Weng et al. BMC Gastroenterology (2017) 17:28 DOI 10.1186/s12876-017-0586-9 RESEARCH ARTICLE Open Access Cytomegalovirus colitis in hospitalized inflammatory bowel disease patients in Taiwan: a referral center study Meng-Tzu Weng1,2,3, Chien-Chih Tung1, Yi-Shuan Lee4, Yew-Loong Leong1,5, Ming-Jium Shieh6, Chia-Tung Shun4, Cheng-Yi Wang1, Jau-Min Wong1 and Shu-Chen Wei1* Abstract Background: Colitis is exacerbated in patients with concurrent cytomegalovirus (CMV) infection and inflammatory bowel disease (IBD). We assessed the prevalence and clinical features of CMV colitis in hospitalized IBD patients. Methods: A retrospective study reviewed the data from January 1, 1998 through December 31, 2013 compiled at the National Taiwan University Hospital. The CMV colitis patients’ demographic data, clinical information, treatment regimens, pathologic findings, and outcome were analyzed. Results: A total of 673 IBD patients were hospitalized during the study period. There were 312 patients diagnosed with Crohn’s disease (CD) and 361 with ulcerative colitis (UC). CMV colitis was diagnosed as having positive inclusion bodies in colonic tissue. Six of the 312 CD patients (1.9%) and five of the 361 UC patients (1.4%) were diagnosed with CMV colitis. Compared to CD patients without CMV colitis, patients with CMV colitis were more often older (p < 0.005). Higher steroid usage was noted in the CMV positive group compared to age and gender matched CMV negative IBD patients (81.8% vs. 51.5%). Eight patients received ganciclovir treatment. Three patients who did not receive antiviral treatment had colitis flare-ups after the index admission. Conclusions: The prevalence of CMV colitis in hospitalized IBD inpatients was 1.6% in Taiwan. Two associated factors for CMV colitis in hospitalized IBD patients were that they were elderly in CD and were on higher doses of steroids. Routine histopathology studies and/or PCR for refractory colitis patients are suggested to diagnose CMV colitis. Once the diagnosis is made, antiviral treatment is recommended to decrease the colitis relapse rate. Keywords: Inflammatory bowel disease, Crohn’s disease, Ulcerative colitis, Cytomegalovirus colitis Background symptomatic clinical manifestations, should be made [5]. Cytomegalovirus (CMV) infection is common and its CMV disease frequently occurs in immunocompromised prevalence has been reported from 40 to 100% in adults patients including transplant recipients, patients with ac- [1]. Primary CMV is generally asymptomatic or presents quired immunodeficiency syndrome (AIDS), and patients as a mild mononucleosis-like syndrome in healthy receiving chemotherapy or steroids [1]. Patients with people [2]. The viremic phase is often self-limited and is inflammatory bowel disease (IBD) are often treated with followed by a lifelong latent phase [3]. Reactivation from immunosuppressive agents which increase the risk of latency can lead to a serious disease in immunocomprom- CMV disease [6]. ised individuals [4]. A distinction between CMV infection, CMV infection should be considered in IBD patients meaning the positive detection of CMV by serology tests that present with fever, leukopenia, lymphadenopathy or PCR, and CMV disease, meaning tissue damage and and splenomegaly [7]. However, CMV colitis need not have these features. There are no characteristic endo- scopic features that are diagnostic of CMV colitis [8]. * Correspondence: [email protected] 1Department of Internal Medicine, National Taiwan University Hospital and CMV infection in existing IBD often worsens the colitis. College of Medicine, No. 7 Chung-Shan South Road, Taipei City, Taiwan Whether CMV is a pathogen or an ‘innocent bystander’ Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Weng et al. BMC Gastroenterology (2017) 17:28 Page 2 of 7 representing a reactivation of a latent virus due to im- flare-up is aggravated symptoms that require augmented munosuppressive therapy is still unclear. A few studies treatment to control said symptoms. According to the have shown the spontaneous disappearance of the virus European guidelines on UC management, steroid- and the limited impact that antiviral therapy has on the refractory colitis is defined as patients who have an ac- course of IBD [9, 10]. Other studies have reported that tive disease despite prednisolone up to 0.75 mg/kg/day CMV colitis superimposed on IBD increases the preva- over a 4 week period [17]. lence of toxic megacolon and of