INTRODUCTION — The genus Yersinia includes 18 species, three of which are important human pathogens: Yersinia pestis, Yersinia enterocolitica, and Yersinia pseudotuberculosis [1,2]. The yersinioses are zoonotic infections of domestic and wild animals; humans are considered incidental hosts that do not contribute to the natural disease cycle.
Y. enterocolitica and Y. pseudotuberculosis cause yersiniosis, a diarrheal illness. The epidemiology, microbiological characteristics, pathogenic determinants and laboratory isolation and characterization of Y. enterocolitica and Y. pseudotuberculosis will be reviewed here.
The clinical manifestations and treatment of these infections are discussed separately. (See "Clinical manifestations and diagnosis of Yersinia infections" and "Treatment and prevention of Yersinia enterocolitica and Yersinia pseudotuberculosis infection".)
Y. pestis causes plague and is discussed separately. (See "Epidemiology, microbiology and pathogenesis of plague (Yersinia pestis infection)" and "Clinical manifestations, diagnosis, and treatment of plague (Yersinia pestis infection)".)
EPIDEMIOLOGY
Reservoirs of infection — Y. enterocolitica strains have been isolated from a variety of vertebrate hosts, including domesticated animals as well as wildlife [3]. Healthy pigs are frequently colonized with strains that cause human illness, such as serotype O:3 and serotype O:9. In pigs, the organism colonizes the tonsils and other oropharyngeal lymphoid tissues; from these sites, it can be shed into the gastrointestinal tract. Y. enterocolitica in swine herds may spread as pigs are transferred from one pig farm to another and then can persist on a farm for many years [4]. The organisms can contaminate retail pork products, including neck trimmings, tonsillar tissue, tongue, and tripe, and can be transferred to other cuts of meat during slaughter [5,6]. Y. pseudotuberculosis has been isolated from a variety of mammals and birds. It causes epizootic disease in European brown hares in Northern Europe, sheep in Australia, and farmed deer in New Zealand [7-9].
Transmission — Transmission of yersiniosis is largely foodborne and occasionally waterborne (table 1). There are also reports of infection related to exposure to household pets [10] and transfusion of blood products [11,12].
Updated information on outbreaks may be found on websites maintained by the United States Centers for Disease Control and Prevention and the US Food and Drug Administration.
Pork consumption is a major mode of transmission for Y. enterocolitica. Case-control studies of sporadic illnesses in Belgium and Norway have noted a strong association between consumption of undercooked or raw pork products and yersiniosis [13,14]. In a Swedish study, strains of Y. enterocolitica isolated from retail pork had the same PFGE profiles as patient isolates [15]. In Norway and New Zealand, sporadic yersiniosis has been associated with drinking untreated surface water [14,16].
Yersiniosis has been associated with preparation of chitterlings, an ethnic winter holiday dish comprised of pig intestines [17-20]. This was first described during an investigation of bacteremia among bottle-fed African American infants in Atlanta, Georgia, in 1989 [18]. Illness was thought to occur as a result of cross contamination of infant bottles or formula during chitterling preparation.
Other outbreaks have been related to contaminated food sources other than pork [21-25], including tofu packaged in untreated spring water [21], post-pasteurization contamination of milk, and, in Norway, mixed salad with radicchio rosso [22-26]. In 2019, an outbreak in Denmark was linked to imported spinach that was also shipped to Sweden, where a simultaneous outbreak occurred; the same strain was identified in both outbreaks through whole-genome sequencing [27]. In one outbreak, an infected food handler was a suspected source of contamination [28], although, in general, direct fecal-oral person-to-person transmission has rarely been described.
In rare cases, Y. enterocolitica septicemia has been observed following transfusion with packed red cells [11]. Yersinia organisms are ferrophilic and capable of multiplying slowly in stored units of red cells at cold temperatures before they are transfused. In one prospective study conducted in 1998 to 2000, the incidence of transfusion-associated Yersinia sepsis was 1 in 23.7 million red cell transfusions [29]. The number of such infections could potentially be reduced by testing blood products for bacterial contamination and by reducing storage time [30]. (See "Transfusion-transmitted bacterial infection".)
Data on the transmission of Y. pseudotuberculosis are limited. Outbreaks have been associated with consumption of contaminated lettuce, carrots, and milk [31-35].
