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Cytomegalovirus reactivation in inflammatory bowel disease: an uncommon occurrence related to corticosteroid dependence

Abstract

Cytomegalovirus promotes mucosal injury in patients with inflammatory bowel disease, historically affecting 10–25% of ulcerative colitis patients with refractory disease. Viral reactivation is likely related to long-term corticosteroid therapy, which is no longer central to maintenance of patients with inflammatory bowel disease. We hypothesize that viral detection rates have decreased in the modern era, reflecting widespread use of immunomodulatory agents to control inflammation. We performed this study to evaluate the relationships between medical regimens and cytomegalovirus detection rates among patients with inflammatory bowel disease. We searched our database for all patients with established inflammatory bowel disease and severe flares diagnosed from 2002 to 2017. Patients maintained with corticosteroid therapy were considered to be corticosteroid-dependent and those treated with other agents were classified as corticosteroid-independent, provided they had not received corticosteroids within 6 months of colonoscopy. Biopsy samples were reviewed for viral inclusions and subjected to cytomegalovirus immunohistochemistry, and rates of viral detection were compared between groups. There were 135 corticosteroid-dependent patients; most had ulcerative colitis flares occurring during the 2002–2009 period. Patients with ulcerative colitis and Crohn disease were equally represented in the corticosteroid-independent group (n = 133) and most were evaluated for disease flares during the 2010–2017 interval. Cytomegalovirus was detected in 13 (8%) cases; 9 (69%) were diagnosed from 2002 to 2009 and all were obtained from corticosteroid-dependent patients (p = < 0.001). We conclude that rates of cytomegalovirus-related enterocolitis are declining among inflammatory bowel disease patients, reflecting a shift away from corticosteroid-based maintenance therapy in favor of more effective agents that do not promote viral reactivation.

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Support: Translational Research Program, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine

References

  1. 1.

    Krech U. Complement-fixing antibodies against cytomegalovirus in different parts of the world. Bull World Health Organ. 1973;49:103–6.

  2. 2.

    de la Hoz RE, Stephens G, Sherlock C. Diagnosis and treatment approaches of cytomegalovirus infections in adult patients. J Clin Virol. 2002;25(Suppl 2):S1–12.

  3. 3.

    Meyers JD, Flournoy N, Thomas ED. Risk factors for cytomegalovirus infection after human marrow transplantation. J Infect Dis. 1986;153:478–88.

  4. 4.

    de Jong MD, Galasso GJ, Gazzard B, et al. Summary of the II international symposium on cytomegalovirus. Antivir Res. 1998;39:141–62.

  5. 5.

    Goodgame RW. Gastrointestinal cytomegalovirus disease. Ann Intern Med. 1993;119:924–35.

  6. 6.

    Olsson J, Wikby A, Johansson B, et al. Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: the Swedish longitudinal OCTO immune study. Mech Ageing Dev. 2000;121:187–201.

  7. 7.

    Yi F, Zhao J, Luckheeram RV, et al. The prevalence and risk factors of cytomegalovirus infection in inflammatory bowel disease in Wuhan, Central China. Virol J. 2013;10:43.

  8. 8.

    Domenech E, Vega R, Ojanguren I, et al. Cytomegalovirus infection in ulcerative colitis: a prospective, comparative study on prevalence and diagnostic strategy. Inflamm Bowel Dis. 2008;14:1373–9.

  9. 9.

    Kim YS, Kim YH, Kim JS, et al. The prevalence and efficacy of ganciclovir on steroid-refractory ulcerative colitis with cytomegalovirus infection: a prospective multicenter study. J Clin Gastroenterol. 2012;46:51–6.

  10. 10.

    Berk T, Gordon SJ, Choi HY, et al. Cytomegalovirus infection of the colon: a possible role in exacerbations of inflammatory bowel disease. Am J Gastroenterol. 1985;80:355–60.

  11. 11.

    Leveque N, Brixi-Benmansour H, Reig T, et al. Low frequency of cytomegalovirus infection during exacerbations of inflammatory bowel diseases. J Med Virol. 2010;82:1694–700.

  12. 12.

    Kambham N, Vij R, Cartwright CA, et al. Cytomegalovirus infection in steroid-refractory ulcerative colitis: a case-control study. Am J Surg Pathol. 2004;28:365–73.

  13. 13.

    Kim JJ, Simpson N, Klipfel N, et al. Cytomegalovirus infection in patients with active inflammatory bowel disease. Dig Dis Sci. 2010;55:1059–65.

  14. 14.

    Criscuoli V, Casa A, Orlando A, et al. Severe acute colitis associated with cytomegalovirus: a prevalence study. Dig Liver Dis. 2004;36:818–20.

  15. 15.

    Kandiel A, Lashner B. Cytomegalovirus colitis complicating inflammatory bowel disease. Am J Gastroenterol. 2006;101:2857–65.

