagnostic test (RDT) preformed, sputum sample was weakly positive. October 9 to 11 2017, eight of his contacts developed mild symptoms and have been isolated October 13 was the last day of monitoring of over 320 contact persons of the probable case Contact tracing is done thoroughly and 577 children and 63 teachers in potential contact with one of the individual identified by contact tracing were given antibiotics.
2 October 2017	Madagascar	73	17	The outbreak started following the death of a 31-year-old male from Ankazobe District in the Central Highlands (Hauts-Plateaux), a plague-endemic area. Since then, the Ministry of Public Health of Madagascar enhanced field investigations, contact tracing, surveillance, and monitoring all close contacts As of 30 September, 10 cities have reported pneumonic plague cases and the three most affected districts include: the capital city and suburbs of Antananarivo (27 cases, 7 deaths), Toamasina (18 cases, 5 deaths), and Faratshio (13 cases, 1 death) In addition to the 73 cases of pneumonic plague, from 1 August to 30 September, 58 cases of bubonic plague including seven deaths have been reported. One additional case of septicaemic plague has also been reported, and one case where the type is not specified
29 September 2017	Madagascar	51	12	On 23 August 2017, a 31-year-old male from Tamatave, visiting Ankazobe District in central highlands, developed malaria-like symptoms. On 27 August, he developed respiratory symptoms during his journey in a shared public taxi from Ankazobe District to Tamatave (via Antananarivo). His condition worsened and he died. In addition to the 51 suspected, probable and confirmed cases of pneumonic plague, and during the same period another 53 cases of bubonic plague including seven deaths have been reported throughout the country. One case of septicaemic plague has also been identified and they were not directly linked to the outbreak. Additionally, 31 people who came into contact with this case either through direct contact with the primary case or had other epidemiological links, became ill, and four cases of them died The outbreak was detected on 11 September, following the death of a 47-year-old woman from Antananarivo, who was admitted to a hospital with respiratory failure caused by pneumonic plague
9 January 2017	Madagascar	62 cases (6 confirmed, 5 probable, 51 suspected)	26 (case fatality rate of 42%)	Of the 11 samples tested, 5 were positive for plague on rapid diagnostic test and 6 are now confirmed at Institut Pasteur laboratory. Of the total reported cases, 5 are classified as pneumonic plague cases and the remaining as bubonic plague Retrospective investigations carried out in those two districts showed that it is possible that the outbreak might have started in mid-August 2016. The investigation in neighbouring villages is still ongoing. On 29 December, an investigation carried out within 25 km of the initial foci in Befotaka district has reported three deaths and is being investigated further for possible linkage to the outbreak
6 September 2015	Madagascar	14	10	The Ministry of Health of Madagascar has notified WHO of an outbreak of plague. The first case was identified on 17 August in a rural township in Moramanga district. The case passed away on 19 August All confirmed cases are of the pneumonic form. Since 27 August, no new cases have been reported from the affected or neighbouring districts
21 November 2014	Madagascar	119	40	On 4 November 2014, WHO was notified by the Ministry of Health of Madagascar of an outbreak of plague. The first case, a male from Soamahatamana village in the district of Tsiroanomandidy, was identified on 31 August. The patient died on 3 September Only 2% of reported cases are of the pneumonic form Cases have been reported in 16 districts of seven regions. Antananarivo, the capital and largest city in Madagascar, has also been affected with 2 recorded cases of plague, including 1 death. There is now a risk of a rapid spread of the disease due to the city’s high population density and the weakness of the healthcare system. The situation is further complicated by the high level of resistance to deltamethrin (an insecticide used to control fleas) that has been observed in the country
10 August 2010	Peru	17	-	As of 30 July 2010, the Ministry of Health in Peru confirmed a total of 17 cases of plague in Ascope province of Department La Libertad. Of these, four are pneumonic plague, 12 are bubonic plague and one was septicemic plague. The onset of symptoms for the last reported case of pneumonic plague was on 11 July 2010. During the investigations, 10 strains of Y. pestis were isolated from humans, rodents and domestic cats
