{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T12:18:06Z","timestamp":1790338686945,"version":"4.1.0"},"reference-count":53,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,3,31]],"date-time":"2020-03-31T00:00:00Z","timestamp":1585612800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus (the human herpesvirus 5) and an opportunistic pathogen that primarily infects HIV-positive and other immuno-compromised patients. Retrospective studies in the field of inflammatory bowel disease (IBD) have suggested a relationship between a concomitant colonic HCMV infection and poor outcomes in patients with an ulcerative colitis (UC) due to the presence of HCMV in surgical specimens of patients with a toxic megacolon or a steroid-resistant UC. Therefore, gastroenterologists have focused on the contribution of HCMV infections in the exacerbation of UC. Numerous studies have addressed the benefits of treating colonic HCMV reactivation in UC using an antiviral treatment. However, its clinical relevance remains uncertain as only a few prospective studies have assessed the direct relationship between clinical outcomes and the viral load of HCMV in colonic tissues. HCMV reactivation can be triggered by inflammation according to fundamental research studies. Thus, optimal control of intestinal inflammation is essential for preventing an HCMV reactivation in the intestinal mucosa. Indeed, several reports have indicated the effectiveness of an anti-tumor necrosis factor-alpha (TNF\u03b1) treatment in patients with an active UC and concomitant HCMV infections. In this review, we describe the mechanism of HCMV reactivation in UC cases and discuss the current issues regarding diagnosis and treatment of HCMV infections in UC patients.<\/jats:p>","DOI":"10.3390\/ijms21072438","type":"journal-article","created":{"date-parts":[[2020,4,1]],"date-time":"2020-04-01T03:44:13Z","timestamp":1585712653000},"page":"2438","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Current Diagnostic and Therapeutic Approaches to Cytomegalovirus Infections in Ulcerative Colitis Patients Based on Clinical and Basic Research Data"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2434-1048","authenticated-orcid":false,"given":"Yoshihiro","family":"Yokoyama","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsukasa","family":"Yamakawa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takehiro","family":"Hirano","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoe","family":"Kazama","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9842-4850","authenticated-orcid":false,"given":"Daisuke","family":"Hirayama","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6774-7868","authenticated-orcid":false,"given":"Kohei","family":"Wagatsuma","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2848-6586","authenticated-orcid":false,"given":"Hiroshi","family":"Nakase","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1002\/rmv.1862","article-title":"Cytomegalovirus latency and reactivation: Recent insights into an age old problem","volume":"26","author":"Dupont","year":"2016","journal-title":"Rev. Med. Virol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1159\/000443198","article-title":"Cytomegalovirus colitis, cytomegalovirus hepatitis and systemic cytomegalovirus infection: Common features and differences","volume":"1","author":"Nakase","year":"2016","journal-title":"Inflamm. Intest. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1111\/ajt.12103","article-title":"AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplantation","volume":"13","author":"Razonable","year":"2013","journal-title":"Am. J. Transplant."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/0002-9343(61)90105-X","article-title":"Cytomegalic inclusion disease and ulcerative colitis; report of a case in a young adult","volume":"30","author":"Powell","year":"1961","journal-title":"Am. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1111\/apt.13124","article-title":"Review article: Cytomegalovirus and inflammatory bowel disease","volume":"41","author":"Sager","year":"2015","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1007\/s10620-006-8006-y","article-title":"Cytomegalovirus infection in patients with ulcerative colitis diagnosed by quantitative real-time PCR analysis","volume":"51","author":"Kou","year":"2006","journal-title":"Dig. Dis. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/S1473-3099(04)01202-2","article-title":"Human cytomegalovirus: Clinical aspects, immune regulation, and emerging treatments","volume":"4","author":"Gandhi","year":"2004","journal-title":"Lancet Infect Dis"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3937","DOI":"10.1073\/pnas.95.7.3937","article-title":"Cytomegalovirus remains latent in a common precursor of dendritic and myeloid cells","volume":"95","author":"Hahn","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1099\/0022-1317-72-9-2059","article-title":"Monocytes are a major site of persistence of human cytomegalovirus in peripheral blood mononuclear cells","volume":"72","author":"Sisson","year":"1991","journal-title":"J. Gen. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S0092-8674(01)80014-3","article-title":"Reactivation of latent human cytomegalovirus by allogeneic stimulation of blood cells from healthy donors","volume":"91","author":"Fish","year":"1997","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s00430-007-0069-7","article-title":"Role of the cytomegalovirus major immediate early enhancer in acute infection and reactivation from latency","volume":"197","author":"Stinski","year":"2008","journal-title":"Med. Microbiol. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1099\/0022-1317-74-11-2333","article-title":"Tumour necrosis factor alpha stimulates the activity of the human cytomegalovirus major immediate early enhancer\/promoter in immature monocytic cells","volume":"74","author":"Stein","year":"1993","journal-title":"J. Gen. