Bacterial Infections of Humans || Yersinia enterocolitica Infections

CHAPTER 44

Yersinia enterocolitica Infections

Ann M. Schmitz and Robert V. Tauxe

1. Introduction

Three bacteria of the genus Yersinia are recognized humanpathogens. Yersinia pestis is the cause of plague, a devas-tating epidemic disease transmitted from rodent reservoirsto humans by the bite of the flea. Y. pestis evolved fromYersinia pseudotuberculosis, a cause of epizootic disease inanimals and mesenteric lymphadenitis in humans, that canbe transmitted through contaminated food.(1) Yersinia ente-rocolitica, recognized as a cause of human illness aroundthe world, also causes intestinal infections and is transmittedfrom animal reservoirs through contaminated food. The var-ious strains of Y. enterocolitica form a heterogenous groupof bacteria that includes both well-established pathogens andnon-pathogenic environmental strains that are ubiquitous interrestrial and freshwater ecosystems. Only a few phenotypicvariants have been conclusively associated with human oranimal disease.(2–4) The principal pathogens for humans aremembers of a few serogroups (O:3, O:9, O:8, O:5,27). Otherstrains have been associated with important animal diseases,but the strains that cause human illness are carried asymp-tomatically in their animal reservoirs and differ from thosestrains that cause disease in animals.

Illness caused by Y. enterocolitica and Y. pseudotuber-culosis is referred to as yersiniosis. Y. enterocolitica is theetiologic agent of a range of clinical entities in humans,although acute enterocolitis is the most frequent manifes-tation. The bacterium also causes postinfectious sequelae,most notably reactive arthritis. Yersinia pseudotuberculosiscauses enteritis and pseudoappendicitis, and may also be

Ann M. Schmitz � University of Wisconsin, Madison, Wisconsin,53706, USA. Robert V. Tauxe � Division of Foodborne, Bac-terial and Mycotic Diseases, National Center for Zoonotic, Vectorborne,and Enteric Diseases, Centers for Disease Control and Prevention, Atlanta,Georgia 30333, USA.

transmitted through contaminated foods, and is only com-mon in northern Eurasia.(5) The present discussion will focuson Y. enterocolitica and its role in a variety of clinicalsyndromes afflicting humans.

2. Historical Background

A description of the organism now known asY. enterocolitica was first published in 1939, by researchersat the New York State public health laboratory, who reported“an unidentified microorganism resembling Bacterium lig-nieri and Pasteurella pseudotuberculosis and pathogenicfor man”, which they subsequently named Bacteriumenterocoliticum.(6) Similar organisms were reported by var-ious researchers in the following 20 years and given vari-ous names, including Pasteurella X, Y. pseudotuberculosistype B, B. enterocolitica, and Les Germes X.

Following widespread epizootics among chinchillas andhares and after the establishment of a causative relationshipwith lymphadenitis in man, and in 1964, Fredericksen pro-posed the species name Y. enterocolitica for this taxon.(7)

The species Y. pseudotuberculosis was distinguished fromY. enterocolitica at this time and has since emerged as animportant cause of infection in northern Russia and Finland,where it causes illness in hares and deer, as well as humanoutbreaks that have been associated with consumption offresh produce.(5,8)

In the 1970s, the organism was recognized worldwide,as improved methods of stool culture facilitated isolation ofthe organism. While better diagnosis as important, it alsoappears likely that a global dissemination of pathogenicstrains occurred at that time.(9) The recognized incidence ofthe infection in Belgium and in some other countries beganto increase dramatically.(10) Coincident with this heightened

A.S. Evans, P.S. Brachman (eds.), Bacterial Infections of Humans, DOI 10.1007/978-0-387-09843-2 44,C© Springer Science+Business Media, LLC 2009

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940 A.M. Schmitz and R.V. Tauxe

awareness, it became evident that the original biochemicalcriteria proposed for the species Y. enterocolitica encom-passed a heterogeneous group of bacteria. Many “Y.enterocolitica-like organisms” were described that differedsubstantially in their biochemical reactions, and severalbiotyping and serotyping schemes were proposed.(11–13)

DNA hybridization techniques finally divided this diversegroup of microbes into eight species with distinctbiochemical profiles: Y. enterocolitica, Y. frederiksenii,Y. kristensenii, Y. intermedia, Y. aldovae, Y. rohdei,Y. mollaretii, and Y. bercovieri.(14–16) “Y. ruckeri”, an eco-nomically important pathogen of farmed fish was proposedas a species in 1978.(17,18)

3. Methodology

3.1. Sources of Mortality Data

In developed countries, where most reported yersin-iosis cases occur, infection with Y. enterocolitica is rarelyfatal. Infection most commonly results in enterocolitis. Asfor many infections, the mortality associated with Y. ente-rocolitica can be difficult to determine, since mortality dataare often not collected in pathogen-specific surveillance,and death certificates tend to underreport many pathogen-specific conditions. Pathogen-specific case-fatality has beenreported in the active surveillance system, Foodborne Dis-eases Active Surveillance Network (FoodNet), in the UnitedStates,(19) and was included in an overall burden of illnessestimate.(20) In a registry-based study linking diagnosis withvital statistics in Denmark, the excess mortality followingdiagnosis of Y. enterocolitica infection could be comparedwith the mortality in the general population.(21) Syndrome-specific fatality rates for gastroenteritis, mesenteric adeni-tis, and terminal ileitis are not known; the few fatal casesreported for these clinical syndromes have been attributed tosevere complications such as intestinal ulceration and peri-tonitis. Extraintestinal manifestations of intestinal Y. ente-rocolitica infection are usually self-limited. Clinical diseasedue to septicemia, most often reported in children or adultscompromised by severe anemia, hemochromatosis, cirrhosis,malignancy, malnutrition, or immunosuppressive therapy, isassociated with higher rates of mortality. In one nosocomialoutbreak, a case–fatality ratio of approximately 50% wasreported in 13 patients with disseminated Y. enterocoliticainfection and a universal mortality in those with underly-ing hemochromatosis.(22) The complications resulting fromdisseminated infection, which include suppurative hepatic,renal, and splenic lesions, osteomyelitis, wound infection, ormeningitis, and from transfusion-associated yersiniosis, alsocarry a higher risk of death.

3.2. Sources of Morbidity Data

Many countries maintain surveillance systems to detectinfections and estimate burden of illness attributable to spe-cific pathogens, though reporting requirements may varysubstantially.(23) In the United States, Y. enterocolitica isnot nationally reportable and is reportable by law in only26 states.(24) In 1996 the Foodborne Diseases ActiveSurveillance Network (FoodNet) began active surveillancefor infection by Y. enterocolitica, and by other pathogensoften transmitted by foods, and now provides annualincidence data.(25) In other countries, such as Sweden,Finland, Ireland and New Zealand, yersiniosis cases arenationally notifiable. Since many clinical laboratories inmost countries do not routinely screen diarrheal stool spec-imens for Y. enterocolitica, it is likely to be underdiag-nosed and underrecognized by clinicians, and underreportedto surveillance. Lack of universal application of labora-tory techniques that favor its isolation, as well as incom-plete reporting of Y. enterocolitica isolates to public healthagencies, also limits the completeness of laboratory-basedsurveillance. Outbreak investigations can provide some addi-tional morbidity data.

3.3. Surveys and Investigations

Surveys of the relative frequency of Y. enterocolitica inpopulations with diarrhea have justified its inclusion as a bac-terial enteric pathogen of importance in some parts of theworld (Section 5.1). Studies in England and Australia haveestimated the pathogen-specific burden of foodborne diseaseincluding that caused by Y. enterocolitica.(26,27) Serologicalsurveys have been conducted in several European countries(reviewed in(28)). However, direct comparison of the resultsis difficult, since different subpopulations were studied andsince a variety of serological assays and antigens were used.