11 August 2009	China	12	3	On 1 August 2009, a cluster outbreak of pulmonary plague cases in the remote town of Ziketan, Qinghai province was reported by the Ministry of Health (MoH), China. On 26th July 2009, the first case was a 32 year old male herdsman, who developed fever and hemoptysis was reported. He died enroute to hospital. On 30 July, 11 people who had close contact with the case (mainly relatives who attended the funeral) were all hospitalized as they developed fever and cough. They were all tested positive for plague. On 2 August 2009, 2 people who helped to bury the corpse, 64 year old father-in-law of the first case and a 37 year old male neighbour of the first case also died. On August 6 2009, the local health authority isolated 332 close contacts for further medical observation, and implemented traffic control around affected area. Preventive measures were taken to stop teh spread. Epidemiological investigation showed that the source of this outbreak was a wild marmot, which had contact with the dog of the index case.
7 November 2006	Democratic Republic of the Congo	1174	50	As of 29 September 2006, WHO received reports of a suspected pneumonic plague outbreak in 4 health zones in Haut-Uele district, Oriental province in the north-eastern part of the country. More than 50 samples have been collected and analysed; however, the diagnosis of plague has not been finally laboratory confirmed.
13 October 2006	Democratic Republic of the Congo	626	42	WHO has received reports of a suspected pneumonic plague outbreak in 2 health zones in Haut-Uele district, the majority reported from Wamba health zone in Oriental province in the northern part of the country However, the low case fatality ratio is unusual for pneumonic plague which suggests that the number of suspected cases may be an overestimation Preliminary results from a rapid diagnosis test in the field found three samples positive, out of eight
14 June 2006	Democratic Republic of the Congo	100	19	Suspected cases of bubonic plague have also been reported but the total number is not known at this time. Preliminary results from rapid diagnostic tests in the area confirm pneumonic plague. Ituri is known to be the most active focus of human plague worldwide, reporting around 1000 cases a year. The first cases in this outbreak occurred in a rural area, in the Zone de Santé of Linga, in mid-May
15 March 2005	Plague in the Democratic Republic of the Congo - update 4	130	57	Reported in Zobia, Bas-Uélé district, Oriental province No cases of bubonic plague have been detected
9 March 2005	Plague in the Democratic Republic of the Congo - update 3	114 cases (110 suspect cases, 4 probable cases)	54	Reported in Zobia, Bas-Uélé district, Oriental province
4 March 2005	Plague in the Democratic Republic of the Congo - update 2	57 cases (54 suspect cases, 3 probable cases)	16	Reported in Zobia, Bas-Uélé district, Oriental province
1 March 2005	Plague in the Democratic Republic of the Congo - update	4 probable cases and 4 suspect cases	1	Reported in Zobia, Bas-Uélé district, Oriental province
18 February 2005	Plague in the Democratic Republic of the Congo	-	61	Reported in Bas-Uele district, Oriental province Preliminary results from rapid diagnostic tests in the area confirm pneumonic plague, and the cases had clinical features compatible with this disease Cases have occurred in workers in a diamond mine in Zobia where c. 7000 people work. The mine was re-opened on 16 December 2004 and the first case occurred on 20 December
10 July 2003	Plague in Algeria - Update 2	10 laboratory confirmed cases and 1 probable case	-	Reported in oran district
3 July 2003	Plague in Algeria - Update	10 cases of which 8 have been laboratory confirmed	-	Reported by Ministry of Health, Algeria 8 cases of bubonic plague and 2 of septicemic plague, of which one was fatal
24 June 2003	Plague in Algeria	10 cases, 8 cases of bubonic plague and 2 of septicemic plague	one fatal case reported	Reported by the Ministry of Health, Algeria in Tafraoui, on the outskirts of Oran
5 June 2002	2002 - Plague in Malawi	71	-	Reported by the Malawian Ministry of Health 71 cases of bubonic plague in the district of Nsanje since the onset of the outbreak on 16 April 2002 Outbreak has so far affected 26 villages, 23 in the Ndamera area, 2 in Chimombo and 1 village in neighbouring Mozambique
20 February 2002	2002 - Plague in India	16 cases of pneumonic plague	4 deaths in Hat Koti village	Reported by the Ministry of Health, India
26 March 2001	2001 - Plague in Zambia	23 hospitalized cases	3 deaths in Petauke district, Eastern Province	The last case reported was 15 March 2001

