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Inflammatory bowel disease associated with Yersinia enterocolitica O:3 infection
European Journal of Internal Medicine 16 (2005) 176 – 182 www.elsevier.com/locate/ejim
Original article
Inflammatory bowel disease associated with Yersinia enterocolitica O:3 infectionB Arve Saeboa,*, Einar Vikb, Ove J. Langec, Ludwig Matuszkiewiczd a Department of Surgery, Molde Hospital, N-6407 Molde, Norway Department of Microbiology, Molde Hospital, N-6407 Molde, Norway c Department of Internal Medicine, Molde Hospital, N-6407 Molde, Norway d Department of Pathology, Molde Hospital, N-6407 Molde, Norway b
Received 24 May 2004; received in revised form 18 October 2004; accepted 4 November 2004
Abstract Background: Certain microorganisms may be associated with the development of inflammatory bowel disease (IBD). These pathogens may possess such properties as immunological capability or tissue invasiveness. An association between Yersinia enterocolitica infection and ulcerative colitis (UC) was suggested 30 years ago, and a connection with Crohn’s disease (CD) may also exist. The aim of this study was to further elucidate the association between Y. enterocolitica O:3 infection and IBD. Methods: During the period 1990 – 1997, antibody response against Y. enterocolitica was estimated in 1588 patients by tube agglutination. Forty-one patients with Y. enterocolitica infection (titer = 320) constituted the study group; 1041 patients without antibody response constituted the control group. The study was completed in 2003, after 6 – 13 years. Results: At diagnosis of Y. enterocolitica infection, UC of acute onset was demonstrated in three males; another suffered from CD. At follow-up, two additional patients had developed UC and two CD. In the control group, 32 patients were diagnosed as having UC and 10 CD. This difference in IBD prevalence is significant (8/41 > 42/1041, p = 0.00035), as were the differences in prevalence of UC and CD separately ( p = 0.006; viz. p < 0.015). Conclusion: The present study supports the concept of the Y. enterocolitica infection as a trigger of chronic IBD. D 2005 Elsevier B.V. All rights reserved. Keywords: Crohn’s disease; Colitis; Ulcerative; Granulomatous disease
1. Introduction There is circumstantial evidence that certain microorganisms are associated with inflammatory bowel disease (IBD), possibly by launching an inflammatory response, and subsequently persist in a non-culturable form still capable of stimulating the immune system. These pathogens may possess such a property as immunological capability or tissue i Reports from the present study have previously been presented as short posters (but not published as abstracts) at: 1. 9th. United European Gastroenterology Week, Amsterdam, October 6 – 10, 2001; 2. 8th. International Symposium on Yersinia, Turku, September 4 – 8, 2002. * Corresponding author. Kviltorpvegen 26, N-6419 Molde, Norway. Tel.: +47 71 21 23 97. E-mail address: [email protected] (A. Saebo).
0953-6205/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2004.11.008
invasiveness. However, even normal intestinal flora may play a role in the continuity of inflammation in Crohn’s disease (CD). Subjects who develop IBD may have impairments, such as a defective mucosal barrier to luminal antigens, or a dysregulated immune response to common antigens [1 –5]; HLA-B27 histocompatibility may play an important determining role [6]. Ulcerative colitis (UC) and CD are heterogeneous disorders of multifactorial etiology [6]. Among other microorganisms, Shigella dysenteriae, Salmonella species, Campylobacter jejuni, and Yersinia enterocolitica have been implicated as possible causative agents of UC [3]. An acute intestinal infection sometimes precedes the first attack [7,8]. Y. enterocolitica [9], Mycobacterium paratuberculosis, Listeria monocytogenes, and paramyxovirus (measles) have been studied in association with CD [10].
A. Saebo et al. / European Journal of Internal Medicine 16 (2005) 176 – 182
The aim of this clinical follow-up study was to further elucidate the association between Y. enterocolitica O:3 infection and the development of IBD.
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antibody titer of 640 was recorded in the case of a male who had suffered from CD for 8 years. Among 18 other patients with acute infection, 10 presented with diarrhea and 6 with steatorrhea (voluminous stools floating on water).
