Plague and Other Yersinia Infections

Definition

Plague is a life-threatening flea-borne disease that is best known as the cause of the Black Death of the Middle Ages. The illness most often presents with regional lymphadenopathy but can also take the form of a primary pneumonia. Plague can be cured if treated promptly with appropriate antimicrobials.

The Pathogen

Plague is caused by Y. pestis , which is a microaerophilic, gram-negative, nonmotile, and nonsporulating coccobacillus that belongs to the family Enterobacteriaceae. Y. pestis can exist as a facultative intracellular pathogen and exhibits bipolar staining with Wayson, Giemsa, and Wright stains ( Fig. 288-1 ). Y. pestis lacks a true capsule but has a carbohydrate-protein envelope comprising the capsular or fraction 1 antigen . Although only one serotype is thought to exist, most isolates can be classified into three principal biovars ( Antiqua, Mediaevalis , and Orientalis ) based on their ability to ferment glycerol and reduce nitrates. All three biovars occur in Asia, which is generally accepted as the continent where plague originated. Two biovars exist in Africa ( Antiqua and Orientalis ), but only Orientalis occurs naturally in the Americas. All are highly virulent and appear to cause virtually identical signs and symptoms in humans.

Epidemiology

Plague is endemic in discrete areas of Africa, Asia, and the Americas ( E-Fig. 288-1 ), including the Western United States ( Fig. 288-2 ). In nature, Y. pestis is maintained by transmission cycles involving certain rodent species and their fleas, which act as vectors. Two general types of cycles have been postulated. Enzootic cycles involve low-level transmission among relatively resistant rodent species and are thought to pose little immediate risk to humans. Spread to more susceptible rodent species, however, can trigger an epizootic cycle in which the pathogen spreads rapidly through the rodent population, causing mass mortality. As rodent hosts die, infected fleas seek blood meals from nonrodent species, including humans. Although nonrodent mammals are typically dead-end hosts, some secondary transmission can occur, and rodent-consuming carnivores and raptors can potentially spread the disease to neighboring areas through the transport of infected rodent fleas. Y. pestis has some capacity to survive in soil, and recent work suggests a possible role for free-living ameba in maintaining Y. pestis in the environment.

Humans can acquire plague through multiple routes, with the bite of an infected rodent flea being by far the most common ( Fig. 288-3 ). Risk is greatest in endemic areas of the developing world where flea-infested commensal rats, especially Rattus rattus and R. norvegicus , live in close proximity to humans. The oriental rat flea, Xenopsylla cheopis, which is a particularly efficient vector of Y. pestis , feeds readily on both rats and humans. In the United States, contact with commensal rats is less common, and most cases result from the bites of fleas from other rodents, such as ground squirrels, prairie dogs, wood rats, and chipmunks. In this setting, flea bites are usually acquired during hiking, hunting, or other outdoor activities. Allowing dogs to sleep in their owners’ beds also appears to increase risk, presumably from the fleas that dogs acquire while roaming outside.

Although less common, humans can also become infected with Y. pestis by close contact with other infected mammals. Percutaneous exposure by direct contact with infected tissues, such as while skinning a rabbit or rodent for meat, or by the bites or scratches of infected carnivores such as cats can transmit the organism. More concerning from a public health perspective is infection acquired by inhalation of infectious droplets. Inhalation of bacteria usually occurs by exposure to animals or humans who have pulmonary plague, and it results in primary pneumonic plague, a form of the disease that is often fatal and can spread from person to person under certain circumstances.

Despite the presence of plague-endemic areas on multiple continents, human infection is relatively uncommon. Prior to the discontinuation of routine notification in 2007, only 1000 to 6000 human plague cases were reported to the World Health Organization (WHO) each year. Over the last half century, the bulk of reported human cases has shifted from southeast Asia to sub-Saharan Africa. According to the most recently released WHO statistics covering the period 2013 through 2018, Madagascar, the Democratic Republic of Congo, Uganda, and Tanzania accounted for 97% of the world’s reported cases (see E-Fig. 288-1 ). Another 3% were reported from three countries in the Americas—Bolivia, Peru, and the United States; Asian countries accounted for only 0.4% of total cases.