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.3748\/wjg.v16.i10.1245","article-title":"Specific endoscopic features of ulcerative colitis complicated by cytomegalovirus infection","volume":"16","author":"Suzuki","year":"2010","journal-title":"World J. Gastroenterol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"301","DOI":"10.4253\/wjge.v8.i6.301","article-title":"Characteristic endoscopic findings and risk factors for cytomegalovirus-associated colitis in patients with active ulcerative colitis","volume":"8","author":"Hirayama","year":"2016","journal-title":"World J Gastrointest Endosc"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1097\/MIB.0b013e31828075ce","article-title":"Looking for endoscopic features of cytomegalovirus colitis: A study of 187 patients with active ulcerative colitis, positive and negative for cytomegalovirus","volume":"19","author":"Iida","year":"2013","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1097\/MIB.0000000000001095","article-title":"The association between CMV viremia or endoscopic features and histopathological characteristics of CMV colitis in patients with underlying ulcerative colitis","volume":"23","author":"Yang","year":"2017","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s00430-007-0066-x","article-title":"The history of cytomegalovirus and its diseases","volume":"197","author":"Ho","year":"2008","journal-title":"Med. Microbiol. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1007\/BF01644118","article-title":"Rapid demonstration of cytomegalovirus in clinical specimens","volume":"15","author":"Rothbarth","year":"1987","journal-title":"Infection"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.3748\/wjg.v22.i3.1321","article-title":"Cytomegalovirus in inflammatory bowel disease: A systematic review","volume":"22","author":"Bulte","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2030","DOI":"10.3748\/wjg.v22.i6.2030","article-title":"Cytomegalovirus and ulcerative colitis: Place of antiviral therapy","volume":"22","author":"Pillet","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"50","DOI":"10.5217\/ir.2015.13.1.50","article-title":"Usefulness of the cytomegalovirus antigenemia assay in patients with ulcerative colitis","volume":"13","author":"Chun","year":"2015","journal-title":"Intest. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.crohns.2013.12.014","article-title":"Clinical utility of cytomegalovirus antigenemia assay and blood cytomegalovirus DNA PCR for cytomegaloviral colitis patients with moderate to severe ulcerative colitis","volume":"8","author":"Kim","year":"2014","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2966","DOI":"10.1097\/MIB.0000000000000958","article-title":"Toward an algorithm for the diagnosis and management of CMV in patients with colitis","volume":"22","author":"Beswick","year":"2016","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"E13","DOI":"10.1002\/ibd.21401","article-title":"Positive finding of colonic polymerase chain reaction for cytomegalovirus DNA is not false positive but a warning for treating patients with ulcerative colitis refractory to immunosuppressive therapies","volume":"17","author":"Nakase","year":"2011","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1111\/apt.12009","article-title":"Letter: Mucosal PCR for cytomegalovirus in refractory ulcerative colitis","volume":"36","author":"Yoshino","year":"2012","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1002\/ibd.20253","article-title":"Usefulness of quantitative real-time PCR assay for early detection of cytomegalovirus infection in patients with ulcerative colitis refractory to immunosuppressive therapies","volume":"13","author":"Yoshino","year":"2007","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2857","DOI":"10.1111\/j.1572-0241.2006.00869.x","article-title":"Cytomegalovirus colitis complicating inflammatory bowel disease","volume":"101","author":"Kandiel","year":"2006","journal-title":"Am. J. Gastroenterol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/j.cgh.2014.09.042","article-title":"Effects of antiviral therapy for patients with inflammatory bowel disease and a positive intestinal biopsy for cytomegalovirus","volume":"13","author":"Jones","year":"2015","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2833","DOI":"10.1097\/MIB.0000000000000556","article-title":"Detection of cytomegalovirus in patients with inflammatory bowel disease: Where to biopsy and how many biopsies?","volume":"21","author":"McCurdy","year":"2015","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1007\/s00428-015-1741-8","article-title":"Diagnosing cytomegalovirus in patients with inflammatory bowel disease\u2014By immunohistochemistry or polymerase chain reaction?","volume":"466","author":"Zidar","year":"2015","journal-title":"Virchows Arch."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1002\/ibd.21275","article-title":"Cytomegalovirus in inflammatory bowel disease: Pathogen or innocent bystander?","volume":"16","author":"Lawlor","year":"2010","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1111\/j.1572-0241.2006.00989.x","article-title":"Cytomegalovirus is frequently reactivated and disappears without antiviral agents in ulcerative colitis patients","volume":"102","author":"Matsuoka","year":"2007","journal-title":"Am. J. Gastroenterol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2001","DOI":"10.1038\/ajg.2011.202","article-title":"Cytomegalovirus load in inflamed intestinal tissue is predictive of resistance to immunosuppressive therapy in ulcerative colitis","volume":"106","author":"Roblin","year":"2011","journal-title":"Am. J. Gastroenterol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.3748\/wjg.v21.i6.1915","article-title":"Human cytomegalovirus and Epstein-Barr virus infection in inflammatory bowel disease: Need for mucosal viral load measurement","volume":"21","author":"Ciccocioppo","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Okahara, K., Nagata, N., Shimada, T., Joya, A., Hayashida, T., Gatanaga, H., Oka, S., Sakurai, T., Uemura, N., and Akiyama, J. (2017). Colonic cytomegalovirus detection by mucosal PCR and antiviral therapy in ulcerative colitis. