Cytomegalovirus and Inflammatory Bowel Disease
Cytomegalovirus and Inflammatory Bowel Disease
Kojima et al. reviewed 126 surgical specimens of patients with UC to explore the clinicopathologic features of CMV and concluded that the clinical prevalence of CMV is higher (15% and 25% for HE and IHC respectively) in patients with severe UC undergoing surgery than in those with refractory UC (1.3% and 8.3%, P < 0.05) and much lower in patients with UC-related dysplasia (0% for both HE and IHC). These results suggest that CMV is associated with the severity of colitis rather than its treatment.
There are many case reports which suggest that colonic CMV superinfection in existing IBD causes more symptoms with increased prevalence of toxic megacolon and surgical intervention, but the issue remains controversial. Domenech et al. reported a colectomy in three out of six patients with active steroid-refractory UC and CMV disease, compared with only 2 of 13 steroid-refractory cases without associated CMV disease. A case–controlled study by Kambhm et al. linked unrecognized and therefore untreated CMV infection in steroid-refractory UC with higher surgical intervention risk.
Matsuoka et al. reported the clinical outcomes in 69 patients with moderate to severe UC, who were tested for CMV reactivation every 2 weeks for 8 weeks using the CMV anti-genemia assay and serum quantitative real-time PCR assay for CMV: 48 patients were sero-positive for CMV but the study showed that clinical outcomes including rates of remission and colectomy were not significantly different among the CMV reactivation-positive and negative patients. These data, then, suggest CMV does not influence the course of the relapse.
There have been two recent studies reporting viral load and outcomes. In 2010, Leveque et al. reported no relationship between colonic CMV DNA load and disease severity in seven patients; in five of six cases not treated with anti-viral therapy, immunosuppression was increased and resulted in clinical improvement. A year later, Roblin et al. reported that there was no correlation between detection of CMV DNA and the Mayo endoscopic score; furthermore the 'threshold of CMV load did not influence the results'. However, Roblin et al. did find a relationship between CMV DNA load and clinical outcome: a positive colonic CMV load was associated with steroid resistance (Likelihood ratio 3, sensitivity 50% and specificity 100%); CMV DNA >250 copies/mg tissue was predictive of resistance to steroids and two immunosuppressives (Likelihood ratio 4.3, sensitivity 100% and specificity 66.6%). They recruited 42 consecutive patients exhibiting moderate to severe flare ups of UC in a prospective observational study. All patients underwent a colonoscopy or flexible sigmoidoscopy <24 h after inclusion and colonic biopsies were taken to measure CMV DNA viral load by real-time PCR. CMV DNA was detected in inflamed tissue of 16 patients. All 42 patients were treated as established by the European guidelines. They received i.v. steroids and those who were steroid resistant at day 7 received second line therapy with either ciclosporin or Infliximab. If clinical remission was not observed then one therapy was switched to another. Eight of the 16 patients positive for colonic CMV DNA failed to respond and were commenced on i.v. Ganciclovir for 10 days followed by oral valganciclovir for 15 days along with immunosuppressive therapy. One patient did not achieve clinical remission and required emergency colectomy. The other seven patients all achieved clinical remission and remained in remission at 6 months with no CMV DNA detected on repeat colonic biopsies at day 30 ± 5 days.
Delvincourt et al. reported that CMV reactivation does not appear to alter the course of IBD flares and that treatment directed at CMV does not impact on IBD course. They carried out a retrospective case–controlled study comparing a population of UC patients (n = 26) with relapses and PCR evidence of CMV viraemia without anti-viral treatment to matched patients with blood negative CMV PCR. They found no difference between the two groups, regarding length of stay (8.7 days vs 9.7 days for CMV+ and CMV− patients respectively; P = 0.42) and colectomy rate (15.4% and 23.1% for CMV+ and CMV− patients respectively; P = 0.48). The same group also looked at 110 hospitalisations for relapse of UC with CMV reactivation (80 diagnosed on blood PCR, 33 on tissue PCR) in three French referral centres; evolution following CMV reactivation diagnosis was compared between those receiving anti-viral treatment and those who did not. There were no differences in the treated and untreated groups of patients with regard to age, gender, IBD type, immunosuppressant, CRP and haemoglobin level. They reported that no differences were observed in CRP level decrease at 10 days and colectomy rate at 3 months (10.6% vs. 13.3%; P = 0.7) between the two groups. They also reported that the group receiving anti-viral treatment had a longer period of hospitalisation (16.3 days vs. 8.3 days; P < 0.001). The findings in this study suggest that patients with latent CMV or reactivation with evidence of CMV viraemia, who are treated with anti-virals have no difference in acute colitis outcomes when compared to those who are not treated with anti-virals. These findings are similar to those of Matsuoka et al.'s study. However, as we have mentioned earlier, latent or subclinical CMV does not correlate with CMV colitis which requires colonic tissue for diagnosis. Delvincourt's group did compare 33 patients who had positive colonic tissue CMV PCR, and reported no difference in outcomes (CRP level drop, length of hospital stay and colectomy rate) between those treated and not treated with anti-virals. However, the CMV DNA cut-off value for diagnosing CMV colitis was not stated and the positive PCR results if low values may have reflected latent CMV detected in colonic tissue.
