INTRODUCTION
Human cytomegalovirus (CMV) infection is common, and the prevalence of CMV infection has been estimated to range from 30% to 100% worldwide, depending on the age of the populations tested.
1 CMV reactivation usually occurs as an opportunistic infection and leads to morbidity or mortality in immunocompromised individuals.
2 Patients with UC are also at high risk for CMV reactivation because they are frequently treated with immunosuppressive drugs.
3 Although whether CMV is a primary aggravating cause or by-product in the exacerbation of UC remains to be elucidated, antiviral therapy has allowed some patients who have not responded to conventional UC treatment to avoid colectomy.
4 The current guideline recommends that CMV colitis should be excluded in immunomodulator refractory cases of IBD before increasing immunomodulator therapy.
5 Therefore, the presence of CMV colitis should be confirmed in patients with an exacerbation of UC, especially refractory colitis.
The CMV antigenemia assay detects the CMV pp65 antigen in circulating polymorphonuclear neutrophils (PMNs) in the blood by staining with fluorescent antibodies that are specific for pp65 antigens.
4 Previous studies have shown that this semiquantitative technique is useful for diagnosing and monitoring CMV infection in immunocompromised patients, such as bone marrow
6 and solid organ (e.g., kidney and liver) transplant recipients,
7,8,9 or those with acquired immunodeficiency syndrome (AIDS).
10,11 Furthermore, CMV antigenemia-guided pre-emptive ganciclovir therapy was effective in patients who received allogenic hematopoietic stem cell transplantation.
12 However, the clinical usefulness of the CMV antigenemia assay in patients with UC has rarely been studied. The aim of this study was to assess whether the CMV antigenemia assay detects CMV colitis and predicts clinical outcomes in patients with moderate-to-severe UC.
Discussion
We determined that positive CMV antigenemia was an independent predictor of steroid refractoriness in patients with moderate-to-severe UC. Although systemic corticosteroids remain the standard treatment for patients with an exacerbation of UC, approximately 27% of patients require an early colectomy after corticosteroids.
19 Rescue therapies, including cyclosporine or infliximab, have been shown to be effective in preventing the requirement for an early colectomy.
20,21,22 Thus, the identification of early predictors of steroid-refractory UC would avoid the ineffective continuation of corticosteroids, and facilitate a more timely initiation second-line rescue therapy.
In this study, both positive CMV antigenemia and CMV colitis were significantly common in patients with steroid-refractory UC. In accordance with our results, previous reports have shown that severe refractory colitis is associated with documented CMV colitis in patients with an exacerbation of UC.
23 Moreover, many retrospective studies have reported that 82% of UC patients with a CMV infection are non-responders to corticosteroids, suggesting that CMV colitis is a probable cause of steroid-refractory UC.
24
In contrast, a previous study demonstrated that CMV reactivation did not affect the rates of remission and colectomy in patients with moderate-to-severe UC.
25 In the study, however, the rate of early rescue therapy with cyclosporine was significantly higher in UC patients with CMV reactivation than in those without CMV reactivation, which could improve the rate of remission in those with CMV reactivation.
25 Therefore, these findings support the hypothesis that early rescue therapy in patients with an exacerbation of UC and concomitant CMV reactivation reduces the requirement for colectomy.
In this study, 7 (63.6%) of the 11 patients with steroid refractoriness improved following rescue therapy with ganciclovir (6 patients) or cyclosporine (1 patient), and there was no association between the detection of CMV antigenemia and need for colectomy. The detection of CMV antigenemia, which is indicative of CMV reactivation, can be a good predictor that allows for the early detection of steroid-refractory UC and indicates the need for rescue therapy. Because the CMV antigenemia assay has a short processing time (less than 6 hours) and does not require a specialized laboratory,
26 it is expected to be a clinically useful method for the early prediction of steroid-refractory UC.
We showed that 75% of steroid-refractory UC patients positive for CMV antigenemia with concomitant CMV colitis went into remission after ganciclovir treatment. Kim et al.
15 reported that ganciclovir might be the treatment of choice in patients with steroid-refractory UC and concomitant CMV infection. In contrast, Matsuoka et al.
25 demonstrated that 72% of patients with CMV reactivation entered remission without antiviral therapy after conventional immunosuppressant therapy, but that none showed any evidence of CMV colitis in their colonic tissue. In an earlier report, 5 of 6 (83.3%) patients with UC and concomitant CMV colitis responded to ganciclovir,
27 a finding that is comparable with our results. These findings suggest that antiviral therapy might be beneficial for patients with steroid-refractory UC and concomitant CMV colitis. Because positive CMV antigenemia showed a high risk of steroid refractoriness, moderate-to-severe UC patients positive for CMV antigenemia should be carefully evaluated for concomitant CMV colitis using endoscopic and histologic examinations. Additionally, early ganciclovir treatment might be considered as a rescue therapy in patients positive for CMV antigenemia with concomitant CMV colitis.
The CMV antigenemia assay is a widely used method for detecting CMV reactivation in a variety of clinical settings.
28 In general, the detection of CMV pp65-positive cells has a sensitivity of 60-100% and a specificity of 83-100% for CMV reactivation.