Shown below is a picture depicting the global distribution of natural plague foci as of March 2016

"WHO | Plague".

References

Risk Factors

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [8]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [9]

Overview

Risk factors for plague include living in rural areas, near animals such as rodents, or in houses where sanitation is poor. People who deal frequently with animals, such as veterinaries, are at higher risk for infection with Yersinia pestis.

Risk Factors

The most important factor associated with the development of plague is the exposure to infected fleas where local rodents are transmitting infection. In the United States, the highest risk of acquiring Yersinia pestis is between February and August (plague season), which corresponds to the timing of the rodent epidemics. Death of the affected rodents is also correlated with better fertility of rodent fleas which are the main vectors for the disease. Other important risk factors for infection by Yersinia pestis include:

• Living in endemic areas especially in warm climates
• Poor sanitation and living conditions
• Unsettled conditions of war and relocation of refugees
• People who handle infected animals (veterinaries)
• People who come in contact with infected animals (hunting, or camping)

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Causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [10]

Overview

The major forms of plague are caused by yersinia pestis living in rodents. The disease is then transferred to humans from the fleas that originally bit the infected rodent.

Causes

Plague is caused by the organism yersinia pestis. Rodents, such as rats, spread the disease to humans. People can get the plague when they are bitten by a flea that carries the plague bacteria from an infected rodent. In rare cases, you may get the disease when handling an infected animal. Certain forms of the plague can be spread from human to human. When someone with pneumonic plague coughs, microscopic droplets carrying the infection move through the air. Anyone who breathes in these particles may catch the disease. An epidemic may be started this way. In the middle ages, massive plague epidemics killed millions of people.

Pathophysiology

A scanning electron micrograph depicting a mass of Yersinia pestis bacteria

• Pathogenicity of Y. pestis is in part due to two anti-phagocytic antigens, named F1 (Fraction 1) and V, both important for virulence. These antigens are produced by the bacterium at 37°C.
• Furthermore, Y. pestis survives and produces F1 and V antigens within blood cells such as monocytes, but not in polymorphonuclear neutrophils. * Natural or induced immunity is achieved by the production of specific opsonic antibodies against F1 and V antigens; antibodies against F1 and V induce phagocytosis by neutrophils.
• A formalin-inactivated vaccine once was available for adults at high risk of contracting the plague until removal from the market by the FDA. It was of limited effectiveness and may cause severe inflammation.
• Experiments with genetic engineering of a vaccine based on F1 and V antigens are underway and show promise; however, bacteria lacking antigen F1 are still virulent, and the V antigens are sufficiently variable, that vaccines composed of these antigens may not be fully protective.

Genetics

• The complete genomic sequence is available for two of the three sub-species of Y. pestis: strain KIM (of biovar Medievalis), and strain CO92 (of biovar Orientalis, obtained from a clinical isolate in the United States); as of 2006, the genomic sequence of a strain of biovar Antiqua has not yet been completed.
• The chromosome of strain KIM is 4,600,755 base pairs long; the chromosome of strain CO92 is 4,653,728 base pairs long. Like its cousins Y. pseudotuberculosis and Y. enterocolitica, Y. pestis is host to the plasmid pCD1.
• In addition, it also hosts two other plasmids, pPCP1 and pMT1 which are not carried by the other Yersinia species. Together, these plasmids, and a pathogenicity island called HPI, encode several proteins which cause the pathogenicity for which Y. pestis is famous.
• Among other things, these virulence factors are required for bacterial adhesion and injection of proteins into the host cell, invasion of bacteria into the host cell, and acquisition and binding of iron harvested from red blood cells.
• Y. pestis is thought to be descendant from Y. pseudotuberculosis, differing only in the presence of specific virulence plasmids.
• A recent comprehensive and comparative proteomics analysis of Y. pestis: strain KIM was recently performed , this analysis focused on the transition to a growth condition mimicking growth in host cells.

