eMedicine Specialties > Infectious Diseases > Bacterial Infections

Pseudotuberculosis (Yersinia)

Author: Asim A Jani, MD, MPH, FACP, Clinician-Educator and Epidemiologist, Consultant, Faculty (Voluntary), University of Central Florida College of Medicine
Coauthor(s): Paul Chen, BS, Student Researcher, Member of American Public Health Association
Contributor Information and Disclosures

Updated: Sep 8, 2008

Introduction

Background

Yersinia pseudotuberculosis is the least common of the 3 main Yersinia species that cause infections in humans. Y pseudotuberculosis primarily causes zoonotic infection in various hosts, including domestic and sylvatic animals and birds, but has been associated with food-borne infection in humans. A few outbreaks of Y pseudotuberculosis infections in humans have been reported. In 2006, Y pseudotuberculosis was implicated in a large point-source outbreak of gastroenteritis attributed to the ingestion of raw grated carrots contaminated during the early phase of the production process. This was supported by epidemiologic, clinical, laboratory, and environmental data.¹

Y pseudotuberculosis infection in humans usually leads to a gastroenteritis (diarrheal component uncharacteristic) characterized by a self-limited mesenteric lymphadenitis that mimics appendicitis. Y pseudotuberculosis invades mammalian cells and survives intracellularly; the primary virulence factor is a plasmid-encoded protein that causes increased invasiveness. Postinfectious complications include erythema nodosum and reactive arthritis. Thus, a major triad for Y pseudotuberculosis infection includes fever, abdominal pain, and rash. In rare cases, it has been associated with septic complications (often in immunocompromised patients with chronic liver diseases).

The bacillus was first described in 1889 and was later renamed twice before the current name, Y pseudotuberculosis, was established in the 1960s. From the late 1920s to the mid 1960s, the organism was identified as Pasteurella pseudotuberculosis and then Shigella pseudotuberculosis. A Russian researcher named Znamenskiy demonstrated that Y pseudotuberculosis was, in fact, a causative agent for clinical illness through self-inoculation.

Because Y pseudotuberculosis infection has zoonotic forms, the animal reservoirs for such transmission include many mammalian and avian hosts, such as dogs, cats, horses, cattle, rabbits, deer, rodents, and birds (eg, geese, turkey, ducks, canaries, cockatoos). An example of occupational exposure to Y pseudotuberculosis related to animal reservoirs involves butchers working in abattoirs slaughtering swine.²

The genus Yersinia also contains the important species Yersinia enterocolitica and Yersinia pestis. Genomic characterization studies using hybridization techniques suggest that the selective loss of certain genes over time allowed interspecies and intraspecies diversity involving Y pseudotuberculosis and Y pestis, the organism that causes plague.

Pathophysiology

Y pseudotuberculosis infections in humans are primarily acquired through the gastrointestinal tract after consumption of contaminated food products. Characteristic of yersinial infections, an inoculum of 10⁹ organisms is often needed to induce infection. Although Y pseudotuberculosis infections generally do not cause diarrheal symptoms, they can cause a range of morbidities, including forms of mesenteric lymphadenitis, granulomatous disease, and dissemination with sepsis. Recent evidence has suggested that Y pseudotuberculosis may also disseminate from sites of bacterial replication within the intestinal tract and not necessarily from regional lymph nodes.³

Because Y pseudotuberculosis does not produce iron-binding compounds, patients with iron-overload states such as hemochromatosis, venous congestion, hemolytic anemia, and cirrhosis are at risk for sepsis.

In 1959, an epidemic that occurred on the Pacific coast of Russia was termed Far East scarlet-like fever (FESLF). Y pseudotuberculosis strains associated with FESLF were recently genetically sequenced, showing mobile gene pools that contain unique plasmids, the expression of which could result in scarlatinoid fever. Interestingly, virulence factors such as the Y pseudotuberculosis –derived mitogen (YPM)—a superantigen—are likely related to the atypical scarlet fever syndromes reported more recently, such as Izumi fever in Japan. YPM includes at least 3 superantigens—YPMa, YPMb, and YPMc—all of which have pathogenetic relevance and differ from other bacterial superantigens.