  16. 16.

    Beaugerie L, Cywiner-Golenzer C, Monfort L, et al. Definition and diagnosis of cytomegalovirus colitis in patients infected by human immunodeficiency virus. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;14:423–9.

  17. 17.

    Cooper HS, Raffensperger EC, Jonas L, et al. Cytomegalovirus inclusions in patients with ulcerative colitis and toxic dilation requiring colonic resection. Gastroenterology. 1977;72:1253–6.

  18. 18.

    Romkens TE, Bulte GJ, Nissen LH, et al. Cytomegalovirus in inflammatory bowel disease: a systematic review. World J Gastroenterol. 2016;22:1321–30.

  19. 19.

    Iida T, Ikeya K, Watanabe F, et al. Looking for endoscopic features of cytomegalovirus colitis: a study of 187 patients with active ulcerative colitis, positive and negative for cytomegalovirus. Inflamm Bowel Dis. 2013;19:1156–63.

  20. 20.

    McCurdy JD, Jones A, Enders FT, et al. A model for identifying cytomegalovirus in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2015;13:131–7. quize7

  21. 21.

    Dieterich DT, Rahmin M. Cytomegalovirus colitis in AIDS: presentation in 44 patients and a review of the literature. J Acquir Immune Defic Syndr. 1991;4(Suppl 1):S29–35.

  22. 22.

    Wethkamp N, Nordlohne EM, Meister V, et al. Identification of clinically relevant cytomegalovirus infections in patients with inflammatory bowel disease. Mod Pathol. 2018;31:527–38.

  23. 23.

    Soderberg-Naucler C, Fish KN, Nelson JA. Interferon-gamma and tumor necrosis factor-alpha specifically induce formation of cytomegalovirus-permissive monocyte-derived macrophages that are refractory to the antiviral activity of these cytokines. J Clin Investig. 1997;100:3154–63.

  24. 24.

    Simon CO, Seckert CK, Dreis D, et al. Role for tumor necrosis factor alpha in murine cytomegalovirus transcriptional reactivation in latently infected lungs. J Virol. 2005;79:326–40.

  25. 25.

    Fietze E, Prosch S, Reinke P, et al. Cytomegalovirus infection in transplant recipients. The role of tumor necrosis factor. Transplantation. 1994;58:675–80.

  26. 26.

    Matsumura K, Nakase H, Kosugi I, et al. Establishment of a novel mouse model of ulcerative colitis with concomitant cytomegalovirus infection: in vivo identification of cytomegalovirus persistent infected cells. Inflamm Bowel Dis. 2013;19:1951–63.

  27. 27.

    Docke WD, Prosch S, Fietze E, et al. Cytomegalovirus reactivation and tumour necrosis factor. Lancet. 1994;343:268–9.

  28. 28.

    Nakase H, Yoshino T, Honzawa Y, et al. Low prevalence of cytomegalovirus infection in patients with Crohn’s disease in comparison with ulcerative colitis: effect of different immune response on prevalence of cytomegalovirus infection. Dig Dis Sci. 2010;55:1498–9.

  29. 29.

    Chan G, Bivins-Smith ER, Smith MS, et al. Transcriptome analysis reveals human cytomegalovirus reprograms monocyte differentiation toward an M1 macrophage. J Immunol. 2008;181:698–711.

  30. 30.

    Soderberg-Naucler C, Nelson JY. Human cytomegalovirus latency and reactivation: a delicate balance between the virus and its host’s immune system. Intervirology. 1999;42:314–21.

  31. 31.

    Hahn G, Jores R, Mocarski ES. Cytomegalovirus remains latent in a common precursor of dendritic and myeloid cells. Proc Natl Acad Sci USA. 1998;95:3937–42.

  32. 32.

    Wada Y, Matsui T, Matake H, et al. Intractable ulcerative colitis caused by cytomegalovirus infection: a prospective study on prevalence, diagnosis, and treatment. Dis Colon Rectum. 2003;46:S59–65.

  33. 33.

    Widmann T, Sester U, Gartner BC, et al. Levels of cytomegalovirus specific CD4 T cells are dynamic and correlate with cytomegalovirus viremia after allogeneic stem cell transplantation. PLoS One. 2008;3:e3634.

  34. 34.

    Ninomiya E, Hattori T, Toyoda M, et al. Glucocorticoids promote neural progenitor cell proliferation derived from human induced pluripotent stem cells. +. 2014;3:527.

  35. 35.

    Cottone M, Pietrosi G, Martorana G, et al. Prevalence of cytomegalovirus infection in severe refractory ulcerative and Crohn’s colitis. Am J Gastroenterol. 2001;96:773–5.

  36. 36.

