—  SPECIALTY CONFERENCE  —

Infectious Disease Pathology

Case 3 - Gastrointestinal Yersinia Enterocolitica Infection

Laura W. Lamps, Univ of AR/Medical Sciences, Little Rock, AR





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Clinical History
The patient is a 12 year old boy with a several month history of vomiting and abdominal pain. He did not complain of diarrhea. Upper GI series showed an ileal stricture. Upper endoscopy was normal. Colonoscopy showed a normal colon; the ileum could not be intubated due to the stricture. The patient underwent a segmental resection of the ileum and right colon.


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Introduction:
This case illustrates the characteristic features of gastrointestinal Yersinia infection, and this infection may closely mimic Crohn's disease.

Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
Sections of the right colon, ileum, and appendix showed large areas of ulceration grossly, with thickening of the wall of the bowel and an ileal stricture just proximal to the ileocecal valve.

Microscopic sections showed broad areas of ulceration as well, along with prominent lymphoid tissue, transmural lymphoid aggregates in a linear pattern, and epithelioid granulomas. The granulomas were associated with prominent lymphoid tissue, and extended transmurally into the subserosal fat. Special stains for AFB and GMS were negative. A research PCR test for Yersinia enterocolitica was positive.

Differential Diagnoses:
The major differential diagnoses for Yersinia infection include other infectious processes, particularly Mycobacteria. The negative AFB stain and the lack of caseous necrosis is evidence against mycobacterial infection, and PCR for mycobacteria can also be useful. Other causes of granulomatous inflammation in the GI tract, such as sarcoidosis, should also be considered (see Case Discussion below).

Crohn's disease is the major entity in the differential diagnosis in this case. Yersinia infection is usually a self limited process with no further sequelae for the patient, although it can sometimes cause chronic gastrointestinal disease. Both Crohn's and yersiniosis may show very similar histologic features, including transmural lymphoid aggregates, skip lesions, and fissuring ulcers. Features that may favor Crohn's include cobblestoning of mucosa and creeping fat grossly, and microcsopic changes of chronicity including marked crypt distortion, thickening of the muscularis mucosa, pyloric metaplasia, and prominent neural hyperplasia. Some cases are indistinguishable on histologic grounds alone. This particular case showed focal neural hyperplasia, but no pyloric-type metaplasia or marked crypt distortion. Interestingly, upon clinical follow-up, this adolescent patient was initially treated on and off based on the clinical presumption of Crohn's disease, and did fairly well although he was still symptomatic.

Interestingly, he did best during the times that he was empirically treated with antibiotics for presumed overgrowth of bacteria in the small bowel. He was eventually lost to follow up.

Final Diagnosis:
Gastrointestinal Yersinia enterocolitica infection

Case Discussion:
Yersinia is one of the most common causes of bacterial enteritis in Western and Northern Europe. It has a worldwide distribution; the incidence of infection is rising within both Europe and the United States, although this may be due to better methods of detection and wider recognition of Yersinia as important enteric pathogens. Y. enterocolitica (YE) and Y. pseudotuberculosis (YP) are the two species pertinent to human gastrointestinal disease.

Yersinia infection can be transmitted by both food and water, and the bacteria are associated with meat, dairy products, chocolate, poultry, and produce. Pork-related infection has been particularly well documented. Infection also can be acquired from animals, albeit rarely. Yersinia has a preference for cold temperatures, thus there is a natural affinity for refrigerated food, and there is speculation that infection is more common in cooler months. Familial, hospital-acquired, transplacental, and transfusion-associated infections also have been well-documented.

These Gram-negative coccobacilli cause appendicitis (primarily granulomatous), ileitis, colitis, and mesenteric lymphadenitis. Infection with either species may cause symptoms and signs of an acute abdomen, chronic abdominal pain, and diarrhea. Although yersiniosis is usually a self-limited process, chronic infections (including chronic colitis) and persistent abdominal pain have been well documented. Risk factors for serious infection include immunocompromise or debilitation, diabetes mellitus, and cirrhosis. Iron overload and desferoxamine therapy are also a risk factor for yersiniosis; iron is an essential growth factor, but these bacteria lack siderophores to capture iron, thus they are dependent upon siderophores synthesized by other bacteria or administered therapeutically (desferoxamine) or an iron-rich environment. Complications of gastrointestinal Yersinia infection include sepsis, abscess formation, perforation, and obstruction from inflammatory masses.

Infants, children, and young adults are most commonly infected. Patients commonly present with diarrhea (variably bloody), abdominal pain (which may be diffuse, periumbilical, or right lower quadrant), nausea, vomiting, and weight loss. Fever, pharyngitis, and leukocytosis may be present as well. Symptoms often have been present for weeks to months, leading to a misdiagnosis of chronic idiopathic inflammatory bowel disease. Reactive polyarthritis and erythema nodosum are also associated with Yersinia infection.

Yersinia is harbored in meats, poultry, milk, eggs, and water, and colonizes many domestic pets and farm animals. Pathogenic Yersinia strains are thought to invade the mucosa of the intestine and multiply within Peyer's patches and the regional nodes to which they drain. Further spread is hematogenous. It is postulated that in some patients organisms can survive for extended periods of time within Peyer's patches, leading to chronic yersiniosis.

