Epidemiology, microbiology and pathogenesis of plague (Yersinia pestis infection)

INTRODUCTION — In the genus Yersinia, three species are important human pathogens: Yersinia pestis, Yersinia enterocolitica, and Yersinia pseudotuberculosis. The yersinioses are zoonotic infections of domestic and wild animals; humans are considered incidental hosts that do not contribute to the natural disease cycle.

Y. pestis causes plague and is transmitted by fleas. The most common clinical manifestation is acute febrile lymphadenitis, called bubonic plague. Less common forms include septicemia, pneumonia, pharyngeal and meningeal plague.

The epidemiology, microbiology and pathogenesis of Y. pestis will be reviewed here. The clinical manifestations, diagnosis, and treatment of Y. pestis are discussed separately. (See "Clinical manifestations, diagnosis, and treatment of plague (Yersinia pestis infection)".)

Issues related to other Yersinia species are discussed separately. (See "Yersiniosis: Infection due to Yersinia enterocolitica and Yersinia pseudotuberculosis".)

HISTORY — Plague has afflicted humans for thousands of years; Y. pestis DNA has been identified in human teeth from Asia and Europe dating back between 2800 and 5000 years ago [1]. Three major plague pandemics have been recorded in human history: the "Plague of Justinian" in the 6th century, again in the 14th century (known as the “Black Death,” which killed up to one-third of the European population or an estimated 17 to 28 million people [2]), and at the end of 19th century following the spread of infection from China [3]. The plague bacillus was isolated during the third pandemic by Alexandre Yersin in 1894 [4]. Over the ensuing 20 years, Y. pestis spread via rats on steamships to port cities on all inhabited continents, including North America. The infection spread to various species of wild rodents, becoming entrenched in rural areas of the Americas, Africa, and Asia.

EPIDEMIOLOGY — Plague is primarily a zoonotic infection of rodents and wild and domestic animals and is transmitted by fleas; humans are considered incidental hosts that do not contribute to the natural disease cycle. Enzootic plague is maintained in nature through flea-borne transmission between partially resistant rodents (enzootic or maintenance hosts). Intermittently, infection may spread to more susceptible animals which function as epizootic or amplifying hosts. In such cases these more susceptible hosts may die in large numbers in an epidemic.

Geographic distribution — Areas of enzootic plague include North America (mainly the southwestern United States and Pacific coastal area), the former Soviet Union, and foci in Africa, Asia, and South America.

From 2000 to 2009, a total of 21,725 cases of plague with 1612 deaths (7.4 percent fatality rate) were reported worldwide from 16 countries [5]. A further 4420 cases of plague were reported to the World Health Organization (WHO) between 2010 and 2018, with 751 associated deaths [6,7]. Incidence data may be underestimated because diagnostic facilities and surveillance systems are inadequate in many areas of the world where plague is endemic or occurs in focal outbreaks.

Since 2000, more than 95 percent of reported cases have been from Africa [5,6,8], although outbreaks involving hundreds of cases have also occurred elsewhere, including Peru and India [4,5]. Plague has also reappeared in some countries after several decades of no reported cases [9-11]. As of 2018, the highest incidence countries were the Democratic Republic of Congo and Madagascar, with 237 of the 243 reported cases in the world residing in these two countries [7]; in Madagascar, cases of bubonic plague occur almost yearly, mainly between September and April [12]. A large outbreak of pneumonic plague in Madagascar that started in the fall of 2017 was notable for affecting major urban centers, since cases typically occur in more remote, rural regions [13].

Alerts and information about global plague outbreaks can be found on the WHO and Centers for Disease Control and Prevention websites.

In the United States, plague is endemic in all of the western states and has extended north and east over the years. The rate of plague in the United States is low, probably because the affected areas are rural and largely uninhabited. A total of 106 cases of human plague were reported in the United States from 2000 to 2018, over 80 percent of which were the bubonic form [14-16]. The vast majority of human cases in the United States have occurred in five states: Arizona, California, Colorado, New Mexico, and Texas. Human disease has also been reported from Oklahoma, Oregon, and Georgia [14,17,18]. In addition, animal and/or flea plague has been identified in western North Dakota and Nebraska.

