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Jentzer A, Veyrard P, Roblin X, Saint-Sardos P, Rochereau N, Paul S, Bourlet T, Pozzetto B, Pillet S. Cytomegalovirus and Inflammatory Bowel Diseases (IBD) with a Special Focus on the Link with Ulcerative Colitis (UC). Microorganisms 2020; 8:1078. [PMID: 32698383 PMCID: PMC7409252 DOI: 10.3390/microorganisms8071078] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/10/2020] [Accepted: 07/12/2020] [Indexed: 12/16/2022] Open
Abstract
Cytomegalovirus (CMV) infects approximately 40% of adults in France and persists lifelong as a latent agent in different organs, including gut. A close relationship is observed between inflammation that favors viral expression and viral replication that exacerbates inflammation. In this context, CMV colitis may impact the prognosis of patients suffering from inflammatory bowel diseases (IBDs), and notably those with ulcerative colitis (UC). In UC, the mucosal inflammation and T helper cell (TH) 2 cytokines, together with immunomodulatory drugs used for controlling flare-ups, favor viral reactivation within the gut, which, in turn, increases mucosal inflammation, impairs corticoid and immunosuppressor efficacy (the probability of steroid resistance is multiplied by more than 20 in the case of CMV colitis), and enhances the risk for colectomy. This review emphasizes the virological tools that are recommended for exploring CMV colitis during inflammatory bowel diseases (IBD) and underlines the interest of using ganciclovir for treating flare-ups associated to CMV colitis in UC patients.
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Affiliation(s)
- Alexandre Jentzer
- GIMAP EA 3064, Medicine Faculty of Saint-Etienne, University of Lyon, 69007 Lyon, France; (A.J.); (P.V.); (X.R.); (N.R.); (S.P.); (T.B.); (B.P.)
- Laboratory of infectious agents and hygiene, University Hospital Saint-Etienne, 42055 Saint-Etienne, France
- Laboratory of Immunology, University Hospital Saint-Etienne, 42055 Saint-Etienne, 42055 Saint-Etienne, France
| | - Pauline Veyrard
- GIMAP EA 3064, Medicine Faculty of Saint-Etienne, University of Lyon, 69007 Lyon, France; (A.J.); (P.V.); (X.R.); (N.R.); (S.P.); (T.B.); (B.P.)
- Department of Gastroenterology, University Hospital Saint-Etienne, 42055 Saint-Etienne, France
| | - Xavier Roblin
- GIMAP EA 3064, Medicine Faculty of Saint-Etienne, University of Lyon, 69007 Lyon, France; (A.J.); (P.V.); (X.R.); (N.R.); (S.P.); (T.B.); (B.P.)
- Department of Gastroenterology, University Hospital Saint-Etienne, 42055 Saint-Etienne, France
| | - Pierre Saint-Sardos
- Laboratory of Bacteriology, University Hospital of Clermont-Ferrand, 63100 Clermont-Ferrand, France;
| | - Nicolas Rochereau
- GIMAP EA 3064, Medicine Faculty of Saint-Etienne, University of Lyon, 69007 Lyon, France; (A.J.); (P.V.); (X.R.); (N.R.); (S.P.); (T.B.); (B.P.)
| | - Stéphane Paul
- GIMAP EA 3064, Medicine Faculty of Saint-Etienne, University of Lyon, 69007 Lyon, France; (A.J.); (P.V.); (X.R.); (N.R.); (S.P.); (T.B.); (B.P.)
- Laboratory of Immunology, University Hospital Saint-Etienne, 42055 Saint-Etienne, 42055 Saint-Etienne, France
| | - Thomas Bourlet
- GIMAP EA 3064, Medicine Faculty of Saint-Etienne, University of Lyon, 69007 Lyon, France; (A.J.); (P.V.); (X.R.); (N.R.); (S.P.); (T.B.); (B.P.)
- Laboratory of infectious agents and hygiene, University Hospital Saint-Etienne, 42055 Saint-Etienne, France
| | - Bruno Pozzetto
- GIMAP EA 3064, Medicine Faculty of Saint-Etienne, University of Lyon, 69007 Lyon, France; (A.J.); (P.V.); (X.R.); (N.R.); (S.P.); (T.B.); (B.P.)
- Laboratory of infectious agents and hygiene, University Hospital Saint-Etienne, 42055 Saint-Etienne, France
| | - Sylvie Pillet
- GIMAP EA 3064, Medicine Faculty of Saint-Etienne, University of Lyon, 69007 Lyon, France; (A.J.); (P.V.); (X.R.); (N.R.); (S.P.); (T.B.); (B.P.)