3.4. Laboratory Diagnosis

3.4.1. Isolation and Identification of theOrganism. Y. enterocolitica belongs to the familyEnterobacteriaceae.(29) It is a gram-negative, oxidase-negative, catalase-positive, nitrate-reductase-positive,facultative anaerobic rod that is typically 0.5–0.8 × 1–3 μmin size. Coccobacillary forms may be seen. It does not form acapsule or spores. Y. enterocolitica is nonmotile at 35–37◦Cbut motile at 25–27◦C, with relatively few, peritrichousflagellae. Some strains of serogroup O:3, however, arenonmotile at both temperatures. In addition, the bacteriumis urease-positive, ferments mannitol, and produces acid

Chapter 44 • Yersinia enterocolitica Infections 941

but not gas from glucose. Y. enterocolitica differs frommost members of the family Enterobacteriaceae by virtueof its slower growth in general and its ability to grow atrefrigerator temperatures.

Bacteriological isolation of the organism is by far themethod of choice for diagnosing Y. enterocolitica infection.The isolation and identification of the bacterium from nor-mally sterile sites like blood are not difficult using stan-dard bacteriological procedures. Recovery of the organismfrom stool, on the other hand, is hampered by the lack ofdistinctive colonial morphology as well as by the organ-ism’s slow growth and the resultant overgrowth of normalfecal flora. Several selective media have been developed toenhance the recovery of Y. enterocolitica from stool spec-imens. While routine enteric media can be used in expe-rienced hands, isolation is more easily accomplished oncefsulodin–irgasan–novobiocin (CIN) agar, a highly selec-tive medium used to recover Y. enterocolitica from stools.On this agar, Y. enterocolitica appears as 0.5- to 1.0-mmdiameter colonies with a dark red “bull’s eye” and transpar-ent border. CIN agar permits the growth of all pathogenicserogroups.(30) Two selective media, Salmonella–Shigella–deoxycholate–calcium (SSDC) agar and irgasan–ticarcillin–potassium chlorate (ITC) enrichment broth, have been spe-cially designed for isolation of O:3, the most commonserogroup.

The use of a cold enrichment step at 4◦C can facilitaterecovery of Y. enterocolitica when the bacterial density islow, such as in the convalescent phase of an infection. How-ever, this procedure may require incubation for weeks and islikely to lead to isolation of non-pathogenic strains, making itof little clinical use.(31) Isolates of Y. enterocolitica identifiedin this fashion must be further characterized before diagnos-tic conclusions are drawn.

Y. enterocolitica is quite heterogeneous with respect tophenotypic, genotypic, and ecological properties. The phe-notypic heterogeneity has enabled the development of sev-eral schemes for subdivision of the bacterium. Serogroupingaccording to O antigens and differentiation of biotypes onthe basis of biochemical properties have been the most use-ful typing methods. Y. enterocolitica has been divided intoapproximately 60 serogroups using O antigens.(13) SeveralO antigen groups may be further subdivided by H antigens.However, the use of H-antigen typing has been hampered byits variable expression and limited availability. The biotyp-ing scheme proposed by Wauters has been widely used; arevision was published in 1987.(32) In addition to serogroup-ing and biotyping, a number of phenotypic and genotypicmethods have been used to subdivide Y. enterocolitica. Thediscriminatory power of the genotypic methods may behigher for serogroup O:8 than for O:3, O:9, and O:5,27.(33)

Molecular subtyping as part of public health surveillance toimprove the detection of diffuse outbreaks has not yet beenimplemented in a routine way for Y. enterocolitica, as it hasbeen for Escherichia coli O157 and Salmonella in the USPulseNet system, though it is likely to be in the future.

In clinical and research laboratories, subtyping isimportant because Y. enterocolitica strains vary in theirability to cause disease, and many strains have no estab-lished pathogenic significance. Surveys of the environmentor of foods conducted without subtyping may identify manyY. enterocolitica strains that are of no public health signif-icance. Fortunately, the great majority of the strains thatcause illness in humans or animals belong to only a fewserogroups and biovars.(2) Somewhat simplified, Y. enteroco-litica may be divided into three groups according to clinicalsignificance: human pathogens, animal pathogens, and envi-ronmental strains, each with different serogroups. The mostimportant human pathogens are O:3 biovar 4; O:5,27 biovar2; O:8 biovar 1B; and O:9 biovar 2, though other serogroupsmay occasionally cause infection.

The strains that are pathogenic for animals include O:1biovar 3, responsible for widespread outbreaks in chinchillas;and O:2 biovar 5, associated with disease in hares, sheep,and goats.(34) The environmental strains include a spectrum ofphenotypic variants with a variety of other serogroups; mostbelong to biovar 1A. These bacteria usually lack human clini-cal significance. Such environmental strains have occasionallybeen involved in human infection, mainly in immunocompro-mised patients and patients with underlying conditions.

Y. enterocolitica may be differentiated from otherspecies of the genus by means of several distinct bio-chemical reactions, and other phenotypic differences. The“Y. enterocolitica-like organisms” include Y. frederiksenii,Y. kristensenii, Y. intermedia, Y. aldovae, Y. rohdei, Y. mol-laretii, and Y. bercovieri.(29) Such species are frequentlyencountered in terrestrial and freshwater ecosystems. Likethe environmental Y. enterocolitica strains, these specieshave not been associated with human or animal disease, withrare and atypical exceptions. Y. ruckeri, an important causeof illness in farmed trout, is not linked to human illness.(18)

3.4.2. Serological Diagnostic Methods. Serodiagno-sis has been developed for research purposes, but is not oftenused for routine diagnosis.(35) Infection with Y. enterocoliticaelicits an immunologic response that can be measured by avariety of techniques, including tube agglutination, indirecthemagglutination, enzyme-linked immunosorbent assay, andindirect immunoflurorescent-antibody assay. (36–38)

Agglutinating antibodies appear soon after the onset ofillness and persist for 2–6 months. Patients with systemicinfection produce a higher antibody titer than do persons withdisease restricted to the gastrointestinal tract.(35)


Cross-reactions complicate the serological diagnosis ofY. enterocolitica infection. Some of these are with other bac-teria. For example, Y. enterocolitica serogroup O:9 sharescross-reacting antigens with Brucella.(29) Antibodies to thy-roid hormone receptors, which are elevated in autoimmunehyperthyroiditis (Graves disease), have been described thatalso have a cross-reacting affinity to Y. enterocolitica anti-gens, though the bacteria play no role in thyroiditis.(39,40) Thedetection of antibodies by immunoblots to certain plasmid-encoded proteins, the Yersinia outer membrane proteins(Yops), has been suggested as a highly specific methodto demonstrate previous Y. enterocolitica infection.(41,42)

Demonstration of specific circulating IgA to the Yops isindicative of recent or persistent infection and is stronglycorrelated with the presence of virulent Y. enterocoliticain the intestinal lymphatic tissue of patients with reactivearthritis.(43)

4. Biological Characteristics of the Organism

Y. enterocolitica is psychrotrophic, which means itcan multiply at temperatures approaching 0◦C, and grow inproperly refrigerated foods.(44) This provides Y. enterocolit-ica with a competitive advantage over many other bacteriafor propagation in environmental reservoirs. The growth ofY. enterocolitica on cooked meats and in milk at low temper-atures is well documented. However, the presence of otherpsychrotrophic organisms in food may inhibit growth ofY. enterocolitica.(45,46) Y. enterocolitica can survive in frozenfoods for long periods.(44) Most virulent strains behave dif-ferently depending on temperature. At room temperature(25–27◦C), they express flagella and so are motile andexpress few virulence factors; while at 37◦C, most strainsare nonmotile, but express an array of virulence factors.(2,47)

This temperature dependence of biologic characteristics maybe important for survival of the organism outside of the hostand for pathogenesis in the host.

Y. enterocolitica is relatively iron dependent. Unlikemost other aerobic bacteria, most strains of Y. enterocolit-ica do not produce iron-binding compounds, or siderophores,and instead depend on siderophores produced by other bac-teria to capture the iron needed for growth. They are alsoable to use hemin as a source of iron.(48) Particularly severeinfections can occur in patients who already have condi-tions of iron overload, especially during treatment with ironchelators that mobilize body iron, and may make it moreeasily available.(49) Y. enterocolitica are also relatively cal-cium dependent, and most virulent strains require calcium-supplemented media to grow at 37◦C. It is thus not a great

surprise that outbreaks of yersiniosis are often traced to vehi-cles that are rich in calcium and iron and that are held refrig-erated and consumed cold.

