Yersiniosis: a forgotten mimicker and confounder of Crohn’s disease

Yersinia is a facultative anaerobe and gut-derived Gram-negative bacterium of the genus Enterobacteriaceae. Three species of Yersinia are pathogenic to humans: Yersinia (Y.) enterocolitica, a disease of increasing medical concern with plenty of diagnostic and therapeutic challenges; Y. pseudotuberculosis, the cause of rodenciosis (a zoonosis); and Y. pestis, the cause of plague, also known as the Black Death [1, 2]. According to the WHO classification, yersiniosis is defined as a disease caused by either Y. enterocolitica or Y. pseudotuberculosis.

Aleksander Yersin first described the Y. pestis bacterium in 1944. Since then, other researchers have undertaken investigations, particularly at times of epidemics, which led to establishment of a new Yersinia genus with subdivisions of species. This classification was based on molecular DNA hybridization techniques and finalized by Brenner et al. in 1976 [3].

Seventy serologic groups of Y. enterocolitica species have been identified so far [4]. In Poland, the predominant pathogenic serotype is 0:3 [5]. Yersinia contains the DNA genetic code and virulence plasmid pYV responsible for synthesis of YadA protein, which has adhesive and invasive properties, secretory Yersinia outer proteins (Yops), and the effector protein Ysc [6, 7]. The high-pathogenicity island 1 protein is involved in synthesis of the siderophores responsible for rapid bacterial growth and virulence [8]. Yersinia has developed several self-defense mechanisms. First, the bacterium is resistant to high temperatures, including boiling point. Therefore, cooked meat, for example, remains an infectious reservoir of bacteria. Second, Yersinia is resistant to low pH, so can survive in the acidic environment of the stomach and pass through to infect the lower parts of the gastrointestinal tract. Of note, Yersinia secretes A and B beta-lactamases, so is resistant to penicillin and first-generation cephalosporins [9]. Moreover, Yersinia thrives at temperatures between 0°C and 45°C. Therefore, the bacterium can survive and reproduce in household refrigerators. However, the optimal temperature to support the life cycle of Yersinia is 22–29°C [10, 11].

Y. enterocolitica and Y. pseudotuberculosis can exist in all climates but are most abundant in temperate regions. Yersinia spp. are natural habitants of soil, water, plants, and, most frequently, the digestive tracts of animals. The most important and largest natural reservoir are pigs, cattle, goats, and geese, followed by foxes, dogs, and birds.

The infection in humans is triggered by consumption of contaminated food or water. Yersinia bacteria are often found in household appliances, particularly refrigerators, which are a common source of contamination [10, 11, 12, 13]. At low temperatures, Yersinia produces a heat-stable enterotoxin that is resistant to high or boiling temperatures. Humans are frequently found to be carriers and to present with asymptomatic bacteraemia. Some authors have reported cross-infection between humans via blood transfusion or dialysis [1, 10, 14].

Yersinia enters the digestive tract in food and releases lipopolysaccharide, which acts as a heat-stable enterotoxin. Once in the digestive tract, the bacteria interact with gut-associated lymphoid tissue via expression of surface adhesion and virulence proteins and enter Peyer’s patches. Intracellular bacteria then proliferate and trigger colitis and/or translocate to lymph nodes, causing reactive lymphadenitis. The rate and scope of these processes depend on the species of Yersinia and its serotype. Yersinia is rarely a cause of sepsis [2, 7, 15, 16, 17].

The clinical picture depends on the bacterial serotype and the age, comorbidities, and immune status of the patient. Yersinia enterocolitica can manifest as acute or subacute, and less frequently as chronic infection. There have been some reports of sporadic familial or endemic infections [9, 10]. The incubation period is several days (usually 3–7). Patients with acute infection present with diarrhea, abdominal pain, and fever but rarely with vomiting. There is usually a short history of symptoms and infected individuals are often initially diagnosed to have viral gastroenteritis, food poisoning, or Crohn’s disease [9, 10, 18, 19].

