Cytomegalovirus disappearance after treatment for refractory ulcerative colitis in 2 patients treated with infliximab and 1 patient with leukapheresis.

To the Editor: Human cytomegalovirus (HCMV) is a herpesvirus widely spread in the general population. In immunocompetent hosts it rarely causes serious illness but the infection can result in Epstein– Barr virus-like mononucleosis syndrome. In immunologically impaired patients the virus may cause serious multiorgan involvement and complications due to the cytomegalovirus-associated disease. The role of HCMV in patients with inflammatory bowel disease (IBD) is not clearly known. Data from the literature have shown a possible role in exacerbating a colitis flare,1,2 while some authors have reported a role as a bystander and innocent observer.3 Virus interaction with the host’s immune system involves both innate and adaptive immunity. T cells play an important role in controlling viral replication and disease development, but do not eliminate the virus completely; all herpesviruses possess the key property of latency and reactivation.4 The virus is maintained in latency in a non-replicative state in myeloid lineage progenitor cells and it reactivates, in response to inflammatory cytokines and chemokines, when peripheral blood monocytes differentiate into macrophages. The virus produces molecules designed to disrupt or manipulate host inflammatory/ immune responses: interleukin 1 and tumor necrosis factor alpha (TNF) support leukocyte activation and recruitment.5 An important clinical question is what to do when, in severe colitis, there is an indication to use infliximab and HCMV is identified in biopsy specimens or in peripheral blood. Is the presence of HCMV a contraindication to infliximab? We reviewed 3 cases of patients with steroid-dependent moderate-to-severe ulcerative colitis (UC) treated with infliximab and/or leukapheresis for active disease in whom a clinical response with virus disappearance was obtained. Three UC patients were admitted to our department for a severe disease relapse (8 bloody bowel movements per day, abdominal pain and tenderness). Therapy with intravenous steroid (methylprednisolone 1 mg/kg/day) was started, but after 5 days the symptoms were stable. Screening for treatment with infliximab was negative. At sigmoidoscopy, colitis activity was severe. In 1 patient antigenemia pp65 for HCMV detection in peripheral blood was positive, but negative in the other 2. Also, in all patients rectal biopsies (morphologic, immunohistochemical, and polymerase chain reaction [PCR] analysis) were positive for HCMV detection. On the basis of this evidence infliximab treatment was avoided in the first patient, who was treated with leukapheresis (8 sessions, blood volume of 1800 mL in 1 hour). The other 2 patients were treated with 3 infusions (0, 2, and 6 weeks) of infliximab at a dose of 5 mg/kg. All the patients obtained a clinical response with symptoms improvement. At the end on the treatments the endoscopic and histological activity was mild and the morphological and immunohistochemical analysis did not detect HCMV, while PCR proved to be positive. In the first patient antigenemia pp65 for HCMV detection in peripheral blood became negative. Previous data have shown that anti-TNF therapy may cause widespread HCMV infection in refractory Crohn’s disease (CD) through vasculitis, which allows the virus to circulate within the shed endothelial cells.6 An interruption of the replicative sequence may induce an HCMV latent state in infected cells determining immunologic tolerance by the host immune system. Fietze et al7 hypothesized that TNFplays a role in the reversal of HCMV latency and that inhibition of TNFrelease or action may be an alternative strategy for preventing HCMV-associated morbidity in allograft recipients. The replication of HCMV could also increase TNFexpression, allowing it to maintain a steady viral load. According to this evidence, some authors have shown a possible role of TNFin the reactivation of HCMV in septic patients.8 The mechanisms of action of leukapheresis devices have been extensively reviewed and are believed to exert an immunomodulatory and/or antiinflammatory effect on patients with systemic inflammatory disease. Dumont et al9 have shown a substantial reduction in the viral genome load in subjects positive for anti-CMV antibodies and HCMV-DNA, evaluated by qualitative PCR, after leukocyte reduction methods. According to this experience, treatment with anti-TNFantibodies and leukapheresis may be carried out without risk of colitis relapse associated with superimposed colonic HCMV infection. Low TNFactivity after infliximab treatment may interfere both with the viral replication and the inflammation maintenance avoiding colitis, while the decrease in circulating HCMV-infected cells after leukapheresis reduces the risk of colitis flare due to superimposed HCMV action. The improvement of colonic inflammation due to these treatments reduces viral replication, and the detection of HCMV in rectal biopsies only by PCR assay may correspond to a latent and non-pathogenic state of the virus. Although the available evidence arises from anecdotal or experimental observations, this report may be an interesting and useful proposal for further Copyright © 2008 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.20742 Published online 6 October 2008 in Wiley InterScience (www.interscience.wiley.com).