Plague (Yersinia pestis)

History

Plague has been credited with causing at least three major pandemics over the past 1500 years. The first struck the Byzantine Empire during the sixth century, killing an estimated 40 million persons in the Mediterranean basin. The second pandemic began in Central Asia and spread west along caravan routes to reach the Crimean Sea port of Kaffa (now Feodosiya in Ukraine) in 1346. In what is believed to be the first use of plague as a weapon, the Mongols, who were battling the Genoese for control of the city, reportedly catapulted bodies of plague victims over the city walls. Genoese ships returning to Italy introduced the disease into several port cities, and from 1347–54, the “Black Death” spread swiftly through Europe and the British Isles, killing an estimated one-third of the population. Although some historians have questioned whether the Black Death was actually caused by plague, evidence from archeologic and transmission studies strongly supports the role of Y. pestis as the causative agent. Plague persisted in Europe for the next 300 years, causing periodic outbreaks before dying out.

The third, or “modern,” pandemic began in China's Yunnan Province in the 1850s. Infection spread along trade routes to Hong Kong, where Alexandre Yersin isolated the causative agent in 1894. Four years later Paul-Louis Simond identified the plague bacillus in the tissues of dead rats and subsequently proposed a role for fleas in transmission. Over the ensuing 20 years steamships helped disseminate Y. pestis– infected rats and fleas to port cities worldwide, including several in North America. Rat-associated plague was soon brought under control in most urban areas; however, infection spread to other species of rodents and became entrenched in rural areas of the Americas, Africa, and Asia. The region most affected has shifted over time from India, where more than 20 million cases occurred during the first half of the 20th century, to war-torn Vietnam during the 1960s and 1970s, and finally to sub-Saharan Africa. Collectively, Madagascar, Uganda, Tanzania, and the Democratic Republic of Congo currently account for the majority of cases reported worldwide.

Along with its historical importance, Y. pestis has considerable potential as a biological weapon. During World War II the Japanese military dropped ceramic bombs with plague-infected fleas over areas of China, apparently causing outbreaks. Both the United States and the Soviet Union evaluated Y. pestis as a potential weapon during the Cold War era, and in the 1980s a Soviet defector to Great Britain revealed that the Russians had succeeded in preparing a powdered aerosolized form, genetically engineered to be resistant to several antibiotics. The potential for misuse by terrorists is considered an important national security threat, requiring special measures for medical and public health preparedness. The plague bacillus is designated as a Tier I (formerly Category A) select agent whose handling is regulated by federal law.

Microbiology

Y. pestis is an aerobic, gram-negative coccobacillus that exhibits bipolar staining with Giemsa, Wright, and Wayson stains. A member of the Enterobacteriaceae, it grows well on blood or MacConkey agar and in nutrient broths, such as brain-heart infusion. When incubated at 37°C, small colonies 1 to 2 mm in diameter are visible on blood or MacConkey agar after 24 to 48 hours. At 72 hours, colonies grown on blood agar can take on a raised, irregular, “fried-egg” morphology. Y. pestis does not form spores and, unlike Y. enterocolitica and Y. pseudotuberculosis, is nonmotile when incubated at lower temperatures. It does not ferment lactose and is citrate, urease, and indole negative.

Genomic studies indicate that Y. pestis evolved recently from the enteric pathogen Y. pseudotuberculosis . The transition from enteric to flea-borne pathogen required the ability to survive in the flea gut and to achieve high concentrations in the blood of mammalian hosts. These traits were endowed in part through the acquisition of two plasmids encoding factors that are differentially expressed at temperatures encountered in fleas and mammals. The 110-kilobase (kb) pMT1/pFra plasmid encodes both Yersinia murine toxin (Ymt), which is necessary for colonization of the flea midgut, and the fraction 1 (F1) envelope antigen, which inhibits phagocytosis in mammals ( Table 229A.1 ). The smaller 9.5-kb pPCP1 plasmid encodes a plasminogen activator protein (Pla protease) that is responsible for temperature-dependent coagulase and fibrinolysin activities. The origins of these plasmids remain uncertain; however, approximately half of the DNA sequences of the pMT1/pFra plasmid are shared with a plasmid of Salmonella enterica serotype Typhi.

As with the other yersiniae, the plague bacillus also has an approximately 70-kb plasmid that mediates expression of virulence factors that prevent production of proinflammatory cytokines, increases resistance to phagocytosis, and enhances intracellular survival. Chromosome-mediated factors include a potent lipopolysaccharide endotoxin and a pigmentation factor, the hemin storage locus (hms), which regulates iron uptake and enables the bacteria to form blockages of the flea gut that enhance transmission.