2. Material and methods 3.2. Abdominal complaints at follow-up Molde Hospital serves a stable village and countryside population of 70,000. During the period 1990 – 1997, antibody response against Y. enterocolitica O:3 was estimated in 1588 patients by tube agglutination. Fortyone patients (25 females, mean age 42.4 years; and 16 males, mean age 36.6 years) who presented with actual or recent Y. enterocolitica infection (antibody titer = 320) were the subjects of the study. Included in the control group were 1041 patients (545 females, mean age 43.0 years; and 496 males, mean age 39.0 years) without antibody response to Y. enterocolitica, while 506 patients (313 females, mean age 43.1 years; and 193 males, mean age 44.4 years) with low antibody titers (20 – 160) were excluded from the study. Patients were followed up in the summer of 2003 after a mean observation time of 9.5 years. Nineteen patients had been hospitalized one or more times, whereas 22 had consulted private practitioners. Clinical data were obtained from the corresponding files and from replies to a clinical questionnaire. Members of the control group were checked against the hospital’s database with regard to the possible development of IBD. The diagnosis of Y. enterocolitica O:3 infection was based on antibody response, as evaluated by bacterial whole cell agglutination (Widal) using alcohol-treated bacterial cells as antigen. Y. enterocolitica O:3 is immunologically specific [11], and an agglutination titer = 320 was recognized as indicative of a current or recent infection. Among 22 patients presenting with acute disease, 8 had titers = 1250; 3 were in the range 5000– 20,000. Titers = 640 were recorded in 8/19 patients who presented with chronic complaints compatible with Yersiniosis. In some cases, antibody response was controlled using the ELISA technique (laboratory of the National Institute of Public Health, Oslo). Isolation of Y. enterocolitica from fecal samples, viz. intestinal biopsies, was successful in two acute cases. 2.1. Statistical analysis Fisher’s exact test for 2 2 tables (two-tailed) was used for comparisons between groups.
During the follow-up period, CD was diagnosed in two patients and colitis in another two. Hence, at the close of the study, 8/41 patients with antibodies against Y. enterocolitica were suffering from IBD. An additional 9 patients complained of chronic diarrhea and 6 of steatorrhea. 3.3. Case reports 3.3.1. Crohn’s disease 3.3.1.1. Case 1. A 16-year-old male (antibody titer 320) was operated upon because of a perianal fistula. Microscopy of the specimen showed epitheloid cell granulomas with multinucleate giant cells (Fig. 1a). Two years later, he underwent emergency ileocecal resection because of ileus. The changes in terminal ileum were focally distributed, with severe lumen reduction and mucosal ulcerations. Microscopy of the surgical specimen revealed epitheloid granulomas (Fig. 1b). 3.3.1.2. Case 2. A 32-year-old female presented with acute pancreatitis (serum amylase level elevated tenfold above the 97.5 percentile) and an antibody titer of 320. Two years later, she was readmitted with 30 bloody stools a day, arthritis, myalgia, aphthous oral lesions, and an antibody titer of 640. Endoscopy revealed colitis. Microscopy of an oral lesion biopsy showed chronic inflammation with epitheloid granulomas indicating CD (Fig. 2). Her bowel disease progressed and 4 years later she underwent total colectomy. Microscopy of the surgical specimen showed unspecific chronic active inflammation. 3.3.1.3. Case 3. A 38-year-old man with an antibody titer of 640, who for 8 years had suffered from CD with perianal fistulation and aphthous oral lesions, underwent sigmoid colon resection because of bowel stricture. Microscopy of the specimen revealed deeply penetrating inflammatory changes, fissures, and crypt abscesses (Fig. 3). Later, progressing disease caused ureteric obstruction, and total colectomy was performed. 3.3.2. Acute terminal ileitis
3. Results 3.1. Abdominal complaints at the time of diagnosis Three male patients presented with UC of acute onset and another with acute infectious terminal ileitis. An
3.3.2.1. Case 4. A 34-year-old man was admitted with right iliac fossa pain. Nine years previously, he had been operated upon because of mesenteric lymphadenitis. A small bowel series showed changes compatible with CD in the terminal ileum. Endoscopy revealed scattered ulcers, and
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Fig. 2. (H – E 100) Microscopy of an aphthous oral lesion biopsy showing inflammatory ulceration with rather deep infiltration in subepithelial tissue. Within frames: granuloma formation with multinucleate giant cells and neutrophile-rich infiltration. Histopathological picture is suggestive of oral involvement in Crohn’s disease.
sulfasalazine. Three years later, his disease recurred as treatment was stopped. 3.3.3.2. Case 6. A 17-year-old man was admitted after suffering 2 weeks from bloody loose stools and a 4-kg weight loss. His Y. enterocolitica antibody titer was 320. A control sample, examined using the ELISA technique, showed an IgM concentration of 420%. Colonoscopy revealed inflammation of the descending colon with crypt
Fig. 1. a. (H – E 40) Perianal fistula specimen. Area within circle shows epithelioid granulomas with multinucleate giant cells. b. (H – E 100) Section from surgical terminal ileum specimen. Thick arrow points to inflammatory infiltrates and epithelioid granulomas. Area within frames shows higher magnification of epithelioid granulomas, indicated by thin arrow.
Y. enterocolitica was cultivated from biopsies. His antibody titer was 10,000 and the clinical diagnosis acute terminal ileitis. He was successfully treated with tetracycline for 1 month and did not subsequently develop CD, although this was the tentative diagnosis by microscopy of biopsy specimens (Fig. 4). 3.3.3. Ulcerative colitis/colitis 3.3.3.1. Case 5. A 25-year-old man was admitted after suffering from bloody diarrhea for 3 months. Endoscopy revealed left-sided colitis with ulcerations, whereas microscopy of a biopsy specimen showed crypt abscesses (Fig. 5). His antibody titer was 320. He was successfully treated with
Fig. 3. (H – E 100) Surgical sigmoid colon specimen. Microphotograph shows deeply penetrating inflammatory changes with development of fissure. In mucosal glands, classical crypt abscesses are found (high magnification in right lower corner of frame). The depth of inflammation and the development of fissures in the intestinal wall are consistent with Crohn’s disease, even without the presence of granulomas.