On physical examination, there is palpable abdominal tenderness and a palpable mass in the right lower abdomen with loud and vivid peristalsis on auscultation. On occasions, Y. enterocolitica, like Crohn’s disease, can mimic acute appendicitis with the presence of a positive Blumberg sign [20, 21, 22]. Extraintestinal disease involves the joints, with signs of redness, edema, warmth, and limitation of joint movement because of stiffness. The large joints are most frequently involved but not symmetrically. Rarely, inflammation of the palmar interdigital and sacroiliac joints is observed [10].

In young children (aged 5–7 years), the disease manifests as gastroenteritis. Watery diarrhea, abdominal pain, and fever (up to 39°C) are common [21, 23]. These symptoms are self-limiting and do not require medical attention. Dehydration due to severe diarrhea might require hospital admission [24]. However, death from Yersinia infection is rare and reported mostly in neonates [11]. The disease can also lead to hepatosplenomegaly and lymphadenopathy and mimic neoplastic disease [25].

Teenagers and adults develop more complex disease and present with a range of symptoms. Watery bloody diarrhea might complicate the disease, along with diffuse abdominal pain located in the middle and right abdomen and a fever of 40°C. Ileocecal involvement may manifest as lymphadenopathy with positive peritoneal signs. Lower right abdominal pain without diarrhea might guide physicians towards a diagnosis of acute appendicitis (the peri-appendiceal sign). Patients with similar symptoms are often referred acutely for surgery with a diagnosis of acute and purulent appendicitis with associated abdominal lymphadenitis and peritoneal fluid [9, 10, 20, 21, 22, 23, 24]. Disease with ileocecal involvement frequently mimics Crohn’s disease. The presence of gastrointestinal and extraintestinal symptoms accompanied by endoscopic findings similar to those found typically in Crohn’s disease frequently mislead physicians in their diagnosis. An incorrect choice of treatment in these situations could have serious consequences for patients.

Untreated yersiniosis can result in chronic infection, which most frequently manifests as seronegative peripheral arthritis with no other symptoms [26]. Approximately 20% of Y. enterocolitica infections are associated with skin lesions manifesting as gangrenous pyoderma or nodular erythema. Other lesions involving skin and connective tissue could also be present. There are case reports of pharyngitis, pneumonia, meningitis, liver and spleen abscesses, inflammation of bone marrow, osteitis, and urinary tract infections [10, 11, 27].

The most severe form of Y. enterocolitica infection is sepsis [11]. Asymptomatic carriers are a potential source of infection. In cases of bacteremia, the course of the disease is sudden with formation of metastatic abscesses, frequently requiring admission to hospital and broad-spectrum antibiotic therapy. Despite intensive care, approximately 20% of patients with severe infection will die [8].

Pathogenic strains of Y. pseudotuberculosis cause symptoms that resemble those of Y. enterocolitica [1, 10]. However, there are some differences. Unlike adults, children and teenagers (aged 6–18 years) may develop mesenteric lymphadenopathy [28]. Colitis is of mild intensity. Extraintestinal manifestations, such as purulent arthritis, osteitis, spleen and liver abscesses, and pneumonia, occur infrequently. Sepsis and other generalized infections are rare in patients with chronic comorbidities, such as liver cirrhosis, diabetes mellitus, and hematologic disorders. A lymphoma-like appearance has also been reported. The most common source of Y. pseudotuberculosis infection is iatrogenic spread via blood transfusion or dialysis. Of note, patients infected with Y. pseudotuberculosis can develop a scarlet fever-like rash and gastrointestinal symptoms with polyarthritis and high fever [1, 10, 11, 28].

Symptomatic disease is more common in individuals with the HLA B27 haplotype. Approximately 10–30% of patients with arthritis are HLA B27-positive.