The virulence of human pathogenic strains of Y. ente-rocolitica has been intensively studied and depends on avariety of molecules and mechanisms. Several of these aremediated by the virulence plasmid of approximately 70 MD,known as pYV.(50) The presence of the plasmid is tightlycorrelated with calcium-dependent growth at 37◦C. Simi-lar plasmids are also present in Y. pseudotuberculosis andY. pestis. Although many virulence determinants are encodedon the chromosome, the presence of the plasmid is an impor-tant marker for virulence. The same plasmid also carries agene for arsenic resistance, and it has been suggested thatthe widespread use of arsenicals in the past to treat swinedysentery and other infections of pigs may have selected forthe presence of the plasmid.(51)

Production of urease occurs at 25–27◦C. The action ofthis enzyme releases ammonia from urea that is present inthe mucous layer of the stomach, buffering local gastric acid-ity, and providing relative acid resistance.(52) Adherence andinvasion of the mucosal cells occurs via invasin and othersurface proteins that are chromosomally encoded.(53) Theorganism produces several additional proteins that enable itto escape host defense mechanisms, including phagocyto-sis and the bactericidal action of serum. Two such proteins,Ail (attachment invasion locus) and YadA (Yersinia adhesinA), are adhesins that also confer resistance to complement-mediated opsonization. The most complex of these viru-lence proteins are the plasmid-mediatedYersinia outer mem-brane proteins (Yops).(54) The Yops are not simple outermembrane proteins, but an extraordinary array of effec-tors that are produced in the bacteria, then secreted andinserted into host cells via a type III secretion system.(55)

The injector apparatus is assembled and armed on the sur-face of the bacteria at 37◦C, and the Yops are injectedon contact with the target cell. The injected Yops havean array of effects on the cells of the mammalian host.They rapidly paralyze phagocytes, block secretion of recruit-ment molecules such as TNF-alpha and IL-8, and appearto inhibit activation of macrophages.(55,56) The cumulativeeffect is that inflammation is suppressed and phagocytosisevaded. In addition, a few strains have genes for an iron-binding siderophore known as yersiniabactin, which can effi-ciently bind iron in iron-deprived sites, permitting continuedrapid growth.(57) Similar virulence mechanisms have beendescribed in Yersinia pseudotuberculosis.

While virulence factors for attachment and invasionexplain invasion and systemic infection, they do not bythemselves account for diarrheal illness. A better candi-date for that characteristic is a specific Yersinia heat-stable


enterotoxin, Yst, which is similar to the heat-stable entero-toxin of enterotoxigenic E. coli. This toxin is produced undera specific combination of temperature, pH, and osmolalityresembling that of the mammalian ileum.(58,59) It is foundalmost exclusively and universally in pathogenic strains ofY. enterocolitica.(60)

Not all strains possess all these mechanisms. Theso-called high pathogenicity island that codes for yersini-abactin and perhaps other virulence factors is present only inY. pseudotuberculosis and biotype 1B of Y. enterocolitica.(57)

Although in general, Y. enterocolitica biotype 1A has beenregarded as avirulent, some strains have been described thatappear to be enteropathogenic, though they lack pYV andother known virulence determinants.(61,62) It is likely thatmore virulence determinants remain to be identified.

A number of assays have been used to differentiatepathogenic and non-pathogenic variants. Most test for thepresence of the pYV plasmid, using such markers as autoag-glutination at 37◦C, calcium-dependent growth restriction at37◦C, resistance to the bactericidal activity of normal humanserum, binding of Congo red dye, ability to invade variouscell cultures, or by direct DNA sequence probing.(44,6364)

Autoagglutination and calcium-dependent growth have beenthe most widely used in vitro tests, though no singleproperty appears to be an absolutely reliable indicator ofthe pathogenic potential. The striking correlation betweenpotential pathogenicity and lack of pyrazinamidase activ-ity, independent of the occurrence of the virulence plasmid,makes this a useful test, which is included in the revisedWauters biotyping scheme.(32) One practical approach com-bines pyrazinamidase, calcium-dependence, Congo red dyeuptake, and phenotypic assays to screen for pathogenicstrains.(65)

5. Descriptive Epidemiology

5.1. Prevalence and Incidence

Y. enterocolitica infections were recognized in the 1970swhen global awareness increased and a widespread dissem-ination may have occurred with real subsequent increases inincidence.(9,66) In Belgium, Finland, Germany, New Zealandand Sweden, Y. enterocolitica surpassed Shigella to rivalSalmonella as a cause of acute bacterial gastroenteritis.Recently reported incidence varies substantially from coun-try to country, from <0.1 per 100,000 in France and Portugalto 13.6 per 100,000 in Lithuania (Table 1).

Several studies have estimated the overall burden of ill-ness due to yersiniosis, adjusting for likely underreporting.In an analysis based on FoodNet data, the reported inci-

Table 1. Annual Incidence of Yersinia Infections in SelectedCountries with Surveillance

Incidence rate per100,000

Country Year population Reference

Australia 2004 1.3 [79]Austria 2004 1.4 [80]Belgium (Flemish

Community)2004 4.8 [80]

Czech Republic 2004 4.9 [80]Denmark 2004 4.2 [80]Estonia 2004 1.1 [80]Finland 2004 13.1 [80]France 2004 <0.1 [80]Germany 2004 7.5 [80]Greece 2004 0.4 [80]Hungary 2004 0.7 [80]Ireland 2004 0.1 [80]Italy 2004 0 [80]Latvia 2004 1.1 [80]Lithuania 2004 13.6 [80]New Zealand 2005 10.9 [72]Norway 2004 2.2 [80]Poland 2004 0.2 [80]Portugal 2004 <0.1 [80]Slovakia 2004 1.4 [80]Slovenia 2004 1.9 [80]Spain∗ 2004 0.5 [80]Sweden 2004 9.0 [80]United Kingdom 2004 0.1 [80]United States 2005 0.36 [25]

∗Only hospitalized cases are reported.

dence of positive cultures in the time span 1996–1999 was0.8/100,000, but after adjusting for the proportion of labo-ratories that do not routinely seek the organisms that inci-dence was estimated to be 5/100,000 among those ill enoughto seek care and be cultured.(67) Broader approaches thatestimate the numbers of all illnesses, rather than just thosebeing cultured, arrive at substantially higher estimates. Itwas estimated that in 1997 in the United States, Y. entero-colitica caused 96,000 illnesses, 1,228 hospitalizations, and3 deaths, of which 90% was foodborne in origin, yieldingan estimated incidence of 36 per 100,000.(20) Using a simi-lar approach, Australian investigators estimated that in 2000,yersiniosis accounted for 2,200 infections and 34 hospital-izations, of which 75% was foodborne in origin, an esti-mated incidence of 115 per 100,000.(27) Using data derivedfrom reported foodborne outbreaks, English investigatorsestimated that the annual burden of yersiniosis in Englandand Wales, 1996–2000, was 129,000 cases of illness, 619hospitalizations, and 3 deaths, an estimated annual incidenceof 250 per 100,000.(67a)


The incidence of illness in a country may change impor-tantly over time. In Belgium, surveillance was started in1967(68) and documented an important increase in incidencein the 1970s.(10) Some of the early part of the increase mayhave been due to improved diagnosis and reporting, but muchof it appeared to be a real increase. The number of casesreported quadrupled from 305 cases in 1975 to 1,469 in 1986,an incidence of approximately 14.7 per 100,000, and thendeclined to 7.1 per 100,000 by 1996.(68) As in other Euro-pean countries, serotype O:3 was the dominant serotype, rep-resenting 79% of strains from 1967 to 1996, though this pro-portion dropped over time. Factors thought to play a role inthis increase included changes in the breeding practices ofswine, in slaughter methods that include trimmed tonsil meatin ground pork, and traditional food habits in Belgium whichinclude regular consumption of undercooked or raw groundpork.(69) Changes in slaughter practice to reduce contamina-tion of ground pork with tonsil tissues, and an education cam-paign about the hazards of raw pork may have contributed tothe decline. In the United States, the incidence of yersinio-sis tracked in FoodNet has decreased by 49% from 1996 to2005, for reasons that remain to be clarified.(25)

