Cytomegalovirus (CMV), which was initially isolated from patients with congenital cytomegalic inclusion disease, is now recognized as an important pathogen in all age groups. In addition to inducing severe birth defects, CMV causes a wide spectrum of disorders in older children and adults, ranging from an asymptomatic subclinical infection to a mononucleosis syndrome in healthyindividuals to disseminated disease in immunocompromised patients. Human CMV is one of several related species-specific viruses that cause similar diseases in various animals. All are associated with the production of characteristic enlarged cells—hence the name cytomegalovirus.
CMV, a β-herpesvirus, has double-strand DNA, four species of mRNA, a protein capsid, and a lipoprotein envelope. Like other herpesviruses, CMV demonstrates icosahedral symmetry, replicates in the cell nucleus, and can cause either a lytic and productive or a latent infection. CMV can be distinguished from other herpesviruses by certain biologic properties, such as host range and type of cytopathology. Viral replication is associated with the production of large intranuclear inclusions and smaller cytoplasmic inclusions. CMV appears to replicate in a variety of cell types in vivo; in tissue culture it grows preferentially in fibroblasts. Although there is little evidence that CMV is oncogenic in vivo, it does transform fibroblasts in rare instances, and genomic transforming fragments have been identified.
CMV has a worldwide distribution. Of newborns in the United States, ∼1% are infected with CMV; the percentages are higher in many less-developed countries. Communal living and poor personal hygiene facilitate early spread. Perinatal and early childhood infections are common. CMV may be present in breast milk, saliva, feces, and urine. Transmission has occurred among young children in day-care centers and has been traced from infected toddler to pregnant mother to developing fetus. When an infected child introduces CMV into a household, 50% of susceptible family members seroconvert within 6 months.
CMV is not readily spread by casual contact but rather requires repeated or prolonged intimate exposure for transmission. In late adolescence and young adulthood, CMV is often transmitted sexually, and asymptomatic carriage in semen or cervical secretions is common. Antibody to CMV is present at detectable levels in a high proportion of sexually active men and women, who may harbor several strains simultaneously. Transfusion of whole blood or certain blood products containing viable leukocytes may transmit CMV, with a frequency of 0.14–10% per unit transfused.
Once infected, an individual generally carries CMV for life. The infection usually remains silent. However, CMV reactivation syndromes develop frequently when T lymphocyte–mediated immunity is compromised—for example, after organ transplantation, in association with lymphoid neoplasms and certain acquired immunodeficiencies (in particular, HIV infection; Chap. 189), or in critically ill patients on intensive care units. Most primary CMV infections in organ transplant recipients (Chap. 132) result from transmission in the graft itself. In CMV-seropositive transplant recipients, infection results from reactivation of latent virus or, less commonly, from reinfection by a new strain. CMV infection may also be associated with diseases as diverse as coronary artery stenosis and malignant gliomas, but these associations require further validation.
Congenital CMV infection can result from either primary or reactivation infection of the mother. However, clinical disease in the fetus or newborn is related almost exclusively to primary maternal infection (Table 182-1). The factors determining the severity of congenital infection are unknown; a deficient capacity to produce precipitating antibodies and to mount T cell responses to CMV is associated with relatively severe disease.
Table 182-1 CMV Disease in the Immunocompromised Host
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Table 182-1 CMV Disease in the Immunocompromised Host
|Population||Risk Factors||Principal Syndromes||Treatment||Prevention|
|Fetus||Primary maternal infection/early pregnancy||Cytomegalic inclusion disease||Ganciclovir for symptomatic neonates||Avoidance of exposure; possibly, maternal treatment with CMV immunoglobulin during pregnancy|
|Organ transplant recipient||Seropositivity of donor and/or recipient; immunosuppressive regimen; high degree of rejection||Febrile leukopenia; pneumonia; gastrointestinal disease||Ganciclovir or valganciclovir||Donor matching; prophylaxis or preemptive therapy with ganciclovir or valganciclovir|
|Bone marrow transplant recipient||Graft-vs.-host disease; older age of recipient; seropositive recipient; viremia||Pneumonia; gastrointestinal disease||Ganciclovir plus CMV immunoglobulin||Donor matching; prophylaxis or preemptive therapy with ganciclovir or valganciclovir|
|Person with AIDS||<100 CD4+ T cells/μL; CMV seropositivity||Retinitis; gastrointestinal disease; neurologic disease||Ganciclovir, valganciclovir, foscarnet, or cidofovir||Oral valganciclovir|
Primary infection with CMV in late childhood or adulthood is often associated with a vigorous T lymphocyte response that may contribute to the development of a mononucleosis syndrome similar to that observed after infection with Epstein-Barr virus (Chap. 181). The hallmark of such infection is the appearance of atypical lymphocytes in the peripheral blood; these cells are predominantly activated CD8+ T lymphocytes. Polyclonal activation of B cells by CMV contributes to the development of rheumatoid factors and other autoantibodies during mononucleosis.
Once acquired, CMV persists indefinitely in host tissues. The sites of persistent infection probably include multiple cell types and various organs. Transmission via blood transfusion or organ transplantation is due to silent infections in these tissues. Autopsy studies suggest that salivary glands and bowel may be sites of latent infection.
If the host's T cell responses become compromised by disease or by iatrogenic immunosuppression, latent virus can be reactivated to cause a variety of syndromes. Chronic antigenic stimulation in the presence of immunosuppression (for example, after tissue transplantation) appears to be an ideal setting for CMV activation and CMV-induced disease. Certain particularly potent suppressants of T cell immunity (e.g., antithymocyte globulin) are associated with a high rate of clinical CMV syndromes, which may follow either primary or reactivation infection. CMV may itself contribute to further T lymphocyte hyporesponsiveness, which often precedes superinfection with other opportunistic pathogens, such as Pneumocystis. CMV and Pneumocystis are frequently found together in immunosuppressed patients with severe interstitial pneumonia.