CMV Colitis Mimicking Recurrent Inflammatory Bowel Disease: Report of Three Cases

Written By: Sam Savage

Published Date: March 23, 2007 Last Edited: March 23, 2007

By Rezania, Dorna; Ouban, Abderrhman; Marcet, Jorge; Kelley, Scott; Coppola, Domenico

The association between cytomegalovirus infection and inflammatory bowel disease challenges both the clinician and the pathologist to establish the correct diagnosis and to prescribe the most appropriate form of therapy. To understand this association the authors report three patients who presented with signs and symptoms mimicking reactivated inflammatory bowel disease who responded poorly to aggressive treatment of inflammatory bowel disease. Microscopic examination, in all three cases revealed numerous nuclear and cytoplasmic viral inclusions, as demonstrated by cytomegalovirus immunohistochemistry, as well as histologic findings consistent with inflammatory bowel disease (ulcerative colitis and/ or Crohn’s disease). Because the clinical pathologic features of cytomegalovirus colitis and inflammatory bowel disease often overlap, and because of the possible coexistence of cytomegalovirus colitis with idiopathic colitis, the possibility of cytomegalovirus infection should be always considered, so that the most appropriate therapy can be instituted for these patients.

CYTOMEGALOVIRUS (CMV) is a ubiquitous virus responsible for infection in about 40 to 100 per cent of adults worldwide. ‘ The vast majority of infections are usually not clinically apparent, but the large variety of clinical manifestations, depending on the site of infection, can make the diagnosis difficult.

When CMV infection involves the colon, patients may present with hematochezia, tenesmus, abdominal pain, fever, malaise, anorexia, and weight loss.2 The vast majority of CMV colitis cases occur in patients who are immunodeficient, particularly those who have deficiency in cell-mediated immunity.3 Thus CMV colitis is often seen affecting patients with acquired immune deficiency syndrome, organ transplant recipients, patients taking immunosuppressive medications, those undergoing chemotherapy and/or radiation therapy, and elderly patients, particularly those who suffer from chronic disease.1 Although the clinical history might help in identifying patients at risk of developing CMV colitis, sometimes the disease may occur without a predisposing clinical background. With respect to colonic involvement, difficulty arises in establishing the clinical diagnosis of CMV colitis when the infection overlaps with idiopathic colitis.

The coexistence of CMV colitis with inflammatory bowel disease (IBD) challenges both the clinician and the pathologist to establish the correct clinical pathological diagnosis and to prescribe the most appropriate form of therapy. Even though both ulcerative colitis and Crohn’s disease have been reported in association with CMV infection, there is a higher prevalence of CMV infection in ulcerative colitis compared with Crohn’s disease.4 We report three cases of CMV colitis arising in a background of ulcerative colitis, and presenting with clinical signs mimicking reactivated IBD.

Case One

A 54-year-old man with a long history of ulcerative colitis (>20 years), was started on a drug regimen that included piperacillin/ tazobactam, fluconazole, and linezolid after presenting with abdominal pain, hematochezia, and fever. Subsequent colonoscopy revealed colonie changes consistent with a clinical diagnosis of reactivated ulcerative colitis. He was treated with a course of corticosteroids, but developed signs of toxic megacolon necessitating urgent colectomy and end ileostomy. His postoperative course was further complicated by rectal stump blowout and multiple pelvic abscesses, causing his hospital stay to be prolonged for 7 weeks. After a protracted hospital course, he developed nausea and vomiting, weakness, fever, and bright-red blood per rectum. Flexible sigmoidoscopy revealed extensive areas of ulceration and pseudopolyps within the stump. Pathology revealed evidence of CMV infection. He was managed medically with ganciclovir and eventually discharged.

Case Two

A 62-year-old Hispanic man with a history of IBD was admitted with a 2-week history of diarrhea, bloating, and abdominal pain. Colonoscopy revealed colonic mucosa with many ulcerations, covered by fibrinopurulent exudates and granulation tissue. Biopsies revealed evidence of CMV colitis. Ganciclovir was prescribed for 2 weeks. Repeat colonoscopy and biopsies showed no improvement. The patient was switched to Foscarnet. The patient later developed fever, with blood cultures positive for Enterococcus fecalis. The patient eventually succumbed to overwhelming sepsis 48 hours later.