Much of the concern regarding plague stems not from the average case counts but from the potential for sudden outbreaks. In August 2017, for example, a man in Madagascar died of pneumonic plague during a long bush taxi ride that triggered an outbreak in which over 2400 suspected cases were identified. Although it is likely that many of these patients did not actually have plague, the economic and social consequences were substantial.

In the United States, plague is found in the continental states west of the 100th meridian. New Mexico accounts for the majority of human cases, followed by Arizona, California, and Colorado (see Fig. 288-2 ). Since 2000, the annual number of cases has ranged from 1 to 17, with most cases occurring in the spring and summer. Cases are occasionally reported in other states, either due to travel to the west or to laboratory exposure, as occurred in Illinois in 2009. Occupation-related infection has occurred among veterinary staff, biologists, and trappers, including cases of primary pneumonic plague among persons handling cats or dogs with signs of plague pneumonia, pharyngitis, or oral abscesses. Although human-to-human spread of primary pneumonic plague has not been confirmed in the United States since 1924, possible person-to-person transmission was identified in 2014 during an outbreak in Colorado.

Concern has been raised that Y. pestis could be used as an agent of bioterrorism ( Chapter 19 ). In most projected scenarios, bioterrorists would spread Y. pestis in an aerosol form, thereby potentially resulting in numerous primary pneumonic cases, a high mortality rate, and widespread panic. The possibility of engineered resistance to antimicrobials would need to be considered during an intentional release of Y. pestis .

Pathobiology

Few bacteria are more pathogenic for humans than Y. pestis . The organism’s virulence reflects the need to achieve high levels of bacteremia in order to ensure onward transmission to uninfected fleas. The process begins when Y. pestis enters the body, usually through the bite of an infected flea or other percutaneous exposure. Some bacteria are killed by polymorphonuclear leukocytes. Other bacteria, however, enter into mononuclear cells and are carried via lymphatics to the regional lymph nodes, where they replicate. Infected lymph nodes, termed buboes ( Fig. 288-4 ), can appear edematous and congested early in the course of illness but exhibit little evidence of inflammatory infiltrates or vascular injury histologically. Within a few days, however, they contain massive numbers of Y. pestis and heavy neutrophil infiltrates, thereby causing the substantial swelling and tenderness that are the hallmark of bubonic plague. As the illness progresses, hemorrhagic necrosis and vascular damage in the node become apparent; some nodes spontaneously rupture. Additional complications, seen in autopsy specimens, include diffuse hemorrhagic splenic necrosis, renal glomeruli containing fibrin thrombi, and multifocal necrosis in the liver.

Of particular concern is hematogenous spread to the lungs, which can result in secondary pneumonic plague. Secondary pneumonic plague initially presents with scant sputum production and diffuse pulmonary infiltrates. Without prompt treatment, Y. pestis spreads from the interstitial spaces of the lung to the pulmonary alveoli; sputum increases in quantity and may become pink or blood tinged. At this point, a patient with secondary pneumonic plague can transmit infection to others through coughed respiratory droplets.

Inhalation of infectious droplets from humans or animals with pneumonic plague causes primary pneumonic infection, which is a rapidly progressive lung infection that is initially lobular, then lobar, and finally multilobar, with large numbers of Y. pestis present in the alveoli and pulmonary secretions ( Fig. 288-5 ).

A small percentage of patients with plague develop septicemia in the absence of recognized buboes, pneumonia, or other signs of localized infection, a condition referred to as primary septicemic plague. These patients commonly have abdominal pain without other localizing symptoms, perhaps reflecting infection through the gastrointestinal tract or by a flea bite on the trunk in a location where regional lymph nodes are mostly internal and not clinically apparent.