- Laboratory of infectious agents and hygiene, University Hospital Saint-Etienne, 42055 Saint-Etienne, France
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Yilmaz Karadag F, Arslan F, Caskurlu H, Cag Y, Vahaboglu H. Efficacy of antiviral treatment in cytomegalovirus detected ulcerative colitis: meta-analysis of available data. Scand J Gastroenterol 2019; 54:1346-1352. [PMID: 31718340 DOI: 10.1080/00365521.2019.1688860] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Aim: This meta-analysis aimed to pool available data regarding the efficacy of ganciclovir treatment among cytomegalovirus-detected ulcerative colitis patients.Methods: We screened PubMed, Ovid, Web of Science and Cochrane databases for relevant studies, and four investigators independently evaluated the studies for eligibility. The primary outcome was surgical resection or death from ulcerative colitis. The data were then pooled via DerSimonian-Laird estimator and Mantel-Haenszel (MH) method, two points added for continuity correction and random-effects model fitted in the Bayesian framework. We first constructed a Bugs model with Student t-distribution as prior for between-study heterogeneity. The model was fitted by Gibbs sampler (JAGS) to produce a marginal posterior distribution.Results: Our screening identified 15 eligible studies for final data synthesis and combined data from 191 ganciclovir-treated and 166 non-treated patients. Effect estimates from the fixed-effects meta-analysis model did not encourage ganciclovir treatment (OR, 1.43; 95% CIs [0-95, 2.16]), with a negligible unaccounted heterogeneity (I2 = 0%). The Bayesian random-effects model generated high-density credible intervals, suggesting a high probability, that future studies will also not encourage ganciclovir treatment (mu, 1.028; 95% credible intervals [0.054, 2.238]; 80% credible intervals [0.401, 1.703]) which indicates that future studies will favor non-treatment of ulcerative colitis with ganciclovir.Conclusions: Data produced in this study do not encourage ganciclovir treatment for UC patients. However, studies included in this analysis were observational, and thus, inherited severe selection bias. We suggest randomized controlled studies be conducted to make firm recommendations in this context.
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Affiliation(s)
- Fatma Yilmaz Karadag
- Enfeksiyon Hastalıkları ve Klinik Mikrobiyoloji, Istanbul Medeniyet Universitesi, Istanbul, Turkey
| | - Ferhat Arslan
- Enfeksiyon Hastalıkları ve Klinik Mikrobiyoloji, Istanbul Medeniyet Universitesi, Istanbul, Turkey
| | - Hulya Caskurlu
- Enfeksiyon Hastalıkları ve Klinik Mikrobiyoloji, Istanbul Medeniyet Universitesi, Istanbul, Turkey
| | - Yasemin Cag
- Enfeksiyon Hastalıkları ve Klinik Mikrobiyoloji, Istanbul Medeniyet Universitesi, Istanbul, Turkey
| | - Haluk Vahaboglu
- Enfeksiyon Hastalıkları ve Klinik Mikrobiyoloji, Istanbul Medeniyet Universitesi, Istanbul, Turkey
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Maeda T, Sakai H, Ozawa N, Sugiyama T, Takada J, Kubota M, Ibuka T, Shirakami Y, Araki H, Shimizu M. Acute cytomegalovirus infection in an immunocompetent patient with ulcerative colitis: A case report. Exp Ther Med 2019; 18:2271-2277. [PMID: 31452714 DOI: 10.3892/etm.2019.7823] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 07/18/2019] [Indexed: 11/06/2022] Open
Abstract
Cytomegalovirus (CMV) is a ubiquitous member of the Herpesviridae family that can present with a variety of clinical manifestations, including encephalitis, retinitis, interstitial pneumonia and colitis. These serious symptoms are generally observed as opportunistic infections in immunocompromised hosts, including patients with acquired immunodeficiency syndrome and those receiving steroids and/or immunosuppressants. Symptomatic CMV infections in patients with ulcerative colitis are found in patients treated with steroids and/or immunosuppressants but rarely affect those who are not taking these agents. The present study reported the case of a young patient without concurrent use of immunosuppressive agents for the treatment of ulcerative colitis. The patient presented with acute mononucleosis and colitis caused by primary CMV infection. This was characterized by the presence of atypical lymphocytes and hepatosplenomegaly, elevation of transaminase levels, serology-positive anti-CMV IgM, and CMV antigenemia. Additionally, CMV-positive cells were histologically detected in colonic biopsy specimens. The patient's symptoms and clinical parameters improved following initiation of intravenous ganciclovir. It was concluded that even if patients with ulcerative colitis are not treated with steroids and/or immunosuppressants, significant attention should be paid to acute CMV infections in the context of severe or persistent colonic inflammation.
