**2.1 Definition**

After the resolution of primary infection, CMV establishes latent infection. CMV can present in KTRs as either active CMV infection or CMV disease [9, 13].

*Primary CMV infection*: CMV infection in a person who was previously CMV seronegative (negative IgM and IgG CMV antibodies).

*Latent CMV infection*: after the resolution of acute (or primary) infection, CMV establishes latent infection. Patients who are CMV seropositive (IgG CMV antibodies) have latent infection. Secondary, symptomatic disease may present later, reflecting either reactivation of latent CMV or, less commonly, reinfection with a novel exogenous strain.

*Active CMV infection* is defined by CMV virus replication in plasma (viral load, viremia). CMV infection can be asymptomatic or symptomatic. The degree of immunosuppression in KTRs may determine progress to CMV disease.

*CMV disease* is defined as the presence of detectable CMV in a clinical specimen accompanied by other clinical manifestations. CMV disease may manifest as either CMV syndrome or tissue-invasive CMV disease [3].

#### **2.2 Clinical features of CMV disease**

#### *2.2.1 CMV syndrome*

For a determination of CMV syndrome, CMV in plasma (quantitative PCR CMV DNA (PCR)) and the presence of at least one of the following symptoms and signs

**39**

*Viral Infections after Kidney Transplantation: CMV and BK*

of disease are necessary: fever ≥38°C, general signs (malaise, myalgia, arthralgias),

In a case of tissue-invasive CMV disease, evidence of particular tissue/organ involvement (hepatitis, colitis, pancreatitis, pneumonitis, nephritis, cystitis, etc.) is based on clinical symptoms and signs associated with a particular organ, positive quantitative PCR CMV DNA in plasma, and, in particular, on the presence of CMV in a given organ or tissue (detected by methods of isolation, histopathology, immunohistochemistry, or hybridization in situ). CMV invasive disease can be most frequently detected in the intestine (40%) followed by the liver (20%), lungs (10%), kidneys (5%), and eyes/brain (1%) [8]. For CMV encephalitis, it is sufficient to prove the presence of CMV in the liquor (PCR) and for CMV pneumonitis

In suspected CMV retinitis, ophthalmological examination is sufficient for the diagnosis. In patients with tissue-invasive disease (particularly in CMV infection of the central nervous system, chorioretinitis, and in CMV infection of the gut), CMV viremia may be absent, so some more invasive diagnostics (lumbar puncture, sigmoidoscopy/colonoscopy) must be proceeded in case of clinical suspicion [14].

In KTRs who present with signs and symptoms suspicious for CMV disease, laboratory confirmation is required to establish the diagnosis. A biopsy with histopathologic examination of tissue is occasionally necessary to diagnose tissue-

A diagnosis of CMV infection is most often confirmed with nucleic acid testing using polymerase chain reaction (PCR) for the detection of CMV DNA. PCR is primarily used to evaluate blood, cerebrospinal fluid, and ocular or vitreous fluid,

Among other tests to detect CMV, the demonstration of CMV p65 antigen in circulating polymorphonuclear leukocytes in the buffy coat has been used both to monitor response to therapy and as a guide to starting treatment in some centers.

The most common serologic tests that detect CMV antibodies (IgM and IgG antibody to CMV) are based on enzyme-linked immunosorbent assay (ELISA). A positive test for CMV IgG indicates that a person was infected with CMV at some time during their life. The presence of CMV IgM cannot be used by itself to diagnose primary CMV infection because IgM can persist for months after primary infection and because IgM can be positive in reactivated CMV infections [16]. On occasion histopathological confirmation of CMV disease is necessary to

Productive CMV infection in the tissue is characterized by a cytopathic viral effect in the biopsy specimen of parenchymal organs and the presence of CMVpositive cells by immunohistochemistry or by in situ hybridization with antibody directed against the immediate early antigen. Additionally, CMV virions may be

although various clinical specimens can be subjected to this assay.

Traditional viral cultures are rarely used to diagnose CMV [15].

prove CMV organ-specific dysfunction.

detected by electron microscopy [17].