Although, as of 2007, no single infectious etiology has been shown to cause Kawasaki disease, the condition appears to be more prevalent among populations exposed to Y pseudotuberculosis infection. Kawasaki disease is found mostly in Japan (170,000 cases over 40 y); however, outbreaks of Kawasaki disease have been reported in Korea, the United States, Finland, and other non-Asian countries. Kawasaki disease and Y pseudotuberculosis infection have similar age, sexual, and temporal predilections (higher incidence in the winter months).⁴ Clinical comparisons of patients with Kawasaki disease with and without laboratory evidence of Y pseudotuberculosis infection has suggested that Y pseudotuberculosis infection may be associated with the development of coronary artery lesions and a poor treatment outcome in patients with Kawasaki disease.⁵

The incubation period of Y pseudotuberculosis infection varies from 5-10 days. Fecal excretion of the organism can occur several weeks after illness but often does not result in secondary person-to-person transmission or clinical relapses. A latent duration of 2-20 days has been reported in sporadic outbreaks, with peak incidence rates at 4 days after ingestion.

Frequency

United States

No specific pattern of Y pseudotuberculosis infection in the United States has been reported. Most Yersinia -related outbreaks in the United States and abroad have been associated with Y enterocolitica rather than Y pseudotuberculosis. In 1976, an outbreak of Y enterocolitica infection in children in Oneida, New York, was caused by contaminated chocolate milk. This was the first food-borne Yersinia -related outbreak reported in the United States, with both of the above Yersinia species being studied. Drinking from well water, mountain streams, and soil is associated with infection. Epidemics of Y pseudotuberculosis infection are uncommon, unlike the increased frequency of outbreaks associated with Y enterocolitica.

International

The distribution of Y pseudotuberculosis infection is worldwide. Most cases occur in winter, probably because of the increased seasonal incidence of infection among animals. The increased prevalence in winter may also be due to the enhanced growth characteristics in cold temperatures. Although many cases of Y pseudotuberculosis infection have been reported in Europe, large-scale outbreaks in the Aomori region of Japan were noted in the early 1990s. Fewer than 30 cases of associated septicemia have been reported in the literature.⁶

In November 1998, 4 laboratory-confirmed cases of Y pseudotuberculosis infection were reported to the British Columbia Centre for Disease Control Society (BCCDCS).⁷ Through a follow-up case-control study evaluating risk factors in a multivariate analysis, possibly contaminated homogenized milk was implicated in the outbreak. In 1991, children consuming untreated drinking water in Okayama, Japan, were exposed to Y pseudotuberculosis, leading to clinical disease.⁸ Isolation of Y pseudotuberculosis in well water has also been reported (in Czechoslovakia).

In the 1980s, outbreaks of Y pseudotuberculosis infection in Finland and Japan constituted most of the sporadic cases reported in the literature. In 1995, 8 cases of Y pseudotuberculosis infection in a Belgian hospital caused gastrointestinal symptoms .⁹ The organism was isolated with stool analysis and careful isolation techniques involving cold-enriched media.

Mortality/Morbidity

Most Y pseudotuberculosis infections are self-limited with a low case-fatality rate. However, the uncommon sepsis-associated illnesses caused by Y pseudotuberculosis infection in patients with chronic liver disease may carry a mortality rate that exceeds 75%.

Race

Y pseudotuberculosis infections appear to have no specific racial or ethnic predilection.

Sex

Y pseudotuberculosis infections are 3 times more common in men than in women. However, the postinfectious complications of erythema nodosum and arthritis are more common in women.

Age

More than 75% of patients with Y pseudotuberculosis infection are aged 5-15 years.

Clinical

History

Symptoms caused by Y pseudotuberculosis infection include abdominal pain (often right lower quadrant location) and fever. Diarrhea is uncommon. Patients who develop the recently described syndrome of Izumi fever may develop additional systemic symptoms. Late complications of yersinial infection may include reactive arthritis and rheumatologic manifestations.

