Etiology

Cytomegalovirus (CMV) is a ubiquitous human viral pathogen. The first descriptive report of histologic changes characteristic of those now associated with CMV infection was originally published in 1904, when protozoan-like cells in the lungs, kidneys, and liver of a syphilitic fetus were seen. It was not until 1956 and 1957 that CMV was isolated in the laboratory. Actual isolation of the virus after transfusion, and observation of elevated antibody titers, occurred in 1966.

Human CMV is classified as a member of the herpes family of viruses (herpesviruses). All the herpesviruses are relatively large, enveloped DNA viruses that undergo a replicative cycle involving DNA expression and nucleocapsid assembly within the nucleus. The viral structure gains an envelope when the virus buds through the nuclear membrane, which in turn is altered to contain specific viral proteins.

Although the herpesviruses produce diverse clinical diseases, they share the basic characteristic of being cell associated. The requirements for cell association vary, but herpesviruses may spread from cell to cell, presumably via intercellular bridges and in the presence of antibody in the extracellular phase. CMV spreads to the lymphoid tissues and proceeds to circulate to systemic lymph nodes. The virus finally comes to rest in the epithelial cells of many tissues. This common characteristic may play a role in the ability of these viruses to produce subclinical infections that can be reactivated under appropriate stimuli.

Epidemiology

CMV infection is endemic worldwide, with most urban adults demonstrating evidence of infection; 50% to 80% of U.S. adults are infected with CMV by age 40 years. The prevalence of CMV seropositivity increases steadily with age. CMV is found in all geographic and socioeconomic groups, but in general it is more widespread in developing countries and areas of lower socioeconomic conditions.

CMV is a major health risk because a large proportion of women, particularly white women, entering their childbearing years lack antibody to CMV. Those at greatest risk of infection are fetuses and immunocompromised persons. CMV is the most common virus transmitted to the fetus. Approximately 1 in 150 children is born with congenital CMV infection, and about 8000 children each year suffer permanent disabilities caused by CMV.

Acquired CMV infection is usually asymptomatic and can persist in the host as a chronic or latent infection. The incubation period is believed to be 3 to 12 weeks.

In most patients, CMV infection is asymptomatic. Occasionally, a self-limited, heterophile-negative, mononucleosis-like syndrome results. CMV hepatitis can also develop.

Symptoms include a sore throat and fever, swollen glands, chills, profound malaise, and myalgia. Lymphadenopathy and splenomegaly may be observed. Infections occurring in healthy immunocompetent individuals usually result in seroconversion. Virus may be excreted in the urine during primary and recurrent CMV infections; it can persist sporadically for months or years. Persons experiencing acquired infection, reinfection with the same or different strains of CMV, or reactivation of a latent infection can excrete the virus in titers as high as 10⁶ infective units/mL in the urine or saliva for weeks or months.

Normal adults and children usually experience CMV infection without serious complications. Infrequent complications of CMV infection in previously healthy individuals, however, include interstitial pneumonitis, hepatitis, Guillain-Barré syndrome, meningoencephalitis, myocarditis, thrombocytopenia, and hemolytic anemia.

CMV infection can be life-threatening in immunosuppressed patients. Infections in these patients may result in disseminated multisystem involvement, including pneumonitis, hepatitis, gastrointestinal (GI) ulceration, arthralgias, meningoencephalitis, and retinitis. Retinitis and encephalitis are common manifestations of disseminated CMV. Ulcerative damage of tissues (e.g., esophagus) is another demonstration of the cytopathic effects of CMV. Interstitial pneumonitis, frequently associated with CMV infection, is a major cause of death after allogeneic bone marrow transplantation. In premature infants, acquired CMV infection can result in atypical lymphocytosis, hepatosplenomegaly, pneumonia, or death.

Transfusion-acquired CMV infections may cause not only mononucleosis-like syndrome, but also hepatitis and increased rejection of transplanted organs. The following three types of CMV infections are possible in blood transfusion recipients:

Congenital Infection

About 1 in 750 children in the United States is born with or develops permanent problems due to congenital CMV infection. In the United States, more than 5000 children/year suffer permanent problems caused by CMV infection.

