*2.4.2 CMV disease in gastrointestinal tract*

Cytomegalovirus infection of the gastrointestinal tract is the most common manifestation of tissue-invasive CMV disease and is a significant cause of morbidity and mortality in the solid organ transplantation recipients. Patients usually present with esophagitis, colitis, and hepatitis; however, infection can occur anywhere in the gastrointestinal tract [17, 24, 25].

Mucosal ulceration was the most common endoscopic finding present in 75% of cases (**Figure 3**). Other endoscopic features include mucosal edema, hyperemia, and nodularity. In a renal transplant patient, cytomegalovirus infection may rarely present as a localized disease, such as inflammatory polyps [26].

Two histologic patterns of GIT tissue injury have been described. In the first form, viral inclusions are typically found in the glandular epithelium with little associated tissue reaction (**Figure 4**). In the second form, CMV inclusions are found in swollen endothelial and stromal cells, especially in areas of ulceration. Typically, mucosal erosion, ulceration, hemorrhage, necrosis, perforation, and/or fistula formation can be detected. CMV colitis is characterized by uneven inflammation in the lamina propria, with active changes and ulcers with abundant purulent exudate (**Figures 3** and **5**) [24].

In contrast to other organs, CMV infection in the colon does not always produce the diagnostic large cells with viral inclusions with owl's eye appearance. Rather, the infected cells can be smaller, up to twice as big as their normal counterparts, and have small basophilic inclusions, often with no characteristic clear halo. They have been called "atypical inclusions" [27].

Diagnosis is usually by histopathology with immunohistochemistry or viral culture of tissue specimens; molecular assays such as quantitative PCR also often have a role (**Figures 4** and **5**).

However, there is little consensus on the specificity of PCR [28–30]. Since CMV typically produces latent infection residing in leukocytes, concern has been raised that positive PCR might therefore not necessarily reflect active disease in the colon but only latent infection. The use of colon tissue alone was therefore not widely considered to provide definitive proof of CMV colitis [13]. Zidar et al. observed good correlation among the density of positive cells by immunohistochemistry, the

**43**

**Figure 5.**

**Figure 4.**

*Viral Infections after Kidney Transplantation: CMV and BK*

*CMV gastritis. Intranuclear inclusion (arrow) in foveolar gastric cell (A) and in endothelial cell (arrow) of a capillary in the lamina propria (both Thricrome stain, 600x). CMV positive Intranuclear inclusions by* 

*CMV colitis in kidney transplant recipient. Focal active colitis with erosions (A, Trichrome stain, 100x). There* 

*was only one positive CMV cell by immunohistochemistry (CMV, 400x).*

*immunohistochemistry (C, CMV, 600x). Scarce mucosal ulcerations seen on gastroscopy (D).*

*DOI: http://dx.doi.org/10.5772/intechopen.86043*

*Viral Infections after Kidney Transplantation: CMV and BK DOI: http://dx.doi.org/10.5772/intechopen.86043*

#### **Figure 4.**

*Perioperative Care for Organ Transplant Recipient*

*2.4.2 CMV disease in gastrointestinal tract*

the gastrointestinal tract [17, 24, 25].

been called "atypical inclusions" [27].

have a role (**Figures 4** and **5**).

(**Figures 3** and **5**) [24].

It is considered to promote rejection episodes by stimulating a T-cell-mediated response. Reinke reported that 85% of patients with late-acute renal allograft rejection with otherwise symptomless CMV infection responded to ganciclovir therapy, which emphasized the indirect role of CMV infection on graft function [23]. CMV infection does not activate classic complement pathway nor trigger the deposition of complement factor C4d along peritubular capillaries; in the case of

Cytomegalovirus infection of the gastrointestinal tract is the most common manifestation of tissue-invasive CMV disease and is a significant cause of morbidity and mortality in the solid organ transplantation recipients. Patients usually present with esophagitis, colitis, and hepatitis; however, infection can occur anywhere in

Mucosal ulceration was the most common endoscopic finding present in 75% of cases (**Figure 3**). Other endoscopic features include mucosal edema, hyperemia, and nodularity. In a renal transplant patient, cytomegalovirus infection may rarely

