HCMV is a member of the Betaherpesvirinae subfamily and, as such, differs from HSV and VZV in several ways. Its replication cycle is signifi cantly longer, and infected cells typically are greatly enlarged and multi nucleated (hence, “cytomegalo-”) as shown in Figure 25.14. There is only one recognized human species of HCMV, but there are many dis tinct strains that can be distinguished by antigenic differences as well as by restriction fragment analysis of their genomes. HCMV is the most common cause of intrauterine infections and congenital abnormalities in the United States. It also represents a serious threat to immunodeficient and immunosuppressed patients.

A. Epidemiology and pathogenesis

Initial infection with HCMV commonly occurs during childhood. Depending on geographic location and socioeconomic group, 35 to 90 percent of the population have antibody against the virus by adulthood.

1. Transmission: Infection in children is usually asymptomatic, and these children continue to shed virus for months in virtually all body fluids, including tears, urine, and saliva. Transmission is by intimate contact with these fluids, although saliva may be the most common source. In adults, the virus can also be transmitted by: 1) sexual means because it is present in semen and vaginal secretions, 2) organ transplants, and 3) blood transfusions. Similarly, virus is present in breast milk, and neonates can be infected by this route. HCMV can also cross the placenta and infect a fetus in utero. Initial replication of the virus in epithelial cells of the respiratory and gastrointestinal (GI) tracts is followed by viremia and infection of all organs of the body. In symptomatic cases, kidney tubule epithelium, liver, and CNS, in addition to the respiratory and GI tracts, are most commonly affected.

2. Latency and reactivation: A distinctive feature of HCMV latency is the phenomenon of repeated episodes of asymptomatic virus shedding over prolonged periods. Latency is probably established in monocytes and macrophages, but other cell types, such as those of the kidney, are also involved.

 B. Clinical significance

 In healthy individuals, primary HCMV infection is usually subclinical (no apparent symptoms). Although most infections occur in child hood, primary infection as an adult may result in a mononucleosis syndrome clinically identical to that caused by EBV . It is estimated that about 8 percent of infectious mononucleosis (IM) cases are caused by HCMV. Persistent fever, muscle pain, and lymphadenopathy are characteristic IM symptoms, as are elevated levels of abnormal lymphocytes and liver enzymes. The major distinguishing feature of HCMV IM is the absence of the heterophile antibodies that characterize IM caused by EBV . Two specific situations have greater clinical significance, namely, con genital infections and infection of immunocompromised patients.

1. Congenital infections: HCMV is the most common intrauterine viral infection. However, there is a great disparity in incidence of fetal infection and severity of outcome, depending on whether the mother is experiencing a primary or recurrent infection. In women experiencing their first HCMV infection during pregnancy (who, therefore, have not yet produced antibodies against HCMV), 35 to 50 percent of fetuses will be infected, and 10 percent of these will be symptomatic (Figure 1). It is known as cytomegalic inclusion disease, and the severity of the symptoms is most pronounced when infection occurs during the first trimester. Results of the infection range from varying degrees of damage to liver, spleen, blood-forming organs, and components of the nervous system to fetal death. Damage to the nervous system is a common cause of hearing loss and mental retardation. Even in infants who are asymptomatic at birth, hearing deficits and ocular damage (for example, chorioretinitis) may appear later and continue to progress during the first few years of life. Congenitally and perinatally infected infants may continue to excrete virus for years after birth, serving as an important virus reservoir.

Fig1. Newborn with congenital cytomegalovirus disease, showing hepatosplenomegaly and rash.

2. Infections of immunosuppressed and immunodeficient patients: Immunosuppressed transplant recipients are multiply at risk from: 1) HCMV present in the tissue being transplanted, 2) virus carried in leukocytes in the associated blood transfusions, and 3) reactivation of their own endogenous latent virus. Immune suppression for the transplant can negate any protective advantage of a seropositive recipient. Destruction of GI tract tissue, hepatitis, and pneumonia are common, the latter being a major cause of death in bone marrow transplant recipients. HCMV infection is also associated with decreased survival of solid tissue grafts (i.e., heart, liver, kidney). HCMV coinfection of patients with HIV infection occurs frequently, probably because of their similar modes of transmission . As a common opportunistic infection in AIDS patients, invasive HCMV infections arising from reactivation of latent virus become increasingly important as CD4+ lymphocyte counts and immune competence decline . Although any organ system can be affected, pneumonia and blindness caused by HCMV retinitis are especially common. Encephalitis, dementia, esophagitis, enterocolitis, and gastritis are other significant problems. In addition, coinfection with HCMV may accelerate the progression of the pathology of AIDS (Figure 2).

Fig2. Incidence of central nervous system (CNS) disease in HIV-1-infected children, with or without cytomegalovirus (CMV) infection.

C. Laboratory identification

Because the incidence of HCMV infection in the population is so high, and periodic inapparent recurrent infections occur frequently, simple detection of virus or anti-HCMV antibody is not generally useful. Recovery of virus is not usually done. Serologic diagnosis using ELISA (or, enzyme-linked immunosorbent assay) techniques can distinguish primary from recurrent infection by demonstrating IgG seroconversion or the presence of HCMV-specific IgM. Direct determination of the presence and amount of viral DNA or proteins in white blood cells is useful as an indicator of invasive disease, whereas extracellular virus in urine or saliva may simply result from asymptomatic recurrence. Any of these techniques can also be used to screen transplant donors and recipients to determine HCMV status.

 D. Treatment and prevention

 Treatment of HCMV infection is indicated primarily in immunocompromised patients (Figure 3). Acyclovir is ineffective because HCMV lacks its own thymidine kinase. However, two inhibitors of HCMV DNA polymerase are available: ganciclovir, a guanine ana log that is phosphorylated by a virus-coded protein kinase, and cidofovir, a deoxycytidine analog. A third inhibitor of DNA polymerase, unrelated to the two just described, is phosphonoformic acid (foscarnet). Ganciclovir is used for invasive infections of trans plant recipients and AIDS patients, but it has considerable toxicity. For retinitis in AIDS patients, toxic adverse effects can be avoided by direct intraocular placement of a ganciclovir-impregnated implant. Following organ transplants, patients are treated prophy lactically with gancyclovir or anti-HCMV Ig. Alternatively, patients are monitored for the first sign of HCMV replication and then treated preemptively with antivirals. A vaccine for active immunization is not available.

Fig3. Drug therapy for cytomegalovirus.. 1-Indicates first-line drugs; 2-indicates alternative drug.