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abscesses by microscopy. This was diagnosed as UC. Olsalazine treatment was instituted. Three years later, a moderate total colitis was demonstrated and treatment was changed to prednisone. 3.3.3.3. Case 7. A 37-year-old man was admitted after suffering for half a year from acute, profuse diarrhea. Endoscopy revealed UC of the descending and sigmoid colon. His Y. enterocolitica antibody titer was 320. A control sample, examined using an ELISA technique, revealed an IgM concentration of 326%. Initially, the patient was treated with prednisolone; later, olsalazine was instituted. He was checked endoscopically four times during the period of observation. 3.3.3.4. Cases 8 and 9. Two females, 43 and 48 years old, developed UC. Both responded well to sulfasalazine treatment. In one of the two patients, the disease relapsed as treatment was stopped after 3 years.
Fig. 5. (H – E 100) Left-sided colitis, biopsy of superficial inflammatory lesion with ulceration and crypt abscesses (one is shown in higher magnification within the frames). Conclusion: changes in chronic active colitis where either ulcerative colitis or Crohn’s disease is possible.
3.4. Development of IBD in the control group Follow-up of the1041 control subjects against the hospital’s IBD database showed that 32 individuals at that time had been diagnosed as having UC and 10 as having CD. This prevalence of IBD is significantly eclipsed by the one observed at follow-up of patients with positive antibodies against Yersinia (8/41 > 42/1041, p = 0.00035). With regard to UC and CD separately, corresponding significant differences in prevalence were observed
(5/41 > 32/1041, p = 0.006 and 3/41 > 10/1041, p < 0.015, respectively). 3.5. Prevalence of Y. enterocolitica infection in IBD patients Among the 1588 patients examined for antibodies against Y. enterocolitica were 53 with UC and 20 with CD. This gives the following prevalence of Y. enterocolitica infection in IBD: 8/73 = 11%, S.D. 3.7%; in UC: 5/53 = 9.4%, S.D. 4%; and in CD: 3/20 = 15%, S.D. 8%. 3.6. IBD associated with other intestinal pathogens During the period 1990 –1997, C. jejuni was cultivated from fecal samples in the case of a 17-year-old male who subsequently developed CD. According to our IBD database, a corresponding case was observed in 1988, prior to the current study. 3.7. Other clinical conditions
Fig. 4. (H – E 40) Acute terminal ileitis, biopsy specimen. Microscopically, there are deep inflammatory changes beyond muscularis mucosae. Interstitial tissue of lamina propria shows severe active inflammatory infiltrates consisting of lymphocytes, plasma cells, and neutrophils focally distributed in the biopsy, e.g., in the area marked with the smaller frame. Higher magnification of the same area within the square frame. There are no crypt abscesses and no granulomas. Focality of changes and deep inflammation, even in the absence of granulomas, favors the microscopical diagnosis of Crohn’s disease.
In addition to intestinal complaints, the patients studied presented a wide spectrum of acute and chronic clinical disorders including reactive arthritis, ankylosing spondylitis, rheumatoid arthritis and iridocyclitis, as well as hepatic, pancreatic, and thyroid disease. A thorough discussion of such manifestations has previously been given [12]; only intestinal inflammation will be discussed here.