Successful evasion of the host’s immune system by Y. pestis is enabled by both chromosomal and plasmid-encoded virulence factors. The ability to escape from the host’s innate immune defenses and disseminate to regional lymph nodes depends in part on a protease (Pla) encoded on the 9.5-kb plasmid that helps degrade fibrin clots and promote the production of excess plasmin, which can affect inflammatory exudates, break down extracellular proteins and basement membranes, and reduce levels of chemoattractants. Another virulence factor, Yersinia outer protein M, is one of many Yersinia outer proteins encoded by genes on the midsized (70 to 75 kb) plasmid of Y. pestis . Although such proteins are degraded by the Pla protease, Yersinia outer protein M is resistant to its activity and probably aids in the dissemination of Y. pestis by competing with platelets for thrombin, thereby reducing clotting, inhibiting the activation of platelets, and lowering local inflammatory responses. Initial invasion and dispersal to regional lymph nodes also depends on the ability of Y. pestis to survive for at least brief periods inside host phagocytes. Survival in such environments is promoted by other Yersinia outer proteins that work in concert with a type III secretory apparatus to deliver into host phagocytes those Yersinia outer proteins that act as intracellular effectors. These effector proteins disturb the cytoskeletal dynamics of phagocytic cells and block their production of proinflammatory cytokines. Affected phagocytes are rendered incapable of killing the invading Y. pestis , thereby allowing this bacterium to survive extracellularly in lymphoid tissues.

Survival of Y. pestis in mammalian hosts also depends on its ability to acquire sufficient quantities of iron for growth. The most important means of iron uptake in Y. pestis is a siderophore (yersiniabactin) system that can effectively compete with host iron-binding molecules for this essential nutrient. The capacity of Y. pestis to survive within host phagocytes is complemented during later stages of infection by the expression of a glycoprotein capsular antigen (caf1 or fraction 1 antigen) that confers resistance to phagocytosis. Expression of caf1 is temperature dependent, being repressed at the cooler temperatures found in the flea vector and upregulated at mammalian host body temperatures.

Clinical Manifestations

The three most commonly observed forms of plague (in order of decreasing occurrence) are bubonic, septicemic, and pneumonic. Unusual manifestations of plague include meningitis, pharyngitis, skin ulcers, and osteomyelitis. In rare instances, Y. pestis has been inoculated through the conjunctiva, thereby resulting in oculoglandular plague. The incubation periods are 2 to 6 days for bubonic plague and 1 to 4 days for primary pneumonic plague.

Bubonic Plague

The characteristic swollen and tender lymph nodes (buboes) of bubonic plague usually appear in nodes located proximal to the site of initial inoculation (see Fig. 288-4 ). Most cases of bubonic plague in the United States are thought to be acquired from flea bites on the legs, as indicated by inguinal or femoral lymph node involvement on the side where the flea bite occurred. Axillary buboes, which are also common, result from the handling of an infected animal or carcass. Cervical buboes are uncommon in the United States but prevalent in some developing countries where people may sleep on the floor, thereby increasing their chance of being bitten about the head and neck by infectious fleas. Occasionally, a skin lesion or small papule appears at the site of an infectious flea bite or other source of inoculation.

As the architecture of the infected lymph nodes breaks down, large numbers of Y. pestis enter the circulation, thereby producing signs and symptoms typical of gram-negative sepsis, including fever, chills, myalgia, arthralgia, headache, malaise, and prostration. Disseminated intravascular coagulation ( Chapter 161 ) can trigger thrombosis within capillaries, vascular necrosis, ecchymoses, acral gangrene, and cutaneous, mucosal, and serosal petechiae ( Fig. 288-6 ).

Untreated patients with bubonic plague become increasingly toxic, remain febrile, and experience tachycardia, agitation, confusion, delirium, and convulsions. Patients also may develop secondary pneumonic plague with cough, sputum, and the ability to transmit primary pulmonary plague (see later) to others.