Cytomegalovirus infection in severe ulcerative colitis patients undergoing continuous intravenous cyclosporine treatment in Japan

Abstract

Aim: To investigate active cytomegalovirus (CMV) infection following the cyclosporine A (CyA) treatment of steroid-refractory ulcerative colitis (UC).

Methods: Twenty-three patients with severe UC not responding to steroid therapy (male 14, and female 9) enrolled at Nagoya University Hospital from 1999 to 2005. They received continuous intravenous infusion of CyA (average 4 mg/kg per day) for 1 mo. Serum and colonic biopsy samples were collected before CyA treatment and 4 d, 10 d, 20 d, and 30 d after treatment. Patients were evaluated for CMV by using serology (IgM antibody by ELISA), quantitative real-time PCR for CMV DNA, and histopathological assessment of hematoxylin and eosin (HE)-stained colonic biopsies. CMV infection was indicated by positive results in any test.

Results: No patients had active CMV infection before CyA treatment. Eighteen of 23 UC patients treated with CyA were infected with active CMV (IgM antibody in 16/23 patients, 69.6%; CMV DNA in 18/23 patients, 78.2%; and inclusion bodies in 4/23 patients, 17.3%). There was no difference in the active CMV-infection rate between males and females. Active CMV infection was observed after approximately 8 d of CyA treatment, leading to an exacerbation of colitis. Fifteen of these 18 patients with active CMV infection (83.3%) required surgical treatment because of severe deteriorating colitis. Treatment with ganciclovir rendered surgery avoidable in three patients.

Conclusion: Our results suggest that active CMV infection in severe UC patients treated with CyA is associated with poor outcome. Further, ganciclovir is useful for treatment of CMV-associated UC after immuno-suppressive therapy.

Figure 1

Comparison of initial CMV detection by day among the three methods (Real-time PCR, CMV IgM, and HE stain).

Figure 2

Change in clinical symptoms (hematochezia and body temperature) between CMV-positive and CMV-negative UC patients during intravenous CyA treatment. Panel A showed the change in the degree of hematochezia. Panel B showed the change in body temperature. The mean values of each group were plotted. Symbols: ◆, CMV positive; ■, CMV negative. ^aP < 0.05.

Figure 3

Change in inflammation markers between CMV-positive and CMV-negative UC patients during intravenous CyA treatment. Panel A showed the change in WBC count. Panel B showed the change in CRP value. The mean values of each group were plotted. Symbols:◆, CMV positive; ■, CMV negative. ^aP < 0.05.

Figure 4

Change in liver function and renal function between CMV-positive and CMV-negative UC patients during intravenous CyA treatment. Panel A showed the change in liver function. The mean values of each group were plotted. Symbols: ◆, aspartate aminotransferase in CMV positive; ■, aspartate aminotransferase in CMV negative; ▲, alanine aminotransferase in CMV positive; ●, alanine aminotransferase in CMV negative. Panel B showed the change in renal function. The mean values of each group were plotted. Symbols: ◆, creatinine in CMV positive; ■, creatinine in CMV negative; ▲, blood urea nitrogen in CMV positive; ●, blood urea nitrogen in CMV negative, respectively. NS represented not significant.

Figure 5

Change in mean CMV IgM value and CMV viral DNA load after CMV infection. Panel A showed the change in mean CMV IgM value after infection. Panel B showed the change in mean CMV viral load after infection.