4. Discussion Molde Hospital’s clinical departments serve a stable population of 70,000 in 11 village and countryside municipalities, whereas its microbiological laboratory
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serves the entire county, the population of which is 250,000. For the completeness of clinical information, only patients living in the above-mentioned 11 municipalities were included in the present study. 4.1. Local incidence of IBD During the 20-year period 1984 –2003, UC was diagnosed in 192 patients (83 females, mean age 41.3 years; and 109 males, mean age 39.3 years). CD was diagnosed in 106 patients (53 females, mean age 37.7 years; and 53 males, mean age 31.9 years). This yields a mean annual incidence of 13.7/105 for UC and 7.6/105 for CD, which concurs well with recent Norwegian observations [13,14]. The present study was not based on a systematic screening for Yersinia infection in a normal population; rather, the patient and control groups studied consisted of patients presenting clinical conditions suspected of being of Yersinia etiology. Antibody response was demonstrated by tube agglutination, which has been widely used in the Nordic countries. Serogroup O:3, prevailing in Norway, is recognized as immunologically stable, practically without cross reactions [11]. However, not all antibody groups are agglutinating, and a more sophisticated diagnostic method might have extended the study population and perhaps elevated the observed prevalence of Y. enterocolitica infection in IBD. 4.2. First admission Diarrhea is a common acute manifestation of Y. enterocolitica infection at all ages [15 – 17]. Right iliac fossa pain is the most common indication for emergency surgery, which regularly reveals mesenteric lymphadenitis or ileal affection [15,16,18– 20]. A favorable clinical course was observed in the case of the patient with acute terminal ileitis, although microscopy of the biopsy specimen suggested CD. Previous follow-up studies have indicated that patients with acute terminal ileitis usually do not develop CD [8,21 – 23]. According to our personal experience (about 30 patients followed), this favorable course does not depend on antibiotic treatment. Three young men presented with acute UC; in two of them, microscopy of biopsy specimens showed crypt abscesses. Previously, it has clearly been shown that an acute intestinal infection may precede the first attack of IBD [7]. Hence, in our national study, two patients were admitted a few months after the acute onset of severe diarrhea. Both later developed chronic disease and underwent bowel resection. Microscopy of surgical specimens showed changes consistent with UC or CD [8]. 4.3. Follow-up Nine patients complained of diarrhea. The observation of sustained or recurrent diarrhea after Y. enterocolitica
infection is in accordance with several previous reports [16,17,24]. In addition to the three young men who presented with acute UC, two developed UC during the follow-up period. One patient had suffered from CD for 8 years when a positive antibody titer was demonstrated. In his case, microscopy of the surgical bowel specimen revealed deeply penetrating inflammation, fissures, and crypt abscesses. His chronic perianal fistulation and apthous oral lesions further support the diagnosis of CD. Two patients developed CD during the period of observation. In both, epitheloid granulomas were demonstrated in intestinal or extraintestinal specimens. CD and UC may both affect the colon. In approximately 10– 20% of cases, it is impossible to distinguish between these two entities. However, our three patients all fulfilled the required features for the diagnosis of CD: the presence of non-necrotizing granulomas or transmural lymphoid aggregates in an area not deeply ulcerated [25]. Extraintestinal granulomatous inflammation may be related to Y. enterocolitica infection. We previously demonstrated it in lymph node biopsies from a patient with erythema nodosum and acute myocarditis [12]; we have also seen it develop in a patient with hepatitis [26]. Corresponding reports have already been published by other authors [27,28]. With regard to the development of IBD, an association between Y. enterocolitica infection and chronic colitis or UC was suggested 30 years ago [29,30]. High frequencies of specific Y. enterocolitica antibodies have been observed among patients with CD [9], UC [11], and collagenous colitis [31,32]. In our previous study, the prevalence of UC significantly exceeded the highest prevalence estimated among the Scandinavian countries [8]. A marked increase has been demonstrated in the responsiveness of mesenteric lymph node mononuclear cells from patients with UC or CD to Y. enterocolitica, as compared to other enterobacteriae, possibly indicating a specific cell-mediated immunity in IBD to Y. enterocolitica [33]. Persistent virulent Y. enterocolitica has been demonstrated in patients with chronic inflammations (intestinal and extraintestinal) by immunoblot techniques [28]. In one study, stool, sera, and gut tissue samples from 59 patients (21 CD, 14 UC, and 24 controls) were examined by culture, immunoblotting, and polymerase chain reaction (PCR). Yersinia species were observed in 63% of CD, 46% of UC, and 36% of controls [34]. In a study on patients with granulomatous appendicitis, two out of ten patients positive for Y. enterocolitica by PCR later developed CD [35]. Correspondingly, in a study on 54 intestinal resection specimens from 52 patients with confirmed CD, a total of 17 resections (31%) contained Yersinia DNA by PCR. Also, mesenteric lymph nodes were positive in eight cases [36]. In rat studies, injection of purified bacterial cell wall fragments produced chronic granulomatous inflammation in the intestinal wall [37].
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Recently, the NOD2 gene on chromosome 16 (regulating host response to pathogens) has been identified as a susceptibility gene for CD. Particular mutations in the gene may be associated with different clinical manifestation of CD [38,39]. The reported observations support the recent concept that the inflammatory response in IBD is probably antigen-, and not autoantigen-, driven. The possibility that some ‘‘autoimmune’’ disorders may actually result from persistent infection may require a reclassification of autoimmune diseases or a broader definition of autoimmunity. If the concept is correct, treatment strategies should shift from the use of immunosuppressive agents toward the development of longterm antibiotic treatment, vaccines, and immunotherapy [40]. In conclusion, the present study further supports the concept that Y. enterocolitica infection may induce IBD. Forty-one patients out of 1588 (2.6%) presented with significant antibody response (titer = 320) to Y. enterocolitica; the difference in prevalence of IBD between study and control groups was, nevertheless, significant. About 11% of IBD cases, observed among all 1588 patients, were associated with Y. enterocolitica infection. Further epidemiological and clinical follow-up studies are required in this field, as information on both the incidence of acute Y. enterocolitica infection and the prevalence of chronic Y. enterocolitica infection is insufficient. In the future, tissue samples from patients with IBD should be examined regularly for microbial DNA.