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Affiliation(s)
- Toshihide Maeda
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Hiroyasu Sakai
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Noritaka Ozawa
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Tomohiko Sugiyama
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Jun Takada
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Masaya Kubota
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Takashi Ibuka
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Yohei Shirakami
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Hiroshi Araki
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Masahito Shimizu
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
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Shivaji UN, Sharratt CL, Thomas T, Smith SCL, Iacucci M, Moran GW, Ghosh S, Bhala N. Review article: managing the adverse events caused by anti-TNF therapy in inflammatory bowel disease. Aliment Pharmacol Ther 2019; 49:664-680. [PMID: 30735257 DOI: 10.1111/apt.15097] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 08/12/2018] [Accepted: 11/23/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Biological therapy is currently widely used to treat IBD. Infliximab, adalimumab and golimumab are currently licensed anti-TNF therapies. Biosimilar anti-TNF monoclonal antibodies are increasingly used. Anti-TNF therapies are widely used and their adverse effects are well characterised, and may cause significant morbidity and mortality in a small proportion of exposed patients. Gastroenterologists need to understand the mechanisms for these effects, recognise these swiftly and manage such events appropriately. AIM To cover the range of potential adverse reactions as a result of biologic therapy and specifically management of these events. METHODS A Medline and Pubmed search was undertaken. Search terms included were "anti-TNF," "infliximab" or "adalimumab" or "golimumab" combined with the keywords "ulcerative colitis" or "Crohn's disease" or "inflammatory bowel disease" and then narrowed to articles containing the keywords "complications," "side effects" or "adverse events" or "safety profile." International guidelines were also reviewed where relevant. RESULTS Adverse events discussed in this review include infusion reactions, blood disorders and infections (including bacterial, viral, fungal and opportunistic infections) as well as autoimmune, dermatological disorders, cardiac and neurological conditions. Malignancies including solid organ, haematological and those linked to viral disease are discussed. CONCLUSIONS Anti-TNF therapy has wide-ranging effects on the immune system resulting in a spectrum of potential adverse events in a small proportion of patients. Research advances are improving the understanding, recognition and management of these adverse events.
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Affiliation(s)
- Uday N Shivaji
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, Birmingham, UK.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Caroline L Sharratt
- National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre, Nottingham, UK.,Nottingham Digestive Diseases Centre, Nottingham University Hospitals, Nottingham, UK
| | - Tom Thomas
- Department of Gastroenterology, University Hospitals Birmingham, Birmingham, UK
| | | | - Marietta Iacucci
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, Birmingham, UK.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Institute of Translational Medicine, Edgbaston, UK
| | - Gordon W Moran
- National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre, Nottingham, UK.,Nottingham Digestive Diseases Centre, Nottingham University Hospitals, Nottingham, UK
| | - Subrata Ghosh
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, Birmingham, UK.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Institute of Translational Medicine, Edgbaston, UK
| | - Neeraj Bhala
- Department of Gastroenterology, University Hospitals Birmingham, Birmingham, UK.,University of Birmingham, Birmingham, UK
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5
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Turner D, Ruemmele FM, Orlanski-Meyer E, Griffiths AM, de Carpi JM, Bronsky J, Veres G, Aloi M, Strisciuglio C, Braegger CP, Assa A, Romano C, Hussey S, Stanton M, Pakarinen M, de Ridder L, Katsanos KH, Croft N, Navas-López VM, Wilson DC, Lawrence S, Russell RK. Management of Paediatric Ulcerative Colitis, Part 2: Acute Severe Colitis-An Evidence-based Consensus Guideline From the European Crohn's and Colitis Organization and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2018; 67:292-310. [PMID: 30044358 DOI: 10.1097/mpg.0000000000002036] [Citation(s) in RCA: 151] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM Acute severe colitis (ASC) is one of the few emergencies in pediatric gastroenterology. Tight monitoring and timely medical and surgical interventions may improve outcomes and minimize morbidity and mortality. We aimed to standardize daily treatment of ASC in children through detailed recommendations and practice points which are based on a systematic review of the literature and consensus of experts. METHODS These guidelines are a joint effort of the European Crohn's and Colitis Organization (ECCO) and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). Fifteen predefined questions were addressed by working subgroups. An iterative consensus process, including 2 face-to-face meetings, was followed by voting of the national representatives of ECCO and all members of the Paediatric Inflammatory Bowel Disease (IBD) Porto group of ESPGHAN (43 voting experts). RESULTS A total of 24 recommendations and 43 practice points were endorsed with a consensus rate of at least 91% regarding diagnosis, monitoring, and management of ASC in children. A summary flowchart is presented based on daily scoring of the Paediatric Ulcerative Colitis Activity Index. Several topics have been altered since the previous 2011 guidelines and from those published in adults. DISCUSSION These guidelines standardize the management of ASC in children in an attempt to optimize outcomes of this intensive clinical scenario.
