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Cytomegalovirus Colitis in Inflammatory Bowel Disease And BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2018-000258 on 27 February 2019. Downloaded from Inflammatory bowel disease Cytomegalovirus colitis in inflammatory bowel disease and after haematopoietic stem cell transplantation: diagnostic accuracy, predictors, risk factors and disease outcome Eirini Mavropoulou, Kristin Ternes, Nicolae-Catalin Mechie, Sebastian Christopher Benjamin Bremer, Steffen Kunsch, Volker Ellenrieder, Albrecht Neesse, Ahmad Amanzada To cite: Mavropoulou E, ABSTRACT Summary box Ternes K, Mechie N-C, et al. Background Concurrent cytomegalovirus (CMV) Cytomegalovirus colitis in colitis in inflammatory bowel disease (IBD) and after What is already known about this subject? inflammatory bowel disease haematopoietic stem cell transplantation (HSCT) is an and after haematopoietic Gastrointestinal cytomegalovirus (CMV) disease is important clinical entity associated with high rates of ► stem cell transplantation: especially prevalent in immunosuppressed patients morbidity and mortality. diagnostic accuracy, predictors, with inflammatory bowel disease or after haemato- Methods A retrospective study of 47 patients with IBD and risk factors and disease poietic stem cell transplantation. CMV can be de- outcome. BMJ Open Gastro 61 HSCT patients was performed regarding the evaluation tected by histological staining methods or by PCR copyright. 2019;6:e000258. doi:10.1136/ of diagnostic accuracy of applied methods, predictors, risk with different diagnostic accuracies. bmjgast-2018-000258 factors for CMV disease manifestation, the proportion of patients with antiviral treatment and disease outcome. What are the new findings? EM and KT contributed equally. Results The sensitivity of quantitative PCR (qPCR) with ► Our findings consolidate the diagnostic certainty a cut-off value of >250 copies/mg for CMV colitis in of the quantitative PCR in intestinal tissue, which Received 28 October 2018 patients with IBD and HSCT patients was 79% and 92%, showed an acceptable sensitivity for diagnosing Revised 27 December 2018 respectively. Predictors for CMV colitis in the IBD cohort CMV colitis. This study is the first that evaluat- Accepted 28 December 2018 were anaemia and the presence of endoscopic ulcers. ed the diagnostic certainty of the cut-off value of Glucocorticoids, calcineurin inhibitors and >2 concurrent >250 copies/mg in patients after allogeneic stem lines of treatment with immunosuppressive drugs could be cell transplantation. The low sensitivity of the his- http://bmjopengastro.bmj.com/ identified as risk factors for CMV colitis in the IBD cohort tological and immunohistochemical examination is with an OR of 7.1 (95% CI 1.7 to 29.9), 21.3 (95% CI 2.4 in line with data from the literature. Anaemia and to 188.7) and 13.4 (95% CI 3.2 to 56.1), respectively. the presence of endoscopic ulcers seem to be pre- Predictors and risk factors for CMV gastroenteritis in dictive factors for CMV colitis. The use of glucocor- the HSCT cohort was the presence of endoscopic ulcers ticoids and immunosuppressive agents as well as (OR 18.6, 95% CI 3.3 to 103.7) and >2 concurrent lines concurrent administration of more than two lines of treatment with immunosuppressive drugs. Antiviral of immunosuppressive drugs increased the risk for therapy was administered in 70% of patients with IBD and CMV colitis. 77% of HSCT patients with CMV disease. 71% of antiviral- treated patients with IBD showed an improvement of How might it impact on clinical practice in the foreseeable future? their disease activity and 14% underwent colectomy. The on October 1, 2021 by guest. Protected © Author(s) (or their mortality rate of HSCT patients was 21% irrespective of ► The additional use of quantitative PCR for detection employer(s)) 2019. Re-use of gastrointestinal CMV disease manifestation in permitted under CC BY-NC. No their CMV status. patients with inflammatory bowel disease and after commercial re-use. See rights Conclusions In addition to the implementation of and permissions. Published histological methods, qPCR may be performed in patients haematopoietic stem cell transplantation may help by BMJ. with suspected high-risk IBD and HSCT patients for CMV facilitate timely diagnosis of CMV disease and im- Department of Gastroenterology colitis. Independent validations of these results in further prove outcome. We believe that the identified risk and Gastrointestinal Oncology, prospective studies are needed. factors and predictors help increase the awareness Universitatsklinikum Gottingen, among physicians in the diagnosis of CMV disease. Gottingen, Germany and haematopoietic stem cell transplanta- Correspondence to Dr Ahmad Amanzada; BACKGROUND tion (HSCT) are at an increased risk for cyto- ahmad. amanzada@ med. uni- Patients with inflammatory bowel disease megalovirus (CMV) infection and disease goettingen. de (IBD) under immunosuppressive therapy given the virus’ tropism for inflamed tissue.1 2 Mavropoulou E, et al. BMJ Open Gastro 2019;6:e000258. doi:10.1136/bmjgast-2018-000258 1 BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2018-000258 on 27 February 2019. Downloaded from Open access Interestingly, patients with medically refractory ulcera- medical records of outpatients and inpatients were tive colitis (UC) are at the highest risk for CMV disease analysed for this study. compared with severe Crohn’s disease (CD), and patients The diagnosis of IBD was based on clinical, laboratory, with pouchitis.3–7 endoscopic, radiologic, and histological parameters. We Following HSCT, CMV infection occurs in up to 25%, included only adult patients with IBD with known CMV and gastrointestinal (GI) CMV disease manifests in 10% status, complete medical records, symptomatic patients of these cases. The mortality rate of these patients is undergoing endoscopic evaluation to assess the disease highly increased and can approach up to 80%.8 Early severity, biopsies for CMV detection (for histology and and accurate differentiation between GI graft versus host PCR) and regular follow-ups. Patients with mild symp- disease (GVHD) and CMV diseases is critical for the clin- toms and clinically a low probability of CMV disease did ical management, because of the fundamentally different not undergo CMV testing and were therefore excluded. treatment strategies. For patients with IBD, early detec- First, stool cultures were analysed in all patients with tion and rapid initiation of antiviral treatment for CMV aggravated symptoms to exclude bacterial (clostridium disease seems to reduce the mortality and colectomy difficile, salmonella, yersinia, campylobacter and rate.9 shigella) or viral (adenovirus, norovirus and rotavirus) The major challenge in the management of patients infection. After exclusion of an infection, intravenous with IBD and HSCT is the differentiation between acute steroids were used as the first-line treatment for acute IBD exacerbation or acute GVHD and CMV colitis. exacerbation management. If clinical symptoms did not In order to differentiate these conditions, endoscopic improve under corticosteroid treatment, endoscopy was examinations have to be performed with sampling of performed to exclude other causes of symptom aggrava- tissue biopsies. tion and to collect an intestinal tissue biopsy. Previous studies which examined the diagnostic accu- The HSCT patients were identified from the comput- racy of haematoxylin and eosin (H&E) staining have erised database of the Clinic for Gastroenterology and shown a sensitivity of only ~10%.10–12 Therefore, an Gastrointestinal Oncology of the University Medical adjunct method to further improve the diagnostic value Center Goettingen using Clinic WinData software by of histological techniques immunohistochemistry (IHC) E&L medical systems, Erlangen, Germany. We searched is recommended. Using this technique, the sensitivity for patients who underwent endoscopic examination due copyright. can be increased up to ~78%.11 13 However, in order to to GI symptoms or suspicion of GI-GVHD. In contrast to achieve adequate sensitivity a high number of biopsy patients with IBD, only a small part of the HSCT patients samples must be examined and a trained pathologist underwent endoscopic procedures. These adult patients must be available at all times.14 Due to these limitations, had malignant and non-malignant haematological quantitative PCR (qPCR) analysis in intestinal tissue spec- diseases and underwent a myeloablative or non-myeloab- lative HSCT at the Clinic for Haematology and Oncology imens was described as a useful addition to clinical and 15 of the University Medical Center Goettingen. The inclu- endoscopic findings for diagnosing CMV GI disease. sion criteria were: (1) known CMV status, (2) complete The aim of this study was to examine the diagnostic medical records and (3) regular follow-ups. Patients with http://bmjopengastro.bmj.com/ accuracy of the above-mentioned methods hypothesising GVHD were excluded. that the additional use of quantitative CMV-DNA-PCR Clinical GI-GVHD was defined as the presence of diar- (qPCR) in intestinal tissue increases the detection rate rhoea, persistent nausea and vomiting, and abdominal of CMV colitis. We further evaluated the risk factors for pain with or without ileus with positive GI-GVHD histo- GI CMV disease in patients with IBD and HSCT patients logical findings.16 and analysed the disease outcome in these cohorts in a The conditioning regimens and GVHD prophylaxis tertiary referral centre. were selected according to ongoing protocols at the University
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