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Original article
Inflammatory bowel disease associated with Yersinia enterocolitica O:3 infectionB Arve Saeboa,*, Einar Vikb, Ove J. Langec, Ludwig Matuszkiewiczd a Department of Surgery, Molde Hospital, N-6407 Molde, Norway Department of Microbiology, Molde Hospital, N-6407 Molde, Norway c Department of Internal Medicine, Molde Hospital, N-6407 Molde, Norway d Department of Pathology, Molde Hospital, N-6407 Molde, Norway b
Received 24 May 2004; received in revised form 18 October 2004; accepted 4 November 2004
Abstract Background: Certain microorganisms may be associated with the development of inflammatory bowel disease (IBD). These pathogens may possess such properties as immunological capability or tissue invasiveness. An association between Yersinia enterocolitica infection and ulcerative colitis (UC) was suggested 30 years ago, and a connection with Crohn’s disease (CD) may also exist. The aim of this study was to further elucidate the association between Y. enterocolitica O:3 infection and IBD. Methods: During the period 1990 – 1997, antibody response against Y. enterocolitica was estimated in 1588 patients by tube agglutination. Forty-one patients with Y. enterocolitica infection (titer = 320) constituted the study group; 1041 patients without antibody response constituted the control group. The study was completed in 2003, after 6 – 13 years. Results: At diagnosis of Y. enterocolitica infection, UC of acute onset was demonstrated in three males; another suffered from CD. At follow-up, two additional patients had developed UC and two CD. In the control group, 32 patients were diagnosed as having UC and 10 CD. This difference in IBD prevalence is significant (8/41 > 42/1041, p = 0.00035), as were the differences in prevalence of UC and CD separately ( p = 0.006; viz. p < 0.015). Conclusion: The present study supports the concept of the Y. enterocolitica infection as a trigger of chronic IBD. D 2005 Elsevier B.V. All rights reserved. Keywords: Crohn’s disease; Colitis; Ulcerative; Granulomatous disease
1. Introduction There is circumstantial evidence that certain microorganisms are associated with inflammatory bowel disease (IBD), possibly by launching an inflammatory response, and subsequently persist in a non-culturable form still capable of stimulating the immune system. These pathogens may possess such a property as immunological capability or tissue i Reports from the present study have previously been presented as short posters (but not published as abstracts) at: 1. 9th. United European Gastroenterology Week, Amsterdam, October 6 – 10, 2001; 2. 8th. International Symposium on Yersinia, Turku, September 4 – 8, 2002. * Corresponding author. Kviltorpvegen 26, N-6419 Molde, Norway. Tel.: +47 71 21 23 97. E-mail address: [email protected] (A. Saebo).
0953-6205/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2004.11.008
invasiveness. However, even normal intestinal flora may play a role in the continuity of inflammation in Crohn’s disease (CD). Subjects who develop IBD may have impairments, such as a defective mucosal barrier to luminal antigens, or a dysregulated immune response to common antigens [1 –5]; HLA-B27 histocompatibility may play an important determining role [6]. Ulcerative colitis (UC) and CD are heterogeneous disorders of multifactorial etiology [6]. Among other microorganisms, Shigella dysenteriae, Salmonella species, Campylobacter jejuni, and Yersinia enterocolitica have been implicated as possible causative agents of UC [3]. An acute intestinal infection sometimes precedes the first attack [7,8]. Y. enterocolitica [9], Mycobacterium paratuberculosis, Listeria monocytogenes, and paramyxovirus (measles) have been studied in association with CD [10].
A. Saebo et al. / European Journal of Internal Medicine 16 (2005) 176 – 182
The aim of this clinical follow-up study was to further elucidate the association between Y. enterocolitica O:3 infection and the development of IBD.
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antibody titer of 640 was recorded in the case of a male who had suffered from CD for 8 years. Among 18 other patients with acute infection, 10 presented with diarrhea and 6 with steatorrhea (voluminous stools floating on water).