Risk factors — Risk factors associated with yersiniosis include consumption of undercooked or raw pork products, exposure to untreated water, blood transfusion, derangements of iron metabolism (such as cirrhosis, hemochromatosis, aplastic anemia, thalassemia, and iron overload), and other comorbid conditions (such as malignancy, diabetes, malnutrition, and gastrointestinal illness).
Individuals with thalassemia are at increased risk for yersiniosis, as patients with thalassemia can develop iron overload in the setting of red cell transfusion and the organism is ferrophilic. However, in one series of patients with thalassemia, severe yersiniosis was observed even when the iron burden was not greatly elevated; the reasons for this observation are not fully understood [36].
Incidence of disease — Sporadic yersiniosis has been observed worldwide. The incidence of disease around the world increased substantially in the 1970s [37]. It was reported frequently in northern Europe, particularly in Belgium, Norway, and the Netherlands; it is rarely observed in tropical countries [38]. The reasons for these geographic patterns are not clear but may reflect the underlying frequency of infection in food animal reservoirs.
In Europe, overall annual incidence was 1.8 cases per 100,000 in 2016 and was highest in Finland (7.4 per 100,000) and Lithuania (5.9 per 100,000) [39], with little change year to year. Incidence in Belgium peaked at 14.7 per 100,000 in 1986, subsequently declined by 2003 to 3.3 per 100,000, and was 3.1 per 100,000 in 2016 [38,40]. The majority of Belgian isolates have been serogroup O:3; 5 percent are serogroup O:9 [40]. In Norway, the incidence has also declined for reasons that may include a combination of public education efforts to reduce consumption of raw or undercooked pork products, changing dietary habits, and efforts by the meat industry to reduce contamination of carcasses during processing [41].
In the United States, the incidence of yersiniosis is lower than in Europe and has decreased since the 1990s, though it has been increasing as more diagnoses have been made using multiplex polymerase chain reaction (PCR) syndromic panels. Although the incidence of diagnosed yersiniosis reported to the Foodborne Disease Active Surveillance program (FoodNet) of the United States Centers for Disease Control and Prevention (CDC) had declined by approximately 59 percent from 1996 to 0.3 per 100,000 in 2015 [42], by 2019, the incidence had increased to 1.4 per 100,000 [43]. This increase likely reflects the greater frequency of testing with multi-pathogen syndromic panels [44]. Almost all yersiniosis in the United States is due to Y. enterocolitica; between 1996 and 2007, only 1 percent of reported yersiniosis was due to Y. pseudotuberculosis [45]. There is some geographic variation within the United States; in 2015, the highest incidence was in Oregon (0.5 cases per 100,000); the lowest was in Tennessee (0.1 cases per 100,000) [42]. Before 1990, the most common serotypes were O:5,27 and O:8; since 1990, O:3 and O:9 have predominated, as in Europe [17]. Accounting for underdiagnosis and under-reporting, the actual number of Y. enterocolitica infections occurring annually in the United States is estimated to be 117,000 [46]. Reported incidence did not change significantly in 2020 during the COVID-19 pandemic [47].
High and increasing rates of Y. enterocolitica infection have been described in New Zealand since the 1990s [48,49]. Incidence there was 24.1 per 100,000 in 2019 [50].
The incidence of Yersinia infections is highest in young children, although the age distribution may be changing in the era of multipathogen syndromic diagnostic panels. In Europe, in 2016, the incidence in children <5 years of age was 7.5 per 100,000 [39]. In the United States, between 1996 and 2009, children <5 years of age comprised 47 percent of Yersinia infections reported to the CDC's FoodNet program [51]. Over this time, the overall incidence among these children dropped from 9.2 to 1.9 per 100,000, and the most substantial decrease was among African American children <5 years old, in whom the incidence dropped from 41.5 per 100,000 in 1996 to 3.5 per 100,000 cases in 2009 (figure 1) [51]. As of 2015, there was little difference in overall incidence across racial or ethnic groups [42]. Yersiniosis is rare among observant Muslim individuals who do not consume pork [13].
Prevention — Basic tenets of safe food production and preparation are important for prevention of yersiniosis (www.foodsafety.gov) [41]. Education about hazards associated with consuming raw pork and changes in the slaughter process may have helped to diminish the incidence in Belgium and Norway [40,41]. Education about the importance of separating chitterling preparation and childcare tasks in the United States may have helped to lower rates among children [52].