A number of biological samples, including blood, urine, stool, cerebrospinal fluid, pus, periarticular fluid, and pharyngeal swab, can be used for detection of Yersinia infection [1, 10, 11]. The diagnostic test of choice is stool analysis, which is performed using cefsulodin-irgasan-novobiocin agar [9, 11, 29]. Yersinia is difficult to detect using simple or routine microbiological medium. In practice, microbiological diagnostic tests are performed at 37°C, the threshold at which other microorganisms thrive and overgrow Yersinia, which confounds the diagnosis [9]. In order to preserve the biological material for correct diagnosis, it should be kept at 4–8°C immediately after drawing. The incubation period is 48 hours at 22°C, after which the bacteria are seeded on MacConkey agar to identify the pathogenic strain. Identification is based on detection of pYV Yersinia plasmid on Congo red-magnesium oxalate agar [30, 31]. The pathogenic strains can be identified as tiny red colonies. Nonpathogenic strains form beige-colored large colonies. The mean time required for the diagnostic procedure should not be longer than 7–10 days [1, 10], but depends on the type of test used.

Following infection, IgM, IgA, and IgG antibodies form in the plasma. Serologic tests and immunoassays (enzyme-linked immunoassay and immunoblot) are the methods of choice. Presence of Yersinia outer proteins (Yops) (less frequently, lipopolysaccharide as a source of somatic antigen O) are used as a diagnostic target. Yop is present only on the surface of pathogenic strains and its detection reflects present or past infection. False-positive tests are possible because of antigenic cross-reactivity with other bacteria (other Yersinia spp., Escherichia coli, Salmonella spp, Brucella spp, Morganella spp). The presence of IgM antibodies is a sign of recent infection; these are replaced in time by IgG antibodies. Patients with chronic disease and extraintestinal manifestations (arthritis) should be investigated for the presence of IgA and/or IgA plus IgG [1, 10, 11, 32, 33].

The length of time over which plasma levels of immunoglobulins are measurable depends on the type of Yersinia and the patient’s age and immune status. When the clinical manifestations are mild, plasma IgM levels could be low or under the threshold of detection; however, in severe cases, IgM levels could be high for up to several months. Other IgG and IgA plasma antibodies circulate over a longer time. The presence of plasma IgA is most frequently associated with additional symptoms, such as migratory arthritis or pyoderma gangrenosum. Dynamic serologic tests should be repeated after 14 days to assess the disease. The rationale for the diagnosis is a rapid rise or fall in plasma antibodies (minimum 4× of the basic levels) [9, 10, 11].

Another technique now frequently used is MALDI-TOF mass spectrometry, which has been introduced as a rapid, accurate, and inexpensive method for diagnosis of bacteria according to specific protein profiles. It is currently replacing standard biochemical characterization in an increasing number of clinical microbiology centers [33, 34].

Molecular techniques based on DNA hybridization, polymerase chain reaction (PCR), and sequencing are available for detection of Y. enterocolitica and Y. pseudotuberculosis species, targeting the yadA or virF gene located on the pYV plasmid. Nevertheless, current reports indicate that molecular tests may soon outcompete standard diagnostic tests. For example, Leli et al. successfully developed a multiplex gastrointestinal polymerase chain reaction (PCR) panel for diagnosis of Y. enterocolitica in patients with infectious diarrhea [34]. Valledor et al. documented the importance of implementing a real-time PCR technique in a clinical algorithm because it allowed for better accuracy and a shortened time to diagnosis in comparison with routine clinical methods [35].

A full blood count could reveal leucocytosis or microcytic anemia, and laboratory investigations could show other biochemical abnormalities (elevated C-reactive protein and erythrocyte sedimentation rate, iron deficiency). Moreover, the patient could have manifestations of malabsorption, and stool examination might reveal the presence of blood and leucocytes.