In New Zealand, infections due to Y. enterocolitica hasincreased since the late 1980s.(70) The frequency of isola-tion of Y. enterocolitica from specimens in the Aucklandarea rose from 0.2% in 1987 to 0.5% in 1989. The mostcommon serogroups seen at that time were O:3 ( 92%) fol-lowed by serogroup O:5/27 (4%) of isolates. In a studyconducted on stool samples collected in the Auckland area1988–1993, Y. enterocolitica was identified as the third mostcommon enteric pathogen isolated after Campylobacter andSalmonella.(71) Serogroup O:3 was most frequently recov-ered and there was no seasonal pattern. Since the 1990s, theincidence of yersiniosis in New Zealand has been one of thehighest in the world and was 10.9 per 100,000 in 2005.(72)

The reported proportion of acute diarrheal illness due toY. enterocolitica has varied depending on geographic loca-tion, time, population, and study. In one study conducted atthe peak of the Belgian epidemic, the percentage of rou-tine stool cultures yielding Y. enterocolitica of serogroupsO:3 and O:9 was as high as 2.5%.(73) In an early studyin Canada, Y. enterocolitica was isolated from 2.8% of thestools submitted at pediatric hospitals.(74) The frequency ofyersiniosis was greater than shigellosis (1.1%) and less thansalmonellosis (4.4%) and was most commonly associatedwith serogroup O:3. In a study of pediatric gastroenteritis inthe United States, conducted at the highest risk time of year,and in a city and population known to be affected, 76 (1%)of 7,290 stool cultures yielded Y. enterocolitica.(75) Studieswith lower yield have also been published. In a study inthe Netherlands, conducted in 1996–1999 to determine the

overall burden of enteric infections, 5 (0.5%) of 857 stoolsfrom diarrheic patients yielded Y. enterocolitica, but noneof the 5 were pathogenic serotypes, and the yield was nodifferent from the cultures of healthy controls.(76) Similarly,an exhaustive study of pediatric gastroenteritis recently con-ducted in Seattle in the United States found only 2 (0.1%) of1,626 stools yielded Y. enterocolitica.(77)

The yield of diagnostic culture may be higher in specificsyndromes. Several studies of patients with the appendicitis-like syndrome have found Y. enterocolitica in up to 9% ofpatients. In Belgium, the isolation rate of Y. enterocolit-ica from appendices removed for clinical appendicitis was3.8%.(73) In a report of 581 persons who underwent appen-dectomy for presumed appendicitis over a 1-year periodin Sweden, 22 cases (3.8%) had bacteriological evidenceof Y. enterocolitica infection.(78) Of those found to haveregional terminal ileitis at surgery, 80% were infected with Y.enterocolitica, as were 13% of those with mesenteric adeni-tis, and 0.5% of those with acute appendicitis. Althoughsometimes present in asymptomatic individuals, surveyshave found carriage rates of less than 1% in asymptomaticcontrols.(74)

The case–fatality rate reported for diagnosed cases ofY. enterocolitica infection in FoodNet was 0.77% for theperiod 2000–2004.(19) The crude 30 day excess mortalityreported from the Danish registry study was 0.14%.(21) Thesame investigators reported that the death rate was signif-icantly elevated out to 180 days after diagnosis even afteradjusting for underlying illness.

5.2. Epidemic Behavior and Contagiousness

Outbreaks of yersiniosis traced to specific sources areunusual, but illuminating (Table 2). It is curious that inrecent years, while both clinical awareness and public healthsurveillance for yersiniosis have been good and improving ina number of countries, very few outbreaks are reported. Forexample, in 2004, none were reported in Australia,(79) andonly two, affecting a total of eight persons were reported inNew Zealand.(72) In 2004 in Europe, a total of 51 outbreaksof yersiniosis were reported, affecting a total of 182 persons.However, for only two outbreaks was a source was reported,one of which was an outbreak of Yersinia pseudotuberculosisinfections in Finland affecting 58 persons.(80) The remain-ing outbreaks, affecting a mean of 2.5 persons each, werereported from Austria, Czech Republic, Denmark, Germanyand Portugal, and a source (raw ground beef) was identi-fied for only one. While few well-characterized outbreaksof enteritis due to Y. enterocolitica have been reported inEurope, several major outbreaks have been described in the


Table 2. Outbreaks of Y. Enterocolitica Infections with Identified Route and Vehicle of Transmission

Author Year published Location No. ill Mode of transmission/vehicle Serogroup Reference

Gutman et al. 1973 North Carolina (family) 16 Contact with sickpuppies?

O:8 [81]

Toivanen et al. 1973 Finland (hospital) 6 Nosocomial O:9 [109]Black et al. 1978 New York (school) 222 Chocolate milk O:8 [82]Aber et al. 1982 Pennsylvania (Brownie

troop)16 Bean sprouts

(contaminated bywater)

— [90]

Ratnam et al. 1982 Canada (hospital) 9 Nosocomial/(person-to-person?)

O:5 [105]

Morse et al. 1984 New York (summer camp) 239 Powdered milk or chowmein (contaminated byfood handler)

O:8 [84]

Tacket et al. 1984 Tennessee, Arkansas,Mississippi

>172 Pasteurized milk O:13,18 [83]

Tacket et al. 1985 Washington 44 Tofu (contaminated bywater)

O:8 [89]

Maruyama 1987 Japan (school) 1,051 Milk O:3 [91]Lee et al. 1990 Georgia 15 Indirect contact with

preparation ofchitterlings

O:3 [88]

Greenwood et al. 1990 United Kingdom(hospital)

36 Pasteurized milk O:10, O:6,30 [85]

Ackers et al. 2000 Vermont and NewHampshire

10 Pasteurized milk O:8 [87]

CDC 2003 Illinois 9 Contact with preparationof chitterlings

O:3 [115]

Jones 2003 Tennessee 12 Contact with preparationof chitterlings

O:3 [114]

Sakai 2005 Japan (nursery school) Cold mixed salad O:8 [93]

United States. The first of these was puzzling. In 1972,16 of 21 individuals from four linked families were affectedin rural North Carolina.(81) The outbreak resulted in twoexploratory laparotomies and two of the afflicted individu-als died, one following surgery. A serogroup O:8 Y. ente-rocolitica was isolated from the spleen of a fatal humancase, and eight others had serologic evidence of recent infec-tion. Although the source was not confirmed, five of ninenewborn puppies associated with one family had died withdiarrheal illness during the week before the first humanillness.

Food is the most common vehicle of transmission inoutbreaks of Y. enterocolitica infection. Several outbreaksinvolved commercial milk, which likely became contam-inated after pasteurization. The first of these occurred in1976, in upstate New York.(82) Illness occurred in 222 schoolchildren and employees, 38 of whom had documentedY. enterocolitica serogroup O:8 infection; 36 individ-uals were hospitalized and 16 appendectomies wereperformed. Illness was associated with the consumption

of chocolate milk purchased in the school cafeteria. Y.enterocolitica was subsequently isolated from a carton ofchocolate milk. As no defects in pasteurization were iden-tified, it was presumed that contamination occurred after-wards, possibly during introduction of chocolate flavor orvitamins.

In 1982, a multistate outbreak caused by serogroupsO:13 and O:18 caused illness in at least 172 persons; 17 indi-viduals underwent appendectomy and 24 cases of extrain-testinal disease were documented.(83) Illness was associatedwith drinking pasteurized milk from a Memphis, Tennesseeplant. Samples from the incriminated lots of milk were notavailable for culture. Again, no flaws in pasteurization wereidentified. A survey revealed that 8.3% of those who drankthe milk became ill; the attack rate was 22.2% in children0–4 years old and 38.5% in children 5–9 years old. In athird outbreak, 53% of persons at a camp experienced illnesscaused by Y. enterocolitica serogroup O:8, and the investi-gation showed that illness was associated with consumptionof reconstituted powdered milk and/or chow mein.(84) The


organism appeared to have been introduced by an ill foodhandler during preparation.