29 However, few studies have examined the diagnostic value for CMV colitis in UC patients. In the present study, the sensitivity and specificity of the positive CMV antigenemia assay for diagnosing CMV colitis in patients with moderate-to-severe UC were 66.7% and 87.1%, respectively. These results are in agreement with those of a recent study showing the diagnostic performance of the CMV antigenemia assay in UC patients.
30
In addition, an earlier study reported that the sensitivity and specificity of the CMV antigenemia assay for CMV gastrointestinal disease were 54% and 88% respectively in 121 patients with secondary immunodeficiency diseases.
31 In 99 immunocompromised patients, none of who had IBD, the sensitivity and specificity of the CMV antigenemia assay for CMV gastrointestinal disease were 65.4% and 93.6%, respectively.
32 Our results in UC patients were comparable with those reported by earlier studies conducted in populations with other immunodeficiency diseases. These findings suggest that the CMV antigenemia assay has low sensitivity but high specificity for detecting CMV colitis in immunocompromised patients regardless of the underlying disease status.
We also determined that the cut-off level of 2 pp65-positive cells per 2×105 PMNs showed the highest sensitivity and specificity for diagnosing CMV colitis. However, this threshold might be of limited value due to the minimal difference in the specificity between the cut-off values of one and 2 pp65-positive cells.
We showed that the maximum level measured in the CMV antigenemia assay in patients with UC was 11 pp65-positive cells per 2×10
5 PMNs. Our results are in agreement with those of a prospective study in which the titer of the CMV antigenemia assay was 1 pp65-positive cell in 47.1% of UC patients positive for CMV antigenemia, and only 1 (5.9%) patient showed more than 10 positive cells.
25 In fact, the ranges of the CMV antigenemia assay vary among patient settings. In a previous report involving patients who underwent autologous marrow or peripheral blood stem cell transplantation, the maximum level of the assay was 135 pp65-positive cells.
33 In other reports, a cut-off level of 25 pp65-positive cells showed the highest PPV for symptomatic CMV infection in renal transplant recipients.
34,35 Therefore, patients with an exacerbation of UC have a relatively low viral load in their blood because they were treated with less intensive immunosuppressive agents than those used for bone marrow or solid organ transplant recipients.
We also demonstrated that a shorter duration of disease was an independent predictor for steroid refractoriness in active UC patients. Some studies have demonstrated that a shorter duration of disease predicts therapeutic failure in active UC patients treated with intravenous corticosteroids,
30,36 while others found no association between duration of disease and the response to systemic corticosteroids.
37,38 Recently, Garcia-Planella et al.
39 demonstrated that the earlier systemic corticosteroids were introduced in the course of UC, the higher the risk of relapse and corticosteroids reintroduction was. It suggests that the sooner systemic corticosteroids are required from the time of UC diagnosis, the poorer is the prognosis. Therefore, close monitoring followed by rescue therapy might be considered for active UC patients who required intravenous high dose corticosteroids in the early course of disease.
Our study has several limitations due to its retrospective nature.
First, selection bias might occur because only hospitalized patients who were tested for CMV antigenemia were included. Because the CMV antigenemia assay was performed based on each physician's decision, it is possible that more patients with concomitant CMV colitis and steroid-refractory UC were included in this study. Moreover, the patients who were enrolled in the tertiary care hospital-based study may be biased toward those with more severe colitis and poorer prognosis than the cases in population-based studies.
Second, the sample size was small. We showed that symptom severity, laboratory parameters such as CRP or serum albumin, disease extent, and endoscopic severity could not predict lack of response to systemic corticosteroids in patients with an exacerbation of UC. Although many studies reported an extreme variety in results regarding the predictive factors for steroid refractoriness in patients with an exacerbation of UC,
19 a significant difference might not have been confirmed among independent predictors due to the selection bias or small sample size in our study.
Third, a follow-up CMV antigenemia assay was not routinely carried out. Among eight steroid-refractory UC patients positive for CMV antigenemia, seroconversion was confirmed by a follow-up CMV antigenemia assay after ganciclovir treatment in three patients who showed improvement. In contrast, it was unclear whether seroconversion could occur in the other 5 patients because they did not undergo the follow-up testing.
Fourth, colonic tissue PCR for CMV DNA was not performed for diagnosing CMV colitis. The guideline recommends that CMV colitis should be evaluated, preferably by tissue PCR or IHC, in refractory UC patients.
5 Moreover, a previous study showed that CMV DNA load in inflamed colonic tissue predicts the resistance to intravenous steroids in patients with exacerbation of UC.
40 This suggests that the detection of CMV DNA in colon tissue without histological features of CMV colitis may represent low-level reactivation of CMV.
Finally PCR detection of CMV DNA in blood was not conducted in this study, and the titers of the CMV antigenemia assays could not be compared to blood CMV DNA levels.
In conclusion, the CMV antigenemia assay has low sensitivity but high specificity for detecting CMV colitis, and may predict steroid refractoriness in patients with moderate-to-severe UC. We suggest that early rescue therapy with cyclosporine or infliximab should be considered in moderate-to-severe UC patients with CMV antigenemia.