Current Diagnostic and Therapeutic Approaches to Cytomegalovirus Infections in Ulcerative Colitis Patients Based on Clinical and Basic Research Data

Abstract

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 (TNFα) 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.

Cytomegalovirus and Inflammatory Bowel Diseases (IBD) with a Special Focus on the Link with Ulcerative Colitis (UC)

“…The mechanism of the pathogenesis of CMV colitis remains poorly understood; replication of the virus in endothelial cells could generate vasculitis associated with microvessel thrombosis and local ulceration, which would induce ischemic colitis [ 33 , 34 ]. The recruitment to the mucosa of CMV-infected monocytes promotes the dissemination of inflammatory macrophages in the inflamed tissue [ 35 , 36 ]. CMV also disrupts epithelial tight junctions, enhancing bacterial translocation as well as inflammation of the gut [ 37 ].…”

“…CMV infection can be demonstrated by using either indirect methods (detection of specific immunoglobulins IgM and IgG) or direct ones (detection of virus or its components). Some of these methods (reviewed in [ 36 , 46 ]) are not suitable for assessing the tissue reactivation of CMV from its intestinal reservoir.…”

“…UC affects the digestive mucosa, with an alteration of the intestinal barrier and microbiota, an exacerbated reaction against digestive tract antigens, including nonpathogenic commensal bacteria, and an alteration of innate and adaptive immune responses, resulting in the local production of many inflammatory cytokines such as TNF-α, IL-6, and IL-23 ( Figure 2 B). TNF-α is capable of recruiting reservoir cells harboring latent virus such as monocytes that differentiate into macrophages and produce viral infectious particles [ 36 , 107 ]. The binding of TNF-α to its receptor activates protein kinase C and NF-κB pathway which, in turn, stimulates the transcription of the IE genes and, thus, viral replication [ 10 , 16 ].…”

Transcription Factors That Regulate the Pathogenesis of Ulcerative Colitis

“…Ulcerative colitis (UC) is one of the inflammatory bowel diseases (IBD) with symptoms such as abdominal pain, fever, malnourishment, fatigue, and weight loss [ 1 ]. UC is characterized by occurrence in the rectum and sigmoid colon of young adults aged 20-40 [ 2 ]. Currently, UC is recognized to be caused by the damages of the intestinal mucosal barrier and neuroendocrine and immune dysfunction due to the interplay of genetics, environment, and psychology [ 3 ], but its specific etiology and pathogenesis are still unclear.…”

Prevalence of UL97 gene mutations in cytomegalovirus reactivation in the colon associated with or without ulcerative colitis

“…In immunocompetent individuals, CMV usually causes self-limiting mild hepatitis, mononucleosis, or subclinical infection [4]. Antiviral treatment with ganciclovir (GCV) has been highly recommended for CMV reactivation, along with anti-tumor necrosis factor (anti-TNF) monoclonal antibody therapy, without losing time, even though there is some debate recently in are ups of refractory UC [5][6][7][8][9].…”