In 1985, a cluster of infections with Y. enterocoliticaserogroups O:10 and O:6,30, biovar 1 was identified in apediatric ward in Great Britain, and few of the childrenhad diarrhea or abdominal pain; culture of the feces of 34yielded one or the other serogroups.(85) The same strainswere isolated from pasteurized milk from a local dairy, deliv-ered to the hospital. Intensive investigation of the dairy indi-cated that although there was no defect in the pasteurizationitself, the organism could be recovered from freshly pasteur-ized milk from the bottle filling line, before it entered thebottles, though not from milk from a carton filling line; anidus of contamination in the bottle filling apparatus wassuspected.(86) In 1995, an outbreak of serogroup O:8 causedillness in 10 patients from Vermont and New Hampshire in1995.(87) Three of these patients were hospitalized and oneunderwent appendectomy. Consumption of pasteurized milkfrom a local dairy was significantly associated with disease.Y. enterocolitica was isolated from one raw milk sample andfrom a fecal sample from a dairy pig. As no defects in pas-teurization or filling apparatus were identified, it was sus-pected that the organism could have been transferred in somefashion from the pigs to the clean bottles waiting to be filled.

Pork is the most important source of sporadic casesof yersiniosis and has also been identified as the vehicle ofcommunity outbreaks. In the United States, an outbreak ofbacteremia and gastroenteritis was recognized in African-American infants in the winter of 1988–1989.(88) The infantswere all formula fed, but the formula was of a variety ofbrands and types, and so was unlikely to be the source of con-tamination. The ill infants had been cared for by persons whowere simultaneously preparing chitterlings, a dish of boiledpork tripe. In the course of preparation, Yersinia appears tohave been transferred from the raw tripe to the infants on theunwashed hands of the caregiver. Y. enterocolitica serogroupO:3 biovar 4 was isolated from 8 of 15 samples of raw porktripe, as well as from the patients. This outbreak heralded theemergence of this subtype in the United States.

Water may also be a source of contamination of foods.An outbreak of 44 Y. enterocolitica infections occurred inWashington between December 1981 and February 1982.(89)

Disease was associated with the ingestion of contaminatedtofu (soybean curd), and Y. enterocolitica serogroup O:8 wasisolated from afflicted individuals. Culture of the tofu, aswell as of the untreated spring water used in the tofu man-ufacturing plant, yielded the same serogroup, O:8. A secondoutbreak involved 16 of 33 (48%) members of a Brownietroop who were infected following the ingestion of beansprouts that had been grown in refrigerated water from a wellthat was shown to be contaminated with Y. enterocolitica;

15 of the children manifested gastrointestinal symptoms anaverage of 6 days following exposure and three underwentappendectomy.(90)

In Japan, epidemic Y. enterocolitica enteritis has beendescribed in communities and schools, but without epidemi-ologic or microbiologic implication of specific sources.(91,92)

One such outbreak occurred in 1972 in a Japanese junior highschool where acute abdominal pain and fever were presentin 198 of 1,086 pupils.(92) Y. enterocolitica serogroup O:3 wasisolatedfromthefecalspecimensof themajorityof ill children;however, a common source of contaminated food or water wasnot identified. In 2003, an outbreak affected 42 children at anursery school in Nara, 16 of which were confirmed by cul-ture as serogroup O:8, biovar 1B; the same strain was isolatedfrom a cold salad served to them the week before.(93)

It is noteworthy that sustained person-to-person trans-mission does not occur with yersiniosis. Rare nosocomialoutbreaks (described in Section 5.9) suggest that person-to-person transmission may have occurred, and thus that routineenteric precautions are warranted. The powdered milk out-break reported above suggests that an infected foodhandlermay be a source, again suggesting that routine foodhandlerprecautions are warranted.

5.3. Geographic Distribution

Y. enterocolitica has been isolated from humans in manycountries of the world but is found most frequently in coolerclimates. Yersiniosis is most commonly reported in north-ern European countries, or in New Zealand in the SouthernHemisphere, and is rarely reported in tropical countries.(66)

This distribution may reflect differences in frequency ofinfection in food animal reservoirs and in culinary practices,as well as more intensive surveillance and appropriate cultur-ing techniques in these areas.(94) The infrequent occurrenceof Y. enterocolitica in some areas of the world may be due inpart to culinary habits, such as avoidance of pork in Muslimcountries.

Differences in the distribution of the different serotypesof Y. enterocolitica isolated from humans appear to be dis-appearing. Serogroup O:3 biovar 4 is the most widespreadin Europe, Japan, Canada, Africa, North America and LatinAmerica. Serogroup O:9 biovar 2 is the second most com-mon in Europe, but its distribution is uneven; while itaccounts for a high percentage of the strains isolated inFrance, Belgium, and the Netherlands, only a few strainshave been isolated in Scandinavia.(95) The relative proportionSerotype O:8 was first reported in Europe in the mid-1980s,when a study in the Netherlands showed 25% of all infectionswere caused by serotype O:8.(37) Until the 1990s the most


frequently reported serogroups in the United States were O:8followed by O:5,27. In more recent years, serogroup O:3 hasbeen on the increase in the United States in both endemicand epidemic infections.(96) This suggests that the epidemi-ology of yersiniosis in the United States has evolved into apattern similar to the picture in Europe, where serogroup O:3predominates.

5.4. Temporal Distribution

A clustering of cases during the cold fall and win-ter months has been reported in some European countries,such as Belgium.(73) A similar seasonality has been reportedfor the frequency with which Y. enterocolitica is isolatedfrom swine and from pork, so the seasonality of infectionsin the swine reservoir may drive the seasonality of infec-tion in humans.(97–99) The association of Y. enterocoliticawith cooler seasons and temperate climates may be linkedto the organism’s ability to multiply at low temperatures (seeSection 4). In the United States, a study from the early 1990sdocumented a sharp increase in the number of cases in win-ter months (December, January, February).(75) More recently,this sharp winter peak in cases has recurred annually (SeeFigure 1).(67) In Australia, one study found that the peak iso-lation period for Y. enterocolitica from children was in thewarm months of December – March.(100)

5.5. Age

Although Y. enterocolitica causes a number of clinicalsyndromes that vary with the age, sex, and health of thehost, children appear to be preferentially affected. Of 359infected patients reported by Mollaret, 47% were between1 and 5 years of age.(101) Vandepitte and Wauters reported1,711 cases of Y. enterocolitica infection occurring in per-

sons less than 1 month to 85 years old; approximately20% of all cases occurred within the first year of life.(10)

Nearly 80% of patients were less than 10 years old. Inthe United States, the incidence of infection is greatest inthe age group less than 1 year old, among whom the inci-dence is 25/100,000, compared to 2.7 per 100,000 for chil-dren aged 1–4, 0.4 among persons aged 5–59 years, and0.5 per 100,000 among persons aged 60 or more.(67) In areview of 142 patients with stool cultures yielding Y. ente-rocolitica at a Children’s Hospital in the United States, themedian age of patients was 5 months with an age range of 18days to 12 years. Of these children, 85% were 12 months ofage or younger.(102) The illness most commonly associatedwith Y. enterocolitica in children less than 5 years old is afebrile diarrheal illness, indistinguishable from that causedby other enteric pathogens (see Section 8.1). Infants lessthan 3 months old with Yersinia enteritis are at greater riskfor bacteremia.(102,103) Children over 5 years old are morelikely to develop symptoms that mimic those of acute appen-dicitis. A dramatic difference in age-specific incidence wasnoted when patients with enteritis were compared with thosewith the appendicitis-like syndrome.(104) While 80% of allpatients with enteritis were less than 5 years old, those witha pseudoappendicitis syndrome were most frequently olderchildren and adults. Most extraintestinal manifestations ofY. enterocolitica infection, including the postinfectioussequelae, are more frequently found in adults than in chil-dren. In hospital outbreaks, it has been noted that the old andthe very young were more often infected and may be pre-disposed by age and physical condition, including immunestatus.(105)

5.6. Sex

In general, rates do not differ by sex. In most studies,males have slightly outnumbered females in all age groups of

0102030405060708090

100

Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun

Num

ber

of c

ases

Whites Blacks Other/Unk

Figure 1. Reported cases of yersiniosis, by month and ethnicity, FoodNet catchment area, United States, 1996–1999, adapted from [67].


