Yersinia enterocolitica and Yersinia pseudotuberculosis

Microbiology

As members of the family Enterobacteriaceae, Y. enterocolitica and Y. pseudotuberculosis are non–spore forming, pleomorphic, non–lactose fermenting gram-negative bacilli that grow under aerobic and anaerobic conditions. They are urease-positive organisms, which distinguishes them from urease-negative Y. pestis. Both Y. enterocolitica and Y . pseudotuberculosis are motile at 25°C but not at 37°C. They grow on brain heart infusion agar, MacConkey agar, and Salmonella-Shigella agar at room temperature and at 37°C and in buffered saline at 4°C. Culture on specific selective media (cefsulodin irgasan novobiocin [CIN] agar), with or without preenrichment in broth or phosphate-buffered saline at 4°C or 16°C, is one protocol for isolating Y. enterocolitica and Y. pseudotuberculosis from stool and other nonsterile sites. They form 2- to 4-mm colonies with a characteristic deep red center (bull's-eye) and a transparent margin on CIN agar. The colonies are difficult to detect after incubation for 24 hours but are easily visible at 48 hours ( Fig. 229B.1 ). Yersinia enterocolitica and Y. pseudotuberculosis can be distinguished from other enteric pathogens and from Y. pestis by biochemical profiles. Strains are differentiated by combined biochemical reactions and serogroups. Six biotypes (1A, 1B, 2, 3, 4, 5) and 60 serogroups of Y. enterocolitica have been described; not all strains are pathogenic for humans. Clinical infections are mostly associated with serogroups O:3, O:9, and O:5,27 and biotypes 2, 3, and 4. The previously dominant serogroup O:8 has been declining in North America. There is a separate system for serotyping Y. pseudotuberculosis, which is also based on somatic antigens. Fourteen serotypes of Y. pseudotuberculosis have been identified, five of which (O:1 to O:5) are considered pathogenic for humans. Serotype O:1 accounts for approximately 80% of isolates from humans.

A multitude of virulence factors allow Y. enterocolitica and Y. pseudotuberculosis to adhere to host cells and tissues and undermine immunologic defenses. The most extensively studied is the type III secretion system (T3SS) that is carried on the pYV virulence plasmid. The T3SS injects Yersinia outer proteins (Yops) directly into the host cell, causing subversion of signaling pathways that suppresses transcription of genes of the innate immune response, inhibition of phagocytosis, and blockage of cytokine production. Chromosomal virulence factors include adhesion proteins YadA (previously known as Yop1), invasin (Inv), Ail, and MyfA; the heat-stable enterotoxin Yst; and the myf operon that encodes genes of a fimbria similar to the CS3 fimbria of enterotoxigenic Escherichia coli. Furthermore, 1B/O:8 strains of Y. enterocolitica contain a high-pathogenicity island that encodes yersiniabactin, a siderophore that enhances iron acquisition. Serogroup O:3 and O:9 isolates of Y. enterocolitica lack this siderophore for iron transport and are less invasive in normal hosts. However, in the setting of iron overload or treatment with therapeutic chelating agents (e.g., deferoxamine), these strains can achieve virulence similar to O:8 strains. Yersinia enterocolitica use flagella ( Fig. 229B.2 ) to help establish contact with the intestinal epithelium. The role that Yst plays in gastroenteritis is controversial. Yst is not detectable in diarrheal stool samples in infected animal models, and some strains carry the yst gene but do not produce the enterotoxin, suggesting the presence of silent genes. Nevertheless, noninvasive 1A strains that cause diarrhea often carry the yst gene as their only virulence factor. Yersinia pseudotuberculosis produces Y. pseudotuberculosis –derived mitogen (YPM), a superantigenic toxin that induces proliferation of human T lymphocytes and causes toxic shock. The genes that code for YPM are not carried by plasmids but are inserted in an unstable locus of the genome.

