Definitive diagnosis requires laboratory confirmation (Table 5.2). The first laboratory method used to diagnose CMV was by urine cytology specimens (Montplaisir1972). The diagnostic gold standard for CMV is culture via shell vial method with human fibroblasts (Ison and Fishman 2005; Spector 1990). In addition to viral isolation, the diagnosis can be established by direct detection of intracellular viral antigens using immunohistochemistry (Fig. 5.4), or in situ hybridization of viral DNA by PCR (Ljungman et al. 2002; Strickler et al. 1990; Zhaori et al. 1996). Identification of serum CMV pp65 antigens detected in leukocytes may also be used as an antigenemia assay (Castagnola et al. 2004; de Maar et al. 2003; Ison and Fishman 2005; Ljungman et al. 2002). The viral load is determined by the antigenemia assay or quantitative PCR which correlates with symptomatic infection (Baldanti et al. 1998; Boeckh and Boivin 1998; Cunha 2010; de Maar et al. 2003; Egan et al. 1995; Guiver et al. 2001; Ison and Fishman 2005; Ljungman et al. 2002; Michaelides et al. 2001; van den Berg et al. 1989). Serologic studies identifying CMV-specific immunoglobulins have limited value as they are not useful in assessing active CMV infection, particularly after transplantation or in the immunosuppressed. However, CMV-specific immunoglobulins are useful in determining the risk of infection at the time of transplantation (de Maar et al. 2003). In immunocompetent individuals, antibodies develop to CMV over the first 4 to 7 weeks after infection. Either a single elevated IgM or a four-fold rise in IgG titers is required to diagnose a recent CMV infection (Cunha 2010; Ison and Fishman 2005).

The inclusions may be confused with those of other herpes viruses such as herpes simplex virus (HSV) and varicella zoster virus (VZV), adenoviruses, or measles virus. Intranuclear inclusions are seen in VZV-, HSV-, and adenovirus-infected cells. Measles virus-infected cells contain basophilic intracytoplasmic inclusions. However, the combination of cytomegaly with both intranuclear and cytoplasmic inclusions are diagnostic features of CMV. Furthermore, these viruses can be distinguished by immunohistochemical stains using antisera specific for VZV, HSV, measles, and adenovirus. Reactive pneumocytes may contain enlarged nuclei but can be differentiated from CMV by a negative CMV immunostain.

For CMV-naïve recipients, using seronegative donors or seronegative or leukocyte-reduced blood products aids in preventing CMV infection (Castagnola et al. 2004). In addition, prophylactic therapy with antiviral agents or through passive immunity with CMV-immune globulin may be useful, especially in the immunosuppressed (de Maar et al. 2003; Ison and Fishman 2005). Vaccines for CMV are not currently available: see below.

Treatment with CMV-reactive drugs such as ganciclovir, valganciclovir, acyclovir, valacyclovir, cidofovir or foscarnet, as well as CMV-specific immune globulin has improved mortality associated with CMV infection, particularly in immunocompromised individuals (Cunha 2010; de Maar et al. 2003; Ison and Fishman 2005; Uhlin et al. 2012). Quantitative assays should be used to monitor the response to therapy due to antiviral resistance. If an appropriate response to therapy does not occur within 2 weeks, molecular testing for antiviral resistance should be obtained (Ison and Fishman 2005). Specific DNA mutations have been identified leading to CMV resistance. The two most common mutations are found in the UL97 and UL54 regions. If resistance to ganciclovir has been identified, foscarnet or cidofovir is often effective (Baldanti et al. 2004; Kotton et al. 2010; Rodriguez et al. 2007; Uhlin et al. 2012). If CMV pneumonitis develops in the immunocompromised, despite prophylactic therapy, it is associated with a high mortality rate, particularly in bone marrow transplant patients (Castagnola et al. 2004; de la Hoz et al. 2002; de Maar et al. 2003; Ljungman 1995).

Currently, there are no licensed CMV vaccines available, but enormous progress has been made during the last decade with a variety of phase 1 and phase 2 clinical trials. Preliminary data shows that there is a reduction of infection/transmission using these vaccines (Sung and Schleiss 2010).

A universal human pathogen, CMV is commonly associated with immunosuppression. CMV infection in immunocompetent individuals does occur but may be clinically silent. The lungs infected with CMV may show nodular foci of necrosis and/or hemorrhage. The microscopic damage inflicted on the lung is characteristic and distinctive. Main features are cytomegaly and the well-known eosinophilic intranuclear inclusion bodies that confer infected cells the so-called owl-eye appearance. The diagnostic gold standard for CMV is cultures via shell vial method with human fibroblasts, but often the diagnosis is suspected on basis of histopathology alone. Prevention can be achieved through passive immunity with CMV immunoglobulin. Therapy with drugs acting against CMV such as ganciclovir is effective and has improved mortality rates, but mutant strains have been recently indentified, leading to drug resistance. Licensed vaccines are not currently available.