Case Three

A 52-year-old woman with a 10-year history of ulcerative colitis and a 6-year history of primary sclerosing cholangitis was hospitalized for exacerbation of ulcerative colitis while taking mesalamine, azathioprine, and prednisone. After several exacerbations of her disease, surveillance colonoscopy with biopsies, revealed pancolitis without dysplasia. She underwent total proctocolectomy with ileostomy. Pathologic examination revealed CMV colitis in a background of IBD.

Materials and Methods

Sections from colon resections were submitted for histologie examination. Each sample was fixed in 10 per cent neutral buffered formalin for 9 hours. After fixation, the tissue samples were processed into paraffin blocks. Four-micrometer-thick tissue sections were obtained from the paraffin blocks and were stained with hematoxylin-eosin stain (Richard-Allan Scientific, Kalamazoo, MI) using standard histologic techniques. Tissue sections were also subjected to immunostain for CMV. We used a rabbit polyclonal CMV antibody (cat. no. A0082; Dako Corporation, Carpinteria, CA) at 1:400 dilution after microwave antigen retrieval (four cycles of 5 minutes each on high in 0.1M citrate buffer). The microwave used is an 1100 W Emerson model AT 736 (Emerson Radio Corp., Parsippany, NJ).

Staining was performed manually using the avidinbiotin- peroxidase complex method (Vectastain ABC Kit; Vector, Burlingame, CA) at room temperature. Endogenous peroxidase and nonspecific background staining were blocked by incubating slides with 3 per cent aqueous hydrogen peroxide for 10 minutes. After washing with phosphate-buffered saline (PBS) for 5 minutes, the slides were blocked with normal serum for 20 minutes, followed by incubation with the primary antibodies for 60 minutes. After rinsing with PBS for 5 minutes, sections were incubated with a biotinylated secondary antibody for 20 minutes. After washing with PBS for 5 minutes, the slides were incubated with avidin-biotin complex for 30 minutes and washed again. Chromogen was developed with 10 mg of 3,3 diaminobenzidine tetrahydrochloride (Sigma) diluted in 12 mL Tris buffer at a pH of 7.6 for 2 minutes. All slides were lightly counterstained with Mayer’s hematoxylin for 30 seconds before dehydration and mounting. Positive controls and nonimmune protein- negative controls were used.

Results

The pathologic examination of the resected bowel in each case revealed a pale, flattened mucosa, which in areas exhibited a nodular cobblestone appearance, punctuated by multiple, deep, round ulcers that ranged in size from 0.7 to 2.8 cm.

Microscopic examination in all three cases revealed colonie mucosa with many ulcerations, covered by fibrinopurulent exudates and with granulation tissue. There was expansion of the lamina propria by a mixed inflammatory infiltrate, rich in plasma cells (Fig. 1). At high power, numerous nuclear and cytoplasmic viral inclusions were seen predominantly in the endothelial cells of the ulcer beds (Fig. 1B). The colonie epithelium also showed architectural distortion with shortening of the crypts and glandular branching, cryptitis and crypt abscesses, basal lymphoplasma cellular infiltrates, and focal mucin depletion with reactive epithelial atypia. No dysplasia was identified (Fig. 2). These changes are consistent with IBD. The viral inclusions showed strong positivity for CMV by immunohistochemistry (Fig. 3).

FIG. 1. (A) Colonic mucosa with cryptitis and expansion of the lamina propria by a mixed inflammatory infiltrate rich in plasma cells. (B) High-power view shows an endothelial cell exhibiting nuclear and cytoplasmic viral inclusions, typical of CMV infection.

FIG. 2. Colonie epithelium with architectural distortion, shortening of the crypts and glandular branching (gb), cryptitis and crypt abscesses, basal lymphoplasma cellular infiltrates (bl), and focal mucin depletion with reactive epithelial atypia. mm, muscularis mucosae; il, intestinal lumen.

FIG. 3. (A, B) Two CMV-infected endothelial cells showing strong CMV positivity by immunohistochemistry.