Epidemiology

The reservoirs for Y. enterocolitica and Y. pseudotuberculosis are diverse and include soil, water, and the intestinal tracts of wild and domestic animals. Most of the environmental strains are avirulent, but those in pigs and their food products are the major source for pathogenic Y. enterocolitica in humans. Yersiniosis has a global distribution and is the third most common zoonosis in Europe. Germany accounts for over half of the reported cases, with an annual incidence of 7.2 per 100,000 population. This may be due to a higher prevalence of Y. enterocolitica and Y. pseudotuberculosis in animal reservoirs, as well as higher pork consumption in Germany compared to other European nations. In the United States, the average annual incidence of yersiniosis is 0.16 cases per 100,000 population. There has been a significant decrease in infections among African Americans less than 5 years of age but an increasing incidence among whites ages 19 to 64 years and Hispanics. This decline in African-American children may be due to educational efforts in the state of Georgia. Infections have been reported in other parts of the world, including South America, Africa, and Asia, but yersiniosis is not considered an important cause of tropical diarrhea. In 2014, a sustained outbreak of yersiniosis from Y . pseudotuberculosis occurred in all the major cities of New Zealand, with 220 laboratory-confirmed cases. Genomic and epidemiologic data suggested a single point-source contamination of the food chain, with subsequent nationwide distribution of contaminated produce. Unlike other enteropathogens, Yersinia infections often occur during winter months and in cold climates.

The majority of cases of gastrointestinal illness occur in children under 5 years of age, whereas mesenteric adenitis and terminal ileitis are more common among older children and adults. In the United States, yersiniosis is more likely to be diagnosed in young children compared with the general population. Transmission of infection occurs by ingestion of contaminated food or water and, less often, by direct contact with infected animals or patients ( Fig. 229B.3 ). The zoonotic reservoirs of Y. enterocolitica are diverse and include pigs, dogs, cats, rodents, bats, sheep, deer, horses, rabbits, cows, beavers, and muskrats. Flies can also be carriers and might facilitate the spread of yersiniosis from animals to humans. In France, Y. pseudotuberculosis tends to be more common in wild animals, particularly birds, rodents, hares, and rabbits, compared to domesticated ones. Yersinia enterocolitica is frequently present on the tonsils and in the alimentary tract of pigs, and transmission can occur by ingesting incompletely cooked pork and by contamination of other foods by pork products. Outbreaks of yersiniosis have been associated with contaminated milk and milk products ; contaminated produce such as bean sprouts, carrots, and lettuce ; and foods contaminated with spring water. The ability of the organisms to grow at 4°C means that refrigerated meats can be sources of infection. Cases of sepsis due to Y. enterocolitica have occurred following transfusion of blood stored between 2°C and 6°C. Occupational exposure to pigs increases the risk of infection in farmers, slaughterhouse workers, and butchers. Among pregnant Danish women with occupational exposures, elevated immunoglobulin G to Y. enterocolitica serogroup O:3 was not a risk factor for adverse pregnancy outcomes. Household transmission likely occurs through the fecal-oral route since children with yersiniosis may excrete the organism in their stool for several weeks. The cecum may become chronically colonized and serve as a reservoir for dissemination of infection to extraintestinal sites.

Systemic infections from Y. enterocolitica and Y. pseudotuberculosis are also observed, particularly in immunosuppressed patients, the elderly, and those with underlying conditions such as iron overload, alcoholism, cirrhosis, diabetes mellitus, cancer, and malnutrition. The association between the treatment of iron overload with deferoxamine and Yersinia sepsis is well recognized in clinical practice. Deferoxamine enhances the growth of Yersinia and also inhibits neutrophil function. Iron-loaded patients with β-thalassemia are at increased risk for severe yersiniosis, even when their body iron burden (as indicated by the serum ferritin level) is only moderately elevated and they are no longer receiving iron-chelating therapy with deferoxamine.

A postinfection reactive polyarthritis can occur and has a predilection for patients with human leukocyte antigen (HLA)-B27, possibly due to molecular mimicry between HLA-B27 antigen and Yersinia antigens. There is also some evidence for an association between Y. pseudotuberculosis infection and Kawasaki disease, possibly due to the YPM superantigen.