Reducing the carriage of Y. enterocolitica in pigs has been proposed through the use of attenuated live Yersinia strains that induce cross-protective immunity [53]; this area requires further investigation. Reducing contamination of produce before and after harvest is an unsolved challenge.
MICROBIOLOGY — Members of the genus Yersinia are gram-negative coccobacilli; they are facultative anaerobes in the family Yersiniaceae (formerly part of the family Enterobacteriaceae) [54,55]. Like others in the family, Y. pseudotuberculosis and Y. enterocolitica are bile tolerant and grow on MacConkey agar, they ferment glucose but not lactose, they are oxidase negative, and reduce nitrate to nitrite.
Y. pseudotuberculosis and Y. enterocolitica are readily differentiated by biochemical tests. Y. enterocolitica ferments sucrose and Y. pseudotuberculosis does not, while Y. pseudotuberculosis ferments rhamnose and melibiose and Y. enterocolitica does not. Y. enterocolitica can be further subtyped into biotypes by a combination of phenotypic markers [56]. They can also be serogrouped using antisera produced against cell surface lipopolysaccharide antigens, known classically as the O antigens [56,57]. For Y. enterocolitica, biogroup and serotype are correlated. The most common are serotype O:9 biotype 2, serotype O:3 biotype 4 and serotype O:8 biotype 1B [58]. A similar serotyping system exists for Y. pseudotuberculosis. Both Y. enterocolitica and Y. pseudotuberculosis can be further subtyped using molecular methods such as pulsed field gel electrophoresis or whole genome sequencing.
Y. enterocolitica exhibits three noteworthy microbiological features. It is psychrophilic, which means that on suitable media it is capable of multiplying at refrigerator temperatures (although its optimum growth temperature is 25 to 28°C). Second, most strains lack efficient intrinsic iron uptake mechanisms, and depend on the iron binding strategies of other bacteria to capture the iron that they need [59]. Conditions associated with iron-overload such as chronic liver disease, hemochromatosis, and thalassemias have been associated with an increased risk of invasive yersiniosis [60]. Third, many virulent strains are relatively calcium dependent, and require calcium-supplemented medium to grow at 37°C.
Certain subtypes of Y. enterocolitica are considered virulent for humans [61]. Isolation of non-virulent types from a non-sterile body site is likely to be an incidental finding. Rapid tests can determine whether an isolate is likely to be pathogenic (see below).
Subtyping by serotyping and/or molecular methods is of epidemiological utility. Biotype and serogroup can provide a clue to the environmental source of an infection [3]. Detecting a cluster of infections of the same molecular subtype may indicate that the cases are linked to a common source.
Laboratory isolation — Definitive laboratory identification of virulent strains depends on isolation of the organism via bacteriologic culture. Most laboratories in North America do not routinely screen for Yersinia species, and the organism grows poorly on the Salmonella-Shigella and Campylobacter agars commonly used for the isolation of stool pathogens [57]. Yersinia grows well on MacConkey agar, but at routine incubation temperatures it forms small colorless lactose-negative colonies, which are easily overlooked by the inexperienced eye unless plates are specifically examined for them [57].
Selective growth medium is recommended in laboratories not familiar with the appearance of the colonies. The most widely studied is cefsulodin-irgasin-novobiocin (CIN) agar, which inhibits the growth of competing flora and produces a characteristic colony morphology (figure 2) [62]. The optimal growth temperature for Yersinia species is 25 to 28°C, which also inhibits the growth of other organisms, even on non-selective MacConkey agar. The organism can be isolated at this temperature within 24 to 48 hours. If a clinician specifically requests Yersinia culture, the laboratory will usually either use CIN media or reincubate the original MacConkey agar culture. CHROMagar Yersinia is reported to be more selective for pathogenic strains of Y. enterocolitica, while Y. pseudotuberculosis does not grow on it at all [63].
The use of a cold enrichment step at 4°C can facilitate recovery of Y. enterocolitica when the bacterial density is low, such as in the convalescent phase of an infection. However, this procedure is likely to lead to isolation of non-pathogenic strains, and may require incubation for weeks, limiting clinical use. Isolates of Y. enterocolitica identified in this fashion must be further characterized before diagnostic conclusions are drawn.