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Affiliation(s)
- Dan Turner
- Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Frank M Ruemmele
- Université Paris Descartes, Sorbonne Paris Cité, APHP, Hôpital Necker Enfants Malades, Paris, France
| | | | - Anne M Griffiths
- The Hospital for Sick Children, University of Toronto, Toronto, Canada
| | | | - Jiri Bronsky
- Department of Paediatrics, University Hospital Motol, Prague, Czech Republic
| | - Gabor Veres
- Ist Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Marina Aloi
- Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome
| | - Caterina Strisciuglio
- Department of Woman, Child and General and Specialistic Surgery, University of Campania "Luigi Vanvitelli," Napoli, Italy
| | | | - Amit Assa
- Schneider Children's Hospital, Petach Tikva (affiliated to the Sackler Faculty of Medicine), Tel Aviv University, Tel Aviv, Israel
| | - Claudio Romano
- Pediatric Department, University of Messina, Messina, Italy
| | - Séamus Hussey
- National Children's Research Centre, Royal College of Surgeons of Ireland and University College Dublin, Ireland
| | | | - Mikko Pakarinen
- Helsinki University Children's Hospital, Department of Pediatric Surgery, Helsinki, Finland
| | - Lissy de Ridder
- Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
| | | | - Nick Croft
- Barts and the London School of Medicine, Queen Mary University of London, London, UK
| | | | - David C Wilson
- Child Life and Health, University of Edinburgh, Edinburgh, UK
| | - Sally Lawrence
- BC Children's Hospital, University of British Columbia, Vancouver BC, Canada
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Cohen S, Martinez-Vinson C, Aloi M, Turner D, Assa A, de Ridder L, Wolters VM, de Meij T, Alvisi P, Bronsky J, Kopylov U. Cytomegalovirus Infection in Pediatric Severe Ulcerative Colitis-A Multicenter Study from the Pediatric Inflammatory Bowel Disease Porto Group of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition. Pediatr Infect Dis J 2018; 37:197-201. [PMID: 29424814 DOI: 10.1097/inf.0000000000001724] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Data on the clinical course and outcomes of pediatric patients with cytomegalovirus (CMV) infection complicating acute severe ulcerative colitis (ASC) are very limited. The aim of our study was to compare outcomes of children with ASC who were CMV positive or CMV negative. METHODS This was a multicenter retrospective case-controlled study, from centers affiliated with the Pediatric Inflammatory Bowel Disease Porto Group of European Society of Pediatric Gastroenterology, Hepatology, and Nutrition. We included CMV-positive children hospitalized for ASC and compared their colectomy rate during hospitalization and up to 1 year thereafter, matched with CMV-negative controls. RESULTS A total of 56 children were included; 15 CMV positive and 41 CMV negative. More CMV-positive patients were resistant to intravenous corticosteroids as compared with CMV negative (93% and 56% respectively, P = 0.009). Fourteen of the CMV-positive children (93%) were treated with ganciclovir [5/14 (36%) with 5 mg/kg and 9/14 (64%) with 10 mg/kg]. During hospitalization, 3 (20%) CMV-positive and 3 (7.8%) CMV-negative patients required colectomy (P = 0.17). By 12 months, 5 (33%) and 5 (13%) CMV-positive and CMV-negative patients required colectomy, respectively (P = 0.049); the significance was not retained on multivariate analysis. CONCLUSIONS A higher prevalence of CMVpositivity was found in pediatric ulcerative colitis patients who required colectomy within 12 months of hospitalization for ASC. Further studies are needed to clarify the impact of CMV infection on the outcome of acute severe colitis in pediatric patients.