patients with Y. enterocolitica diarrhea. For example, in oneBelgian study, the sex distribution of patients with Y. entero-colitica showed more males (54.7%) relative to females.(73)

Surveillance data in New Zealand for 2005 showed higherincidence in males (11.8 per 100,000) than females (9.4per 100.000).(72) In FoodNet, the rates for 2004 were 0.47per 100,000 in males and 0.39 in females, though theserations are reversed in other years.(19) The sexes tend to beequally affected in outbreaks of mesenteric adenitis. Ery-thema nodosum is seen more commonly in females.(106)

5.7. Occupation

The organism has been found frequently in samples fromswine in slaughterhouses, where it may readily be transferredto employees at all stages during slaughtering and processing(see Section 6). Seroepidemiological studies have indicatedthat occupational exposure to pigs is a risk factor.(107,108)

5.8. Race and Ethnicity

Race and ethnicity are important because they mayreflect differences in specific exposures. In the United States,the incidence of yersiniosis is low among whites (0.5 per mil-lion), whereas among African-Americans the incidence ofinfection is higher (3.4 per 100,000).(67) The highest ratesof all were seen African-American infants among whomthe incidence of culture-confirmed infections was 143 per100,000. The winter peak was largely driven by infectionsin the African-American population, probably because of theseasonal exposure to chitterlings (Figure 1). Rates of infec-tion have been shown to be lower in Muslim populations,which avoid pork.(69) In New Zealand, the highest rates ofinfection (20.8 per 100, 000) were reported among those ofethnic backgrounds other than European, Maori, and otherPacific Peoples, followed by those of European ethnicity (9.1per 100,000). The lowest rates were reported among Maori(4.9 per 100,000) and Pacific Peoples.(72)

5.9. Occurrence in Different Settings

Y. enterocolitica among hospital populations typicallyoccurs as sporadic illness and very rarely as outbreaks(Table 2). Some underlying health conditions, such as ironoverload and HIV infection, can predispose persons toyersiniosis. Excess iron favors growth and virulence of thisiron-dependent organism. The first nosocomial outbreak ofY. enterocolitica was reported from Finland in 1973 and

involved six hospital employees who became ill approxi-mately 10 days after a schoolgirl with Y. enterocolitica enteri-tis was admitted to their hospital. Spread of the infection,in this and other hospital outbreaks, appeared to be fromthe index patient to the staff and subsequently from per-son to person.(109) Another nosocomial outbreak occurredin Canada in 1980, in which nine patients in total wereidentified, some only by enrichment culture, with possi-ble transmission from the index patient through fomites.(105)

In a study of sporadic Yersinia infections in hospitalizedpatients conducted 1987–1990, it was reported that 5 of 18had developed diarrhea after being hospitalized for unre-lated conditions, and thus were likely to represent nosoco-mial infections.(110)

Outbreaks have been reported among children attendinginstitutions for collective care in eastern Europe, in whicha foodborne source was suspected, though not proven.(111)

A number of outbreaks have occurred in schools in Japan,without an identified source.(91)

5.10. Socioeconomic Factors

There is little published information suggesting thatsocioeconomic factors affect the occurrence of Y. enterocol-itica infection.

6. Mechanisms and Routes of Transmission

Y. enterocolitica can be transmitted through food, water,and occasionally by contact with animals. Rare transfusion-associated cases have also been reported. Transmission byperson-to-person contact is also rare. Foodborne transmis-sion is the most common route for sporadic infections andis predominantly associated with consumption of pork. Anepidemiological case–control study of sporadic yersinio-sis in Belgium documented the importance of consump-tion of undercooked or raw ground pork, often in the formof raw pork meatballs consumed informally in the kitchenduring food preparation.(69) In Norway, an epidemiologicalcase–control study showed that cases of yersiniosis werestrongly associated with eating undercooked pork andsausage products and that they generally preferred their meatto be either raw or rare, though very few reported actu-ally eating raw pork.(112) In New Zealand, an epidemio-logical case–control study of sporadic cases also showed astrong association with eating pork, though the extent ofcooking was not established.(113) In 1988–1989, as notedabove, an outbreak of infection due to serogroup O:3 amongAfrican-American infants in the United States showed that


preparation of raw pork intestines as a holiday food known aschitterlings by the infant’s caregiver was significantly asso-ciated with illness.(88) Since that outbreak, similar winterclusters have been investigated, with similar findings. Sur-veys in four cities in the winter of 1989–1990 identifiedclusters of infections around the holidays of Thanksgiving,Christmas, New Years, and Martin Luther King Day.(96) In2001, a cluster of 12 cases of Yersinia gastroenteritis inblack infants was investigated in Tennessee, all of whichwere exposed to preparation of chitterlings, compared toonly 35% of ethnicity and age-matched controls.(114) Expo-sure was often indirect, and was not necessarily through thecaregiver, leading the authors to recommend that chitterlingsbe routinely irradiated. A cluster of nine infants in Chicagowith Y. enterocolitica gastroenteritis were investigated in thewinter of 2002–2003; of these eight had exposure to chit-terlings, and serotype O:3 was isolated both from childrenand from chitterlings.(115) Raw pork contamination is partic-ularly likely for offal, and ground pork, and strains isolatedfrom pork are difficult to distinguish from those isolated fromhumans.(3,33)

Untreated drinking water can be another source of spo-radic yersiniosis. Consumption of untreated surface waterwas identified as a risk factor for infection with serogroupO:3 in the case–control study in Norway.(112) Similarly inNew Zealand, being connected to the town water supply wassignificantly protective, suggesting that drinking untreatedwater was associated with infection.(113)

Y. enterocolitica has been isolated from many domes-ticated animals and wildlife. Frequently these strains aredifferent from those that have been shown to infecthumans. Swine are frequently healthy reservoirs for strainspathogenic to humans, such as serotype O:3 and serotypeO:9. In a survey of swineherds conducted in 2000 in theUnited States, 3.8% of 2,793 fecal samples yielded Y. ente-rocolitica that were ail-positive, and of these 79% wereserotype O:3 and had the pYV plasmid.(116) The same surveyfound that at least one pig was positive on 47% of premisessampled. A survey of pigs at slaughter in Norway found12% positive for Y. enterocolitica serotype O:3, biotype 4,and a similar survey in Sweden found 8% positive.(117) InSweden, strains of Y. enterocolitica isolated from pork hadthe same pulsed-field gel electrophoresis patterns as thoseisolated from patients.(118) Dogs, cats, and rodents may occa-sionally be fecal carriers of serogroups O:3 and O:9, andapparent transmission from dogs and cats to humans has beenreported.(119) Rodents were identified as a possible source ofinfection with serogroup O:8 in Japan.(120)

Some of the most serious, though rare, cases of yersinio-sis have resulted from blood transfusions.(121) Ten such caseswere reported in the United States between 1991 and 1996

and cases have been reported in other countries as well.(121)

A prospective study conducted in the United States between1998 and 2000 showed that the incidence of transfusion-associated cases of Yersinia sepsis was 1 per 23.7 millionred cell transfusions.(122) Such cases typically follow trans-fusion of packed red cells that had been held refrigerated forseveral weeks after donation. It is presumed that the donorshad undetected bacteremia and that the bacteria had theopportunity to multiply during the holding time. Follow-ing experimental inoculation into packed red cells at 4◦C,Y. enterocolitica enter log phase growth in the third week andproduce high levels of enterotoxin by 28 days.(123) Just suchan asymptomatic bacteremia was detected in a blood donorvia routine screening, though the recipient, who was receiv-ing broad spectrum antibiotics at the time of transfusion, hadno ill effects.(124)

7. Pathogenesis and Immunity

Human infection with Y. enterocolitica is usuallyacquired by the oral route. The dose required to cause dis-ease in humans is unknown, though one volunteer becameill after consuming 3.5 × 109 organisms.(104) The incubationperiod typically averages 4–6 days in the outbreak setting.Following ingestion, enteric infection leads to proliferationof Y. enterocolitica in the lumen of the bowel and in thelymphoid tissue of the intestine.(44) Secretion of enterotoxinwhile in the lumen presumably is related to the onset of diar-rhea. In the terminal ileum, the bacteria enter the layer ofmucous on the gut surface and adhere to the luminal mem-brane of the enterocytes of the gut wall. Once they pene-trate and traverse the enterocyte, they show tropism for thegut-associated lymphoid tissue and multiply in the Peyer’spatches and mesenteric lymph follicles, causing a massiveinflammatory response. In a self-limited infection, the bacte-ria are then gradually eliminated. In some persons at higherrisk, particularly those with iron-overload syndromes, infec-tion can disseminate from the gastrointestinal tract throughthe portal vein to produce distant infections throughout thebody.