Routes of transmission — Humans acquire plague via bites of rodent fleas, scratches or bites from infected domestic cats, direct handling of infected animal tissues, inhalation of respiratory secretions from infected animals, inhalation of aerosolized droplets from infected humans, or by exposure during postmortem examination and laboratory handling or testing [3,17,19-22]. Flea bites are the most common route of transmission of plague to humans, followed by contact with infected animals. In about 14 percent of cases, the source of infection is unknown.

Animals, including domestic pets, can acquire plague via bites of rodent fleas and ingestion of contaminated animal tissues. More than 200 mammalian species have been reported to be infected with Y. pestis, including squirrels, prairie dogs, rabbits, field mice, chipmunks, rats, bobcats, domestic cats, and camels. Rodents are the most important hosts [4].

Infected domestic cats and dogs may result in the transmission of plague to human via their carriage of infected fleas [18,23]. Plague-infected pets may be febrile, lethargic, anorectic, and have cervical, mandibular, or inguinal lymphadenopathy (buboes) [23,24]. In 2014, four cases of primary pneumonic plague in Colorado occurred following close contact with an ill pet dog, suggesting direct transmission from the dog [25,26]. Between 1977 and 1998, 23 human cases of plague associated with cats were reported by the US Centers for Disease Control and Prevention (CDC) from eight western states, representing 8 percent of the reported cases of plague during that time [27]. The incidence of infection did not increase during the summer months, unlike cases of plague associated with fleas. Inhalation was a more common route of acquisition involving cats. Approximately 25 percent of the cases resulting from contact with cats occurred among veterinarians and their assistants [4,27].

About 30 species of fleas are proven vectors of plague [4,28]. The most efficient flea vector is Xenopsylla cheopis, the oriental rat flea; different flea vectors may be important in different regions. The most important flea vector in North America is Oropsylla montana [29]. The human body louse (Pediculus humanus) has been proposed as an additional vector of Y. pestis based on the fact that body lice can transmit plague experimentally and because Y. pestis has been detected in head and body lice in humans with naturally acquired plague [30-32]; a modeling study suggested that body lice, rather than fleas, may have actually been the primary vectors for Y. pestis during the second pandemic (ie, "Black Death"), although this is hotly debated [33].

Plague could be used as a bioterrorism agent [34]. (See "Identifying and managing casualties of biological terrorism".)

MICROBIOLOGY — Y. pestis is a gram-negative coccobacillus that exhibits bipolar staining with Giemsa, Wright’s, or Wayson staining (picture 1). It grows aerobically on most culture media, including blood agar and MacConkey agar. Commercial automated laboratory identification systems may incorrectly identify Y. pestis as other species (eg, Acinetobacter or Pseudomonas) [18]. Laboratory technicians should be alerted regarding cases of suspected plague, as transmission can occur via laboratory exposure.

Genetic studies indicate that Y. pestis evolved from the enteric pathogen Y. pseudotuberculosis shortly before the first known pandemics of human plague [35-37]. This transition from an enteric to a flea-borne pathogen was made possible by the acquisition of two unique plasmids, coupled with the inactivation of genes required for survival in the mammalian gut [3,37-39].

Three distinct biovars of the Y. pestis clone, Antiqua, Medievalis, and Orientalis, have been described, and a fourth biotype (Microtus) has been proposed [36,40]. These biovars appear to have emerged before any recorded epidemics. Genotyping performed on dental pulp from the remains of eight individuals who probably died in the first and second pandemics (6^th century and 14^th century respectively) identified sequences that matched those of the biovar Orientalis [41].

PATHOGENESIS — The pathogenesis of plague consists of two components: transmission of infection from fleas to the mammalian host, and the host response to infection.