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Kopylov U, Papamichael K, Katsanos K, Waterman M, Bar-Gil Shitrit A, Boysen T, Portela F, Peixoto A, Szilagyi A, Silva M, Maconi G, Har-Noy O, Bossuyt P, Mantzaris G, Barreiro de Acosta M, Chaparro M, Christodoulou DK, Eliakim R, Rahier JF, Magro F, Drobne D, Ferrante M, Sonnenberg E, Siegmund B, Muls V, Thurm T, Yanai H, Dotan I, Raine T, Levin A, Israeli E, Ghalim F, Carbonnel F, Vermeire S, Ben-Horin S, Roblin X. Impact of Infliximab and Cyclosporine on the Risk of Colectomy in Hospitalized Patients with Ulcerative Colitis Complicated by Cytomegalovirus-A Multicenter Retrospective Study. Inflamm Bowel Dis 2017; 23:1605-1613. [PMID: 28590343 DOI: 10.1097/mib.0000000000001160] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Cytomegalovirus (CMV) is frequently detected in patients with ulcerative colitis (UC). The impact of CMV infection on the outcome of UC exacerbation remains unclear. The benefit of combining antiviral with anti-inflammatory treatment has not been evaluated yet. The aim of this study was to compare the outcome of CMV-positive hospitalized patients with UC treated with antiviral therapy either alone or combined with salvage anti-inflammatory therapy (infliximab [IFX] or cyclosporine A [CsA]). METHODS This was a multicenter retrospective study of hospitalized CMV-positive patients with UC. The patients were classified into 2 groups: antiviral-if treated with antivirals alone; combined-if treated with both antiviral and anti-inflammatory therapy. The outcomes included the rate of colectomy in both arms during the course of hospitalization and after 3/12 months. RESULTS A total of 110 patients were included; 47 (42.7%) patients did not receive IFX nor CsA; 36 (32.7%) received IFX during hospitalization or within 1 month before hospitalization; 20 (18.1%) patients received CsA during hospitalization; 7 (6.4%) were exposed to both IFX and CsA. The rate of colectomy was 14.5% at 30 days, 20.0% at 3 months, and 34.8% at 12 months. Colectomy rates were similar across treatment groups. No clinical and demographic variables were independently associated with the risk of colectomy. CONCLUSIONS IFX or cyclosporine therapy is not associated with additional risk for colectomy over antiviral therapy alone in hospitalized CMV-positive patients with UC.
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Affiliation(s)
- Uri Kopylov
- 1Department of Gastroenterology, Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; 2Department of Gastroenterology, Evaggelismos Hospital, Athens, Greece; 3Department of Clinical and Experimental Medicine, KU Leuven, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium; 4Department of Gastroenterology, University Hospital of Ioannina, Ioannina, Greece; 5Department of Gastroenterology, Rambam Health Care Campus, B. Rappaport Faculty of Medicine, the Technion, Haifa, Israel; 6Shaare Zedek Medical Center, Digestive Diseases Institute, Jerusalem, Israel; 7Department of Gastroenterology, Herlev University Hospital, Herlev, Denmark; 8Department of Gastroenterology, Hospital Universidade Coimbra, Coimbra, Portugal; 9Department of Gastroenterology, Centro Hospitalar São João, Porto, Portugal; 10Department of Gastroenterology, Jewish General Hospital, Montreal, Québec, Canada; 11Department of Gastroenterology, Luigi Sacco' University Hospital, Milan, Italy; 12Department of Gastroenterology, Imelda GI Clinical Research Center, Bonheiden, Belgium; 13IBD Unit, Gastroenterology Department, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain; 14Department of Gastroenterology, Hospital Universitario de La Princesa, Madrid, Spain; 15Department of Gastroenterology, CHU Dinant Godinne, UCL Namur, Yvoir, Belgium; 16Department of Gastroenterology, University Medical Centre Ljubljana, Slovenia; 17Department of Medicine (Gastroenterology, Infectious Diseases, Rheumatology), Charité-Universitätsmedizin Berlin, Berlin, Germany; 18Department of Gastroenterology and Hepatology, CHU Saint-Pierre, Université Libre de Bruxelles, Brussels, Belgium; 19Department of Gastroenterology and Liver Diseases, IBD Center, Tel Aviv Sourasky Medical Center, Affiliated to the Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel; 20Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; 21Department of Gastroenterology, Hadassah Medical Center, Jerusalem, Israel; 22Service de Gastroentérologie, Hôpital Universitaire de Bicêtre, Université Paris Sud, Assistance Publique-Hôpitaux de Paris, le Kremlin Bicêtre, Paris, France; and 23Department of Gastroenterology, CHU de Saint-Etienne, Saint Etiennne, France
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Campos ST, Portela FA, Tomé L. Cytomegalovirus, inflammatory bowel disease, and anti-TNFα. Int J Colorectal Dis 2017; 32:645-650. [PMID: 28084548 DOI: 10.1007/s00384-017-2752-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/06/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND PURPOSE Anti-TNFα agents emerged in inflammatory bowel disease (IBD) as an effective option in situations that, otherwise, would be refractory to medical therapy. Cytomegalovirus infection may present with a high spectrum of manifestations and lead to high morbidity and mortality. However, its clinical significance in IBD course remains unknown and data on its association with anti-TNFα are limited. AIMS This study aims to evaluate cytomegalovirus (CMV) infection/disease in patients with IBD treated with anti-TNFα; if possible, possible risk factors associated with CMV infection/disease in IBD patients under anti-TNFα as well as the influence of CMV infection/disease in IBD course would be determined. METHODS During three consecutive years, all IBD patients starting infliximab in our department were included. Cytomegalovirus status before anti-TNFα was evaluated. Data regarding IBD, therapeutic and IBD course after infliximab, were recorded. CMV analysis was performed with polymerase chain reaction (PCR)-cytomegalovirus in peripheral blood and colonoscopy with biopsies (histopathology/immunohistochemistry). RESULTS We included 29 patients: female-83%; Crohn's disease-51.8%, ulcerative colitis-44.8%, non-classified colitis-3.4%; 23 cytomegalovirus seropositive. Median follow-up: 19 months (3-36). During follow-up, 14 patients were under combination therapy with azathioprine and 5 did at least 1 cycle of corticosteroids. Twenty-one patients responded to infliximab. We registered 8 exacerbations of IBD. Four patients discontinued infliximab: none had CMV infection. We documented 1 case of intestinal cytomegalovirus infection-detected in biopsies performed per protocol in an asymptomatic UC patient, who responded to valganciclovir without infliximab discontinuation. CONCLUSIONS Infliximab, with/without immunosuppression, does not confer an increased risk of (re)activation of cytomegalovirus. Cytomegalovirus was not responsible neither for significant morbidity nor mortality in IBD.