Severe Colitis and Steroid Resistance
Kojima et al. reviewed 126 surgical specimens of patients with UC to explore the clinicopathologic features of CMV and concluded that the clinical prevalence of CMV is higher (15% and 25% for HE and IHC respectively) in patients with severe UC undergoing surgery than in those with refractory UC (1.3% and 8.3%, P < 0.05) and much lower in patients with UC-related dysplasia (0% for both HE and IHC). These results suggest that CMV is associated with the severity of colitis rather than its treatment.
There are many case reports which suggest that colonic CMV superinfection in existing IBD causes more symptoms with increased prevalence of toxic megacolon and surgical intervention, but the issue remains controversial. Domenech et al. reported a colectomy in three out of six patients with active steroid-refractory UC and CMV disease, compared with only 2 of 13 steroid-refractory cases without associated CMV disease. A case–controlled study by Kambhm et al. linked unrecognized and therefore untreated CMV infection in steroid-refractory UC with higher surgical intervention risk.
Matsuoka et al. reported the clinical outcomes in 69 patients with moderate to severe UC, who were tested for CMV reactivation every 2 weeks for 8 weeks using the CMV anti-genemia assay and serum quantitative real-time PCR assay for CMV: 48 patients were sero-positive for CMV but the study showed that clinical outcomes including rates of remission and colectomy were not significantly different among the CMV reactivation-positive and negative patients. These data, then, suggest CMV does not influence the course of the relapse.
There have been two recent studies reporting viral load and outcomes. In 2010, Leveque et al. reported no relationship between colonic CMV DNA load and disease severity in seven patients; in five of six cases not treated with anti-viral therapy, immunosuppression was increased and resulted in clinical improvement. A year later, Roblin et al. reported that there was no correlation between detection of CMV DNA and the Mayo endoscopic score; furthermore the 'threshold of CMV load did not influence the results'. However, Roblin et al. did find a relationship between CMV DNA load and clinical outcome: a positive colonic CMV load was associated with steroid resistance (Likelihood ratio 3, sensitivity 50% and specificity 100%); CMV DNA >250 copies/mg tissue was predictive of resistance to steroids and two immunosuppressives (Likelihood ratio 4.3, sensitivity 100% and specificity 66.6%). They recruited 42 consecutive patients exhibiting moderate to severe flare ups of UC in a prospective observational study. All patients underwent a colonoscopy or flexible sigmoidoscopy <24 h after inclusion and colonic biopsies were taken to measure CMV DNA viral load by real-time PCR. CMV DNA was detected in inflamed tissue of 16 patients. All 42 patients were treated as established by the European guidelines. They received i.v. steroids and those who were steroid resistant at day 7 received second line therapy with either ciclosporin or Infliximab. If clinical remission was not observed then one therapy was switched to another. Eight of the 16 patients positive for colonic CMV DNA failed to respond and were commenced on i.v. Ganciclovir for 10 days followed by oral valganciclovir for 15 days along with immunosuppressive therapy. One patient did not achieve clinical remission and required emergency colectomy. The other seven patients all achieved clinical remission and remained in remission at 6 months with no CMV DNA detected on repeat colonic biopsies at day 30 ± 5 days.
Delvincourt et al. reported that CMV reactivation does not appear to alter the course of IBD flares and that treatment directed at CMV does not impact on IBD course. They carried out a retrospective case–controlled study comparing a population of UC patients (n = 26) with relapses and PCR evidence of CMV viraemia without anti-viral treatment to matched patients with blood negative CMV PCR. They found no difference between the two groups, regarding length of stay (8.7 days vs 9.7 days for CMV+ and CMV− patients respectively; P = 0.42) and colectomy rate (15.4% and 23.1% for CMV+ and CMV− patients respectively; P = 0.48). The same group also looked at 110 hospitalisations for relapse of UC with CMV reactivation (80 diagnosed on blood PCR, 33 on tissue PCR) in three French referral centres; evolution following CMV reactivation diagnosis was compared between those receiving anti-viral treatment and those who did not. There were no differences in the treated and untreated groups of patients with regard to age, gender, IBD type, immunosuppressant, CRP and haemoglobin level. They reported that no differences were observed in CRP level decrease at 10 days and colectomy rate at 3 months (10.6% vs. 13.3%; P = 0.7) between the two groups. They also reported that the group receiving anti-viral treatment had a longer period of hospitalisation (16.3 days vs. 8.3 days; P < 0.001). The findings in this study suggest that patients with latent CMV or reactivation with evidence of CMV viraemia, who are treated with anti-virals have no difference in acute colitis outcomes when compared to those who are not treated with anti-virals. These findings are similar to those of Matsuoka et al.'s study. However, as we have mentioned earlier, latent or subclinical CMV does not correlate with CMV colitis which requires colonic tissue for diagnosis. Delvincourt's group did compare 33 patients who had positive colonic tissue CMV PCR, and reported no difference in outcomes (CRP level drop, length of hospital stay and colectomy rate) between those treated and not treated with anti-virals. However, the CMV DNA cut-off value for diagnosing CMV colitis was not stated and the positive PCR results if low values may have reflected latent CMV detected in colonic tissue.