**2.4 Histological features of tissue-invasive disease**

/L). In a case of suspected CMV nephritis in KTRs, kidney graft rejec-

/L), atypical lymphocytosis (≥5%), and thrombocytopenia

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

tion should always be ruled out [3].

in bronchoalveolar flushing (PCR).

leukopenia (≤3.5 × 109

*2.2.2 Tissue-invasive disease*

(≤100 × 109

**2.3 Diagnosis**

invasive CMV disease.

of disease are necessary: fever ≥38°C, general signs (malaise, myalgia, arthralgias), leukopenia (≤3.5 × 109 /L), atypical lymphocytosis (≥5%), and thrombocytopenia (≤100 × 109 /L). In a case of suspected CMV nephritis in KTRs, kidney graft rejection should always be ruled out [3].

### *2.2.2 Tissue-invasive disease*

*Perioperative Care for Organ Transplant Recipient*

significantly more frequent in KTRs older than 65 years.

seronegative (negative IgM and IgG CMV antibodies).

CMV syndrome or tissue-invasive CMV disease [3].

**2.2 Clinical features of CMV disease**

transplantation, including kidney [1, 3].

**2. CMV infection**

reactivation.

**2.1 Definition**

novel exogenous strain.

*2.2.1 CMV syndrome*

protocols in order to detect early BK reactivation are important. BKN might be successfully managed with a reduction of baseline immunosuppression but is potentially harmful since it may be associated with increased risk of rejection [4–6].

CMV is a double-DNA virus of the herpesvirus family transmitted via saliva, body fluids, or tissue. There are various, species-specific strains of cytomegalovirus [7]. Seroprevalence ranges between 30 and 70% in Europe and North America. Following primary infection, CMV establishes latency in myeloid progenitor cells and can be transiently reactivated in a healthy host without causing disease, similar to polyomaviruses. However, CMV reactivates frequently and causes disease in KTRs in the setting of immunocompromised, typically in the first 2–3 months after transplantation [8, 9]. CMV viremia in the 1–6 months after transplantation is

Reinfection (primary infection with a different human strain) can also occur [10]. CMV infection is the most common infectious disease following solid organ

In addition to the direct effects of viral infection, CMV infection and disease have been associated with acute and chronic rejection and diminished patient and graft survival [2]. The transplanted kidney itself is only rarely affected by CMV

The greatest recognized risk factor for CMV disease is a serological mismatch between the donor and the recipient (the recipient is CMV IgG seronegative and the donor is CMV IgG seropositive: D+/R−). Furthermore, CMV D+/R+ and CMV D−/R+ transplantations are of intermediate risk for the development of disease, and CMV

After the resolution of primary infection, CMV establishes latent infection. CMV can present in KTRs as either active CMV infection or CMV disease [9, 13]. *Primary CMV infection*: CMV infection in a person who was previously CMV

*Latent CMV infection*: after the resolution of acute (or primary) infection, CMV establishes latent infection. Patients who are CMV seropositive (IgG CMV antibodies) have latent infection. Secondary, symptomatic disease may present later, reflecting either reactivation of latent CMV or, less commonly, reinfection with a

*Active CMV infection* is defined by CMV virus replication in plasma (viral load,

*CMV disease* is defined as the presence of detectable CMV in a clinical specimen accompanied by other clinical manifestations. CMV disease may manifest as either

For a determination of CMV syndrome, CMV in plasma (quantitative PCR CMV DNA (PCR)) and the presence of at least one of the following symptoms and signs

viremia). CMV infection can be asymptomatic or symptomatic. The degree of

immunosuppression in KTRs may determine progress to CMV disease.

D−/R− transplantation is considered as low risk (<5% incidence) [11, 12].

**38**

In a case of tissue-invasive CMV disease, evidence of particular tissue/organ involvement (hepatitis, colitis, pancreatitis, pneumonitis, nephritis, cystitis, etc.) is based on clinical symptoms and signs associated with a particular organ, positive quantitative PCR CMV DNA in plasma, and, in particular, on the presence of CMV in a given organ or tissue (detected by methods of isolation, histopathology, immunohistochemistry, or hybridization in situ). CMV invasive disease can be most frequently detected in the intestine (40%) followed by the liver (20%), lungs (10%), kidneys (5%), and eyes/brain (1%) [8]. For CMV encephalitis, it is sufficient to prove the presence of CMV in the liquor (PCR) and for CMV pneumonitis in bronchoalveolar flushing (PCR).