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Affiliation(s)
- Sara T Campos
- Gastroenterology Department, Centro Hospitalar e Universitário de Coimbra, Praçeta Prof. Mota Pinto, 3000-075, Coimbra, Portugal.
| | - Francisco A Portela
- Gastroenterology Department, Centro Hospitalar e Universitário de Coimbra, Praçeta Prof. Mota Pinto, 3000-075, Coimbra, Portugal
| | - Luís Tomé
- Gastroenterology Department, Centro Hospitalar e Universitário de Coimbra, Praçeta Prof. Mota Pinto, 3000-075, Coimbra, Portugal
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Pillet S, Pozzetto B, Roblin X. Cytomegalovirus and ulcerative colitis: Place of antiviral therapy. World J Gastroenterol 2016; 22:2030-2045. [PMID: 26877608 PMCID: PMC4726676 DOI: 10.3748/wjg.v22.i6.2030] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Revised: 11/19/2015] [Accepted: 12/19/2015] [Indexed: 02/06/2023] Open
Abstract
The link between cytomegalovirus (CMV) infection and inflammatory bowel diseases remains an important subject of debate. CMV infection is frequent in ulcerative colitis (UC) and has been shown to be potentially harmful. CMV reactivation needs to be diagnosed using methods that include in situ detection of viral markers by immunohistochemistry or by nucleic acid amplification techniques. Determination of the density of infection using quantitative tools (numbers of infected cells or copies of the genome) is particularly important. Although CMV reactivation can be considered as an innocent bystander in active flare-ups of refractory UC, an increasing number of studies suggest a deleterious role of CMV in this situation. The presence of colonic CMV infection is possibly linked to a decreased response to steroids and other immunosuppressive agents. Some treatments, notably steroids and cyclosporine A, have been shown to favor CMV reactivation, which seems not to be the case for therapies using anti-tumor necrosis factor drugs. According to these findings, in flare-ups of refractory UC, it is now recommended to look for the presence of CMV reactivation by using quantitative tools in colonic biopsies and to treat them with ganciclovir in cases of high viral load or severe disease.
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10
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Antiviral Therapy in Steroid-refractory Ulcerative Colitis with Cytomegalovirus: Systematic Review and Meta-analysis. Inflamm Bowel Dis 2015. [PMID: 26197450 DOI: 10.1097/mib.0000000000000489] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND The role of antiviral therapy in patients with ulcerative colitis (UC) with cytomegalovirus (CMV) remains unclear. We therefore performed a systematic review and meta-analysis to assess the association between antiviral therapy and the risk of colectomy. METHODS Multiple electronic databases were searched systematically through July 2014 for studies reporting the risk of colectomy in patients with UC with CMV stratified by treatment with antiviral agents. Colectomy rates were assessed for the overall cohort and stratified by corticosteroid (CS) refractoriness. We estimated summary odds ratios and 95% confidence intervals, using random-effects model, and used Grading of Recommendations Assessment, Development, and Evaluation criteria to appraise the quality of evidence. RESULTS Fifteen observational studies (333 patients with UC with CMV, 43.2% treated with antiviral agents) were identified, of which 8 stratified patients according to CS-refractory disease (55.4% treated with antiviral agents). Antiviral therapy resulted in a significantly lower risk of colectomy in patients with CS-refractory disease (odds ratio, 0.20; 95% confidence interval, 0.08-0.49; I = 0%) but not in the overall population of patients with UC (odds ratio, 0.92; 95% confidence interval, 0.31-2.76; I = 65). The quality evidence was low. The results were stable when restricting the analysis to patients with a tissue diagnosis of CMV and studies that defined CS-refractory disease as a failure to respond to intravenous CS. CONCLUSIONS Antiviral therapy may benefit a subgroup of patients with UC who are refractory to CS. Further prospective trials are required to confirm these findings.