• Other clinical problems associated with the enteric form of Y pseudotuberculosis infection have included terminal ileitis and intussusception, especially in children. In two thirds of clinical cases, enterocolitis may result and generally lasts 1-3 weeks.
• Izumi fever, a syndrome, has been characterized by scarlatiniform rash, systemic symptoms, and features shared with Kawasaki disease (eg, coronary artery aneurysms). Acute renal failure has been reported, although very rarely.
• Other manifestations of infection may include erythema nodosum, arthralgias, reactive arthritis, and ankylosing spondylitis. Y pseudotuberculosis infection has also been documented to cause lumbar facet joint disease.¹⁰
• Far East scarlatinoid fever was first described in the context of Y pseudotuberculosis infection. A scarlatinoid-appearing rash involving the head and neck, upper and lower extremity erythema, mucous membrane enanthem, and strawberry tongue characterize this syndrome.
• In 1998, a single case report described culture isolation of Y pseudotuberculosis from a prostatic focus in a 55-year-old man. Although no obvious environmental factors were implicated in the clinical syndrome, the patient was treated successfully with a sulfa-based regimen of oral antibiotics.¹¹
• In 2006, Hadou et al reported on an abdominal aortic aneurysm infected by Y pseudotuberculosis in an elderly patient with underlying coronary heart disease.¹²
• As mentioned above, Y pseudotuberculosis infection has been associated with ingestion of contaminated food items, including fresh produce (eg, raw carrots), and has been known to cause gastroenteritis and erythema nodosum. Gastrointestinal illness should prompt an inquiry of food history and other persons who may have also been infected in case of an outbreak to document a potential point-source etiology.
• Although Y pseudotuberculosis is not generally considered an opportunistic pathogen, two recent reports have described fever and altered mental status due to Y pseudotuberculosis infection in immunosuppressed patients infected with HIV. These patients had underlying Y pseudotuberculosis sepsis without the typical gastrointestinal manifestations. Perhaps because of their low CD4 cell counts (<200 cells/µL), the presumed activation of T lymphocytes (particularly CD4) by YPM superantigens may have been blunted in these patients.⁶

Physical

Physical findings caused by Y pseudotuberculosis infection may be grouped into 3 main categories—systemic, enteric, and rheumatologic. The predominant and often self-limited presentation of Y pseudotuberculosis infection is that of a febrile gastroenteritis with right lower quadrant abdominal pain.

• Systemic findings may include fever, skin rash, strawberry tongue, hypotension, and lymphadenopathy.
• Enteric findings include abdominal tenderness with or without rebound indicative of peritoneal involvement. Tenderness may be exquisite over McBurney point.
• Rheumatologic involvement may include joint effusion, tenderness, or decreased range of movement and may be asymmetric in distribution.
• Erythema nodosum lesions (often erythematous indurated tender areas on the anterior surface of the lower extremities) may be found.
• A sporotrichoid pattern (lymphocutaneous spread) of disease has been associated with Y pseudotuberculosis infection.¹³
• Ophthalmic findings such as uveitis and conjunctivitis have also been reported.

Causes

The syndromes associated with Yersinia infections are primarily caused by ingestion or contact with the pathogenic species of Yersinia. The less-common species— Y enterocolitica and Y pseudotuberculosis —have been associated with enteric syndromes. Y pseudotuberculosis has several serotypes (I-VI); the O group, types I and II, are mainly responsible for infection in humans, with type 1 likely responsible for 80% of human disease. Cross-reactivity between bacterial proteins and host antigens plays a role in the development of reactive disease. Iron overload appears to have a significant role in the genesis of the septic variants of the disease.

The following are the major virulence factors associated with Y pseudotuberculosis (specific mechanisms of pathogenicity have not been fully elucidated):