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0183951"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2718","DOI":"10.1097\/MIB.0000000000000489","article-title":"Antiviral therapy in steroid-refractory ulcerative colitis with cytomegalovirus: Systematic review and meta-analysis","volume":"21","author":"Shukla","year":"2015","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1093\/ecco-jcc\/jjw071","article-title":"Cytomegalovirus infection in ulcerative colitis is related to severe inflammation and a high count of cytomegalovirus positive cells in biopsy is a risk for colectomy","volume":"10","author":"Bugajski","year":"2016","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1097\/MCG.0b013e3182160c9c","article-title":"The prevalence and efficacy of ganciclovir on steroid-refractory ulcerative colitis with cytomegalovirus infection: A prospective multicenter study","volume":"46","author":"Kim","year":"2012","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1080\/00365521.2019.1688860","article-title":"Efficacy of antiviral treatment in cytomegalovirus detected ulcerative colitis: Meta-analysis of available data","volume":"54","author":"Yilmaz","year":"2019","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1111\/j.1572-0241.2001.03620.x","article-title":"Prevalence of cytomegalovirus infection in severe refractory ulcerative and Crohn\u2019s colitis","volume":"96","author":"Cottone","year":"2001","journal-title":"Am. J. Gastroenterol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1002\/ibd.20498","article-title":"Cytomegalovirus infection in ulcerative colitis: A prospective, comparative study on prevalence and diagnostic strategy","volume":"14","author":"Vega","year":"2008","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"511","DOI":"10.2147\/IDR.S149784","article-title":"Is cytomegalovirus infection related to inflammatory bowel disease, especially steroid-resistant inflammatory bowel disease? A meta-analysis","volume":"10","author":"Lv","year":"2017","journal-title":"Infect. Drug Resist."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.crohns.2013.12.013","article-title":"Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease","volume":"8","author":"Rahier","year":"2014","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1038\/s41379-019-0258-0","article-title":"Cytomegalovirus reactivation in inflammatory bowel disease: An uncommon occurrence related to corticosteroid dependence","volume":"32","author":"Hissong","year":"2019","journal-title":"Mod. Pathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/j.crohns.2012.12.003","article-title":"Effect of intensive granulocyte and monocyte adsorptive apheresis in patients with ulcerative colitis positive for cytomegalovirus","volume":"7","author":"Fukuchi","year":"2013","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1159\/000321911","article-title":"Effect and safety of granulocyte-monocyte adsorption apheresis for patients with ulcerative colitis positive for cytomegalovirus in comparison with immunosuppressants","volume":"84","author":"Yoshino","year":"2011","journal-title":"Digestion"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1097\/MIB.0000000000000412","article-title":"Infliximab does not worsen outcomes during flare-ups associated with cytomegalovirus infection in patients with ulcerative colitis","volume":"21","author":"Pillet","year":"2015","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1002\/ibd.21047","article-title":"TNF-\u03b1 is an important pathogenic factor contributing to reactivation of cytomegalovirus in inflamed Mucosa of colon in Patients with ulcerative colitis: Lesson from clinical experience","volume":"16","author":"Nakase","year":"2010","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_49","first-page":"81","article-title":"Polymerase chain reaction for detection of mucosal cytomegalovirus infection in patients with acute ulcerative colitis","volume":"32","author":"Gloria","year":"2019","journal-title":"Ann. Gastroenterol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5","DOI":"10.5217\/ir.2014.12.1.5","article-title":"Diagnosis and treatment of ulcerative colitis with cytomegalovirus infection: Importance of controlling mucosal inflammation to prevent cytomegalovirus reactivation","volume":"12","author":"Nakase","year":"2014","journal-title":"Intest. Res."},{"key":"ref_51","first-page":"1951","article-title":"Establishment of a novel mouse model of ulcerative colitis with concomintant cytomegalovirus infection: In vivo identification of cytomegalovirus persisitent infected cells","volume":"19","author":"Matsumura","year":"2013","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1007\/s00535-007-2103-3","article-title":"Clinicopathologic characterstics of clinically relevant cytomegalovirus infection in inflammatory bowel disease","volume":"42","author":"Kuwabara","year":"2007","journal-title":"J. Gastroenterol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"698","DOI":"10.4049\/jimmunol.181.1.698","article-title":"Transcriptome analysis reveals human cytomegalovirus reprograms monocyte differentiation toward an M1 macrophage","volume":"181","author":"Chan","year":"2008","journal-title":"J. Immunol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/7\/2438\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:13:57Z","timestamp":1760174037000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/7\/2438"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,31]]},"references-count":53,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["ijms21072438"],"URL":"https:\/\/doi.org\/10.3390\/ijms21072438","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,31]]}}}