surgical intervention In our study, CMV colitis is defined as having at least risks [11, 12]. Some case reports and series have also one inclusion body detected by haematoxylin and eosin shown that patients with severe UC unresponsive to (H&E) or immunohistochemistry staining in 10 to 20 immunosuppressive agents, improve after antiviral treat- high-power fields of the colorectal mucosa. A latent ment for CMV colitis [13, 14]. CMV infection is the carrying of the CMV genome with- This study assessed the prevalence and the clinical out having active replication or manifestations of clinical features of CMV disease in hospitalized IBD patients in a symptoms [18]. Four to six biopsies were taken from the medical center in Taiwan, evaluated the severity of CMV ulcerative area when there was a disease flare-up. colitis by histology and its impact on IBD patients, searched A single, experienced pathologist who was blinded to the possible associated factors,andcomparedtheoutcomes the clinical data reviewed the hematoxylin and eosin between IBD patients with and without CMV colitis. staining (H&E) and CMV immunohistochemial (IHC) stained slides of the study period. Immunohistochemical Methods studies were performed with monoclonal anti-CMV The institutional review board of the National Taiwan antibodies (clone CCH2 and DDG9; Dako) in a single University Hospital (NTUH) ethics committee approved section followed by staining with an Avidin-Biotin com- this study. This retrospective study reviewed the IBD pa- plex (ABC) using standard techniques [19]. The number tients admitted to NTUH, a referral medical center in of CMV-positive cells was expressed using a semiquanti- Taiwan, from January 1, 1998 through December 31, tative scale: rare, easy to find, or numerous [20, 21]. 2013. The patients were identified from the computer- The clinical condition guided the physician’s decision ized databases of the NTUH using the International on whether to administer antiviral drugs. The antiviral Classification of Disease (2001 version) for disease cod- therapy in this study consisted of Gancyclovir 250 mg ing (ulcerative colitis (UC) as 556, Crohn’s disease (CD) per 12 h and was administered for 2–4 weeks. as 555, respectively). All data were completely reviewed by the same gastroenterologist. Statistical analysis The definition and criteria for UC and CD diagnosis in- The results are expressed as a median and range. The cluded the combination of clinical, endoscopic, and histo- Chi-squared test or two-tailed Fisher exact test were logical features and the exclusion of an infectious etiology. used to compare qualitative variables in IBD patients The definition of a clinical flare up is one requiring admis- with a CMV infection. Student’s t-test was used for sion and retreatment with steroids or the need for new quantitative variables. These analyses were carried out medications to control disease activity. Colitis was classi- using the SPSS 11.0 program (SPSS, Paris, France). A fied as proctitis (E1), left sided (E2), and extensive (E3) in p-value of less than 0.05 was considered significant. UC [15] and ileal (L1), colonic (L2) and ileocolonic (L3) in CD [16] according to the Montreal classifications. The se- Results verity of ulcerative colitis was classified according to the Demographic characteristics of patients Truelove and Witts severity index. During the 15 years from 1998 to 2013, a total of 673 In the NTUH, the clinical practice for treating admitted IBD patients were hospitalized. There were 312 patients UC patients due to aggravated symptoms was an initial diagnosed with CD and 361 with UC. Of these patients, stool culture to exclude infection. If there was no evidence 11 (1.6%) were diagnosed with CMV colitis (seven of infection, intravenous steroids were used as the first line female and four male). The median age of the patients of acute stage management. If the condition did not im- was 47.3 years (range of 21 to 6o years) in UC and prove, a further colonoscopy was performed to exclude 61.3 years (range of 21 to 66 years) in CD. Regarding the other causes of symptom aggravation and a biopsy was patients with IBD, there were no significant differences performed when possible and necessary at that time. between the positive and negative CMV colitis groups in Clinical data including demographic data, clinical gender and operation risk. Among the CD patients, the symptoms, treatment regiments before CMV diagnosis,