Imaging studies are useful for clinical diagnostic purposes. An ultrasound examination of the abdomen may detect enlarged mesenteric lymph nodes and signs of intestinal inflammation, such as wall thickening, in the ileocecal region [36]. Ultrasound findings should be confirmed by colonoscopy. The differential diagnosis includes Crohn’s disease, other infectious diseases such as tuberculosis or salmonellosis, and autoimmune disorders leading to terminal ileitis, such as Behcet’s disease [37].

The endoscopic picture resembles that of Crohn’s disease, namely edema of the granular mucosa, aphthous and ulcerative lesions, and sometimes strictures and narrowing of the colonic lumen. However, there are some differences. In a case series of patients with yersiniosis, Matsumoto et al. found that the lesions were most commonly located in the terminal ileum, ileocecal valve, and cecum (similar to Crohn’s disease) and that the most typical findings were round or oval mucosal elevations with or without small ulcerations [37]. This is in contrast with the typical manifestations of Crohn’s disease, in which longitudinal and serpiginous ulcerations forming a cobblestone pattern can be found [37]. There are also some rare case reports in which yersiniosis manifested as a tumor (with liver metastases), a perianal ulcer, or massive rectal bleeding [38, 39, 40]. Histopathological examination rarely adds anything of diagnostic value. The presence of a variety of inflammatory cells could be microscopically identified as giant cell granuloma in both Crohn’s disease and yersiniosis. Microscopic analysis of a postsurgical specimen is helpful in differentiation; unlike in Crohn’s disease, Yersinia infiltrates are detected mainly at the mucosal surfaces. Figures 1 and 2 show the endoscopic findings in Crohn’s disease and Figures 4 and 5 present an endoscopic picture of Y. enterocolitica infection. The differential diagnosis of both diseases is presented in Table 1.

Fig. 1

Fig. 2

Fig. 3

Fig. 4

Treatment of Y. enterocolitica depends on the clinical picture, including severity of infection and presence of extraintestinal manifestations. Mild forms of the disease manifesting with diarrhea and abdominal pain of short duration are most frequently self-limiting and do not require treatment. Dehydration complicating the course of the disease might require rehydration and admission to the hospital. The presence of bacteremia associated with high fever might require antipyretic drugs, rehydration, and broad-spectrum antibiotics [9]. Given that Yersinia secrete A and B beta-lactamases, a combination of antibiotics should be prescribed, for example a fluoroquinolone plus an aminoglycoside, a fluoroquinolone plus a third-generation cephalosporin, or a third-generation cephalosporin plus an aminoglycoside [5, 41, 42]. The duration of antibiotic treatment should be 10–14 days. Treatment of mild forms of yersiniosis is controversial, with the statement of no treatment to fluoroquinolones alone [1, 10]. Treatment of yersiniosis caused by Y. pseudotuberculosis is more efficacious and straightforward because this bacterium does not produce beta-lactamases. Therefore, treatment with ampicillin (or one of its derivatives), an aminoglycoside, a fluoroquinolone, and a tetracycline is advocated [43]. Surgery is reserved for complicated cases.

Diagnosis of Yersinia infection is not straightforward but should be included in the differential diagnosis in patients with abdominal symptoms and extraintestinal manifestations. Misdiagnosis of yersiniosis as Crohn’s disease can result in incorrect or delayed treatment followed by debilitating complications. It is important to note that the differential diagnosis is not simple because Yersinia is frequently found in inflammatory and non-inflammatory areas of the ileum in patients with Crohn’s disease [44]. Several medical aspects need to be considered, including when to reassess the patient after antibiotic therapy, when to repeat diagnostic tests including colonoscopy, and when to introduce immunosuppressive therapy in relation to ongoing or completed antimicrobial treatment. These medical uncertainties are heightened by the concept that Y. enterocolitica may induce inflammatory bowel disease, given that approximately 11% of patients with new-onset Crohn’s disease also had Y. enterocolitica infection [45]. Therefore, medical practitioners should always be aware of Y. enterocolitica infection and keep it in mind in patients with new onset or aggravation of abdominal symptoms who have been diagnosed or are suspected to have Crohn’s disease.