Dr Mohammad Sadrkabir. The American Journal of GASTROENTEROLOGY 2011.

Cytomegalovirus Load in Inflamed Intestinal Tissue Is Predictive of Resistance to Immunosuppressive Therapy in Ulcerative Colitis

Editor:

Dr Mohammad SadrkabirCytomegalovirus Load in Inflamed Intestinal Tissue Is Predictive of Resistance to Immunosuppressive Therapy in Ulcerative Colitis

The American Journal of GASTROENTEROLOGY2011

INTRODUCTION

40100% of adults exhibiting stigmata of past infection. CMV persists in a latent form throughout the lifetime of the infected subject and viral replication can be reactivated in situations of immunosuppression .Conversely, CMV has been implicated in exacerbation of IBD, but its role remains unclear. Retrospective studies reported the presence of CMV in the surgical specimens of patients with ulcerative colitis (UC) who underwent colectomy because of toxic megacolon or steroid resistance. The treatment of CMV infection by ganciclovir improves the clinical outcome of patients , suggesting that CMV infection may influence the evolution of UC by triggering acute flare-ups.Because of the small sample size of the studies and the diversity of situations, no definite conclusions can be drawn from the available data. Another source of bias is the variety of techniques used to characterize CMV infection or disease in these studies. Although histological examination, together with detection of CMV in blood or biopsies, is now recommended , the clinical implications of the detection of CMV genome in bowel tissue are still debated .In this study, the CMV DNA load was quantified by real-time polymerase chain reaction (PCR) in biopsy samples of UC patients before the instauration of immunosuppressive therapies. The results were compared with endoscopic and histological findings. Thresholds were defined that could predict resistance to different immunosuppressive regimens in UC. METHODS

From January to November 2009, a single-center, prospective, observational study was carried out in 42 adult patients exhibiting moderate to severe acute flare-ups of UC. The clinical activity was assessed by the Lichtiger score: moderate and severe colitis were defined by a score between 7 and 10, and >10, respectively. At inclusion, the patients could receive azathioprine (AZA) or purinethol at stable doses for 3 months, and mesalamine for 1 month. For the 15 patients receiving AZA at inclusion, the rate of 6-thioguanine nucleotide, a marker of treatment efficacy , was above 250pmol/8108 erythrocytes.

Exclusion criteria were as follows:

(i) patients who received oral corticosteroids (CS) for >7 days or intravenous (IV) CS before hospitalization; (ii) patients treated by cyclosporine (CsY), methotrexate, infliximab (IFX), or adalimumab;(iii) pregnant women; (iv) patients under 18 or over 75 years of age; (v) patients participating in other clinical or therapeutic trials; (vi) patients exhibiting immunodeficiency (HIV infection, hypogammaglobulinemia, severe malnutrition, etc.); (vii) patients with proctitis;(viii) patients presenting Clostridium difficile infection in stool culture.

General procedures at inclusion

All included patients underwent colonoscopy or flexible sigmoidoscopy 250copies/mg and the remaining three with between 10 and 250copies/mg) were resistant to CS but responded to IFX treatment (+CsY in one case). The CMV DNA load was found to be stable in four cases and under the rate of 10copies/mg of tissue in the last one. Interestingly, all these patients responded spontaneously to treatment.

By contrast, the two remaining patients exhibited high CMV load (>250copies/mg) in the first biopsy and were resistant to three lines of treatment: one of them required an emergency colectomy and the other a colectomy 2 months later. The only patient for whom the initially positive intestinal viral load was not controlled had an initial DNA load between 10 and 250copies/mg; this patient responded spontaneously to CsY treatment.

Determination of factors associated with CMV detection in intestinal tissueFour factors were evaluated : clinical activity, phenotype, previous treatment by AZA, and resistance to steroids or to three lines of treatment. The sole factor that remained in the model after multivariate analysis was the resistance to steroids or to three lines of treatment (risk ratio: 4.7; 95% confidence interval: 1.222.5; P250copies/mg of tissue was predictive of a resistance to three successive lines of treatment with a sensitivity of 100% and a specificity of 66.6% (LR+=4.33; AUROC=0.85; P