Impact of Epstein-Barr virus infection in patients with inflammatory bowel disease

Abstract

A high prevalence of Epstein-Barr virus (EBV) infection in patients with inflammatory bowel disease (IBD) has been reported in many case reports and studies; thus, the association between EBV and IBD has gained increasing attention. Patients with IBD are at an increased risk of opportunistic EBV infection owing to the common use of immunomodulators. EBV infection in IBD patients can cause various complications, including superimposed viral colitis, which is associated with chronicity, exacerbation, and poor prognosis of refractory IBD, and can induce progression to lymphoproliferative disorders, such as EBV-positive mucocutaneous ulcer (EBVMCU), lymphomatoid granulomatosis (LYG), hemophagocytic lymphohistiocytosis (HLH) and diffuse large B-cell lymphoma (DLBCL). It has been suggested to screen for EBV before initiating immunosuppressive therapy and monitor the status of EBV infection in patients with IBD, especially those who are EBV-seronegative and have a risk of primary EBV infection. Clinicians should also be careful of misdiagnosing IBD and EBV-associated lymphoproliferative diseases due to similarities in both clinical symptoms and endoscopic manifestations. Withdrawal of immunosuppressants has been shown to be an effective strategy to achieve remission of disease at the time of EBV diagnosis, but antiviral therapy remains controversial. The present review aims to describe the characteristics of the complications caused by EBV infection and generalize the recent research progress on and challenges caused by EBV infection in IBD patients. The literature for writing this review was collected from 'PubMed' research engine. The keywords 'inflammatory bowel disease and Epstein-Barr virus' or 'ulcerative colitis and Epstein-Barr virus' or 'Crohn's disease and Epstein-Barr virus' were used to collect the literature and relevant papers were collected to help writing this review.

Keywords: Epstein–Barr virus; immunosuppression; inflammatory bowel disease; lymphoproliferative diseases; viral colitis.

Figure 1

The mechanism and outcome of Epstein–Barr virus (EBV) reactivation in the intestinal mucosa. After primary infection, EBV can express different proteins (latency I, II, III) in latently infected B cells that can be recognized and controlled by cytotoxic T lymphocytes and natural killer (NK) cells, and EBV can exist permanently in resting memory B cells (latency 0/I) in healthy immunocompetent individuals. In addition, EBV can also infect NK or T cells, with prolonged latent infection. However, EBV can be reactivated from latency 0/I to cause lytic infection with active production of virus, and latently infected B or NK/T cells can undergo activation and proliferation due to EBV replication associated with the long-term use of immunosuppressive agents or biologics, which impairs cellular immunity, causing superimposed viral colitis and even B-cell or NK/T-cell lymphoproliferative diseases. Moreover, EBV infection can also spread from lymphocytes to enterocytes, where lytic replication occurs, destroying the mucosal tissue.

Figure 2

The endoscopic manifestations of intestinal NKTCL (cases from Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine). (A) Extensive and irregular ulcers in the sigmoid colon, accompanied by mucosal hyperplasia and covered with yellow and white adhesive material. (B) Multiple large, irregular ulcers covered with white adhesive material in the transverse colon and sigmoid colon. (C) A large bulging lesion involving one half of the lumen with a sunken ulcer in the center covered with pus in the ileum and large ulcerative foci in the colon (30 cm from the anus). (D) Annular mucosal proliferative lesion with mucosal hyperemia and edema in the transverse colon. (E) Circumferential large proliferative lesion in the ileocecum and numerous circular ulcers in the transverse colon. (F) Multiple, irregular ulcers with rigid, narrow and congestive lumen in the sigmoid colon.