2. Material and methods 3.2. Abdominal complaints at follow-up Molde Hospital serves a stable village and countryside population of 70,000. During the period 1990 – 1997, antibody response against Y. enterocolitica O:3 was estimated in 1588 patients by tube agglutination. Fortyone patients (25 females, mean age 42.4 years; and 16 males, mean age 36.6 years) who presented with actual or recent Y. enterocolitica infection (antibody titer = 320) were the subjects of the study. Included in the control group were 1041 patients (545 females, mean age 43.0 years; and 496 males, mean age 39.0 years) without antibody response to Y. enterocolitica, while 506 patients (313 females, mean age 43.1 years; and 193 males, mean age 44.4 years) with low antibody titers (20 – 160) were excluded from the study. Patients were followed up in the summer of 2003 after a mean observation time of 9.5 years. Nineteen patients had been hospitalized one or more times, whereas 22 had consulted private practitioners. Clinical data were obtained from the corresponding files and from replies to a clinical questionnaire. Members of the control group were checked against the hospital’s database with regard to the possible development of IBD. The diagnosis of Y. enterocolitica O:3 infection was based on antibody response, as evaluated by bacterial whole cell agglutination (Widal) using alcohol-treated bacterial cells as antigen. Y. enterocolitica O:3 is immunologically specific [11], and an agglutination titer = 320 was recognized as indicative of a current or recent infection. Among 22 patients presenting with acute disease, 8 had titers = 1250; 3 were in the range 5000– 20,000. Titers = 640 were recorded in 8/19 patients who presented with chronic complaints compatible with Yersiniosis. In some cases, antibody response was controlled using the ELISA technique (laboratory of the National Institute of Public Health, Oslo). Isolation of Y. enterocolitica from fecal samples, viz. intestinal biopsies, was successful in two acute cases. 2.1. Statistical analysis Fisher’s exact test for 2 2 tables (two-tailed) was used for comparisons between groups.
During the follow-up period, CD was diagnosed in two patients and colitis in another two. Hence, at the close of the study, 8/41 patients with antibodies against Y. enterocolitica were suffering from IBD. An additional 9 patients complained of chronic diarrhea and 6 of steatorrhea. 3.3. Case reports 3.3.1. Crohn’s disease 3.3.1.1. Case 1. A 16-year-old male (antibody titer 320) was operated upon because of a perianal fistula. Microscopy of the specimen showed epitheloid cell granulomas with multinucleate giant cells (Fig. 1a). Two years later, he underwent emergency ileocecal resection because of ileus. The changes in terminal ileum were focally distributed, with severe lumen reduction and mucosal ulcerations. Microscopy of the surgical specimen revealed epitheloid granulomas (Fig. 1b). 3.3.1.2. Case 2. A 32-year-old female presented with acute pancreatitis (serum amylase level elevated tenfold above the 97.5 percentile) and an antibody titer of 320. Two years later, she was readmitted with 30 bloody stools a day, arthritis, myalgia, aphthous oral lesions, and an antibody titer of 640. Endoscopy revealed colitis. Microscopy of an oral lesion biopsy showed chronic inflammation with epitheloid granulomas indicating CD (Fig. 2). Her bowel disease progressed and 4 years later she underwent total colectomy. Microscopy of the surgical specimen showed unspecific chronic active inflammation. 3.3.1.3. Case 3. A 38-year-old man with an antibody titer of 640, who for 8 years had suffered from CD with perianal fistulation and aphthous oral lesions, underwent sigmoid colon resection because of bowel stricture. Microscopy of the specimen revealed deeply penetrating inflammatory changes, fissures, and crypt abscesses (Fig. 3). Later, progressing disease caused ureteric obstruction, and total colectomy was performed. 3.3.2. Acute terminal ileitis
3. Results 3.1. Abdominal complaints at the time of diagnosis Three male patients presented with UC of acute onset and another with acute infectious terminal ileitis. An
3.3.2.1. Case 4. A 34-year-old man was admitted with right iliac fossa pain. Nine years previously, he had been operated upon because of mesenteric lymphadenitis. A small bowel series showed changes compatible with CD in the terminal ileum. Endoscopy revealed scattered ulcers, and
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Fig. 2. (H – E 100) Microscopy of an aphthous oral lesion biopsy showing inflammatory ulceration with rather deep infiltration in subepithelial tissue. Within frames: granuloma formation with multinucleate giant cells and neutrophile-rich infiltration. Histopathological picture is suggestive of oral involvement in Crohn’s disease.
sulfasalazine. Three years later, his disease recurred as treatment was stopped. 3.3.3.2. Case 6. A 17-year-old man was admitted after suffering 2 weeks from bloody loose stools and a 4-kg weight loss. His Y. enterocolitica antibody titer was 320. A control sample, examined using the ELISA technique, showed an IgM concentration of 420%. Colonoscopy revealed inflammation of the descending colon with crypt
Fig. 1. a. (H – E 40) Perianal fistula specimen. Area within circle shows epithelioid granulomas with multinucleate giant cells. b. (H – E 100) Section from surgical terminal ileum specimen. Thick arrow points to inflammatory infiltrates and epithelioid granulomas. Area within frames shows higher magnification of epithelioid granulomas, indicated by thin arrow.
Y. enterocolitica was cultivated from biopsies. His antibody titer was 10,000 and the clinical diagnosis acute terminal ileitis. He was successfully treated with tetracycline for 1 month and did not subsequently develop CD, although this was the tentative diagnosis by microscopy of biopsy specimens (Fig. 4). 3.3.3. Ulcerative colitis/colitis 3.3.3.1. Case 5. A 25-year-old man was admitted after suffering from bloody diarrhea for 3 months. Endoscopy revealed left-sided colitis with ulcerations, whereas microscopy of a biopsy specimen showed crypt abscesses (Fig. 5). His antibody titer was 320. He was successfully treated with
Fig. 3. (H – E 100) Surgical sigmoid colon specimen. Microphotograph shows deeply penetrating inflammatory changes with development of fissure. In mucosal glands, classical crypt abscesses are found (high magnification in right lower corner of frame). The depth of inflammation and the development of fissures in the intestinal wall are consistent with Crohn’s disease, even without the presence of granulomas.