Susceptibility

• The traditional first line treatment for Y. pestis has been streptomycin, chloramphenicol, tetracycline, and fluoroquinolones.
• There is also good evidence to support the use of doxycycline or gentamicin.
• It should be noted that strains resistant to one or two agents specified above have been isolated: treatment should be guided by antibiotic sensitivities where available.

Images

Male Xenopsylla cheopis (oriental rat flea) engorged with blood. This flea is the primary vector of plague in most large plague epidemics in Asia, Africa, and South America. Both male and female fleas can transmit the infection.

References

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Differential Diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [11]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [12]; Alison Leibowitz [13]

Overview

The differential diagnosis for yersina pestis infection is dependent on the clinical syndrome (bubonic plague, septicimic plague, pneumonic plague, or pharyngeal plague). Bubonic plague should be differentiated from other causes of lymphadenopathy, such as streptococcal or staphylococcal lymphadenitis, infectious mononucleosis, cat-scratch fever, and tularemia. Septicemic plague should be differentiated from non-specific sepsis syndrome and gram negative sepsis. The differential diagnosis for pneumonic plague includes infections that cause community-acquired pneumonia, such as pneumococcal or streptococcal pneumonia, viral pneumonia, hemophilus influenzae, and anthrax.

Differential Diagnosis

Bubonic Plague

Conditions that also cause lymphadenopathy:

• Streptococcal or staphylococcal adenitis (Staphylococcus aureus, Staphylococcus pyogenes)
  • Purulent or inflamed lesion often noted distal to involved nodes (ie, pustule, infected traumatic lesion)
  • Involved nodes more likely to be fluctuant
  • Associated ascending lymphangitis or cellulitis may be present (generally not seen with plague)

• Infectious mononucleosis

• Tularemia (Francisella tularensis)
  • Ulcer or pustule often present distal to involved nodes
  • Clinical course rarely as fulminant as in plague
  • Systemic toxicity uncommon

• Cat scratch fever (Bartonella henselae)
  • History of contact with cats; usually history of cat scratch
  • Indolent clinical course; progresses over weeks
  • Primary lesion at site of scratch often present (small papule, vesicle)
  • Systemic toxicity not present

• Mycobacterial infection, including scrofula (Mycobacterium tuberculosis and other Mycobacterium species)
  • With scrofula, adenitis occurs in cervical region
  • Usually painless
  • Indolent clinical course
  • Infections with species other than M tuberculosis more likely to occur in immunocompromised patients

• Lymphatic filariasis
• Tick typhus

Conditions that also cause intra-abdominal lymphadenopathy:

• Appendicitis
• Acute cholecystitis
• Enterocolitis

Condition that also causes inguinal lymphadenopathy:

• Lymphogranuloma venereum (Chlamydia trachomatis)
  • Adenitis occurs in the inguinal region
  • History of sexual exposure 10-30 days previously
  • Suppuration, fistula tracts common
  • Although LGV buboes may be somewhat tender, exquisite tenderness usually absent
  • Although patients may appear ill (headache, fever, myalgias), systemic toxicity not present

• Chancroid (Haemophilus ducreyi)
  • Adenitis occurs in the inguinal region
  • Ulcerative lesion present
  • Systemic symptoms uncommon; toxicity does not occur

• Primary genital herpes
  • Herpes lesions present in genital area
  • Adenitis occurs in the inguinal region
  • Although patients may be ill (fever, headache), severe systemic toxicity not present

• Primary or secondary syphilis (Treponema pallidum)
  • Enlarged lymph nodes in the inguinal region
  • Lymph nodes generally painless
  • Chancre may be noted with primary syphilis

• Strangulated inguinal hernias
  • Evidence of bowel involvement

Septicemic Plague

Conditions that manifest similarly:

• Non-specific sepsis syndrome
• Gram negative sepsis

Pneumonic Plague

Pneumonic plague should be differentiated from the following diseases:

