Yersinia pestis is a nonmotile, non–spore-forming, gram-negative bacillus with a tendency toward pleomorphism and bipolar staining. It is a member of the Enterobacteriaceae family (see Chapter 33) and shares features of the other Yersinia pathogenic for humans (Y pseudotuberculosis, Y enterocolitica), such as virulence plasmids and multiple Yersinia outer membrane proteins (Yops). In addition, Y pestis has two virulence plasmids, which code for a glycoprotein gel-like capsule called the F1 antigen and enzymes with phospholipase, protease, fibrinolytic, and plasminogen-activating activity. Yersinia pestis also has its own adhesin similar to the invasins of the other Yersinia.
✺ Member of Enterobacteriaceae
✺ Yops, glycoprotein capsule, and enzymes are present
The term plague is often used generically to describe any explosive pandemic disease with high mortality. Medically, it refers only to infection caused by Y pestis, and this appellation was justly earned because Y pestis was the cause of the most virulent epidemic plague of recorded human history, the Black Death of the Middle Ages. In the 14th century, the estimated population of Europe was 105 million; between 1346 and 1350, 25 million died of plague. Pandemics continued through the end of the 19th century and the early 20th century despite elaborate quarantine measures developed in response to the obvious communicability of the disease. Yersin isolated the etiologic agent in China in 1894 and named it after his mentor, Pasteur (Pasteurella pestis). The name was later changed to honor Yersin (Yersinia pestis).
Black Death continued into 20th century
Plague is a disease of rodents transmitted by the bite of rat fleas (Xenopsylla cheopis) that colonize them. It exists in two interrelated epidemiologic cycles, the sylvatic and the urban (Figure 36–2). Endemic transmission among wild rodents in the sylvatic (Latin sylvaticus, belonging to or found in the woods) is the primary reservoir of plague. When infected rodents enter a city, circumstances for the urban cycle are created. Humans can enter the cycle from the bite of the flea in either environment. However, chances are greater in the urban setting, particularly with crowding and poor sanitation.
✺ Sylvatic transmission among rodents is primary reservoir
The epidemiology of plague. A. In the sylvatic cycle, fleas leaving infected rodents, such as mice and prairie dogs, pass the infection to others in the population. Humans rarely contact these rodents but when they do, the flea bite transmits plague. B. In the urban cycle, masses of rats are in closer contact with humans, and bites from infected fleas transmit the infection to many. In both cycles, initial transmissions result in bubonic plague. Bacteremia with Y pestis may infect the lungs to cause pneumonic plague. Pneumonic plague is transmitted human to human by the respiratory route without the involvement of fleas.
The plagues of the Middle Ages are examples of the urban cycle involving rats and humans. When food is scarce in the countryside, rats migrate to cities. This facilitates rat-to-rat transmission and brings the primary reservoir into closer contact with humans. When the number of nonimmune rats is sufficient, epizootic plague develops among them, with bacteremia and high mortality. Fleas feeding on the rats become infected, and the bacteria multiply in their intestinal tract eventually blocking the proventriculus, a valve-like organ connecting the esophagus to the midgut. When the rat dies, the fleas seek a new host, which is usually another rat but may be a nearby human. Because of the intestinal blockage, the infected flea regurgitates Y pestis into the new bite wound. Therefore, the probability of transmission to humans is greatest when both rat population and rat mortality are high.
✺ Rat migration to cities increases human risk
✺ Fleas regurgitate into bite wounds
✺ Bubo is initial lesion
✺ Pneumonia is contagious
The bite of the flea is the first event in the development of a case of bubonic plague, which, even if serious enough to kill the patient, is not contagious to other humans. However, some patients with bubonic plague develop a secondary pneumonia by bacteremic spread to the lungs. This pneumonic plague is highly contagious person to person by the respiratory droplet route. It is not difficult to understand how rapid spread proceeds in conjunction with crowded unsanitary conditions and continued flea-to-human transmission. A 20th century urban plague epidemic is vividly described through the eyes of a physician in Albert Camus’ novel, The Plague.