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abscesses by microscopy. This was diagnosed as UC. Olsalazine treatment was instituted. Three years later, a moderate total colitis was demonstrated and treatment was changed to prednisone. 3.3.3.3. Case 7. A 37-year-old man was admitted after suffering for half a year from acute, profuse diarrhea. Endoscopy revealed UC of the descending and sigmoid colon. His Y. enterocolitica antibody titer was 320. A control sample, examined using an ELISA technique, revealed an IgM concentration of 326%. Initially, the patient was treated with prednisolone; later, olsalazine was instituted. He was checked endoscopically four times during the period of observation. 3.3.3.4. Cases 8 and 9. Two females, 43 and 48 years old, developed UC. Both responded well to sulfasalazine treatment. In one of the two patients, the disease relapsed as treatment was stopped after 3 years.
Fig. 5. (H – E 100) Left-sided colitis, biopsy of superficial inflammatory lesion with ulceration and crypt abscesses (one is shown in higher magnification within the frames). Conclusion: changes in chronic active colitis where either ulcerative colitis or Crohn’s disease is possible.
3.4. Development of IBD in the control group Follow-up of the1041 control subjects against the hospital’s IBD database showed that 32 individuals at that time had been diagnosed as having UC and 10 as having CD. This prevalence of IBD is significantly eclipsed by the one observed at follow-up of patients with positive antibodies against Yersinia (8/41 > 42/1041, p = 0.00035). With regard to UC and CD separately, corresponding significant differences in prevalence were observed
(5/41 > 32/1041, p = 0.006 and 3/41 > 10/1041, p < 0.015, respectively). 3.5. Prevalence of Y. enterocolitica infection in IBD patients Among the 1588 patients examined for antibodies against Y. enterocolitica were 53 with UC and 20 with CD. This gives the following prevalence of Y. enterocolitica infection in IBD: 8/73 = 11%, S.D. 3.7%; in UC: 5/53 = 9.4%, S.D. 4%; and in CD: 3/20 = 15%, S.D. 8%. 3.6. IBD associated with other intestinal pathogens During the period 1990 –1997, C. jejuni was cultivated from fecal samples in the case of a 17-year-old male who subsequently developed CD. According to our IBD database, a corresponding case was observed in 1988, prior to the current study. 3.7. Other clinical conditions
Fig. 4. (H – E 40) Acute terminal ileitis, biopsy specimen. Microscopically, there are deep inflammatory changes beyond muscularis mucosae. Interstitial tissue of lamina propria shows severe active inflammatory infiltrates consisting of lymphocytes, plasma cells, and neutrophils focally distributed in the biopsy, e.g., in the area marked with the smaller frame. Higher magnification of the same area within the square frame. There are no crypt abscesses and no granulomas. Focality of changes and deep inflammation, even in the absence of granulomas, favors the microscopical diagnosis of Crohn’s disease.
In addition to intestinal complaints, the patients studied presented a wide spectrum of acute and chronic clinical disorders including reactive arthritis, ankylosing spondylitis, rheumatoid arthritis and iridocyclitis, as well as hepatic, pancreatic, and thyroid disease. A thorough discussion of such manifestations has previously been given [12]; only intestinal inflammation will be discussed here.