In suspected CMV retinitis, ophthalmological examination is sufficient for the diagnosis. In patients with tissue-invasive disease (particularly in CMV infection of the central nervous system, chorioretinitis, and in CMV infection of the gut), CMV viremia may be absent, so some more invasive diagnostics (lumbar puncture, sigmoidoscopy/colonoscopy) must be proceeded in case of clinical suspicion [14].

#### **2.3 Diagnosis**

In KTRs who present with signs and symptoms suspicious for CMV disease, laboratory confirmation is required to establish the diagnosis. A biopsy with histopathologic examination of tissue is occasionally necessary to diagnose tissueinvasive CMV disease.

A diagnosis of CMV infection is most often confirmed with nucleic acid testing using polymerase chain reaction (PCR) for the detection of CMV DNA. PCR is primarily used to evaluate blood, cerebrospinal fluid, and ocular or vitreous fluid, although various clinical specimens can be subjected to this assay.

Among other tests to detect CMV, the demonstration of CMV p65 antigen in circulating polymorphonuclear leukocytes in the buffy coat has been used both to monitor response to therapy and as a guide to starting treatment in some centers. Traditional viral cultures are rarely used to diagnose CMV [15].

The most common serologic tests that detect CMV antibodies (IgM and IgG antibody to CMV) are based on enzyme-linked immunosorbent assay (ELISA). A positive test for CMV IgG indicates that a person was infected with CMV at some time during their life. The presence of CMV IgM cannot be used by itself to diagnose primary CMV infection because IgM can persist for months after primary infection and because IgM can be positive in reactivated CMV infections [16].

On occasion histopathological confirmation of CMV disease is necessary to prove CMV organ-specific dysfunction.

#### **2.4 Histological features of tissue-invasive disease**

Productive CMV infection in the tissue is characterized by a cytopathic viral effect in the biopsy specimen of parenchymal organs and the presence of CMVpositive cells by immunohistochemistry or by in situ hybridization with antibody directed against the immediate early antigen. Additionally, CMV virions may be detected by electron microscopy [17].

#### **Figure 1.**

*CMV gastritis with focal active and chronic inflammation (A, Trichrome stain, 100x). Immunohistochemical stain against CMV antigen shows numerous CMV-positive cells (B, CMV, 100x).*

In daily practice, CMV reactivation is most frequently detected in GIT biopsies, including the colon and stomach (**Figure 1**). In contrast to polyomaviruses, CMV invasive disease is only sporadically detected in transplanted kidney [18, 19]. Histological features of CMV replication-related lesions in native kidneys are similar to those in renal transplants [20, 21].

#### *2.4.1 CMV disease in kidneys*

CMV nephritis is characterized by virally induced direct tissue injury and by biopsy-proven cytopathic changes. Cytopathic changes are typically focal and detected in tubular epithelial cells or endothelial cells (**Figure 2**).

Three patterns have been observed: pattern I with large intranuclear inclusions in tubular epithelial cells with interstitial nephritis, pattern II with central large eosinophilic intranuclear inclusions in endothelial cells, and rarely, CMV infection may occur as acute glomerulonephritis (pattern III) [18]. CMV infection may also affect podocytes.

In the predominant tubular involvement, tubular CMV infection is usually accompanied by variable interstitial inflammation. In addition, monocyte inclusions in the interstitial infiltrate may be observed. Occasionally, a dense nodular mononuclear and plasma cell infiltrate is present in the interstitium, sometimes reminiscent of granuloma. Focal necrosis and microabscesses are rarely observed. Prominent tubulitis reminiscent of T-cell-mediated rejection characteristic in BKN is absent.

The involvement of endothelial cells is characterized by a central large eosinophilic intranuclear inclusions surrounded by a circumferential halo resembling a typical owl's eye. Glomerular and peritubular capillary endothelial cells may

**41**

**Figure 2.**

inflammation is not prominent [18].