Although urban plague epidemics have been essentially eliminated by rat control and other public health measures, sylvatic transmission cycles persist in many parts of the world, including North America. These cycles involve nonurban mammals such as prairie dogs, deer mice, rabbits, and wood rats. Transmission between them involves fleas. Coyotes or wolves may be infected by the same fleas or by ingestion of infected rodents. By their nature, the reservoir animals rarely come in contact with humans; when they do, however, the infected fleas they carry can transmit Y pestis. The most common circumstance is a child who is exploring the outdoors, comes across a dead or dying prairie dog, and pokes, carries, or touches it long enough to be bitten by the fleas leaving the animal. The result is a sporadic case of bubonic plague, which occasionally becomes pneumonic.
✺ Nonepidemic disease is linked to animal contact
Sylvatic plague, which exists in most continents, is common in Southeast Asia, but is not found in Western Europe or Australia. In the United States, the primary enzootic areas are the semiarid plains of the western states. Infected animals and fleas have been detected from the Mexican border to the arid eastern half of Washington State. The geographic focus of human plague in the United States is in the “four corners” area, where Arizona, New Mexico, Colorado, and Utah meet, but cases have occurred in California, west Texas, Idaho, and Montana. Most years, as many as 15 cases of plague are reported, although this number rose to 30 to 40 in the mid-1980s. These variations are strongly related to changes in the size of the sylvatic reservoir.
✺ Most US cases are in arid western states
It should not be surprising that the molecular pathogenesis of plague is quite complex, given its extremely high virulence in both insect and mammalian environments. Of more than 20 known virulence factors, some are deployed primarily in the flea, whereas others are produced only in the rodent or human victim. Yersinia pestis has regulatory systems that sense temperature, calcium, and surely other environmental triggers to turn the production of appropriate virulence factors on or off. At ambient temperature (20–28°C) in the flea, factors that facilitate multiplication of the organism (fibrinolysin, phospholipase) and blockage of the proventriculus (coagulase, polysaccharide biofilm) are produced. The flea, sensing starvation, feeds voraciously but due to the intestinal blockage repeatedly regurgitates blood and bacteria into the bite wound. In this wound (rat or human), Y pestis is suddenly moved into a new environment.
Multiplication in flea foregut aided by low temperature virulence factors
✺ Flea regurgitates bacteria into bite wound
In a new warm-blooded (35-37°C) host, Y pestis produces a second set of virulence factors including the F1 capsule, a plasminogen activator (Pla), and the Yops (Figure 36–3). At this temperature it also synthesizes a form of lipopolysaccharide (LPS) that is not recognized by the TLRs that respond to gram-negative bacteria. The F1 protein forms a gel-like capsule with antiphagocytic properties that allow the bacteria to persist and multiply. Pla facilitates metastatic spread through enzymatic activity and adhesion to extracellular matrix proteins. The Yops, though named as a protein family (YopA, YopB, and so on), have diverse biologic activities that fall into two categories. The first is direct destructive enzymatic activity directed at host cells. The other set of actions disrupt intracellular function and are mediated through injection secretion systems (type III). Once inside host cells, including professional phagocytes, these secreted proteins disrupt signaling pathways, destroy cytoskeleton structure, trigger apoptosis, and inhibit cytokine production and acidification of phagosomes.
✺ F1 capsule, Pla, Yops produced at 37°C
✺ F1 is antiphagocytic
✺ Yops destroy and disrupt
Plague, cellular view. (Top) Yersinia pestis is growing in the flea and producing virulence factors unique to that environment. Bacteria are regurgitated as part of the flea’s feeding on human skin and reach the subepithelial tissues. Here, triggered by environmental cues such as a new warmer temperature (37°C), they start to produce a new set of virulence factors unique to mammalian victims such as the F1 protein capsule. (Left) Yersinia pestis attaches to an epithelial cell. (Middle) Yersina outer membrane proteins (Yops) begin to be produced. Some are injected by a type III secretion system, others are secreted on the surface. (Right) The cell is destroyed and the organisms evade phagocytosis to enter the bloodstream. PMNs, polymorphonuclear neutrophils.