When the localized abdominal pain and fever suggestappendicitis, the patient may wind up on the operating table.The findings at surgery in patients with terminal ileitis aregrossly visible, and nearly pathognomonic of yersiniosis.They include extensive mesenteric adenopathy with mat-ted lymph nodes. When tissue is removed and examinedmicroscopically, the pathologist notes cellular infiltratesinclude lymphoid hyperplasia, epithelioid granulomas, andnecrotic suppurative lesions in which the gram-negativeorganisms are easily demonstrated.


Human infection with pathogenic strains of Y. ente-rocolitica stimulates development of specific antibodies.Although there is considerable evidence that both natural andexperimental infection can confer some degree of immunity,the degree to which it is serogroup-specific, and the preciseextent and duration of such immunity remain to be deter-mined. In mice, infection with plasmid-containing strains ofY. enterocolitica protects against subsequent challenge withYersinia pestis.(125,126)

The postinfectious syndromes appear to be related to theimmunologic response to the intestinal infection. The patho-genesis of reactive arthritis caused by Yersinia infection islikely to be related to an immune response to Yersinia anti-gens that cross-react with host antigens in susceptible per-sons. However, the nature of the putative inciting Yersiniaantigen has not been determined. Host tissue type is the pre-dominant co-factor; HLA-B27 is typically present.(127–129)

T-cells derived from the joint fluid of patients withreactive arthritis have been reported to selectively killHLA-B27-bearing cells that are also infected with Y.enterocolitica.(128) Patients with Y. enterocolitica-inducedreactive arthritis show a chronically elevated IgA level toa series of virulence-associated, plasmid-encoded proteins(Yops) that are produced by the bacterium.(41,42) Erythemanodosum, the other common post-yersiniosis sequel, doesnot appear to be associated with HLA-B27.(129)

8. Patterns of Host Response

8.1. Clinical Features

Y. enterocolitica infections in humans can range fromasymptomatic carriage to acute gastroenteritis to pseu-doappendicitis to a fatal and overwhelming sepsis, andvary with the host as well as with the infecting strain.(2,130)

Several organ systems may be involved with Y. enteroco-litica infection, either by directly or by immunologicallymediated mechanisms, and the clinical manifestations canmimic other more common diseases. Patients may presentwith gastroenteritis, mesenteric adenitis, terminal ileitis,reactive oligoarthritis, erythema nodosum, exudativepharyngitis, or septicemia and coincident complications.Extra-gastrointestinal infections present as osteomyelitis,meningitis, and pulmonary and intra-abdominal abscesses.Other less frequently reported syndromes include carditis,ophthalmitis, glomerulonephritis, hepatitis, pancreatitis, andhemolytic anemia.

Acute, uncomplicated gastroenteritis is by far themost frequently encountered manifestation, particularly inchildren.(74,103) Acute Yersinia gastroenteritis is marked by

diarrhea, abdominal pain, fever, and less frequently nauseaand vomiting. This syndrome resembles acute infection withother enteric pathogens, and is not readily differentiated clin-ically, though abdominal pain occurring with Yersinia infec-tion is often in the right lower quadrant, which is a diagnosticclue.

Symptoms of Y. enterocolitica enteritis typically persistfor 1–3 weeks, longer than those of other enteric bacterialpathogens, and occasionally may last for several months.

Tonsillitis is not uncommon in acute yersiniosis, beingreported by nearly 20% of patients in sporadic case series and22% in one outbreak.(69,83131) Y. enterocolitica was isolatedfrom throat cultures in 14 patients from this outbreak, illus-trating the propensity of the organisms to infect lymphoidtissue such as the tonsils.(132) Since no other cause of acutebacterial diarrhea routinely produces pharyngitis, this symp-tom can be helpful in suspecting the diagnosis.

The syndromes of mesenteric adenitis, terminal ileitis,or both are more likely in older children and adults(131) (seeSection 5.5). In these patients, diarrhea is less prominent,while findings of fever, right lower-quadrant pain, and leuko-cytosis often mimic those of acute appendicitis. The pseu-doappendicitis syndrome has been reported in 3–15% ofcases (see Section 5.1). While most cases are probably self-limited, the gut wall can be compromised and severe intesti-nal disease, small-bowel gangrene, and death have beenreported.

A variety of extraintestinal manifestations may accom-pany enteric infection with Y. enterocolitica. Since intesti-nal symptoms may be mild or asymptomatic, many patientspresent with syndromes that mimic a host of other non-enteric diseases, and thus present a diagnostic challengeto the physician. The most common extraintestinal formof Y. enterocolitica infection is reactive arthritis. A non-suppurative arthritis has been reported most frequentlyin persons of northern European descent. In Scandinavia,10–30% of adults with Y. enterocolitica infection developinflammation of the knees, wrists, or ankles a few days to1 month after the onset of diarrhea.(133) Cultures of syn-ovial fluid cultures are generally negative. Symptoms usu-ally resolve after 1–6 months but may become chronic insome patients.(134) The HLA B27 tissue type is a clearlydemonstrated co-factor.(127) Reactive arthritis, sometimesaccompanied by conjunctivitis and urethritis, as wellas chronic progressive ankylosing spondylitis have beendescribed in individuals with the HLA B27 antigen followingY. enterocolitica infection.(129,135)

Erythema nodosum occurs in up to 30% of Scandinaviancases, most of whom are women.(106) In the majority of cases,erythema nodosum resolves spontaneously within a month.This complication has not been linked to HLA type B27. The


causative agents of reactive arthritis and erythema nodosumbelong to serogroups O:3 or O:9. These manifestations havebeen relatively rare in the United States, an observation thathas been related to the geographic distribution of serogroups.However, an increase in cases with postinfectious manifes-tations of yersiniosis would not be unexpected, parallel tothe emergence of serogroup O:3 in the United States (seeSection 5.3).

Septicemia due to Y. enterocolitica is seen almost exclu-sively in infants or in individuals with underlying disease.(2)

Those with cirrhosis and disorders of iron excess are partic-ularly predisposed to infection and increased mortality. Thecases of septicemia and shock that follow transfusion withpacked red cells illustrate the severe nature of the infectionsin compromised recipients.(121) The blood donors for thesecases are typically asymptomatic, which means that asymp-tomatic bacteremia among health adults occasionally occurs.

Transient carriage and excretion of both pathogenic andnon-pathogenic Y. enterocolitica may occur following expo-sure to the bacterium. High rates of asymptomatic carriagehave been reported in connection with outbreaks.(89) How-ever, inapparent infection with Y. enterocolitica was detectedin less than 1% of individuals in large surveys.(78) In patientswith Y. enterocolitica enteritis, the organism may be excretedin low numbers in the stools for a long time after symptomshave resolved. In a study of Norwegian patients, convales-cent carriage of Y. enterocolitica O:3 was detected in 47% of57 patients.(131) In these persons, the organism was carriedfor a median of 40 days (range, 17–116 days).