    Matsuoka K, Kobayashi T, Ueno F, et al. Evidence-based clinical practice guidelines for inflammatory bowel disease. J Gastroenterol. 2018;53:305–53.

  37. 37.

    Lichtenstein GR, Abreu MT, Cohen R, et al. American Gastroenterological Association Institute medical position statement on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology. 2006;130:935–9.

  38. 38.

    Khan KJ, Dubinsky MC, Ford AC, et al. Efficacy of immunosuppressive therapy for inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol. 2011;106:630–42.

  39. 39.

    Prefontaine E, Sutherland LR, Macdonald JK, et al. Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev. 2009; CD000067. https://doi.org/10.1002/14651858.CD000067.

  40. 40.

    Feagan BG, Fedorak RN, Irvine EJ, et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn’s disease. North American Crohn’s Study Group Investigators. N Engl J Med. 2000;342:1627–32.

  41. 41.

    Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn’s disease. The North American Crohn’s Study Group Investigators. N Engl J Med. 1995;332:292–7.

  42. 42.

    Sandborn WJ, Feagan BG. The efficacy of azathioprine and 6-mercaptopurine for the prevention of postoperative recurrence in patients with Crohn’s disease remains uncertain. Gastroenterology. 2004;127:990–3.

  43. 43.

    Reinecker HC, Steffen M, Witthoeft T, et al. Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn’s disease. Clin Exp Immunol. 1993;94:174–81.

  44. 44.

    Reimund JM, Wittersheim C, Dumont S, et al. Mucosal inflammatory cytokine production by intestinal biopsies in patients with ulcerative colitis and Crohn’s disease. J Clin Immunol. 1996;16:144–50.

  45. 45.

    Clark M, Colombel JF, Feagan BC, et al. American gastroenterological association consensus development conference on the use of biologics in the treatment of inflammatory bowel disease, June 21-23, 2006. Gastroenterology. 2007;133:312–39.

  46. 46.

    Schreiber S, Rutgeerts P, Fedorak RN, et al. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn’s disease. Gastroenterology. 2005;129:807–18.

  47. 47.

    Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology. 2007;132:52–65.

  48. 48.

    Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med. 2004;350:876–85.

  49. 49.

    Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002;359:1541–9.

  50. 50.

    Lichtenstein GR, Rutgeerts P, Sandborn WJ, et al. A pooled analysis of infections, malignancy, and mortality in infliximab- and immunomodulator-treated adult patients with inflammatory bowel disease. Am J Gastroenterol. 2012;107:1051–63.

  51. 51.

    Rahier JF, Magro F, Abreu C, et al. Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis. 2014;8:443–68.

  52. 52.

    Shale MJ, Seow CH, Coffin CS, et al. Review article: chronic viral infection in the anti-tumour necrosis factor therapy era in inflammatory bowel disease. Aliment Pharmacol Ther. 2010;31:20–34.

  53. 53.

    Askling J, Fored CM, Brandt L, et al. Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden. Arthritis Rheumatol. 2005;52:1986–92.

  54. 54.

    Ryu HH, Lee EY, Shin K, et al. Hepatitis B virus reactivation in rheumatoid arthritis and ankylosing spondylitis patients treated with anti-TNFalpha agents: a retrospective analysis of 49 cases. Clin Rheumatol. 2012;31:931–6.

  55. 55.

    Bonovas S, Fiorino G, Allocca M, et al. Biologic therapies and risk of infection and malignancy in patients with inflammatory bowel disease: a systematic review and network meta-analysis. Clin Gastroenterol Hepatol. 2016;14:1385–97. e10

  56. 56.

    Lavagna A, Bergallo M, Daperno M, et al. Infliximab and the risk of latent viruses reactivation in active Crohn’s disease. Inflamm Bowel Dis. 2007;13:896–902.

  57. 57.

    Park SC, Jeen YM, Jeen YT. Approach to cytomegalovirus infections in patients with ulcerative colitis. Korean J Intern Med. 2017;32:383–92.

  58. 58.

    D’Ovidio V, Vernia P, Gentile G, et al. Cytomegalovirus infection in inflammatory bowel disease patients undergoing anti-TNFalpha therapy. J Clin Virol. 2008;43:180–3.

  59. 59.

    Criscuoli V, Mocciaro F, Orlando A, et al. Cytomegalovirus disappearance after treatment for refractory ulcerative colitis in 2 patients treated with infliximab and 1 patient with leukapheresis. Inflamm Bowel Dis. 2009;15:810–1.

  60. 60.

    Nakase H, Chiba T. TNF-alpha is an important pathogenic factor contributing to reactivation of cytomegalovirus in inflamed mucosa of colon in patients with ulcerative colitis: lesson from clinical experience. Inflamm Bowel Dis. 2010;16:550–1.

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The authors declare that they have no conflict of interest.

Correspondence to Erika Hissong.

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