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Wu XW, Yang MF, Li N, Wang FY. Unfavorable outcome of antiviral therapy in cytomegalovirus-positive ulcerative colitis may be due to inappropriate study inclusion in meta-analysis. World J Gastroenterol 2015; 21:1689-1690. [PMID: 25663793 PMCID: PMC4316116 DOI: 10.3748/wjg.v21.i5.1689] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 11/13/2014] [Accepted: 12/16/2014] [Indexed: 02/06/2023] Open
Abstract
Some previous articles reported that antiviral treatment was effective to reduce the colectomy rate in ulcerative colitis (UC) patients with cytomegalovirus (CMV) infection. Kopylov et al recently carried out a systematic review and meta-analysis to evaluate the impact of antiviral therapy on CMV-positive UC. The results showed that patients who received antiviral treatment had a higher risk of 30-d colectomy. We found that in this meta-analysis, some studies were inappropriately included, leading to an unfavorable outcome of anti-CMV therapy in UC patients.
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Ozturk K. Antiviral treatment in patients with cytomegalovirus positive ulcerative colitis. World J Gastrointest Pathophysiol 2014; 5:589-590. [PMID: 25401002 PMCID: PMC4231523 DOI: 10.4291/wjgp.v5.i4.589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Revised: 06/29/2014] [Accepted: 09/17/2014] [Indexed: 02/06/2023] Open
Abstract
Cytomegalovirus (CMV) is a common virus in patients with ulcerative colitis receiving immunosuppressive drugs. Many studies suggested that CMV infection is an exacerbating factor in patients with ulcerative colitis. The role of CMV in exacerbations of ulcerative colitis has been discussed. One of studies starting this discussion is an article entitled “CMV positive ulcerative colitis: A single center experience and literature review” by Kopylov et al. However, we think that there are some points that should be emphasized about the study. Especially, the small number of patients in the study has led to meaningless results. Large controlled prospective trials are needed to clarify the benefit of antiviral therapy for active ulcerative colitis patients.
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Maconi G, Lombardini M, Furfaro F, Bezzio C, Zerbi P, Ardizzone S. Long-term outcome of inflammatory bowel diseases with cytomegalovirus colitis: effect of antiviral treatment. Eur J Gastroenterol Hepatol 2014; 26:1146-51. [PMID: 25089547 DOI: 10.1097/meg.0000000000000175] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE The role of cytomegalovirus (CMV) reactivation in the outcome of inflammatory bowel diseases (IBDs) is unclear. Uncertainties remain on the treatment of CMV infection, especially in patients with a viral load just above the normal value in the blood or with very few positive cells in colonic biopsies. This retrospective cohort study reports the long-term outcome of 38 active IBD patients with CMV infection, 13 of whom received an antiviral treatment. PATIENTS AND METHODS Thirty patients with ulcerative colitis (UC) and eight patients with Crohn's colitis with active colitis and CMV infection, diagnosed by detection of at least one CMV inclusion by histology and immunohistochemistry and/or with the CMV antigen test or the CMV DNA test, were studied. Their clinical history at 6 months and up to 1 year following hospital discharge was reviewed. Clinical remission at hospital discharge and recurrences requiring new treatments or colectomy were considered major outcomes of the study. The features of treated and untreated patients were compared using the Fisher exact test and the Student t-test. RESULTS All patients showed rare CMV inclusions, and only three had positive blood CMV PCR. Thirteen patients received antiviral treatment, whereas 25 patients did not. No patient underwent colectomy during the hospitalization. The 12-month cumulative rate of clinical relapse requiring new treatment or colectomy was 23% in patients treated with antivirals and 50% in untreated patients (P=0.165). However, in patients with UC and in those with steroid-dependent/refractory disease, antiviral treatment was associated with a significantly higher clinical remission rate at 12 months (77.8 vs. 45%, P=0.049, and 77.8 vs. 19.4%, P=0.038, respectively). CONCLUSION In IBD patients with active CMV colitis, antiviral treatment seems to have a marginal impact in the short term, during the treatment of the acute phase, but it may have some beneficial effect in maintaining remission up to 1 year of follow-up in patients with UC and steroid-dependent/refractory disease.