Two histologic patterns of GIT tissue injury have been described. In the first form, viral inclusions are typically found in the glandular epithelium with little associated tissue reaction (**Figure 4**). In the second form, CMV inclusions are found in swollen endothelial and stromal cells, especially in areas of ulceration. Typically, mucosal erosion, ulceration, hemorrhage, necrosis, perforation, and/or fistula formation can be detected. CMV colitis is characterized by uneven inflammation in the lamina propria, with active changes and ulcers with abundant purulent exudate

In contrast to other organs, CMV infection in the colon does not always produce the diagnostic large cells with viral inclusions with owl's eye appearance. Rather, the infected cells can be smaller, up to twice as big as their normal counterparts, and have small basophilic inclusions, often with no characteristic clear halo. They have

Diagnosis is usually by histopathology with immunohistochemistry or viral culture of tissue specimens; molecular assays such as quantitative PCR also often

*Mucosal ulcerations in CMV colitis of kidney transplant recipient are common endoscopic findings.*

However, there is little consensus on the specificity of PCR [28–30]. Since CMV typically produces latent infection residing in leukocytes, concern has been raised that positive PCR might therefore not necessarily reflect active disease in the colon but only latent infection. The use of colon tissue alone was therefore not widely considered to provide definitive proof of CMV colitis [13]. Zidar et al. observed good correlation among the density of positive cells by immunohistochemistry, the

positive C4d deposition, concurrent ABMR should be considered.

present as a localized disease, such as inflammatory polyps [26].

**42**

**Figure 3.**

*CMV gastritis. Intranuclear inclusion (arrow) in foveolar gastric cell (A) and in endothelial cell (arrow) of a capillary in the lamina propria (both Thricrome stain, 600x). CMV positive Intranuclear inclusions by immunohistochemistry (C, CMV, 600x). Scarce mucosal ulcerations seen on gastroscopy (D).*

#### **Figure 5.**

*CMV colitis in kidney transplant recipient. Focal active colitis with erosions (A, Trichrome stain, 100x). There was only one positive CMV cell by immunohistochemistry (CMV, 400x).*

morphology, and the number of viral copies by qPCR in IBD patients. Both immunohistochemistry and qPCR can therefore be successfully used for diagnosing CMV reactivation, at least in CMV reactivation in patients with IBD. The optimal sites for endoscopic biopsies to obtain specimens with the highest values of CMV are the base and the edge of ulcers [28, 31].

#### **2.5 Prevention of CMV disease**

CMV can be prevented in two ways: by prophylaxis and by preemptive treatment. Both options are effective for preventing CMV disease [32–34].

#### *2.5.1 CMV prophylaxis therapy*

CMV prophylaxis is widely used in the transplantation setting and has been associated with reductions in CMV disease, mortality, and graft rejection. Prophylaxis refers to the administration of antiviral drugs to all patients (universal prophylaxis) or to a subgroup of patients at higher risk of viral replication (specific prophylaxis) for a predetermined period of time. In KTRs, prophylaxis therapy aims to prevent CMV infection and, consequently, CMV-associated disease. According to current guidelines, universal prophylaxis is recommended in patients with high risk (i.e., those who have D+/R− CMV IgG or who have received T-cell depletion for induction prior to transplantation). Antiviral drug treatment should begin immediately after transplantation or after the use of antilymphocyte antibodies. Patients with low to intermediate risk can undergo preemptive treatment instead of prophylaxis [35].

Until recently, the emphasis on prophylaxis with prophylactic agents focused on early disease occurring in high-risk patients, with the duration of prophylaxis typically no longer than 3 months. Although early-onset CMV infection was usually sufficiently controlled, the reported incidence of delayed-onset CMV infection following the completion of a 3-month course of preventive therapy was high, and, consequently, prophylactic therapy in most centers was extended to 6 months in the group of KTRs at most risk (D+/R−) [36, 37].