*Viral Infections after Kidney Transplantation: CMV and BK*

be infected. In some nuclei, a smudgy-appearing intranuclear inclusion can be detected. In the cytoplasm of viral-infected cells, there are sometimes small basophilic cytoplasmic viral inclusions. When endothelial cells are predominantly CMV-infected cells, tubular epithelium tends to be spared. In such cases, interstitial

*CMV nephritis in transplanted kidney: focal interstitial inflammation and cytopathic changes in scarce tubular epithelial cells (A, hematoxylin eosin (HE), 200x). CMV inclusions are confirmed by immunohistochemistry* 

CMV nephritis may be associated with concurrent antibody- and T-cellmediated rejection in 30% of cases [22]. In contrast to polyomavirus, CMV often replicates in endothelial and inflammatory cells. Distinction between infection-

able, only rarely are scarce glomerular IgG deposits detected [20–22].

driven inflammation and rejection may be difficult.

*(B, CMV, 400x). Courtesy of Danica Galešič Ljubanović and Petar Šenjug.*

Immunofluorescence with a standard panel of antibodies is usually unremark-

Immunomodulation of the immune response might be the most important indirect effect of CMV infection on kidney graft, rather than direct CMV nephritis.

*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 2.**

*Perioperative Care for Organ Transplant Recipient*

similar to those in renal transplants [20, 21].

*2.4.1 CMV disease in kidneys*

**Figure 1.**

In daily practice, CMV reactivation is most frequently detected in GIT biopsies, including the colon and stomach (**Figure 1**). In contrast to polyomaviruses, CMV invasive disease is only sporadically detected in transplanted kidney [18, 19]. Histological features of CMV replication-related lesions in native kidneys are

*CMV gastritis with focal active and chronic inflammation (A, Trichrome stain, 100x). Immunohistochemical* 

CMV nephritis is characterized by virally induced direct tissue injury and by biopsy-proven cytopathic changes. Cytopathic changes are typically focal and

Three patterns have been observed: pattern I with large intranuclear inclusions in tubular epithelial cells with interstitial nephritis, pattern II with central large eosinophilic intranuclear inclusions in endothelial cells, and rarely, CMV infection may occur as acute

In the predominant tubular involvement, tubular CMV infection is usually accompanied by variable interstitial inflammation. In addition, monocyte inclusions in the interstitial infiltrate may be observed. Occasionally, a dense nodular mononuclear and plasma cell infiltrate is present in the interstitium, sometimes reminiscent of granuloma. Focal necrosis and microabscesses are rarely observed. Prominent tubulitis reminiscent of T-cell-mediated rejection characteristic in

The involvement of endothelial cells is characterized by a central large eosinophilic intranuclear inclusions surrounded by a circumferential halo resembling a typical owl's eye. Glomerular and peritubular capillary endothelial cells may

glomerulonephritis (pattern III) [18]. CMV infection may also affect podocytes.

detected in tubular epithelial cells or endothelial cells (**Figure 2**).

*stain against CMV antigen shows numerous CMV-positive cells (B, CMV, 100x).*

**40**

BKN is absent.

*CMV nephritis in transplanted kidney: focal interstitial inflammation and cytopathic changes in scarce tubular epithelial cells (A, hematoxylin eosin (HE), 200x). CMV inclusions are confirmed by immunohistochemistry (B, CMV, 400x). Courtesy of Danica Galešič Ljubanović and Petar Šenjug.*

be infected. In some nuclei, a smudgy-appearing intranuclear inclusion can be detected. In the cytoplasm of viral-infected cells, there are sometimes small basophilic cytoplasmic viral inclusions. When endothelial cells are predominantly CMV-infected cells, tubular epithelium tends to be spared. In such cases, interstitial inflammation is not prominent [18].

Immunofluorescence with a standard panel of antibodies is usually unremarkable, only rarely are scarce glomerular IgG deposits detected [20–22].

CMV nephritis may be associated with concurrent antibody- and T-cellmediated rejection in 30% of cases [22]. In contrast to polyomavirus, CMV often replicates in endothelial and inflammatory cells. Distinction between infectiondriven inflammation and rejection may be difficult.

Immunomodulation of the immune response might be the most important indirect effect of CMV infection on kidney graft, rather than direct CMV nephritis.

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 positive C4d deposition, concurrent ABMR should be considered.