4. Discussion Molde Hospital’s clinical departments serve a stable population of 70,000 in 11 village and countryside municipalities, whereas its microbiological laboratory
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serves the entire county, the population of which is 250,000. For the completeness of clinical information, only patients living in the above-mentioned 11 municipalities were included in the present study. 4.1. Local incidence of IBD During the 20-year period 1984 –2003, UC was diagnosed in 192 patients (83 females, mean age 41.3 years; and 109 males, mean age 39.3 years). CD was diagnosed in 106 patients (53 females, mean age 37.7 years; and 53 males, mean age 31.9 years). This yields a mean annual incidence of 13.7/105 for UC and 7.6/105 for CD, which concurs well with recent Norwegian observations [13,14]. The present study was not based on a systematic screening for Yersinia infection in a normal population; rather, the patient and control groups studied consisted of patients presenting clinical conditions suspected of being of Yersinia etiology. Antibody response was demonstrated by tube agglutination, which has been widely used in the Nordic countries. Serogroup O:3, prevailing in Norway, is recognized as immunologically stable, practically without cross reactions [11]. However, not all antibody groups are agglutinating, and a more sophisticated diagnostic method might have extended the study population and perhaps elevated the observed prevalence of Y. enterocolitica infection in IBD. 4.2. First admission Diarrhea is a common acute manifestation of Y. enterocolitica infection at all ages [15 – 17]. Right iliac fossa pain is the most common indication for emergency surgery, which regularly reveals mesenteric lymphadenitis or ileal affection [15,16,18– 20]. A favorable clinical course was observed in the case of the patient with acute terminal ileitis, although microscopy of the biopsy specimen suggested CD. Previous follow-up studies have indicated that patients with acute terminal ileitis usually do not develop CD [8,21 – 23]. According to our personal experience (about 30 patients followed), this favorable course does not depend on antibiotic treatment. Three young men presented with acute UC; in two of them, microscopy of biopsy specimens showed crypt abscesses. Previously, it has clearly been shown that an acute intestinal infection may precede the first attack of IBD [7]. Hence, in our national study, two patients were admitted a few months after the acute onset of severe diarrhea. Both later developed chronic disease and underwent bowel resection. Microscopy of surgical specimens showed changes consistent with UC or CD [8]. 4.3. Follow-up Nine patients complained of diarrhea. The observation of sustained or recurrent diarrhea after Y. enterocolitica
infection is in accordance with several previous reports [16,17,24]. In addition to the three young men who presented with acute UC, two developed UC during the follow-up period. One patient had suffered from CD for 8 years when a positive antibody titer was demonstrated. In his case, microscopy of the surgical bowel specimen revealed deeply penetrating inflammation, fissures, and crypt abscesses. His chronic perianal fistulation and apthous oral lesions further support the diagnosis of CD. Two patients developed CD during the period of observation. In both, epitheloid granulomas were demonstrated in intestinal or extraintestinal specimens. CD and UC may both affect the colon. In approximately 10– 20% of cases, it is impossible to distinguish between these two entities. However, our three patients all fulfilled the required features for the diagnosis of CD: the presence of non-necrotizing granulomas or transmural lymphoid aggregates in an area not deeply ulcerated [25]. Extraintestinal granulomatous inflammation may be related to Y. enterocolitica infection. We previously demonstrated it in lymph node biopsies from a patient with erythema nodosum and acute myocarditis [12]; we have also seen it develop in a patient with hepatitis [26]. Corresponding reports have already been published by other authors [27,28]. With regard to the development of IBD, an association between Y. enterocolitica infection and chronic colitis or UC was suggested 30 years ago [29,30]. High frequencies of specific Y. enterocolitica antibodies have been observed among patients with CD [9], UC [11], and collagenous colitis [31,32]. In our previous study, the prevalence of UC significantly exceeded the highest prevalence estimated among the Scandinavian countries [8]. A marked increase has been demonstrated in the responsiveness of mesenteric lymph node mononuclear cells from patients with UC or CD to Y. enterocolitica, as compared to other enterobacteriae, possibly indicating a specific cell-mediated immunity in IBD to Y. enterocolitica [33]. Persistent virulent Y. enterocolitica has been demonstrated in patients with chronic inflammations (intestinal and extraintestinal) by immunoblot techniques [28]. In one study, stool, sera, and gut tissue samples from 59 patients (21 CD, 14 UC, and 24 controls) were examined by culture, immunoblotting, and polymerase chain reaction (PCR). Yersinia species were observed in 63% of CD, 46% of UC, and 36% of controls [34]. In a study on patients with granulomatous appendicitis, two out of ten patients positive for Y. enterocolitica by PCR later developed CD [35]. Correspondingly, in a study on 54 intestinal resection specimens from 52 patients with confirmed CD, a total of 17 resections (31%) contained Yersinia DNA by PCR. Also, mesenteric lymph nodes were positive in eight cases [36]. In rat studies, injection of purified bacterial cell wall fragments produced chronic granulomatous inflammation in the intestinal wall [37].
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Recently, the NOD2 gene on chromosome 16 (regulating host response to pathogens) has been identified as a susceptibility gene for CD. Particular mutations in the gene may be associated with different clinical manifestation of CD [38,39]. The reported observations support the recent concept that the inflammatory response in IBD is probably antigen-, and not autoantigen-, driven. The possibility that some ‘‘autoimmune’’ disorders may actually result from persistent infection may require a reclassification of autoimmune diseases or a broader definition of autoimmunity. If the concept is correct, treatment strategies should shift from the use of immunosuppressive agents toward the development of longterm antibiotic treatment, vaccines, and immunotherapy [40]. In conclusion, the present study further supports the concept that Y. enterocolitica infection may induce IBD. Forty-one patients out of 1588 (2.6%) presented with significant antibody response (titer = 320) to Y. enterocolitica; the difference in prevalence of IBD between study and control groups was, nevertheless, significant. About 11% of IBD cases, observed among all 1588 patients, were associated with Y. enterocolitica infection. Further epidemiological and clinical follow-up studies are required in this field, as information on both the incidence of acute Y. enterocolitica infection and the prevalence of chronic Y. enterocolitica infection is insufficient. In the future, tissue samples from patients with IBD should be examined regularly for microbial DNA.
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