Fleas become infected by feeding on a bacteremic host. The classic mechanism of flea transmission is called the "blocked flea model." Y. pestis colonizes the flea midgut, replicates, and creates a blockage of the flea intestine [39,42]. Starved of sustenance, "blocked" fleas feed aggressively, regurgitating bacteria into the bite wound at each feed attempt [4,43]. Subsequent experimental studies have suggested that flea transmission can also occur by "mechanical transmission" or "early phase transmission," in which Y. pestis is sequentially transmitted by "non-blocked" fleas within a few hours to days after taking a blood meal from an infected mammalian host [44]. Early phase transmission may be related to post-infection esophageal reflux in the flea [45]. This reflux appears to be triggered by ingestion of blood from rats or guinea pigs, but not mice or gerbils, likely because poorly soluble rat or guinea pig hemoglobin crystallizes in the flea gut and fails to completely seal the midgut during digestion. It has been estimated that the minimum infectious dose for mammals is less than 10 organisms by the subcutaneous route [3,4].

Following human infection, invading organisms are carried via lymphatics to the regional lymph nodes, where they initiate an intense inflammatory reaction, creating a bubo [3]. Survival and replication within macrophages is probably of greatest importance in the early stages of infection [46]. Dissemination is facilitated by the Yersinia outer protein J, which kills macrophages and permits the bacterium to spread to nearby cells in the lymph node and subsequently into the systemic circulation [47]. After dissemination, necrotic foci containing extracellular Y. pestis form and progressively increase in size [3,4]. This progressive extracellular course is facilitated by impairment of local immune cell function [48] and inhibition of neutrophil degranulation by other Yersinia outer proteins [49].

Bacteremia is common and can lead to sepsis, pneumonia, and hemorrhagic lesions in various organs. In the absence of therapy, plague sepsis and endotoxemia lead to release of proinflammatory mediators. The resulting systemic inflammatory response syndrome may lead to disseminated intravascular coagulation, bleeding, organ failure, and shock [50]. Affected tissues contain inflamed microvasculature occluded by fibrin thrombi, resulting in necrosis and hemorrhage. Purpuric skin lesions arise on the extremities and trunk; they begin with erythema and subsequently change to a dark purple, and in patients who survive, eventually slough. Gangrene can occur at the tips of the fingers, toes, ears and nose [51].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Plague".)

SUMMARY

●Yersinia pestis causes plague and is transmitted by fleas; it is a zoonotic infection of domestic and wild animals. Humans are considered incidental hosts that do not contribute to the natural disease cycle. (See 'Introduction' above.)

●Areas of enzootic plague include North America (mainly the southwestern United States and Pacific coastal area), the former Soviet Union, and foci in Africa, Asia, and South America. (See 'Geographic distribution' above.)

●Humans acquire plague via bites of rodent fleas, scratches or bites from infected domestic cats, direct handling of infected animal tissues, inhalation of respiratory secretions from infected animals, inhalation of aerosolized droplets from infected humans, or by laboratory exposure. (See 'Routes of transmission' above.)

●Y. pestis is a gram-negative coccobacillus that exhibits bipolar staining with Giemsa, Wright’s, or Wayson staining. It grows aerobically on most culture media, including blood agar and MacConkey agar. (See 'Microbiology' above.)

●The pathogenesis of plague consists of two components: transmission of infection from fleas to the mammalian host, and the host response to infection. It has been estimated the minimum infectious dose for mammals is less than 10 organisms by the subcutaneous route. The invading organisms are carried via lymphatics to the regional lymph nodes, where they initiate an intense inflammatory reaction, creating a bubo. (See 'Pathogenesis' above.)

●Bacteremia is common and can lead to sepsis, pneumonia, and hemorrhagic lesions in various organs. In the absence of therapy, plague sepsis and endotoxemia lead to release of proinflammatory mediators. The resulting systemic inflammatory response syndrome may lead to disseminated intravascular coagulation, bleeding, organ failure, and shock. Purpuric skin lesions can arise on the extremities and trunk. Gangrene can occur at the tips of the fingers, toes, ears and nose. (See 'Pathogenesis' above.)