The use of multi-pathogen syndromic diagnostic panels for fecal specimens has expanded. In 2018, 68 percent of yersiniosis cases reported to the United States Centers for Disease Control and Prevention (CDC) Foodborne Diseases Active Surveillance Network were diagnosed using such culture-independent panels; approximately half of those positive specimens that were cultured yielded a Yersinia [44]. The performance of panels that include a Y. enterocolitica target is difficult to measure because of the rarity of infection [64-66]. Just as with culture of cold-enriched specimens, characterization of the pathogen isolate obtained from reflex culture of the original specimen will still be helpful to determine whether it is pathogenic or not. Reflex culture of specimens that test positive by nucleic acid amplification tests (NAATs) is recommended to help guide treatment and for public health surveillance [67]. Multi-analyte panels typically do not include Y. pseudotuberculosis targets and will not detect that pathogen.
In addition to biotype and serotype determination, several rapid tests have been developed to identify pathogenic strains. They are highly specific and sensitive for fresh isolates, although the virulence plasmid can be lost when strains are stored [68]. The presence of pyrazinamidase also is strongly correlated with virulence, and is part of the Wauters biotype schema [56]. Use of Congo red-magnesium oxalate agar (CR-MOX) facilitates detection of the virulence plasmid capable of binding Congo Red dye, and calcium dependent growth at 37 degrees [69]. Polymerase chain reaction (PCR) assays for the presence of specific chromosomal and plasmid-associated virulence determinants have also been used [70].
Serologic assays have been described and used in some epidemiologic studies, but are of limited clinical utility due to crossreactivity [71].
PATHOGENESIS — Pathogenic Y. enterocolitica pass through the stomach, adhere to gut epithelial cells, invade the gut wall, localize in lymphoid tissue within the gut wall and in regional mesenteric lymph nodes, and evade the host's cell-mediated immune response. A 70 kilodalton virulence plasmid known as pYV has been associated with pathogenic Y. enterocolitica. Variants of this plasmid are also present in Y. pseudotuberculosis and Y. pestis, and the presence of the plasmid is closely correlated with calcium-dependency [72]. The organism’s capacity to produce urease releases ammonia from urea, which buffers local gastric acidity and provides relative acid resistance [73]. Adherence and invasion of the mucosal cells occurs via invasin and other surface proteins [74].
The organism elaborates additional proteins that allow it to evade host defense mechanisms, including phagocytosis and the bactericidal action of serum. Two such proteins, Ail (attachment invasion locus) and YadA, are adhesins that also confer resistance to complement-mediated opsonization. The most complex of these additional proteins are the Yersinia outer membrane proteins (Yops), which are encoded by a 70 kilodalton virulence plasmid [75]. The presence of this plasmid is an important virulence determinant, although some pathogenic strains that lack the virulence plasmid have been described.
The Yops are not simple outer membrane proteins, but an extraordinary array of effectors that are injected into host cells via a type III secretion system [76]. The injector apparatus is assembled at 37 degrees, and injection occurs on contact with the target cell. The injected Yops rapidly paralyze phagocytes, block secretion of recruitment molecules such as TNF-alpha and IL-8, and appear to inhibit activation of macrophages [76,77]. The cumulative effect is suppression of inflammation and evasion of phagocytosis.
Some Y. enterocolitica strains have genes for an iron-binding siderophore known as yersiniabactin, which can efficiently bind iron in iron deprived sites, permitting continued rapid growth of Y. enterocolitica biotype 1B [78]. Similar virulence mechanisms have been described in Y. pseudotuberculosis.
The expression of many of these virulence characteristics is temperature dependent [3]. At 25°C, the organism is motile and expresses urease and inv, while at 37°C the organism is non-motile but other virulence factors are expressed [79]. This temperature dependence may be important for survival of the organism outside of the host and for pathogenesis in the host.
A specific Yersinia heat-stable enterotoxin Yst has been described which is similar to the heat stable enterotoxin of enterotoxigenic E. coli [80,81]. Yst is secreted under temperature, pH, and osmolality conditions similar to that of the mammalian ileum [80,81].
A distinct strain of Y. pseudotuberculosis associated with the Far East Asia scarlet-like fever syndrome produces a superantigen, Y. pseudotuberculosis-derived mitogen A, that likely plays a role in the pathogenesis [82].