The organisms eventually reach the regional lymph nodes through the lymphatics, where they multiply rapidly and produce a hemorrhagic suppurative lymphadenitis known clinically as the bubo. Spread to the bloodstream quickly follows. The extreme systemic toxicity that develops with bacteremia appears to be due to LPS endotoxin combined with the many actions of Yops, proteases, and other extracellular products. The bacteremia causes seeding of other organs, most notably the lungs, and produces a necrotizing hemorrhagic pneumonia known as pneumonic plague.
✺ Bubo progresses to bacteremia
✺ LPS and other products produce shock
Recovery from bubonic plague appears to confer lasting immunity, but for obvious reasons the mechanisms in humans have not been extensively studied by modern immunologic methods. Animal studies suggest that antibody against the F1 capsular glycoprotein is protective by enhancing phagocytosis, but cell-mediated mechanisms are required for intracellular killing.
Anticapsular antibody may be protective
The incubation period for bubonic plague is 2 to 7 days after the flea bite. Onset is marked by fever and the painful bubo, usually in the groin (bubo is from the Greek boubon for “groin”) or, less often, in the axilla (Figure 36–4). Without treatment, 50% to 75% of patients progress to bacteremia and die in gram-negative septic shock within hours or days of development of the bubo. About 5% of victims develop pneumonic plague with mucoid, then bloody sputum. Primary pneumonic plague has a shorter incubation period (2-3 days) and begins only with fever, malaise, and a feeling of tightness in the chest. Cough, production of sputum, dyspnea, and cyanosis develop later in the course. Death on the second or third day of illness is common, and there are no survivors without antibiotic therapy. A terminal cyanosis seen with pneumonic plague is responsible for the term Black Death. Even today, plague pneumonia is almost always fatal if appropriate treatment is delayed more than a day from the onset.
✺ Bubonic plague mortality is 50% to 75% in untreated cases
✺ Pneumonic plague is fatal if untreated
Terminal cyanosis = Black Death
Bubonic plague. A swollen bubo is seen in the axilla of this child. (Reproduced with permission from Connor DH, Chandler FW, Schwartz DQ, et al: Pathology of Infectious Diseases. Stamford CT: Appleton & Lange, 1997.)
Gram-stained smears of aspirates from the bubo typically show bipolar-staining gram-negative bacilli. An immunofluorescence technique is available in public health laboratories for immediate identification of smears or cultures. Yersinia pestis is readily isolated on the media used for other members of the Enterobacteriaceae (blood agar, MacConkey agar), although growth may require more than 24 hours of incubation. The appropriate specimens are bubo aspirate, blood, and sputum. Laboratories must be notified of the suspicion of plague to avoid delay in the bacteriologic diagnosis and to guard against laboratory infection.
Immunofluorescent staining is rapid
Cultures grow on routine media
Gentamicin or streptomycin with or without doxycycline is the treatment of choice for both bubonic and pneumonic plague. Ciprofloxacin or chloramphenicol (if meningitis is present) are alternatives. Timely treatment reduces the mortality of bubonic plague to less than 10%, but the mortality rate of human cases of plague reported in developed countries is still around 20% because of delays in initiation of appropriate therapy.
Gentamicin or streptomycin for primary treatment
Urban plague has been prevented by rat control and general public health measures such as use of insecticides. Sylvatic plague is virtually impossible to eliminate because of the size and dispersion of the multiple rodent reservoirs. Disease can be prevented by avoidance of sick or dead rodents and rabbits. Eradication of fleas on domestic pets, which have been known to transport infected fleas from wild rodents to humans, is recommended in endemic areas. The continued presence of fully virulent plague in its sylvatic cycle poses a risk of extension to the urban cycle and epidemic disease in the event of major disaster or social breakdown. Chemoprophylaxis with doxycycline or ciprofloxacin is recommended for those who have had close contact with a case of pneumonic plague. It is also used for the household contacts of a person with bubonic plague, because they may have had the same flea contact. A formalin-killed plague vaccine once used for those in high-risk occupations is no longer available.
✺ Avoid sick or dead wild rodents
✺ Chemoprophylaxis for respiratory exposure