Several medications are available: acyclovir, valacyclovir, intravenous ganciclovir, oral ganciclovir, and valganciclovir. Ganciclovir takes precedence over acyclovir. In a clinical setting, the most commonly used medication for prophylaxis is oral valganciclovir with dose adjustment according to kidney function [38].

The prophylaxis should be initiated immediately after transplantation. The decision on the duration of prophylaxis depends on the CMV serostatus of the donor (D) and recipient (R), of the organ transplant, and the degree of immune deficiency in the transplant recipient.

#### *2.5.1.1 Prophylaxis in D+/R− recipient*

In D+/R−, prophylaxis should last for 3–6 months. According to recent research, many transplant centers are opting for a 6-month prophylaxis, which has been associated with a significant decrease in the incidence of late CMV disease, compared to 3-month prophylaxis. Valganciclovir at a dosage of 900 mg orally once daily with the dose adjusted for renal function is used in most centers for a period of 6 months following transplantation.

#### *2.5.1.2 Prophylaxis in D+/R+ or D−/R+*

In D+/R+ or D−/R+, prophylaxis should last for 3 months. Extension to 6 months is suggested for KTRs who have received antilymphocyte antibody

**45**

*Viral Infections after Kidney Transplantation: CMV and BK*

induction. Valganciclovir at 900 mg orally once daily for 3 months following transplantation, with the dose adjusted for renal function, is the standard prophylactic

There is little risk of CMV infection in these patients. Precautions for transfu-

Theoretically, a method of minimizing the risk of CMV infection would be to avoid transplantation of a seropositive organ into a seronegative recipient. Historically, before the advent of antiviral prophylaxis, many units avoided transplanting CMV-positive solid organs into CMV-negative recipients. However, given the shortage of donor organs, such an approach is difficult to practice in these

One area in which CMV matching remains relevant is in the elective use of blood

Passive immunoprophylaxis has been explored in solid organ transplantation in a number of randomized trials, whereby hyperimmune globulin provided significant overall protection from severe disease, with a reduced rate of CMV disease to approximately half of that seen in the placebo groups. Intravenous treatment is generally less convenient for the patient and health-care provider and carries the

With quantitative monitoring of CMV DNA in plasma (viral load, viremia) once a week (sometimes twice a week), CMV viremia can be detected before the occurrence of symptomatic infection. However, the exact cutoff point of plasma CMV concentration to initiate preemptive treatment (from a few hundred to several thousand copies of CMV DNA in 1 ml of plasma) is not known. The decision to initiate preemptive treatment is therefore individual and depends mainly on the

The benefits of this type of strategy are that fewer patients are exposed to antivirals and for a shorter period of time (fewer side effects, fewer interactions with

Intravenous ganciclovir (5 mg/kg every 12 h or a dose adjusted to creatinine clearance) is used for preemptive treatment in a patient with a high viral load (>50,000 copies of CMV DNA in 1 ml of plasma), in severe renal impairment, and in pediatric patients; otherwise, valganciclovir (900 mg every 12 h, or a dose adjusted to creatinine clearance) is recommended. If there is no CMV disease, the CMV viremia is checked for the first time after 7–10 days of preemptive treatment, afterward being monitored every 7–10 days. It is recommended to continue with

products. Where it is known that both donor and recipient are seronegative for CMV, leukodepleted blood and blood products are available and should be used to

sion of blood and blood products of CMV-positive donors are required [35].

*2.5.2 Additional considerations in the prevention of CMV in kidney transplant* 

*DOI: http://dx.doi.org/10.5772/intechopen.86043*

minimize the risk of primary infection [39].

theoretical risk of transmitting blood-borne viruses [39].

degree and duration of immunosuppression [40].

*2.5.2.2 Passive immunoprophylaxis*

*2.5.3 Preemptive therapy*

other medicines, lower costs).

therapy in most centers.

*recipients*

*2.5.2.1 CMV matching*

settings.

*2.5.1.3 Prophylaxis in D−/R−*

induction. Valganciclovir at 900 mg orally once daily for 3 months following transplantation, with the dose adjusted for renal function, is the standard prophylactic therapy in most centers.