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Affiliation(s)
- Giovanni Maconi
- aGastroenterology Unit bPathology Unit, Department of Biomedical and Clinical Sciences, 'L. Sacco' University Hospital, Milan, Italy
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Lübbert C, Weis S. [Drug therapy of infectious diarrhea. Part 2: Chronic diarrhea]. Internist (Berl) 2014; 54:1513-9. [PMID: 23917963 DOI: 10.1007/s00108-013-3337-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Diarrheal diseases are among the most common diseases worldwide. In this review the current treatment recommendations for acute (Part 1) and chronic (Part 2) infectious diarrhea are summarized and typical enteropathogens are discussed. The second part of the article describes chronic diarrhea, its related pathogens and treatment. In contrast to acute diarrhea which is mainly caused by viral and typical bacterial pathogens, chronic diarrhea has mainly non-infectious origins. Protozoal pathogens, such as Giardia lamblia and Entamoeba histolytica in particular are found and more rarely bacterial pathogens, such as Tropheryma whipplei. Opportunistic pathogens cause diarrhea in immunocompromised patients, such as in HIV patients. In these patients cytomegalovirus (CMV) colitis or infections with Cryptosporidium spp., Cyclospora cayetanensis, Isospora belli or microsporidia have to be considered. Besides targeted specific antimicrobial therapy, anti-retroviral drugs improving the underlying immunosuppression and thus the reconstitution of the adaptive immune response remain a cornerstone of the treatment in HIV-positive patients.
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Affiliation(s)
- C Lübbert
- Fachbereich Infektions- und Tropenmedizin, Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Department für Innere Medizin, Neurologie und Dermatologie, Universitätsklinikum Leipzig, AöR, Liebigstr. 20, 04103, Leipzig, Deutschland,
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Seicean A, Moldovan-Pop A, Seicean R. Ulcerative colitis worsened after Clostridium difficile infection: efficacy of infliximab. World J Gastroenterol 2014; 20:5135-5140. [PMID: 24803831 PMCID: PMC4009553 DOI: 10.3748/wjg.v20.i17.5135] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 01/25/2014] [Accepted: 02/17/2014] [Indexed: 02/06/2023] Open
Abstract
The incidence of Clostridium difficile (C. difficile) infection (CDI) is 1.8%-5.7% in admitted patients with ulcerative colitis (UC). CDI can worsen UC and increase the risk for colectomy or even death, thus necessitating therapy escalation, such as increasing the corticoid therapy or starting a biologic treatment. Several reported cases with infliximab therapy have provided favorable outcomes in UC patients with CDI, suggesting that infliximab treatment may be protective; however, the optimal infliximab treatment regimen for UC patients with CDI remains to be established. Here, we report a case of worsening UC in the presence of recurrent CDI. The patient had received prior ciprofloxacin and immunosuppressive therapy during a prolonged hospital stay. The deterioration in the patient's condition likely resulted from the ability of C. difficile to promote relapsing of UC by activating the immune response. Ultimately, the patient was treated with a high dose of infliximab after a low trough level of infliximab at week 8 was identified, yielding better clinical results. Infliximab was found to be safe after repetitive episodes of CDI. The trough level of infliximab was therefore a useful indicator to guide therapy and correlated well with the patient's outcome.
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Kopylov U, Eliakim-Raz N, Szilagy A, Seidman E, Ben-Horin S, Katz L. Antiviral therapy in cytomegalovirus-positive ulcerative colitis: A systematic review and meta-analysis. World J Gastroenterol 2014; 20:2695-2703. [PMID: 24627606 PMCID: PMC3949279 DOI: 10.3748/wjg.v20.i10.2695] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Revised: 10/22/2013] [Accepted: 01/08/2014] [Indexed: 02/07/2023] Open
Abstract
AIM: To evaluate the impact of antiviral treatment on cytomegalovirus (CMV)-positive ulcerative colitis patients.
METHODS: We performed a systematic review and meta-analysis (MA) of comparative cohort and case-control studies published between January 1966 and March 2013. Studies focusing on colectomy series and studies including only less than 3 patients in the treated or non-treated arm were excluded. The primary outcome was colectomy within 30 d of diagnosis. Secondary outcomes included colectomy during the follow-up period Subgroup analyses by method of detection of CMV, study design, risk of bias and country of origin were performed. Quality of studies was evaluated according to modified New-Castle Ottawa Scale.
RESULTS: After full-text review, nine studies with a total of 176 patients were included in our MA. All the included studies were of low to moderate quality. Patients who have received antiviral treatment had a higher risk of 30-d colectomy (OR = 2.40; 95%CI: 1.05-5.50; I2 = 37.2%). A subgroup analysis including only patients in whom CMV diagnosis was based did not demonstrate a significant difference between the groups (OR = 3.41; 95%CI: 0.39-29.83; I2 = 56.9%). Analysis of long-term colectomy rates was possible for 6 studies including 110 patients. No statistically significant difference was found between the treated and untreated groups (OR = 1.71; 95%CI: 0.71-4.13; 6 studies, I2 = 0%). Analysis of mortality rate was not possible due to a very limited number of cases. Stratification of the outcomes by disease severity was not possible.
CONCLUSION: No positive association between antiviral treatment and a favorable outcome was demonstrated. These findings should be interpreted cautiously due to primary studies’ quality and potential biases.
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