• Yersinia species have several plasmid virulence factors encoded. More specifically, Y pseudotuberculosis has a 70-kd plasmid that encodes for a contact-dependent type III secretion system that delivers virulence factors known as Yersinia outer proteins (Yops). This mode of delivery is crucial for the pathogenicity of Y pseudotuberculosis. The major Yops include the following:
  • YopE enters host mammalian cells through a type III secretion system. It is a RhoGTPase-activating protein (RhoGAP) that targets the RhoGTPase activity of GTP-binding proteins. In various host cells, this RhoGAP catalytic activity of YopE has been shown to play a role in the disruption of actin filament arrangement, promotion of cell rounding, prevention of host cell membrane pores that would result because of entry of type III translocation machinery, and inhibition of phagocytosis. Additionally, YopE (along with YopH and YopJ) plays a role in dampening proinflammatory signals of the host cell by decreasing the production of interleukin-8. In contrast to wild-type Y pseudotuberculosis, A YopE- mutant form of Y pseudotuberculosis given orally to mice lacked the ability to colonize the spleen.
  • YopJ disrupts host cell functioning by binding to the superfamily of protein kinases, thereby blocking key phosphorylation steps. Ultimately, this process decreases the production of cellular interleukin-8 and tumor necrosis factor. YopJ inhibits nuclear factor-kappa B (NF-kB) and mitogen-activated protein kinase (MAPK) signaling pathways and promotes apoptosis in macrophages. YopJ works alongside YopE and YopH in the critical process of depressing proinflammatory signals by the host cell. YopJ is translocated into the host cell through a type III secretion system.
  • YopT is a virulent factor that is not found in all pathogenic strains of Y pseudotuberculosis. YopT is also translocated to the host cell through a type III secretion system. Like YopE, YopT plays a role in disrupting actin filament arrangement (thus also contributing to cell rounding) and preventing phagocytic activity by the host cell. The catalytic activity of YopT has been shown to be that of a cysteine protease.
  • YopH is a virulence factor that shares many of the roles described for YopE. YopH takes part in disrupting actin filament arrangement, decreasing the production of interleukin-8, contributing to cell rounding, and preventing phagocytic activity by the host cell. The tyrosine phosphatase activity of YopH is thought to contribute to the antiphagocytic and actin filament disruption roles. Like many other virulent Yops, YopH is translocated to the host cell by the type III secretion system.
• YopB is a protein that makes up part of the type III secretion system that is required to translocate many virulence factors of Y pseudotuberculosis. YopB is thought to trigger a proinflammatory signal from the host cell when the type III secretion system docks onto the plasma membrane of the host cell.
• YopD is another protein that makes up part of the type III secretion system. It has been shown to be an important component because YopD- mutants cannot accomplish translocation. Additionally, YopD is integral in the formation of pores on the host plasma membrane during the infection process.
• Another virulence factor is the superantigen YPM, an exotoxin. Superantigens are generally bacterial or viral classes of proteins that mediate immune system activation. YPM selectively stimulates T lymphocytes that have V beta–containing gene segments and induce excessive amounts of inflammatory cytokines. These appear to correlate with increased systemic symptoms. This is analogous to the role of superantigens in other diseases, such as Kawasaki disease and even staphylococcal and streptococcal toxic shock syndromes.
• Another group that mediates Y pseudotuberculosis pathogenesis is collectively known as adhesion molecules.
  • These proteins bind onto the host cell and facilitate the internalization of Y pseudotuberculosis into the host. Two major proteins in this group are invasin and yadA. Y pseudotuberculosis strains that have the Inv gene (which encodes invasin) have enhanced invasion properties for epithelial host cells. Invasin of Y pseudotuberculosis binds to integrins on the M cells of Peyer patches. These integrins also bind to collagen and fibronectin.
  • Invasin is also involved in promoting the internalization of bacteria across these eukaryotic M cells. The yadA outer membrane protein binds to laminin, collagen, and fibronectin that are themselves bound to their respective beta-1 integrin receptors on the cell surface. These binding interactions contribute to the processes of bacterial adhesion onto the host cell surface and bacterial internalization into the host cell.
• Another molecular mechanism of pathogenesis is the high pathogenicity island (HPI) of Y pseudotuberculosis. It contains the gene that codes for yersiniabactin, the important siderophore used for iron uptake. HPI is common among the highly pathogenic species of Yersinia. Furthermore, transfer of HPI genes to a biotype 2 strain of Y enterocolitica, which ordinarily displays low pathogenicity, has been shown to increase its virulence level. The significant role that pathogenic islands play in the virulence of a wide variety of infectious bacteria continues to be recognized.
• Another important mechanism of virulence is the Yersinia twin arginine translocation (tat) pathway, which is incorporated into the metabolism of gram-negative bacteria, leading to secreted proteins that are functionally important for motility and acid resistance. In addition, cytotoxic necrotizing factors (CNFs) are associated with Escherichia coli (CNF1) and Y pseudotuberculosis (CNFy) and are approximately 60% genetically homologous. Despite having different cellular receptors, the CNFs can lead to endothelial cell invasion and contribute to pathogenesis.

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