Yersinia preferentially involves the ileum, right colon, and appendix, although any area of the bowel can be affected. Involvement may be segmental or patchy. Grossly, involved bowel has a thickened, edematous wall with nodular inflammatory masses centered on Peyer's patches. Aphthoid and linear ulcers may be seen, along with mucosal friability, edema, and loss of vascular pattern. Exudates are variably present. The macroscopic findings may mimic chronic idiopathic inflammatory bowel disease, particularly Crohn's disease. Involved appendices are enlarged and hyperemic, similar to nonspecific acute suppurative appendicitis, and perforation is common. Involved lymph nodes may show gross foci of necrosis.

The inflammatory pattern in yersiniosis is variable. Both suppurative and granulomatous patterns of inflammation may be seen, and a mixture of the two is common. YE typically features epithelioid granulomas, along with hyperplastic Peyer's patches and overlying ulceration. Caseous necrosis is rare, but some cases (particularly YP infection) show granuloams with central microabscesses, often accompanied by mesenteric adenopathy. There is significant overlap between the histological features of YE and YP infection, however, and either species may show epithelioid granulomas with prominent lymphoid cuffing, lymphoid hyperplasia, transmural lymphoid aggregates, mucosal ulceration, and lymph node involvement. The transmural inflammation, fissuring and/or aphthoid ulcers, focal architectural distortion, presence of skip lesions, and granulomas may closely mimic Crohn's disease. Some patients show only an "acute self-limited/infectious colitis" type pattern.

Involved mesenteric lymph nodes often show follicular hyperplasia with scattered microabscesses and epithelioid granulomas. Nonspecific reactive lymphoid hyperplasia without microabscesses or granulomas is also a frequent finding in infected patients.

Culture is the mainstay of diagnosis, although Yersinia may be very difficult to culture in patients who are not bacteremic. If yersiniosis is suspected, pharyngeal culture may also be helpful, since the organism can cause pharyngitis and persist in the lymphoid tissue of this area for some time. As above, successful culture also requires cold enrichment. Serologic studies may also be helpful if there is a marked elevation in titer. However, there is significant cross-reactivity with other organisms, as well as problems with false negativity in immunocompromised patients, the elderly, and young children. Molecular detection by PCR works very well, and can be performed out of paraffin blocks, but is not widely available. Gram stains are usually not helpful for the diagnosis of Yersinia, since the organisms are small, hard to detect, and almost impossible to distinguish from other enteric flora.

The differential diagnosis primarily includes other infectious processes and Crohn's disease. Acid fast stains, mycobacterial PCR, and the presence of a positive PPD help distinguish Yersinia infection from mycobacterial infection. Granulomas are unusual in Salmonella infection, and stool cultures are invaluable in yielding a diagnosis of salmonellosis. Sarcoidosis, foreign body reaction to fecal material, and granulomatous inflammation secondary to delayed (interval) appendectomy with antibiotic therapy are also in the differential diagnosis of Yersinia-associated granulomatous appendicitis. Lymphogranuloma venereum and cat scratch disease may affect the mesenteric lymph nodes and produce similar histologic features, but these organisms (especially cat scratch disease) only rarely involve the bowel itself.

Crohn's disease and yersiniosis may be extremely difficult to distinguish from one another. In addition to the gross and microscopic similarities, Yersinia DNA has been detected in many cases of longstanding Crohn's disease; however, the significance of this remains unclear. Features favoring Crohn's disease include fistula formation, cobblestoning of mucosa, presence of creeping fat, and histologic changes of chronicity including marked crypt distortion, thickening of the muscularis mucosa, pyloric metaplasia, and prominent neural hyperplasia. However, some cases are simply indistinguishable on histologic grounds alone.

Isolated granulomatous appendicitis, in the past, was frequently interpreted as representing primary Crohn's disease of the appendix. However, patients with granulomatous inflammation confined to the appendix rarely (less than ten percent) develop generalized inflammatory bowel disease.

Review of the Literature/Treatment Options :
Most gastrointestinal Yersinia infections in immunocompetent patients are either self-limited, or resolve with a course of oral antibiotics. Debilitated patients, patients with iron overload, or those in whom the infection has disseminated may require intensive supportive care and IV antibiotics. Occasionally surgery is indicated for bowel obstruction or GI bleeding. Cases of Yersinia-associated granulomatous appendicitis usually present similarly to nonspecific acute appendicitis, and thus proceed to appendectomy. Usually no further treatment is indicated for these patients.

Conclusion(s):
Yersinia infection of the GI tract should be considered when the histologic features described above are present, especially in the context of a patient who 1) has an atypical presentation for Crohn's disease, especially if symptoms are of acute onset (although it is important to remember that intestinal yersiniosis can also be a chronic process); 2) has ingested food associated with Yersinia infection preceding the illness 3) has granulomatous appendicitis; and/or 4) has features suggestive Crohn's disease, but something is odd, such as numerous granulomas, lack of features of chronicity, or lymph nodes with numerous granulomas. The distinction between Crohn's disease and yersiniosis is very important, since the treatment, natural histories and chronic sequelae of the two diseases are so different.

Since the distinction may be impossible to make on histologic grounds alone, ancillary tests such as stool culture, PCR, and serologic studies should be used to help clarify the diagnosis.

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