DISCUSSION

The association between ulcerative colitis and concomitant CMV infection was first described in 1961.5 The overlapping features of these two conditions have been identified, and a pathogenetic link between IBD and CMV colitis has been proposed.6

Initially, the coexistence of CMV and ulcerative colitis became evident via single case reports, and an estimate of the prevalence of this occurrence was unclear. Recent prospective analysis of a cohort of patients with severe colitis has indicated the incidence of CMV in this setting to be \as high as 36 per cent.7

The symptoms of CMV colitis are specific and mimic the symptoms of IBD.7 CMV infection increases the severity of IBD and it is a major cause of severe refractory colitis, making both timely and proper diagnosis crucial. Clinically apparent CMV colitis with superimposed IBD is associated with a significantly higher rate of complications and mortality following surgical intervention.8 Recognition and proper diagnosis of CMV colitis in the course of IBD is extremely important and can be life-saving, thus necessitating a high index of suspicion, especially in cases of refractory IBD.

Pathologic features of CMV colitis overlap with those of IBD. The degree of inflammation and ulceration caused by the infection makes the evaluation of the degree of activity of IBD difficult and/or impossible.

Although the clinical consequences of having CMV colitis in association with IBD are known, the pathogenetic link between these two conditions is still unclear. It is not clear whether CMV is a cause of IBD flare or simply an innocent bystander. It is known that patients with IBD are at greater risk for CMV infection because of the use of immunosuppressive agents, including steroids, thiopurines, methotrexate, and others. The altered immunity in malnourished IBD patients, and the tropism of CMV for areas of inflammation in IBD, act in concert to facilitate CMV infection in the small and large intestines.

The occurrence of CMV weeks or months before the diagnosis of IBD has also suggested a possible etiologic role of CMV in IBD.9 It has been postulated that viral proteins expressed on the cell surface of CMV-infected cells might initiate an immune and/or autoimmune response in the susceptible host, leading to the development of IBD.10 Further, investigations have shown that CMV infection causes direct induction of major histocompatibility complex surface antigen expression and increased cytokine production,11,12 leading to autoimmune damage and, possibly, IBD.9

Treatment resistance in IBD may be secondary to reduced glucocorticoid receptor and/or glucocorticoid ligand, or to DNA binding affinity of nuclear factorκB. It has been postulated that a superimposed viral infection may also contribute to the establishment of resistance to treatment.13,14

In summary, we report three cases of CMV colitis arising in a background of IBD. Because the clinical pathologic features of CMV colitis and IBD often overlap, and because of the frequent coexistence of CMV colitis with idiopathic colitis, the possibility of CMV infection should always be suspected, so that the most appropriate therapy can be instituted for these patients.

REFERENCES

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2. Maconi G, Colombo E, Zerbi P, et al. Prevalence, detection rate and outcome of cytomegalovirus infection in ulcerative colitis patients requiring colonic resection. Dig Liver Dis 2005;37: 418- 23.

3. Rachima C, Maoz E, Apter S, et al. Cytomegalovirus infection associated with ulcerative colitis in immunocompetent individuals. Postgrad Med J 1998;74:486-91.

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9. Pfau P, Kochman M, Furth E, et al. Cytomegalovirus colitis complicating ulcerative colitis in the steroid-naive patient. Am J Gastroenterol. 2001;96:895-9.

10. Orvar K, Murray J, Garment G, et al. Cytomegalovirus infection associated with onset of inflammatory bowel disease. Dig Dis Sci 1993:38:2307-10.

11. Van Days WT, Jonges E, Bruggeman CA, et al. Direct induction of MHC class I but not class II expression of endothelial cells by cytomegalovirus infection. Transplantation 1989;48: 469-72.

12. Iwamoto GK, Monick MM, Clark BP, et al. Modulation of interleukin-1 beta gene expression by the immediate early genes of human cytomegalovirus. J Clin Invest 1990;85:1853-7.

13. Leung DY, Spahn JD, Szefler SJ. Immunologic basis and management of steroid-resistant asthma. Allergy Asthma Proc 1999;20:9-14.

14. Ardite E, Panes J, Miranda M, et al. Effects of steroid treatment on activation of nuclear factor kappa B in patients with inflammatory bowel disease. Br J Pharmacol 1998;24:431-2.

DORNA REZANIA, M.D.,* ABDERRHMAN OUBAN, M.D.,* JORGE MARCET, M.D.,[dagger] SCOTT KELLEY, M.D.,[double dagger] DOMENICO COPPOLA, M.D.*[double dagger]

From the Departments of * Pathology and [dagger] Surgery, University of South Florida, College of Medicine and

the [double dagger] Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute,

Tampa, Florida

Address correspondence and reprint requests to Domenico Coppola, M.D., Professor of Oncology/Pathology Chief, Anatomic Pathology Division, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612.

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