Y. enterocolitica biotype 1A has generally been regarded as avirulent, although some strains have been described that are clearly enteropathogenic even though they lack pYV and other known virulence determinants [61,83]. Therefore, it is likely that more virulence determinants remain to be identified.
Immunologic sequelae — The pathogenesis of reactive arthritis caused by Yersinia infection is likely to be related to an immune response to Yersinia antigens that cross-react with host antigens in susceptible individuals. The putative inciting Yersinia antigen has not been determined. Host tissue type appears to be the predominant co-factor; HLA-B27 is typically present [84]. T-cells derived from the joint fluid of patients with reactive arthritis have been reported to selectively kill HLA-B27–bearing cells that are also infected with Y. enterocolitica [85]. Although biotype 1A is usually regarded as avirulent, it may lead to reactive arthritis [86].
Erythema nodosum has also been reported in association with yersiniosis; it does not appear to be associated with HLA-B27 [87].
SUMMARY
●Epidemiology
•Incidence – Yersinia enterocolitica and Yersinia pseudotuberculosis cause yersiniosis, a diarrheal illness. Illness due to Y. enterocolitica is more common than illness due to Y. pseudotuberculosis. Overall, Y. enterocolitica infection occurs more frequently in Europe than in North America; it is rarely observed in tropical countries. (See 'Incidence of disease' above.)
•Reservoirs of infection – Y. enterocolitica strains have been isolated from a variety of vertebrate hosts, including domesticated animals as well as wildlife. Healthy pigs are frequently colonized with strains that cause human illness. In pigs, the organism colonizes the tonsils and other oropharyngeal lymphoid tissues; from these sites, it can be shed into the gastrointestinal tract. The organisms can contaminate retail pork products including neck trimmings, tonsillar tissue, tongue, and tripe and can be transferred to other cuts of meat during slaughter. (See 'Reservoirs of infection' above.)
•Transmission – Transmission of yersiniosis is largely foodborne. Pork consumption is a major mode of transmission; other outbreaks related to food contamination have also been reported. In rare cases, Y. enterocolitica septicemia has been observed following transfusion with packed red cells. Yersinia organisms are ferrophilic and capable of multiplying at cold temperatures prior to transfusion. (See 'Transmission' above.)
•Risk factors – Risk factors associated with yersiniosis include consumption of undercooked or raw pork products, exposure to untreated water, blood transfusion, derangements of iron metabolism (such as cirrhosis, hemochromatosis, aplastic anemia, thalassemia, and iron overload), and other comorbid conditions (such as malignancy, diabetes, malnutrition, and gastrointestinal illness). (See 'Risk factors' above.)
•Prevention – Basic tenets of safe food production and preparation are important for prevention of yersiniosis (www.foodsafety.gov). In particular, it is important to separate the task of preparing raw pork from that of caring for an infant. (See 'Prevention' above.)
●Microbiology
•Microbiology – Y. enterocolitica exhibits three noteworthy microbiological features. It is capable of multiplying at refrigerator temperatures (although its optimum growth temperature is 25 to 28°C); many strains lack efficient intrinsic iron uptake mechanisms, and virulent strains require calcium-supplemented medium to grow at 37°C. (See 'Microbiology' above.)
•Laboratory isolation – (see 'Laboratory isolation' above):
-Yersinia grows well on MacConkey agar, but at routine incubation temperatures it forms small colorless lactose-negative colonies, which are easily overlooked unless plates are specifically examined for them. Selective growth medium is recommended in laboratories not familiar with the appearance of the colonies. The most widely studied is cefsulodin-irgasin-novobiocin (CIN) agar, which inhibits the growth of competing flora and produces a characteristic colony morphology (figure 2). After initial isolation, additional characterization may be helpful as some Y. enterocolitica are likely to be non-pathogenic.
-Rapid diagnosis of Y. enterocolitica infections is available on commercial multiplex polymerase chain reaction platforms, but these can detect avirulent as well as virulent strains. Culture and further characterization of isolates can assess virulence.
●Pathogenesis - Pathogenic Y. enterocolitica pass through the stomach, adhere to gut epithelial cells, invade the gut wall, localize in lymphoid tissue within the gut wall and in regional mesenteric lymph nodes, and evade the host's cell-mediated immune response. They can evoke reactive immune phenomena, including reactive arthritis and erythema nodosum. (See 'Pathogenesis' above.)