Y. pestis isolates can be classified into three principal biovars based on their ability to ferment glycerol and reduce nitrate. It has been postulated that these biovars—Antigua, Medievialis, and Orientalis—reflect strains associated with the first, second, and third pandemics, respectively. Various molecular methods suggest, however, that these biovars do not correlate fully with phylogenetic relationships, and although Orientalis is associated with the third pandemic, the association of earlier pandemics with specific biovars remains uncertain.

Epidemiology

Although not the scourge it once was, plague remains a threat in areas of Africa, Asia, and the Americas, including the western United States ( Fig. 229A.1 ). Before 2007, when required notification was discontinued, between 1000 and 6000 cases were reported annually to the World Health Organization (WHO) from 25 countries. Nearly 80% of cases were reported from Africa, 15% from Asia, and the remainder from the Americas. During 2010–15, only about 500 plague cases were reported annually to WHO. Nevertheless, the potential for cases and outbreaks persists, especially in rural areas of Madagascar, Uganda, and the Democratic Republic of Congo. In 2017 an outbreak of pneumonic plague was reported in the capital city of Madagascar, with more than 2700 suspect cases identified. Although the true number of infections was likely far lower, the social and economic impact was substantial. As demonstrated by reports of human plague cases in Algeria and Libya, the disease can reemerge in an area even after decades of quiesence.

In the United States plague has been reported since 1900. Initially restricted to port cities, plague is currently endemic in the 17 contiguous western states extending from the Pacific Coast to the Great Plains. A total of 437 cases in humans were reported during 1970– 2010 (≈10 cases per year), with 60 deaths (14% mortality). During 2010–16 there were 2 to 16 cases per year in the United States. Approximately 80% of human cases occur in New Mexico, Arizona, and Colorado and 10% in California ( Fig. 229A.2 ). Human plague is most common during May through October, when fleas are active; wintertime cases are rare and often associated with hunting. Males are slightly more likely to be infected, and more than half of cases occur in persons younger than 20 years. Incidence is highest among Native Americans and Hispanics, although non-Hispanic whites account for the majority of cases. Within endemic areas, elevated plague risk is associated with close contact with rodents and their feline and canine predators, the presence of harborage and food sources for wild rodents in the vicinity of homes, and possibly a failure to control fleas on pet dogs and cats. Expanding suburban development in prime plague habitat has led to increasing cases in some areas and a shift toward higher socioeconomic groups in recent years. Travelers with plague can present a diagnostic challenge when encountered outside endemic areas (peripatetic plague) and may trigger concern about possible terrorist exposures.

Natural Cycles

The epizootiology of plague is complex and not completely understood ( Fig. 229A.3 ). Fundamentally a flea-transmitted disease of rodents, plague is found in endemic foci scattered throughout the world. Different foci involve different rodent and flea species, each with their own ecology and predilection for disease. Perhaps triggered by climatic conditions, epizootics characterized by explosive spread and sudden mass mortality among susceptible rodents occur periodically. Epizootics promote dispersal of infected fleas and increase the risk for transmission to humans, especially when rodent species living in close proximity to humans are involved. Worldwide, the most concerning are the peridomestic rats, Rattus rattus and Rattus norvegicus, and their highly efficient flea vectors, Xenopsylla cheopis and Xenopsylla braziliensis. In the western United States epizootics occur among ground squirrels ( Spermophilus spp.), prairie dogs ( Cynomus spp.), and chipmunks ( Tamias spp.), as well as less familiar rodent species.

How Y. pestis survives in nature between epizootics is uncertain. One hypothesis holds that the organism continues to circulate slowly and undetected in enzootic cycles involving rodent species that are less susceptible to fulminant infection. An alternative hypothesis holds that although the organism dies rapidly on inanimate surfaces, it may be able to survive in a niche within the soil, periodically infecting burrowing rodent hosts. This second hypothesis has received support recently by the demonstration that Y. pestis can replicate within certain free-living ameba, an ability that may also relate to the organism's capacity as a facultative intracellular pathogen.