• Inhalational anthrax (Bacillus anthracis)
  • Widened mediastinum and pleural effusions seen on CXR or chest CT
  • Not true pneumonia; minimal sputum production
  • Hemoptysis uncommon (if present, suggests diagnosis of plague)

• Tularemia (Francisella tularensis)
  • Clinical course not as rapid or fulminant as in pneumonic plague

• Mycoplasmal pneumonia (Mycoplasma pneumoniae)
  • Rarely as fulminant as pneumonic plague

• Pneumonia caused by Chlamydia pneumoniae
  • Rarely as fulminant as pneumonic plague

• Legionnaires' disease (Legionella pneumophila or other Legionella species)
  • Rarely as fulminant as pneumonic plague
  • Community outbreaks of Legionnaires' disease often involve exposure to cooling systems
  • Legionellosis and many other diseases caused by bacterial agents (S aureus, S pneumoniae, H influenzae, K pneumoniae, M catarrhalis) usually occur in persons with underlying pulmonary or other disease or in the elderly

• Psittacosis (Chlamydia psittaci)
  • Rarely as fulminant as pneumonic plague
  • Result of bird exposure

• Other bacterial agents (eg, Staphyloccocus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae, Moraxella catarrhalis)
  • Rarely as fulminant as pneumonic plague
  • Usually occur in persons with underlying pulmonary or other disease or in the elderly

• Influenza
  • Influenza generally seasonal (October-March in United States) or involves history of recent cruise ship travel or travel to tropics

• Hantavirus
  • Exposure to excrement (urine or feces) of mice with Hantavirus

• RSV
  • RSV usually occurs in children (although may be cause of pneumonia in elderly); tends to be seasonal (winter/spring)

• CMV
  • CMV usually occurs in immunocompromised patients

• Q fever (Coxiella burnetii)
  • Exposure to infected parturient cats, cattle, sheep, goats
  • Severe pneumonia not prominent feature

• Leptospirosis

• Hantavirus pulmonary syndrome

• viral pneumonia

References

Natural History, Complications & Prognosis

Natural History

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [14] Associate Editor(s)-in-Chief: Serge Korjian, Yazan Daaboul

Overview

The complications of Yersina pestis infection are dependent on the clinical syndrome (bubonic plague, septicimic plague, pneumonic plague, or pharyngeal plague). Bubonic plague can be complicated by septicemia, pneumonia, or meningitis. The complications of septicemic plague include gangrene of distal upper and lower extremities and tip of the nose due to small vessel thrombosis, disseminated intravascular coagulopathy (DIC), and adult respiratory distress syndrome (ARDS). The complications of pneumonic plague are septicemia, abscess formation, and cavitation. If plague patients are not administered specific antibiotic therapy, the disease can progress rapidly to death. Approximately 14% (1 in 7) of all plague cases in the United States are fatal.

Complications

Complications of Yersinia pestis

Bubonic Plague
Septicemia Pneumonia Meningitis
Septicemic Plague
Gangrene of distal upper and lower extremities and tip of the nose due to small vessel thrombosis Disseminated intravascular coagulopathy (DIC) Adult respiratory distress syndrome (ARDS) Meningitis Pneumonia Hepatic or splenic abscess Endophthalmitis Generalized lymphadenopathy
Pneumonic Plague
Septicemia Abscess formation Cavitation

^{Adapted from Koirala et al. Plague: disease, management, and recognition of act of terrorism. Infect Dis Clin N Am.2006;20:273-87}

Prognosis

Despite being a treatable disease, plague is still associated with a high case fatality rate, often attributable to late recognition and inappropriate antibiotic therapy. Untreated bubonic plague has a case fatality of rate 50-60%, with proper identification and prompt treatment the case fatality decreases to around 7%. Untreated septicemia or pneumonic plague is almost universally fatal if untreated early on. Even with proper therapy the latter may lead to mortality rates as high as 50%.

References

Complications

The bubonic plague, or black death, is an extremely serious disease. If untreated, there is a significant possibility of death. It can also lead to certain respiratory infections such as pneumonia.

It can lead to pneumonia, spread of infection through blood to whole body(septicemia), shock and even death if left untreated.

Diagnosis

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Treatment

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