Clinical Manifestations

The incubation period after ingestion of the organism is 1 to 11 days, with diarrhea lasting for a few days to a few weeks (average of 2 weeks). Patients shed organisms in their feces and remain infectious during the symptomatic period. Yersinia enterocolitica presents as an invasive diarrhea characterized by fever, abdominal pain, mucus- and blood-containing stools, and the presence of fecal leukocytes. Nausea and vomiting affects 15% to 40% of cases. Perforation of the ileum and rectal bleeding can occur in serious infections. Patients with mesenteric adenitis ( Fig. 229B.4 ) or terminal ileitis have fever and right lower quadrant pain, which is more common in older children and adolescents and may be clinically indistinguishable from acute appendicitis (pseudoappendicitis). When evaluating patients suspected of having acute appendicitis, computed tomographic scanning of the abdomen and pelvis may help avoid exploratory laparotomy by revealing a normal appendix and enlarged mesenteric lymph nodes. Thickening and ulcerations of the terminal ileum and cecum can be seen on endoscopy, with raised round lesions on Payer patches, and can led to massive rectal bleeding. Complications following gastrointestinal infections can include granulomatous enterocolitis and granulomatous appendicitis. Convalescent carriage of Y. enterocolitica in stool of untreated individuals may occasionally extend for weeks to months in a small percentage of those infected.

Yersinia pseudotuberculosis is more likely to cause abdominal pain and fever than diarrhea in all age groups. The most common manifestation in humans is mesenteric adenitis, which, like Y . enterocolitica, causes an acute appendicitis–like syndrome with fever and right lower quadrant abdominal pain. The infection is usually self-limited.

Acute pharyngitis can occur from Y. enterocolitica, with or without diarrhea, and fatalities have been reported. The organism can also cause community-acquired pneumonia without accompanying diarrhea or other gastrointestinal symptoms. Skin and soft tissue infections usually result from failure of the skin barrier on distal body parts, followed by spread of the infection to the regional lymph nodes from the ruptured skin. Appropriate antibiotic therapy and surgical drainage are essential, because failures have occurred after common empirical antibiotics for cellulitis (e.g., vancomycin or cefazolin) were used.

Sepsis from Y. enterocolitica and Y. pseudotuberculosis is uncommon and presents as a severe illness with fever and leukocytosis. Patients are often elderly or have underlying medical conditions such as diabetes mellitus, liver disease, hemochromatosis, or iron overload. Human immunodeficiency virus infection has also been shown to be a risk factor for Y. pseudotuberculosis sepsis. Septicemic patients may develop hepatic or splenic abscesses, peritonitis, septic arthritis, psoas abscesses, osteomyelitis, endocarditis, myocarditis, mycotic aneurysms, or meningitis. Rapid-onset septic shock is seen in transfusion-transmitted Y. enterocolitica, which is caused by a preformed endotoxin. Serotype O:9 was implicated in a fatal case of posttransfusion sepsis from contaminated red blood cells following a vaginal delivery.

Far East scarlet-like fever (FESLF) has been associated with certain strains of Y. pseudotuberculosis in eastern Russia, Korea, and Japan (Izumi fever). These strains produce the superantigenic toxin YPM (described earlier), which is integral to the pathogenesis of FESLF. Six stages of FESLF have been identified :

• 1

  The incubation period, which is asymptomatic and lasts 7 to 10 days.

• 2

  The initial onset, in which fever, rigors, headache, myalgias, arthralgias, weakness, loss of appetite, swelling of scleral vessels, coryza, abdominal pain, and hyperemia of the face, neck, and conjunctiva occur.

• 3

  The accrual stage, which occurs 3 days after symptom onset and is characterized by high fevers, abdominal symptoms, and a scarlet fever–like rash.

• 4

  Remission, which usually occurs 6 days after disease onset and is characterized by a decrease in the severity of most symptoms, most notably fever, with persistence of rash and increased jaundice.

• 5

  Recurrence with exacerbation, which typically occurs 8 days after disease onset and has an increase in symptom severity, with the exception of fever, with desquamation occurring and jaundice becoming maximal.

• 6

  Convalescence, which usually occurs after 12 days with gradual resolution of all symptoms, including rash, desquamation, and jaundice.