Transmission to Humans

Humans become infected with Y. pestis through flea bites, direct contact with tissues or secretions of infected animals, or rarely through inhalation of infectious aerosols (see Fig. 229A.3 ). Flea-borne transmission is especially common during epizootics when large numbers of rodents die and their fleas seek alternative sources for a blood meal. Hunters become infected through direct inoculation while skinning or handling carcasses of infected rodents, rabbits and hares, wild cats, and coyotes. Direct inoculation is associated with an increased risk for septicemia and death, possibly because the bacterium, coming directly from a warm-blooded host, is already expressing F1 antigen and thus less susceptible to phagocytosis. Consumption of uncooked meat from camels, goats, and other ungulates, which are also susceptible to infection, has been identified as the source of small outbreaks in northern Africa, the Middle East, and Central Asia. Aerosols generated while handing infected animals can also pose a risk, as demonstrated by the case of a US wildlife biologist who developed primary pneumonic plague after necropsying an infected mountain lion. Although generally “dead-end” hosts, humans who develop pneumonic plague can transmit the infection to close contacts through respiratory droplets.

Domestic pets are also an important source of potential exposure. Domestic cats that eat infected rodents develop pharyngeal infections that can be transmitted directly to humans through respiratory droplets, causing primary pneumonic plague. Although dogs appear less likely to become clinically ill when infected, fulminant pneumonia in dogs with transmission to owners has been reported. In addition, dogs may play a role in increasing human exposure by transporting rodent fleas into the home, especially if they are allowed to sleep on their owner's bed at night. Laboratory infections, once common, are rare under current practices. Nevertheless, in 2009 a US laboratory researcher died of sepsis caused by an attenuated strain of Y. pestis that lacked the virulence genes necessary for iron absorption. Postmortem evaluation revealed that the worker had undiagnosed hemochromatosis.

Pathogenesis

Fleas become infected when feeding on a bacteremic host. In the cooler environment of the flea, the bacillus expresses a variety of factors that facilitate colonization of the flea midgut, replication, and blockage of the flea intestine (see Table 229A.1 ). Starved of sustenance, “blocked” fleas feed aggressively, regurgitating bacteria into the bite wound. Many of the inoculated bacteria are likely phagocytized and killed by polymorphonuclear lymphocytes; however, a few are taken up by mononuclear cells and carried via lymphatics to the regional lymph nodes. Growing at 37°C, the bacteria begin expressing F1 envelope antigen, enhancing their ability to resist subsequent phagocytosis by polymorphonuclear lymphocytes. Within the lymph node, the bacilli stimulate an intense inflammatory response that is detectable clinically as a bubo. Microscopic examination of the fully developed bubo reveals invasion by polymorphonuclear leukocytes, hemorrhagic necrosis with destruction of normal architecture, and dense concentrations of extracellular bacilli. Bacteremia is common and, in the absence of specific therapy, can lead to secondary pneumonia, disseminated intravascular coagulation, acute renal failure, and irreversible shock. Blockage of vessels in cooler acral sites, including fingers, toes, ears, and nose, can lead to gangrene ( Fig. 229A.4 ), a startling feature that may have given rise to the name “Black Death.” Pathogenesis of pneumonic plague is marked by a rapid, destructive proinflammatory phase that results in rapid death.

Clinical Manifestations

Plague takes several different clinical forms, depending in part on the route of exposure. In the United States 80% to 85% of patients present with primary bubonic plague, 15% with septicemic plague, and 1% to 3% with pneumonic or other forms of plague. The usual incubation period is 2 to 7 days but can be as short as 1 day for patients with primary pneumonic plague.

Bubonic Plague

Bubonic plague results from cutaneous exposure and is characterized by the sudden onset of high fever, chills, weakness, and headache. A bubo or swelling of regional lymph nodes becomes apparent in the groin, axilla, or neck within the first day. Buboes vary from 1 to 10 cm and elevate the overlying skin, which may be warm and erythematous. Palpation typically elicits extreme tenderness. Bubonic plague is distinguished from other forms of lymphadenitis by its sudden onset, the intensity of inflammation in the bubo, and the usual absence of obvious skin lesions or associated ascending lymphangitis ( Fig. 229A.5 ). Nevertheless, careful examination distal to the bubo will occasionally reveal a small papule or scab demarcating the site of the flea bite. Rarely, ulcers or eschars may develop, which can be confused with those of anthrax or tularemia ( Fig. 229A.6 ). The differential diagnostic possibilities for bubonic plague include cat-scratch disease, staphylococcal or streptococcal lymphadenitis, tularemia, filarial lymphadenitis, chancroid and other sexually transmitted diseases, and strangulated hernia.