Intestinal infection with Y. enterocolitica is usuallyself-limited and antimicrobial treatment is not routinelyneeded. Life-threatening sepsis, however, requires treat-ment. Antibiotic treatment has not been shown to shortenthe duration of acute gastroenteritis due to Y. enterocolit-ica. In a retrospective case series from Norway, treatmentwas not associated with a decreased duration of illness(18 days versus 21 days).(131) No clinical benefit was demon-strated in a small prospective, placebo-controlled trial oftrimethoprim–sulfamethoxazole in Canadian children.(136)

However, the organism rapidly disappeared from the stoolsin both studies. There is also no evidence that early antimi-crobial therapy reduces the frequency or severity of chronicsequelae.(137) Treatment of life-threatening infections withfluoroquinolones or third-generation cephalosporins hasbeen associated with a decrease in mortality.(138)

Y. enterocolitica have been shown to be sus-ceptible in vitro to aminoglycosides, chloramphenicol,tetracycline, trimethoprim–sulfamethoxazole, and third-generation cephalosporin antibiotics.(2,139,140) Most strainsproduce a β-lactamase, making them resistant to peni-cillin, ampicillin, and first-generation cephalosporins.(141)

The recent emergence of reduced susceptibility to fluo-roquinolones in Y. enterocolitica in southern Europe mayherald coming challenges to treatment of life-threateninginfections.(142)

8.2. Diagnosis

Diagnosis depends on isolating the organism from a clin-ical specimen, such as stool or blood. Y. enterocolitica can beeasily isolated from sterile sites with routine bacterial culturemethods The diagnosis of Y. enterocolitica gastroenteritisrequires a degree of clinical suspicion and specific consid-eration in the clinical laboratory, so that selective isolationmedia are used for stool culture (see Section 3.4.1). Ente-rocolitis caused by Y. enterocolitica cannot easily be differ-entiated clinically from acute infections due to other entericbacterial and viral pathogens.(2,131) However, Y. enterocol-itica infection can present with distinguishing features thatsuggest the diagnosis. Tonsillitis and localized right lower-quadrant abdominal pain are diagnostic clues. A recent his-tory of consumption of undercooked pork, drinking untreatedwater, or contact with pigs may suggest the diagnosis ofyersiniosis (see Section 6). The diagnosis should also be con-sidered when joint pains or erythema nodosum appears inpersons with previous diarrheal illness, recurrent diarrhea, orabdominal pain.

Serological diagnosis can be useful in research studiesto determine the role of Y. enterocolitica in postinfectioussyndromes and other late manifestations (see Section 3.4.2).Several limitations of serodiagnosis make it problematic foruse in clinical practice, including cross-reactions with otherbacterial species and the prevalence of seropositive individu-als in the healthy population.

9. Control and Prevention

9.1. General Concepts

Basic tenets of safe food production and preparation arecritical to preventing these infections. Preventive measuresthat reduce contamination and improve hygiene during allstages of pig and pork processing are essential to reduceinfection with serogroups O:3 and O:9. The organism maybe difficult to control at the farm level. At slaughter, rou-tine visual inspection will not detect the organism, as swineare healthy carriers of Y. enterocolitica, and bacteria fromthe oral cavity or intestinal contents may easily contami-nate the carcasses and the environment in the slaughterhouse.Improved hygiene at critical control points is needed, with


special attention during: (1) circumanal incision and removalof the intestines; (2) excision of the tongue, pharynx, andparticularly the tonsils which often harbor Yersinia; (3) meatinspection procedures that involve cutting into the mandibu-lar lymph nodes; and (4) deboning of head meat.(34,45,117)

Changes in slaughtering procedures, including technologicalimprovements, may be required to reduce contamination dur-ing these activities. Routine treatment of raw pork and rawpork products with electron beam irradiation would greatlydecrease infections arising from this route.(143)

Routine pasteurization of milk is another fundamentalprevention measure for yersiniosis and many other infec-tions. Milk-associated outbreaks of yersiniosis illustrate theneed for careful sanitation measures to prevent contamina-tion of milk after pasteurization, through contamination ofthe dairy environment and of empty containers before theyare filled with milk. Particular care is needed in dairies thatfeed pigs leftover “swill” milk, as the transit of milk cansto and from the pigs can connect milk production and pigpens.(83,87)

Preventive and control measures should also focus oninforming all people involved in production, procession,and final preparation of food about the importance of goodhygienic practices. Strict hygiene is particularly necessarybecause Y. enterocolitica is able to propagate at temperaturesapproaching 0◦C (Section 4).

The consumer can prevent infections through wise foodchoices and good kitchen hygiene. Infections can be pre-vented by not consuming raw unpasteurized milk, and rawor undercooked pork. Separating the two tasks of caring foran infant and simultaneously preparing raw pork intestines orother raw pork dishes can prevent illness in the infant.(88,114)

Y. enterocolitica is sensitive to chlorination, so propertreatment of drinking water should eliminate the risk ofinfection from this source.

Testing units of packed red cells for the presence ofbacterial endotoxin, and limiting the shelf-life of packedred cells may be helpful in preventing transfusion-associatedsepsis.(122)

9.2. Antibiotic and Chemotherapeutic Approachesto Prophylaxis

Antibiotic or chemotherapeutic approaches to prophy-laxis are not indicated.

9.3. Immunization.

Vaccines against Y. enterocolitica infections have notbeen developed. The high frequency of immune-mediatedcomplications of yersiniosis in humans has tempered enthu-siasm for such research. Attenuated strains have been used as

a means of delivering other antigens in experimental vaccinemodels.(144,145)

10. Unresolved Problems

Despite better understanding of the biological proper-ties of the organism and its unique geographic and envi-ronmental distribution, many questions about the ecology,epidemiology, and pathogenicity of Y. enterocolitica remainunanswered. In many parts of the world, its importanceis simply unknown. In New Zealand, a high incidenceremains unexplained. To date, the important declines in inci-dence in Belgium and the United States suggest that con-trol is certainly possible, though in the latter case the actualreasons for the decline are obscure. The development ofstandardized and approved laboratory methods is neededto allow optimal recovery of all pathogenic serogroupsand to provide adequate differentiation between pathogenicand non-pathogenic variants. Standardized practical molec-ular subtyping methods that allow better differentiationwithin species and serogroup are needed to assist in publichealth surveillance, outbreak detection, and epidemiologicalinvestigation.

Although considerable progress has been made in ourunderstanding of the routes of transmission and reservoirsfor Y. enterocolitica, well-designed epidemiological investi-gations, particularly case-control studies, are needed to iden-tify risk factors and determine their relative importance inendemic areas. Intervention studies are required to assess theefficacy of specific and nonspecific control and preventivemeasures to reduce colonization on the farm, contaminationat the slaughterhouse, growth during storage, and spread inthe kitchen. The strong association of the pathogenic strainswith the swine reservoir suggests that specific interventionsto immunize swine or otherwise reduce transmission amongpigs may offer benefits to human health.

Great strides have been made in our understanding atthe molecular level of the mechanisms by which Y. entero-colitica causes disease. However, further clarification of therole of the virulence determinants is needed. The evolution-ary links between Y. enterocolitica, Y. pestis, and Y. pseudo-tuberculosis suggest that this genus may offer more generalanswers to the questions about how pathogens evolve, howthey develop specific tissue tropisms, and how they becomeable to evade host immune response. All three share mam-malian hosts, an ability to infect via the gastrointestinal tract,and cross-protective antigens. The historical puzzle of theapparent resistance of some medieval European populationsto bubonic plague might be explained by cross-protectiondue to infections with other endemic Yersinia. The persistingclinical puzzles of human yersiniosis need to be unraveled,


including the role of iron in enhancing disease; the relation-ship of Y. enterocolitica to the immune system to produce adiversity of autoimmune phenomena; the potential benefit ofearly diagnosis and treatment; and the nature, efficacy, andduration of natural immunity.

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142. Capilla, S., Ruiz, J., Goni, P., Castillo, J., Rubio, M., Jimenez de Anta,M., et al. (2004). Characterization of the molecular mechanisms ofquinolone resistance in Yersinia enterocolitica O:3 clinical isolates.J Antimicrob Chemother, 53, 1068–1071.

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12. Suggested Reading

Cornelis, G.R. Yersinia Type III secretion: Send in the effectors. J Cell Biol-ogy 158:401–8 (2002).

Cover, T. L., and Aber, R. C., Yersinia enterocolitica, N. Engl. J. Med.321:16–24 (1989).

Ostroff, S.M. Yersinia as an emerging infection: Epidemiologic aspects ofyersiniosis. Contrib Microbiol Immunol 13:5–10 (1995).

Robins-Browne, R. M., Yersinia enterocolitica, Chapter 11 in: Food Micro-biology. Fundamentals and Frontiers , 2nd edition ,(M. P. Doyle, L.R. Beuchat, and T. J. Montville, eds.), ASM Press, Washington DC,2001.

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