The classic congenital CMV syndrome is manifested by a high incidence of neurologic symptoms, as well as neuromuscular disorders, jaundice, hepatomegaly, and splenomegaly (Fig. 21-1). Petechia is the most common clinical sign, seen in about 50% of CMV-infected infants.

Congenitally infected newborns, especially those who acquire CMV during a maternal primary infection, are more prone to develop severe cytomegalic inclusion disease (CID). The severe form of CID may be fatal or can cause permanent neurologic sequelae, such as intracranial calcifications (Fig. 21-2), mental retardation, deafness, vision defects, microcephaly, and motor dysfunction. Psychomotor impairment is seen in 51% to 75% of survivors. Hearing loss is observed in 21% to 50% and visual impairment in 20% of patients. Infants without symptoms at birth may develop hearing impairment and neurologic impairment later.

CMV infection is known to alter the immune system and to produce overt manifestations of infection. Infection interferes with immune responsiveness in normal and immunocompromised individuals. This diminished responsiveness results in a decreased proliferative response to the CMV antigen, which persists for several months. In patients with CMV mononucleosis-like syndrome, alterations of T lymphocyte subsets result, producing an increase in the absolute number of CD8+ lymphocytes and a decrease in CD4+ lymphocytes. These subset abnormalities persist for months.

Questions have been raised regarding CMV as a potentially oncogenic virus because viral antigens and nucleic acids have been found in human malignancies, including adenocarcinoma of the colon, carcinoma of the cervix, cancer of the prostate, and Kaposi’s sarcoma. CMV does have transforming properties in vitro. Although considerable circumstantial evidence exists linking CMV to human malignancies, especially Kaposi’s sarcoma, a direct cause and effect relationship has not been established.

Laboratory Evaluation

In immunocompromised patients, CMV serology is not recommended. The preferred method for diagnosis is culture of virus and/or polymerase chain reaction (PCR). A variety of methods can be used for screening purposes (Table 21-1).

A fourfold rise in IgG antibody titer suggests, but does not prove, recent CMV infection. The presence of IgG antibody in

infants complicates the interpretation of serologic results during the first 6 months of life because the antibody may be maternal in origin.

The CMVscan Card Test^∗ is a passive latex agglutination test for the detection of IgM and IgG CMV antibodies. It can be used as a diagnostic tool or to screen donor specimens for antibodies to CMV in human serum and plasma. This assay can be performed qualitatively on undiluted serum to identify antibodies to CMV and quantitatively using serial twofold dilutions to determine the titer of CMV antibody.

In this procedure, latex particles previously sensitized with CMV viral antigen are mixed with serum. If antibody to CMV is present, the agglutinated particles will be macroscopically visible. In the absence of specific antibody or in with low antibody concentration, the latex particles will not agglutinate in the reaction mixture and the particles will appear smooth and evenly dispersed.

The absence of CMV antibodies suggests no viral exposure, whereas the presence of CMV antibodies indicates previous exposure to the virus. Recurrent infection, if it occurs, may not be as severe as primary infection. Because CMV is a bloodborne pathogen, infection is of greatest concern with newborn infants requiring transfusion and immunosuppressed allograft recipients.

The procedural protocol is posted on the website.

Diluted samples are incubated in antigen-coated wells. CMV antibodies, if present, are immobilized in the wells. Residual sample is eliminated by washing and draining, and conjugate (enzyme-labeled antibodies to human IgG) is added and incubated. If IgG antibodies to CMV are present, the conjugate will be immobilized in the wells. Residual conjugate is eliminated by washing and draining and the substrate is added and incubated. In the presence of the enzyme, the substrate is converted to a yellow end product, which is read photometrically for an absorbance maximum at 405 nm. The intensity of the absorbance at 405 nm is proportional to the amount of antibody to CMV present in the sample.

The procedural protocol is posted on the website.

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